Language：Japanese   Publisher：The Japan Society of Hepatology  

Importance of ALT levels of >30 in patients with MASLD: Nara Declaration 2023
The Nara Declaration 2023 recommends that patients with ALT levels of >30 U/L and those who have steatosis, diabetes, hypertension, and/or dyslipidemia should be referred to a hepatologist, considering the results of the FIB4 index and/or platelet count. ALT levels of >30 U/L is a simple and useful indicator and, when combined with the FIB4 index and platelet count, can detect MASLD cases that require further treatment and follow-up. Moreover, among patients with MAFLD and ALT levels of ≤30 U/L, the FIB4 index may be useful for identifying those at risk of MASLD. The Nara Declaration 2023 is an important and convenient guideline that provides primary care doctors with specific indications for referral to a hepatologist. When combined with the FIB4 index, ALT levels of >30 U/L is expected to predict high-risk MASLD cases.

DOI： 10.2957/kanzo.65.186

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Background and aims: The diagnostic performance of the Fibrosis-4 (FIB-4) index and nonalcoholic fatty liver disease (NAFLD) fibrosis score (NFS) is poor in patients with type 2 diabetes mellitus (T2DM). We determined the usefulness of the Enhanced Liver Fibrosis (ELF) test in patients with T2DM.
Methods: A total of 1228 patients with biopsy-proven NAFLD were enrolled. The diagnostic performance of the ELF test for predicting advanced fibrosis in participants with or without T2DM was evaluated in comparison with the FIB-4 index and NFS.
Results: Overall, the area under the curve of the ELF test for predicting advanced fibrosis was greater (0.828) than that of the FIB-4 index (0.727) and NFS (0.733). The diagnostic performance of the ELF test (area under the curve, 0.820) was also superior to that of the FIB-4 index (0.698) and NFS (0.700) in patients with T2DM. With the low cutoff values for each noninvasive test, the ELF test provided an acceptable false negative rate (cutoff value 9.8, 6.7%) in this population, unlike the FIB-4 index (1.30, 14.5%) and NFS (-1.455, 12.4%). After propensity score matching to avoid selection bias including age, sex, body mass index, and the prevalence of advanced fibrosis, the ELF test with a low cutoff value showed a high sensitivity (≥91.4%) and a high negative predictive value (≥96.8%), irrespective of the presence or absence of T2DM.
Conclusions: The high diagnostic performance of the ELF test for predicting advanced fibrosis in individuals with or without T2DM could address an unmet medical need for accurate assessment of liver fibrosis in patients with diabetes and NAFLD.

DOI： 10.1016/j.cgh.2023.11.022.

Language：Others   Publishing type：Research paper (scientific journal)   Publisher：Clinical and Molecular Hepatology  

Background/Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) was recently proposed as an alternative disease concept to nonalcoholic fatty liver disease (NAFLD). We aimed to investigate the prognosis of patients with biopsy-confirmed MASLD using data from a multicenter study. Methods: This was a sub-analysis of the Clinical Outcome Nonalcoholic Fatty Liver Disease (CLIONE) study that included 1,398 patients with NAFLD. Liver biopsy specimens were pathologically diagnosed and histologically scored using the NASH Clinical Research Network system, the FLIP algorithm, and the SAF score. Patients who met at least one cardiometabolic criterion were diagnosed with MASLD. Results: Approximately 99% of cases (n=1,381) were classified as MASLD. Patients with no cardiometabolic risk (n=17) had a significantly lower BMI than patients with MASLD (20.9 kg/m2 vs. 28.0 kg/m2, P<0.001), in addition to significantly lower levels of inflammation, ballooning, NAFLD activity score, and fibrosis stage based on liver histology. These 17 patients had a median follow-up of 5.9 years, equivalent to 115 person-years, with no deaths, liver-related events, cardiovascular events, or extrahepatic cancers. The results showed that the prognosis for pure MASLD was similar to that for the original CLIONE cohort, with 47 deaths and one patient who underwent orthotopic liver transplantation. The leading cause of death was extrahepatic cancer (n=10), while the leading causes of liver-related death were liver failure (n=9), hepatocellular carcinoma (n=8), and cholangiocarcinoma (n=4). Conclusions: Approximately 99% of NAFLD cases were considered MASLD based on the 2023 liver disease nomenclature. The NAFLD-only group, which is not encompassed by MASLD, had a relatively mild histopathologic severity and a favorable prognosis. Consequently, the prognosis of MASLD is similar to that previously reported for NAFLD.

DOI： 10.3350/cmh.2023.0515

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Language：Others   Publishing type：Research paper (scientific journal)   Publisher：Annals of Diagnostic Pathology  

Current WHO terminology and recent publications have classified tumoral (grossly visible) intraductal pre-invasive neoplasms of bile duct (TIDN) into three categories: intraductal papillary neoplasm of bile duct (IPNB), intraductal papillary oncocytic neoplasm (IOPN), and intraductal tubulopapillary neoplasm (ITPN). A total of 227 cases of TIDN and related lesions ≥3 mm in height were examined by 10 biliary pathologists referring to these 3 categories and two pathologic gradings: two-tiered system (low- and high-grade dysplasia) and modified types 1 and 2 subclassification. Among them, IPNB was the most frequent (183 cases), followed by IOPN (28 cases), while ITPN was rare (2 cases), and interobserver agreement in this classification was “substantial” (κ-value, 0.657). The interobserver agreement of two-tiered grading system of TIDN was “slight” (κ-value, 0.201), while that of modified types 1 and 2 subclassification was “moderate” (κ-value, 0.515), and 42 % were of type 1, and 58 % were of type 2. Type 1 TIDN showed occasional stromal invasion (6.7 %), whereas type 2 TIDN was frequently associated with stromal invasion (49.6 %) (p < 0.01). In conclusion, the classification of TIDN into three categories and modified types 1 and 2 subclassification are a practically applicable classification and grading system for TIDN.

DOI： 10.1016/j.anndiagpath.2023.152247

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Background and Aims: The diagnostic performance of the Fibrosis-4 (FIB-4) index and nonalcoholic fatty liver disease (NAFLD) fibrosis score (NFS) is poor in patients with type 2 diabetes mellitus (T2DM). We determined the usefulness of the Enhanced Liver Fibrosis (ELF) test in patients with T2DM. Methods: A total of 1228 patients with biopsy-proven NAFLD were enrolled. The diagnostic performance of the ELF test for predicting advanced fibrosis in participants with or without T2DM was evaluated in comparison with the FIB-4 index and NFS. Results: Overall, the area under the curve of the ELF test for predicting advanced fibrosis was greater (0.828) than that of the FIB-4 index (0.727) and NFS (0.733). The diagnostic performance of the ELF test (area under the curve, 0.820) was also superior to that of the FIB-4 index (0.698) and NFS (0.700) in patients with T2DM. With the low cutoff values for each noninvasive test, the ELF test provided an acceptable false negative rate (cutoff value 9.8, 6.7%) in this population, unlike the FIB-4 index (1.30, 14.5%) and NFS (−1.455, 12.4%). After propensity score matching to avoid selection bias including age, sex, body mass index, and the prevalence of advanced fibrosis, the ELF test with a low cutoff value showed a high sensitivity (≥91.4%) and a high negative predictive value (≥96.8%), irrespective of the presence or absence of T2DM. Conclusions: The high diagnostic performance of the ELF test for predicting advanced fibrosis in individuals with or without T2DM could address an unmet medical need for accurate assessment of liver fibrosis in patients with diabetes and NAFLD.

DOI： 10.1016/j.cgh.2023.11.022

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Language：Japanese   Publisher：(一社)日本肝臓学会  

肝生検を施行されたMASLD(metabolic dysfunction-associated steatotic liver disease)における「ALT>30U/L」の有用性とその意義についてFIB-4 Index、血小板数を組み合わせて検討した。1994年12月～2020年12月に肝生検を施行されたNAFLD(Non-alcoholic fatty liver disease)1398例のうちMASLDに該当する1381例を対象とした。stage≧2は614例に認め、そのうちALT>50U/Lは470例(76%)であった。ALT>30U/LにすることによりALT30～50U/Lの症例を追加で拾い上げることができ、stage≧2は578例(94%)とより多くの線維化進展したMASLDの検出が可能となった。FIB-4 IndexでみてみるとFIB-4 Index>1.3は全体で805症例に認められたが、ALT>50U/Lから>30U/Lに基準値を変えることにより、572例(71%)から742例(92%)に検出可能症例が増加した。同様に血小板20×10^4/μL未満の557例においてもALT>50U/Lから>30U/Lにすることにより367例(66%)から509例(91%)の症例も検出可能となった。FIB-4 Indexと血小板を組み合わせることにより、治療適応になるMASLD症例の取りこぼしが少なくすることが期待された。

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DOI： 10.1186/s40792-024-01820-1

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Language：English   Publisher：Springer Berlin Heidelberg  

49歳男性。特に既往や家族歴、飲酒歴、ウイルス感染歴などなかった。定期検診の腹部超音波検査で肝S7/8に2cm径の腫瘍および軽度の脂肪肝を伴う低エコー病変が認められた。単純CTでは高吸収域を示した。MRIでは、腫瘍はT1強調画像で境界部に高信号、内部に低信号を呈し、T2強調画像では低信号を示した。Gd-EOB-DTPA造影MRIでは、病変に脂肪が含まれており、EOB取り込みも認められた。以上より高分化型肝細胞癌(HCC)を疑い、腹腔鏡下S7/8部分切除術を施行した。患者は術後10日目に合併症なく退院した。病理組織検査の結果、過形成性病変や腺腫などの腫瘍性病変は認められず、肝小葉壊死を伴う再生性肝変化と診断した。

Language：Japanese   Publisher：(公社)日本医学放射線学会  

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DOI： 10.1200/JCO.2024.42.3_suppl.493

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Language：Japanese   Publisher：(一社)日本消化管学会  

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Background: Papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC) are common differentiated thyroid cancers, but the detection of a collision tumor is an extremely rare event. Case presentation: The patient was a 69-year-old Japanese female with multiple cervical lymph node swellings and a thyroid tumor. Preoperative fine needle aspiration cytology of the enlarged lymph node revealed a cytological diagnosis of papillary thyroid carcinoma (PTC). A total thyroidectomy, right cervical dissection and paratracheal dissection were performed. Histopathological and immunohistochemical analyses of resected specimens revealed a collision tumor of PTC and FTC. Multiple metastases of papillary carcinoma were found in the dissected lymph nodes. In the PTC lesion, IHC for BRAF (V600E) was positive but negative for the FTC lesion. Genetic analyses further revealed a TERT promoter C228T mutation in PTC and a NRAS codon 61 mutation in FTC. The patient died of recurrent cancer 8 months after surgery. Conclusions: A case of a collision tumor of PTC and FTC is very rare, and even fewer cases have been subjected to genetic scrutiny. The present case was successfully diagnosed by pathological examination using immunohistochemical and genetic analyses. The TERT promoter mutation in the PTC lesion was consistent with the aggressive behavior of the cancer.

DOI： 10.1186/s13044-023-00167-3

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Background: Elevated creatinine concentrations often indicate acute renal injury and renal biopsies are considered in this situation. However,pseudohypercreatininemia is potential cause of elevated creatinine concentrations, and invasive interventions should be avoided. Case presentation: A 54-year-old woman underwent surgery for descending aortic dissection.Nine days postoperatively, her creatinine concentration increased from 1 mg/dl to 5.78 mg/dl (normal range, 0.47–0.7 mg/dl). Azotemia and hyperkalemia were absent and physical examination findings were unremarkable. Cystatin C concentration was 1.56 mg/l (normal range, 0.56–0.8 mg/l) and pseudohypercreatininemia was suspected. Testing with different reagents showed a creatinine concentration of 0.84 mg/dl. Immunoglobulin (Ig)G was markedly elevated, and creatinine and IgG fluctuated in parallel, suggesting the cause of the pseudohypercreatininemia. IgG4 was also elevated at 844 mg/dl. Immunosuppressive steroid therapy effectively decreased the IgG concentration and resolved the pseudohypercreatininemia. Conclusions: In cases of elevated creatinine concentration with the presence of abnormal proteins, pseudohypercreatininemia should be considered. We report a rare case of pseudohypercreatininemia caused by polyclonal IgG.

DOI： 10.1186/s12882-023-03275-2

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Language：Others   Publishing type：Research paper (scientific journal)   Publisher：Biomaterials Advances  

Subcutaneous transplantation aims to enhance the growth and functionality of transplanted cells for therapeutic outcomes in tissue engineering. However, the limited subcutaneous vascular network poses a challenge. Conventional methods involve co-transplantation with endothelial cells or angiogenic scaffold implantation, but they have drawbacks like tissue inflammation, compromised endothelial cell functionality, and the risk of repeated scaffold transplantation. Effective techniques are needed to overcome these challenges. This study explores the potential of G/O-NGD, a gel-in-oil nanogel dispersion, as a transdermal carrier of proliferative factors to promote angiogenesis in subcutaneous graft beds before cell transplantation. We observed robust subcutaneous angiogenesis by delivering varying amounts of bFGF using the G/O-NGD emulsion. Quantitative analysis of several parameters confirmed the efficacy of this method for building a subcutaneous vascular network. G/O-NGD is a biodegradable material that facilitates localized transdermal delivery of bFGF while maintaining its activity. The findings of this study have significant implications in both medical and industrial fields.

DOI： 10.1016/j.bioadv.2023.213628

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DOI： 10.11477/mf.1403203389

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Aim: The noninvasive tests (NITs) Agile 3+ and Agile 4 effectively identify patients with nonalcoholic fatty liver disease (NAFLD) complicated with advanced fibrosis (F3–4) and cirrhosis (F4), respectively. Little information is available on associations between Agile scores and intra-/extrahepatic events. The aim of this study was to determine the predictive performance of Agile scores for intra-/extrahepatic events in Asian patients with biopsy-proven NAFLD. Methods: We undertook a retrospective multicenter cohort study to investigate associations between intra-/extrahepatic events and two Agile scores, Agile 3+ and Agile 4. The scores were obtained by combining clinical parameters and liver stiffness measurement using transient elastography. Results: Among 403 enrolled patients, 11 had liver-related events (LREs), including seven with hepatocellular carcinoma (HCC). The incidence of LREs and HCC showed a stepwise increase in the advanced fibrosis group (F3–4), Agile 3+ rule-in (F3–4, highly suspected), and Agile 4 rule-in (F4, highly suspected) groups, compared to their counterparts. Hazard ratios for LREs in the advanced fibrosis group, Agile 3+ rule-in, and Agile 4 rule-in groups were 4.05 (p = 0.03), 23.5 (p = 0.003), and 45.5 (p < 0.001), respectively. The predictive performance results for Agile 3+ and Agile 4 were 0.780 and 0.866, respectively, which were higher than for fibrosis (0.595). Unlike for LREs, Agile scores failed to identify patients with extrahepatic events, including cardiovascular events and extrahepatic cancer. Conclusions: Agile 3+ and Agile 4 scores are excellent NITs for predicting LREs in patients with NAFLD, possibly without histological assessment.

DOI： 10.1111/hepr.13938

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Adenocarcinoma, not otherwise specified (NOS) is a heterogenous group of salivary gland tumors that likely contains distinct tumors that have not yet been characterized. Indeed, in recent years, cases previously diagnosed as adenocarcinoma, NOS have been recategorized into novel tumor designations such as secretory carcinoma, microsecretory adenocarcinoma, and sclerosing microcystic adenocarcinoma. We sought to describe a distinctive, hitherto-undescribed salivary gland tumor encountered in the authors' practices. Cases were pulled from the surgical pathology archives of the authors' institutions. Histologic, immunohistochemical, and clinical findings were tabulated, and targeted next-generation sequencing was performed on all cases. Nine cases were identified, arising in 8 women and 1 man ranging from 45 to 74 years (mean, 56.7 y). Seven tumors (78%) arose in the sublingual gland, while 2 (22%) arose in the submandibular gland. The cases shared a distinctive morphologic appearance. They were biphasic, with ducts scattered among a predominant polygonal cell with round nuclei, prominent nucleoli, and pale eosinophilic cytoplasm. These cells were arranged as trabeculae and palisaded as pseudorosettes around hyalinized stroma and vessels, resembling a neuroendocrine tumor. Four of the cases were well-circumscribed, while the remaining 5 showed infiltrative growth including perineural invasion in 2 (22%) and lymphovascular invasion in 1 (11%). Mitotic rates were low (mean, 2.2/10 HPFs); necrosis was absent. By immunohistochemistry, the predominant cell type was strongly positive for CD56 (9 of 9) and variably positive for pan-cytokeratin (AE1/AE3) (7 of 9) with patchy S100 (4 of 9), but negative for synaptophysin (0 of 9) and chromogranin (0 of 9), while the ducts were strongly positive for pan-cytokeratin (AE1/AE3) (9 of 9) and CK5/6 (7 of 7). Next-generation sequencing did not reveal any fusions or obvious driver mutations. All cases were resected surgically, with external beam radiation also done in 1 case. Follow-up was available in 8 cases; there were no metastases or recurrences after 4 to 160 months (mean, 53.1 mo). A dual population of scattered ducts with a predominance of CD56-positive neuroendocrine-like cells characterizes a unique salivary gland tumor which is often encountered in the sublingual glands of women, for which we propose the term "palisading adenocarcinoma." Although the tumor was biphasic and had a neuroendocrine-like appearance, it lacked convincing immunohistochemical evidence of myoepithelial or neuroendocrine differentiation. Although a subset showed unequivocally invasive growth, this tumor appears to behave in an indolent manner. Moving forward, recognition of palisading adenocarcinoma and its separation from other salivary adenocarcinomas, NOS will facilitate a better understanding of the characteristics of this previously unrecognized tumor.

DOI： 10.1097/PAS.0000000000002091

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Background and Aims: Both fibrosis status and body weight are important for assessing prognosis in nonalcoholic fatty liver disease (NAFLD). The aim of this study was to identify population clusters for specific clinical outcomes based on fibrosis-4 (FIB-4) index and body mass index (BMI) using an unsupervised machine learning method. Methods: We conducted a multicenter study of 1335 biopsy-proven NAFLD patients from Japan. Using the Gaussian mixture model to divide the cohort into clusters based on FIB-4 index and BMI, we investigated prognosis for these clusters. Results: The cohort consisted of 223 cases (16.0%) with advanced fibrosis (F3–4) as assessed from liver biopsy. Median values of BMI and FIB-4 index were 27.3 kg/m2 and 1.67. The patients were divided into four clusters by Bayesian information criterion, and all-cause mortality was highest in cluster d, followed by cluster b (P = 0.001). Regarding the characteristics of each cluster, clusters d and b presented a high FIB-4 index (median 5.23 and 2.23), cluster a presented the lowest FIB-4 index (median 0.78), and cluster c was associated with moderate FIB-4 level (median 1.30) and highest BMI (median 34.3 kg/m2). Clusters a and c had lower mortality rates than clusters b and d. However, all-cause of death in clusters a and c was unrelated to liver disease. Conclusions: Our clustering approach found that the FIB-4 index is an important predictor of mortality in NAFLD patients regardless of BMI. Additionally, non-liver-related diseases were identified as the causes of death in NAFLD patients with low FIB-4 index.

DOI： 10.1111/jgh.16326

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Language：English   Publisher：John Wiley & Sons Australia, Ltd  

アジア人の非アルコール性脂肪性肝疾患(NAFLD)における肝内/肝外イベントに対するAgileスコアの予測能を明らかにするため、多施設共同後ろ向きコホート研究を実施した。対象はNAFLD患者403例(男性40.2%、年齢中央値60歳)で、Agile 3+ rule-in患者は145例、Agile 4 rule-in患者は46例であった。11例が肝関連イベント(LRE)を経験した(肝細胞癌7例)。進行線維症(F3～4)群、Agile 3+ rule-in群、Agile 4 rule-in群におけるLREのハザード比はそれぞれ4.05(p=0.03)、23.5(p=0.003)、45.5(p<0.001)であった。Agile 3+とAgile 4の予測性能は線維症よりも高かった。肝外イベントとして、主要有害心血管イベントが7件、心血管疾患が7件、肝外癌イベントが11件あった。Agileスコアは肝外イベント患者を同定できなかった。

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Background: Multicystic biliary hamartoma (MCBH) is an extremely rare benign liver lesion characterized by a gross well-circumscribed multicystic honeycomb appearance. This report presents a MCBH case with a marked peribiliary gland component which showed unusual histology. Case Presentation: A 63-year-old Japanese male was admitted to our hospital for a detailed examination of a hepatic cystic lesion, which was originally detected 14 years ago and had slowly enlarged. A preoperative imaging study revealed a well-demarcated multicystic lesion without communication to the biliary tracts. The possible clinical diagnoses were mucinous cystic neoplasm (MCN) or MCBH. The lesion was successfully resected by purely laparoscopic right anterior sectionectomy. The cut surfaces of resected specimens grossly exhibited a well-circumscribed multicystic lesion with a thick septum. Histologically, the cyst wall was covered by cuboidal epithelial cells resembling epithelium of the bile duct while abundant small ducts, which morphologically resembled peribiliary glands, were observed among the fibrous stroma of the thick septum. Although possible pathological diagnosis varied, including intrahepatic cholangiocarcinoma, intraductal papillary neoplasm of the bile duct, biliary adenofibroma, MCN and MCBH, the lesion was finally diagnosed as MCBH with a marked peribiliary gland component. Conclusions: MCBH can contain abundant peribiliary glands in the fibrous stroma. A pathologist should be careful not to diagnose such peribiliary glands in MCBH as neoplastic glands.

DOI： 10.1007/s12029-022-00893-1

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Background: Clinical trials enroll patients with active fibrotic nonalcoholic steatohepatitis (NASH) (nonalcoholic fatty liver disease [NAFLD] activity score ≥ 4) and significant fibrosis (F ≥ 2); however, screening failure rates are high following biopsy. We developed new scores to identify active fibrotic NASH using FibroScan and magnetic resonance imaging (MRI). Methods: We undertook prospective primary (n = 176), retrospective validation (n = 169), and University of California San Diego (UCSD; n = 234) studies of liver biopsy-proven NAFLD. Liver stiffness measurement (LSM) using FibroScan or magnetic resonance elastography (MRE), controlled attenuation parameter (CAP), or proton density fat fraction (PDFF), and aspartate aminotransferase (AST) were combined to develop a two-step strategy—FibroScan-based LSM followed by CAP with AST (F-CAST) and MRE-based LSM followed by PDFF with AST (M-PAST)—and compared with FibroScan-AST (FAST) and MRI-AST (MAST) for diagnosing active fibrotic NASH. Each model was categorized using rule-in and rule-out criteria. Results: Areas under receiver operating characteristic curves (AUROCs) of F-CAST (0.826) and M-PAST (0.832) were significantly higher than those of FAST (0.744, p = 0.004) and MAST (0.710, p < 0.001). Following the rule-in criteria, positive predictive values of F-CAST (81.8%) and M-PAST (81.8%) were higher than those of FAST (73.5%) and MAST (70.0%). Following the rule-out criteria, negative predictive values of F-CAST (90.5%) and M-PAST (90.9%) were higher than those of FAST (84.0%) and MAST (73.9%). In the validation and UCSD cohorts, AUROCs did not differ significantly between F-CAST and FAST, but M-PAST had a higher diagnostic performance than MAST. Conclusions: The two-step strategy, especially M-PAST, showed reliability of rule-in/-out for active fibrotic NASH, with better predictive performance compared with MAST. This study is registered with ClinicalTrials.gov (number, UMIN000012757).

DOI： 10.1111/hepr.13927

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Background and Aims: This study aimed to histologically validate atrial structural remodelling associated with atrial fibrillation. Methods and results: Patients undergoing atrial fibrillation ablation and endomyocardial atrial biopsy were included (n = 230; 67 ± 12 years old; 69 women). Electroanatomic mapping was performed during right atrial pacing. Voltage at the biopsy site (Vbiopsy), global left atrial voltage (VGLA), and the proportion of points with fractionated electrograms defined as ≥5 deflections in each electrogram (%Fractionated EGM) were evaluated. SCZtotal was calculated as the total width of slow conduction zones, defined as regions with a conduction velocity of <30 cm/s. Histological factors potentially associated with electroanatomic characteristics were evaluated using multiple linear regression analyses. Ultrastructural features and immune cell infiltration were evaluated by electron microscopy and immunohistochemical staining in 33 and 60 patients, respectively. Fibrosis, intercellular space, myofibrillar loss, and myocardial nuclear density were significantly associated with Vbiopsy (P =. 014, P <. 001, P <. 001, and P =. 002, respectively) and VGLA (P =. 010, P <. 001, P =. 001, and P <. 001, respectively). The intercellular space was associated with the %Fractionated EGM (P =. 001). Fibrosis, intercellular space, and myofibrillar loss were associated with SCZtotal (P =. 028, P <. 001, and P =. 015, respectively). Electron microscopy confirmed plasma components and immature collagen fibrils in the increased intercellular space and myofilament lysis in cardiomyocytes, depending on myofibrillar loss. Among the histological factors, the severity of myofibrillar loss was associated with an increase in macrophage infiltration. Conclusion: Histological correlates of atrial structural remodelling were fibrosis, increased intercellular space, myofibrillar loss, and decreased nuclear density. Each histological component was defined using electron microscopy and immunohistochemistry studies.

DOI： 10.1093/eurheartj/ehad396

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Language：English   Publisher：John Wiley & Sons Australia, Ltd  

活動性線維化非アルコール性脂肪性肝炎(NASH)を識別する新たなスコアを検討した。肝生検で証明された非アルコール性脂肪性肝疾患(NAFLD)患者の前向きコホート(176例)、後ろ向き検証コホート(169例)、カリフォルニア大学サンディエゴ校(UCSD)コホート(234例)を解析した。2段階の診断法F-CAST[FibroScanで測定した肝硬度(LSM)の後に制御減衰パラメータ(CAP)+アスパラギン酸アミノトランスフェラーゼ(AST)]およびM-PAST[磁気共鳴エラストグラフィー(MRE)で測定したLSMの後にプロトン密度脂肪分画(PDFF)+AST]を、FibroScan-AST(FAST)およびMRI-AST(MAST)と比較した。rule-in基準に従うと、F-CAST(81.8%)とM-PAST(81.8%)の陽性的中率はFAST(73.5%)とMAST(70.0%)より高かった。rule-out基準に従うと、F-CAST(90.5%)とM-PAST(90.9%)の陰性的中率はFAST(84.0%)とMAST(73.9%)より高かった。検証コホートとUCSDコホートではF-CASTとFASTのROC曲線下面積に有意差はなかったが、M-PASTの診断性能はMASTより高かった。以上より、活動性線維化NASHの診断においてM-PASTはMASTより優れた性能を示した。

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Objective: Liver stiffness measurements (LSMs) and controlled attenuation parameters (CAPs) obtained using vibration-controlled transient elastography (VCTE) are recognized non-invasive methods of assessing liver histology. The usefulness of CAP for predicting liver-related events (LREs: hepatocellular carcinoma, decompensation, bleeding varices) is not well understood worldwide. Our aim was to re-evaluate the cutoff values of LSM/CAP in Japan and to examine whether LSM/CAP can predict LRE. Methods: Japanese NAFLD patients (n = 403) who underwent both liver biopsy and VCTE were enrolled. We determined optimal cutoff values of LSM/CAP diagnoses for fibrosis stage and steatosis grade and investigated their clinical outcome based on LSM/CAP values. Results: The LSM cutoff values for F1 to F4 are 7.1, 7.9, 10.0 and 20.2 kPa, and the CAP cutoff values for S1 to S3 are 230, 282 and 320 dB/m. During a median follow-up of 2.7 y (range: 0.0–12.5 y), 11 patients developed LREs. The incidence of LREs in the LSM Hi (≥8.7) group was significantly higher than that in the LSM Lo (<8.7) group (p = 0.003), and the incidence in the CAP Lo (<295) group was higher than that in CAP Hi (≥295) group (p = 0.018). Considering LSM and CAP together, the risk of LRE was higher in the LSM Hi CAP Lo group than in the LSM Hi CAP Hi group (p = 0.03). Conclusion: We set LSM/CAP cutoff values to diagnose liver fibrosis and steatosis in Japan. Our study determined that NAFLD patients with high LSM and low CAP values are at high risk for LREs.

DOI： 10.1016/j.ultrasmedbio.2023.03.023

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Language：Japanese   Publisher：日本臨床細胞学会-九州連合会  

背景 甲状腺好酸性細胞型濾胞腺腫は75%以上が好酸性細胞からなる濾胞腺腫の1亜型である.時に核異型が目立つが,組織学的な良悪性診断は通常の濾胞腺腫に準じる.今回,穿刺吸引細胞診(Fine-needle Aspiration:FNA)で悪性を疑った甲状腺好酸性細胞型濾胞腺腫の一例を経験した.症例 60代男性.甲状腺左葉の約3cm大の腫瘤に対し,FNAが施行された.FNA検体ではライトグリーン好性の顆粒状細胞質と著明な核の大小不同を有する異型細胞が出現しており,悪性と判断するも組織型推定に窮した.切除の方針となり,甲状腺左葉切除検体が術中迅速に提出された.迅速時の捺印細胞診でも術前FNAと同様の異型細胞を認めたが,凍結標本の組織所見と肉眼所見とを併せて「好酸性細胞型濾胞性腫瘍を疑うが良悪性の判定困難」と報告した.切除検体の組織学的検討では,p53の核内発現率とKi-67標識率より悪性のポテンシャルが示唆されたが,悪性の根拠たる被膜・脈管侵襲は認めず,好酸性細胞型濾胞腺腫の最終診断とした.結語 甲状腺のFNA検体で好酸性細胞を示唆するライトグリーン好性の顆粒状細胞質を認めた場合,好酸性細胞型濾胞腺腫の可能性を考慮して慎重な良悪性判定を行う必要がある.(著者抄録)

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Background and Aims: Noninvasive tests (NITs) have prognostic potential, but whether NITs are comparable with liver biopsy is unclear. This study aimed to examine the prognostic accuracy of NITs for liver-related mortality (LRM) and events (LREs) in patients with biopsy-proven nonalcoholic fatty liver disease (NAFLD). Methods: We investigated 1313 patients with NAFLD. Patients were assigned to low-risk, indeterminate-risk, and high-risk groups using conventional cutoff values of each FIB-4 and NAFLD fibrosis score (NFS) and to stage 0–2 and stage 3–4 groups using the fibrosis stage. Survival and Cox regression analyses of the prognostic potential of NITs for LRM/LREs were conducted. Results: During a median follow-up of 4.5 years, regarding to FIB-4, the incidence rate (/1000 person-years) in the low risk was zero for LRM and 0.5 for LREs. In contrast, the rate in stage 0–2 was 1.3 for LRM and 2.8 for LRE. The adjusted hazard ratios (aHRs) for LREs in the high risk compared with the low risk were 32.85 (P < 0.01). The aHRs in stage 3–4 compared with stage 0–2 were 2.68 (P = 0.02) for LREs and 2.26 (P = 0.582) for LRM. In the same fibrosis stage, the incidence of LRM/LREs was more frequent with a higher risk stratification. The same trend was observed for NFS. Conclusions: NITs accurately predict LRM and LREs as well as a liver biopsy in Japanese patients with NAFLD. Patients in the low risk may not require close follow-up for at least 5 years. The simple NITs could be an acceptable alternative method to performing a liver biopsy for the prognosis of NAFLD.

DOI： 10.1111/jgh.16144

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Aim: Agile 3+ and Agile 4 scores, based on liver stiffness measurement (LSM) by transient elastography and clinical parameters, were recently reported to be effective in identifying advanced fibrosis and cirrhosis in nonalcoholic fatty liver disease (NAFLD). This study aimed to validate the utility of these scores in Japanese patients with NAFLD. Methods: Six hundred forty-one patients with biopsy-proven NAFLD were analyzed. The severity of liver fibrosis was pathologically evaluated by one expert pathologist. The LSM, age, sex, diabetes status, platelet count, and aspartate aminotransferase and alanine aminotransferase levels were used to calculate Agile 3+ scores, and the parameters above excluding age were used for Agile 4 scores. The diagnostic performance of the two scores was evaluated using receiver operating characteristic (ROC) curve analysis. Sensitivity, specificity, and predictive values of the original low cut-off (for rule-out) value and high cut-off (for rule-in) value were tested. Results: For diagnosis of fibrosis stage ≥3, the area under the ROC (AUROC) was 0.886, and the sensitivity of the low cut-off value and the specificity of the high cut-off value were 95.3% and 73.4%, respectively. For diagnosis of fibrosis stage 4, AUROC, the sensitivity of the low cut-off value, and the specificity of the high cut-off value were 0.930, 100%, and 86.5%, respectively. Both scores had higher diagnostic performance than the FIB-4 index and the enhanced liver fibrosis score. Conclusions: Agile 3+ and Agile 4 are reliable noninvasive tests to identify advanced fibrosis and cirrhosis in Japanese NAFLD patients with adequate diagnostic performance.

DOI： 10.1111/hepr.13890

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Language：English   Publisher：John Wiley & Sons Australia, Ltd  

非アルコール性脂肪性肝疾患(NAFLD)の日本人患者において、進行性線維化および肝硬変の特定にAgile 3+とAgile 4スコアが有用かどうか検討した。2012～2021年に肝生検と肝硬度測定を受け、NAFLDが証明された患者を後ろ向きに調べた。ROC曲線解析でAgile 3+とAgile 4スコアの診断能を評価し、除外診断(rule-out)の低カットオフ値、診断(rule-in)の高カットオフ値の感度、特異度、予測値を算出した。診断能を既存のFIB-4 indexとELF(Enhanced Liver Fibrosis)スコアと比較した。患者641例(年齢17～86歳、女性56.2%)を解析した。Agile 3+による線維化ステージ3以上の診断のROC曲線下面積(AUROC)は0.886、低カットオフ値の感度は95.3%、高カットオフ値の特異度は73.4%であった。Agile 4による線維化ステージ4の診断のAUROC、低カットオフ値の感度、高カットオフ値の特異度はそれぞれ0.930、100%、86.5%であった。両スコアは、FIB-4 indexおよびELFスコアより診断能が高かった。以上より、NAFLD日本人患者においてAgile 3+とAgile 4スコアは進行性線維化および肝硬変の診断に用いることが可能と考えられた。

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The relationship between baseline serum albumin level and long-term prognosis of patients with nonalcoholic fatty liver disease (NAFLD) remains unknown. This is a sub-analysis of the CLIONE (Clinical Outcome Nonalcoholic Fatty Liver Disease) study. The main outcomes were: death or orthotopic liver transplantation (OLT), liver-related death, and liver-related events (hepatocellular carcinoma [HCC], decompensated cirrhosis, and gastroesophageal varices/bleeding). 1383 Japanese patients with biopsy-confirmed NAFLD were analyzed. They were divided into 3 groups based on serum albumin: high (>4.0 g/dL), intermediate (3.5–4.0 g/dL), and low (<3.5 g/dL). Unadjusted hazard ratio [HR] of the intermediate albumin group, compared with the high albumin group, were 3.6 for death or OLT, 11.2 for liver-related death, 4.6 for HCC, 8.2 for decompensated cirrhosis, and 6.2 for gastroesophageal varices (all risks were statistically significant). After adjusting confounding factors, albumin remained significantly associated with death or OLT (intermediate vs. high albumin group: HR 3.06, 95% confidence interval [CI] 1.59–5.91, p < 0.001; low vs. high albumin group: HR 22.9, 95% CI 8.21–63.9, p < 0.001). Among biopsy-confirmed NAFLD patients, those with intermediate or low serum albumin had a significantly higher risk of death or OLT than those with high serum albumin.

DOI： 10.3390/nu15092014

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Aim: Impacts of platelet counts at the time of liver biopsy on hepatocellular carcinoma (HCC) development in patients with nonalcoholic fatty liver disease (NAFLD) remain unknown. The aim of this study was to investigate the prognostic value of platelet counts in patients with biopsy-confirmed NAFLD using data from a multicenter study. Methods: One thousand three hundred ninety-eight patients were included in this subanalysis of the CLIONE (Clinical Outcome Nonalcoholic Fatty Liver Disease) in Asia study. Liver biopsy specimens were pathologically diagnosed, and histologically scored using the NASH Clinical Research Network system. Demographic, clinical, laboratory, and pathological data were collected. Results: During a median follow-up period of 4.6 years (range, 0.3–21.6 years), which corresponds to 8874 person-years, 37 patients developed HCC. Using a cut-off baseline platelet count of 192 × 109/L, the lower platelet group had a higher HCC rate than the higher platelet group (6.7% vs. 0.4%; p < 0.001). This cut-off value significantly stratified the event-free rate for HCC. Lower platelet counts were associated with an increased risk of HCC development. Relative to patients with platelet counts of 192 × 109/L, patients with platelet counts of 100 × 109/L had an unadjusted hazard ratio (HR) for HCC development of 7.37 (95% confidence interval [CI], 3.81–14.2) and an adjusted HR of 11.2 (95% CI, 3.81–32.7; p < 0.001), adjusting for age, sex, NASH, and diabetes. Conclusions: Baseline platelet counts of 192 × 109/L and lower are associated with a higher risk of developing HCC in patients with biopsy-confirmed NAFLD and require active surveillance.

DOI： 10.1111/hepr.13884

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Language：Japanese   Publisher：日本臨床外科学会  

症例は71歳,男性.以前より胆石の指摘があり,術前の腹部MRIで胆石症と胆嚢腺筋症の術前診断となり,腹腔鏡下胆嚢摘出術を施行.切除標本で25mm大の粘膜下腫瘤様の隆起を認め,割面で多房性の嚢胞性病変と判明.病理組織学的検査で,胆嚢腺筋症と胆嚢壁内に限局した粘液性上皮による多房性の嚢胞性病変を認めた.嚢胞上皮はMUC5ACとMCU6が部分的に陽性で胃型粘液の特徴を示し,一部でlow gradeの異型上皮を認めた.自験例は胆嚢壁内に限局した壁内発育型の嚢胞性病変であり,形態的にintramural multicystic mucinous neoplasm with low-grade intraepithelial neoplasiaと表現した.まれな病理像であったため報告する.(著者抄録)

Language：English   Publisher：John Wiley & Sons Australia, Ltd  

多施設共同コホート研究であるCLIONE(Clinical Outcome Nonalcoholic Fatty Liver Disease)研究のサブ解析を実施し、非アルコール性脂肪性肝疾患(NAFLD)患者における血小板数の予後予測能について検討した。NAFLD患者1398例(男性599例、平均54.5±14.2歳)を解析対象とした。評価項目は人口統計学的特徴、各種臨床所見(糖尿病、高血圧、脂質異常症などの有無)、各種検査データ(血小板数など)、病理学的データなどとした。その結果、追跡期間中央値4.6年、追跡期間は8874人・年に37例が肝細胞癌を発症していた。また、ベースラインの血小板数に基づき、血小板低値群495例、血小板高値群903例に分けて検討した。その結果、血小板低値群では血小板高値群と比較して、肝細胞癌発症率が高かった(6.7%対0.4%、p<0.001)。Kaplan-Meier曲線解析の結果、カットオフ値192×10^9/Lは肝細胞癌無イベント率を有意に層別化していた。血小板数低下と肝細胞癌発症リスク上昇には関連が認められた。血小板数192×10^9/Lと比較した場合の血小板数100×10^9/Lの交絡因子調整前ハザード比は7.37(95%CI 3.81～14.2、p<0.001)、調整後ハザード比は11.2(95%CI 3.81～32.7、p<0.001)であった。以上から、血小板数が肝細胞癌の発症に及ぼす潜在的な影響が示され、血小板数の少ない患者に対する積極的なサーベイランスを行う必要性が示唆された。

Language：Others   Publishing type：Research paper (scientific journal)   Publisher：Advanced Fiber Materials  

In this article the affiliation details for Author Muhammad Shafiq were incorrectly given. They should have been assigned as shown below. The original article has been corrected. Department of Chemical Engineering, Faculty of Engineering, Graduate School, Kyushu University, 744 Motooka, Nishi-Ku, Fukuoka, 819–0395, Japan Department of Biotechnology, Faculty of Science and Technology, University of Central Punjab (UCP), Lahore, 54,000, Pakistan.

DOI： 10.1007/s42765-023-00261-z

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Injuries to the nervous system account for the widespread morbidity, mortality, and discomfort worldwide. Artificial nerve guidance conduits (NGCs) offer a promising platform for nerve reconstruction, however, they require extracellular matrix (ECM)-like features to better mimic the in vivo microenvironment. Consequently, this research was aimed to fabricate heparin/growth factors (GFs)-immobilized artificial NGCs. Heparin was covalently immobilized onto aligned electrospun polycaprolactone/gelatin (PCL/Gel) nanofibers. Thereafter, basic fibroblast growth factor (bFGF) and nerve growth factor (NGF) were preferentially immobilized on heparinized nanofibers; the immobilization efficiency of GFs was found to be 50% with respect to (w.r.t.) their initial loaded amounts. The in vivo implantation of NGCs in a sciatic nerve defect model revealed the successful retention (~ 10% w.r.t the initial loaded amount) and bioactivity of NGF for up to 5 days. The permeability of bovine serum albumin (BSA) from nanofibrous membranes was further assessed and found to be comparable with the commercialized cellulose acetate membranes. The bioactivity of NGCs was assessed in a sciatic nerve defect model in rats for short-term (1 week) and long-term (1-month). The NGCs displayed good structural stability and biocompatibility in vivo. The in vivo evaluation revealed the accumulation of host cells into the transplanted NGCs. Taken together; these heparin/GFs-immobilized artificial NGCs may have broad implications for nerve regeneration and related tissue engineering disciplines. Graphical Abstract: [Figure not available: see fulltext.].

DOI： 10.1007/s42765-022-00244-6

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Aim: The enhanced liver fibrosis (ELF) test is a noninvasive method for diagnosing hepatic fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). This multicenter cohort study aimed to evaluate the accuracy of the ELF test and compare it with other noninvasive tests in Japan. Methods: We analyzed 371 Japanese patients with biopsy-proven NAFLD. We constructed area under the receiver operator characteristic curves (AUROC) to determine the diagnostic accuracies of the ELF test, the Mac-2-binding protein glycosylation isomer (M2BPGi), the Fibrosis-4 (FIB-4) index, and combinations of these indices. Results: In patients with F0/F1/F2/F3/F4 fibrosis, the median values of the ELF test were 8.98/9.56/10.39/10.92/11.41, respectively. The AUROCs of the ELF test for patients with F0 versus F1–4, F0–1 versus F2–4, F0–2 versus F3–4, and F0–3 versus F4 fibrosis were 0.825/0.817/0.802/0.812, respectively. The AUROCs of the ELF test were greater than those of the FIB-4 index and M2BPGi at each fibrosis stage. Respective low and high cut-off values yielded sensitivities and specificities for predicting advanced fibrosis (≥F3) of 91.1% and 50.8%, and 38.5% and 92.8%, respectively. For F3 or F4 fibrosis, the combined values from the ELF test and FIB-4 index showed a sensitivity of 98.5%, and the combined values from the ELF test and M2BPGi assay showed a specificity of 97.5%. Conclusions: In Japan, the ELF test predicts NAFLD-related fibrosis from its early stages. The diagnostic ability of the ELF test was not inferior to that of other indices, and the combined values of ELF plus other indices were more accurate.

DOI： 10.1111/hepr.13871

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Language：English   Publisher：John Wiley & Sons Australia, Ltd  

1990年1月から2020年2月までに6施設で登録された日本人非アルコール性脂肪性肝疾患(NAFLD)患者を対象に、Enhanced Liver fibrosis(ELF)検査の診断能を推定し、他の非侵襲的検査と比較した。NAFLD患者371例(年齢17～85歳)を対象とした。ROC曲線下面積(AUC)を作成し、ELF検査、Mac-2結合蛋白糖鎖修飾異性体(M2BPGi)、Fibrosis-4(FIB-4)指標、それらの指標の組み合わせの診断精度を検討した。その結果、F0/F1/F2/F3/F4線維症患者では、ELF検査の中央値はそれぞれ8.98/9.56/10.39/10.92/11.41であった。F0対F1-4、F0-1対F2-4、F0-2対F3-4、F0-3対F4線維症の患者に対するELF検査のAUCは、それぞれ0.825/0.817/0.802/0.812であった。低いカットオフ値9.80と高いカットオフ値11.30では、進行線維症(≧F3)の予測に対する感度と特異度は、それぞれ91.1%と50.8%、38.5%と92.8%であった。F3またはF4線維症では、ELF検査とFIB-4指標を組み合わせた値は98.5%の感度を示し、ELF検査とM2BPGiアッセイを組み合わせた値は97.5%の特異度を示した。以上より、ELF検査の診断能力は他の指標より劣っておらず、ELFと他の指標の組み合わせはより正確であった。

Language：Others   Publishing type：Research paper (scientific journal)   Publisher：Colloids and Surfaces B: Biointerfaces  

Skin regeneration is hindered by poor vascularization, prolonged inflammation, and excessive scar tissue formation, which necessitate newer strategies to simultaneously induce blood vessel regeneration, resolve inflammation, and induce host cell recruitment. Concurrent deployment of multiple biological cues to realize synergistic reparative effects may be an enticing avenue for wound healing. Herein, we simultaneously deployed SDF (stromal cell-derived factor)− 1α, VEGF (vascular endothelial growth factor)-binding peptide (BP), and GLP (glucagon like peptide)− 1 analog, liraglutide (LG) in core/shell poly(L-lactide-co-glycolide)/gelatin fibers to harness their synergistic effects for skin repair in healthy as well as diabetic wound models in rats. Microscopic techniques, such as SEM and TEM revealed fibrous and core/shell type morphology of membranes. Boyden chamber assay and scratch-wound assay displayed significant migration of HUVECs (human umbilical vein endothelial cells) in SDF-1α containing fibers. Subcutaneous implantation of membranes revealed higher cellular infiltration in SDF-1α loaded fibers, especially, those which were co-loaded with LG or BP. Implantation of membranes in an excisional wound model in healthy rats further showed significant and rapid wound closure in dual cues loaded groups as compared to control or single cue loaded groups. Similarly, the implantation of dressings in type 2 diabetes rat model revealed fast healing, skin appendages regeneration, and blood vessel regeneration in dual cues loaded fibers (SDF-1α/LG, SDF-1α/BP). Taken together, core/shell type fibers containing bioactive peptides significantly promoted wound repair in healthy as well as diabetic wound models in rats.

DOI： 10.1016/j.colsurfb.2023.113140

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Ultraviolet (UV) radiation from the sun or artificial sources is one of the primary causes of skin damage, including sunburns, tanning, erythema, and skin cancer. Among the three different types of UV rays, UVB rays have a medium wavelength that can penetrate the epidermal layer of the skin, resulting in sunburn, suntan, blistering, and melanoma in case of chronic exposure. This study aimed to evaluate the preventive and therapeutic effects of a gel-in-oil nanogel dispersion (G/O-NGD) as a transdermal delivery biomolecular carrier for skin damage caused by UVB light. The efficacy of this carrier against UVB-induced skin damage was investigated in vivo by delivering different growth factors (GFs) encapsulated in a G/O-NGD. Artificial UVB light was used to induce skin damage in nude mice, followed by the transdermal application of five GF [vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), epidermal growth factor (EGF), transforming growth factor (TGF)-1, and insulin-like growth factor (IGF)-α]-immobilized G/O-NGD. Among these GFs, VEGF and bFGF promoted angiogenesis, while EGF, TGF-1, and IGF-α promoted the repair and regeneration of damaged cells. The results showed that G/O-NGD was superior to heparin-immobilized G/O-NGD in reducing UVB-induced skin damage, such as erythema, epidermal water reduction, inflammation, and dermis thickening. In addition, G/O-NGD could prevent and treat abnormal follicle proliferation caused by UVB rays and exhibited potential to repair lipid glands. Overall, our results demonstrate the potential of G/O-NGDs for the treatment of UVB-induced skin damage.

DOI： 10.1021/acsomega.2c07343

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Background & Aims: There are no detailed reports of clinical outcomes in Asian patients with nonalcoholic fatty liver disease (NAFLD) who undergo liver biopsy. We aimed to investigate the clinical outcomes of a large cohort of Asian patients with biopsy-proven NAFLD and evaluate the specific effects of nonalcoholic steatohepatitis and fibrosis stage. Methods: This multicenter registry-based retrospective cohort study, called the CLIONE (Clinical Outcome Nonalcoholic Fatty Liver Disease) in Asia, included 1398 patients. Results: The median follow-up period was 4.6 years (range, 0.3–21.6 years), representing a total of 8874 person-years of follow-up. During that time, 47 patients died, and 1 patient underwent orthotopic liver transplantation. The leading cause of death was nonhepatic cancer (n = 10). The leading causes of liver-related death were liver failure (n = 9), hepatocellular carcinoma (HCC) (n = 8), and cholangiocellular carcinoma (n = 4). During follow-up, 37 patients developed HCC, 31 developed cardiovascular disease, and 68 developed nonhepatic cancer (mainly breast, stomach, and colon/rectum). Among our cohort of patients with NAFLD, liver-specific mortality was 2.34/1000 person-years (95% confidence interval [CI], 1.52–3.58), overall mortality was 5.34/1000 person-years (95% CI, 4.02–7.08), and HCC incidence was 4.17/1000 person-years (95% CI, 3.02–5.75). Liver fibrosis was independently associated with liver-related events but not overall mortality. Conclusions: Liver-related mortality was the leading cause of mortality in Asian patients with biopsy-confirmed NAFLD. Although fibrosis stage was independently associated with liver-related events, it was not associated with overall mortality after adjusting for confounders, such as histologic features of steatohepatitis.

DOI： 10.1016/j.cgh.2022.01.002

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Purpose: To assess the dependency of the Time to enhancement (TTE) of breast lesions and normal breast parenchyma from menopausal status and menstrual cycle using ultrafast compressed sensing (CS) -accelerated dynamic contrast-enhanced (DCE) MRI. Methods: This institutional review board approved retrospective study included 89 breast cancers, 22 benign lesions and 131 normal breast parenchymal foci. A prototypical ultrafast DCE sequence obtained 30 phases with 2.9 s temporal resolution. Mean and median TTE of all breast cancers, benign lesions and normal breast parenchymal foci were assessed. we also assessed whether there were any differences in TTE regarding the menopausal status and menstrual cycle. Results: The TTE of breast cancer was significantly shorter than that of benign lesions and normal breast parenchymal foci in both the premenopausal status (5.8 vs. 8.7 and 8.7 s, respectively) (p = 0.0028 and < 0.0001, respectively) and postmenopausal status (5.8 vs. 11.6 and 11.6 s, respectively) (p < 0.0001 in both). The TTE of parenchymal foci in the premenopausal status was significantly shorter than that in the postmenopausal status (p = 0.0025). Although the TTE interval between cancer and parenchymal foci in premenopausal status is shorter than that in postmenopausal status, the AUCs in the pre- and postmenopausal status for differentiating breast cancer and parenchymal foci were comparable with using different cutoff TTE values. There were no differences in TTE regarding the menstrual cycle. Conclusions: The TTE derived from ultrafast CS-accelerated DCE MRI was useful to differentiate breast cancer from benign lesions and normal breast parenchymal foci in both pre- and postmenopausal status.

DOI： 10.1016/j.mri.2022.11.006

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Background and Aims: Nonalcoholic fatty liver diseases (NAFLD) and nonalcoholic steatohepatitis (NASH) can cause hepatocellular carcinoma (HCC). We examined histological features and reported noninvasive markers/models for stratifying the risk of HCC development in patients with biopsy-proven NAFLD or NASH. Methods: A total of 1389 patients who had a histological diagnosis of NAFLD or NASH based on liver biopsy and underwent regular surveillance for HCC were included. The ability to predict HCC development was compared between histological features including liver fibrosis and NAFLD activity score, and noninvasive markers/models including aMAP (age, male, albumin–bilirubin, and platelet) score, FIB-4 (Fibrosis-4) index, and ALBI (albumin-bilirubin) score calculated at the time of biopsy. Results: The C index of aMAP score was 0.887, which was consistent with the original report, comparable to FIB-4 index (0.878), and higher than those of ALBI score (0.789), histological liver fibrosis (0.723), and NAFLD activity score (0.589). The hazard ratios for HCC development in the aMAP intermediate and high-risk groups were 21.0 (95% confidence interval [CI], 3.6–402.0) and 110.3 (95% CI, 16.3–2251.4), respectively, in comparison to the aMAP score low-risk group. Those in the FIB-4 index moderate- and high-fibrosis groups were 10.3 (95% CI, 1.7–199.8) and 93.1 (95% CI, 16.3–1773.8), respectively, in comparison to the FIB-4 index mild-fibrosis group. No patients in the aMAP score low-risk group developed HCC during the study period. Conclusion: For stratifying the risk of HCC development in patients with biopsy-proven NAFLD or NASH, both aMAP score and FIB-4 index showed high discriminative ability as noninvasive markers, which were superior histological features.

DOI： 10.1016/j.gastha.2023.07.018

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Background: Anaplastic lymphoma kinase rearrangement-associated renal cell carcinoma (ALK-RCC) is an extremely rare tumor and ALK-RCC that mimics mucinous tubular and spindle cell carcinoma (MTSCC) has been very reported only in one instance. Case presentation: A 42-year-old Japanese woman was admitted to our hospital for the treatment of a left renal tumor measuring 5 cm in maximum dimension. She underwent a laparoscopic left nephrectomy. Histologically, the tumor formed tubular or focally papillary structures with a small amount of spindle-shaped tumor cells against the background of prominent extracellular mucin. Although the tumor cells were negative for immunohistochemistry (IHC) of alpha-methylacyl-CoA racemase (AMACR) and lymph node metastasis was presented (these are atypical findings for MTSCC), we initially diagnosed the tumor as MTSCC based on its morphological characteristics with mucin deposition. However, an additional IHC analysis revealed that the tumor cells were diffusely positive for ALK-IHC. In addition, TPM3 exon 8 – ALK exon 20 fusion gene was detected by RNA sequencing. The tumor was thus correctly diagnosed as ALK rearrangement-associated renal cell carcinoma (ALK-RCC). Conclusions: Since the use of molecular targeted therapy with an ALK inhibitor for ALK-RCC is promising, the correct pathological diagnosis of ALK-RCC is quite important. We strongly recommend that ALK-IHC be routinely performed for renal tumors with negative AMACR staining that mimic MTSCC.

DOI： 10.1186/s13000-022-01238-z

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Language：Others   Publishing type：Research paper (scientific journal)   Publisher：Journal of Neuropathology and Experimental Neurology  

GPI anchorless prion diseases (GPIALPs) show numerous coarse prion protein (PrP) deposits in the CNS but neuropil spongiform changes are mild and the incidence of dementia is low. Here, we examined differences in resident microglial phenotypes between GPIALP (D178fs25) and the other prion diseases Gerstmann-Sträussler-Scheinker (GSS) disease and sporadic Creutzfeldt-Jakob disease (sCJD) with respect to homeostasis and activation. Immunohistochemistry was performed on 2 GPIALP (D178fs25), 4 GSS (P102L), and 4 sCJD cases. Homeostatic microglia expressing TMEM119 and P2RY12 were preserved in GPIALP compared to GSS and sCJD. Microglia/macrophage activation in GSS and sCJD was associated with the extent of spongiform change. Immunoelectron microscopy revealed TMEM119 and P2RY12 in PrP plaque cores. Activated microglia/macrophages expressing HLA-DR and CD68 were predominant in GSS and sCJD whereas in GPIALP, homeostatic microglia were retained and activated microglia/macrophages were rarely observed. These data suggest that PrP deposition in GPIALP is less toxic and that microglia may be immune-tolerant to PrP deposition. This may be associated with milder tissue damage and a low incidence of dementia. Whereas microglia/macrophage activation is considered to be a reaction to tissue injury, this study shows that the degree of microglia/macrophage activity might influence the extent of tissue damage.

DOI： 10.1093/jnen/nlac098

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Background and Aim: Older age, type 2 diabetes mellitus (T2DM), and obesity are known risk factors for liver-related events (LREs). We investigated the impacts of T2DM and obesity on LRE according to age in Japanese patients with non-alcoholic fatty liver disease (NAFLD). Methods: We performed a subanalysis of a retrospective cohort study (CLIONE in Asia), including 1395 patients with biopsy-proven NAFLD. The median follow-up was 4.6 years. Results: The median age was 57 years, and 36.2% had T2DM. The median body mass index (BMI) was 27.4, and 28.5% were severely obese (BMI ≥ 30). During follow-up, 37 patients developed hepatocellular carcinoma (HCC), and 58 patients developed LRE. In patients younger than 65 years, advanced fibrosis (hazard ratio [HR] 7.69, P < 0.001) and T2DM (HR 3.37, P = 0.017) were HCC risk factors, and advanced fibrosis (HR 9.40, P < 0.001) and T2DM (HR 2.51, P = 0.016) were LRE risk factors. In patients 65 years and older, advanced fibrosis (HR 4.24, P = 0.010) and obesity (HR 4.60, P = 0.006) were HCC risk factors, and advanced fibrosis (HR 4.22, P = 0.002) and obesity (HR 4.22, P = 0.002) were LRE risk factors. Conclusion: Type 2 diabetes mellitus and obesity contributed to LRE in younger and older patients, respectively, along with advanced fibrosis. Therefore, controlling T2DM in patients younger than 65 years and controlling weight in patients 65 years and older could prevent LRE. The development of age-dependent screening and management strategies is necessary for patients with NAFLD.

DOI： 10.1111/jgh.16019

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Dendriform pulmonary ossification is a subtype of pulmonary ossification that causes ectopic lung tissue ossification.1 Although the exact mechanism is unclear, it is thought to be caused by fibroblasts associated with lung injury.2 The ossification can be idiopathic or secondary and is typically observed as linear or branching structures on computed tomography (CT).3-5 We encountered a case of massive dendriform pulmonary ossification with atypical CT findings in a patient with a history of occupational dust exposure.

DOI： 10.1097/RTI.0000000000000672

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Language：Others   Publishing type：Research paper (scientific journal)   Publisher：Journal of Cancer Research and Clinical Oncology  

Purpose: Pancreatic undifferentiated carcinoma (UDC) is a rare tumor with a worse prognosis than pancreatic ductal adenocarcinoma (PDAC). Recent study showed that UDC exhibits loss of SMARCB1, which is one of the subunits of the SWI/SNF complex. However, whether there are abnormalities of other SWI/SNF complex subunits in UDC has remained unknown. In this study, we attempted to clarify whether the loss of SWI/SNF complex subunits is related to the pathogenesis of UDC by comparing undifferentiated component (UC) and ductal adenocarcinoma component (DAC). Methods: Genetic analysis of the ten UCs and six DACs was performed. The expression of ARID1A, SMARCA2, SMARCA4, SMARCB1, SMARCC1, and SMARCC2 in formalin-fixed, paraffin-embedded tumor tissues collected by surgical resection from 18 UDC patients was evaluated immunohistochemically. Moreover, two pancreatic cell lines were evaluated for the effects of siARID1A on the mRNA and protein expression of E-cadherin, vimentin, and epithelial-mesenchymal transition (EMT)-related markers by qRT-PCR, western blotting, and immunofluorescence staining. Results: UCs tended to have a higher frequency of mutation in ARID1A, SMARCA4, and SMARCC2 than DACs. Immunohistochemically, UCs revealed reduced/lost expression of ARID1A (72%), SMARCB1 (44%), SMARCC1 (31%), and SMARCC2 (67%). Reduced/lost expression of ARID1A, SMARCB1, and SMARCC2 was significantly more frequently observed in UCs than in DACs. In the pancreatic cell lines, western blotting and qRT-PCR showed that the downregulation of ARID1A increased the expression of vimentin and EMT-related markers. Conclusion: Our results suggest that the abnormality of SWI/SNF complex subunits, especially ARID1A, is one of the factors behind the morphological change of UDC.

DOI： 10.1007/s00432-021-03860-8

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The differential effects of sporadic Creutzfeldt-Jakob disease (sCJD) on the hippocampus and other neocortical areas are poorly understood. We aimed to reveal the histological patterns of cellular prion protein (PrPC) and abnormal prion protein (PrPSc) in hippocampi of sCJD patients and normal controls (NCs). Our study examined 18 postmortem sCJD patients (MM1, 14 cases; MM1 + 2c, 3 cases; MM1 + 2t, 1 case) and 12 NCs. Immunohistochemistry was conducted using 4 primary antibodies, of which 3 targeted the N-terminus of the prion protein (PrP), and 1 (EP1802Y) targeted the C-terminal domain. PrPC expression was abundant in the hippocampus of NCs, and the distribution of PrPC at CA3/4 was reminiscent of synaptic complexes. In sCJD cases with a disease history of <2 years, antibodies against the N-terminus could not detect synapse-like PrP expression at CA4; however, EP1802Y could characterize the synapse-like expression. PrPSc accumulation and spongiform changes became evident after 2 years of illness, when PrPSc deposits were more noticeably detected by N-terminal-specific antibodies. Our findings highlighted the chronology of histopathological alterations in the CA4 region in sCJD patients.

DOI： 10.1093/jnen/nlac078

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Background and Aim: Non-alcoholic fatty liver disease (NAFLD) can progress in non-obese patients as in obese patients. Reports on long-term prognosis in non-obese NAFLD patients are controversial. Therefore, we aimed to examine the long-term prognosis of non-obese patients with NAFLD. Methods: This single-center, retrospective cohort study enrolled biopsy-proven non-obese and obese NAFLD patients between January 2002 and December 2011 and followed them up until 31 March 2021, for death and clinical events (cardiovascular and liver-related events and extrahepatic cancers). Results: Of the 223 NAFLD patients, 58 (26.0%) were non-obese. Compared with obese patients, they had a lower fibrosis stage (0.8 ± 0.80 vs 1.2 ± 0.91; P = 0.004), milder lobular inflammation (0.9 ± 0.7 vs 1.1 ± 0.7; P = 0.02), and significantly lower serum creatinine, total bilirubin, ferritin, and type IV collagen 7S and higher high-density lipoprotein levels. After a median follow-up of 8.9 years, no significant difference was noted in mortality between the two groups (2 [3.4%] non-obese vs 5 [3.0%] obese; log-rank test, P = 0.63). Twelve patients (20.7%) in the non-obese group and 32 (19.4%) in the obese group had clinical events. Although the obese group had a higher incidence of clinical events during the first 10 years of follow-up, the non-obese group had a higher incidence after that (log-rank test, P = 0.67). The non-obese group had a high incidence of malignancy (9 [15.5%] non-obese vs 14 [8.3%] obese; P = 0.13). Conclusion: Non-obese NAFLD does not necessarily have a good prognosis, and some cases have a poor prognosis such as extrahepatic cancers. Further validation is required in the future.

DOI： 10.1002/jgh3.12808

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DOI： 10.1253/circj.CJ-21-1080

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Objectives This study aimed to establish a reliable and reproducible categorized diagnostic classification system with identification of key features to achieve accurate pathological diagnosis of endoscopic ultrasound-guided fine needle aspiration biopsy (EUS-FNAB) samples of pancreatic lesions. Methods Twelve pathologists examined virtual whole-slide images of EUS-FNAB samples obtained from 80 patients according to proposed diagnostic categories and key features for diagnosis. Fleiss κ was used to assess the concordance. Results A hierarchical diagnostic system consisting of the following 6 diagnostic categories was proposed: inadequate, nonneoplasm, indeterminate, ductal carcinoma, nonductal neoplasm, and unclassified neoplasm. Adopting these categories, the average κ value of participants was 0.677 (substantial agreement). Among these categories, ductal carcinoma and nonductal neoplasm showed high κ values of 0.866 and 0.837, respectively, which indicated the almost perfect agreement. Key features identified for diagnosing ductal carcinoma were necrosis in low-power appearance; structural atypia/abnormalities recognized by irregular glandular contours, including cribriform and nonuniform shapes; cellular atypia, including enlarged nuclei, irregular nuclear contours, and foamy gland changes; and haphazard glandular arrangement and stromal desmoplasia. Conclusions The proposed hierarchical diagnostic classification system was proved to be useful for achieving reliable and reproducible diagnosis of EUS-FNAB specimens of pancreatic lesions based on evaluated histological features.

DOI： 10.1097/MPA.0000000000002179

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Objectives: Weight loss improves the liver pathophysiological status of nonalcoholic fatty liver disease (NAFLD) patients. However, there are few studies that investigate the accurate relationships between nutritional intake and disease progression in NAFLD patients. Methods: A total of 37 biopsy-confirmed NAFLD patients were enrolled in this study. Clinical and nutritional control data of 5074 persons were obtained from the National Institute of Health and Nutrition. Each NAFLD subject recorded dietary intake for seven consecutive days using a dietary questionnaire and photographs of each meal. A dietitian analyzed and quantified the nutritional data in each patient. We further analyzed the nutritional intake of NAFLD patients in three groups according to the following criteria: (1) liver fibrosis degree (advanced, early), (2) gender (male, female), and (3) body mass index (BMI) (high, low). Results: Excesses or deficiencies of multiple nutrients were found in NAFLD patients compared with control subjects. In addition, there were variations in nutritional intake. (1) The intake of vitamins A, B6, and E, pantothenic acid, soluble dietary fiber, and salt was lower in the advanced fibrosis group than in the early fibrosis group. (2) Fat intake was higher in male patients, and dietary fiber intake was lower in both male and female patients compared with control subjects. (3) Saturated fatty acid intake was higher, and copper and vitamin E intakes were lower in patients with high BMI than with low BMI. Conclusions: Our study demonstrates that differences were found in some nutrient intake of NAFLD patients and controls and according to the severity of the conditions (liver fibrosis degree, BMI).

DOI： 10.3390/nu14173453

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Language：Others   Publishing type：Research paper (scientific journal)   Publisher：Cancers  

We compared the preplanned histopathological responses of resected liver metastases from patients who received modified FOLFOX6 plus bevacizumab or modified FOLFOX6 plus cetuximab for liver-limited colorectal metastases in the ATOM trial. Fibrosis and viable tumor cells in tumor regression grade (TRG), infarct-like necrosis in modified TRG (mTRG), and dangerous halo (DH) were assessed. Fifty-five patients (28 and 27 patients in the bevacizumab and cetuximab arms, respectively) were divided into the low (viable tumor cells ≤ 50%) and high (>50%) TRG or mTRG groups. DH was characterized as absent/rare or focal/diffuse. Compared to the bevacizumab arm, the cetuximab arm was more effective, with respect to low TRG (13 vs. 23 patients) and absent/rare DH (14 vs. 19 patients), respectively. Low mTRG was similarly observed in both arms. Low TRG/mTRG and absent/rare DH showed better relapse-free survival (RFS) than high TRG/mTRG and focal/diffuse DH. In the bevacizumab arm, a significant difference in RFS existed between the low and high TRG groups, while in the cetuximab arm, for TRG, mTRG, and DH, the low and absent/rare groups demonstrated significantly longer RFS than the high and focal/diffuse groups, respectively. TRG could estimate RFS in patients who underwent liver metastasectomy after bevacizumab or cetuximab chemotherapy.

DOI： 10.3390/cancers14184392

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Language：Others   Publishing type：Research paper (scientific journal)   Publisher：Virchows Archiv  

Consultation by subspecialty experts is the most common mode of rendering diagnosis in challenging cases in pathological practice. Our study aimed to highlight the diagnostic benefits of whole-slide image (WSI)-based remote consultation. We obtained diagnostically challenging cases from two institutions from the years 2010 and 2013, with histological diagnoses that contained keywords “probable,” “suggestive,” “suspicious,” “inconclusive,” and “uncertain.” A total of 270 cases were selected for remote consultation using WSIs scanned at 40 ×. The consultation process consisted of three rounds: the first and second rounds each with 12 subspecialty experts and the third round with six multi-expertise senior pathologists. The first consultation yielded 44% concordance, and a change in diagnosis occurred in 56% of cases. The most frequent change was from inconclusive to definite diagnosis (30%), followed by minor discordance (14%), and major discordance (12%). Out of the 70 cases which reached the second round, 31 cases showed discrepancy between the two consultants. For these 31 cases, a consensus diagnosis was provided by six multi-expertise senior pathologists. Combining all WSI-based consultation rounds, the original inconclusive diagnosis was changed in 140 (52%) out of 266 cases. Among these cases, 80 cases (30%) upgraded the inconclusive diagnosis to a definite diagnosis, and 60 cases (22%) changed the diagnosis with major or minor discordance, accounting for 28 cases (10%) and 32 cases (12%), respectively. We observed significant improvement in the pathological diagnosis of difficult cases by remote consultation using WSIs, which can further assist in patient healthcare. A post-study survey highlighted various benefits of WSI-based consults.

DOI： 10.1007/s00428-022-03327-2

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Language：Japanese   Publisher：断層映像研究会  

症例は70歳代男性。夜間頻尿を主訴に近医を受診。血液検査でPSA値が11.0ng/mlと高値であり前医紹介となった。前医施行の単純MRIで前立腺に多房性嚢胞性腫瘤を認め、STUMP(stromal tumors of uncertain malignant potential)やcystadenoma、cystadenocarcinomaなどが疑われた。更なる精査、加療目的に当院泌尿器科紹介となった。当院施行の造影MRIでは前立腺背側の両葉で移行域、辺縁域にまたがる48×46×55mmの辺縁分葉状の腫瘤を認めた。内部はT2強調像でやや不均一かつ著明な高信号を呈し、隔壁様の構造が多発していた。T1強調像では大部分は低信号を呈し、腫瘤右側には出血や高粘稠度の液貯留を疑う高信号域を認めた。有意な拡散制限は認めず、dynamic studyでは辺縁優位に漸増性の増強効果を認めた。CTでは腫瘤辺縁にわずかに石灰化を認めた。前立腺生検が施行され、10/10本よりmucinous adenocarcinomaの所見が得られた。他部位に原発巣を示唆する所見はなく、前立腺原発のmucinous adenocarcinomaが強く疑われた。前立腺のmucinous adenocarcinomaは全前立腺癌の0.4%と稀な疾患である。腫瘍内に少なくとも25%以上のムチンを含むと定義されている。今回の症例は手術未施行であるが、全身検索および局所の画像所見からは前立腺原発のmucinous adenocarcinomaとして矛盾しない所見であった。画像所見上の鑑別としてSTUMPやcystadenoma、cystadenocarcinomaなどが挙げられたが、所見によってはこれらとの鑑別は困難となる場合も多い。前立腺のmucinous adenocarcinomaの画像所見についての報告は少なく、今回文献的考察を含めて報告する。(著者抄録)

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INTRODUCTION: No reports on both blood and fecal bile acids (BAs) in patients with nonalcoholic fatty liver disease (NAFLD) exist. We simultaneously assessed the serum and fecal BA patterns in healthy participants and those with NAFLD. METHODS: We collected stool samples from 287 participants from 5 hospitals in Japan (healthy control [HC]: n = 88; mild fibrosis: n = 104; and advanced fibrosis group: n = 95). Blood samples were collected and analyzed for serum BAs and 7α-hydroxy-4-cholesten-3-one (C4)-a surrogate marker for BA synthesis ability-from 141 patients. Concentrations of BAs, including cholic acid (CA), deoxycholic acid (DCA), chenodeoxycholic acid, ursodeoxycholic acid, and lithocholic acid (LCA), were measured using liquid chromatography-mass spectrometry. RESULTS: The total fecal BA concentration was significantly higher in the NAFLD group with worsening of fibrosis than in the HC group. Most of the fecal BAs were secondary and unconjugated. In the fecal BA fraction, CA, DCA, chenodeoxycholic acid, ursodeoxycholic acid, and LCA were significantly higher in the NAFLD than in the HC group. The total serum BA concentration was higher in the NAFLD group with worsening of fibrosis than in the HC group. In the serum BA fraction, CA, LCA, and C4 concentrations were significantly higher in the NAFLD than in the HC group. DISCUSSION: Fecal and serum BA and C4 concentrations were high in patients with NAFLD with worsening of fibrosis, suggesting involvement of abnormal BA metabolism in NAFLD with fibrosis progression. Abnormalities in BA metabolism may be a therapeutic target in NAFLD with fibrosis.

DOI： 10.14309/ctg.0000000000000503

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Background and Aims: Despite that hepatic fibrosis often affects the liver globally, spatial distribution can be heterogeneous. This study aimed to investigate the effect of liver stiffness (LS) heterogeneity on concordance between MR elastography (MRE)-based fibrosis staging and biopsy staging in patients with NAFLD. Approach and Results: We retrospectively evaluated data from 155 NAFLD patients who underwent liver biopsy and 3 Tesla MRE and undertook a retrospective validation study of 169 NAFLD patients at three hepatology centers. Heterogeneity of stiffness was assessed by measuring the range between minimum and maximum MRE-based LS measurement (LSM). Variability of LSM was defined as the stiffness range divided by the maximum stiffness value. The cohort was divided into two groups (homogenous or heterogeneous), according to whether variability was below or above the average for the training cohort. Based on histopathology and receiver operating characteristic (ROC) analysis, optimum LSM thresholds were determined for MRE-based fibrosis staging of stage 4 (4.43, kPa; AUROC, 0.89) and stage ≥3 (3.93, kPa; AUROC, 0.89). In total, 53 had LSM above the threshold for stage 4. Within this group, 30 had a biopsy stage of <4. In 86.7% of these discordant cases, variability of LSM was classified as heterogeneous. In MRE-based LSM stage ≥3, 88.9% of discordant cases were classified as heterogeneous. Results of the validation cohort were similar to those of the training cohort. Conclusions: Discordance between biopsy- and MRE-based fibrosis staging is associated with heterogeneity in LSM, as depicted with MRE.

DOI： 10.1002/hep.32302

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Language：Others   Publishing type：Research paper (scientific journal)   Publisher：Genes  

There is an association between nonalcoholic fatty liver disease (NAFLD) and atherosclerosis, but the genetic risk of atherosclerosis in NAFLD remains unclear. Here, a single-nucleotide polymorphism (SNP) of the heat shock 70 kDa protein 8 (HSPA8) gene was analyzed in 123 NAFLD patients who had been diagnosed using a liver biopsy, and the NAFLD phenotype including the maximum intima–media thickness (Max-IMT) of the carotid artery was investigated. Patients with the minor allele (A/G or G/G) of rs2236659 showed a lower serum heat shock cognate 71 kDa protein concentration than those with the major A/A allele. Compared with the patients with the major allele, those with the minor allele showed a higher prevalence of hypertension and higher Max-IMT in men. No significant associations between the HSPA8 genotype and hepatic pathological findings were identified. In decision-tree analysis, age, sex, liver fibrosis, and HSPA8 genotype were individually associated with severe carotid artery atherosclerosis (Max-IMT ≥ 1.5 mm). Noncirrhotic men aged ≥ 65 years were most significantly affected by the minor allele of HSPA8. To predict the risk of atherosclerosis and cardiovascular disease, HSPA8 SNP genotyping might be useful, particularly for older male NAFLD patients.

DOI： 10.3390/genes13071265

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Language：Others   Publishing type：Research paper (scientific journal)   Publisher：Surgery Today  

Purpose: At present, ≥ 20% of patients experience clinically relevant postoperative pancreatic fistula (POPF) after distal pancreatectomy (DP). Methods: We developed a new bioabsorbable pancreatic clip (BioPaC) made of polycaprolactone that does not crush the pancreatic parenchyma during occlusion of the pancreatic stump. We confirmed the efficacy of this BioPac in a porcine DP model and compared it to a linear stapling device (Reinforce®). Results: Pigs were killed at 1 month after DP. In the BioPaC group, all swine (n = 3) survived well without POPF. In the Reinforce® group (n = 2), one pig died early at postoperative day 7 with Grade C POPF (amylase 43 700 U/l), and the other survived until 1 month at scarification with biochemical leakage of POPF (amylase 3 725 U/l). Pathologically, the main pancreatic duct and pancreatic parenchyma were well closed by BioPaC. Conclusion: The newly developed BioPaC is effective in a porcine DP model.

DOI： 10.1007/s00595-021-02435-x

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Language：English   Publisher：シュプリンガー・ジャパン(株)  

膵尾部切除に際して膵断端閉塞中に膵実質を破断させないようなポリカプロラクトン製の新規生体吸収性膵臓クリップ(BioPaC)を作製し、その有効性を検討した。体重25～30kgの健常ブタを用いて実験を行い、手術では膵尾部を脾静脈と後腹膜から切離した後、脾膵葉の最も厚みのある部分を、BioPaCを用いて閉鎖した。対照にはReinforceを用いてBioPaCと同様の処理を施した。BioPaCは長さ59mm、高さ6mm、厚み5mm、クランプ時の幅16mm、クランプ時のギャップ4mmという構造であった。Reinforceを使用したブタ2匹のうち1匹は術後7日目に死亡し、グレードCの術後膵液漏(POPF)と診断された。もう1匹は術後30日まで生存したが、膵断端周囲に著明な腹腔内癒着が観察された。BioPaCを用いた3匹の術後経過は良好で、POPFの発症は認められなかった。病理学的所見ではBioPaCによって主膵管と膵実質の閉鎖が得られていた。ブタ膵尾部切除モデルにおいてBioPaCは有効であることが示された。

Language：Japanese   Publisher：日本臨床細胞学会-九州連合会  

背景 反応性中皮細胞は時に強い核異型を呈し、しばしば良悪性の鑑別が問題となる。今回、腹腔鏡下肝嚢胞開窓術中に採取された嚢胞液に反応性中皮細胞が出現し、腺癌との鑑別が問題となった1例を経験した。症例 60歳代女性。肝右葉を占拠する長径17cm大の感染が疑われる肝嚢胞に対して、経皮的穿刺ドレナージが行われた。一旦嚢胞は縮小したが再増大したため、腹腔鏡下肝嚢胞開窓術が施行された。嚢胞開窓後に採取された肝嚢胞内容液が術中迅速細胞診に提出され、核腫大した異型細胞集塊を1ヶ所に認めた。出現数は少ないが腺癌を否定できない異型細胞と報告した。細胞診の結果を受け、肝右葉切除術が施行された。切除検体の組織学的検討において、嚢胞壁を被覆する上皮に異型は認められず、漿膜側に中皮マーカー陽性を示す反応性中皮細胞を多数認めた。迅速細胞診で悪性を疑った異型細胞は反応性中皮細胞であったと結論し、最終的に単純性肝嚢胞と診断した。結論 経皮的穿刺ドレナージの経歴から、反応性中皮細胞が出現しうる状況であることを認識していれば、迅速細胞診で正診に至った可能性がある。教訓的な症例であるため、ここに報告する。(著者抄録)

Language：English   Publishing type：Research paper (scientific journal)   Publisher：British Journal of Neurosurgery  

We herein report the effectiveness of contralateral osteotomy of the pedicle and posterolateral elements for en bloc resection (COPPER) of paraspinal and spinal tumours. This surgical method allows for complete resection of the localized tumour in the lateral posterior lesion without removing the entire vertebral body, as in total en bloc spondylectomy. Complete resection of paraspinal and spinal tumours is challenging for spinal surgeons because of anatomical complexities. Although the COPPER method has been introduced as a less invasive surgical procedure for wide resection of spinal tumours, no studies have reported the usefulness of this technique. We identified three patients with paraspinal or spinal tumours who underwent wide resection using the COPPER method and reviewed their clinical, radiological, and pathological outcomes. In all cases, we resected the spinal and paraspinal tumours extending to the anterior column and extravertebral component using the modified COPPER method. All patients underwent en bloc resection with a negative margin. We report three cases of spinal and paraspinal tumours extending to the anterior column and extravertebral component.

DOI： 10.1080/02688697.2022.2076809

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To investigate useful cytological features for differential diagnosis of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), this study cytologically compared HCC to ICC using image analysis software. Touch smear specimens of surgically resected specimens were obtained from a total of 61 nodules of HCC and 16 of ICC. The results indicated that the major/minor axis ratio of ICC is significantly larger than that of HCC (1.67 ± 0.27 vs. 1.32 ± 0.11, p < 0.0001) in Papanicolaou staining. This result means that the nucleus of HCC is close to round and the nucleus of ICC is close to an oval. This significant difference in the major/minor axis ratio between ICC and HCC was consistently observed by the same analyses using clinical samples of cytology (4 cases of HCC and 13 cases of ICC) such a fine-needle aspiration, brushing and ascites (ICC: 1.45 ± 0.13 vs. HCC: 1.18 ± 0.056, p = 0.004). We also confirmed that nuclear position center-positioned nucleus (p < 0.0001) and granular cytoplasm (p <0.0001) are typical features of HCC tumor cells compared to ICC tumor cells. The research study found a significant difference in the nuclear morphology of HCC (round shape) and ICC (oval shape) in Papanicolaou-stained cytology specimens. This simple and objective finding will be very useful for the differential cytodiagnosis of HCC and ICC.

DOI： 10.3390/cancers14092301

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Background & Aims: As alternatives to the expensive liver biopsy for assessing liver fibrosis stage in patients with nonalcoholic fatty liver disease (NAFLD), we directly compared the diagnostic abilities of magnetic resonance elastography (MRE), vibration-controlled transient elastography (VCTE), and two-dimensional shear wave elastography (2D-SWE). Methods: Overall, 231 patients with biopsy-proven NAFLD were included. Intra- and inter-observer reproducibility was analyzed using intraclass correlation coefficient in a sub-group of 70 participants, in whom liver stiffness measurement (LSM) was performed by an elastography expert and an ultrasound expert who was an elastography trainee on the same day. Results: Valid LSMs were obtained for 227, 220, 204, and 201 patients using MRE, VCTE, 2D-SWE, and all three modalities combined, respectively. Although the area under the curve did not differ between the modalities for detecting stage ≥1, ≥2, and ≥3 liver fibrosis, it was higher for MRE than VCTE and 2D-SWE for stage 4. Sex was a significant predictor of discordance between VCTE and liver fibrosis stage. Skin-capsule distance and the ratio of the interquartile range of liver stiffness to the median were significantly associated with discordance between 2D-SWE and liver fibrosis stage. However, no factors were associated with discordance between MRE and liver fibrosis stage. Intra- and inter-observer reproducibility in detecting liver fibrosis was higher for MRE than VCTE and 2D-SWE. Conclusions: MRE, VCTE, and 2D-SWE demonstrated excellent diagnostic accuracy in detecting liver fibrosis in patients with NAFLD. MRE demonstrated the highest diagnostic accuracy for stage 4 detection and intra- and inter-observer reproducibility. UMIN Clinical Trials Registry No. UMIN000031491.

DOI： 10.1016/j.cgh.2020.12.016

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BACKGROUND: Low-voltage areas (LVAs) in the atria of patients with atrial fibrillation are considered local fibrosis. We hypoth-esized that voltage reduction in the atria is a diffuse process associated with fibrosis and that the presence of LVAs reflects a global voltage reduction. METHODS AND RESULTS: We examined 140 patients with atrial fibrillation and 13 patients with a left accessory pathway (con-trols). High-density bipolar voltage mapping was performed using a grid-mapping catheter during high right atrial pacing. Global left atrial (LA) voltage (VGLA) in the whole LA and regional LA voltage (VRLA) in 6 anatomic regions were evaluated with the mean of the highest voltage at a sampling density of 1 cm2. Patients with atrial fibrillation were categorized into quartiles by VGLA. LVAs were evaluated at voltage cutoffs of 0.1, 0.5, 1.0, and 1.5 mV. Twenty-eight patients with atrial fibrillation also underwent right atrial septum biopsy, and the fibrosis extent was quantified. Voltage at the biopsy site (Vbiopsy) was recorded. VGLA results by category were Q1 (<4.2 mV), Q2 (4.2–5.6 mV), Q3 (5.7–7.0 mV), and Q4 (≥7.1 mV). VRLA at any region was reduced as VGLA decreased. VGLA and VRLA did not differ between Q4 and controls. The presence of LVAs increased as VGLA decreased at any voltage cutoff. Biopsies revealed 11±6% fibrosis, which was inversely correlated with both Vbiopsy and VGLA (r=–0.71 and –0.72, respectively). Vbiopsy was correlated with VGLA (r=0.82). CONCLUSIONS: Voltage reduction in the LA is a diffuse process associated with fibrosis. Presence of LVAs reflects diffuse voltage reduction of the LA.

DOI： 10.1161/JAHA.121.024521

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The histological diagnosis of type 1 autoimmune pancreatitis (AIP) based on the findings obtained by an endoscopic ultrasound-guided fine needle biopsy (EUS-FNB) is feasible, but the diagnostic consistency of this method has not been confirmed. We determined the interobserver agreement among 20 pathologists regarding the diagnosis of type 1 AIP, including the distinction from pancreatic ductal adenocarcinoma (PDAC) using large tissue samples obtained by EUS-FNB. After guidance for diagnosing AIP with biopsy tissues was provided, a round 2 was performed. The median sensitivity and specificity for diagnosing PDAC vs. non-neoplastic diseases were 95.2% and 100%, respectively. In groups of specialists (n = 7) and the generalists (n = 13), Fleiss’ к-values increased from 0.886 to 0.958 and from 0.750 to 0.816 in round 2. The concordance was fair or moderate for obliterative phlebitis and storiform fibrosis but slight for ductal lesion of type 1 AIP. Discordant results were due to ambiguous findings and biopsy tissue limitations. Among the specialists, the ratio of cases with perfect agreement regarding the presence of storiform fibrosis increased in round 2, but agreement regarding obliterative phlebitis or ductal lesions was not improved. Although the histological definite diagnosis of type 1 AIP was achieved by most observers in > 60% of the cases, the confidence levels varied. Because some ambiguities exist, the histological diagnostic levels based on the diagnostic criteria of type 1 AIP should not be taken for granted. Guidance is effective for improving accurate PDAC diagnoses (notably by recognizing acinar-ductal metaplasia) and for evaluating storiform fibrosis.

DOI： 10.1007/s00428-021-03236-w

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Sodium glucose cotransporter-2 inhibitors (SGLT2is) are now widely used to treat diabetes, but their effects on nonalcoholic fatty liver disease (NAFLD) remain to be determined. We aimed to evaluate the effects of SGLT2is on the pathogenesis of NAFLD. A multicenter, randomized, controlled trial was conducted in patients with type 2 diabetes with NAFLD. The changes in glycemic control, obesity, and liver pathology were compared between participants taking ipragliflozin (50 mg/day for 72 weeks; IPR group) and participants being managed without SGLT2is, pioglitazone, glucagon-like peptide-1 analogs, or insulin (CTR group). In the IPR group (n = 25), there were significant decreases in hemoglobin A1c (HbA1c) and body mass index (BMI) during the study (HbA1c, −0.41%, P < 0.01; BMI, −1.06 kg/m2, P < 0.01), whereas these did not change in the CTR group (n = 26). Liver pathology was evaluated in 21/25 participants in the IPR/CTR groups, and hepatic fibrosis was found in 17 (81%) and 18 (72%) participants in the IPR and CTR groups at baseline. This was ameliorated in 70.6% (12 of 17) of participants in the IPR group and 22.2 % (4 of 18) of those in the CTR group (P < 0.01). Nonalcoholic steatohepatitis (NASH) resolved in 66.7% of IPR-treated participants and 27.3% of CTR participants. None of the participants in the IPR group developed NASH, whereas 33.3% of the CTR group developed NASH. Conclusion: Long-term ipragliflozin treatment ameliorates hepatic fibrosis in patients with NAFLD. Thus, ipragliflozin might be effective for the treatment and prevention of NASH in patients with diabetes, as well as improving glycemic control and obesity. Therefore, SGLT2is may represent a therapeutic choice for patients with diabetes with NAFLD, but further larger studies are required to confirm these effects.

DOI： 10.1002/hep4.1696

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Language：Japanese   Publisher：(一社)日本神経学会  

症例は54歳女性.2015年11月に急性型成人T細胞白血病(adult T cell leukemia,以下ATLと略記)を発症し,翌年3月に同種造血幹細胞移植を受けた.2019年5月に急激に認知機能障害が出現し,頭部MRIで大脳白質病変を認めた.髄液検査では蛋白の上昇を認めた.脳生検ではCD8陽性のT細胞を主体とする炎症細胞が白質へ浸潤していた.肺・腸管の慢性移植片対宿主病(graft versus host disease,以下GVHDと略記)の既往と病理所見から慢性GVHDの中枢神経病変(central nervous system involvement of GVHD,以下CNS-GVHDと略記)と診断した.ステロイドとミコフェノール酸モフェチルによる免疫療法を行い,認知機能障害と髄液所見の改善を得た.本症例はATLにおけるCNS-GVHDの初の報告であり,脳生検による診断の重要性と免疫療法の有効性を示した.(著者抄録)

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: Several noninvasive markers have been developed to predict nonalcoholic steatohepatitis (NASH). We investigated the predictive value of the cytokeratin-18 fragment (CK18-F) level and FIB-4 index for diagnosing NASH in patients with nonalcoholic fatty liver disease (NAFLD). METHODS: A total of 246 patients histologically diagnosed with NASH (n = 185) or nonalcoholic fatty liver (n = 61) were enrolled. We analyzed weighted receiver operating characteristic (ROC) curves for the prediction of NASH and determined the relationship between the CK18-F level and the histological features of NASH. In addition, we investigated the predictive value of the combination of the CK18-F level and FIB-4 index for diagnosing NASH. RESULTS: The area under the ROC curve (AUROC) value of the CK18-F level was 0.77. With a CK18-F cutoff level of 260 U/L, the sensitivity and specificity for diagnosing NASH were 82.7 and 57.4&#37;, respectively. Multiple comparisons showed that the CK18-F level did not differ among fibrosis stages but did significantly differ among hepatocyte ballooning grades. Overall, 95.7&#37; (66/69) of patients with a FIB-4 index of ≥2.67 had NASH. In patients with a FIB-4 index of <2.67, the AUROC value of the CK18-F level for predicting NASH was 0.77 and a CK18-F cutoff level of 260 U/L resulted in a sensitivity and specificity of 82.4 and 56.9&#37;. CONCLUSIONS: The CK18-F level had a good predictive ability for diagnosing NASH in patients with NAFLD. Additionally, the combination of the CK18-F level and FIB-4 index accurately and noninvasively predicted NASH, even those with a low FIB-4 index.

DOI： 10.1097/MEG.0000000000002176

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BACKGROUND: Mac-2 binding protein (M2BP) glycosylated isomer (M2BPGi) is a serum marker of liver fibrosis; M2BPGi is a glycosylated form of M2BP. Hepatocytes and hepatic stellate cells (HSCs) have been studied to determine the source of M2BP. This study proposes to identify the origin of M2BP in fibrotic liver. METHODS: Using liver fibrosis tissue specimens from 15 patients with liver cancer, M2BP mRNA and M2BP were detected by in situ hybridization and immunohistochemistry, respectively. The expression levels of M2BP mRNA were evaluated with scores of 3, 2, and 1. Fluorescent in situ hybridization was carried out to evaluate the distribution of M2BP mRNA and the activated-HSC marker αSMA mRNA; multicolor fluorescent immunohistochemistry was used for protein localization of M2BP, αSMA, and CD68. The Kruskal-Wallis test analyzed the relationship between M2BP mRNA expression and existing serum fibrosis markers. RESULTS: M2BP mRNA was expressed in spindle-shaped cells along the fibrous septa and in the perisinusoidal area of the fibrotic liver. The HSC markers αSMA mRNA and M2BP mRNA were colocalized in the spindle-shaped cells; on the protein level, M2BP was expressed in Kupffer cells. M2BP mRNA expression was positively correlated with serum M2BPGi levels. Aspartate transaminase-to-platelet ratio index, Fibrosis-4, hyaluronic acid, and the 15-minute indocyanine green retention rate were significantly correlated with M2BP mRNA expression. CONCLUSIONS: M2BP mRNA transcription in fibrotic liver was primarily observed in HSCs but not at the M2BP level, which suggests that HSCs might produce and introduce M2BP to Kupffer cells and serum.

DOI： 10.1111/hepr.13648

Language：English   Publishing type：Research paper (scientific journal)  

Cerebral infarction (CI) severely affects the prognosis of patients with malignancy. The aim of the study was to compare the pathology of CI between cases with and without malignancy focusing on intracranial Mönckeberg's atherosclerosis. Among 778 autopsy cases of craniotomy, 53 cases of "cerebral infarction without malignancy group" (CI group), 50 cases of "malignant tumor without CI group" (MT group), and 39 cases of "cerebral infarction with malignancy group" (CM group) were identified. Mönckeberg's atherosclerosis was mainly found in the basal ganglia and its prevalence in the CM group (38.5&#37;) was significantly higher than in the MT group (12.0&#37;, p = 0.005), and apparently higher than in the CI group (18.9&#37;, p = 0.057). The CI group was significantly older, had higher BMIs, and a greater prevalence of hypertension and atrial fibrillation compared to the CM group. In addition, the prevalence of chronic renal disease was significantly lower in the CM group (2.6&#37;, p = 0.012) than in the CI group (20.8&#37;). Our results indicated that Mönckeberg's atherosclerosis was often found in the basal ganglia of CM cases and that intracranial Mönckeberg's atherosclerosis is a potential risk factor for CI in patients with advanced stage malignancy.

DOI： 10.3390/cancers13205234

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The effect of the skin-capsular distance (SCD) on the controlled attenuation parameter (CAP) for diagnosis of liver steatosis in patients with nonalcoholic fatty liver disease (NAFLD) remains unclear. The SCD was measured using B-mode ultrasound, and the CAP was measured using the M probe of FibroScan®. According to the indications of the M probe, 113 patients with an SCD of ≤ 25 mm were included in the present study. The association between the SCD and CAP was investigated, and the diagnostic performance of the SCD-adjusted CAP was tested. The SCD showed the most significant positive correlation with the CAP (ρ = 0.329, p < 0.001). In the multiple regression analysis, the SCD and serum albumin concentration were associated with the CAP, independent of pathological liver steatosis. According to the multivariate analysis, two different formulas were developed to obtain the adjusted CAP using the SCD and serum albumin concentration as follows: adjusted CAP (dB/m) = CAP - (5.26 × SCD) and adjusted CAP (dB/m) = CAP - (5.35 × SCD) - (25.77 × serum albumin concentration). The area under the receiver operating characteristic curve for diagnosis of a steatosis score ≥ 2 of adjusted CAP was 0.678 and 0.684 respectively, which were significantly greater than the original CAP (0.621: p = 0.030 and p = 0.024). The SCD is associated with the CAP independent of liver steatosis. Adjustment of the CAP using the SCD improves the diagnostic performance of the CAP in NAFLD.

DOI： 10.1038/s41598-021-94970-3

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Invasive gallbladder carcinoma (GBC) is preceded by two main types of precursor lesions: intracholecystic papillary-tubular neoplasms (ICPNs) and biliary intraepithelial neoplasias (BilINs). Invasive GBCs with an ICPN component have more favorable prognoses than those without an ICPN component. Some BilINs show a relatively exophytic papillary pattern but do not meet the ICPN criteria; at our institution, we call these papillary neoplasias. To clarify the clinical significance of papillary neoplasia, we herein examined 80 invasive GBCs and classified them into three groups based on the type of preinvasive lesions: those with ICPN (ICPN group, n = 35), those with papillary neoplasia (pap-neoplasia group, n = 13), and those without ICPN/papillary neoplasia (group without ICPN/pap-neoplasia, n = 32). We then compared the prognostic differences and characterized the tumors of each group by determining the immunohistochemical expressions of various biomarkers. The overall survival periods of the ICPN and pap-neoplasia groups were significantly longer than that of the group without ICPN/pap-neoplasia (P < 0.0001, P = 0.0036, respectively). Multivariate analysis revealed that lacking ICPN/papillary neoplasia was independently associated with poor prognosis (P = 0.0007), as were poor differentiation (P = 0.0395), presence of preoperative symptoms (P = 0.0488), and advanced stage (P = 0.0234). Invasive components of the ICPN and pap-neoplasia groups were characterized by higher expressions of p16 and p53 compared with those of the group without ICPN/pap-neoplasia. The prognoses of the invasive GBCs with either papillary neoplasia or ICPN were thus more favorable than those of the invasive GBCs without ICPN/pap-neoplasia. Invasive GBCs with exophytic papillary preinvasive lesions (ICPN and papillary neoplasia) may be biologically different from those without such lesions.

DOI： 10.1016/j.humpath.2021.05.001

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BACKGROUND: The prognosis of advanced laryngeal cancer is unfavorable despite advances in multidisciplinary therapy. Dendritic cells (DCs) play a central role in antitumor immunity. Tumor-infiltrating CD1a+ DCs have been reported to be associated with clinical outcomes in carcinomas of various organs, but the clinical impact of CD1a+ DCs in laryngeal cancer remains to be unequivocally established. METHODS: We retrospectively analyzed the cases of 57 patients with Stage III or IV laryngeal cancer who underwent a total laryngectomy. Immunohistochemistry detection of CD1a, S100 and CD8 was performed on representative resected specimens. CD1a+ DCs, S100+ DCs and CD8+ cytotoxic T-lymphocytes (CTLs) were evaluated, and the cases divided into high and low groups according to the cut-off of the median values for each of these 3 parameters. RESULTS: Compared to the CD1a-low group, the CD1a-high group had more advanced cases and showed significantly worse disease-specific survival (DSS) (P = 0.008) and overall survival (OS) (P = 0.032). The analyses of S100 DCs and CD8+ CTLs revealed no significant impact on clinical outcomes. However, multivariate analysis revealed that infiltration of CD1a+ DCs was an independent unfavorable prognostic factor for both DSS (P = 0.009) and OS (P = 0.013). CONCLUSIONS: Our results demonstrated that the infiltration of CD1a+ DCs was associated with unfavorable clinical outcomes in patients with advanced laryngeal cancer who underwent a total laryngectomy as the initial treatment.

DOI： 10.1186/s12885-021-08715-6

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND AND AIM: Gut microbiota composition is associated with the pathogenesis of non-alcoholic fatty liver disease. However, the association between gut microbiota composition and non-alcoholic fatty liver disease in non-obese patients remains unclear. We compared clinical parameters and gut microbiota profiles of healthy controls and non-obese and obese patients with non-alcoholic fatty liver disease. METHODS: We examined the clinical parameters and gut microbiota profiles by 16S rRNA sequences and short-chain fatty acid levels in fecal samples from 51 non-obese patients with non-alcoholic fatty liver disease (body mass index <25 kg/m2 ) and 51 obese patients with non-alcoholic fatty liver disease (body mass index ≥30 kg/m2 ) who underwent pathological examination and 87 controls at five hospitals in Japan. RESULTS: Although no significant differences between the non-obese and other groups were observed in alpha diversity, a significant difference was found in beta diversity. We observed a significant decrease in serum alanine aminotransferase levels, Eubacterium population, and butyric acid levels in non-obese patients with non-alcoholic fatty liver disease compared with those in obese patients with non-alcoholic fatty liver disease. A significant negative correlation was found between the stage of hepatic fibrosis and Eubacterium abundance in non-obese patients with non-alcoholic fatty liver disease. CONCLUSIONS: The decrease in the abundance of Eubacterium that produces butyric acid may play an important role in the development of non-alcoholic fatty liver disease in non-obese individuals. This study was registered at the University Hospital Medical Information Network clinical trial registration system (UMIN000020917).

DOI： 10.1111/jgh.15487

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Histopathological diagnosis of pancreatic ductal adenocarcinoma (PDAC) on endoscopic ultrasonography-guided fine-needle biopsy (EUS-FNB) specimens has become the mainstay of preoperative pathological diagnosis. However, on EUS-FNB specimens, accurate histopathological evaluation is difficult due to low specimen volume with isolated cancer cells and high contamination of blood, inflammatory and digestive tract cells. In this study, we performed annotations for training sets by expert pancreatic pathologists and trained a deep learning model to assess PDAC on EUS-FNB of the pancreas in histopathological whole-slide images. We obtained a high receiver operator curve area under the curve of 0.984, accuracy of 0.9417, sensitivity of 0.9302 and specificity of 0.9706. Our model was able to accurately detect difficult cases of isolated and low volume cancer cells. If adopted as a supportive system in routine diagnosis of pancreatic EUS-FNB specimens, our model has the potential to aid pathologists diagnose difficult cases.

DOI： 10.1038/s41598-021-87748-0

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BACKGROUND: Hepatocellular adenoma (HCA) subtypes are considered as risk factors for malignant transformation; thus, an accurate diagnosis is important. We report a case of resected HCA previously diagnosed as unclassified HCA using immunohistochemistry, subsequently discovered to harbor a mutation in exon 3 of the beta (β)-catenin gene using deoxyribonucleic acid (DNA) sequencing. CASE PRESENTATION: The patient was a 26-year-old woman who was referred to our hospital because of a 150-mm tumor in the right lobe of the liver. Considering the possibility of malignancy, we performed right lobe hepatectomy. Based on the histopathological and immunohistochemical findings, the tumor was diagnosed as an unclassified HCA. Next, we performed sequencing of DNA isolated from the tumor and identified a mutation in exon 3 of β-catenin, suggesting that the tumor contained an activating mutation of the β-catenin gene. CONCLUSION: β-Catenin mutations in HCA cannot be detected by immunohistochemistry alone, and molecular analysis is required to accurately diagnose and evaluate its prognosis.

DOI： 10.1186/s40792-021-01131-9

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Growth factors (GFs) are signaling molecules that are principle mediators in tissue regeneration. Biomaterial scaffolds employed as wound dressings are often hampered by their limitations to deliver GFs exogenously due to their instability and low half-life. The key to overcome this challenge lies in the better organization and use of endogenous pro-regenerative GFs released at regenerative site, with an aim to minimize the sole dependency on exogenous factors. Considering such challenges, this research utilizes the exogenous and endogenous GFs sequestering capability of heparin functionalized PCL/gelatin co-spun nanofabrics to mediate synergistically driven tissue regeneration by utilizing combined therapeutic effect of exogenous and endogenous GFs, and thereby minimizing the sole dependency on exogenous GFs for tissue regeneration. Basic fibroblast growth factor (bFGF) was chosen as GF for exogenous loading whereas vascular endothelial growth factor (VEGF) was chosen as a representative example to demonstrate the endogenous pro-regenerative GF sequestration capability of fabricated nanofabrics. From our results, the fabricated nanofabrics showed loading efficiency of 80&#37; for exogenous bFGF and can sequester 15-fold more amount of endogenous VEGF compared to non-heparin functionalized nanofibrous dressings. When applied as wound dressings, heparin functionalized nanofibers showed better therapeutic capability compared to control groups that were treated using patches without heparin functionalization, indicating endogenously driven tissue regeneration. This was indicated by significant higher number of newly formed skin appendages, lesser scarring and lower inflammatory levels in newly formed granulation. Additionally, further improvements in therapeutic effect was observed when exogenous bFGF was employed indicating effectiveness of synergistically mediated tissue regeneration.

DOI： 10.1016/j.cej.2020.126518

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Gallbladder cancer (GBC) is an aggressive malignancy with a poor prognosis. Antigen-presenting dendritic cells (DCs) play a central role in antitumor immunity. DCs expressing CD1a (CD1a-DCs) are considered immature DCs. The aim of this study was to evaluate the clinical impact of CD1a-DC infiltration into GBC tissue. Seventy-five patients with GBC (excluding non-invasive and intramucosal cancer) were enrolled. Immunohistochemistry for CD1a, S100 and CD8 was performed using representative surgically resected specimens. The cases were divided into a high CD1a-DC group (27 cases, 36&#37;) and low CD1a-DC group (48 cases, 64&#37;) according to the degree of CD1a-DC infiltration/aggregation. The high CD1a-DC group contained fewer patients with distant metastasis (P = 0.039) and more patients given postoperative chemotherapy (P = 0.038). The high CD1a-DC group had significantly longer overall survival (P = 0.001) and disease-specific survival (P = 0.002) than the low CD1a-DC group. In contrast, S100-DC and CD8+ tumor-infiltrating lymphocyte statuses were without effect on OS or DSS. The results of multivariate analyses indicated that the degree of infiltration/aggregation of CD1a-DCs was an independent prognostic factor associated with a favorable prognosis after surgery.

DOI： 10.1016/j.tranon.2020.100923

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BACKGROUND AND AIM: Non-alcoholic fatty liver disease (NAFLD) is typically associated with metabolic syndrome and diabetes, and insulin resistance is involved in its pathogenesis. However, the relationship between insulin secretion and NAFLD is unclear. We aimed to characterize the relationship between fasting insulin secretory function (ISF), evaluated using the homeostatic model assessment-beta cell function (HOMA-β) and the severity of fibrosis during NAFLD. METHODS: A-β was calculated in 188 patients with biopsy-confirmed NAFLD, and the correlations between Log HOMA-β and clinical parameters, including hepatic fibrosis, were calculated. RESULTS: Log HOMA-β was significantly lower in NAFLD patients with significant fibrosis (stages 2-4) than in those in the early stages (stages 0-1) (median [interquartile range]) (2.1 [1.9-2.4] vs 2.0 [1.8-2.2], P = 0.04). The prevalence of significant fibrosis decreased with increasing Log HOMA-β: it was 59.2% in participants with low ISF (Log HOMA-β < 1.85), 43.6% in those with intermediate ISF (1.85 ≤ Log HOMA-β < 2.25), and 68.0% in those with high ISF (Log HOMA-β ≥ 2.25). Patients with lower Log HOMA-β had lower current body mass index (BMI), BMI at 20 years of age, and peak lifetime BMI than patients with intermediate or high Log HOMA-β. CONCLUSIONS: Fasting ISF decreased alongside the development of liver fibrosis in NAFLD, suggesting that an impaired β cell function has a characteristic finding of significant liver fibrosis in relatively nonobese Japanese patients.

DOI： 10.1002/jgh3.12367

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Nonalcoholic fatty liver disease (NAFLD) is based on the concept of pathological morphology as well as clinical findings, and is broadly categorized into nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). The differential diagnosis between NAFL and NASH is important because NASH has the potential to progress to cirrhosis and hepatocellular carcinoma. NAFL is simple hepatic steatosis without hepatocellular injury, while NASH is characterized by macrovesicular steatosis, inflammation, and ballooning hepatocytes with a predominantly centrilobular (zone 3) distribution. Liver biopsy is a useful test for diagnosing NAFLD, but it is invasive. Therefore, various noninvasive methods including diagnostic imaging have been developed in recent years. To verify their usefulness, it is necessary to clarify in detail how the pathological findings are reflected in the image findings as imaging and histopathological findings are closely related. We describe the main histological features of NAFLD, i.e., steatosis, inflammation, ballooning hepatocytes, Mallory-Denk bodies, and fibrosis, as well as the evolutional process to liver cirrhosis.

DOI： 10.1007/s10396-020-01061-3

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The biopsy-based diagnosis of autoimmune pancreatitis (AIP) is difficult but is becoming imperative for pathologists due to the increased amount of endoscopic ultrasound-guided biopsy tissue. To cope with this challenge, we propose guidance for the biopsy diagnosis of type 1 AIP. This guidance is for pathologists and comprises three main parts. The first part includes basic issues on tissue acquisition, staining, and final diagnosis, and is intended for gastroenterologists as well. The second part is a practical guide for diagnosing type 1 AIP based on the AIP clinical diagnostic criteria 2018. Inconsistent histological findings, tips for evaluating IgG4 immunostaining and key histological features including the ductal lesion and others are explained. Storiform fibrosis and obliterative phlebitis are diagnostic hallmarks but are sometimes equivocal. Storiform fibrosis is defined as spindle-shaped cells, inflammatory cells and fine collagen fibers forming a flowing arrangement. Obliterative phlebitis is defined as fibrous venous obliteration with inflammatory cells. Examples of each are provided. The third part describes the differentiation of AIP from pancreatic ductal adenocarcinoma (PDAC), focusing on histological features of acinar-ductal metaplasia in AIP, which is an important mimicker of PDAC. This guidance will help standardize pathology reports of pancreatic biopsies for diagnosing type 1 AIP.

DOI： 10.1111/pin.12994

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AIM: Liver biopsy is still required for the diagnosis of hepatocellular ballooning and inflammation, which are important histological features of non-alcoholic steatohepatitis. We undertook this multicenter, cross-sectional study to identify novel blood markers for the diagnosis of hepatocellular ballooning. METHODS: We enrolled 176 patients, of whom 132 were proven by liver biopsy as having non-alcoholic fatty liver disease (NAFLD) and classified as non-ballooning (ballooning grade 0) (n = 83) or ballooning (ballooning grade 1 and 2) (n = 49) by a central pathology review. We carried out gas chromatography-mass spectrometry, hydrophilic interaction liquid chromatography tandem mass spectrometry, and lipidomics with plasma. RESULTS: As correlates of hepatocellular ballooning, among the clinical parameters, serum type IV collagen 7S correlated most significantly with the ballooning grade (correlation coefficient [CC] = 0.463; P < 0.001). Among the metabolic/lipidomic markers, phosphatidylcholine (PC) (aa-44:8) correlated most significantly with the ballooning grade (CC = 0.394; P < 0.001). The area under the receiver operating characteristic curve of type IV collagen 7S, choline, and lysophosphatidylethanolamine (LPE) (e-18:2), was 0.846 (95% confidence interval, 0.772-0.919). CONCLUSIONS: Plasma levels of PC were positively correlated, and those of lysophosphatidylcholine and LPE were negatively correlated with hepatocellular ballooning in NAFLD patients. These non-invasive metabolic/lipidomic-based plasma tests might be useful to distinguish between cases of NAFLD with and without hepatocellular ballooning.

DOI： 10.1111/hepr.13528

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AIM: Combined hepatocellular cholangiocarcinoma (cHCC-CCA) is a very rare subtype of primary liver carcinoma; therefore, its clinicopathological characteristics have not yet been elucidated in detail. The aim of the study was to reveal the clinicopathological characteristics and prognostic factors of cHCC-CCA after hepatic resection (HR) METHODS: A total of 124 patients who underwent curative HR for cHCC-CCA between 2000 and 2016 were enrolled in this multi-institutional study conducted by the Kyushu Study Group of Liver Surgery. Clinicopathological analysis was performed from the viewpoint of patient prognosis. RESULTS: A total of 62 patients (50%) had early recurrence within 1.5 years after HR, including 36 patients (58%) with extrahepatic recurrence. In contrast, just four patients (3%) had late recurrence occurring >3 years after HR. The independent predictors of early recurrence were as follows: des-gamma carboxyprothrombin >40 mAU/mL (odds ratio 26.2, P = 0.0117), carbohydrate antigen 19-9>37 IU/l (odds ratio 18.0, P = 0.0200), and poorly differentiated HCC or CCA (odds ratio 11.2, P = 0.0259). CONCLUSIONS: Half of the patients with cHCC-CCA had early recurrence after HR. Preoperative elevation of des-gamma carboxyprothrombin or carbohydrate antigen 19-9 and the existence of poorly differentiated components of HCC or CCA in resected specimens are predictors of its early recurrence.

DOI： 10.1111/hepr.13507

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AIM: Recently, FibroScan-AST (FAST) score was reported to be effective for identifying non-alcoholic steatohepatitis (NASH) with significant activity and fibrosis in non-alcoholic fatty liver disease (NAFLD). The aim of this study was to confirm the diagnostic accuracy of FAST score of Japanese patients and compare the cut-off values and diagnostic accuracy between the FibroScan M and XL probes. METHODS: Eighty-two and 84 patients were included the verification and validation sets, respectively. All patients were diagnosed with NAFLD by biopsy by two central expert pathologists. Liver stiffness measurements and controlled attenuation parameter were carried out, and diagnostic performance was evaluated using receiver operating characteristic (ROC) curve analysis. RESULTS: No significant difference existed in FAST score between the M and XL probes (0.489 vs. 0.483, P = 0.187). No significant difference existed in the area under the ROC between the two probes (M, 0.7598; XL, 0.7614; P = 0.958). According to the Youden index, the cut-off value using the M probe was 0.57 with 68.2% sensitivity and 78.3% specificity. For the XL probe, the cut-off value was 0.56 with 68.2% sensitivity and 73.3% specificity. To obtain sensitivity and specificity values higher than 90%, cut-off values of 0.35 and 0.66 were chosen for the M probe and 0.32 and 0.63 were chosen for the XL probe. CONCLUSIONS: There was no significant difference in diagnostic accuracy of FAST score between the FibroScan M and XL probes. The FAST score can be used to identify NASH with significant risk in Japanese patients regardless of probe selection.

DOI： 10.1111/hepr.13508

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AIM: The Enhanced Liver Fibrosis (ELF) test comprises a logarithmic algorithm combining three serum markers of hepatic extracellular matrix metabolism. We aimed to evaluate the performance of ELF for the diagnosis of liver fibrosis and to compare it with that of liver stiffness measurement (LSM) by FibroScan in non-alcoholic fatty liver disease. METHODS: ELF cut-off values for the diagnosis of advanced fibrosis were obtained using receiver operating characteristic analysis in patients with biopsy-confirmed non-alcoholic fatty liver disease (training set; n = 200). Diagnostic performance was analyzed in the training set and in a validation set (n = 166), and compared with that of LSM in the FibroScan cohort (n = 224). RESULTS: The area under receiver operating characteristic curve was 0.81 for the diagnosis of advanced fibrosis, and the ELF cut-off values were 9.34 with 90.4% sensitivity and 10.83 with 90.6% specificity in the training set, and 89.8% sensitivity and 85.5% specificity in the validation set. There was no significant difference in the area under the receiver operating characteristic curve between ELF and LSM (0.812 and 0.839). A combination of ELF (cut-off 10.83) and LSM (cut-off 11.45) increased the specificity to 97.9% and the positive predictive value, versus ELF alone. Sequential use of the Fibrosis-4 index (cut-off 2.67) and ELF (cut-off 9.34) increased the sensitivity to 95.9%. CONCLUSIONS: ELF can identify advanced liver fibrosis in non-alcoholic fatty liver disease, and its diagnostic accuracy is comparable to that of FibroScan. According to the clinical setting, combinations or sequential procedures using other non-invasive tests complement the diagnostic performance of ELF for the identification of advanced fibrosis.

DOI： 10.1111/hepr.13495

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BACKGROUND: Liver biopsy has been the standard procedure for diagnosing and evaluating the severity of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH); however, interobserver discordance remains a critical issue in its pathological diagnosis. METHODS AND RESULTS: We examined the concordance rates of pathological scoring and diagnosis between pathologists at individual institutions (local diagnosis) and two central pathologists specialized in liver pathology (central diagnosis). A total of 150 patients with NAFLD underwent prospective liver biopsies. NAFLD activity score (NAS) and fibrosis stage were evaluated, and NASH was determined according to Matteoni's classification. NAS, scores for all NAS components, and fibrosis stage were diagnosed at a lower degree by central compared with local diagnosis. NASH was diagnosed in 34% of the patients according to central pathologists compared with 54% according to local pathologists (P < 0.001). The concordance rates for NAS, steatosis, inflammation, ballooning, fibrosis, and NASH diagnosis were 26.7, 62.7, 51.3, 48.7, 43.3, and 50.7%, respectively. The correlation coefficient between local and central diagnoses was the lowest for the scoring of ballooning (ρ = 0.218). CONCLUSION: Concordance rates among pathologists for the evaluation of NAFLD are currently poor, and simple and reliable diagnostic and evaluation criteria are urgently needed to improve the clinical management of NAFLD patients.

DOI： 10.1002/jgh3.12289

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BACKGROUND: Hepatocellular adenoma (HCA) is conventionally considered a rare benign liver tumor, but advanced studies have revealed that HCA is heterogeneous, and may include a type that is prone to malignant transformations. Differentiation between well-differentiated hepatocellular carcinoma and focal nodular hyperplasia is necessary to diagnose hepatocellular adenoma through imaging; however, the tumor marker of hepatocellular carcinoma, protein induced by vitamin K absence, or antagonist II (PIVKA-II), is rarely positive in hepatocellular adenoma. CASE PRESENTATION: A 44-year-old woman presented to our hospital with complaints of loss of appetite and weight loss. Multidetector row computed tomography revealed a liver tumor (diameter, 80 mm) that was enhanced in the arterial phase. Her serum PIVKA-II level was very high (3327 mAU/mL). Based on the enlargement of the mass and the results of the diagnostic imaging, hepatocellular adenoma or hepatocellular carcinoma was suspected, and we considered the possibility of a malignant transformation due to the high level of serum PIVKA-II; thus, we performed hepatectomy. Histological examination showed brown pigment deposition in the hepatocytes, which was determined to be lipofuscin granules. Based on immunohistochemical findings, the diagnosis was unclassified hepatocellular adenoma. Immunohistochemical examinations revealed that the adenoma cells in the tumor were positive for PIVKA-II. Her serum PIVKA-II level returned to normal after the resection. CONCLUSIONS: We present a case of unclassified hepatocellular adenoma with brown pigment deposition and elevation of serum PIVKA-II level. For the differentiation of liver tumors with high levels of PIVKA-II and hypervascular mass, hepatocellular adenoma should be considered.

DOI： 10.1186/s40792-020-00853-6

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Gerstmann-Sträussler-Scheinker (GSS) disease with P102L mutation and familial Creutzfeldt-Jakob disease (CJD) with V180I mutation are 2 major hereditary prion diseases in Japan. GSS and some familial CJD [V180I] exhibit characteristic prion protein (PrP) plaques. Overexpression of the astrocytic water channel proteins aquaporin (AQP) 1 and AQP4 was recently reported in sporadic CJD. To clarify the pathological characteristics of AQP1 and AQP4 in prion disease patient brains with plaque-type deposition, we investigated 5 patients with GSS, 2 patients with CJD [V180I], and 2 age-matched control cases without neurological diseases using immunohistochemistry and double immunofluorescence methods. We demonstrated that there is the intense expression of AQP1 and AQP4 around prion plaques, especially in distal astrocytic processes deep inside these plaques. Similar results have been reported in the senile plaques and ghost tangles of Alzheimer disease brains and a protective role of AQP4 in which AQP4 is redistributed toward the plaques and works as a barrier against the deleterious effects of these plaques has been suggested. Our results, which show a similar clustering of AQPs around PrP plaques, therefore support the possibility that AQPs also have a protective role in plaque formation in prion diseases.

DOI： 10.1093/jnen/nlaa010

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BACKGROUND: Few studies have evaluated both liver fibrosis and steatosis in patients with nonalcoholic fatty liver disease (NAFLD) using both FibroScan® M and XL probes. This study was performed to investigate the accuracy of both FibroScan® probes to diagnose liver fibrosis and steatosis in patients with NAFLD. METHODS: We prospectively enrolled 137 consecutive patients with clinically suspected NAFLD in our joint-research facilities. Liver biopsies, liver stiffness measurements (LSMs), and controlled attenuation parameter (CAP) measurements were performed, and 122 patients with NAFLD diagnosed pathologically by central pathologists were included in the final analysis. RESULTS: Reliable LSM results were obtained in 85.2% (M) and 89.3% (XL) of patients, and CAP was reliable in 90.2% (M) and 90.2% (XL). The median LSM was significantly lower with the XL than M probe, and CAP was significantly higher with the XL than M probe. The optimal cut-off values for diagnosing the fibrosis stage were lower for LSM with the XL than M probe (stage ≥ 2, 6.7 vs. 7.0; stage ≥ 3, 8.2 vs. 10.8; stage 4, 14.3 vs. 16.8, respectively), whereas those of CAP were higher for the XL than M probe (score of ≥ 2, 273 vs. 267; score of 3, 302 vs. 286, respectively). There were no significant differences in accuracy of the LSM and CAP between the probes. CONCLUSIONS: Liver fibrosis and steatosis could be equally evaluated with FibroScan® M and XL probes in patients with NAFLD. There was no significant difference in diagnostic accuracy between the two probes using probe-specific cut-off values.

DOI： 10.1007/s00535-019-01635-0

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AIM: To identify potential biomarkers for tumor progression and patient outcomes in cervical squamous cell carcinoma. METHODS: We examined the expressions of CK7 and CK17 as potential markers of the squamo-columnar junction, and podoplanin as a basal cell marker using surgical and biopsy samples of patients in grade 3 cervical intraepithelial neoplasia (n = 30), operable invasive carcinoma (OP group, n = 53) and inoperable invasive carcinoma before radiotherapy and/or chemotherapy (RC group, n = 76). RESULTS: The positive rates of CK7 and podoplanin in invasive carcinoma were significantly lower than those in grade 3 cervical intraepithelial neoplasia (P = 0.001, P < 0.0001). The positive rates of CK7 and podoplanin in the RC group were significantly lower than those in the OP group (P < 0.0001, P = 0.04), while CK17 expression showed significantly higher positivity in the RC group than in the OP group (P < 0.0001). Negative CK7 expression showed a potential impact on overall survival in early-stage patients. In the RC group, the prevalence of cases with post-therapeutic residual carcinoma cells was higher in the CK7-negative group than in the positive group (P = 0.003). We found that decreased expression of CK7 could be a prognostic factor in early-stage cervical cancer patients. CONCLUSION: This result may provide strategies and suggestions for new treatment options and follow-up practices in managing patients with cervical cancer.

DOI： 10.1111/jog.14108

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BACKGROUND: Hepatocellular carcinoma (HCC) may lead to extrahepatic metastasis (EHM). Most patients with EHM had either intrahepatic stage III or IVA tumor at the site of metastases. Herein, we present the case of a fairly rare 1.5-cm small-diameter HCC with right adrenal gland tumor having an inferior vena cava (IVC) tumor thrombus. CASE PRESENTATION: A 75-year-old man had a 1.5-cm hepatocellular carcinoma (HCC) in segment 8 of the liver and a 3.0-cm right adrenal gland tumor with inferior vena cava (IVC) tumor thrombus. He underwent partial hepatectomy, right adrenalectomy, and IVC tumor thrombectomy. Tumor resection was successful, but the tumor progressed rapidly, and the patient died 8 months after the operation. Immunohistochemical staining revealed that both HCC cells and adrenal tumor cells were positive for HCC markers Glypican-3 and alpha-fetoprotein. In terms of adrenal carcinoma markers vimentin and Melan-A, vimentin was negative in the HCC and adrenal tumor, and Melan-A was negative in the HCC. In adrenal tumor, slight positivity of Melan-A was observed, but the intensity of staining was clearly weak compared with that in normal adrenal glands. CD133, one of the stem cell markers, was positive in both HCC and adrenal tumor cells. Next-generation amplicon sequencing analyses were performed using DNA derived from the HCC, adrenal tumor, and normal liver tissue. After exome data analyses for representative HCC-related genes as TERT, CTNNB1, TP53, and ARID2, TP53 mutation (exon3: c.G351 T: p.R117S) was found in both HCC cells and adrenal tumor cells. Conversely, no significant mutations in other genes were observed. These pathological findings and sequencing results showed that the adrenal tumor might be an adrenal metastasis of HCC in spite of small primary tumor size. CONCLUSIONS: This case suggests that the right adrenal tumor was a metastasis of HCC. Immunohistochemical staining and gene mutation analyses using NGS are very useful in differentiating the tumor origin.

DOI： 10.1186/s40792-019-0705-7

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Giant cell arteritis is a granulomatous inflammation of large and medium-sized arteries, occurring predominantly in older women. In this case, a 76-year-old woman was hospitalized for examination because of a high C-reactive protein (CRP) level, but nothing remarkable was found on thoracicoabdominal computed tomography (CT) or head magnetic resonanse imaging (MRI). On the 46th day from the first visit, she died suddenly due to cardiac tamponade. On pathological autopsy, we found the cause of death to be acute aortic dissection (Stanford type A) due to giant cell arteritis occurred in the ascending aorta. Histologically, granulomatous vasculitis with giant cells was recognized in the ascending aorta, thoracic descending aorta and abdominal aorta and their branches. Interestingly, similar granulomatous vasculitis was also found in the medium and small vessels of other plural organs, including the heart, liver, uterine corpus, and its appendages. To our knowledge, giant cell arteritis with multiple-organ granulomatous changes has not been reported before. We herein reported a unique autopsy case of giant cell arteritis in a patient not treated with medication.

DOI： 10.1111/pin.12845

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Human prion diseases including sporadic Creutzfeldt-Jakob disease (sCJD), inherited prion diseases, and acquired human prion diseases are lethal neurodegenerative diseases. One of the major sources of iatrogenic Creutzfeldt-Jakob disease was human growth hormone (hGH-iCJD) derived from contaminated cadaveric pituitaries. The incidence of hGH-iCJD has decreased since changing from growth hormone extracted from human cadaveric pituitaries to recombinant pituitary hormones. However, extensive analysis on the localization and detecting of abnormal prion protein in the pituitary gland are limited. In this study, we examined 9 autopsied brains and pituitary glands from 6 patients with prion disease (3 Gerstmann-Sträussler-Scheinker disease, 2 sCJD, and 1 dura mater graft-associated CJD) and 3 individuals with nonprion diseases. Western blot analysis of pituitary samples demonstrated unique glycoforms of normal cellular prion protein with molecular weights of 30-40 kDa, which was higher than the typical 25-35 kDa prion protein in brains. Proteomic analysis also revealed prion protein approximately the molecular weight of 40 kDa in pituitary samples. Moreover, proteinase K-resistant Prion protein was frequently detected in pituitary samples of the prion diseases. Immunohistochemistry for Prion protein revealed mosaic cellular distribution preferentially in growth hormone- or prolactin-producing cells.

DOI： 10.1093/jnen/nlz075

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Intrahepatic cholangiocarcinoma is a rare malignant biliary neoplasm that causes a poor prognosis even after curative hepatectomy. Liver metastasis is the major recurrence pattern of intrahepatic cholangiocarcinoma; therefore, the prevention of liver metastasis is a desirable objective. The aim of this study is to identify gene(s) related to liver metastasis of intrahepatic cholangiocarcinoma and to examine the inhibitory effects on metastasis of intrahepatic cholangiocarcinoma by controlling such gene(s). We collected 3 pairs of intrahepatic cholangiocarcinoma frozen samples, and 36 pairs (primary and metastatic lesions) of intrahepatic cholangiocarcinoma formalin-fixed paraffin-embedded samples, from patients who underwent surgical resection at hospitals related to the Kyushu Study Group of Liver Surgery between 2002 and 2016. We carried out cDNA microarray analyses and immunohistochemistry to identify candidate genes, and evaluated one of them as a therapeutic target using human cholangiocarcinoma cell lines. We identified 4 genes related to liver metastasis using cDNA microarray, and found that CXCL12 was the only gene whose expression was significantly higher in liver metastasis than in primary intrahepatic cholangiocarcinoma by immunohistochemistry (P = .003). In prognosis, patients in the high CXCL12 group showed a significantly poor prognosis in disease-free (P < .0001) and overall survival (P = .0004). By knockdown of CXCL12, we could significantly suppress the invasive and migratory capabilities of 2 human cholangiocarcinoma cell lines. Therefore, CXCL12 might be associated with metastasis and poor prognosis in intrahepatic cholangiocarcinoma.

DOI： 10.1111/cas.14151

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BACKGROUND: Tumor immune reactions not only provide host defense but also accelerate tumor immune escape and phenotype switching. Here, we examined the association of programmed cell death ligand 1 (PD-L1) expression with epithelial-mesenchymal transition (EMT)-associated markers in pancreatic ductal adenocarcinoma (PDA) within the context of the tumor microenvironment. MATERIALS AND METHODS: PDA samples from 36 patients were analyzed for PD-L1, vimentin, E-cadherin, and Snail expressions and for PDA cell and immune cell infiltration. PD-L1 expression and EMT in PDA cell lines under conditions of altering interferon gamma (IFN-γ) signals were also assessed. RESULTS: Immunohistochemistry revealed a significant correlation between vimentin and PD-L1 expression, whereas double staining showed them to be simultaneously expressed by PDA cells. Positive vimentin expression was associated with the infiltration of a lower number of CD8+ T cells and a higher number of FoxP3+ cells and poor patient prognosis (P = 0.03). PDA tumor cells promoted PD-L1 expression and EMT under the presence of IFN-γ, which was inhibited by the signal transducer and activator of transcription (STAT)1 small interfering RNA. CONCLUSIONS: Strong correlations were observed between PD-L1 expression, EMT, and the immunosuppressive tumor microenvironment. Targeting STAT1 combined with PD-1/PD-L1 immunotherapy may improve outcomes for patients with PDA.

DOI： 10.1016/j.jss.2019.02.038

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BACKGROUND: CRTC1-MAML2 fusion is often detected in low- or intermediate-grade salivary mucoepidermoid carcinoma (MEC), and it is associated with a favorable clinical course. Primary MEC of the liver is an extremely rare, aggressive tumor, and no study has investigated CRTC1-MAML2 fusion. CASE PRESENTATION: A 79-year-old Japanese female presented with an approx. 5-cm hepatic mass lesion. We surgically resected the lesion under the clinical diagnosis of intrahepatic cholangiocarcinoma. The histological and immunohistochemical findings were consistent with high-grade MEC, consisting of squamoid, mucin-producing, and intermediate tumor cells. Our RT-PCR analysis revealed the presence of CRTC1-MAML2 fusion. This fusion gene was further confirmed by direct sequencing. The patient is still alive almost 10 years after the surgery. CONCLUSION: This is the first case report of primary MEC of the liver with CRTC1-MAML2 fusion, with long survival. The present case has significant implications for the entity of primary MEC of the liver which should be distinguished from adenosquamous carcinoma.

DOI： 10.1186/s13000-019-0863-8

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AIM: Hepatocellular carcinoma (HCC) is the second leading cause of cancer mortality worldwide. An excess of iron in liver tissue causes oxidative stress, leading to hepatocellular carcinogenesis. Iron metabolism, which is regulated by a complex mechanism, is important for cancer cell survival. The aim of this study is to clarify the role of iron regulatory protein in the progression of HCC and in patient outcome. METHODS AND RESULTS: We first investigated the mRNA level of iron metabolism-related genes, including hepcidin, ferroportin 1 (FPN-1) and transferrin receptor (TFR)-1/2. TFR-1/2 protein expression was then evaluated in surgical specimens from 210 cases using immunohistochemistry, and we compared clinicopathological factors with TFR-1/2 expression. The mRNA expression levels of TFR-1 were significantly increased in HCC tissues compared with adjacent non-cancerous tissues (P = 0.0013), but there were no differences in other genes. High expression of TFR-1 in HCC was associated with the absence of alcohol abuse (P = 0.0467), liver cirrhosis (P < 0.0001), higher alpha-fetoprotein (AFP; P < 0.0001), smaller tumour size (P = 0.0022), poor histological differentiation (P < 0.0001) and morphological features (P < 0.0001). In contrast, high expression of TFR-2 in HCC was associated with lower AFP (P < 0.0001), well-differentiated histological grade (P < 0.0001) and morphological features (P = 0.0010). Multivariate analysis for both overall survival and recurrence-free survival indicated that high TFR-1 expression was a significant prognostic factor for poor outcome. CONCLUSIONS: We found an inverse correlation of TFR-1 and TFR-2 expression in AFP and tumour differentiation. TFR-1 overexpression suggests a higher risk of recurrence and death in HCC patients following liver resection.

DOI： 10.1111/his.13847

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AIM: To evaluate the accuracy of the ADNEX MR SCORING system for characterising adnexal masses. MATERIALS AND METHODS: An institutional review board approved this retrospective study. The study population comprised 663 women who underwent magnetic resonance imaging (MRI) from January 2007 to December 2014 to characterise 778 adnexal masses that were indeterminate under ultrasonography (590 benign and 188 malignant). Two radiologists independently reviewed the MRI images. The masses were scored from 1 to 5 according to the ADNEX MR SCORING system. The diagnostic performance of the system was evaluated by receiver operating characteristic (ROC) analysis. Masses scored 4 or greater were considered malignant (including tumours of borderline malignancy or low malignant potential). RESULTS: The malignancy rates of masses with scores of 2, 3, 4 and 5 were 1.9% (8/419), 12.8% (19/149), 62.6% (57/91) and 87.4% (104/119) for reader 1 and 2.1% (9/424), 13.6% (20/147), 67.6% (71/105) and 86.3% (88/102) for reader 2, respectively. The areas under the ROC curves for the differentiation of benign and malignant masses were 0.929 and 0.923, respectively; the sensitivity, specificity and accuracy of diagnosis were 85.6% (161/188), 91.7% (541/590), and 90.2% (702/778) for reader 1 and 84.6% (159/188), 91.9% (542/590), and 90.1% (701/778) for reader 2, respectively. Tumours of borderline malignancy or low malignant potential had a higher rate of misclassification (46.1%) than other malignant tumours (6–7.4%). CONCLUSION: The ADNEX MR SCORING system was highly accurate in differentiating benign and malignant adnexal masses, although it may be less accurate for tumours of borderline malignancy or low malignant potential.

DOI： 10.1016/j.crad.2018.10.014

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Mitochondrial quality control (MQC) protects against potentially damaging events, such as excessive generation of mitochondrial reactive oxygen species (mtROS). We investigated the contribution of the two major MQC processes, namely, mitophagy and Mieap-induced accumulation of lysosomes within mitochondria (MALM), to the response to hypoxia of two human gastric cancer (GC) cell lines. We found that hypoxia increased mtROS generation and cell invasion in 58As9, but not in MKN45, although the transcription factor hypoxia-inducible factor 1α was induced in both cell lines. Colocalisation of lysosomes with mitochondria was found only in hypoxic MKN45 cells, suggesting that hypoxia-induced MQC functions normally in MKN45 but may be impaired in 58As9. Hypoxia did not lead to decreased mitochondrial mass or DNA or altered appearance of autophagosomes, as judged by electron microscopy, suggesting that mitophagy was not induced in either cell line. However, western blot analysis revealed the presence of the MALM-associated proteins Mieap, BNIP3 and BNIP3L, and the lysosomal protein cathepsin D in the mitochondrial fraction of MKN45 cells under hypoxia. Finally, Mieap knockdown in MKN45 cells resulted in increased mtROS accumulation and cell invasion under hypoxia. Our results suggest that hypoxia-induced MALM suppresses GC cell invasion by preventing mtROS generation.

DOI： 10.1038/s41598-019-39563-x

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: The needs for human epidermal growth factor receptor 2 (HER-2) and/or programmed death-ligand 1 (PD-L1) evaluations in gastric cancer are dramatically increasing. Although the importance of standardization of sample fixation has been widely recognized, most of the evidence regarding the fixation duration or type of fixing solution are based on breast cancer. AIM: To investigate the real effects of fixation conditions on HER-2 testing or PD-L1 testing for gastric cancer using gastrectomy specimens. METHODS: Thirty-two patients who underwent gastrectomy for gastric cancer were enrolled. Their resected specimens were each divided into four pieces and fixed in four strictly controlled different durations (6 h, 24 h, and 48 h, and 1 wk) by 10% formalin (n = 22) or 10% neutral buffered formalin (NBF) (n = 10). Immunohistochemistry (IHC) of HER-2 and PD-1 was performed, and a pathology examination was conducted. In the HER-2-immunoreactive cases, all four specimens were subjected to dual-color in situ hybridization (DISH). Five cases were assessed as HER-2-positive by IHC and DISH. We used the cut-off values of 1%, 10%, and 50% to assess the IHC findings of PD-L1. RESULTS: No significant difference was observed in comparisons between the shorter fixation period groups (6 h, 24 h, and 48 h) and the prolonged fixation period (1 wk) group in the HER-2 and PD-L1 analyses. Although no significant difference was observed between 10% formalin and 10% NBF within 1 wk of fixation, the superiority of 10% NBF was confirmed in a long-term (> 3 mo) fixation in both the HER-2 and PD-L1 analyses. CONCLUSION: In this small-numbered pilot study, prolonged fixation within 1 wk showed no inferiority in HER-2 or PD-L1 testing. However, a large-numbered prospective study is needed to obtain conclusive results.

DOI： 10.12998/wjcc.v7.i4.419

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: We sought to clarify the prevalence of occult hepatitis B virus (HBV) infection (OBI) and to determine whether OBI affects the surgical outcomes in curatively resected Japanese patients with hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC). METHODS: A total of 257 patients with HCV-related HCC who underwent curative surgical resection were enrolled. All enrolled patients were serologically negative for HBV surface antigen and positive for HCV antibody. DNA was extracted from formalin-fixed paraffin-embedded liver tissue. OBI was determined by the HBV-DNA amplification of at least two different sets of primers by TaqMan real-time polymerase chain reaction. Surgical outcomes were evaluated according to overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS). RESULTS: OBI was identified in 15 of the 257 (5.8%) cases. In the multivariate analyses, the factors significantly correlated with OS were BMI >25 (P=0.0416), portal vein invasion (P=0.0065), and multiple tumors (P=0.0064). The only factor significantly correlated with DSS was T-stage (P=0.0275). The factors significantly correlated with DFS were liver fibrosis (P=0.0017) and T-stage (P=0.0001). The status of OBI did not show any significant correlation with OS, DSS or DFS, but a weak association with DSS (P=0.0603) was observed. CONCLUSIONS: The prevalence of OBI was 5.8% in 257 cases of HCV-related HCC. Although a weak association between DSS and OBI was observed, and statistical analyses were limited by small number of OBI cases, no significant correlation between OBI and surgical outcomes was detected.

DOI： 10.21037/hbsn.2018.10.01

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Hepatic carcinosarcomas, which include both carcinomatous and sarcomatous elements, are uncommon in adults. Although carcinosarcoma in hepatocellular carcinoma is occasionally reported, carcinosarcoma in intrahepatic cholangiocarcinoma (ICC) is an extremely rare ICC variant. Few such cases have been reported in English and no large study of its clinicopathological features exists. CASE PRESENTATION: Here, we report a 60-year-old man with an asymptomatic hepatic B infection who developed hepatic carcinosarcoma from an otherwise normal liver. The 6.0-cm tumor was accidentally discovered by PET-CT in a cancer examination. Serum examinations showed no elevation of tumor markers. He underwent left and caudate lobectomy of the liver. The diagnosis of intrahepatic cholangiocarcinoma with sarcomatous stroma was based on thorough pathologic examination and immunohistochemical staining. The tumor exhibited adenocarcinomatous and sarcomatous components; the adenocarcinomatous element was positive for epithelial markers, the sarcomatous element was positive for mesenchymal markers, but negative for epithelial markers. The patient made an uneventful recovery after surgery. At present, 14 months after surgery, he remains well with no evidence of tumor recurrence. CONCLUSIONS: We report an unusual case of hepatic carcinosarcoma (intrahepatic cholangiocarcinoma with sarcomatous stroma) and discuss the etiology and prognosis of this rare disease.

DOI： 10.1186/s40792-018-0543-z

Language：English  

DOI： 10.1080/10428194.2018.1427859

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Intracholecystic papillary neoplasm (ICPN) is defined as papillary tumors detected macroscopically in the gallbladder. We report a case of ICPN which exhibited the atypical form like a submucosal tumor. CASE PRESENTATION: A 70-year-old man was admitted to our hospital because of hepatic disorder. Computed tomography and magnetic resonance imaging showed irregular thickening of the wall within the gallbladder fundus. Because the lesion might have been malignant, we performed laparoscopic cholecystectomy and liver bed resection. Macroscopic findings showed the mucosal surface of the tumor was smooth, and its form was similar to that of a submucosal tumor. Histopathological examination revealed papillary tumors within the mass with low-grade dysplasia; therefore, we diagnosed ICPN. CONCLUSION: In the present case, ICPN was resembling a submucosal tumor macroscopically because the tumors arose into the Rokitansky-Aschoff sinus and the adenomyomatous hyperplasia was merged with the ICPN. It is necessary to consider the possibility of tumor lesions within adenomyomatous hyperplasia.

DOI： 10.1186/s40792-018-0524-2

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: To identify novel autoantibodies for neuropathic pain (NeP). METHODS: We screened autoantibodies that selectively bind to mouse unmyelinated C-fiber type dorsal root ganglion (DRG) neurons using tissue-based indirect immunofluorescence assays (IFA) with sera from 110 NeP patients with various inflammatory and allergic neurologic diseases or other neuropathies, and 50 controls without NeP including 20 healthy subjects and 30 patients with neurodegenerative diseases or systemic inflammatory diseases. IgG purified from IFA-positive patients' sera was subjected to Western blotting (WB) and immunoprecipitation (IP) using mouse DRG lysates. Immunoprecipitates were analyzed by liquid chromatography tandem mass spectrometry (LC-MS/MS) to identify target autoantigens. RESULTS: Antiunmyelinated C-fiber type DRG neuron antibodies were more frequent in patients with NeP than non-NeP subjects (10% vs 0%; p < 0.05). These autoantibodies were all from the IgG2 subclass and colocalized mostly with isolectin B4- and P2X3-positive pain-conducting small neurons but not with S100β-positive myelinated neurons. WB revealed a common immunoreactive band (approximately 220kDa). IP and LC-MS/MS studies identified plexin D1 as a target autoantigen. Immunoadsorption tests with recombinant human plexin D1 in IFA revealed that all 11 anti-small DRG neuron antibody-positive patients had anti-plexin D1 antibodies. Application of anti-plexin D1 antibody-positive patient sera to cultured DRG neurons increased membrane permeability, leading to cellular swelling. NeP patients with anti-plexin D1 antibodies commonly developed burning pain and current perception threshold abnormalities for C-fibers. Main comorbidities were atopy and collagen-vascular disease. Immunotherapies ameliorated NeP in 7 treated cases. INTERPRETATION: Anti-plexin D1 antibodies are a novel biomarker for immunotherapy-responsive NeP. Ann Neurol 2018;84:208-224.

DOI： 10.1002/ana.25279

Language：Others  

DOI： 10.1111/cyt.12532

Language：English   Publishing type：Research paper (scientific journal)  

Imaging of a 53-year-old Japanese man revealed two tumors in the liver and a tumor in the head of the pancreas with a swelling lymph node. A needle biopsy for the liver tumors was performed, revealing a neuroendocrine tumor. Enucleation, lymphadenectomy, and partial hepatectomy were performed. The microscopic examination identified many tumor cells with intracytoplasmic inclusions arranged in a nested, cord, or tubular fashion. The intracytoplasmic inclusions displayed densely eosinophilic globules and displaced the nuclei toward the periphery, which constitutes "rhabdoid" features. The tumor cells were positive for synaptophysin and weakly positive for NCAM, but negative for chromogranin A. Epithelial markers (AE1/AE3 and CAM5.2) accentuated intracytoplasmic globules. Pancreatic neuroendocrine tumors with rhabdoid features are very rare. Generally, rhabdoid features are aggressive and dedifferentiated characteristics of various types of tumor. Pancreatic neuroendocrine tumors containing rhabdoid cells tend to display extrapancreatic spread at the time of presentation, although some of these tumors with rhabdoid features are not always associated with aggressive behavior.

DOI： 10.1007/s00428-018-2398-x

Language：English   Publishing type：Research paper (scientific journal)  

Our recent genome-wide association study found that the NELFCD/CTSZ locus was significantly associated with progression of primary biliary cholangitis (PBC) to jaundice stage in the Japanese population. In this study, we investigated the role of cathepsin Z in the etiology and pathology of PBC. Serum cathepsin Z levels were measured using enzyme-linked immunosorbent assay. The expression and localization of cathepsin Z in liver specimens were analyzed by western blotting and immunohistochemistry. In PBC patients, serum cathepsin Z levels were significantly increased with disease progression. In addition, its levels were positively correlated with alanine transaminase, aspartate transaminase and total bilirubin, and were negatively correlated with platelet count and albumin. Cathepsin Z expression was markedly increased in hepatocytes at later stages of PBC, and its localization was altered from the peri-bile canaliculus to the cytoplasm, where a fraction was no longer colocalized with endosomal/lysosomal vesicles. Similar altered expression of cathepsin Z was observed in end-stage of other cholestatic liver diseases including sepsis, obstructive jaundice, and Alagille syndrome. Our results indicate that altered expression and localization of cathepsin Z in hepatocytes are characteristic features of PBC and other cholestatic liver diseases, and are implicated in the progression of PBC.

DOI： 10.1038/s41598-018-30146-w

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Clear cell carcinoma commonly occurs in the ovary and kidney, and clear cell cholangiocarcinoma was rarely reported. Differential diagnosis which the origin of the tumor located on the liver surface is intrahepatic or extrahepatic was difficult. Herein, we report a case of clear cell adenocarcinoma mimicking liver cancer. CASE PRESENTATION: This was a 55-year-old female who had the tumor with cystic component in the liver. She was performed hepatectomy and diagnosed as clear cell adenocarcinoma. Histopathological evaluation revealed intra-cystic clear cell adenocarcinoma. The tumor has ductal structure including mucin and atypical nuclear with clear cytoplasm. The tumor was separated from the liver and the diaphragm. The expression of Pax8 was positive, but the expression CK7 and HNF1β was positive and that of CD10 and ER was negative, which indicate that the tumor has the feature of clear cell carcinoma of ovary, not renal cell carcinoma nor cholangiocarcinoma. CONCLUSIONS: Our experience with this patient suggests that this tumor may originate from the endometriosis onto the diaphragm from the detailed results of immunohistochemical staining.

DOI： 10.1186/s40792-018-0500-x

Language：English   Publishing type：Research paper (scientific journal)  

UNLABELLED: Primary liver carcinomas with both hepatocytic and cholangiocytic differentiation have been referred to as "combined (or mixed) hepatocellular-cholangiocarcinoma." These tumors, although described over 100 years ago, have attracted greater attention recently because of interest in possible stem cell origin and perhaps because of greater frequency and clinical recognition. Currently, because of a lack of common terminology in the literature, effective treatment and predictable outcome data have been challenging to accrue. This article represents a consensus document from an international community of pathologists, radiologists, and clinicians who have studied and reported on these tumors and recommends a working terminology for diagnostic and research approaches for further study and evaluation. CONCLUSION: It is recommended that diagnosis is based on routine histopathology with hematoxylin and eosin (H&E); immunostains are supportive, but not essential for diagnosis. (Hepatology 2018;68:113-126).

DOI： 10.1002/hep.29789

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Small hepatocellular carcinomas (HCC ≤3 cm) are generally considered to have low malignant potential; however, some of them display pathological microvascular invasion (MVI). METHODS: Between 1991 and 2013, 414 patients with a single HCC ≤3 cm underwent curative hepatic resection (HR). Predictors for MVI were identified. Using another cohort (149 patients during 2000-2014), our predictors for MVI in HCC ≤3 cm were validated. In 428 patients with a single HCC ≤3 cm who had predictors for MVI, survival was compared among anatomical HR (n = 149), partial HR (n = 227), and radiofrequency ablation (RFA) (n = 52). RESULTS: The positive rate of MVI reached 40.6% (168/414 patients). Independent predictors for MVI were as follows: tumor diameter ≥2 cm (odds ratio 1.84, P = .0052), alpha-fetoprotein (AFP) ≥200 ng/mL (odds ratio 1.82, P = .0466), and des-gamma-carboxy prothrombin (DCP) ≥40 mAU/mL (odds ratio 1.79, P = .0126). Matching at least one predictor among these three could predict MVI in HCC ≤3 cm well (sensitivity 82.8%, positive predictive value [PPV] 48.7%). This criterion could also predict MVI in HCC ≤3 cm well in another cohort (sensitivity 82.8%, PPV 30.3%). In patients with single HCC ≤3 cm matching our criterion for predicting MVI, anatomical HR led to significantly better survival in both disease-free (hazard ratio 0.689, P = .0231) and overall (hazard ratio 0.589, P = .0316) survivals. CONCLUSION: Matching at least one factor among three (tumor diameter ≥2 cm, AFP ≥200 ng/mL, or DCP ≥40 mAU/mL) can predict MVI in HCC ≤3 cm. In such patients, anatomical HR would be recommended to improve survival.

DOI： 10.1002/ags3.12057

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Mucinous cholangiocarcinoma (MC) is a very rare variant of intrahepatic cholangiocarcinoma. MC is characterized by rapid growth, widespread metastasis, and poor prognosis. We report a case of resected MC of the liver. CASE PRESENTATION: We found a 13.6-cm hypovascular tumor in the left hepatic lobe of a 68-year-old man, which we initially diagnosed as a mass-forming intrahepatic cholangiocarcinoma. Left lobe and caudate resection was performed without major intraoperative or postoperative complications. He was discharged home on postoperative day 9 and had no recurrence for 6 months. Pathological examination showed a mucous lobulated tumor with abundant mucus in the cytoplasm and extracellular regions. After differential diagnosis that considered invasive intraductal papillary neoplasm of the bile duct and metastatic liver tumors from the digestive tract, this tumor was diagnosed as a cholangiocarcinoma rare variant: primary mucinous carcinoma of the liver. CONCLUSION: Analysis of previous reports suggests that primary MC of the liver could be classified into two subtypes: pure MC and combined hepatocellular carcinoma and MC. Notably, the latter has been reported only in patients with chronic liver disease, whereas the former has only been reported in patients with no underlying disease.

DOI： 10.1186/s40792-018-0450-3

Language：English  

DOI： 10.1111/pin.12645

Language：English   Publishing type：Research paper (scientific journal)  

Clear cell carcinoma (CCC) of the uterine cervix without prenatal diethylstilbestrol exposure is rare, and its etiology is unclear. We present a case of cervical CCC presenting as a submucosal tumor, which strongly suggests an association between cervical endometriosis and cervical CCC. A 56-year-old postmenopausal Japanese woman visited a gynecologic clinic with a complaint of watery vaginal discharge. A few atypical cells suggesting adenocarcinoma were detected in a cervical cytologic specimen. Magnetic resonance imaging revealed a cystic lesion with a solid component at the uterine cervix. Under a tentative diagnosis of cervical cancer, surgery was performed. Although a freshly resected specimen initially showed no tumorous lesion in the cervical mucosa, cutting of the mucosa revealed a solid tumor with a final diagnosis of CCC. The findings of aggregation of hemosiderin-laden macrophages and ectopic endometrium adjacent to the tumor strongly suggest that this tumor arose from cervical endometriosis.

DOI： 10.1097/PGP.0000000000000386

Language：English   Publishing type：Research paper (scientific journal)  

AIM: To investigate the association between smoking habits and surgical outcomes in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) (B-HCC) and hepatitis C virus (HCV)-related HCC (C-HCC) and clarify the clinicopathological features associated with smoking status in B-HCC and C-HCC patients. METHODS: We retrospectively examined the cases of the 341 consecutive patients with viral-associated HCC (C-HCC, n = 273; B-HCC, n = 68) who underwent curative surgery for their primary lesion. We categorized smoking status at the time of surgery into never, ex- and current smoker. We analyzed the B-HCC and C-HCC groups' clinicopathological features and surgical outcomes, i.e., disease-free survival (DFS), overall survival (OS), and disease-specific survival (DSS). Univariate and multivariate analyses were performed using a Cox proportional hazards regression model. We also performed subset analyses in both patient groups comparing the current smokers to the other patients. RESULTS: The multivariate analysis in the C-HCC group revealed that current-smoker status was significantly correlated with both OS (P = 0.0039) and DSS (P = 0.0416). In the B-HCC patients, no significant correlation was observed between current-smoker status and DFS, OS, or DSS in the univariate or multivariate analyses. The subset analyses comparing the current smokers to the other patients in both the C-HCC and B-HCC groups revealed that the current smokers developed HCC at significantly younger ages than the other patients irrespective of viral infection status. CONCLUSION: A smoking habit is significantly correlated with the overall and disease-specific survivals of patients with C-HCC. In contrast, the B-HCC patients showed a weak association between smoking status and surgical outcomes.

DOI： 10.3748/wjg.v24.i1.58

Language：English   Publishing type：Research paper (scientific journal)  

AIM: The histological features of clinically chronic autoimmune hepatitis (AIH) have been well established, with interface hepatitis and plasma cell infiltration as hallmark lesions, however, the immunoserological and histological features of recent-onset and acute AIH remain undefined. The goal of this study was to define the immunoserological and histological differences between AIH with acute presentation and chronic AIH. METHODS: Thirty-two consecutive patients with well-characterized AIH who had undergone a liver biopsy were identified at our institution. These patients were divided into two groups. Sixteen patients whose liver dysfunction had persisted for at least 12 months were defined as chronic AIH (C-AIH) patients, and 16 patients whose liver dysfunction had been within normal limits for >12 months previously, and had only recently been found to have abnormal function for the first time, were defined as AIH with acute presentation (AIH-a) patients. Various biological and histological characteristics were compared between these two patient groups. RESULTS: No significant differences were found between the groups for age, body mass index, serum levels of total bilirubin, transaminase, alkaline phosphatase, prothrombin activity, immunoglobulin, titers of antinuclear antibody, or diagnostic scores between the groups. Histologically, there was no significant difference in the degree of interface hepatitis, plasma cell infiltration, or centrilobular necrosis between AIH-a and C-AIH patients. However, histological active findings such as activity, lobular inflammation, rosette formation, spotty necrosis, seroid-laden macrophages, and single cell necrosis were significantly more frequent in AIH-a patients, whereas portal fibrosis was significantly more frequent in C-AIH patients. Only one case among the 16 AIH-a patients was confirmed as acute AIH, showing massive centrilobular necrosis with a mild degree of portal inflammation and interface hepatitis. All patients with AIH-a and C-AIH responded well to corticosteroid or ursodeoxycholic acid treatment. CONCLUSIONS: Patients with AIH-a could not be distinguished from C-AIH patients clinically or immunoserologically. Based on the histopathological findings of the liver, almost all cases of AIH-a might be exacerbations of non-symptomatic pre-existing C-AIH.

DOI： 10.1111/hepr.12875

Language：English   Publishing type：Research paper (scientific journal)  

AIM: To investigate the prevalence, clinicopathological characteristics and surgical outcomes of occult hepatitis B virus (HBV) infection (OBI) in patients with non-B, non-C (NBNC) hepatocellular carcinoma (HCC). METHODS: This study retrospectively examined the cases of 78 NBNC patients with curative resection for HCC for whom DNA could be extracted from formalin-fixed paraffin-embedded tissue. OBI was determined by the HBV-DNA amplification of at least two different sets of primers by TaqMan real-time polymerase chain reaction. Possibly carcinogenetic factors such as alcohol abuse, diabetes mellitus, obesity and non-alcoholic steatohepatitis (NASH) were examined. Surgical outcomes were evaluated according to disease-free survival (DFS), overall survival (OS) and disease-specific survival (DSS). RESULTS: OBI was found in 27/78 patients (34.6%) with NBNC HCC. The OBI patients were significantly younger than the non-OBI cases at the time of surgery (average age 63.0 vs 68.1, P = 0.0334) and the OBI cases overlapped with other etiologies significantly more frequently compared to the non-OBI cases (P = 0.0057). OBI had no impact on the DFS, OS or DSS. Only tumor-related factors affected these surgical outcomes. CONCLUSION: Our findings indicate that OBI had no impact on surgical outcomes. The surgical outcomes of NBNC HCC depend on early tumor detection; this reconfirms the importance of a periodic medical examination for individuals who have NBNC HCC risk factors.

DOI： 10.4254/wjh.v9.i35.1286

Language：Others  

DOI： 10.1111/cyt.12443

Language：English   Publishing type：Research paper (scientific journal)  

This study aimed to establish a therapeutic strategy targeting hypoxic cancer cells in gastric carcinoma (GC). YC-1 is a HIF-1α inhibitor, and we revealed that low-dose YC-1 (10 µM) suppressed HIF-1α expression, and induced hypoxia-dependent apoptosis in the GC cell line 58As9. This hypoxia-specific apoptosis induction by YC-1 involved excessive reactive oxygen species (ROS) generation. The apoptotic effect of 10 µM YC-1 was enhanced by additional glucose (G) and insulin (I) treatments. RT-PCR demonstrated that 10 µM YC-1 reduced hypoxia-induced expression of HIF-1α targets involved in anaerobic glycolysis. Metabolic analysis showed that YC-1 shifted glucose metabolism in hypoxic cells from anaerobic glycolysis to oxidative phosphorylation (OXPHOS). Additional GI accelerated membranous GLUT1 translocation, elevating glucose uptake, and increased acetyl-CoA levels, leading to more ROS generation in hypoxic YC-1-treated cells. Finally, we evaluated the anti-cancer effect of low-dose YC-1 (1 mg/kg) + G (2 g/kg) and I (1 unit/3 g G) treatment in xenograft models. YC-1 + GI therapy strongly inhibited tumour growth. Immunohistochemical analysis demonstrated that YC-1 + GI reduced HIF-1α expression and pimonidazole accumulation in tumours. Conversely, YC-1 + GI increased intra-tumoral 8-OHdG and levels of apoptosis markers. Low-dose YC-1 + GI is a unique therapy targeting hypoxic GC cells that generates lethal ROS via forced activation of OXPHOS.

DOI： 10.1038/s41598-017-12929-9

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Cholangiolocellular carcinoma (CoCC) is thought to be derived from hepatic progenitor cells. Because of its origin, CoCC has diverse clinicopathological and imaging findings. Here, we report a case of small CoCC that was difficult to diagnose preoperatively. CASE PRESENTATION: A 62-year-old woman was confirmed with a small liver nodule in the left lobe 2 years after a sustained virological response of hepatitis C virus. The size of the nodule was 11.9 × 6.1 mm, and 6 months later, the size increased to 12.5 × 7.8 mm. The doubling time of this tumor was 285 days. The tumor revealed peripheral early enhancement and delayed internal staining in dynamic computed tomography images and marked high intensity in diffusion-weighted magnetic resonance imaging scans. These imaging findings resembled those of cholangiocellular carcinoma (CCC). The tumor was removed by laparoscopic lateral sectionectomy. Pathological findings revealed that the tumor was composed of small cuboidal cells and showed irregular anastomosis small grand. Immunohistochemical findings showed that the tumor cells were negative for Hep-par 1 and positive for cytokeratin 19. Epithelial membrane antigen staining was positive for the membranous side of the lumen. According to these pathological findings, the tumor was diagnosed as CoCC. CONCLUSION: Although some characteristic imaging findings are reported for CoCC, they are not specific because of the variety in pathological findings. Especially, small CoCCs might have poor characteristic imaging findings and may be difficult to distinguish from CCC in the images. However, slow tumor growth might be one of the characteristics to suspect the possibility of a CoCC.

DOI： 10.1186/s40792-017-0377-0

Language：English  

DOI： 10.1111/pin.12549

Language：English   Publishing type：Research paper (scientific journal)  

In intraductal papillary mucinous neoplasms (IPMNs), the presence of a mural nodule showing a papillary or nodular proliferation of tumor cells in the dilated pancreatic duct is an indication for resection of IPMN. Solute carrier family 2, facilitated glucose transporter member 1, known as glucose transporter type 1 (SLC2A1/GLUT1) mediates cellular glucose uptake in many carcinomas and is correlated with increased 18F-fluorodeoxyglucose (18F-FDG) uptake. We examined SLC2A1/GLUT1 expression in the mural nodules of 180 IPMN specimens to distinguish malignant/benign tumors. A mural nodule was detected in 80 (44.4%) of the IPMNs, and was detected in 18.6% (13/70) of the IPMN-low (dysplasia) specimens, 36.1% (13/36) of the IPMN-int, 93.3% (28/30) of the IPMN-high, and 59.1% (26/44) of the IPMN-inv (with an associated invasive carcinoma) specimens. The sensitivity for detecting mural nodules was 81.7% by endoscopic ultrasonography, 70% by contrast-enhanced computed tomography and 54% by endoscopic retrograde cholangiopancreatography. SLC2A1/GLUT1 expression in the mural nodules was recognized in the basal and basolateral cytomembrane of tumor cells and was expressed in 15.4% (2/13) of the IPMN-low, 15.4% (2/13) of the IPMN-int, 71.4% (20/28) of the IPMN-high and 84.6% (22/26) of the IPMN-inv groups. The SLC2A1/GLUT1 expression was significantly higher in the IPMN-high and IPMN-inv mural nodules than in those of the IPMN-low and IPMN-int groups. Our findings suggest that SLC2A1/GLUT1 is expressed late in the adenoma-carcinoma sequence during carcinogenesis in IPMN, and SLC2A1/GLUT1 act as therapeutic target for malignant IPMN.

DOI： 10.1016/j.humpath.2017.03.008

Language：English   Publishing type：Research paper (scientific journal)  

Pancreatic ductal adenocarcinoma (PDA) is associated with an immunosuppressive tumor-microenvironment (TME) that supports the growth of tumors and mediates tumors enabling evasion of the immune system. Expression of programmed cell death ligand 1 (PD-L1) and loss of human leukocyte antigen (HLA) class I on tumor cells are methods by which tumors escape immunosurveillance. We examined immune cell infiltration, the expression of PD-L1 and HLA class I by PDA cells, and the correlation between these immunological factors and clinical prognosis. PDA samples from 36 patients were analyzed for HLA class I, HLA-DR, PD-L1, PD-1, CD4, CD8, CD56, CD68, and FoxP3 expression by immunohistochemistry. The correlations between the expression of HLA class I, HLA-DR, PD-L1 or PD-1 and the pattern of tumor infiltrating immune cells or the patients' prognosis were assessed. PD-L1 expression correlated with tumor infiltration by CD68+ and FoxP3+ cells. Low HLA class I expression was an only risk factor for poor survival. PD-L1 negative and HLA class I high-expressing PDA was significantly associated with higher numbers of infiltrating CD8+ T cells in the TME, and a better prognosis. Evaluation of both PD-L1 and HLA class I expression by PDA may be a good predictor of prognosis for patients. HLA class I expression by tumor cells should be evaluated when selecting PDA patients who may be eligible for treatment with PD-1/PD-L1 immune checkpoint blockade therapies.

DOI： 10.1002/cam4.1087

Language：English   Publishing type：Research paper (scientific journal)  

Spalt-like transcriptional factor 4 (SALL4), a stem marker, is reactivated in several cancers. A previous study has demonstrated that SALL4 interacts with the nucleosome remodeling deacetylase complex, which contains histone deacetylase 1 (HDAC1) and histone deacetylase 2 (HDAC2). In this study, we investigated the expression status of SALL4, HDAC1, and HDAC2 and their relationship with phosphatase and tensin homolog deleted on chromosome 10 (PTEN) by immunohistochemical analysis of the posthepatectomy specimens of 135 patients with hepatocellular carcinoma who were treated at our hospital. Ninety-two frozen samples were subjected to quantitative reverse-transcription polymerase chain reaction analysis to detect the messenger RNA levels of PTEN. Seventy-six (56%) of 135 patients were positive for SALL4, and this group had a higher prevalence of hepatitis B antigen, a higher value of α-fetoprotein (AFP) and protein induced by vitamin K absence (PIVKAII) and poor histologic differentiation. The 5-year survival rate was significantly lower in the SALL4-positive group. High HDAC1 expression (51%) was correlated with a poor histologic differentiation and a poor prognosis. High HDAC2 expression (46%) was associated with a higher prevalence of hepatitis B antigen positivity, a poor histologic differentiation and higher prevalence of vascular invasion, and a lower 5-year survival rate. Coexpression of SALL4 with HDAC1 and/or HDAC2 was correlated with underexpression of PTEN. Moreover, multivariable analysis revealed that coexpression of SALL4 with HDAC1 and/or HDAC2 was predictive of an unfavorable prognosis. Our data thus suggested that the combination of SALL4, HDAC1, and HDAC2 may provide a potential target for molecular therapy.

DOI： 10.1016/j.humpath.2017.03.007

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVES: To determine whether washout characteristics of dynamic contrast-enhanced computed tomography (CT) could predict survival in patients with extrahepatic cholangiocarcinoma (EHC). METHODS: This study collected 46 resected cases. All cases were examined by dynamic contrast study on multidetector-row CT. Region-of-interest measurements were obtained at the non-enhanced, portal venous phase and delayed phase in the tumour and were used to calculate the washout ratio as follows: [(attenuation value at portal venous phase CT - attenuation value at delayed enhanced CT)/(attenuation value at portal venous phase CT - attenuation value at unenhanced CT)] × 100. On the basis of the median washout ratio, we classified the cases into two groups, a high-washout group and low-washout group. Associations between overall survival and various factors including washout rates were analysed. RESULTS: The median washout ratio was 29.4 %. Univariate analysis revealed that a lower washout ratio, venous invasion, lymphatic permeation and lymph node metastasis were associated with shorter survival. Multivariate analysis identified the lower washout ratio as an independent prognostic factor (hazard ratio, 3.768; p value, 0.027). CONCLUSIONS: The washout ratio obtained from the contrast-enhanced CT may be a useful imaging biomarker for the prediction of survival of patients with EHC. KEY POINTS: • Dynamic contrast study can evaluate the aggressiveness of extrahepatic cholangiocarcinoma. • A lower washout ratio was an independent prognostic factor for overall survival. • CT can predict survival and inform decisions on surgical options or chemotherapy.

DOI： 10.1007/s00330-016-4621-y

Language：Others  

Intrahepatic cholangiocarcinomas exhibit histological diversity in terms of morphological architectures, background liver diseases, mucin production, stromal reactions of inflammatory cells or fibrosis, the presence of premalignant lesions, and the coexistence of metastatic lesions. ICCs are classified according to anatomical location and histological characteristics as perihilar large duct type and peripheral small duct type. The different biological and molecular features of the two types of ICC support the hypothesis that perihilar type ICC and peripheral type ICC arise from different backgrounds, different carcinogenic pathways, and different cell origins. It may be important to understand these differences of tumor characteristics for the clinical management of ICCs.

DOI： 10.1007/978-981-10-3500-5_12

Language：Others  

DOI： 10.1111/jgh.13655

Language：English   Publishing type：Research paper (scientific journal)  

AIM: To analyzed the correlation between smoking status and surgical outcomes in patients with non-B non-C hepatocellular carcinoma (NBNC-HCC), and we investigated the patients' clinicopathological characteristics according to smoking status. METHODS: We retrospectively analyzed the consecutive cases of 83 NBNC-HCC patients who underwent curative surgical treatment for the primary lesion at Saga University Hospital between 1984 and December 2012. We collected information about possibly carcinogenic factors such as alcohol abuse, diabetes mellitus, obesity and smoking habit from medical records. Smoking habits were subcategorized as never, ex- and current smoker at the time of surgery. The diagnosis of non-alcoholic steatohepatitis (NASH) was based on both clinical information and pathological confirmation. RESULTS: Alcohol abuse, diabetes mellitus, obesity and NASH had no significant effect on the surgical outcomes. Current smoking status was strongly correlated with both overall survival (P = 0.0058) and disease-specific survival (P = 0.0105) by multivariate analyses. Subset analyses revealed that the current smokers were significantly younger at the time of surgery (P = 0.0002) and more likely to abuse alcohol (P = 0.0188) and to have multiple tumors (P = 0.023). CONCLUSION: Current smoking habit at the time of surgical treatment is a risk factor for poor long-term survival in NBNC-HCC patients. Current smokers tend to have multiple HCCs at a younger age than other patients.

DOI： 10.3748/wjg.v23.i8.1397

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVES: To evaluate the relationship between the enhancement pattern of intrahepatic cholangiocarcinomas (ICCs) in the hepatic arterial phase (HAP) of dynamic hepatic CT and the clinicopathological findings with special reference to the perihilar type and the peripheral type. METHODS: Forty-seven patients with pathologically proven ICCs were enrolled. Based on the enhancement pattern in the HAP, the lesions were classified into three groups: a hypovascular group (n=13), rim-enhancement group (n=18), and hypervascular group (n=16). The clinicopathological findings were compared among the three groups. RESULTS: Perihilar-type ICCs were significantly more frequently observed in the hypovascular group than in the rim-enhancement and hypervascular groups (p=0.006 and p <0.001, respectively). Lymphatic invasion, perineural invasion, and biliary invasion were significantly more frequent in the hypovascular group than the rim- enhancement group (p=0.001, p=0.025 and p=0.029, respectively) or hypervascular group (p <0.001, p <0.001 and p=0.025, respectively). Patients with hypovascular lesions showed significantly poorer disease-free survival than patients with rim-enhancing or hypervascular lesions (p=0.001 and p=0.001, respectively). Hypovascularity was an independent preoperative prognostic factor for disease-free survival (p<0.001). CONCLUSIONS: Hypovascular ICCs in the HAP tend to be of perihilar type and to have more malignant potential than other ICCs. KEY POINTS: • Hypovascular ICCs have greater malignant potential than rim-enhancing and hypervascular ICCs. • Hypovascular ICCs show a higher frequency of perihilar-type ICCs. • Perihilar-type ICCs do not always display distal ductal wall thickening.

DOI： 10.1007/s00330-016-4386-3

Language：Others  

Biliary and pancreatic cancers are the most lethal cancer types, since both are often diagnosed at an advanced stage and no effective therapies have been developed for them. Anatomically, the biliary tract and pancreas are located close to each other in the upper abdomen. Both develop from the endoderm foregut by regulating multiple signaling molecules and trascription factors. Biliary tract cancers consist of intrahepatic cholangiocarcinoma (ICC), extrahepatic cholangiocarcinoma (ECC), gallbladder cancer, and cancer of the ampulla. ECC is divided into a perihilar type (70% of cases) and a distal type (30%). More than 80% of pancreatic tumors are pancreatic ductal adenocarcinoma (PDAC). Some 60-70% of PDAC are located in the head of the pancreas and more than 10% are in the body or tail. ECC and PDAC in the pancreas head show common clinical manifestations, and the differential diagnosis of these two cancers is difficult. However, in the UICC/AJCC classification of PDAC of the pancreas head, adenocarcinomas originating from the distal bile duct are considered separate entities, and the TNM staging criteria are different. ECC and PDAC share lots of similar characteristics in 1) epidemiological risk factors, such as obesity, diabetes, smoking, and alcohol; 2) premalignant lesions, such as biliary intraepithelial neoplasia (BilIN), pancreatic intraepithelial neoplasia (PanIN), intraductal papillary neoplasm of the bile duct (IPNB), and intraductal papillarymucinous neoplasm (IPMN) of the pancreas; 3) macroscopic and microscopic features of cancer morphology, spread, or invasion; 4) immunophenotypes of cancer cells and surrounding stromal cells; 5) molecular abnormalities, especially in KRAS, p53, or Smad4 mutations; and 6) possible molecular target therapy, such as the tyrosine kinase receptor pathway. Although many striking similarities are found in these two types of cancer, some differences in clinical and pathological features include an association with preceding chronic inflammation as a cancer risk (ECC > PDAC), the prevalence of gene mutations (PDAC > ECC) and other mutations, the frequency of a special variant of adenocarcinoma (PDAC > ECC), and intestinal differentiation of cancer cells (ECC > PDAC). The combination of molecular findings and the histological classification of pancreatic and biliary cancers may improve diagnostics, therapeutics, and prognostics.

Language：English   Publishing type：Research paper (scientific journal)  

AIM: To investigated the association between the tumor cells' expression of E-cadherin and the numbers of several types of inflammatory cells infiltrating into the invasive portion of gallbladder cancer (GBC). METHODS: We analyzed 50 GBC cases for which a sufficient amount of tumor tissues for tissue microarray (TMA) had been saved. Three tissue cores (3.0 mm) of invasive lesion from each case were used for the TMA. The 4-μm cut sections on slides were immunostained using primary antibodies including E-cadherin for cancer cells, leukocyte common antigen for leukocyte, myeloperoxidase for neutrophils, CD3 for T cells, CD4 for helper T cells, CD8 for killer T cells, CD20 for B cells and CD68 for macrophages. The immunostained slides were digitally analyzed by imaging analysis software. RESULTS: A significant inverse correlation between the number of infiltrating CD8+ cells at invasive areas and the expression of E-cadherin by cancer cells was observed (P = 0.0001), although the degree of this correlation was relatively weak (R = 0.32). The number of CD8+ cells and the cancer cells' E-cadherin expression were also significantly correlated with tumor differentiation (well-differentiated vs poorly differentiated) (P = 0.0467 and P = 0.0294, respectively). Inverse correlation of T-stage and the number of CD8+ cell infiltration was observed with statistical significance in comparison of T2 and T3 cases (P = 0.0324). CONCLUSION: Our findings indicate an inverse correlation of CD8+ T cell infiltration and cancer cells' E-cadherin expression at invasive areas of GBC. Further analyses are essential to test these findings.

DOI： 10.12998/wjcc.v5.i1.1

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: The aim of this study was to evaluate the clinical significance of preoperative classification of intrahepatic cholangiocarcinoma (ICC) into perihilar and peripheral types using dynamic computed tomography (CT). PATIENTS AND METHODS: A retrospective cohort study was performed to analyze the differences in clinical characteristics between perihilar and peripheral ICC samples from patients between 1990-2014. RESULTS: A total of 87 patients were divided into three ICC subtypes; perihilar (n=34), peripheral (n=44), and unclassifiable ICC (n=9). The positive rates of pathological lymphatic infiltration (ly) (p=0.02) and perineural invasion (pn) (p<0.0001) were significantly higher in perihilar ICC. There was no significant difference in the disease-free survival rate (p=0.2268); however, the overall survival rate of perihilar ICC was significantly worse (p=0.0031). The rate of systemic recurrence (>3 nodules) was significantly higher in perihilar ICC (p=0.0135). CONCLUSION: In perihilar ICC, the local tumor invasions such as ly and pn were more frequent. Therefore, it is important in such cases to attempt to achieve a sufficient tumor margin. Systemic recurrences were more frequent in perihilar ICC, so perioperative chemotherapy should be conducted as well.

DOI： 10.21873/anticanres.11260

Language：Others   Publishing type：Research paper (scientific journal)  

Aim To clarify the frequency of fatty change in moderately and poorly differentiated hepatocellular carcinomas (mHCCs and pHCCs) and its relationship to arterial blood flow. Materials and methods One hundred and thirty-six surgically resected HCC lesions were studied. All patients had undergone dynamic magnetic resonance imaging (MRI) with chemical-shift-encoded water–fat imaging (CSI). The presence of fat was identified by a signal drop-off on CSI and confirmed at pathology. Lesions were classified into four groups in the arterial phase; G1, hypointense; G2, isointense; G3, slightly and heterogeneously hyperintense; G4, markedly and homogeneously hyperintense. The number of cumulative arteries (CAs) in the tumours in the pathology examination were counted. Results A fat component was observed significantly more frequently in the pHCCs (13/21; 61.9%) compared to the mHCCs (32/101; 31.7%; p=0.013). The numbers of lesions in each group were as follows: (G1, G2, G3, G4) = (18, 9, 23, 4) in the HCCs with fat; (1, 6, 24, 51) in the HCCs without fat (p<0.001); (5, 5, 18, 4) in the mHCCs with fat; (0, 3, 19, 47) in the mHCCs without fat (p<0.001); (11, 0, 2, 0) in the pHCCs with fat; (0, 2, 3, 3) in the pHCCs without fat (p=0.001). The number of CAs in the fat-containing HCCs (5.5±2.9) was significantly lower than that in the HCCs without fat (10.8±5.3; p<0.001). Conclusion A fat component was more commonly observed in the pHCCs than in the mHCCs. The present results showed a possible mechanism of fatty change in mHCCs and pHCCs in relation to decreased arterial blood supply.

DOI： 10.1016/j.crad.2016.04.020

Language：English   Publishing type：Research paper (scientific journal)  

The present study aimed to investigate the prognostic usefulness of the expression of glucose transporter type 1 (GLUT-1) and GLUT-2, hypoxia-inducible factor 1α (HIF-1α) and insulin-like growth factor II messenger RNA-binding protein 3 (IMP3) in pancreatic neuroendocrine tumors (pNETs). Immunohistochemical staining for GLUT-1, GLUT-2, HIF-1α and IMP3 was performed in 70 pNET specimens. The expression of GLUT-1 and HIF-1α was significantly higher in the World Health Organization grade 2 (G2), neuroendocrine carcinoma cases and mixed-type pNETs compared with the G1 cases. Vessel invasion, a high Ki-67 labeling index and a high mitotic count were significantly more frequent in the GLUT-1- and HIF-1α-positive cases compared with the negative cases. Lymph node metastasis was significantly higher in the GLUT-1-positive cases than in the negative cases. Insulin expression was significantly higher in the IMP3-positive cases than the negative cases. The GLUT-1 expression group experienced a significantly poor disease-free survival rate compared with the negative GLUT-1 expression group. HIF-1α expression was significantly correlated with poor disease-free survival and overall survival rates. A multivariate analysis revealed that lymph node metastasis was an independent risk factor for disease-free survival in all cases. In the G1/G2 group, tumor size and lymph node metastasis were independent risk factors for disease-free survival. Overall, the results suggested that GLUT-1 is a useful prognostic biomarker for pNETs.

DOI： 10.3892/ol.2016.5092

Language：English   Publishing type：Research paper (scientific journal)  

Malignant transformation of hepatocellular adenoma (HA) is relatively rare and has been reported to be associated with dysregulation of the β-catenin pathway. The presence of bone marrow metaplasia in HA is an uncommon histological characteristic. The current report presents the case of a 46-year-old woman with glycogen storage disease type I (von Gierke's disease) who underwent resection of hepatocellular carcinoma (HCC) arising in a HA with associated bone marrow metaplasia producing three series of hematopoietic cells. The serum level of proteins induced by des-gamma-carboxy prothrombin (DCP) gradually increased as the tumors grew; following hepatic resection, DCP levels returned to normal. Nuclear accumulation of β-catenin was shown in HCC by immunohistochemistry; however, no mutation was detected in exon 3 of β-catenin. To the best of our knowledge, this is the first report of HA with absolute bone marrow metaplasia producing three series of hematopoietic cells. This occurrence suggests that elevated DCP may be an indicator of malignant transformation of HA.

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Molecular profiling in gastric cancer (GC) is important for diagnosis and treatment. In this study, we investigated signal transduction pathways that might induce chromosomal instability in GC. METHODS: Epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), and p-AKT expression were analyzed using immunohistochemistry, and chromosomal instability was assessed by DNA aneuploidy using laser scanning cytometry, in a total of 202 GC cases. RESULTS: The rate of EGFR expression and p-AKT expression was 70.3 and 34.2 %, respectively, in GC patients. In total, 57.5 % of GC patients exhibited DNA aneuploidy, and p-AKT positively correlated with EGFR and HER2 (p = 0.0127 and p = 0.00031, respectively). Patients with EGFR overexpressing GC showed shorter disease-specific survival than the other cases (hazard ratio 2.00, 95 % confidence interval 1.19-3.53; p = 0.0104). Moreover, EGFR and p-AKT expression was significantly correlated with DNA aneuploidy (p = 0.0002 and p = 0.0302, respectively). CONCLUSIONS: Our data showed that both EGFR and p-AKT overexpression were clearly associated with DNA aneuploidy. Aneuploidy could be a useful marker for therapies that target EGFR.

DOI： 10.1245/s10434-016-5097-3

Language：English   Publishing type：Research paper (scientific journal)  

AIM: Combined hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) (cHCC-CC) is a rare biphasic liver cancer. Recent studies have demonstrated that cHCC-CC originates from hepatic progenitor cells (HPCs). Spalt-like transcription factor 4 (SALL4) is a marker for a progenitor subclass of HCC with an aggressive phenotype. However, little has been revealed about SALL4 expression in cHCC-CC. The aims of this study were to report SALL4 immunopositivity and the results of clinicopathological analysis in cHCC-CC, and to examine the two different nuclear immunostaining patterns for SALL4. METHODS AND RESULTS: We defined the diffuse finely granular nuclear immunostaining pattern as immunopositive for SALL4; this was observed in eight (8.9%) of 90 cHCC-CCs. SALL4 immunopositivity was significantly associated with immunopositivity for α-fetoprotein, glypican 3, and epithelial cell adhesion molecule (EpCAM). There was no relationship between SALL4 immunopositivity and prognosis. We confirmed SALL4 mRNA expression in samples with a punctuate/clumped immunostaining pattern, which showed a significantly lower rate of immunopositivity for EpCAM than those with a diffuse finely granular pattern. CONCLUSIONS: SALL4 immunopositivity is not a prognostic factor in cHCC-CC; however, it is associated with α-fetoprotein, glypican 3 and EpCAM immunopositivity, indicating the mechanism of carcinogenesis. Further study is necessary to interpret the immunostaining pattern for SALL4.

DOI： 10.1111/his.12806

Language：English   Publishing type：Research paper (scientific journal)  

Tumor budding is a major risk factor for T1 colorectal cancer. Quality control of the pathological diagnosis of budding is crucial, irrespective of the pathologist's experience. This study examines the interobserver variability according to pathologists' experience and evaluates the influence of cytokeratin (CK) immunostaining in the assessment of budding. Hematoxylin-eosin (HE) and CK-immunostained slides of 40 cases with T1 primary colorectal cancer were examined. Budding grades were individually evaluated by 12 pathologists who we categorized into three groups by their experience (expert, with >10 years of experience (n = 4), senior, with 5-10 years (n = 4), and junior, < 5 years (n = 4)). The results revealed a tendency for the more experienced pathologists to assign higher budding grades compared to the less-experienced pathologists. In the junior group, the interobserver variability obtained with HE slides was poor, but it was markedly improved in the evaluation using CK-immunostained slides. The benefit of CK immunostaining was only slight in the expert group. CK immunostaining would be useful when a pathologist is not experienced enough or does not have enough confidence in the assessment of budding.

DOI： 10.1111/pin.12374

Language：English   Publishing type：Research paper (scientific journal)  

Mps One Binder Kinase Activator (MOB)1A/1B are core components of the Hippo pathway that coactivate large tumor suppressor homolog (LATS) kinases. Mob1a/1b double deficiency in mouse liver (LMob1DKO) results in hyperplasia of oval cells and immature cholangiocytes accompanied by inflammatory cell infiltration and fibrosis. More than half of mutant mice die within 3 wk of birth. All survivors eventually develop liver cancers, particularly combined hepatocellular and cholangiocarcinomas (cHC-CCs) and intrahepatic cholangiocellular carcinomas (ICCs), and die by age 60 wk. Because this phenotype is the most severe among mutant mice lacking a Hippo signaling component, MOB1A/1B constitute the critical hub of Hippo signaling in mammalian liver. LMob1DKO liver cells show hyperproliferation, increased cell saturation density, hepatocyte dedifferentiation, enhanced epithelial-mesenchymal transition and cell migration, and elevated transforming growth factor beta(TGF-β)2/3 production. These changes are strongly dependent on Yes-Associated Protein-1 (Yap1) and partially dependent on PDZ-binding motif (Taz) and Tgfbr2, but independent of connective tissue growth factor (Ctgf). In human liver cancers, YAP1 activation is frequent in cHC-CCs and ICCs and correlates with SMAD family member 2 activation. Drug screening revealed that antiparasitic macrocyclic lactones inhibit YAP1 activation in vitro and in vivo. Targeting YAP1/TAZ with these drugs in combination with inhibition of the TGF-β pathway may be effective treatment for cHC-CCs and ICCs.

DOI： 10.1073/pnas.1517188113

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVES: As a strategy to diagnose early-stage pancreatic ductal adenocarcinoma (PDAC) is urgently needed, we aimed to clarify characteristics of early-stage PDAC. METHODS: We retrospectively reviewed medical records of 299 consecutive patients who underwent R0 or R1 surgical resection for PDAC between 1994 and 2013 and compared clinical characteristics between patients with early-stage (stages 0-I by Japanese General Rules for Pancreatic Cancer) and advanced-stage (stages II-IV) disease. Diagnostic processes were also analyzed. RESULTS: Twenty-four patients (8%) had early-stage PDAC (stage 0: 11; stage I: 13). Univariate and multivariate analyses showed that presence or history of intraductal papillary mucinous neoplasm (P < 0.01), history of pancreatitis (P < 0.01), and presence or history of extrapancreatic malignancies (P = 0.01) independently predicted detection of early-stage PDAC. Cytological examination during endoscopic retrograde pancreatography cytology was ∼65% sensitive in preoperative diagnosis of early-stage PDAC, whereas other imaging modalities were only 29% to 38% sensitive; 9 of 24 early-stage PDACs were diagnosed by endoscopic retrograde pancreatography cytology alone. CONCLUSIONS: Endoscopic retrograde pancreatography cytology for patients with intraductal papillary mucinous neoplasm or pancreatitis may help diagnose early-stage PDAC. Surveillance of extrapancreatic malignancies might also provide opportunities to detect early-stage PDAC as a second malignancy.

DOI： 10.1097/MPA.0000000000000393

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Determining the indications for adjuvant chemotherapy (CT) in patients with hormone receptor (HR)-positive/HER2-negative breast cancer are difficult. The transcription factors GATA-binding protein 3 (GATA-3) and Forkhead-box protein A1 (FOXA1) are crucial for the hormone responsive phenotype of breast cancer. This study evaluated whether the expression of GATA-3 and FOXA1 is a prognostic and predictive marker of outcomes in patients with HR-positive/HER2-negative breast cancer. METHODS: The expression of GATA-3 and FOXA1 was analyzed immunohistochemically in 214 patients with invasive breast cancer to evaluate the association with the clinicopathological features and the prognosis. RESULTS: GATA-3 expression was positively correlated with FOXA1 expression (P < 0.0001). Both GATA-3 and FOXA1 were positively correlated with ER (P < 0.0001 each) and PR expression (P = 0.0001 and P = 0.0009, respectively), and inversely correlated with nuclear grade (P = 0.0002 and P = 0.0018, respectively) and Ki67 index (P = 0.0052 and P = 0.0049, respectively). Expression of GATA-3 and FOXA1 was associated with better prognosis. FOXA1 was an independent favorable prognostic marker in HR-positive/HER2-negative breast cancer. Disease-free survival rates were similar in patients with HR-positive/HER2-negative breast cancer and high FOXA1 expression given adjuvant hormone therapy (HT) alone and those given CT plus HT. CONCLUSION: GATA-3 and FOXA1 are associated with a less aggressive phenotype and a better prognosis in patients with HR-positive/HER2-negative breast cancer. FOXA1 may be useful in identifying those patients who may not require adjuvant CT.

DOI： 10.1007/s12282-013-0515-x

Language：English   Publishing type：Research paper (scientific journal)  

This chapter covers a range of important topics in the evaluation of the microvascular invasion (MVI) in hepatocellular carcinoma (HCC) before treatment. The malignant potential of HCC is reflected by the types of MVI such as portal venous (vp), hepatic vein (vv) or bile duct (b) infiltration. The identification of the type of MVI in HCC has a key role in decisions regarding the effective treatment of HCC. Here, we describe the possible and important predictors of MVI in HCC.

DOI： 10.1159/000438475

Language：English   Publishing type：Research paper (scientific journal)  

A 77-year-old Japanese woman was transported to a nearby hospital due to sudden abdominal pain and transient loss of consciousness. Abdominal computed tomography (CT) suggested hemoperitoneum and hepatic nodule. She was conservatively treated. Contrast-enhanced CT two months later revealed an increased mass size, and the enhancement pattern suggested the possibility of hepatocellular carcinoma (HCC). Under a clinical diagnosis of HCC, transcatheter arterial chemoembolization (TACE) was performed. A subsequent imaging study revealed that most of the lipiodol used for the embolization was washed out. Therefore, surgical resection was performed. Histologically, the nodule contained numerous inflammatory cells including small lymphocytes, plasma cells and macrophages. Notably, epithelioid granulomatous features with multinucleated giant cells were observed in both the nodule and background liver. Some of the multinucleated giant cells contained oil lipid. Among the infiltrating inflammatory cells, spindle-shaped, histiocytoid or myoid tumor cells with eosinophilic cytoplasm were found. The tumor cells were positive for Melan A and HMB45. The nodule contained many IgG4-positive plasma cells; these were counted and found to number 72.6 cells/HPF (range: 61-80). The calculated IgG4:IgG ratio was 33.2%. The nodule was finally diagnosed as previously ruptured inflammatory angiomyolipoma modified by granulomatous reaction after TACE.

DOI： 10.3748/wjg.v21.i32.9675

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: The incidence of hepatitis B virus surface antigen-negative and hepatitis C virus antibody-negative hepatocellular carcinoma (NBNC-HCC) is gradually increasing. METHODS: A retrospective cohort study was performed in 694 patients who underwent curative hepatic resection for primary HCC from January 1990 to December 2011. RESULTS: In the NBNC-HCC group (n = 110), the complication rate of diabetic mellitus (38 %) was significantly higher than that of the B-HCC group (n = 110; 17 %), and their rate of alcohol abuse (38 %) was significantly higher than that of both the B-HCC (26 %) and C-HCC groups (n = 474; 22 %). In the NBNC-HCC group, the tumor diameter (4.5 ± 3.6 cm) was significantly larger than that of the C-HCC group (2.9 ± 1.8 cm), but the rate of histological cirrhosis (37 %) was significantly lower than those of both the B-HCC (67 %) and C-HCC (53 %) groups. There were no significant differences regarding overall and disease-free survival among the three groups. In the NBNC-HCC group, multiple intrahepatic or distant recurrences (25 %) were significantly higher than in the C-HCC group (17 %), and the rate of recurrence more than 2 years after hepatic resection (24 %) was significantly higher than that of the B-HCC group (12 %). CONCLUSIONS: The surgical outcomes of patients with NBNC-HCC were not significantly different compared with those of the patients with B-HCC or C-HCC. There was a substantial population with late recurrence among the patients with NBNC-HCC after curative hepatic resection, and thus not only long-term follow-up but also the early establishment of preventive methods for HCC recurrence from NBNC-hepatitis are necessary.

DOI： 10.1245/s10434-014-4261-x

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Vascular invasion of hepatocellular carcinoma (HCC) has a high incidence of recurrence after liver transplantation. Patients with microvascular invasion (MVI) show a high tumor grade; however, some show a good prognosis. This retrospective study aimed to investigate whether the degree of MVI affects prognosis after living-donor liver transplantation. METHODS: A total of 142 patients with HCC who had undergone living-donor liver transplantation were histologically evaluated about the number of invaded vessels and the maximum number of invading carcinoma cells. Patients with MVI were classified into two subgroups: high MVI group (n = 38), which showed more than 50 carcinoma cells in the vessels, with multiple invaded vessels; and low MVI group (n = 17), which showed MVI, but not high MVI. RESULTS: Analysis of recurrence-free survival showed that high MVI group had significantly poorer outcomes than the other groups (P < 0.001). High MVI group had significantly higher α-fetoprotein levels, des-γ-carboxy prothrombin levels, number of tumors, a larger tumor size, and a higher percentage of poorly differentiated HCC than non-MVI group. High MVI was an independent prognostic factor for recurrence-free survival (P = 0.030). Among patients exceeding the Milan criteria (n = 61), high MVI group had significantly poorer outcomes than the other groups for recurrence-free survival (P = 0.003). Patients in high MVI group had significantly higher des-γ-carboxy prothrombin levels and a larger tumor size than non-MVI group. High MVI was an independent prognostic factor for recurrence-free survival (P = 0.014). CONCLUSION: In living-donor liver transplantation for HCC, high MVI is a novel pathologic marker for predicting prognosis.

DOI： 10.1097/TP.0000000000000489

Language：Japanese   Publishing type：Research paper (scientific journal)  

[A case of drug-induced liver injury caused by Keishi-karyukotsu-boreito and Shin-i-seihaito].
A 43-year-old woman was admitted to our hospital due to liver dysfunction. She had a history of liver injury induced by the herbal medicine Keishi-karyukotsu-boreito, which occurred at the age of 35 years. On the present occasion, she had taken the herbal medicine Shin-i-seihaito to treat her sinusitis for one month. We diagnosed liver injury caused by Shin-i-seihaito, and her liver dysfunction normalized after discontinuation of Shin-i-seihaito. This is the first reported case of drug-induced liver injury caused by the herbal medicines Keishi-karyukotsu-boreito and Shin-i-seihaito.

DOI： 10.11405/nisshoshi.112.1054

Language：English  

DOI： 10.1111/pin.12307

Language：English   Publishing type：Research paper (scientific journal)  

A 63-year-old man diagnosed with locally advanced pancreatic ductal adenocarcinoma (PDAC; stage IIa) was treated with chemotherapy (gemcitabine, 5-fluorouracil and cisplatin) followed by radiotherapy. He had complete response by imaging and relapse-free survival for 11 years. However, he subsequently presented with local tumor recurrence and underwent pancreaticoduodenectomy followed by chemotherapy; a partial response was achieved. As in liver metastasis of colonic cancer, complete response by imaging in PDAC may not mean pathological complete response. We would propose the importance of adjuvant surgery for a patient with PDAC with complete response by imaging after chemoradiotherapy.

Language：English   Publishing type：Research paper (scientific journal)  

Results from the Trastuzumab for Gastric Cancer (ToGA) trial highlighted the clinical significance of trastuzumab in the treatment of HER2 (Human Epidermal Growth Factor Receptor type 2)-positive gastric cancer. However, whether expression of HER2 is related to prognosis of gastric cancer is still controversial. A total of 360 consecutive patients with gastric cancer who underwent surgical resection in our Department from 1994 to 2007 were analyzed. We performed immunohistochemical analysis of HER2 expression. HER2 expression level was classified into four scores (0, 1+, 2+ and 3+). There were 37 (10%) patients with a score of 3+. A score of 3+ was defined as being HER2-positive. Recurrence-free survival was worse in HER2-positive cases (p=0.045). When the analysis was conducted with intestinal types of cancer, RFS was considerably worse in the HER2-positive group (p=0.011). HER2 expression may have potential as a prognostic factor for intestinal cancer types. Further research is warranted.

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND/AIM: Combined hepatocellular-cholangiocarcinoma (cHC-CC) is found unexpectedly in explanted or resected liver specimens. The current study evaluated the longterm outcomes of living-donor liver transplantation (LDLT) between patients with cHC-CC and hepatocellular carcinoma (HCC). PATIENTS AND METHODS: We performed 178 LDLT including 8 patients of pathologically and immunohistochemically diagnosed cHC-CC who all underwent LDLT with a preoperative diagnosis of HCC by imaging study. RESULTS: Out of the 8 patients, 6 were within the Milan criteria and all were within the Kyushu University criteria. The 1-, 5- and 10-year overall survival (OS) and disease-free survival (DFS) rates after LDLT for patients with cHC-CC were 87.5, 72.9 and 48.6% and 85.7, 85.7 and 85.7%, respectively. The OS and DFS between patients with cHC-CC and HCC were not statistically different. CONCLUSION: LDLT for patients with cHC-CC using the Milan criteria or the Kyushu University criteria, as well as HCC, could have an acceptable long-term outcome.

Language：Others   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/jgh.12849

Language：English   Publishing type：Research paper (scientific journal)  

Pulmonary manifestations associated with food allergy are rich in variety. We report the first case of food-induced granulomatous interstitial pneumonia mimicking hypersensitivity pneumonitis (HP). A 77-year-old woman with respiratory symptoms was referred to our hospital. We performed a surgical lung biopsy, which showed the features of granulomatous interstitial pneumonia. Her clinical history resembled those observed in HP. However, avoidance of exposure to the causative antigens did not improve her symptoms. Moreover, the patient had some features inconsistent with HP, such as elevated serum IgE levels, blood eosinophilia, intrathoracic lymphadenopathies and pleural effusion. Therefore, we pursued another extrinsic non-inhaled antigen as the cause of pulmonary involvements. We noted that she had been eating homemade rice bran pickles, and pulmonary involvements were induced by an ingestion challenge test. We suggest that granulomatous interstitial pneumonia may be a rare subtype of the pulmonary manifestations associated with food allergy.

DOI： 10.1136/bcr-2014-208261

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Anastomotic leakage is a major complication after anterior resection for rectal cancer. The double-stapling technique (DST) is the main method for creating a colorectal anastomosis. However, the rate of anastomotic leakage after DST remains high, and the technical risk factors have not been well established. MATERIALS AND METHODS: Five methods of colorectal anastomosis were performed on the porcine rectum and colon: single-stapled double-purse-string (SSDP), DST, side-to-side with a linear stapler (SS-L), side-to-side with a circular stapler (SS-C), and SS-C with hand-sewn reinforcement (n = 6 for each method). In each group, burst pressures were tested, paying special attention to the locations of the first disruptions. The anastomosis line, including staples, was embedded in polyester resin, and polished sections were examined histologically. RESULTS: Burst pressures were significantly higher in the SS-L and SS-C than those in the SSDP and DST groups (P < 0.001) and were higher in the SS-C with hand-sewn reinforcement than those in the SS-L and SS-C groups (P < 0.001). Remarkably, in the SSDP, DST, and SS-C groups, the first disruptions occurred on the staple line created by the circular stapler. CONCLUSIONS: The experimentally strongest colorectal anastomosis created with instruments currently in use was a SS-C. This anastomosis does not overlap staple lines and does not require a purse-string suture. Hand-sewn reinforcement was effective in increasing the anastomotic strength.

DOI： 10.1016/j.jss.2014.11.045

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: The aims of this study were to investigate the GNAS mutational status in pancreatic intraductal papillary mucinous neoplasm (IPMN) with and without distinct pancreatic ductal adenocarcinoma (PDAC) and to evaluate the significance of GNAS analysis using duodenal fluid (DF) in patients with IPMN. METHODS: The clinicopathologic features of 110 patients with IPMN including 16 with distinct PDAC were reviewed. The GNAS status in the IPMN tissue and 23 DF specimens was assessed by sensitive mutation scanning methods. RESULTS: The GNAS mutation rate in IPMN with distinct PDAC was significantly lower than that in IPMN without PDAC (4/16, 25%, vs 61/94, 65%; P = 0.0047). By multivariate analysis, GNAS wild-type and gastric type IPMNs were significantly associated with distinct PDAC. Of 45 GNAS wild-type IPMNs, 10 (43%) of 23 gastric type IPMNs had distinct PDAC, whereas only 2 (9%) of 22 non-gastric type IPMNs had distinct PDAC (P = 0.017). The GNAS status in DF was consistent with that in tissue in 21 (91%) of 23 patients. CONCLUSIONS: Distinct PDACs frequently develop in the pancreas with gastric type IPMN without GNAS mutations. Duodenal fluid DNA test would predict the GNAS status of IPMN, whereas the detection of the gastric subtype using noninvasive test remains to be determined.

DOI： 10.1097/MPA.0000000000000258

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Mucin production in primary liver neoplasms is typically interpreted as evidence for biliary differentiation. However, we have observed benign and malignant liver tumors that have abundant extracellular myxoid/mucinous material, yet have only evidence of hepatocellular differentiation. To further characterize these unusual findings, 9 cases were identified and further studied. Four cases were hepatic adenomas, whereas 5 were hepatocellular carcinomas. Extracellular myxoid/mucinous material was diffuse in 7 cases and patchy in 2 cases. The extracellular myxoid/mucinous material was typically weakly mucicarmine positive (N=6) and Alcian blue positive (N=8). All tumors were well differentiated, and none had evidence for biliary differentiation by morphology or immunohistochemistry. The hepatic adenomas arose in nondiabetic and nonobese patients. Both the hepatic adenomas and the hepatocellular carcinomas were strongly and diffusely HepPar1 positive, CK19 negative, and showed loss of LFABP protein expression. These findings indicate that extracellular myxoid/mucinous material in isolation should not be interpreted as cholangiocarcinoma. Furthermore, the unique morphology, the clinical characteristics, and the immunophenotype results suggest that myxoid hepatic adenomas and hepatocellular carcinoma may be unique tumor variants.

DOI： 10.1097/PAS.0000000000000382

Language：English   Publishing type：Research paper (scientific journal)  

Anterior gradient 2 (AGR2), a member of the protein disulfide isomerase family, has been implicated in various cancers including pancreatic ductal adenocarcinoma (PDAC) and is known to promote cancer progression. However, the prognostic value of AGR2 expression and the interaction with epithelial-mesenchymal transition (EMT) remain unclear. We investigated the clinical significance of AGR2 and EMT markers in PDAC patients by immunohistochemical analyses. Although AGR2 expression was not observed in normal pancreas, all pancreatic precursor neoplastic lesions were positive for AGR2, even at the earliest stages, including pancreatic intraepithelial neoplasia-1A, AGR2 expression was reduced in 27.7% (54/195 cases) of PDAC patients. AGR2 downregulation correlated with EMT markers (vimentin overexpression and reduced membranous E-cadherin expression), high Union for International Cancer Control stage (P<0.0001), high histological cellular grade (P<0.0001), and adverse outcome (P<0.0001). In vitro, targeted silencing of AGR2 in cancer cells using siRNA reduced cell proliferation, colony formation, cell invasiveness, and migration, but did not alter EMT markers. To confer a more aggressive phenotype and induce EMT in PDAC cells, we co-cultured PDAC cell lines with primary-cultured pancreatic stellate cells (PSCs) and found that AGR2 was downregulated in co-cultured PDAC cells compared with PDAC monocultures. Treatment with transforming growth factor beta-1 (TGF-β), secreted from PSCs, decreased AGR2 expression, whereas inhibition of TGF-β signaling using recombinant soluble human TGF-β receptor type II and TGF-β-neutralizing antibodies restored AGR2 expression. We conclude that AGR2 downregulation is a useful prognostic marker, induced by EMT, and that secreted TGF-β from PSCs may partially contribute to AGR2 downregulation in PDAC patients. AGR2 downregulation does not induce EMT or a more aggressive phenotype, but is a secondary effect of these processes in advanced PDAC.

DOI： 10.1038/labinvest.2014.138

Language：English   Publishing type：Research paper (scientific journal)  

Intrahepatic cholangiocarcinomas (ICCs) are made up of heterogenous carcinomas arising from different anatomical sites of the liver. Two types of candidate stem/progenitor cells of the biliary tree are postulated to exist at the peribiliary glands for large bile ducts and at the canals of Hering for small ducts and hepatocytes. According to the recent observations, ICCs can be subclassified into two types: tumors involving the large bile ducts comparable in size to the intrahepatic second branches and composed of a tubular or papillary component with tall columnar epithelium, and tumors involving the smaller duct than segmental branches and composed of small tubules with cuboidal epithelium. Perihilar large duct type ICCs can be interpreted as arising from large bile duct type ICCs, and peripheral small duct type ICCs may arise from small bile duct type or ductular type ICCs. Chronic biliary inflammation induces neoplastic change of the large bile ducts and thereby progression to the perihilar large duct type ICC, which can be grossly classified into periductal filtrating type ICC and intraductal growth type ICC, while chronic hepatitis or cirrhosis induces mass-forming peripheral small duct type ICC. The different morphological and molecular features, including stromal components and tumor vasculature, support the hypothesis that perihilar large duct type ICCs and peripheral small duct type ICCs arise from different backgrounds, have different carcinogenetic pathways, and exhibit different biologic behaviors.

DOI： 10.1002/jhbp.154

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Recently, a novel marker, hyperglycosylated Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA(+)-M2BP), was developed for liver fibrosis using the glycan "sugar chain"-based immunoassay; however, the feasibility of WFA(+)-M2BP for assessing liver fibrosis has not been proven with clinical samples of hepatitis. METHODS: Serum WFA(+)-M2BP values were evaluated in 200 patients with chronic liver disease who underwent histological examination of liver fibrosis. The diagnostic accuracy of WFA(+)-M2BP values was compared with various fibrosis markers, such as ultrasound based-virtual touch tissue quantification (VTTQ), magnetic resonance imaging based-liver-to-major psoas muscle intensity ratio (LMR), and serum markers, including hyaluronic acid, type 4 collagen, and aspartate transaminase to platelet ratio index (APRI). RESULTS: Serum WFA(+)-M2BP levels in patients with fibrosis grades F0, F1, F2, F3, and F4 had cutoff indices 1.62, 1.82, 3.02, 3.32, and 3.67, respectively, and there were significant differences between fibrosis stages F1 and F2, and between F2 and F3 (P < 0.01). The area under the receiver operating characteristic curves for the diagnosis of fibrosis (F ≥ 3) using serum WFA(+)-M2BP values (0.812) was almost comparable to that using VTTQ examination (0.814), but was superior to the other surrogate markers, including LMR index (0.766), APRI (0.694), hyaluronic acid (0.683), and type 4 collagen (0.625) (P < 0.01 each). CONCLUSIONS: Serum WFA(+)-M2BP values based on a glycan-based immunoassay is an accurate, reliable, and reproducible method for the assessment of liver fibrosis. This approach could be clinically feasible for evaluation of beneficial therapy through the quantification of liver fibrosis in hepatitis patients if this measurement application is commercially realized.

DOI： 10.1007/s00535-014-0946-y

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common solid tumors worldwide. Surgery is potentially curative, but high recurrence rates worsen patient prognosis. The interaction between the proteins programmed cell death 1 (PD-1) and programmed cell death 1 ligand 1 (PD-L1) is an important immune checkpoint. The significance of PD-L1 expression and human leukocyte antigen class I (HLA class I), recognized by CD8 T cells, in the prognosis of patients with HCC remains to be determined. METHODS: We assessed the levels of PD-L1 and HLA class I expression on HCC samples from 80 patients who had undergone hepatectomy at our institution, and evaluated the correlations between PD-L1 and HLA class I expression and patient prognosis. RESULTS: High HLA class I expression was correlated with significantly better recurrence-free survival (RFS), but not overall survival (OS). Multivariate analysis showed that high HLA class I expression was an independent predictor of improved RFS. Low expression of PD-L1 on HCC tended to predict better OS, but the difference was not statistically significant. PD-L1 expression on HCC correlated with the number of CD163-positive macrophages and HLA class I expression with CD3-positive cell infiltration. Univariable and multivariable analyses showed that combined PD-L1 low/HLA class I high expression on HCCs was prognostic for improved OS and RFS. CONCLUSIONS: PD-L1 status may be a good predictor of prognosis in HCC patients with high HLA class I expression. Novel therapies targeting the PD-L1/PD-1 pathway may improve the prognosis of patients with HCC.

DOI： 10.1007/s00535-014-0933-3

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVES: To clarify the relationship between the biological behaviour of hepatocellular carcinomas (HCCs) and their signal intensity in the hepatobiliary phase of gadoxetic acid-enhanced MR imaging with a special focus on the signal heterogeneity. METHODS: A total of 68 patients with 70 pathologically proven HCCs were enrolled. On the basis of the signal intensity in the hepatobiliary phase, the lesions were classified into three groups: group 1, homogeneous hypointensity (n = 44); group 2, heterogeneous hyperintensity (n = 20); and group 3, homogeneous hyperintensity (n = 6). The clinicopathological findings were compared among the three groups. RESULTS: The tumour size and the serum level of protein induced by vitamin K absence or antagonist-II (PIVKA-II) were significantly higher in group 2 compared to group 1 (p = 0.0155, p = 0.0215, respectively) and compared to group 3 (p = 0.0330, p = 0.0220, respectively). The organic anion transporting polypeptide 8 (OATP8) expression in group 2 and group 3 was significantly higher than in group 1 (p < 0.0001, p < 0.0001, respectively). Group 2 showed a significantly lower disease-free survival rate compared to group 1 (p = 0.0125), and group 2 was an independent prognostic factor for disease-free survival (p = 0.0308). CONCLUSIONS: HCCs in the hepatobiliary phase that are heterogeneously hyperintense on gadoxetic acid-enhanced MR imaging have more malignant potential than other types of HCCs. KEY POINTS: • Heterogeneous uptake of gadoxetic acid suggests more malignant potential in HCC • Uptake of gadoxetic acid does not suggest less malignancy in HCC • Evaluation of signal heterogeneity on gadoxetic acid-enhanced MR imaging is useful.

DOI： 10.1007/s00330-014-3349-9

Language：English  

DOI： 10.1002/lt.23996

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Micro RNAs (miRNAs) are small noncoding RNAs that have gained attention as key molecules in the malignant characteristics of cancers, and several recent investigations also have identified some miRNAs as potential key regulators to inhibit the malignant characteristics of tumors. MiRNA-373 (miR-373) has recently been reported to induce E-cadherin, which is a key regulator of epithelial-mesenchymal transition (EMT). However, the role of miR-373 in the characteristics of cancer cells is not still well known. METHODS: We investigated the expression levels of miR-373 in pancreatic cancer cell lines and its effect on the invasiveness of pancreatic cancer by using in vitro and in vivo models. We also analyzed the expression of miR-373 using formalin-fixed paraffin-embedded (n = 152) and microdissected frozen (n = 57) samples from pancreatic tissues. RESULTS: The levels of miR-373 expression were low in pancreatic cancer cell lines. In formalin-fixed paraffin-embedded and microdissected frozen samples, miR-373 expression was significantly down-regulated in pancreatic cancer compared with that in healthy pancreas (P < 0.001 and P = 0.005, respectively). We also found that reexpression of miR-373 repressed transforming growth factor-β-induced EMT, leading to inhibition of invasiveness of cancer cells. Furthermore, reexpression of miR-373 significantly inhibited peritoneal dissemination in vivo (P < 0.001). CONCLUSIONS: MiR-373 is down-regulated in pancreatic cancer, and its reexpression represses the invasiveness of pancreatic cancer cells.

DOI： 10.1245/s10434-014-3676-8

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVES: The 2012 international consensus guidelines for the management of intraductal papillary mucinous neoplasm (IPMN) of the pancreas stratified patients into 2 clinical categories, "high-risk stigmata" and "worrisome features," and recommended different therapeutic strategies for these groups. The aim of this study was to elucidate the significance of these categories in terms of predicting malignant IPMNs. METHODS: The medical records of 100 consecutive patients who underwent pancreatectomy for IPMNs were retrospectively reviewed. Seventy patients with branch duct IPMNs (BD-IPMNs) were stratified into 3 groups. The relationships between the number of predictive factors and histopathologic grade were investigated. RESULTS: The prevalence rates of malignant IPMN, invasive carcinoma, and lymph node metastasis in the high-risk group were 80%, 55%, and 20%, respectively, with these percentages significantly increasing in a stepwise manner according to the number of predictive factors. In contrast, there was no significant correlation between the number of worrisome features and grade of malignancy in patients stratified as having worrisome BD-IPMNs. CONCLUSIONS: The number of high-risk stigmata correlated significantly with the grade of malignancy of BD-IPMNs. The presence of at least 1 high-risk stigma in patients with BD-IPMNs indicates a need for pancreatectomy with lymphadenectomy.

DOI： 10.1097/MPA.0000000000000199

Language：English   Publishing type：Research paper (scientific journal)  

Morphologic features and neoplastic potentials of bile duct adenoma (BDA) and von Meyenburg complex (VMC)-like duct arising in chronic liver disease were unknown. Thirty-five BDAs and 12 VMC-like duct lesions were observed in 39 cases with chronic liver disease. BDAs were divided into the EMA-cytoplasmic type (n = 14) and EMA-luminal type (n = 21). EMA-cytoplasmic BDA composed of a proliferation of cuboidal to low-columnar cells forming an open lumen with NCAM(+)/MUC6(-), resembling an interlobular bile duct. EMA-luminal BDA showed uniform cuboidal cells with narrow lumen, and NCAM(++)/MUC6(++), resembling a ductular reaction. VMC-like duct showed positive MUC1 expression and negative MUC6. The expression of S100P, glucose transporter-1 (GLUT-1) and insulin-like growth factor II mRNA-binding protein 3 (IMP-3) were not detected in three lesions. p16 expression was higher than those of the ductular reaction, and the Ki67 and p53 indexes were very low (<1.0%). Large-sized EMA-luminal BDA shows sclerotic stroma. We classified small nodular lesions of ductal or ductular cells in chronic hepatitis and cirrhosis into the following groups: BDA, interlobular bile duct type; BDA, ductular/peribiliary gland type; and VMC-like duct. They may be reactive proliferation rather than neoplastic lesions.

DOI： 10.1111/pin.12209

Language：English   Publishing type：Research paper (scientific journal)  

Gallbladder cancer (GBC) shows a marked geographical variation in its incidence. Middle-aged and elderly women are more commonly affected. Risk factors for its development include the presence of gallstones, chronic infection and pancreaticobiliary maljunction. Controversy remains in regard to the theory of carcinogenesis from adenomyomatosis, porcelain gallbladder and adenoma of the gallbladder. The surgical strategy and prognosis after surgery for GBC differ strikingly according to T-stage. Discrimination of favorable cases, particularly T2 or T3 lesions, is useful for the selection of surgical strategies for individual patients. Although many candidate factors predicting disease progression, such as depth of subserosal invasion, horizontal tumor spread, tumor budding, dedifferentiation, Ki-67 labeling index, p53 nuclear expression, CD8+ tumor-infiltrating lymphocytes, mitotic counts, Laminin-5-gamma-2 chain, hypoxia-inducible factor-1a, cyclooxygenase-2 and the Hedgehog signaling pathway have been investigated, useful prognostic makers or factors have not been established. As GBC is often discovered incidentally after routine cholecystectomy and accurate preoperative diagnosis is difficult, close mutual cooperation between surgeons and pathologists is essential for developing a rational surgical strategy for GBC.

DOI： 10.12998/wjcc.v2.i10.515

Language：English   Publishing type：Research paper (scientific journal)  

AIM: The apelin-APJ system regulates angiogenesis, and is overexpressed in several types of cancer. The aim of this study was to clarify the role of the apelin-APJ system in the angiogenesis of hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Expressions of angiogenic factors and vascular markers were investigated in specimens from 90 HCC patients. A subcutaneous HCC tumor mouse model was treated with the APJ antagonist, F13A, and tumor growth and vascular development were assessed. RESULTS: APJ expression was observed in arteriole-smooth muscle. Higher amounts of APJ(+)-arteriole and apelin were detected in tumors (p<0.001 for both). APJ(+)-arteriole and apelin expression were more commonly observed in moderately- and poorly-differentiated than in well-differentiated HCC (p ≤ 0.003). HCC with irregular dilated arteries expressed higher levels of apelin (p=0.012). Tumor growth was inhibited by treatment with F13A (p<0.001), and arterioles were decreased in the treated group (p=0.047), in vivo. CONCLUSION: Apelin-APJ is overexpressed, and works as a signal for arteriogenesis in HCC.

Language：English   Publishing type：Research paper (scientific journal)  

INTRODUCTION: The relationship between the washout pattern and constituent cell in adrenal hyperplasia (AH) has not been fully investigated. The purpose of this study was to elucidate the radiological or pathological factors determining the washout pattern of AH on dynamic CT. METHODS: Ten patients with 14 surgically proven AHs were enrolled. Dynamic CT was scanned before (pre-contrast image) and 60 seconds (early phase) and 240 seconds (delayed phase) after administration of iodine contrast. The absolute percentage washout (APW) of each nodular lesion was calculated using the following formula: APW(%) = (TAearly-TAdelay)/(TAearly-TApre) × 100, when TApre, TAearly and TAdelay were defined as tumour attenuation values of pre-contrast, early and delayed phases, respectively. Pathologically, the clear cell ratio (CCR) constituting each nodular lesion was qualitatively assessed. Regression analysis was performed to evaluate a correlation between each pair of CCR, TApre, (TAearly-TAdelay) and APW. RESULTS: There was a significant correlation between each pair of CCR, TApre and APW. CCR decreased as TApre increased (r = 0.81, P < 0.001). APW increased as CCR decreased (r = 0.80, P < 0.001) or as TApre increased (r = 0.74, P < 0.01). CONCLUSIONS: The key factors of washout pattern of AH on dynamic CT were CCR and TApre. The difference in constituent cell was associated with variability in APW of AH.

DOI： 10.1111/1754-9485.12211

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVES: This study investigated the association between several biological markers and fluorine-18 fluorodeoxyglucose (FDG) uptake in patients with hepatocellular carcinoma. METHODS: Forty-two patients with hepatocellular carcinoma who underwent FDG positron emission tomography were included in the study. Tumor sections were immunohistochemically stained for phosphorylated signal transducer and activator of transcription 3 (pSTAT3), hypoxia-inducible factor 1α (HIF1α), glucose transporter 1 (GLUT1), GLUT2, GLUT3, and GLUT4. RESULTS: The high standardized uptake value (SUV) group showed larger tumor size, more frequent vascular invasion, and poorer differentiation compared with the low SUV group. The high SUV group also showed significantly higher immunohistochemical expression of pSTAT3, HIF1α, and GLUT1. The GLUT1 high-expression group showed higher α-fetoprotein (a tumor marker) and poorer differentiation than did the GLUT1 low-expression group. CONCLUSIONS: Our study indicates that FDG uptake is associated with the expression of pSTAT3, HIF1α, and GLUT1 in hepatocellular carcinoma. The expression of these proteins shows a correlation with poor differentiation and vascular invasion.

DOI： 10.1309/AJCPG8AFJ5NRKLLM

Language：English   Publishing type：Research paper (scientific journal)  

A thickened, enhanced cyst wall on imaging examinations is one of the "worrisome features" described in the consensus guidelines for management of intraductal papillary mucinous neoplasm of the pancreas (IPMN). Podoplanin (PDPN) expression by cancer-associated fibroblasts is known to be an indicator of poor prognosis in some types of cancer. We performed immunohistochemical staining for alpha-smooth muscle actin (α-SMA) in IPMN lesions and determined the pathological wall thickness by measuring the thinnest and thickest α-SMA-positive parts of the wall of the largest cyst in each case, and the mean of these two values was recorded as the wall thickness. The thickness of the pathological wall increased with progression from IPMN with low-grade dysplasia to IPMN with an invasive carcinoma. The pathological wall was thicker in IPMN with main duct involvement, nongastric-type IPMN, and IPMN with mural nodules. We also stained for PDPN and assessed the thickness of cyst wall staining as for α-SMA. The thickness of the PDPN-positive cyst wall varied in a pattern similar to the thickness of the α-SMA-positive pathological cyst wall. PDPN-positive stromal fibroblasts in the invasive component of IPMN-IC were evaluated as a ratio to α-SMA-positive fibroblasts. A high ratio (>50 %) of PDPN-positive stromal fibroblasts was a predictor of poor outcome. PDPN expression in the cyst wall correlates with the progression of IPMN. PDPN may be a significant prognostic marker of IPMN-IC.

DOI： 10.1007/s00428-014-1610-x

Language：English   Publishing type：Research paper (scientific journal)  

AIMS: Of the recognized precursor lesions of pancreatic adenocarcinoma, pancreatic intraepithelial neoplasia (PanIN) is the most common form. However, little is known about the relationship between the grade of PanIN and prognosis for patients with invasive ductal carcinoma. METHODS AND RESULTS: In 124 patients with invasive ductal carcinoma, we examined the grade and number of PanIN lesions in all slides of resected pancreas. The prevalence rates of PanIN-1A, PanIN-1B, PanIN-2 and PanIN-3 were 86%, 84%, 57% and 30%, respectively. We allocated PanIN-2 and PanIN-3 cases into a PanIN-high group, and cases showing PanIN-1A, PanIN-1B or absence of PanIN into a PanIN-low group. In clinicopathological analysis, PanIN-high status was significantly correlated with the number of PanIN lesions (P < 0.0001). Disease-free and overall survival were statistically better in the PanIN-high group than in the PanIN-low group (P = 0.0005 and P = 0.0003). Univariate and multivariate analyses revealed that tumour size and PanIN-low status were statistically significant factors for a poorer prognosis (P = 0.042 and P = 0.007). CONCLUSIONS: In a pathological examination, it is important to evaluate the grade and number of PanINs in assessing the prognosis of pancreatic cancer.

DOI： 10.1111/his.12397

Language：English   Publishing type：Research paper (scientific journal)  

Glucose transporter (GLUT)-1 is expressed in malignant tumors and correlated with poor outcome in several cancers. Biliary intraepithelial neoplasia (BilIN) is considered to be a precursor or a noninvasive lesion of invasive cholangiocarcinoma. We examined GLUT-1 and GLUT-2 expression in 149 intrahepatic cholangiocarcinomas and 39 BilINs immunohistochemically and evaluated their correlation with clinicopathological findings and patient outcome in intrahepatic cholangiocarcinoma. Furthermore, we examined the role of GLUT-1 on migration and invasion of cholangiocarcinoma cells using GLUT-1 siRNA. In intrahepatic cholangiocarcinoma, GLUT-1 expression was frequently observed near the necrotic areas, whereas GLUT-2 expression tended to be observed in adenocarcinoma of large bile ducts. Compared with the GLUT-1-negative group, the GLUT-1-positive group showed significantly larger tumor size (P = .0031), poor differentiation (P < .0001), frequent lymphatic invasion (P = .0031) and lymph node metastasis (P < .0001), and high HIF-1α expression (P = .0297). GLUT-2 expression was significantly correlated with good differentiation (P = .0015), perihilar location (P < .0001), perineural invasion (P = .0049), and lymph node metastasis (P = .0248). The patients with GLUT-1-positive tumors showed poor disease related survival (P < .0001). The numbers of migrating and invading cells were significantly decreased in GLUT-1 siRNA transfectants of cholangiocarcinoma cells. Although, GLUT-1 was expressed in all grades of BilINs, GLUT-2 was expressed only in high-grade BilINs. Our results suggest that GLUT-1 expression correlates aggressive behavior and poor prognosis, and that GLUT-1 might be a therapeutic target of cholangiocarcinoma. GLUT-2 expression may be associated with cholangiocarcinogenesis of large bile duct and is a helpful marker for detecting high-grade BilIN lesions in atypical bile ducts.

DOI： 10.1016/j.humpath.2014.03.008

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: HER2 testing in gastric cancer differs from testing in breast cancer because of inherent differences in tumor biology; gastric cancer more frequently shows HER2 heterogeneity and incomplete membrane staining. The aim of the present study was to evaluate the frequency and accuracy of detection of HER2 expression by application of standard criteria in Japanese patients with gastric cancer. MATERIAL AND METHODS: A total of 198 tumor specimens were assessed for HER2 expression by immunohistochemistry (IHC) using the antibodies HercepTest™ and 4B5. Both hand-operated and automated IHC were performed. RESULTS: HER2 expression differed according to the IHC method and antibodies used. HER2 IHC3+ tumors were identified in 21 (10%) and 7 (3.5%) cases by hand-operated and automated IHC, respectively. CONCLUSION: Among patients with gastric cancer, FISH may be performed in cases of IHC1+ by automated IHC. Further research is required to clarify the relevance of HER2 staining and scoring for the clinical response to HER2-targeted therapy.

Language：English   Publishing type：Research paper (scientific journal)  

Biliary tract carcinoma develops within the intrahepatic or extrahepatic biliary tree and gallbladder. Primary sclerosing cholangitis, hepatolithiasis, congenital choledochal cyst, liver fluke infection, pancreatobiliary maljunction, toxic exposures and hepatitis virus infection are risk factors for the development of human biliary carcinoma. The precise molecular abnormalities of biliary carcinogenesis are still unknown, but chronic inflammatory conditions induce the production of reactive oxygen or nitrogen species leading to DNA damage. Recent studies indicate that cholangiocarcinoma of the large bile duct may arise in premalignant lesions such as biliary intraepithelial neoplasm (BilIN) and intraductal papillary neoplasm of the bile duct (IPNB). BilIN and IPNB are generally confined to the large and septal-sized bile duct. BilINs are occasionally observed in non-biliary liver cirrhosis as well as chronic biliary disease. In contrast, the precursor lesion of intrahepatic cholangiocarcinoma of the small bile duct type remains unclear. We herein demonstrated the histological characteristics of different tumor development pathways from premalignant lesion to carcinoma in different sites of the biliary tree.

DOI： 10.1002/jhbp.71

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: We conducted a phase II trial to evaluate the efficacy and safety of preoperative chemotherapy with docetaxel (DTX) plus S-1 for resectable advanced gastric cancer. PATIENTS AND METHODS: A total of 47 patients from 14 centers were centrally registered. Patients received DTX (35 mg/m(2)) on days 1 and 15, and daily oral administration of S-1 (80 mg/m(2)/day) for days 1-14 every 4 weeks for two courses, followed by gastrectomy with D2 lymphadenectomy. The primary endpoint was pathological response rate (pRR). This study was registered in the UMIN clinical trial registry (UMIN000000875). RESULTS: The primary endpoint pRR was 47 % (90 % confidence interval (CI), 34-60 %; p < 0.0001). The response rate to preoperative chemotherapy using Response Evaluation Criteria in Solid Tumors (RECIST) was 34 %. Forty-six patients (98 %) underwent surgery, and curative resection was performed in 44 patients. Thirty-seven patients completed the protocol treatment. The most common toxicities of neoadjuvant chemotherapy were grade 3/4 neutropenia (42 %), febrile neutropenia (4 %), grade 2 anorexia (21 %), and fatigue (15 %). Treatment-related death and operative mortality was not observed in this study. CONCLUSIONS: The combination of docetaxel and S-1 was well tolerated. This is promising as a preoperative chemotherapy regimen for patients with potentially resectable advanced gastric cancer.

DOI： 10.1245/s10434-014-3594-9

Language：English   Publishing type：Research paper (scientific journal)  

Myofibroblasts in the stroma of pancreatic cancers promote tumor proliferation, invasion and metastasis by increasing extracellular matrix and secretion of several growth factors. In contrast, the role of myofibroblasts at peritoneally disseminated sites of pancreatic cancer has not yet been determined. This study was designed to assess the role of myofibroblasts at peritoneally disseminated sites of pancreatic cancer. Three primary cultures of human peritoneal myofibroblasts (hPMFs) were established from disseminated sites of pancreatic cancer and their interactions with the SUIT-2 and CAPAN-1 human pancreatic cancer cell lines were analyzed in vitro. Using a model in BALB/c nu/nu mice, we compared the dissemination ability of intraperitoneally implanted pancreatic cancer cells, with and without hPMFs, and examined the presence of green fluorescent protein (GFP)-labeled hPMFs at peritoneally disseminated sites in mice. hPMFs significantly promoted the migration and invasion of pancreatic cancer cells (P<0.05), while the cancer cells significantly promoted the migration and invasion of hPMFs (P<0.05). In vivo, the number of peritoneally disseminated nodules, more than 3 mm in size, was significantly greater in mice implanted with cancer cells plus hPMFs compared to mice implanted with cancer cells alone, with GFP-labeled hPMFs surviving in the peritoneal cavity of the former. hPMFs promote the peritoneal dissemination of pancreatic cancer. The cancer-stromal cell interaction in the peritoneal cavity may be a new therapeutic target to prevent the dissemination of pancreatic cancer.

DOI： 10.3892/ijo.2014.2391

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BACKGROUND & AIMS: The microvascular invasion of cancer cells (mvi) is a good prognostic factor after hepatic resection (HR) and liver transplantation for hepatocellular carcinoma (HCC). This study aimed to predict mvi in patients with HCC. METHODS: We studied 63 hepatectomized patients with HCC who had HCC without any extrahepatic metastases and vascular invasion, which were detected during preoperative evaluation. The preoperative clinicopathological data of these patients were analysed to predict presence of mvi. A scoring system was designed using significant risk factors. This system was applied to another series of 34 patients with HCC who underwent HR, and was evaluated for validation. RESULTS: Tumour size, serum des-gamma-carboxy prothrombin (DCP) levels and the maximum standardized uptake value (SUVmax) on 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography were independent clinical predictors for mvi after multivariate analyses. Tumour size, serum DCP levels, and values of SUVmax were used to plot a receiver operating characteristic curve for predicting mvi. Areas under the curve of tumour size, serum DCP levels and SUV max values, were 0.8652, 0.8027 and 0.7848 respectively. Maximal sensitivity and specificity were obtained when the tumour size was 3.6 cm, SUVmax was 4.2, and the serum DCP level was 101 mAU/ml. A scoring system was designed using these three variables. The sensitivity and specificity of our scoring system were 100% and 90.9%, respectively, in the validation test. CONCLUSION: Our scoring system for mvi, consisting of tumour size, serum DCP levels, and SUV max, provides a precise prediction of mvi.

DOI： 10.1111/liv.12459

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: It is difficult to predict the malignant potential of pancreatic neuroendocrine tumors (PNETs) precisely. This study investigated the validity of a new grading system adopted by the World Health Organization 2010 classification to determine risk factors for recurrence of PNETs. METHODS: Data of 70 patients with PNETs who underwent curative resection were retrospectively examined by uni- and multivariate analyses. Histopathological findings were re-reviewed by experienced pathologists. NET G1 was defined as mitotic count <2 per 10 high power fields (HPF) and/or ≤2% Ki67 index, and NET G2 as 2-20 mitosis per 10 HPF and/or 3-20% Ki67 index. RESULTS: There were 58 patients with NET G1 and 12 with NET G2. Incidence of recurrence was 11.4%. Univariate analysis demonstrated significant risk factors for recurrence including NET G2 of histological grade (P = 0.0089), male gender (P = 0.0333), tumor size ≥ 20 mm (P = 0.0117), lymph node metastasis (P = 0.0004), liver metastasis (P < 0.0001), lymphatic invasion (P = 0.046), and neural invasion (P = 0.0002). By multivariate analysis, histological grade (hazard ratio; 59.76, P = 0.0022) and neural invasion (hazard ratio; 147.49, P = 0.0016) were significantly associated with recurrence of PNETs. CONCLUSIONS: This study confirmed the prognostic relevance of the new grading classification and that evaluation of perineural invasion and histological grade should be considered as prognostic predictors in well-differentiated PNETs (NET G1 and G2).

DOI： 10.1002/jhbp.47

Language：English   Publishing type：Research paper (scientific journal)  

The role of tumor-associated macrophages (TAMs) in hepatocellular carcinoma (HCC) has not been fully investigated. The aim of the present study was to clarify whether TAMs are associated with the angiogenesis of HCC during its multistep development, especially at an early stage. Forty‑three well-differentiated HCCs and 30 well- to moderately differentiated HCCs (nodule-in-nodule lesion) were used. We immunohistochemically assessed microvessel density (by CD34) and macrophage count (by CD68 or CD163). Computed tomography hepatic angiography (CTHA) was performed for 26 well-differentiated HCCs and all 30 well- to moderately differentiated HCCs. The pathological analysis of the 43 well-differentiated HCCs revealed a positive correlation between microvessel density and macrophage count (p=0.0026, r=0.4486). Based on the CTHA findings, 26 well-differentiated HCCs classified into a hyperattenuation group (n=14) and a hypo- or isoattenuation group (n=12). The microvessel density and macrophage count of the hyperattenuation group were significantly higher than those of the hypo- or isoattenuation group (p=0.0372 and p=0.0476). In the 30 well- to moderately differentiated HCCs, microvessel density of the moderately differentiated components was significantly higher than that of the well-differentiated components (p<0.0001). However, the macrophage count of the moderately differentiated component was significantly lower than that of the well-differentiated component (p<0.0001). All the moderately differentiated components showed marked hyperattenuation on CTHA. Tumor vascularity was correlated with macrophage count in the tumor when limited to well-differentiated HCCs. TAMs may have a role in promoting angiogenesis of HCC at an early stage during its multistep development.

DOI： 10.3892/or.2014.3138

Language：English   Publishing type：Research paper (scientific journal)  

Hepatoid or α-fetoprotein (AFP)-producing adenocarcinomas of stomach growing in a solid pattern are highly aggressive tumors. It is difficult to detect hepatoid differentiation solely based on findings from hematoxylin and eosin stainings, especially in small biopsy specimens. Gastric adenocarcinomas with hepatoid differentiation should be distinguished from solid-type gastric adenocarcinoma because of their different biological behavior. We immunohistochemically analyzed hepatocellular markers (AFP, glypican 3, and Hepatocyte paraffin 1 [HepPar-1]) and possible markers of gastric hepatoid adenocarcinoma (Sal-like protein 4 [SALL4] and palate, lung, and nasal epithelium carcinoma-associated protein [PLUNC]) to detect hepatoid differentiation in 45 gastric hepatoid adenocarcinomas and 47 nonhepatoid solid-type poorly differentiated adenocarcinomas. There were a higher incidence of vascular invasion (P = .0055) and distant metastasis (P = .0458) in hepatoid adenocarcinoma than in nonhepatoid adenocarcinoma. AFP, SALL4, HepPar-1, and glypican 3 were significantly higher in hepatoid adenocarcinoma than in nonhepatoid adenocarcinoma. All 5 markers were positive in both the hepatoid/solid and the tubular component. In hepatoid adenocarcinoma, the frequency of distant metastasis was significantly higher in SALL4-negative cases than in SALL4-positive cases (P = .0381). HepPar-1 was associated with liver metastasis (P = .0452). PLUNC was correlated with lymph node metastasis (P = .0375). There was a significant difference in the survival rate between HepPar-1-positive and HepPar-1-negative groups (P = .0437). The coexpression of PLUNC and SALL4 and the other coexpression of HepPar-1 and PLUNC were associated with poorer prognosis (P = .0181 and P = .0443, respectively). AFP, SALL4, HepPar-1, and glypican 3 are useful for the detection of hepatoid differentiation. A combination of PLUNC, HepPar-1, and SALL4 could be a reliable prognostic indicator in hepatoid adenocarcinoma of the stomach.

DOI： 10.1016/j.humpath.2014.02.003

Language：Others   Publishing type：Research paper (scientific journal)  

Introduction Few studies to date have investigated the causes of late graft mortality after living-donor liver transplantation (LDLT) for primary biliary cirrhosis (PBC). Patients and Methods Fifty-five LDLTs for PBC were retrospectively reviewed. Factors prognostic of graft survival after LDLT were investigated, and histologic findings in patients with late graft loss were assessed. Results The 1-, 5-, and 10-year cumulative graft survival rates were 85.1%, 82.5%, and 66.9%, respectively. Multivariate Cox regression analysis found that male donor and ≥4 HLA mismatches were independently associated with poor graft survival. Among the 13 grafts lost, 5 were lost >1 year after LDLT, including 1 each due to chronic rejection, veno-occlusive disease, and obliterative portal venopathy, and 2 to other causes. Pathologic reviews of the serial biopsy specimens and explanted grafts from these 5 patients, with graft rejections from "chronic immune-mediated reaction syndrome," showed reciprocal changes over time. No patient died of recurrent PBC. Conclusions Male donor and ≥4 HLA mismatches were independent factors associated with poor graft survival. Late graft mortality after LDLT for PBC in some patients was due to chronic immune-mediated reaction syndrome, including chronic rejection, veno-occlusive disease, and obliterative portal venopathy, but not to recurrent PBC. © 2014 by Elsevier Inc. All rights reserved.

DOI： 10.1016/j.transproceed.2014.02.021

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Metadherin (MTDH) plays functional roles in the tumorigenesis and tumor progression of various cancers. This study investigated the associations between MTDH and the clinicopathological features in primary breast carcinomas to clarify the role of MTDH in the phenotypes and prognosis of breast cancer. METHODS: A total of 195 primary invasive breast cancer samples were evaluated. The MTDH DNA copy number and MTDH mRNA expression were analyzed by quantitative genomic polymerase chain reaction (PCR) and quantitative reverse transcriptase PCR. MTDH protein expression was analyzed by immunohistochemistry. RESULTS: A positive correlation was found between the expression of MTDH protein and mRNA expression and the MTDH DNA copy number. MTDH overexpression was significantly associated with a high nuclear grade, negative estrogen receptor (ER) and progesterone receptor (PR) expression, high Ki67 index, poor disease-free survival (P = 0.0001), poor distant metastasis-free survival (P = 0.009), and poor overall survival (P = 0.0101). MTDH overexpression showed a particularly negative impact on the prognosis in node-negative patients. A multivariate analysis showed MTDH overexpression to be independently associated with a poor disease-free survival rate [HR 3.45, 95 % confidence interval (CI) 1.69-6.84, P = 0.0010] and a poor distant metastasis-free survival rate (HR 2.39, 95 % CI 1.08-5.01, P = 0.0319). CONCLUSION: MTDH overexpression contributes to an aggressive phenotype, thus leading to a poor prognosis for primary invasive breast cancer.

DOI： 10.1007/s12282-012-0398-2

Language：English   Publishing type：Research paper (scientific journal)  

We herein report a case of invasive micropapillary carcinoma (IMPC) involving extensive lymph node metastasis with no recurrence for over 7 years. A 41-year-old female presented with pain and a swelling mass in the left axillary region, which had been present for several months. The tumor measured 1.6 cm in diameter in the middle of upper area of the left breast. Based on the findings of a core needle biopsy the pathological diagnosis was IMPC or mucinous carcinoma. The cytology of the left axillary lymph node was positive for metastatic carcinoma. The patient underwent a left mastectomy and a left axillary dissection (level I to III). The postoperative pathological diagnosis was IMPC with mucin production, and the number of metastatic lymph nodes was 59. The patient was given adjuvant chemotherapy (four courses of 5-fluorouracil, epirubicin and cyclophosphamide (FEC) and four courses of docetaxel), radiation for the left chest wall, supraclavicular and internal thoracic area, and then received tamoxifen for 5 years. The patient has remained recurrence-free for over 7 years. IMPC is known to be an aggressive histological type associated with a high incidence of lymph node metastasis and a poor prognosis. It seems that long-term survival was obtained by performing sufficient medical treatment. Prognostic factors other than the number of lymph node metastases may also exist.

DOI： 10.1186/1477-7819-12-84

Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: Interferon-induced graft dysfunction (IGD) is a poorly defined, unrecognized, but potentially serious condition for patients receiving antiviral drugs after liver transplantation for hepatitis C. METHODS: We evaluated the characteristics of 80 patients who received pegylated interferon-based antiviral treatment for hepatitis C after living donor liver transplantation (LDLT). RESULTS: Eight patients experienced IGD either during (n = 6) or after completing (n = 2) antiviral treatment. Pathological diagnosis included acute cellular rejection (ACR, n = 1), plasma cell hepatitis (PCH, n = 2), PCH plus ACR (n = 3), and chronic rejection (CR, n = 2). One patient with CR initially presented with PCH plus ACR and the other presented with ACR; both had apparent cholestasis. The six patients with ACR or PCH without cholestasis were successfully treated by discontinuing antiviral treatment and increasing immunosuppression, including steroids. By contrast, both of the patients with CR and cholestasis experienced graft loss, despite aggressive treatment. Univariate analysis showed that pegylated interferon-α2a-based treatment (75 vs. 26.4 %, p < 0.01) was the only significant factor for IGD, and was associated with decreased 5-year graft survival (93.4 vs. 71.4 %, p = 0.04). CONCLUSIONS: IGD is a serious condition during or even after antiviral treatment for hepatitis C after LDLT. Early recognition, diagnosis, discontinuation of interferon, and introduction of steroid-based treatment may help to save the graft.

DOI： 10.1007/s12072-013-9496-2

Language：English   Publishing type：Research paper (scientific journal)  

To investigate the relationship between oxidative stress and gastric carcinogenesis of poorly differentiated adenocarcinoma in young patients, we analyzed the surgically resected specimens of 22 young patients (21-30 years) and 29 older patients (41-72 years) with intramucosal gastric cancer of the poorly differentiated type. We used immunohistochemical staining to evaluate the expression of 8-hydroxydeoxyguanosine (8OHdG), induced nitric oxide synthetase (iNOS), and antioxidant enzymes (thioredoxin [TRX] and peroxiredoxin [PRDX1, 2 and 3]). We assessed these proteins in the cancer, noncancerous gastric foveolar epithelium and noncancerous mucosal neck. In both the young and older patient groups, the 8OHdG and TRX expressions were gradually increased in cancer cells compared with the noncancerous foveolar epithelial cells and the noncancerous mucosal neck cells (P < 0.001). Although the iNOS and PRDXs expressions were increased in the noncancerous mucosal neck cells compared with the noncancerous foveolar epithelial cells, regardless of age (P < 0.001), the iNOS and PRDX2 expression in the cancer cells were significantly reduced in the young patients compared with the older patients (P < 0.001, P < 0.05). In conclusion, the reduced expression of iNOS or PRDX2 may play an important role in the carcinogenesis of gastric cancer associated with Helicobacter pylori-induced chronic active gastritis in young patients.

DOI： 10.1111/pin.12152

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVES: Aberrant expression of several microRNAs (miRs) has been reported in various neoplasms including intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. MicroRNA-196a (miR-196a) is up-regulated in Barrett esophagus (characterized by intestinal metaplasia) and in colorectal cancer; this relationship between intestinal characteristics and miR-196a might also be applicable to intestinal-type IPMNs. The aim of this study was to evaluate whether intestinal-type IPMNs can be discriminated from non-intestinal-type IPMNs by the expression level of miR-196a in tissue and pancreatic juice samples. METHODS: Thirty-seven formalin-fixed paraffin-embedded tissue samples (including 3 of normal pancreatic ducts) and 36 pancreatic juice samples were obtained. The expression level of miR-196a measured by quantitative reverse transcription-polymerase chain reaction assays was compared between intestinal-type and non-intestinal-type IPMNs. RESULTS: MicroRNA-196a expression in intestinal-type IPMN tissue samples (n = 18) was significantly higher than that of non-intestinal-type IPMNs (n = 16) (P < 0.001). Similarly, miR-196a expression in pancreatic juice samples of intestinal-type IPMNs (n = 6) was significantly higher than that of non-intestinal-type IPMNs (n = 30) (P = 0.008), and the sensitivity and specificity for prediction of intestinal-type IPMNs using pancreatic juice samples were both 83%. CONCLUSIONS: Elevated expression of miR-196a in pancreatic juice samples is predictive of intestinal-type IPMNs.

DOI： 10.1097/MPA.0000000000000042

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND AND STUDY AIMS. Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis compared with other solid pancreatic tumors. Diagnosis of PDAC in the earliest possible stage is important to improve the prognosis. Although endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) has been the gold-standard modality for diagnosing pancreatic lesions, its diagnostic yield is not satisfactory for pancreatic tumors smaller than 20 mm. The purpose of this study was to determine the EUS findings that are useful for differentiating PDAC from other solid pancreatic tumors when the lesions are smaller than 20 mm. PATIENTS AND METHODS. We performed a retrospective review of 126 patients with pancreatic tumors smaller than 20 mm who had undergone EUS. According to the final pathological diagnoses, they were categorized into either the PDAC or non-PDAC group. We, then, compared the EUS findings between the two groups. RESULTS. Among the 126 patients, we diagnosed PDAC in 75 patients and non-PDAC in the remaining patients, including neuroendocrine tumor in 43 patients, intraductal papillary mucinous carcinoma in 3 patients, solid pseudopapillary neoplasm in 2 patients, and inflammatory pseudotumor in 3 patients. Of all EUS findings, three factors were significantly indicative of PDAC: an irregular tumor edge, main pancreatic duct dilation, and tumor location in the pancreatic head. The predicted probability for PDAC was 80%, 92.6%, and 74.1%, respectively. CONCLUSIONS. EUS could be a useful modality for differentiating PDAC from other solid pancreatic tumors, when the diagnostic yield of EUS-FNA is unsatisfactory, even for lesions smaller than 20 mm.

DOI： 10.3109/00365521.2013.878745

Language：English   Publishing type：Research paper (scientific journal)  

We herein present a 71-year-old man who underwent pancreatoduodenectomy with the diagnosis of follicular pancreatitis. We could not completely deny malignancy by a preoperative imaging study. Endoscopic ultrasonography-guided fine needle aspiration biopsy demonstrated clusters of benign acinar cells and no proliferation of atypical lymphoid cells or rich plasma cells. Histologically, the prominent lymphoid follicle formation was seen in an ill-defined mass, 15 mm in size, in the pancreatic parenchyma. Duct-centered fibrotic rims were seen in the pancreatic ducts accompanied by mild fibrotic change between the follicles and obliterative phlebitis. No neoplastic epithelial cells were observed in the resected specimen, and infiltrating lymphocytes did not show any morphological atypia and monoclonal proliferation by immunohistochemical staining with B and T cell markers. In addition, we could exclude IgG4-related disease, because plasmacytic cells were rarely positive for IgG4. Although follicular pancreatitis is rare, this mass-forming inflammatory disease (pancreatitis) should be included in the preoperative differential diagnosis of pancreatic cancer.

DOI： 10.1016/j.prp.2013.09.005

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVES: To clarify the recurrence pattern after resection of main duct intraductal papillary mucinous neoplasms (MD-IPMNs) using molecular analyses and determine the most adequate treatment strategy. BACKGROUND: The most appropriate resection line for MD-IPMNs remains an unresolved issue. METHODS: Medical records of 56 patients with pancreatectomy were retrospectively reviewed. Histological subtypes and Kras/GNAS mutations were assessed in patients with recurrence in the remnant pancreas. RESULTS: Forty-nine patients underwent partial pancreatectomy and 7 underwent total pancreatectomy. Thirty-six patients (64%) had malignant MD-IPMNs. Recurrence was observed in 7 of 49 patients (14%), including 6 with malignant IPMNs and 1 with pancreatic ductal adenocarcinoma, all of whom underwent remnant pancreatectomy. The cumulative disease-specific survival rate of patients with pancreatic recurrence was greater than that of patients with extrapancreatic recurrence (P < 0.001). Although the pancreatic margin status at the initial operation did not affect the pancreatic recurrence rate, all 4 recurrent IPMNs examined had histological subtypes and Kras/GNAS mutations identical to those of the initial lesions. Four patients experienced recurrence in the remnant pancreas or systemic recurrence after resection of high-grade dysplasia of MD-IPMN. Three of the 56 patients had concomitant pancreatic ductal adenocarcinomas and MD-IPMNs. CONCLUSIONS: One-step total pancreatectomy can be avoided, and remnant total pancreatectomy would lead to favorable outcomes even in patients with pancreatic recurrence, some cases of which seem to involve residual lesions. Postoperative surveillance of high-grade dysplasia should be performed as if malignant, and close attention should be paid to the occurrence of concomitant pancreatic ductal adenocarcinomas in patients with MD-IPMNs.

DOI： 10.1097/SLA.0b013e3182a690ff

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVES: Glucagon-like peptide 1 (GLP-1) interacts with its specific high-affinity receptor, glucagon-like peptide 1 receptor (GLP-1R), and induces cellular growth and inhibition of apoptosis in pancreatic β cells. The aim of this study was to investigate the significance of GLP-1R expression in pancreatic neuroendocrine tumors (PNETs). METHODS: Glucagon-like peptide 1 receptor expression was semiquantitatively evaluated by immunohistochemical staining in 50 resected PNETs, and the correlation between the GLP-1R expression and clinicopathologic features was investigated. RESULTS: There were 23 PNETs with positive expression and 27 PNETs with negative expression of GLP-1R. Positive expression of GLP-1R was more frequently observed in insulinoma than in gastrinoma and nonfunctioning tumor (P < 0.05). Although expression status of GLP-1R did not affect the prognosis of the patients with PNETs (P = 0.82), most of the metastatic sites such as lymph node and liver showed positive staining for GLP-1R (8 of 11 PNETs, 73%). CONCLUSIONS: Glucagon-like peptide 1 receptor would be a diagnostic marker of insulinoma and might become a molecular target for treatment of metastatic PNETs and hormonal regulation of insulin.

DOI： 10.1097/MPA.0b013e3182a71537

Language：English   Publishing type：Research paper (scientific journal)  

Frozen human tissues are necessary for research purposes, but tissue banking methods have not changed for more than a decade. Many institutions use cryovial tubes or plastic molds with an optimal cutting temperature compound. However, these methods are associated with several problems, such as samples sticking to one another and the need for a larger storing space. We established an efficient tissue freezing and storing procedure ("tissue tablet method") applicable to both molecular analysis and frozen tissue microarray. Tissue samples were chopped into tiny fragments and embedded into tablet-shaped frozen optimal cutting temperature compound using our original tissue-freezing plate. These tablets can be sectioned and stored in cryovial tubes. We compared the tissue quality of tablet-shaped samples with that of conventional optimal cutting temperature blocks and found no significant difference between them. Tissue microarray is a key method to utilize tissue-banking specimens. However, most tissue microarrays require the coring out of cylindrically shaped tissues from formalin-fixed, paraffin-embedded tissue blocks. Antigenic changes and mRNA degradation are frequently observed with formalin-fixed, paraffin-embedded samples. Therefore, we have applied tablet-shaped samples to construct frozen tissue microarrays with our original mounting base. Constructed tissue microarray sections showed good morphology without obvious artifact and good immunohistochemistry and in situ hybridization results. These results suggest that the quality of arrayed samples was sufficiently appropriate for research purposes. In conclusion, the tissue tablet method and frozen tissue microarray procedure can save time, provides easy tissue handling and processing, and satisfies the demands of research methodologies and tissue banking.

DOI： 10.1016/j.humpath.2013.08.013

Language：English   Publishing type：Research paper (scientific journal)  

We herein present the case of a 77-year-old man who had fever and right hypochondriac pain. He visited his doctor and underwent contrast computed tomography (CT), and he was suspected to have a liver abscess. He received an antibiotic treatment and his symptoms soon disappeared, but the tumor did not get smaller and its density on contrast CT image got stronger. He underwent biopsy and moderately differentiated hepatocellular carcinoma (HCC) was found. Extended left hepatic and caudate lobectomy was performed. Histological examination showed moderately differentiated HCC with narrowing and occlusion both in the arteries and portal veins associated with mild chronic inflammation. The mechanisms of spontaneous regression of HCC, such as immunological reactions and tumor hypoxia, have been proposed. In our case, histological examination showed the same findings. However, the mechanism is complex, and therefore further investigations are essential to elucidate it.

DOI： 10.1159/000362440

Language：English   Publishing type：Research paper (scientific journal)  

Flat epithelial lesions of the biliary tract cannot be detected by the image analysis, and the diagnosis entirely depends on pathological examination. The biliary tract is often affected by inflammatory conditions, and the resultant changes of the biliary epithelium make it difficult to differentiate them from neoplasia. Thus, the pathological diagnosis of biliary flat epithelial lesions can be challenging. In the biliary tract, there are several forms of intraepithelial neoplasia of the flat type, and biliary intraepithelial neoplasia (BilIN) is known as one of such lesions that represent the multistep cholangiocarcinogenesis. In this article, the diagnostic criteria and the differential diagnosis of biliary flat epithelial lesions, particularly focusing on BilIN, were presented and discussed to provide help to advance clinical and research applications of the BilIN system.

DOI： 10.1007/s00535-013-0810-5

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Patients with intraductal papillary mucinous neoplasm (IPMN) of the pancreas may have concomitant distinct pancreatic ductal adenocarcinoma (PDAC). We evaluated the safety and usefulness of intraoperative irrigation cytology of the remnant pancreas (IICP) during pancreatectomy to detect remnant distinct PDAC in patients with IPMN. METHODS: The records of all 48 patients with IPMN who underwent IICP during partial pancreatectomy at our institution from April 2007 to March 2012 were reviewed retrospectively. After division of the pancreas, a 4-French tube was inserted into the main pancreatic duct of the remnant pancreas from the cut edge, and fluid for cytologic examination was obtained by saline irrigation through the tube. If the third IICP was positive, patients underwent additional pancreatic resection. Clinical and pathologic outcomes were evaluated. RESULTS: The third IICP was positive in 5 patients. Postoperative pathologic examination showed that these patients all had remnant distinct PDAC in the additionally resected specimen, which was not detectable on preoperative imaging examination or on intraoperative macroscopic examination, ultrasonography, or palpation. This PDAC was stage 0 in 4 patients and stage III in 1 patient. No procedure-related complications were observed. One patient developed peritoneal metastasis after 10 months, 1 developed liver metastasis after 20 months, and 1 developed PDAC in the remnant pancreas after 24 months. CONCLUSION: IICP seems to be a safe and useful method for detection of early stage PDAC concomitant with IPMN that cannot be detected by preoperative imaging or intraoperative examination.

DOI： 10.1016/j.surg.2013.06.059

Language：English   Publishing type：Research paper (scientific journal)  

We evaluated the expression of the androgen receptor (AR) to determine its significance in breast cancer. AR expression levels were analyzed in 250 invasive breast cancers by immunohistochemistry and any association with the clinicopathological features was evaluated. AR expression was higher in estrogen receptor (ER)-positive cases than in ER-negative cases (P < 0.0001). AR expression was associated with ER level, and it increased with age in ER-positive cases. The cut-off value was determined to be 75% (Cancer Res. 2009;69:6131-6140), and AR expression was considered to be high in 155 (62%) cases. High AR expression significantly correlated with lower nuclear grade (P < 0.0001), ER and progesterone receptor (PR) positivity (P < 0.0001 and P = 0.0022), HER2 negativity (P = 0.0113), lower Ki67 index (P < 0.0001) and a longer disease-free survival (DFS) and distant metastasis-free survival (DMFS) (P = 0.0003 and 0.0107). This association between a high AR expression and a good DFS and DMFS was significant for ER-positive tumors (P < 0.0001 and P = 0.0018); however, no association existed between AR expression and prognosis for ER-negative tumors. In patients ≤51 years old, a high AR expression level significantly correlated with a better prognosis, but this was not significant in patients who were 50 or younger. Multivariate Cox hazard analyses revealed AR expression to be independently associated with a good prognosis in overall patients (HR 0.46, P = 0.0052) and in the ER-positive cohort (HR 0.34, P = 0.0009). AR expression is associated with a less aggressive phenotype and a good prognosis in patients with ER-positive breast cancer. This is considered to be a specific phenomenon for postmenopausal breast cancer patients.

DOI： 10.1002/cam4.138

Language：Japanese   Publishing type：Research paper (scientific journal)  

[A case of portal hypertension after 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) chemotherapy].
A 46-year-old man with cancer of the sigmoid colon with hepatic metastasis underwent sigmoidectomy, partial hepatectomy, and cholecystectomy in May 2008. He subsequently received 10 cycles of a modified 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) regimen as adjuvant chemotherapy from June 2008 to December 2008, following which he developed thrombocytopenia and splenomegaly. In May 2011, upper gastrointestinal endoscopy was performed, which revealed esophageal and gastric varices. The varices were treated endoscopically with ligation and balloon-occluded retrograde transvenous obliteration. A liver biopsy was performed to determine the cause of the portal hypertension in the absence of severe hepatic dysfunction or liver cirrhosis. The biopsy revealed obliteration of the peripheral portal veins with sinusoidal dilatation without fibrosis or inflammatory cell infiltration in the hepatic lobules. Oxaliplatin-based chemotherapy has been associated with hepatovascular injury, such as sinusoidal dilatation and fibrosis, resulting in non-cirrhotic portal hypertension as seen in this case.

DOI： 10.11405/nisshoshi.110.2119, 10.2957/kanzo.61.358_references_DOI_UKRW5UlBD1NDFXslFg78J5YToE0, 10.5833/jjgs.2017.0194_references_DOI_UKRW5UlBD1NDFXslFg78J5YToE0

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Interactions between cancer cells and surrounding cancer-associated fibroblasts (CAFs) play an important role in cancer progression. Invasive ductal carcinoma (IDC) of the pancreas is characterized by abundant fibrous connective tissue called desmoplasia. Podoplanin (PDPN) is a lymphatic vessel marker (D2-40), and expression of PDPN by stromal CAFs has been reported to be a prognostic indicator in various types of cancer. METHODS: Expression of PDPN in pancreatic IDCs was assessed by immunohistochemical examination in 105 patients who underwent pancreatic resection. Primary CAFs were established from pancreatic cancer tissue obtained by surgery. Quantitative reverse transcription-polymerase chain reaction and flow cytometric analysis were performed to investigate PDPN expression in CAFs. We sorted CAFs according to PDPN expression, and analyzed the functional differences between PDPN+ CAFs and PDPN- CAFs using indirect co-culture with pancreatic cancer cell lines. We also investigated the culture conditions to regulate PDPN expression in CAFs. RESULTS: PDPN expression in stromal fibroblasts was associated with lymphatic vessel invasion (P = 0.0461), vascular invasion (P = 0.0101), tumor size ≥ 3 cm (P = 0.0038), histological grade (P = 0.0344), Union for International Cancer Control classification T stage (P = 0.029), and shorter survival time (P < 0.0001). Primary CAFs showed heterogeneous PDPN expression in vitro. Moreover, migration and invasion of pancreatic cancer cell lines (PANC-1 and SUIT-2) were associated with PDPN expression in CAFs (P < 0.01) and expression of CD10, matrix metalloproteinase (MMP) 2, and MMP3. In cultured CAFs, PDPN positivity changed over time under several conditions including co-culture with cancer cells, different culture media, and addition of growth factor. CONCLUSIONS: PDPN-expressing CAFs enhance the progression of pancreatic IDC, and a high ratio of PDPN-expressing CAFs is an independent predictor of poor outcome. Understanding the regulation of the tumor microenvironment is an important step towards developing new therapeutic strategies.

DOI： 10.1186/1476-4598-12-168

Language：English   Publishing type：Research paper (scientific journal)  

Roundabout 1 (Robo1) is a transmembrane receptor of the immunoglobulin family. Slit2 is one of its ligands. The function of Slit2/Robo1 signaling in the development of intrahepatic cholangiocarcinoma (ICC) remains to be elucidated. We examined the immunohistochemical expression of Robo1 and Slit2 and their clinicopathologic implications in 132 cases of ICC. Also, small interfering RNA of Robo1 was transfected into a high-expression ICC cell line, and a Robo1 vector was transfected into a low-Robo1 expression ICC cell line. The effect of Robo1 suppression and overexpression in cell proliferation and migration of cultured ICC cells with Slit2 stimulation was investigated. Immunohistochemical study of ICC in the low-Robo1 expression group showed larger tumors (P = .015), a higher Ki-67 labeling index (P = .021), and low expression of Slit2 (P = .0005). The low-Slit2 expression group frequently showed perineural invasion (P = .036) and lymph node metastases (P = .013). Low Robo1 expression was associated with a poor prognosis (P = .0207). Robo1 suppression in Huh28 cells tended to promote cell proliferation and migration, whereas Robo1 overexpression in RBE cells significantly suppressed cell proliferation and migration. Low Robo1 expression was associated with cell proliferation and migration in ICC and was one of the adverse prognostic factors in patients with these tumors.

DOI： 10.1016/j.humpath.2013.03.022

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVES: CD105 expression correlates with prognosis for several cancers. However, its significance in pancreatic cancer is unclear. METHODS: We analyzed CD105 expression in resected pancreatic cancer tissue and pancreatic cancer cell lines, compared the properties of CD105(+) and CD105(-) cells using quantitative RT-PCR and migration assays, and evaluated the relationship between CD105(+) cells and pancreatic stellate cells (PSCs). RESULTS: Immunohistochemistry showed that the frequency of CD105 expression was higher in pancreatic cancer than that in normal tissue(8% vs 0%, respectively). In flow cytometry, CD105 was expressed in pancreatic cancer cells, whereas weak CD105 expression was detected in normal pancreatic ductal epithelial cells. Quantitative RT-PCR showed that E-cadherin mRNA expression was suppressed and vimentin mRNA was overexpressed in CD105(+) cells (P < 0.05). Migration of CD105(+) cancer cells was strongly enhanced (more than that of CD105(+) cells) in coculture with PSCs (P < 0.05). CD105 expression did not correlate to clinicopathologic characteristics or the Kaplan-Meier survival analysis. CONCLUSIONS: Suppression of an epithelial marker and over expression of a mesenchymal marker suggest that epithelial-mesenchymal transition is induced in CD105(+) pancreatic cancer cells. CD105(+) pancreatic cancer cell migration is strongly enhanced by PSCs, suggesting that these cells play a role in the pancreatic cancer microenvironment.

DOI： 10.1097/MPA.0b013e318293e7bd

Language：English   Publishing type：Research paper (scientific journal)  

Immunoglobulin light chain-associated (AL) amyloidosis is a multisystemic disorder characterized by extracellular deposition of immunoglobulin light chain produced by a proliferative plasma cell clone. Although the liver is the major organ involved in AL amyloidosis, hepatic involvement is often clinically asymptomatic and severe intrahepatic cholestasis as the primary manifestation of the disease is rare. A 60-year-old man with severe jaundice, massive ascites and highly elevated alkaline phosphatase was diagnosed with AL amyloidosis by a transjugular liver biopsy. He had undergone a yearly medical check that showed no abnormalities except for mild elevation of serum γ-glutamyltransferase at 1 year before admission. Owing to his poor condition and rapidly progressive liver and renal dysfunction, neither stem cell transplantation nor a combination of chemotherapeutic agents could be applied, and he died 1.5 months after admission. An autopsy revealed amyloid deposition in the systemic organs, and there was no evidence of multiple myeloma. Continuous elevation of γ-glutamyltransferase may be a useful marker for early diagnosis of fatal hepatic amyloidosis.

DOI： 10.1007/s12328-013-0406-x

Language：English   Publishing type：Research paper (scientific journal)  

Recently, various studies have shown that insulin-like growth factor II messenger RNA-binding protein-3 (IMP3) is a useful diagnostic marker for malignant lesions and a prognostic marker for poor survival in several kinds of tumors. However, the value of IMP3 as a diagnostic and prognostic marker in intraductal papillary mucinous neoplasm (IPMN) of pancreas has been unclear until now. In this study, we examined IMP3 immunohistochemical expression in 190 resection samples and 15 biopsy samples of IPMN and analyzed the value of IMP3 as a diagnostic and prognostic marker. IMP3 expression was recognized in 71.8% (28/39) of IPMNs with high-grade dysplasia and in 81.3% (26/32) of IPMNs with an associated invasive carcinoma (IPMN-IC), but it was not found in any IPMNs with low-grade dysplasia or in IPMNs with intermediate dysplasia. IMP3 expression was significantly higher in cancerous lesions (IPMN with high-grade dysplasia and IPMN-IC) than in noncancerous lesions (IPMN with low-grade dysplasia and IPMN with intermediate-grade dysplasia), with a sensitivity of 76.1% and a specificity of 100% (P < .001). We also identified a significant difference in IMP3 expression between cancerous lesions and noncancerous lesions in biopsy specimens (P = .027). In IPMN-IC, disease-specific survival was significantly shorter in the high-expression group (>50% tumor staining) than in the low-expression group (≤50% tumor staining; P = .0069). In conclusion, our findings show that IMP3 is a useful diagnostic marker for distinguishing between noncancerous and cancerous lesions and is a valuable prognostic biomarker in IPMN.

DOI： 10.1016/j.humpath.2012.12.020

Language：English   Publishing type：Research paper (scientific journal)  

Intraductal papillary mucinous neoplasms (IPMNs) and pancreatic intraepithelial neoplasia (PanINs) are important premalignant lesions of pancreatic cancer. Ezrin is a member of the ezrin, radixin, and moesin protein family and acts as a cross-linker between the plasma membrane and the actin cytoskeleton. We investigated the roles of ezrin during carcinogenesis in IPMN and invasive ductal carcinoma and examined whether ezrin was a prognostic factor. We examined ezrin and phosphorylated ezrin (p-ezrin) expression in 131 IPMNs, 47 PanINs, and 59 invasive ductal carcinomas by immunohistochemical staining. Ezrin and p-ezrin (tyr354) expressions were significantly higher in IPMN with an associated invasive carcinoma, compared with those in IPMN with high-grade dysplasia (P = .03 and P = .0007, respectively). In all grades of PanINs, ezrin and p-ezrin (tyr353) were highly expressed. In patients with invasive ductal carcinoma, the presence of PanIN-2 or PanIN-3 was significantly correlated with positive ezrin and p-ezrin (tyr353) expression of the invasive ductal carcinoma component (P = .01 and P = .0004). The negative p-ezrin (tyr353) expression group of invasive ductal carcinoma showed a significantly worse prognosis than did the positive p-ezrin (tyr353) expression group by survival analysis (P = .04) and was a statistically significant adverse prognostic factor by both univariate and multivariate analyses (P = .048 and P = .015). Ezrin phosphorylation sites differ between the developments of IPMN and PanIN. Although p-ezrin (tyr354) expression in IPMNs is associated with tumor invasion, p-ezrin (tyr353) expression in invasive ductal carcinoma plays an important role not in tumor invasion and metastasis but in the early development of PanINs.

DOI： 10.1016/j.humpath.2012.12.001

Language：Japanese   Publishing type：Research paper (scientific journal)  

[A case of liver metastasis from gastric cancer responding completely to S-1/docetaxel chemotherapy].
A 68-year-old man was introduced to our hospital with right lower abdominal pain. Endoscopic examination and abdominal CT revealed gastric cancer with liver metastasis. We started chemotherapy using S-1(120 mg/body/day), orally administered for 2 weeks followed by a 2-week rest period, and docetaxel(35 mg/m(2)), administered intravenously on day 1 and 15 as 1 course. After 4 courses of chemotherapy, the liver tumor reduced markedly and no new cancerous region was found by examination; therefore total gastrectomy and partial hepatectomy were performed. Histological examination showed an undifferentiated adenocarcinoma remaining as Grade 1b in the resected stomach. A resected specimen of the liver showed necrotic tissue without any cancer cells. This case suggests that S-1/docetaxel chemotherapy may reduce the stage of unresectable liver metastasis from gastric cancer and make a curative operation possible.

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: To clarify the prognostic value of the preoperative blood neutrophil-to-lymphocyte ratio (NLR) in patients undergoing hepatectomy for hepatocellular carcinoma (HCC). BACKGROUND: Although a high NLR has been reported to be a predictor of poor survival in patients with various cancers, it has not been extensively examined in patients with HCC. METHODS: This retrospective study enrolled 958 patients who underwent hepatectomy without preoperative therapy for HCC from 1996 to 2009. Clinicopathological parameters, including NLR, were evaluated to identify predictors of overall and recurrence-free survival after hepatectomy. Univariate and multivariate analyses were performed, using the Cox proportional hazards model. The best cutoff was determined with time-dependent receiver operating characteristic curve. To determine the mechanism of NLR elevation, immunohistological examination using CD163 staining was performed in 150 patients. RESULTS: Univariate and multivariate analyses showed that NLR was an independent prognostic factor in overall and recurrence-free survival. The best cutoff of NLR was 2.81, and 238 of 958 patients (24.8%) had NLR of more than 2.81. The 5-year survival rate after hepatectomy was 72.9% in patients with NLR less than 2.81 and 51.5% in those with NLR 2.81 or more (P < 0.0001). CD163-positive cell counts were significantly higher in tumors in the group with NLR 2.81 or more than in the group with NLR less than 2.81 (P = 0.0004). CONCLUSIONS: Our results show that NLR is an independent predictor of survival after hepatectomy in patients with HCC. Accumulation of tumor-associated macrophages in the tumor is associated with a high NLR.

DOI： 10.1097/SLA.0b013e318297ad6b

Language：English   Publishing type：Research paper (scientific journal)  

Pancreatic hamartoma is a rare tumor, and its characteristic histopathologic features have not yet been fully evaluated. In this study, we collected 9 cases of pancreatic hamartoma to elucidate distinctive histopathologic features that can serve to establish this tumor as a clear disease entity and thus formulate useful histopathologic criteria for this tumor. The cases comprised 4 men and 5 women with a mean age of 62.7 years. The average tumor diameter was 3.3 cm. All patients underwent surgical treatment, and none showed any recurrence postoperatively. Macroscopically, pancreatic hamartomas were well-demarcated tumors with a solid or solid and cystic appearance. Microscopically, these tumors comprised mature acini and small-sized to medium-sized ducts showing a distorted architecture with various amounts of fibrous stroma. Strikingly, the tumors consistently lacked concentric elastic fibers in their duct walls, peripheral nerves, and well-formed islets of Langerhans, all of which exist in both the normal and atrophic pancreas. Immunohistochemically, scattered chromogranin A-positive neuroendocrine cells were observed in the acinar and ductal components. Ductal components were positive for S-100 protein. Spindle-shaped stromal cells expressed CD34 and/or c-kit. These histopathologic features were distinct from those of 5 cases of pancreatic ductal adenocarcinoma, 3 cases of type 1 autoimmune pancreatitis (lymphoplasmacytic sclerosing pancreatitis), 3 cases of alcoholic chronic pancreatitis, and 5 cases of normal pancreas. In conclusion, pancreatic hamartomas share some distinctive histopathologic features and clinical outcomes (neither recurrence nor metastasis) that allow them to be interpreted as malformative lesions. The term "hamartoma" is appropriate for these unique lesions.

DOI： 10.1097/PAS.0b013e318283ce4c

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: To identify a high-risk group of patients with pancreatic ductal adenocarcinoma (PDAC), independently arising in the pancreas with intraductal papillary mucinous neoplasm (IPMN), using histopathologic subtypes. BACKGROUND: Pathologic features of IPMN with distinct PDAC, including histopathologic subtypes of IPMN and PDAC phenotypes, have not been well characterized. Mucin expression patterns and the mutational status of GNAS and KRAS are useful to explore the relationship between these 2 lesion types. METHODS: Clinicopathologic data of 179 resected IPMNs and 180 resected PDACs without IPMNs as a control group were reviewed. IPMNs were classified into 4 grades (low-grade, intermediate-grade, high-grade dysplasia, and an associated invasive carcinoma) and 4 subtypes (gastric, intestinal, pancreatobiliary, and oncocytic). The expression of MUC1, MUC2, MUC5AC, MUC6, and CDX2 was investigated by immunohistochemistry in IPMNs and PDACs with and without IPMNs. The mutational status of GNAS and KRAS was evaluated by cycle sequencing in PDACs and pre-/coexisting IPMNs. RESULTS: Twenty-six synchronous or metachronous PDACs were identified in 20 patients (11.2%) with IPMNs. Occurrence of concomitant PDACs was more frequently observed in gastric-type IPMNs (18/110, 16.4%) compared with intestinal (1/49, 2.0%), pancreatobiliary (1/17, 5.9%), or oncocytic-type (0/3, 0%) (P = 0.047). Both PDACs with and without IPMNs were frequently positive for MUC1, MUC5AC, and MUC6 expression, as assessed by immunohistochemistry, but were negative for MUC2 and CDX2. The mucin-staining patterns were similar to those of invasive tubular adenocarcinoma arising from gastric-type IPMNs. Mutation of GNAS within codon 201 was not detected in PDACs and gastric-type IPMNs, whereas most of these exhibited KRAS mutations. However, the R201H GNAS mutation was detected in 1 intestinal-type IPMN with distinct PDAC. CONCLUSIONS: Mucin expression patterns demonstrate that PDAC without GNAS mutations of an aggressive phenotype frequently arise in the pancreas with benign gastric-type IPMN in the absence of GNAS mutations.

DOI： 10.1097/SLA.0b013e31828cd008

Language：English   Publishing type：Research paper (scientific journal)  

The prognosis of gallbladder cancer (GBC) remains poor despite recent advances in diagnostics and therapeutic strategies. Although the role of microRNAs (miRs) in GBC have not been well documented, miR-155 is known to be associated with inflammation-associated carcinogenesis in various types of cancers. The aim of this study was to investigate the clinical significance of miR-155 expression and the biological functions of miR-155 in GBC. The expression levels of miR-155 in surgically resected GBCs and gallbladders with pancreaticobiliary maljunction (PBM) were assessed by quantitative reverse transcription-polymerase chain reaction. The relationship between the expression levels of miR-155 and clinicopathological features of GBCs was analyzed. Human GBC cell lines were transfected with miR-155 inhibitors or mimics, and the effects on proliferation and invasion were assessed. miR-155 was significantly overexpressed in GBCs when compared with that in gallbladders with PBM (p=0.007) and normal gallbladders (p=0.04). The high expression level of miR-155 in GBCs was significantly associated with the presence of lymph node metastasis (p=0.01) and a poor prognosis (p=0.02). In vitro assays showed that aberrant expression of miR-155 significantly enhanced GBC cell proliferation and invasion. In conclusion, high miR-155 expression correlates with the aggressive behavior of GBCs, and miR-155 may become a prognostic marker and therapeutic target for GBC.

DOI： 10.3892/or.2013.2443

Language：English   Publishing type：Research paper (scientific journal)  

Inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) have been implicated in chronic inflammatory conditions and carcinogenesis. However, little is known about the biological significance of iNOS and COX-2 in cholangiocarcinoma or its precursors or metastatic lesions. We examined iNOS and COX-2 immunohisotochemical expression in 40 biliary intraepithelial neoplasias, 134 primary intrahepatic cholangiocarcinoma cases, and 27 metastatic lymph nodes and analyzed the correlations with grade of atypia of biliary intraepithelial neoplasia, clinicopathological factors and outcomes of intrahepatic cholangiocarcinoma. iNOS and COX-2 expression was highly expressed in reactive epithelium and biliary intraepithelial neoplasia. In intrahepatic cholangiocarcinoma, lymphatic invasion and lymph node metastasis were significantly correlated with negative iNOS expression (P = .0002, P = .0324, respectively) and positive COX-2 expression (P = .0012, P = .0063, respectively). Vascular endothelial growth factor-C expression was associated with COX-2 expression (P = .0053), but not with iNOS expression. COX-2 expression in primary intrahepatic cholangiocarcinoma was higher than that in metastatic lymph nodes (P < .0001). COX-2-positive expression indicated a poor intrahepatic cholangiocarcinoma outcome (P = .0273). This study indicates that iNOS and COX-2 may play roles in carcinogenesis via biliary intraepithelial neoplasia, but play different roles in metastasis of intrahepatic cholangiocarcinoma. COX-2 may participate in a higher lymphatic invasion and metastasis via the vascular endothelial growth factor-C pathway.

DOI： 10.1016/j.humpath.2012.09.004

Language：English   Publishing type：Research paper (scientific journal)  

AIM: Cholestatic hepatitis C is one of the most serious but still unaddressed disorders after liver transplantation. METHODS: In this study, we analyzed 49 patients who underwent living-donor liver transplantation (LDLT) to treat hepatitis C virus (HCV) infection. RESULTS: Five patients developed cholestatic hepatitis C, with total bilirubin of 15.2 ± 3.1 mg/dL at diagnosis 6.2 ± 1.0 weeks after LDLT. Univariate analysis showed that larger graft to standard liver volume ratio, higher HCV RNA titer at 2 weeks, earlier peak HCV RNA titer and cytomegalovirus infection were the significant risk factors. The development of cholestatic hepatitis C was not significantly associated with interleukin-28B genotype (rs8099917); four out of five affected patients had the T/T genotype. Multivariate analysis showed that higher HCV RNA titer at 2 weeks was the only significant factor (P = 0.026) for the development of cholestatic hepatitis C. Receiver-operator curve analysis showed that that HCV RNA titer of more than 7.2 log10 IU/mL was the optimal cut-off for characterizing cholestatic hepatitis C. All of the patients were serum HCV RNA negative after treatment with pegylated interferon and ribavirin and all the patients are alive. CONCLUSION: Early extensive viremia, but not the rs8099917 genotype, was the only predictor for cholestatic hepatitis C after LDLT.

DOI： 10.1111/hepr.12003

Language：English   Publishing type：Research paper (scientific journal)  

AIM: The role of (18) F-fluorodeoxyglucose positron emission tomography (FDG-PET) in the diagnosis and staging of primary liver cancer has been demonstrated in several reports. However, no preoperative evaluations of sarcomatous hepatocellular carcinoma (HCC) and combined hepatocellular and cholangiocarcinoma (cHCC-CC) with FDG-PET have been reported so far. METHODS: Fifty-three HCC patients and three cHCC-CC patients who received liver resection or living-donor liver transplantation were enrolled in this study. All 56 patients had undergone preoperative FDG-PET, and a total of 67 HCC and three cHCC-CC were analyzed histologically. The relationship between clinicopathological features and the maximum standardized uptake value (SUVmax) of tumors were evaluated. RESULTS: The detection rate of HCC by FDG-PET was 43.3 %, and the sensitivity of FDG-PET for the detection of HCC was significantly associated with tumor differentiation, tumor size and microvascular invasion. All three cHCC-CC were detected by FDG-PET. The SUVmax values of the three sarcomatous HCC (SUVmax 14.1, 18.6 and 25.0) and the three cHCC-CC (SUVmax 9.9, 12.0 and 13.0) were higher than that of the poorly differentiated HCC (mean SUVmax 5.7 ± 2.3). CONCLUSION: SUVmax may be a useful diagnostic tool for the preoperative evaluation of the aggressiveness of primary liver cancers such as sarcomatous HCC and cHCC-CC.

DOI： 10.1111/j.1872-034X.2012.01107.x

Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: Triple-negative breast cancer (TNBC), characterized by the absence of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2, is a highly heterogeneous disease. Recent studies suggest that there are links between TNBC and the epithelial-mesenchymal transition (EMT). To identify prognostic biomarkers and novel therapeutic targets, vimentin, one of the most major factors associated with EMT was investigated in TNBC. MATERIALS AND METHODS: Sporadic invasive ductal carcinoma specimens were obtained from 659 Japanese patients, and 90 (14 %) cases were diagnosed as TNBC. The vimentin mRNA and protein expression levels were evaluated by quantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry. RESULTS: The mRNA expression of vimentin was significantly upregulated in the basal-type breast cancer cell line. Immunohistochemically, the vimentin expression was significantly higher (p = 0.0042) in TNBC compared with the other subtypes. Vimentin expression was associated with a younger age (p = 0.016), high nuclear grade (p = 0.023) and high Ki67 expression (p < 0.0001), and a poorer prognosis in terms of both the recurrence-free survival (RFS) (p = 0.0058) and overall survival (OS) (p = 0.013) in TNBC patients. A multivariate analysis showed that vimentin expression was an independent prognostic factor for the RFS (p = 0.043). Vimentin expression was also associated with a significantly shorter RFS (p = 0.021) and OS (p = 0.017) in patients with basal-like breast cancer (BLBC). CONCLUSIONS: The elevated expression of vimentin contributes to the aggressive phenotype and poor prognosis in TNBC. Vimentin expression might be useful as a biomarker for the prognosis of TNBC.

DOI： 10.1007/s00432-013-1376-6

Language：English   Publishing type：Research paper (scientific journal)  

This report describes a rare case of hepatocellular carcinoma (HCC) producing granulocyte colony-stimulating factor (G-CSF). A 46-year-old male with chronic hepatitis B, who presented with fever, general malaise, loss of appetite, and weight loss, had a huge liver mass in the portal region. He had marked granulocytosis and his serum level of G-CSF was elevated. Complete tumor resection was performed, and the pathological assessment of the resected specimen revealed HCC with extensive sarcomatous changes and immunohistochemical staining for G-CSF and G-CSF receptor. Only a few cases of G-CSF-producing HCC have been reported, and this is the first case of G-CSF-producing HCC that also expressed G-CSF receptor.

DOI： 10.1007/s00595-012-0202-0

Language：English   Publishing type：Research paper (scientific journal)  

Kindlin-1 is a novel focal adhesion protein that belongs to the kindlin family. Expression of kindlin-1 has recently been reported in lung and colon cancers, but there have been no studies on its expression in pancreatic cancer. This study aimed to investigate the expression and function of kindlin-1 in pancreatic cancer. Quantitative RT-PCR of Kindlin-1 mRNA was performed in various pancreatic cancer cell lines as well as normal pancreatic epithelial cells and fibroblasts. Immunohistochemical analysis of kindlin-1 was performed for pancreatic cancer tissues. The effects of kindlin-1 on the proliferation, migration and invasion of pancreatic cancer cells were investigated using an RNA interference technique. Kindlin-1 mRNA was highly expressed in the pancreatic cancer cell lines, but only slightly expressed in normal pancreatic epithelial cells and fibroblasts. The Kindlin-1 protein was heterogeneously expressed in the cytoplasm and membrane of pancreatic cancer cells, while normal ductal epithelial cells and stromal cells showed no expression. In vitro experiments involving knockdown of kindlin-1 in AsPC-1 and KP-2 cells revealed that the migratory and invasive abilities of the cells were significantly decreased (P<0.001), while the proliferation abilities were not affected. The present findings suggest that kindlin-1 expression is involved in the progression of pancreatic cancer via enhancement of cell migration and invasion.

DOI： 10.3892/ijo.2013.1838

Language：English   Publishing type：Research paper (scientific journal)  

Gastric carcinoma with lymphoid stroma (GCLS) is a unique variant of gastric carcinoma that represents prominent lymphocytic infiltration and is correlated with Epstein-Barr virus (EBV) infection. Ezrin expression and activation are crucial in tumor metastasis and induce cell migration of EBV-related nasopharyngeal carcinomas. Using immunohistochemical methods, the expression of total and phosphorylated ezrin (p-ezrin), Thr567, was examined in 104 GCLS cases, including 78 EBV-positive and 26 EBV-negative cases, as well as 29 non-GCLS cases. Positive ezrin expression was detected to be at markedly higher levels in GCLS compared to non-GCLS (P<0.0001). Furthermore, ezrin expression was detected to be at higher levels in EBV-positive compared to EBV-negative GCLS (P=0.0294). High expression of p-ezrin in GCLS was associated with positive lymph node metastasis (P=0.0187). In summary, these results demonstrated that ezrin overexpression is correlated with the histologic characteristics of GCLS and EBV infection. Phosphorylation of ezrin may, therefore, contribute to lymph node metastasis in GCLS.

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Intraductal papillary mucinous neoplasm (IPMN) of the pancreas is often found with distinct pancreatic ductal adenocarcinoma (PDAC) in the same pancreas. The aim of this study was to clarify whether endoscopic retrograde pancreatography (ERP) would be useful for the early detection of concomitant PDACs in patients with IPMNs. METHODS: Medical records of 179 patients who were histologically confirmed to have IPMNs after resection between 1987 and 2011 were reviewed. The patients having concomitant PDACs were selected, and the diagnostic abilities to detect concomitant PDACs of computed tomography (CT), magnetic resonance imaging (MRI), endoscopic ultrasonography (EUS), and ERP were compared between early (stages 0-I according to Japanese General Rules for Pancreatic Cancer) and advanced (stages II-IV) PDACs. RESULTS: A total of 23 PDACs developed synchronously or metachronously in 20 patients, and the prevalence of PDACs concomitant with IPMNs was 11.2 % (20/179). Sensitivities of CT (16 vs. 87 %), MRI (29 vs. 93 %), and EUS (29 vs. 92 %) in the early group were significantly lower than those in the advanced group (p < 0.01). On the other hand, the sensitivity of ERP in the early group was as high as that in the advanced group (86 vs. 82 %, respectively, p > 0.99). Among 7 early PDACs, 3 were diagnosed only by ERP. CONCLUSIONS: ERP has an important role in the early diagnosis of distinct PDACs in patients with IPMNs. Further investigation is necessary to clarify the indication and the timing of ERP during management of IPMNs in term of early detection of concomitant PDACs.

DOI： 10.1007/s00534-012-0541-7

Language：English   Publishing type：Research paper (scientific journal)  

The prognosis of patients with hepatocellular carcinoma (HCC) may be improved by novel treatments focusing on the characteristic metabolic changes of this disease. Therefore, we analyzed the biological interactions of metabolic features with the degree of tumor differentiation and the level of malignant potential in 41 patients with completely resectable HCC. The expression levels in resected samples of mRNAs encoded by genes related to tumor metabolism and metastasis were investigated, and the correlation between these expression levels and degrees of differentiation was analyzed. Of the 41 patients, 2 patients had grade I, 27 had grade II, and 12 had grade III tumors. Reductions in the levels of 3-hydroxyacyl-CoA dehydrogenase (HADHA) and acyl-CoA oxidase (ACOX)-2 mRNAs, and increases in pyruvate kinase isoenzyme type M2 (PKM2) mRNA were significantly correlated with the progression of de-differentiation. Analysis of partial correlation coefficients showed that the level of PKM2 mRNA expression was significantly correlated with those of pro-angiogenic genes, vascular endothelial growth factor (VEGF) and ETS-1. Moreover, the levels of VEGF-A and ETS-1 mRNA expression were independently correlated with that of the epithelial-mesenchymal transition (EMT)‑related gene SNAIL. These findings suggest that reductions in fatty acid oxidation and responses to hypoxia may affect the progression of malignant phenotypes in HCC.

DOI： 10.3892/mmr.2012.1201

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: In liver transplantation (LT) for adult biliary atresia (BA), we often encounter a cirrhotic deformation of the native liver. We aimed to investigate a morphological study of the removed livers and the patient's clinical status. METHODS: We examined 8 BA patients who had undergone LT in adulthood at our hospital. The presence of hypertrophic or atrophic areas of the removed liver was recorded macroscopically. We graded the microscopic findings in the porta hepatis area, a hypertrophic area, and an atrophic area, respectively. Moreover, we investigated the relationship between these morphological findings and the pre-transplant clinical status (MELD score). RESULTS: Macroscopically, a hypertrophic area existed in central liver in all cases (8/8 cases), while an atrophic area was existed in peripheral liver (7/8 cases). Microscopically, an atrophic area was the most severely impaired, while the porta hepatis and hypertrophic area were relatively intact. The pathological score in a compensatory hypertrophic area was strongly correlated with the MELD score. CONCLUSIONS: This study suggests that the partial shrinking is not uncommon in BA cirrhotic liver. It may be due to the imbalance of bile drainage by the different segment. The patient's pre-transplant status depends on the compensatory hypertrophic liver.

DOI： 10.1007/s00383-012-3183-6

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVES: Branch duct intraductal papillary mucinous neoplasms of the pancreas (BD-IPMNs) often are composed of multifocal lesions. We aimed to clarify the clinicopathologic features of multifocal BD-IPMNs. METHODS: Medical records of 211 patients with BD-IPMNs (169 solitary and 42 multifocal) were retrospectively analyzed. We compared the pathological grade of resected IPMNs and the resulting clinical course between solitary and multifocal BD-IPMNs. RESULTS: Sixty-nine patients (54 with solitary and 15 with multifocal BD-IPMNs) underwent pancreatectomy, and of these patients, 62 exhibited at least 1 malignant predictor. There was no significant difference in the prevalence of malignancy in the resected BD-IPMNs between the 2 groups. In the remaining 142 patients who exhibited no malignant predictors, both groups demonstrated no differences in morphologic changes of BD-IPMNs. Seventeen distinct ductal carcinomas were identified in both groups, and there was no difference in the prevalence of ductal carcinoma between the 2 groups. Moreover, there was no significant difference in the disease-specific survival rate between the 2 groups. CONCLUSIONS: In patients with multifocal BD-IPMNs, resection is only warranted for lesions that exhibit malignancy predictors; moreover, closer attention to the potential presence or development of distinct ductal carcinoma in patients with multifocal and solitary BD-IPMNs is warranted.

DOI： 10.1097/MPA.0b013e31824b22c6

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND/AIMS: Endoscopic submucosal dissection (ESD) is gaining wider acceptance for the treatment of early gastric carcinoma (EGC) and its indication has been extended to mucosal gastric carcinoma with undifferentiated component in some institutes. Our aims were to confirm the frequency of lymph node metastasis in such cases and clarify the demarcation in indications for ESD. METHODOLOGY: We evaluated medical data of 287 patients with mucosal gastric carcinoma who underwent surgical resection between 1996 and 2008. The tumours were histologically classified into purely differentiated (PD), differentiated-predominant mixed (DPM), undifferentiated-predominant mixed (UPM) and purely undifferentiated (PU) types. RESULTS: Lymph node metastasis was identified in seven (2.4%) of the 287 patients and was detected more frequently in UPM (10%, two of 20) and PU (4%, four of 98), compared with PD (none of 148) (p=0.01 and 0.02, respectively). In mixed-type carcinoma, size was a significant risk factor for lymph node metastasis (p=0.04). CONCLUSIONS: It might be better to select gastrectomy rather than ESD for the treatment of mucosal gastric carcinoma with an undifferentiated component.

DOI： 10.5754/hge10130

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: A dilated orifice of the duodenal papilla found during screening endoscopy or ERCP is well-known as one of the specific findings of intraductal papillary mucinous neoplasm (IPMN). However, its clinical significance is still unclear. OBJECTIVE: To assess the diagnostic significance of a dilated orifice of the duodenal papilla and evaluate whether this could be a factor predictive of malignancy or a subtype of IPMN. DESIGN: Retrospective study. SETTING: University hospital. PATIENTS: This study involved 149 patients who underwent pancreatectomy for IPMN between January 1987 and June 2011. INTERVENTION: ERCP. MAIN OUTCOME MEASUREMENTS: The rate of malignant and intestinal type IPMNs in patients with and without papillary dilation. RESULTS: A dilated orifice of the duodenal papilla was significantly associated with intestinal type IPMN (P < .001), but this finding could not predict the malignant grade of IPMN (P = .13). Multivariate analysis revealed that a dilated orifice was a significant factor for predicting intestinal type in both main duct (P = .01) and branch duct IPMNs (P < .001). LIMITATIONS: The validity of the definition of papillary dilation, selection bias, and a retrospective study. CONCLUSION: A dilated orifice of the duodenal papilla could be a significant factor for predicting intestinal type IPMN. This may lead to better clinical management of patients with IPMN.

DOI： 10.1016/j.gie.2012.03.682

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Frequency and characteristics of metachronous occurrence of multifocal intraductal papillary mucinous neoplasms (IPMNs) or distinct pancreatic ductal adenocarcinomas (PDACs) in the remnant pancreas during follow-up evaluation after pancreatectomy for IPMNs have not been well known. The aim of this study was to investigate the outcomes after resection of IPMNs, especially focusing on the metachronous occurrence of multifocal IPMNs and distinct PDACs. METHODS: Medical records of 172 patients who underwent resection of IPMNs were reviewed retrospectively, and the data regarding the occurrence of metachronous IPMNs or PDACs in the remnant pancreas during a mean postoperative follow-up period of 64 months were collected. RESULTS: The incidence including synchronous and metachronous multifocal occurrence of IPMNs was 20% (34 of 172), and that of distinct PDACs was 9.9% (17 of 172). Ten metachronous IPMNs developed in the remnant pancreas after a mean time of 23 postoperative months (range, 12-84 mo), and 2 with main duct IPMNs (both were carcinoma in situ) required remnant pancreatectomy. Six distinct PDACs developed in the remnant pancreas after a mean time of 84 postoperative months (range, 12-150 mo). Four of them were found to have a tumor with a size of less than 2 cm, whereas the remaining 2 PDACs were found to be unresectable more than 10 years after resection of IPMNs. CONCLUSIONS: Intense long-term follow-up evaluation is necessary for the early detection of metachronous occurrence of distinct PDACs as well as malignant IPMNs after resection of IPMNs.

DOI： 10.1016/j.amjsurg.2011.04.007

Language：Others   Publishing type：Research paper (scientific journal)  

The purpose of this study is to propose a new concept of primary graft dysfunction (PGD) after living donor liver transplantation (LDLT), characterized by delayed functional hyperbilirubinemia (DFH) and a high early graft mortality rate. A total of 210 adult-to-adult LDLT grafts without anatomical, immunological or hepatitis-related issueswere included. All of the grafts with early mortality (n = 13) caused by PGD in LDLT had maximum total bilirubin levels >20 mg/dL after postoperative day 7 (p < 0.001). No other factors, including prothrombin time, ammonia level or ascites output after surgery were associated with early mortality. Thus, DFH of >20 mg/dL for >seven consecutive days occurring after postoperative day 7 (DFH-20) was used to characterize PGD. DFH-20 showed high sensitivity (100%) and specificity (95.4%) for PGD with early mortality. Among the grafts with DFH-20 (n = 22), those with early mortality (n = 13) showed coagulopathy (PTINR > 2), compared with those without mortality (p = 0.002). Pathological findings in the grafts with DFH-20 included hepatocyte ballooning and cholestasis, which were particularly prominent in the centrilobular zone. PGD after LDLT is associated with DFH-20 caused by graft, recipient and surgical factors, and increases the risk of early graft mortality. © Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons.

DOI： 10.1111/j.1600-6143.2012.04052.x

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Because of the rarity and variety of pancreatic neuroendocrine tumors (PNETs), there have been few reports regarding the indication for lymph node dissection in patients with these tumors. This study aimed to evaluate the risk of lymph node metastasis of PNETs based on the tumor size and hormonal production. METHODS: Data for a total of 66 patients who had PNETs resected at our department between 1987 and 2010 were retrospectively studied. The clinicopathological features, including the disease-specific survival rate, were assessed based on the status of lymph node metastasis at the time of initial surgical resection. Then the cut-off point of tumor size to predict lymph node metastasis was estimated. RESULTS: There were 12 patients (18%) with lymph node metastasis. The frequency of lymph node metastasis tended to be higher in gastrinomas than that in other tumors (43 vs. 15%; P = 0.08). The size of PNETs with lymph node metastasis was significantly larger than that of the PNETs without metastasis (P = 0.04). The postoperative survival rate in the PNET patients with lymph node metastasis was significantly lower than that in the patients without metastasis (P < 0.0001). Only 2 (8%) of 26 PNETs with a tumor size of <15 mm had lymph node metastasis, and both of these were gastrinomas. On the other hand, 10 (25%) of the remaining 40 PNETs with a tumor size of ≥15 mm had lymph node metastasis. Notably, there were no PNETs with lymph node metastasis in 22 non-gastrinomas with a tumor size of <15 mm. CONCLUSIONS: Non-gastrinomas with a tumor size of ≥15 mm and all gastrinomas would be an indication for pancreatectomy with lymph node dissection.

DOI： 10.1007/s00535-012-0540-0

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BACKGROUND: Hepatocellular carcinoma (HCC) ≤ 2 cm in diameter is considered to have a low potential for malignancy. METHODS: A retrospective review was undertaken of 149 patients with primary solitary HCC ≤ 2 cm who underwent initial hepatic resection between 1994 and 2010. The independent predictors of the microinvasion (MI) such as portal venous, hepatic vein, or bile duct infiltration and/or intrahepatic metastasis were identified by multivariate analysis. Prognosis of patients with HCC ≤ 2 cm accompanied by MI was compared to that of patients with HCC ≤ 2 cm without MI. RESULTS: Forty-three patients with HCC ≤ 2 cm had MI in patients (28.9%). Three independent predictors of the MI were revealed: invasive gross type (simple nodular type with extranodular growth or confluent multinodular type), des-γ-carboxy prothrombin (DCP) >100 mAU/ml, and poorly differentiated. Disease-free survival rates of patients with HCC ≤ 2 cm with MI (3 year 44%) were significantly worse than those for HCC ≤ 2 cm without MI (3 year 72%). This disadvantage of disease-free survival rate of patients with HCC ≤ 2 cm with MI could be dissolved by hepatic resection with a wide tumor margin of ≥ 5 mm (P = 0.04). CONCLUSIONS: Even in cases of HCC ≤ 2 cm, patients who are suspected of having invasive gross type tumors in preoperative imaging diagnosis or who have a high DCP level (>100 mAU/ml) are at risk for MI. Therefore, in such patients, hepatic resection with a wide tumor margin should be recommended.

DOI： 10.1245/s10434-011-2195-0

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PURPOSE: To elucidate the correlation between hypervascular hepatocellular carcinoma (HCC) enhancement patterns on dynamic MR imaging and histological findings. MATERIALS AND METHODS: Surgically proven 46 hypervascular HCCs of forty-one patients were enrolled. For each HCC, the signal intensity in the portal phase (SIPP) was evaluated. In this study, high, iso-, or low intensity in the portal phase was hypothesized as late, moderate, or early washout pattern, respectively. The SIPP of each HCC was correlated to histological grade and architectural subtypes that represent degrees of trabecular structure. For the trabecular HCCs, the thickness of tumor plate was also correlated for indirect estimation of tumor sinusoid. RESULTS: There was a significant correlation between the SIPP vs. histological grade and also vs. architectural subtypes, namely the degree of trabecular structure. Washout of hypervascular HCC occurred earlier as the histological grade advanced and the histological architecture got closer to pure trabecular HCC. For the trabecular HCCs, the thickness of tumor plate correlated significantly with SIPP or histological grade. Hypervascular HCCs with thicker tumor plates showed worse histological grade and earlier washout pattern. CONCLUSIONS: Histological grade of hypervascular HCC may be predicted using SIPP. The thickness of tumor plate, resultantly the size of sinusoid between tumor plates, can account for the relationship between washout pattern and histological grade in the trabecular HCCs.

DOI： 10.1016/j.ejrad.2011.02.056

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BACKGROUND: Assessing indications for adjuvant chemotherapy (CT) in patients with hormone receptor (HR)-positive/human epidermal receptor 2 (HER2)-negative breast cancer remains a challenge for oncologists. In this study, we evaluated whether forkhead-box protein A1 (FOXA1) expression was a prognostic and predictive marker for HR-positive breast cancer. METHODS: FOXA1 expression was analyzed immunohistochemically in 239 primary breast cancers. Associations between FOXA1 expression and clinicopathological characteristics and prognosis were evaluated. RESULTS: FOXA1 expression was positively correlated with estrogen receptor (ER) (P<0.0001) and progesterone receptor (PR) expression (P=0.0011), and inversely correlated with nuclear grade (P=0.0048) and Ki67 index (P=0.0112). High FOXA1 was associated with longer recurrence-free survival (RFS) in all cases (P<0.0001) and in ER-positive cases (P<0.0001), but not in ER-negative cases. In addition, FOXA1 expression was associated with good prognosis, regardless of the Ki67 index, in HR-positive cases. FOXA1 was an independent prognostic factor on multivariate analysis in all cases and in ER-positive cases. Among HR-positive/HER2-negative cases with high FOXA1 expression, there was no difference in RFS between those given hormone therapy (HT) alone and those given CT plus HT. CONCLUSIONS: In HR-positive breast cancer, FOXA1 expression was significantly associated with good prognosis. FOXA1 expression may be a useful marker for HR-positive/HER2-negative breast cancer to identify patients with good prognosis who may not require CT.

DOI： 10.1245/s10434-011-2094-4

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: International consensus guidelines for the management of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas provide several factors that can be used to predict which IPMNs will become malignant.The sensitivity of each factor's predictive accuracy, however, is relatively low, making it difficult to determine the appropriate treatment in individual cases. The aim of this study was to investigate whether increasing the number of predictive factors might augment the sensitivity of the established guidelines to detect malignant IPMNs. METHODS: The medical records of 138 patients with IPMNs resected at our institution were reviewed. Possible malignant predictors were analyzed by univariate and multivariate analysis, and the effects of the number of factors and the predictive score of the pathologic results were examined. The cutoff points for the number of predictors to discriminate between malignant and nonmalignant IPMNs were established by constructing receiver operating characteristic curves. RESULTS: A predictive analysis could not be carried out for the main duct IPMNs because of the high prevalence of malignancy and the small number of significant predictors associated with them. For malignant branch duct IPMNs, however, we identified 4 predictive factors that helped determine the correct diagnosis as follows: (1) the presence of a cyst ≥30 mm in diameter; (2) the presence of mural nodules; (3) a history of acute pancreatitis; and (4) atypical results of pancreatic juice cytology. An increase in the number of these factors significantly affected the sensitivity to predict malignancy. The area under the curve for the number of predictors for malignant branch duct IPMNs was 0.856, and the sensitivity and specificity were 96% and 71%, respectively, when the cutoff point was set at 2. The predictive scoring system also showed the same values of sensitivity and specificity for the number of factors. CONCLUSION: Patients with branch duct IPMNs who have 2 or more of the 4 predictive factors described above should undergo standard pancreatectomy with lymph node dissection, whereas patients who present with 0 or 1 predictive factor can be treated by minimal pancreatectomy without nodal dissection or by careful observation without resection. All patients with main duct IPMNs, therefore, should be treated with resection as suspected malignancies.

DOI： 10.1016/j.surg.2011.07.009

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PURPOSE: We analyzed the feasibility and safety of our preliminary surgical approach for total hepatic resection of the right hepatic vein drainage area (THR-RHV) with the aid of three-dimensional computed tomography (3D-CT) guidance. METHODS: Clinical findings and 3D-CT volumetry results were investigated in five patients who underwent THR-RHV for a hepatic malignant tumor close to the right hepatic vein (RHV). RESULTS: The mean estimated remnant liver volume after a conventional right lobectomy was 474 ml, whereas that after THR-RHV was 614 ml, indicating that 140 ml (13.8%) of additional liver volume had been preserved by performing THR-RHV. The median operative time, mean ischemic time, and mean blood loss during surgery were 406 min, 51 min, and 587 ml, respectively. Histological examinations confirmed a negative surgical margin in all five patients. The mean liver volume estimated by 3D-CT was 458 ml, whereas the mean actual resected liver volume was 468 g, resulting in a mean error ratio of 3.1%. CONCLUSIONS: THR-RHV allowed for a higher remnant liver volume than that after conventional right lobectomy of the liver, and proved feasible with acceptable perioperative results. This technique thus promotes both safety and curability for patients with a tumor close to the RHV.

DOI： 10.1007/s00595-011-0021-8

Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: The aim of this study was to reveal the relationship between intratumoral uptake of gadoliniumethoxylbenzyldiethylenetriaminepentaacetic acid (Gd-EOB-DTPA) of hepatocellular carcinoma (HCC) in the hepatobiliary phase and pathological features. MATERIALS AND METHODS: Sixty HCC nodules were confirmed at pathology in 56 patients who had undergone dynamic MRI. T1-weighted 3D gradient echo sequences before and 20 min (hepatobiliary phase) after the injection of Gd-EOB-DTPA were performed. Uptake of Gd-EOB-DTPA was defined as an increase in signal intensity in the hepatobiliary phase compared with the precontrast scan. All surgical specimens were fixed with formalin and then digitally photographed. The relationship between Gd-EOB-DTPA uptake and histological findings, including a macroscopic greenish area, was examined. RESULTS: MR images showed uptake of Gd-EOB-DTPA in twenty-two nodules. Histological findings indicated twenty-six nodules contained a greenish area. There is a significant correlation between HCC showing Gd-EOB-DTPA uptake and the presence of a greenish area (p<0.001). On a nodule-by-nodule basis, more than two-thirds of the area of Gd-EOB DTPA uptake coincides with the greenish part in only 12 of 22 lesions (54.5&#37;). More than two-thirds of the greenish area coincided with that of Gd-EOB-DTPA uptake in only 10 of 26 cases (38.5&#37;). CONCLUSION: The area of Gd-EOB-DTPA uptake does not always match the greenish part, but HCC with uptake of Gd-EOB-DTPA significantly correlated with green HCC.

DOI： 10.1016/j.ejrad.2010.10.032

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AIMS: To investigate nuclear atypical in papillary gastric adenocarcinoma (PGA). METHOD AND RESULTS: Hundred cases of PGA were classified into two groups according to nuclear pleomorphism and nuclear polarity; these groups were designated as high nuclear grade and low nuclear grade. Correlations between nuclear grade and clinicopathological features were evaluated for prognostic value. In order to evaluate which types of biological factors influence nuclear atypia, the expression of gastric-type mucin phenotype, p53, HER2 and Ki-67 detected by immunohistochemistry and DNA ploidy detected by laser scanning cytometry. The high nuclear grade group correlated with deeper wall invasion, the presence of lymphatic and venous invasion and the positivity of lymph node metastasis. High nuclear grade was an independent prognostic factor for disease-free survival. Moreover, significant correlations were observed between high nuclear grade and positivity of gastric-type mucin phenotype, p53 and HER2 and DNA aneuploidy. CONCLUSION: Nuclear grade could be a new and useful morphological predictor for high malignant potential in PGA.

DOI： 10.1111/j.1365-2559.2011.04035.x

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AIMS: Hitherto, biliary intraepithelial neoplasia (BilIN) has been described in chronic biliary disease but rarely in non-biliary liver cirrhosis (LC). Intraepithelial neoplasia of the pancreas shows alterations in the expression of cell cycle and mucin core proteins. The aim of this study was to evaluate BilIN and reactive biliary lesions in biliary disease and non-biliary LC. METHODS AND RESULTS: BilIN was found in 51&#37; (33 of 65) of liver tissue cases of biliary disease, and in 11&#37; (34 of 310) of the LC group. Immunohistologically, MUC5AC, an 'early phase' protein, and Ki67, reflecting 'late phase' expression, were identified with increasing degrees of dysplasia in both groups, but that expression was significantly higher in the biliary disease group. 'Early phase' cell cycle proteins, p16 (decrease) and p21 (increase) altered in both biliary and LC groups with increasing degrees of dysplasia. CONCLUSIONS: We found BilIN in the large bile ducts of hepatitis B virus- and hepatitis C virus-related LC as well as in cases related to a biliary aetiology. The LC group was significantly less likely to show changes in the expression of MUC5AC and proliferative activity than the biliary group. Alterations in p16 and p21 reflected increasing degrees of dysplasia in both groups.

DOI： 10.1111/j.1365-2559.2011.04011.x

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BACKGROUND: MicroRNAs (miRNAs) have been gaining attention as new, key molecules that contribute to carcinogenesis. In pancreatic cancer, previous profiling analyses of miRNA expression have shown that several miRNAs are differently expressed in normal and cancerous tissues. Several pancreatic cancer-specific miRNAs differed, however, in each analysis. METHODS: We investigated the miRNA expression profiles of the pancreatic cancer cell lines CAPAN-1 and CFPAC1 and an immortalized human normal pancreatic ductal epithelial cell line (HPDE) using a high-throughput, TaqMan, qRT-PCR array analysis. We also analyzed the expression levels of this miRNA in microdissected (n = 15) and formalin-fixed, paraffin-embedded (FFPE) (n = 115) samples from pancreatic cancers by quantitative RT-PCR. Finally, we investigated the effects of this miRNA on the invasiveness of pancreatic cancer cells. RESULTS: Based on the microarray analysis, miR-372, miR-146a, miR-204, miR-10a, and miR-10b showed particularly large differences (>10-fold changes) between both pancreatic cell lines and HPDE cells. Thirteen of the 15 pancreatic cancer cell lines showed 2.1- to 36.4-fold (median, 15.3-fold) greater levels of miR-10b than HPDE cells. Microdissection analysis revealed that miR-10b exhibited greater expression levels in pancreatic cancer cells (n = 5) than in normal pancreatic ductal cells (n = 10) (P < .020). Analysis of FFPE samples showed that high miR-10b expression was associated with a lesser overall survival (P = .014). Furthermore, miR-10b correlated with the invasiveness of pancreatic cancer cells (P < .01). CONCLUSION: miR-10b is overexpressed in pancreatic cancer and may be involved in the invasiveness in pancreatic cancer cells, thereby leading to a poor prognosis.

DOI： 10.1016/j.surg.2011.06.017

Language：Japanese   Publishing type：Research paper (scientific journal)  

[A case of hepatocellular carcinoma with respiratory failure caused by widespread tumor microemboli].
A 76-year-old man with hepatocellular carcinoma (HCC) was admitted to our hospital suffering from rapidly progressing dyspnea. Chest computed tomography on admission merely showed ground-glass patterns in both lung fields without thrombi in the pulmonary trunk. On the third day, pulmonary blood flow scintigraphy was performed because of progression of his dyspnea, and showed multiple defects indicating widespread thrombi in the peripheral pulmonary arteries. He died of respiratory failure on day 13. A needle necropsy revealed the presence of multiple foci of adenocarcinoma nests in the lungs, suggesting venous thrombi from the poorly differentiated HCC. Although HCC frequently metastasizes to the lung, patients with lung metastasis rarely result in respiratory failure. It is well known that some patients with adenocarcinoma including HCC can develop respiratory failure owing to pulmonary tumor thrombotic microangiopathy (PTTM). In our case, however, pathological examination showed widespread tumor microemboli in the lung, but no stenosis or fibrocellular intimal proliferation in the small arteries and arterioles, which are essential findings of PTTM. Although we concluded that the respiratory failure in this case was mainly caused by widespread tumor microemboli, it remains unclear why such dissemination rapidly developed.

DOI： 10.15017/20445

Language：English   Publishing type：Research paper (scientific journal)  

We report on three cases of cystic neoplasms of the liver with mucinous epithelium. Case 1 showed a low-grade cystic neoplasm with ovarian-like stroma (OS). Case 2 showed a low-grade cystic neoplasm without OS, and case 3 showed a high-grade cystic neoplasm without OS. In all three cases, bile duct communication (BDC) was absent. Currently, pancreatic mucinous cystic neoplasm (MCN) and intraductal papillary mucinous neoplasm of the pancreas (IPMN) are clearly distinguishable. However, MCN of the liver and intraductal papillary neoplasm of the bile duct (IPN-B) are not as easily distinguished. According to the latest WHO classification (2010), these conditions are classed as typical MCN of the liver, MCNs of the liver without OS, or IPN-Bs without BDC. The clinicopathological differences between MCN without OS and IPN-B without BDC are controversial. We present three cases describing these presentations and discuss the difficulties related to the diagnostic criteria used to distinguish between MCN of the liver and IPN-B.

DOI： 10.1016/j.prp.2011.07.006

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Portal venous invasion is one of the most important prognostic factors after surgical resection of hepatocellular carcinoma. Microscopic portal venous invasion can be evaluated histologically. We examined 280 hepatocellular carcinomas with microscopic portal venous invasion (n = 125) or without it (n = 155) for 3 characteristics: the number of invaded portal vessels, the maximum number of invading carcinoma cells, and the farthest distance from the tumor. Univariate analysis of overall and disease-free survival revealed that the number of invaded portal vessels and the number of invading carcinoma cells were poor prognostic factors. Therefore, we classified patients with microscopic portal venous invasion into 2 groups: a high-microscopic portal venous invasion group, in which there were multiple invaded portal venous vessels (≥2) and more than 50 invading carcinoma cells (n = 57), and a low-microscopic portal venous invasion group, in which microscopic portal venous invasion was observed but with invasion of only a single portal venous vessel or fewer than 50 invading carcinoma cells (n = 68). The high-microscopic portal venous invasion group showed significantly higher α-fetoprotein levels, larger tumor size, and higher frequencies of poorly differentiated histology, capsule infiltration, and intrahepatic metastasis compared with the low-microscopic portal venous invasion group (P = .0496, P < .0001, P = .0431, P = .0180, and P = .0012, respectively). The high-microscopic portal venous invasion group showed poorer overall survival and disease-free survival rates than the low-microscopic portal venous invasion group (P = .0004 and P = .0003), and the high-microscopic portal venous invasion group was an independent prognostic factor for disease-free survival (P = .0259). We proposed a new definition for classifying microscopic portal venous invasion and documented the necessity of definite histologic evaluation of it.

DOI： 10.1016/j.humpath.2010.12.016

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: The object of the current study was to review the outcomes of hepatic resection for hepatocellular carcinoma (HCC) ≥ 10 cm. METHODS: Between 1995 and 2007, fifty-three patients with HCC ≥ 10 cm underwent hepatic resection, and clinical data were compared to those of patients with non-surgical treatment (n = 12). Surgical results for HCC ≥ 10 cm were compared to those of patients with HCC < 10 cm (n = 412). The independent poor prognostic factors of the patients with HCC ≥ 10 cm were identified. RESULTS: Overall survival was significantly better in patients with hepatic resection for HCC ≥ 10 cm than in those with non-surgical treatment (P < 0.01). Survival rates of patients with hepatic resection for HCC ≥ 10 cm were 35&#37; at 5 years. Morbidity and mortality rate were statistically equal. The independent poor prognostic factors of patients with hepatic resection for HCC ≥ 10 cm were revealed: T4 status, macroscopic tumor thrombus in portal vein (VP+), and the use of intra-operative transfusion. CONCLUSION: Hepatic resections for HCC ≥ 10 cm are safe and efficacious. Minimizing intra-operative blood loss and the establishment of an effective systemic treatment for patients with HCC ≥ 10 cm in T4 appear to be critical.

DOI： 10.1002/jso.21931

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVES: Although intestinal-type intraductal papillary mucinous carcinoma (IPMC) is reported to have a better prognosis, few studies have addressed its invasive pattern. The meaning of "minimal invasion" (MI) in IPMC also remains unclear. We investigated the prognosis of intraductal papillary mucinous neoplasm (IPMN) focusing on MI and subtypes. METHODS: We evaluated 71 patients with IPMC among a total of 179 patients with resected IPMN. RESULTS: Although 2 of 10 MI-IPMC patients had lymph node metastasis, there were no disease-specific deaths among the MI-IPMC patients. Minimally invasive IPMCs were more frequently observed in intestinal-type IPMC (23/33 cases) than in non-intestinal-type IPMCs (16/38 cases; P = 0.019). Among 32 patients with massively invasive IPMC, the prognosis was significantly better for patients with intestinal-type IPMC than for patients with non-intestinal-type IPMC (P = 0.013). When confined to massively invasive IPMC, tubular invasion (P < 0.001) and lymphatic (P = 0.001) or serosal (P = 0.021) invasion were less frequently observed in intestinal-type IPMC than in non-intestinal-type IPMC. CONCLUSIONS: Invasive carcinoma derived from intestinal-type IPMN is associated with MI, colloid carcinoma, and less invasive behavior.

DOI： 10.1097/MPA.0b013e318214fa86

Language：English   Publishing type：Research paper (scientific journal)  

Dysadherin is a cancer-associated cell membrane glycoprotein that down-regulates E-cadherin and plays important roles in tumor progression and metastasis. Differentiated-type gastric carcinoma can be classified into 2 histologic subtypes according to the presence of poorly differentiated components: a mixed type (differentiated carcinoma with poorly differentiated components) and a pure type (purely differentiated-type adenocarcinoma). We studied the clinicopathologic features of 318 cases of differentiated-type gastric carcinoma with submucosal invasion and evaluated the immunohistochemical expression of dysadherin and E-cadherin. We also evaluated 46 cases of metastatic lymph nodes. Tumors with combined dysadherin-positive (≥50&#37;) expression and E-cadherin-negative (<50&#37;) expression had significantly higher proportions of the moderately differentiated type, deeper submucosal invasion, positivity of lymphatic permeation, and positivity of lymph node metastasis than tumors with other combinations of dysadherin and E-cadherin expression (P = .0009, P = .0015, P = .0273, and P = .0187, respectively). Moreover, the frequency of dysadherin-positive (≥50&#37;) expression was higher in the mixed type (60.3&#37;) than in the pure type (12.4&#37;) (P < .0001), whereas the frequency of E-cadherin-negative (<50&#37;) expression was higher in the mixed type (84.5&#37;) than in the pure type (50.5&#37;) (P < .0001). The frequency of dysadherin expression in the metastatic lymph nodes (80.4&#37;) was significantly higher than that in the primary tumors (45.7&#37;) (P = .001). Dysadherin-positive (≥50&#37;) expression and E-cadherin-negative (<50&#37;) expression may be correlated with the mixed type. Combined dysadherin-positive (≥50&#37;) expression and E-cadherin-negative (<50&#37;) expression may be valuable information for predicting aggressive tumor behavior.

DOI： 10.1016/j.humpath.2010.08.016

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S100P is expressed in several kinds of malignant tumors. Intracellular S100P interacts with ezrin, and extracellular S100P activates the receptor for advanced glycation endproducts. However, little is known about the biological significance of S100P and related proteins in cholangiocarcinoma. Biliary intraepithelial neoplasia (BilIN) is a precursor lesion of hilar or perihilar cholangiocarcinoma. We examined S100P, ezrin, and the receptor for advanced glycation end product expression in 39 BilIN and 110 intrahepatic cholangiocarcinoma (ICC) cases, and analyzed its relationship with clinicopathologic factors and outcomes. S100P expression increased from reactive epithelium to low-grade BilIN to high-grade BilIN. S100P and ezrin expression rates in perihilar-type ICC were higher than those in peripheral-type ICC (P<0.0001, P=0.0008, respectively). S100P nuclear expression in peripheral-type ICC significantly correlated with vascular invasion (P=0.0209), lymphatic invasion (P=0.0003), and lymph node metastasis (P=0.003). S100P and ezrin expression was significantly correlated. S100P-positive and ezrin-positive cases indicate shorter survival in survival analysis of the peripheral type (P=0.001, P=0.0728, respectively). Our results suggest that S100P-ezrin signaling has different roles of carcinogenesis of perihilar ICC and an aggressive course of peripheral ICC.

DOI： 10.1097/PAS.0b013e31820ffdf1

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BACKGROUND: Accurate preoperative imaging is an important aspect of patient evaluation before liver transplantation for hepatocellular carcinoma (HCC) because the size and number of tumors are indicators of posttransplant prognosis. This study aimed to evaluate the preoperative detectability of HCC and clarify the role of preoperative assessment on prognosis after living donor liver transplantation (LDLT). METHODS: Eighty-one patients who underwent LDLT for HCC accompanied by liver cirrhosis were reviewed. A total of 149 nodules were pathologically diagnosed as HCCs. The pathologic findings were correlated with preoperative results from contrast-enhanced computed tomography, magnetic resonance imaging, and computed tomography with angiography. RESULTS: The detectability of small HCCs (<1 cm) and well-differentiated HCCs was significantly reduced. Forty-six of 81 cases were preoperatively judged to meet the Milan criteria, although 16 of these failed to meet the criteria according to postoperative pathologic examination. However, recurrence-free survival in the 16 cases was similar to that in the 30 cases who met the criteria. CONCLUSIONS: The preoperative diagnostic accuracy of radiologic imaging for small-sized, well-differentiated HCCs requires improvement. However, these undetected HCCs have little effect on prognosis after LDLT, and current imaging modalities therefore provide acceptable methods of preoperative LDLT evaluation.

DOI： 10.1097/TP.0b013e318208134e

Language：Others   Publishing type：Research paper (scientific journal)  

Background: The gross classification of hepatocellular carcinoma (HCC) has been reported to be a significant prognostic factor for patients with HCC undergoing partial hepatectomy. The present study investigated whether the gross classification of HCC is also a prognostic factor in living donor-related liver transplantation (LDLT). Methods: Some 119 patients undergoing LDLT for HCC were identified retrospectively from a prospective institutional database containing information on all LDLTs carried out between 1996 and 2009. Patients were divided into three groups according to the gross classification of the largest tumour in the explanted liver: type 1 HCC, single nodular type (81 patients); type 2, single nodular type with extranodular growth (21); and type 3, contiguous multinodular type (17). Clinicopathological factors and recurrence-free survival rates were compared. Results: Recurrence-free survival rates for the whole group were 87·7 per cent at 1 year, 83·5 per cent at 3 years and 81·0 per cent at 5 years after LDLT. Type 3 HCC was associated with large tumour size, poor histological grade, a high incidence of microvascular invasion and multiple tumours. Independent predictors of poor recurrence-free survival were preoperative serum level of des-Î-carboxy prothrombin exceeding 300 mAU/ml, microvascular invasion and type 3 HCC. Conclusion: The gross classification of HCC was an independent predictor for recurrence of HCC in patients undergoing LDLT. Copyright © 2010 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.

DOI： 10.1002/bjs.7311

Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: The aim of the present study was to evaluate the performance of multidetector-row CT (MDCT) and magnetic resonance imaging (MRI) in diagnosing hepatocellular carcinoma (HCC) preoperatively in living related liver transplantation (LRLT) recipients with liver cirrhosis and HCC. MATERIALS AND METHODS: A total of 25 LRLT recipients with 89 pathologically proved HCCs underwent dynamic 4-row MDCT (5 mm collimation) and MRI within 1 month before LRLT. The images were reviewed for the diagnosis of HCC on a tumor-by-tumor basis by three observers independently and randomly using explanted specimens as the gold standard. The diagnostic accuracy of these techniques in the detection of HCC was assessed with alternative free response receiver operating characteristic (ROC) analysis. The sensitivity and positive predictive values were evaluated. RESULTS: The average values of the area under the ROC curve (Az) of MRI images were higher than those obtained with MDCT; however, no significant difference was observed (P > 0.05). The overall sensitivity of HCC with MRI was higher than that with MDCT, especially in the case of HCCs <20 mm. CONCLUSION: A better diagnostic performance regarding HCCs in LRLT recipients was achieved with MRI than with MDCT, although no significant difference was observed.

DOI： 10.1007/s11604-010-0528-8

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A 50-year-old woman was admitted because of abdominal fullness due to bilateral ovarian tumors, pleural effusion, and ascites associated with breast cancer. Although chemotherapy and the removal of ascites were performed periodically, the ascites did not disappear. The cytology of the ascites did not indicate malignancy. Pseudo-Meigs' syndrome caused by metastasis to both ovarian tumors was suspected. The patient underwent a bilateral salpingo-oophorectomy, and the pathological diagnosis was bilateral metastatic ovarian tumors from breast cancer. The ascites and pleural effusion resolved after the surgery, with the consequent improvement of the patient's quality of life; however, she unfortunately died 4 months later due to hepatic failure caused by multiple metastases.

DOI： 10.1007/s00595-009-4187-2

Language：English   Publishing type：Research paper (scientific journal)  

Ovarian mucinous neoplasms of gastro-intestinal type (GI-type) are known to be a heterogeneous tumor composed of benign, borderline and non-invasive and invasive malignant lesions. The presence of infiltrative invasion is also known to be an important prognostic factor of this neoplasm. Laminin γ 2 chain, known to stimulate tumor cell invasion and migration, has not been sufficiently investigated in ovarian mucinous neoplasms. The purpose of this study was thus to clarify the role of laminin γ 2 in ovarian mucinous neoplasms of GI-type. We selected each morphological phase of tumor development from 61 cases of mucinous neoplasms of the GI-type: 55 adenoma lesions, 60 borderline lesions, 20 microinvasive lesions, 17 intraepithelial carcinoma lesions, 38 expansile invasive carcinoma lesions, 19 infiltrative invasive carcinoma lesions and 5 mural nodules lesions; and evaluated the localization of laminin γ 2 in the lesions using immunohistochemical method. The staining pattern was classified into i) basement membranous (BM), ii) cytoplasmic (CYT) and iii) stromal (S) pattern. The BM pattern was characteristic in adenoma, borderline, and interaepithelial and expansile invasive carcinoma lesions. The CYT and S patterns were characteristic in infiltrative invasive lesions. The staining pattern of mural nodules was similar to that of infiltrative invasion. The infiltrative invasion of GI-type ovarian mucinous neoplasms may be promoted by cytoplasmic and/or stromal expression of laminin γ 2 chain.

DOI： 10.3892/or-00001019

Language：English   Publishing type：Research paper (scientific journal)  

Intraductal papillary mucinous neoplasm is characterized by cystically dilated main and/or branch pancreatic duct with mucus. According to the degree of atypia, intraductal papillary mucinous neoplasm is classified into 3 groups: adenoma, borderline, and carcinoma. Furthermore, intraductal papillary mucinous neoplasm is considered to progress through an adenoma-carcinoma sequence like colorectal carcinoma. Programmed cell death 4 is a recently identified tumor suppressor that was found to inhibit translation. Programmed cell death 4 has been reported to inhibit tumorigenesis, tumor progression, proliferation, invasion, and metastasis in several human malignancies. We examined 108 cases of intraductal papillary mucinous neoplasm by immunohistochemistry and revealed that programmed cell death 4 expression was recognized in both the nucleus and cytoplasm in intraductal papillary mucinous neoplasm. The positive rate of programmed cell death 4 was 79&#37;, 43&#37;, and 10&#37; in adenoma, borderline, and carcinoma, respectively. The positive rate of programmed cell death 4 decreased from adenoma to carcinoma (P < .0001, both adenoma versus borderline and borderline versus carcinoma), indicating that programmed cell death 4 might inhibit tumor progression in intraductal papillary mucinous neoplasm. Programmed cell death 4 expression had a strong relationship with p21 expression (P < .0001) and an inverse correlation with Ki-67 labeling index (r = -0.6255, P < .0001). Thus, programmed cell death 4 might inhibit the proliferation of intraductal papillary mucinous neoplasm; and its inhibition might partly result from cell cycle arrest caused by the up-regulation of p21. In conclusion, programmed cell death 4 may inhibit tumor progression in intraductal papillary mucinous neoplasm; and the loss of programmed cell death 4 expression is representative of the malignant potential of intraductal papillary mucinous neoplasm including the proliferative activity. Therefore, programmed cell death 4 can be an important biomarker for intraductal papillary mucinous neoplasm.

DOI： 10.1016/j.humpath.2010.02.019

Language：Japanese   Publishing type：Research paper (scientific journal)  

[A case of subacute necrotizing lymphadenitis with recurrent aseptic meningitis associated with persistent high titer of anti-nuclear antibody occurring over a short period of time].
A 35-year-old woman developed recurrent aseptic meningitis three times over a period of 16 months. Each episode followed swelling of her cervical lymph nodes. During the third episode, microscopic findings of biopsied specimens from a cervical lymph node indicated subacute necrotizing lymphadenitis (SNL). While she responded poorly to NSAIDs, steroids rapidly improved her fever, headache and swollen lymph nodes. Since the first episode, anti-nuclear antibody (ANA) and anti-SS-A antibody was positive and the titer of ANA increased with each episode. SNL is a benign and self-limited disease, and the appearance of autoantibodies is usually transient. It is possible that a persistent immune abnormality is related to recurrences of aseptic meningitis with SNL.

DOI： 10.5692/clinicalneurol.50.728, 10.2169/internalmedicine.6494-20_references_DOI_AwNa6llXZ9j97b8W8s8agGc86kC

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: The aim of this study was to elucidate the predictors of extrahepatic hepatocellular carcinoma (HCC) recurrence after hepatectomy. MATERIALS AND METHODS: A cohort of 252 patients with HCC who underwent hepatectomy following a recurrence were reviewed. The patients were categorized into 2 groups according to the pattern of their initial recurrence. Clinicopathological and survival data were compared between the groups. RESULTS: Of the 252 patients, 218 had intrahepatic recurrence (IHR) (86.5&#37;) and 34 had extrahepatic recurrence (EHR) (13.5&#37;) as their initial recurrence. The mean duration of time until the initial recurrence after hepatectomy of the EHR and IHR groups was 1.8 and 2.2 years, respectively. The rate of recurrence within 6 months after hepatectomy of EHR and IHR groups was 35.3 and 14.2&#37;, respectively (P = .002). The 3-, 5-, and 10-year cumulative survival rates of EHR group were 60.3, 24.0, and 6.0&#37;, respectively, which were significantly lower than that of IHR group (74.5, 57.7, and 23.1&#37;, P = .004). A multivariate analysis showed that blood loss during surgery and microscopic hepatic vein invasion remained as independent risk factors for increased EHR after hepatectomy for HCC. Furthermore, the combination of these 2 independent factors showed a significant association with the EHR. CONCLUSIONS: EHR of HCC was associated with early recurrence and a poor survival after a hepatectomy. The combination of 2 independent factors for EHR, the presence of microscopic hepatic vein invasion and the blood loss during surgery, may be useful for predicting the risk for occurrence of EHR during the follow-up period.

DOI： 10.1245/s10434-010-1076-2

Language：English   Publishing type：Research paper (scientific journal)  

Mallory bodies (MBs) and hyaline globules (HGs) are recognized as hepatocellular cytoplasmic inclusions in liver diseases. We reviewed 123 intrahepatic cholangiocarcinomas (ICCs) and encountered 16 cases (13.0&#37;) in which cancer cells had MB-type inclusions and/or HG-type inclusions, both of which are positive for p62 and ubiquitin. The HG type was present in all 16 cases, and 5 cases contained the MB type. Of 16 patients, 12 had chronic liver disease that was related to alcoholic abuse in 4, hepatitis B surface antigen-positive in 3, and hepatitis C virus antibody-positive in 8. Viral infection and liver cirrhosis were more common in ICCs with p62+ inclusions (P = .0004 and P = .0199, respectively). Of 16 ICCs, 15 with hyaline inclusions had a peripheral tumor location (P = .0052). On ultrastructural examination, the MB type had an electron-dense fibrillar appearance, while the HG type appeared as rounded masses of granular materials. Our results suggest that intracytoplasmic hyaline bodies occasionally can be found in cholangiocarcinoma with chronic liver disease related to viral hepatitis or alcoholic intake.

DOI： 10.1309/AJCP53YVVJCNDZIR

Language：English   Publishing type：Research paper (scientific journal)  

AIM: Cholangiolocellular carcinoma (CoCC) is currently considered to originate from hepatic progenitor cells. The purpose of this study was to evaluate the imaging features of cholangiolocellular carcinoma of the liver. MATERIALS AND METHODS: Five cases of surgically resected cases of CoCC from 4 institutions were retrospectively evaluated. All of the five patients underwent contrast-enhanced dynamic CT. MRI and angio-CT including CT during arterioportography (CTAP) and CT during hepatic arteriography were performed in 3 and 2 patients, respectively. Histological evaluation was also performed and was correlated with radiographic findings. RESULTS: On dynamic CT or MRI, the lesions presented hypervascular tumors with delayed washout in 2 cases and in the other 3 cases, the lesions showed peripheral enhancement with concentric delayed filling. On CTAP, the continued existence of portal veins or tiny spots of portal flow was identified in the tumors. Fibrous capsule or tumor necrosis was not observed. CONCLUSION: CoCC tumors have the dual imaging characteristics of hepatocellular carcinoma and cholangiocarcinoma. The absence of a fibrous capsule, the absence of tumor necrosis, peripheral location within the liver, and the presence of portal venous penetration within the tumor also appear to be characteristic features.

DOI： 10.1016/j.ejrad.2009.09.010

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: The present study was conducted to clarify the pathological factors in patients who underwent surgery for mass-forming type intrahepatic cholangiocarcinoma (IHC). METHODS: From 1982 to July 2004, a total of 60 liver resections for mass-forming type IHC were performed at Kyushu University and its affiliated institutions. Portal venous, lymphatic, hepatic venous, and serosal invasion was examined by univariate and multivariate analyses for their prognostic value. The portal venous (PV) invasion index was defined as follows: PV0, portal venous invasion (-) and intrahepatic metastasis (-); PV1, portal venous invasion (+) or intrahepatic metastasis (+); PV2, portal venous invasion (+) and intrahepatic metastasis (+). The lymphatic invasion (LI) index was defined as follows: LI0, lymphatic duct invasion (-) and lymph node metastasis (-); LI1, intrahepatic lymphatic duct invasion (+) or lymph node metastasis (+); LI2, intrahepatic lymphatic duct invasion (+) and lymph node metastasis (+). RESULTS: In univariate analysis, statistically significant prognostic factors for poor outcome were tumor size (>5 cm), serosal invasion (+), PV1 or PV2, LI1 or LI2, histological grade (moderate and poor), hepatic venous invasion (+) and noncurative resection. After multivariate analysis, the lymphatic invasion index and histological grade were statistically independent prognostic factors for overall survival and recurrence-free survival. CONCLUSIONS: In patients with mass-forming type IHC, lymphatic invasion is the most important invasion pathway, compared with serosal and portal and hepatic venous invasion. Stratification of the lymphatic invasion pathway by lymphatic invasion, including intrahepatic lymphatic duct invasion and lymph node metastasis, is a good predictor for prognosis in patients after hepatectomy for mass-forming type IHC.

DOI： 10.1245/s10434-010-0929-z

Language：English   Publishing type：Research paper (scientific journal)  

Intraductal papillary mucinous neoplasms of the pancreas are subclassified based on morphological features, and different immunohistochemical profiles have been identified in association with the subtypes. We previously reported that S100P was an early developmental marker of pancreatic carcinogenesis and that there was higher S100P expression in intraductal papillary mucinous neoplasms than in normal pancreatic ductal epithelium. However, there have been no reports on novel diagnostic markers to distinguish intraductal papillary mucinous neoplasm from nonneoplastic lesions. Surgical specimens of intraductal papillary mucinous neoplasm obtained from 105 patients were investigated using immunohistochemistry. S100P expression was not detected in normal pancreatic ductal epithelium but was detected in all intraductal papillary mucinous neoplasm cells (100&#37;) with diffuse nuclear or nuclear/cytoplasmic staining. MUC5AC was also expressed in most of the intraductal papillary mucinous neoplasms (102/105; 97&#37;). Furthermore, S100P was clearly expressed in the invasive component of intraductal papillary mucinous neoplasms (32/32; 100&#37;), including perineural and lymphatic and minimal invasion. On the other hand, MUC5AC was expressed in only 23 cases of 32 invasive components (P < .01). These data suggest that the S100P antibody may be a useful marker for detecting all types of intraductal papillary mucinous neoplasms.

DOI： 10.1016/j.humpath.2009.11.007

Language：English   Publishing type：Research paper (scientific journal)  

Extrahepatic bile duct (EBD) carcinoma is a relatively rare neoplasm worldwide, and its prognostic outcome remains unfavorable. Therefore, it is necessary to investigate molecular biologic features of EBD carcinomas. Focal adhesion kinase (FAK) plays a pivotal role in cell adhesion, survival, migration, and signal transduction, but FAK expression in EBD carcinomas has not been evaluated. We measured FAK expression in 76 EBD carcinomas using immunohistochemistry and evaluated its correlation with tumor progression, clinicopathologic factors, and patient outcome. FAK was expressed specifically in the cytoplasm of all normal biliary epithelia (100&#37;). Most dysplastic epithelia also showed positive FAK expression except for 2 cases (92&#37;), whereas EBD carcinomas showed positive FAK expression in 53 (77&#37;) of 76 cases (P < .001, versus normal epithelia). FAK expression tended to be gradually reduced along as dysplasia progressed to carcinoma. Although FAK expression had no association with clinicopathologic factors, the positive FAK expression group showed significantly better survival than the negative FAK expression group (P < .05). However, FAK expression was not an independent prognostic factor by multivariate analysis. In conclusion, FAK expression was significantly lower in EBD carcinomas than in normal biliary epithelia and decreased expression of FAK seemed to be indicative of a poor prognosis, suggesting that FAK might play an inhibitory role for tumor progression in EBD carcinomas. It is important to notice the role of FAK in tumor progression when treatments targeting FAK are performed.

DOI： 10.1016/j.humpath.2009.09.018

Language：English   Publishing type：Research paper (scientific journal)  

Hepatocellular carcinoma develops in a multistep process. Previous studies have revealed changes in blood supply in hepatocellular carcinoma during its carcinogenesis. However, little is known about the relationship between tumor vasculature and the biological behavior of moderately differentiated hepatocellular carcinoma which demonstrates varied degrees of biological behavior. We immunohistochemically assessed intratumoral arterial vessel density (by high-molecular-weight caldesmon and calponin) and microvessel density (by CD34) in 123 cases of moderately differentiated hepatocellular carcinomas, and compared these densities with clinicopathological findings. Arterial vessel density and microvessel density of 19 well-differentiated and 37 poorly differentiated hepatocellular carcinomas were also evaluated. The arterial vessel density of moderately differentiated hepatocellular carcinomas with capsule formation, infiltration to the capsule, portal venous invasion, and high Ki-67 labeling index was lower than that of moderately differentiated hepatocellular carcinomas without these pathological findings (high-molecular-weight caldesmon: P < .0001, P = .0074, P = .0009, P = .0244, calponin: P < .0001, P = .0695, P = .0033, and P = .0155, respectively). The low arterial vessel density group (<10) of moderately differentiated hepatocellular carcinomas tended to show poorer overall survival than the high arterial vessel density group (>or=10) (high-molecular-weight caldesmon: P = .0347, calponin: P = .0404). The arterial vessel density and microvessel density of moderately differentiated hepatocellular carcinomas were significantly higher than those of well-differentiated hepatocellular carcinomas (high-molecular-weight caldesmon: P = .022, calponin: P = .027, CD34: P = .036) and poorly differentiated hepatocellular carcinomas (high-molecular-weight caldesmon, calponin and CD34: P < .0001). The moderately differentiated hepatocellular carcinomas with lower arterial vessel density had more malignant potential than those with higher arterial vessel density. The changes of arterial vessel density in moderately differentiated hepatocellular carcinomas were suggested.

DOI： 10.1016/j.humpath.2009.11.011

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Intraductal papillary mucinous neoplasm (IPMN) of the pancreas is divided into 4 subtypes: an intestinal type, a gastric type, a pancreatobiliary type, and an oncocytic type. The purposes of this study were to clarify the outcomes and the characteristics of invasive carcinoma derived from IPMN (invasive IPMC) by focusing on these subtypes with a comparison to conventional invasive ductal carcinoma (IDC) of the pancreas. METHODS: A total of 30 patients with invasive IPMC were reviewed, and the tumors were divided into 2 pathologic subtypes, intestinal and nonintestinal type. The prognosis and characteristics of the 2 subtypes were evaluated. Furthermore, the prognosis of 119 patients with conventional IDC was compared with that of patients with invasive carcinoma derived from the intestinal or nonintestinal type IPMN. RESULTS: The 5-year survival rate of patients with the nonintestinal type (0.0&#37;) was as poor as that of patients with conventional IDC (19.9&#37;; P = .67). The patients with the intestinal type (66.7&#37;) had a more favorable prognosis than patients with conventional IDC (P < .001). The nonintestinal type was characterized by positive lymphatic invasion and tubular invasive pattern. CONCLUSION: Invasive carcinoma derived from the nonintestinal type IPMN characterized by lymphatic invasion and tubular invasive pattern is associated with a poor prognosis.

DOI： 10.1016/j.surg.2009.11.011

Language：English   Publishing type：Research paper (scientific journal)  

We present a case of a sclerosed hemangioma (SH) of the liver that showed a high apparent diffusion coefficient (ADC) value. The patient was undergoing preoperative evaluation for a metastatic breast cancer lesion when a liver mass with a diameter of 3 cm was found. It was described as a heterogeneously hyperechoic mass on ultrasonography and as a well-defined, lobulated mass with early peripheral enhancement and internal heterogeneous enhancement in the delayed phase on computed tomography. The fat-suppressed T2-weighted images demonstrated a heterogeneously hyperintense mass, which showed an ADC value of 2.01 x 10(-3) mm(2)/s. Liver metastasis and cholangiocellular carcinoma could not be excluded based on the imaging findings. After surgery, a definite diagnosis of SH was obtained. Microscopically, many hyalinized portions with poor cellular and fibrous components were observed in the tumor, and this hyalinization accompanied with liquiform degeneration, which may have been one of the causes of the high ADC value. We discuss the diagnostic value of diffusion-weighted imaging for SH of the liver.

DOI： 10.1007/s11604-009-0407-3

Language：English   Publishing type：Research paper (scientific journal)  

We report the case of a patient demonstrating multiple gastric carcinoids with hypergastrinemia. A 50-year-old Japanese woman was admitted to our hospital for the further examination of multiple carcinoids of the stomach with hypergastrinemia, although she was asymptomatic. However, based on our clinical examination, this case seemed to be neither type I nor II carcinoid. We performed a total gastrectomy with D1 lymph node dissection. A pathological examination showed numerous endocrine micronests, hyperplasia of the parietal cells extending to the foveolar neck region, and numerous dilated oxyntic glands filled with eosinophilic secretions. Many parietal cells exhibited vacuolated cytoplasms and apical snouts. Furthermore, the dilated glands at the base of the mucosa had hyperchromatic nuclei and ciliated surfaces. The postoperative serum gastrin level was soon normalized to 47 pg/ml. This is only the third reported case of multiple gastric carcinoids with hypergastrinemia due to an intrinsic abnormality in the acid secretion of the parietal cells.

DOI： 10.1007/s00595-009-4032-7

Language：English   Publishing type：Research paper (scientific journal)  

Recently the authors proposed a new staging and grading system for primary biliary cirrhosis (PBC) that takes into account necroinflammatory activity and histological heterogeneity. Herein is proposed a convenient version of this system. Scores for fibrosis, bile duct loss, and chronic cholestasis were combined for staging: stage 1, total score of 0; stage 2, score 1-3; stage 3, score 4-6; and stage 4, score 7-9. Cholangitis activity (CA) and hepatitis activity (HA) were graded as CA0-3, and HA0-3, respectively. Analysis of interobserver agreement was then conducted. Digital images of 62 needle liver biopsy specimens of PBC were recorded as virtual slides on DVDs that were sent to 28 pathologists, including five located overseas. All participants were able to apply this version in all 62 cases. For staging, kappa was 0.385 (fair agreement) and the concordance rate was 63.9&#37;. For necroinflammatory activity, the kappa and concordance rate were 0.110 (slight agreement) and 36.9&#37; for CA, and 0.197 (slight agreement) and 47&#37; for HA, respectively. In conclusion, this new staging and grading system for PBC seems to be more convenient and practical than those used at present, but more instruction and guidance are recommended for the grading of necroinflammatory activity in practice.

DOI： 10.1111/j.1440-1827.2009.02500.x

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND AND OBJECTIVES: Fascin is an actin-bundling protein and induces membrane protrusions and cell motility after the formation of lamellipodia or filopodia. Fascin expression has been reported to be associated with progression or prognosis in various neoplasms, but the role of fascin in hepatocellular carcinoma (HCC) remains unknown. The aim of this study was to investigate the clinicopathological and prognostic relevance of fascin by immunohistochemistry. METHODS: A total of 137 patients with HCC were stained with anti-fascin antibody. The tumor cells having unequivocal cytoplasmic and/or membranous fascin immunoreactivity were defined as fascin-positive. RESULTS: Immunohistochemically, 23 (16.8&#37;) HCCs having unequivocal fascin immunoreactivity were found. Tumors showing fascin expression were larger and less differentiated than those showing no fascin expression (P = 0.0239 and 0.0018, respectively). Portal venous invasion, bile duct invasion, and intrahepatic metastasis were detected significantly more frequently in fascin-positive group (P = 0.0029, 0.0333, and 0.0403, respectively). In addition, high alpha-fetoprotein (AFP) levels were significantly associated with the fascin expression in HCC (P = 0.0116). Fascin-positive group had significantly poorer outcomes than fascin-negative group and was an independent prognostic factor for disease-free survival. CONCLUSIONS: Fascin might become a novel marker of progression in HCC and a significant indicator of a poor prognosis for patients with HCC.

DOI： 10.1002/jso.21377

Language：English   Publishing type：Research paper (scientific journal)  

AIMS: To identify the role of CD10 expression of tumour-associated fibroblastic cells in the progression of cholangiocarcinoma (CC). METHODS AND RESULTS: The CD10 expression of fibroblastic cells was investigated immunohistochemically in 167 cases of intrahepatic and extrahepatic CC and 29 cases of biliary dysplasia, comparing the clinicopathological parameters. CD10 expression of fibroblastic cells was observed in 5.7&#37; (4/70) of peripheral intrahepatic CC, 29.2&#37; (14/48) of hilar intrahepatic CC, and 57.1&#37; (28/49) of extrahepatic CC. As for biliary dysplasia, CD10 expression of fibroblastic cells was observed in 4.3&#37; (1/23) in the hepatic hilum and 20&#37; (3/15) in the extrahepatic bile duct. CD10 expression had a strong relationship with the anatomical location of CC, and was more frequently detected in the periductal infiltrating type of hilar intrahepatic CC (P < 0.0001) and in less differentiated cases in extrahepatic CC (P = 0.0151). CD10 expression was observed more frequently in CC than in biliary dysplasia of hepatic hilum (P = 0.0365) and extrahepatic bile duct (P = 0.0262). CD10 expression was not a prognostic indicator in CC. CONCLUSIONS: We suggest that CD10+ fibroblasts are more involved in the progression of hilar and extrahepatic CC than of peripheral intrahepatic CC.

DOI： 10.1111/j.1365-2559.2009.03398.x

Language：English   Publishing type：Research paper (scientific journal)  

Inflammatory pseudotumor (IPT) is a heterogeneous group of lesions occurring in various organs, which is histologically characterized by fibroblastic and myofibroblastic proliferation with inflammatory infiltrate. Inflammatory myofibroblastic tumor (IMT) is a neoplastic counterpart of IPT, which shows aberrant expression of ALK and its gene translocation. In contrast, the concept "immunoglobulin (Ig)G4-related IPT" in the lung, liver, and pancreas has recently been proposed as a member of IgG4-related sclerosing disease. In this study, we compared the histopathologic features with an emphasis on IgG4 expression between 22 cases of IMT and 16 cases of IgG4-related sclerosing disease, including chronic sclerosing sialadenitis (n=8), mass-forming autoimmune pancreatitis (n=3), sclerosing cholangitis (n=1), retroperitoneal fibrosis (n=2), and chronic sclerosing dacryoadenitis (n=2). Bland-looking spindle cell proliferation with fibrosis and inflammatory infiltrate of lymphocytes and plasma cells was the common morphologic feature in both lesions. Obstructive phlebitis was observed in all of the IgG4-related sclerosing lesions, but in only 1/22 (4.5&#37;) of IMT. The immunohistochemical expression of ALK was observed in 15/22 (68.2&#37;) of IMT and 0/16 (0&#37;) of IgG4-related sclerosing disease. The number of IgG4-positive plasma cells and the ratio of IgG4+/ IgG+ plasma cells were each significantly lower in IMT than in IgG4-related sclerosing disease [mean 6.4/HPF vs. 178.3/HPF (P<0.0001), 3.0&#37; vs. 67.5&#37; (P<0.0001), respectively]. The results suggest that IgG4 does not play an important role in the pathogenesis of IMT. In addition, the evaluation of IgG4+ plasma cells and the ratio of IgG4+/IgG+ plasma cells and the presence of obstructive phlebitis may be useful for the differential diagnosis between IMT and IgG4-related sclerosing disease.

DOI： 10.1097/PAS.0b013e3181a5a207

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: A new definition of infiltration to the capsule (fc-inf) has been proposed as a novel marker for predicting the prognosis of 88 patients with hepatocellular carcinoma (HCC). The current aim was to present evidence to develop the fibrous capsule and fc-inf, from the Japanese histological findings for HCC, and to validate their biological significances and predictive power of survival in a large series. METHODS: A total of 365 HCCs were divided into HCCs without the fibrous capsule (NC type; n = 135) and HCCs with the fibrous capsule (FC type; n = 230). Then, FC type was subclassified into two types: extracapsular infiltrating (EC) type (n = 125), in which cancer cells penetrated outside the fibrous capsule, and intracapsular (IC) type (n = 105), in which the infiltrating cancer cells stayed inside the fibrous capsule. RESULTS: The proportion of less histological differentiation and portal venous invasion was higher in FC type than in NC type. The fibrous capsule came to be observed according to the increase of tumor size (P < 0.0001). FC type had significantly poorer outcome for overall survival than NC type (P = 0.0022). EC type showed more intrahepatic metastasis than IC type. The macroscopic subclassifications were significantly affected the presence of fc-inf. EC type had significantly poorer outcome for disease-free survival than IC type (P = 0.0132) and was an independent prognostic factor for disease-free survival (P = 0.0482). CONCLUSIONS: Fc-inf defined as extracapsular penetration was verified to be a novel marker for predicting prognosis, and presence of fc-inf might be predicted by tumor gross features.

DOI： 10.1245/s10434-009-0453-1

Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: LIM domain only 2 (LMO2) has been identified as a novel oncogene associated with carcinogenesis and better prognosis in several malignant tumors. We investigate the involvement of LMO2 in pancreatic cancer. EXPERIMENTAL DESIGN: We evaluated LMO2 expression in cultured cells, bulk tissues, and microdissected cells from pancreatic cancers by quantitative reverse transcription-polymerase chain reaction and immunohistochemistry. RESULTS: Of 164 pancreatic cancers, 98 (60&#37;) were positive for LMO2 expression. LMO2 was more frequently detected in high-grade pancreatic intraepithelial neoplasia (PanIN) lesions (PanIN-2 and -3) than in low-grade PanIN lesions (PanIN-1A and -1B; P < .001) and was not detected in normal pancreatic ductal epithelium. The LMO2 messenger RNA levels were significantly higher in invasive ductal carcinoma cells than in normal pancreatic cells as evaluated by quantitative reverse transcription-polymerase chain reaction analyses of microdissected cells (P = .036). We also found higher incidence of LMO2 expression in histologic grade G1/G2 cancers than in grade G3 cancers (P < .001). The median survival time of LMO2-positive patients was significantly longer than that of LMO2-negative patients (P < .001), and multivariate analyses revealed that high LMO2 expression was an independent predictor of longer survival (risk ratio, 0.432, P < .001). Even among patients with a positive operative margin, LMO2-positive patients had a significant survival benefit compared with LMO2-negative patients. We further performed a large cohort study (n = 113) to examine the LMO2 messenger RNA levels in formalin-fixed paraffin-embedded samples and found similar results. CONCLUSIONS: LMO2 is a promising marker for predicting a better prognosis in pancreatic cancer.

DOI： 10.1593/neo.09418

Language：Others   Publishing type：Research paper (scientific journal)  

DOI： 10.1097/PAS.0b013e31819f584d

Language：English   Publishing type：Research paper (scientific journal)  

AIMS: To assess the relationship between arterial blood supply and the progression of intrahepatic cholangiocarcinoma (ICC). METHODS AND RESULTS: The intratumoral arterial vessel density (AVD) was assessed in 76 cases of mass-forming type of ICC using anti-h-caldesmon antibody, a marker of smooth muscle cells, and AVD compared with pathological findings. AVD was directly correlated with the presence of intratumoral portal tracts (P < 0.0001) and inversely correlated with the grade of tumour necrosis (P = 0.0013). AVD was inversely correlated with vascular invasion and lymph node metastasis (P = 0.0159 and P = 0.0023, respectively). The hilar type of ICC had lower AVD regardless of tumour size, whereas the peripheral type with high AVD showed branching ductular formation composed of cuboidal cells with mild nuclear atypia. AVD was found to be an independent prognostic factor on multivariate survival analysis (P = 0.0013). CONCLUSIONS: This study demonstrates that intratumoral arterial vessels reflect engulfed portal tracts in ICC and decreased arterial vessels indicate aggressive tumour behaviour. Our results could contribute to clinical tumour staging and more effective therapy.

DOI： 10.1111/j.1365-2559.2009.03240.x

Language：English   Publishing type：Research paper (scientific journal)  

Fascin is an actin-bundling protein that induces membrane protrusions and cell motility after the formation of lamellipodia or filopodia. Fascin expression has been associated with progression or prognosis in various neoplasms; however, its role in intrahepatic cholangiocarcinoma is unknown. Tumor sections from 84 patients with intrahepatic cholangiocarcinoma and 16 patients with intrahepatic biliary dysplasia were stained with antifascin antibody. Fascin mRNA expression, measured by real-time reverse transcription-polymerase chain reaction in 20 frozen samples, was compared with the immunohistochemical results. Furthermore, the expression of cyclin D1 was compared with that of fascin. Immunohistochemically, fascin expression was absent or sporadic in normal biliary epithelium, whereas high expression (>70&#37; of tumor cells) was found in 2 (12.5&#37;) dysplasias and 30 (35.7&#37;) intrahepatic cholangiocarcinomas. The difference between the fascin mRNA concentrations in the high-expression and low-expression groups was significant (P = .0082). Tumors showing high expression were poorly differentiated (P = .0019), and among poorly differentiated intrahepatic cholangiocarcinoma, larger tumors (>5 cm) were more likely than smaller lesions to have high fascin expression (P = .0205). A significant correlation was observed between fascin and cyclin D1 immunoreactivity (P = .0289). Patients whose tumors expressed fascin abundantly had a poorer outcome (P = .0085), and fascin overexpression was an independent prognostic factor (P = .0477). Fascin is expressed early in biliary carcinogenesis and might contribute to poor differentiation and to growth of intrahepatic cholangiocarcinoma. It is a significant indicator of a poor prognosis for patients with intrahepatic cholangiocarcinoma.

DOI： 10.1016/j.humpath.2008.06.029

Language：Japanese  

[Histopathology and molecular biological behaviors in human malignant neoplasms].

DOI： 10.15017/13540

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND AND AIM: Transcatheter arterial chemoembolization (TACE) is now the mainstay of treatment for non-curative hepatocellular carcinoma (HCC), and hoped to have chemotherapeutic and ischemic effects; however, the histopathological changes of HCC caused by TACE have not been sufficiently discussed so far. We aimed to assess the morphological and immunohistochemical features of HCC treated with TACE by immunostaining cytokeratin (CK) 7, CK14, CK19 and vimentin, and to correlate these data with observed clinicopathological characteristics. METHODS: Eighty cases of surgically resected HCC with preoperative TACE and 146 cases of HCC resected without TACE as a control were analyzed. RESULTS: The incidences of intrahepatic metastasis, poorly differentiated histology, multinucleated giant cells, mitotic figures and cytoplasmic inclusion bodies in the TACE group were significantly higher than those in the non-TACE group. The TACE group showed reactivity for CK7 in 56.3&#37; (45/80) of patients, CK14 in 12.5&#37; (10/80), CK19 in 23.8&#37; (19/80) and vimentin in 6.3&#37; (5/80) of patients. CK19 expression in the TACE group was significantly higher than in the non-TACE group (P = 0.0423). There was no correlation between immunoreactivity and the number of times TACE was carried out, but the expression of CK19 and vimentin in the massive necrotic group was higher than that in the mild necrotic group (P = 0.0197, P = 0.0229, respectively). Only TACE was an independent determinant of CK19 expression in all cases by multivariate analysis. CONCLUSIONS: These results suggest that preoperative TACE may have an impact on the biliary phenotype of HCC. Some post-therapeutic HCC patients might develop HCC with a biliary phenotype indicating more aggressive malignancies.

DOI： 10.1111/j.1440-1746.2008.05601.x

Language：English   Publishing type：Research paper (scientific journal)  

The fibrous capsule is a unique characteristic of hepatocellular carcinoma (HCC) and acts as a barricade preventing the spread of cancer cells. Infiltration to the capsule (fc-inf) is the invasive feature in HCC; however, there are no reports of a detailed investigation regarding fc-inf. We selected 88 HCCs of <or=5 cm in diameter, when considered together with both the single nodular and the single nodular with extranodular growth types. We classified the infiltrating pattern into 2 types: extracapsular (EC) infiltrating type (n=38), in which cancer cells infiltrated outside the capsule and touched the existing liver parenchyma, and intracapsular (IC) infiltrating type (n=50), in which the infiltrating cancer cells stayed inside the capsule. The distance of infiltration and the capsular thickness were measured and the ratio of capsular infiltration (CI index) was calculated. There were no clinicopathologic differences between the 2 types, but the capsular thickness of IC type was greater than that of EC type (P<0.0001). EC type showed a poorer outcome for the overall survival and the disease-free survival (P=0.0210 and P=0.0115, respectively) and EC type was an independent prognostic factor for a disease-free survival (P=0.0158). However, CI index did not correlate with any clinicopathologic factors or the patient prognosis in IC type. We propose a new definition of fc-inf as a histologic feature of cancer cells penetrating to the liver parenchyma through the fibrous capsule. It may be closely related to the patient prognosis and may therefore, become a new and useful pathologic factor.

DOI： 10.1097/PAS.0b013e31817a8ed5

Language：English   Publishing type：Research paper (scientific journal)  

The major differential diagnostic problem presented by atypical polypoid adenomyofibroma (atypical polypoid adenomyoma) (APA), which usually affects young women, is the exclusion of well-differentiated endometrial carcinoma invading the myometrium. This distinction, however, is of great clinical importance from the standpoint of treatment because reproductive conservation is feasible for patients with APA. Recently, CD10, known to be a marker of endometrial stromal cells, was reported to be also expressed in cells immediately surrounding the neoplastic glands invading the myometrium [Am J Surg Pathol 27 (2003) 786-789; Mod Pathol 16(1) (2003) 22-27]. However, CD10 expression in the myofibromatous component of APA has not been previously examined in the literature. We therefore decided to examine whether the CD10-immunostaining pattern in APA is different from that in myoinvasive carcinoma. Furthermore, we also attempted to obtain any histopathologic findings that may offer some insight regarding the histogenesis of APA. Seven cases of APA were immunostained for CD10 using curettage or polypectomy specimens, in addition to hysterectomy specimens in 1 case. Areas with more fibrotic rather than muscular stroma were focally observed in 4 cases. The pattern of staining was compared with hysterectomy specimens taken from 19 cases in which well- to moderately differentiated endometrioid adenocarcinoma had deeply invaded the myometrium (outer two thirds of the myometrium) but was not associated with adenomyosis. In 6 of 7 cases of APA, CD10 was never expressed in the myofibromatous stromal components. In 1 case of APA, the fascicles of fibrotic and muscular mesenchymal cells in the interglandular areas were focally and weakly positive for CD10. All 19 myoinvasive carcinomas expressed CD10 to some extent in cells immediately surrounding the neoplastic myoinvasive glands (fringe-like staining pattern). The proportion of the myoinvasive nests immediately surrounded by CD10-positive mesenchymal cells was as follows: mean, 74&#37;; median, 80&#37;; minimum, 5&#37;; maximum, 100&#37;. The fringe-like CD10-staining pattern was not observed in APA. Furthermore, we identified a gradual transformation from preexisting endometrial stromal cells (CD10 positive) into the typical myofibromatous stromal component (CD10 negative) of APA in 1 case. In conclusion, this study demonstrated differences in the CD10 immunoreactivity or immunostaining pattern between the stromal components of APA and myoinvasive endometrial carcinoma. This difference should lead to a more accurate diagnosis of APA (pseudo-myoinvasive lesion). Furthermore, the histogenesis of APA may perhaps be explained by "myofibromatous metaplasia" of the endometrial stromal cells.

DOI： 10.1016/j.humpath.2008.02.006

Language：English   Publishing type：Research paper (scientific journal)  

We describe the histopathologic features of 2 cases of biliary neoplasia with extensive intraductal spread arising in liver cirrhosis. The prevalence of this type of biliary neoplasia may be 0.4&#37; from the review of 468 cases of cirrhotic liver. Histologic analysis revealed that the micropapillary proliferation of the atypical biliary epithelium composed of columnar cells with enlarged nuclei diffusely extended superficially from the septal intrahepatic bile duct to the reactive ductules associated with liver cirrhosis. Both cases exhibited prominent fibrous or sclerotic stroma near the biliary lesion. Immunohistochemical analysis revealed a characteristic cytokeratin and mucin expression pattern (CK7++, CK19++, CK20+, MUC1+/-, MUC2-, MUC5AC+, MUC6-). The tumor cytoplasm was focally positive for laminin gamma2 together with linear staining of the basement membrane. Proliferative activity confirmed by Ki67 staining was relatively high. Both patients were disease-free for 3 years after the operation. We believe that the possibility of biliary neoplasia with extensive intraductal spread should be considered to be a variant of biliary intraepithelial neoplasia.

DOI： 10.1016/j.humpath.2007.10.031

Language：Others   Publishing type：Research paper (scientific journal)  

An unusual primary adenomatoid tumour arising in the normal liver is described. Hepatectomy was performed, and the patient is alive and free of disease 1 year postsurgery. Grossly, the tumour showed a haemorrhagic cut surface with numerous microcystic structures. Histological examination revealed cystic or angiomatoid spaces of various sizes lined by cuboidal, low-columnar, or flattened epithelioid cells with vacuolated cytoplasm and round to oval nuclei. The epithelioid cells were entirely supported by proliferated capillaries and arteries together with collagenous stroma. Immunohistochemical studies showed that the epithelioid cells were strongly positive for a broad spectrum of cytokeratins (AE1/AE3, CAM5.2, epithelial membrane antigen and cytokeratin 7) and mesothelial markers (calretinin, Wilms' tumour 1 and D2-40). These cells were negative for Hep par-1, carcinoembryonic antigen, neural cell adhesion molecule, CD34, CD31 and HMB45. Atypically, abundant capillaries were observed; however, the cystic proliferation of epithelioid cells with vacuoles and immunohistochemical profile of the epithelioid element were consistent with hepatic adenomatoid tumour.

DOI： 10.1136/jcp.2007.054684

Language：English   Publishing type：Research paper (scientific journal)  

Lymph node metastasis via lymphatic vessels is related with an adverse outcome in many tumors. It is unclear whether lymphatic spread needs the development of the new lymphatic vessels or the expression of lymphangiogenetic factor in intrahepatic cholangiocarcinoma. The aim of this study was to assess the role of lymphangiogenesis, vascular endothelial growth factor-C (VEGF-C) expression, and D2-40-positive myofibroblastic cells for lymphatic spread and patient outcome in 88 cases of intrahepatic cholangiocarcinoma. We also assessed VEGF-C expression in 15 cases of metastatic lymph nodes. There was a significant correlation between lower lymphatic vessel density in the tumor center and positive lymphatic invasion (P=0.0100). Poorly differentiated cholangiocarcinoma showed higher lymphatic vessel density in the tumor periphery and in the peritumoral area (P=0.0315 and P=0.0360, respectively). Lymphatic invasion was observed higher in the peritumoral area (63&#37;, 24/38) and in the tumor periphery (79&#37;, 30/38) than in the tumor center (27&#37;, 9/38). There was no significant correlation between the proliferative lymphatic vessels and pathologic features; however, lymphatic invasion was significantly associated with VEGF-C expression (P=0.0006), and the VEGF-C expression was seen in 12 of 15 cases (80&#37;) of metastatic lymph node. Nodal metastasis was correlated with D2-40-positive myofibroblasts (P=0.0161). VEGF-C expression was an independent prognostic factor by multivariate survival analysis (P=0.0131). Our findings suggest that VEGF-C has an important role in lymphatic invasion via the preexisting lymphatic vessels in the tumor margin, and that lymphangiogenesis does not play a direct role in lymphatic metastasis. D2-40-positive myofibroblasts may contribute to lymphatic metastasis.

DOI： 10.1038/modpathol.3800985

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: The objective of our study was to clarify the sequential changes of arterial blood supply during the development of hepatocellular carcinoma (HCC) with an emphasis on its late stage. MATERIALS AND METHODS: Sixty HCC nodules were confirmed at pathology in 59 patients who had undergone CT hepatic arteriography and CT during arterioportography (CTAP). Lesions were classified into one of the four groups: group 1, nodules that appeared to show preserved portal perfusion on CTAP and showed hypo- or isoattenuation on CT hepatic arteriography; group 2, very hyperattenuating on CT hepatic arteriography; group 3, hyperattenuating on CT hepatic arteriography; and group 4, hypo- or isoattenuating on CT hepatic arteriography. Groups 2, 3, and 4 showed the portal perfusion defect on CTAP. These hemodynamic patterns were compared among different histologic grades. We also examined the number of unpaired arteries and the Ki-67 labeling index of the tumor pathologically. RESULTS: The numbers of lesions in each group were as follows for groups 1, 2, 3, and 4, respectively: 17, one, two, and 0 well-differentiated HCCs; 0, 10, nine, and one moderately differentiated HCC; and 0, three, 12, and five poorly differentiated HCCs. The lesions showed significantly different hemodynamic patterns among different histologic grades (Cramer's V = 0.6919, p < 0.0001). The number of unpaired arteries showed a strong correlation with Ki-67 labeling index in well-differentiated HCC and moderately differentiated HCC (rho = 0.673, p < 0.0001) and a moderate inverse correlation with Ki-67 labeling index in poorly differentiated HCC (rho = -0.540, p = 0.0185). CONCLUSION: In the late stage of HCC development, the arterial blood supply significantly decreases as the histologic grade progresses.

DOI： 10.2214/AJR.07.2117

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: We have reported that hepatic arterial steroid injection is an effective therapy to rescue patients from fulminant or severe acute hepatic failure. We speculate that a high concentration of steroid suppresses inflammatory processes in the liver directly by restraining activated inflammatory cells, including macrophages. To analyse the detailed mechanism, steroid injection via the portal vein was performed in an experimental model of liver damage. METHODS: Rats subjected to lipopolysaccharide and d-galactosamine injection were treated with a methylprednisolone injection via the tail vein or the portal vein. The survival rate, serum levels of inflammatory cytokines and apoptotic cell counts in the liver were analysed. RESULTS: The survival rate was significantly improved by steroid injection, especially via the portal vein. Serum values of alanine aminotransferase, tumor necrosis factor-alpha and interferon-gamma were reduced in the treated groups, especially the group given portal venous injections. Apoptotic cell counts in the liver were significantly lower in the group injected with steroid via the portal vein. CONCLUSION: In the model rats, high concentrations of steroid in the liver acted on inflammatory cells and suppressed inflammatory cytokines and liver cell death. The mechanism is suggested to be the same for arterial steroid injection therapy in patients with acute hepatic failure.

DOI： 10.1111/j.1478-3231.2007.01590.x

Language：English   Publishing type：Research paper (scientific journal)  

Aquaporin-1 (AQP-1) has been found to be important in bile formation across cell membranes of the biliary epithelium, and thus it has been suggested that AQP-1 is involved in the pathogenesis of hepatobiliary disease. To clarify the role of AQP-1 in the development of intrahepatic cholangiocarcinoma, we determined AQP-1 expression in the normal bile duct, 21 cases of biliary dysplasia, and in 112 cases of intrahepatic cholangiocarcinoma by immunohistochemical analysis. Mucus core protein 5AC expression, a poor prognostic marker of intrahepatic cholangiocarcinoma, was also assessed in intrahepatic cholangiocarcinoma cases. High (>50&#37;) expression of AQP-1 was detected in 16&#37; (9/58) of the normal large bile ducts examined, and in 48&#37; (10/21) of the biliary dysplasia samples originating from large bile ducts. High (>50&#37;), low (<or=50&#37;), and negative AQP-1 expression was observed in 46 (41&#37;), 20 (19&#37;), and 46 (41&#37;) cases of intrahepatic cholangiocarcinoma, respectively. Large tumor size (>40 mm) and poorly differentiated histology were significantly more prevalent in the negative AQP-1 group than in the high AQP-1 group. Low or negative AQP-1 expression was associated with positive lymph node metastasis (P=.0001). AQP-1 expression was found to inversely correlate with that of mucus core protein 5AC, and their distributions tended to be complementary. The low and negative AQP-1 expression was an independent prognostic factor by multivariate survival analysis. We concluded that AQP-1 is up-regulated in biliary dysplasia, as compared with in the normal large bile duct, and down-regulation of AQP-1 is associated with mucin production and aggressive progression of intrahepatic cholangiocarcinoma.

DOI： 10.1016/j.humpath.2007.04.016

Language：English   Publishing type：Research paper (scientific journal)  

Histone deacetylase (HDAC) activity is one of the widely used and well-established mechanisms for regulation of various genes in cancer. To identify which subtype of class I HDACs are overexpressed in cancers, we analyzed the expression of class I HDAC isotypes composed of HDAC1, 2, 3 and 8 in several cell lines and human cancer tissues, including cancer of the stomach, esophagus, colon, prostate, breast, ovary, lung, pancreas and thyroid. The results showed that >75&#37; of human cancer tissues and their corresponding non-cancerous epithelium showed high expression of these class I HDACs. However, the immunoreactivity of HDAC8 in both prostatic cancer tissue and non-cancerous prostate glands was lower than that in other cancer tissues. Furthermore, 5-40&#37; of cancer tissues overexpressed class I HDACs, when compared with normal epithelium. The results suggest the potential usefulness of HDAC inhibitors for the treatment of a wide variety of human cancers.

DOI： 10.3892/or.18.4.769

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Although intraductal papillary mucinous neoplasm (IPMN) of the pancreas is acceptable as a distinct disease entity, the concept of mucin-secreting biliary tumors has not been fully established. CASE PRESENTATION: We describe herein a case of mucin secreting biliary neoplasm. Imaging revealed a cystic lesion 2 cm in diameter at the left lateral segment of the liver. Duodenal endoscopy revealed mucin secretion through an enlarged papilla of Vater. On the cholangiogram, the cystic lesion communicated with bile duct, and large filling defects caused by mucin were observed in the dilated common bile duct. This lesion was diagnosed as a mucin-secreting bile duct tumor. Left and caudate lobectomy of the liver with extrahepatic bile duct resection and reconstruction was performed according to the possibility of the tumor's malignant behavior. Histological examination of the specimen revealed biliary cystic wall was covered by micropapillary neoplastic epithelium with mucin secretion lacking stromal invasion nor ovarian-like stroma. The patient has remained well with no evidence of recurrence for 38 months since her operation. CONCLUSION: It is only recently that the term "intraductal papillary mucinous neoplasm (IPMN)," which is accepted as a distinct disease entity of the pancreas, has begun to be used for mucin-secreting bile duct tumor. This case also seemed to be intraductal papillary neoplasm with prominent cystic dilatation of the bile duct.

DOI： 10.1186/1477-7819-5-98

Language：English   Publishing type：Research paper (scientific journal)  

The human growth factor receptor-bound protein 7 (Grb7) is an adaptor molecule and is related to cell invasion. In this present study, we investigated the clinical and biological significance of Grb7 expression in human hepatocellular carcinoma (HCC). We reviewed 64 consecutive patients who had undergone liver resection for HCC, and we investigated the correlation between Grb7 expression and clinical outcome. To analyze the biological behavior of Grb7 in vitro and in vivo, we established Grb7 stable knockdown HCC cells using RNA interference technology. The positive staining of Grb7 protein was correlated with portal venous invasion (P < 0.01), hepatic venous invasion (P < 0.01), and intrahepatic metastasis (P < 0.05). Positive expression of Grb7 was significantly correlated with focal adhesion kinase (FAK) protein levels in HCC (P < 0.01). The Grb7- and FAK-positive group showed a significantly poorer prognosis as compared with the Grb7- and FAK-negative group (P < 0.05). Grb7 knockdown HCC cells exhibited significantly lower levels of invasion potential (P < 0.05) and motility (P < 0.05) than the control cells in vitro; moreover, Grb7 knockdown HCC cells showed delayed onset of the tumors compared with the control cells in vivo. Grb7 expression can modulate the invasive phenotype of HCC. Grb7 plays an important role in HCC progression and is strongly associated with expression of FAK. Grb7 could be a therapeutic target in HCC.

DOI： 10.1158/1541-7786.MCR-06-0282

Language：English   Publishing type：Research paper (scientific journal)  

The 14-3-3sigma gene has been implicated in G2/M cell cycle arrest by p53, and the loss of 14-3-3sigma protein expression has been reported in diverse human cancers. However, the role of 14-3-3sigma in the signaling pathway of the cell cycle in the progression of intrahepatic cholangiocarcinoma has not been well understood. To clarify the role of 14-3-3sigma, we examined the protein expressions of 14-3-3sigma, cyclin B1, and p53 in 93 cases of intrahepatic cholangiocarcinoma by immunohistochemical staining. We also examined the correlation between these expressions and survival rate and clinicopathologic factors such as sex, age, tumor grade (ie, pathologic differentiation, tumor size, lymphatic permeation, vascular invasion, perineural invasion, lymph node metastasis), and tumor stage. Positive 14-3-3sigma protein expression (>30&#37; of tumor cells) was observed in 67.7&#37; (63/93) of cases of intrahepatic cholangiocarcinoma and was inversely correlated with cyclin B1 expression. No correlation was found between 14-3-3sigma expression and p53 expression or clinicopathologic factors; however, decreased 14-3-3sigma expression was an independent prognostic factor by multivariate survival analysis (P = .0282). Extensive methylation of 14-3-3sigma was found by methylation-specific polymerase chain reaction and sequence; however, no significant correlation was detected between methylation states and protein expression. These results indicate that depressed 14-3-3sigma protein is involved in the uncontrolled cell cycle in intrahepatic cholangiocarcinoma and that the decreased expression of 14-3-3sigma protein is a significant indicator of poor prognosis for patients with intrahepatic cholangiocarcinoma.

DOI： 10.1016/j.humpath.2006.12.014

Language：English   Publishing type：Research paper (scientific journal)  

It is important to clarify the histologic progression of intrahepatic cholangiocarcinoma (ICC) in consideration of its origin from the intrahepatic large or small biliary ducts. On the basis of the gross and histologic assessment, we classified 87 cases of ICC smaller than 5 cm in diameter into hilar type (H-ICC, n=38) or peripheral type (P-ICC, n=49) to compare their clinical and histologic features. Biliary dysplasia was observed in 65.8&#37; (25/38) of H-ICC cases, whereas hepatitis virus infection and liver cirrhosis were associated with 46.7&#37; (21/45) and 28.6&#37; (14/49) of P-ICC, respectively. The frequency of perineural invasion, lymph node metastasis, and extrahepatic recurrence of H-ICC was significantly higher than that of P-ICC (P<0.0001, 0.0106, and 0.0279, respectively). H-ICC cases showed frequent vascular invasion and intrahepatic metastasis even with small tumor size, compared with P-ICC cases. H-ICC showed large duct involvement within the tumor, and in the cases of large tumor size, intraductal spread was detected in the tumor periphery. P-ICC of small size contained preserved architecture of the portal tracts. The survival of patients with H-ICC was worse than that of patients with P-ICC (P=0.0121). The independent and best prognostic factor by multivariate analysis was intrahepatic metastasis for H-ICC and lymph node metastasis for P-ICC. Our results suggest that ICCs derived from a different level of biliary ducts were related to different premalignant conditions and different tumor progression. Some ICCs arising from the large biliary duct are likely to exhibit an aggressive course even in cases of small tumor size. The recognition of the above events induces the proper therapy.

DOI： 10.1097/PAS.0b013e31802b34b6

Language：English   Publishing type：Research paper (scientific journal)  

Hepatoid adenocarcinoma is an extrahepatic tumor characterized by morphological similarities to hepatocellular carcinoma. The lesions contain a tubular adenocarcinoma that seems to develop "hepatoid" features, but the relation between the tubular adenocarcinomatous and the hepatoid components remains unclear. We compared the cellular phenotypes of 23 cases of hepatoid adenocarcinoma of the stomach having tubular adenocarcinomatous components with 69 cases of non-hepatoid adenocarcinoma of the stomach. Afterward, we examined the expression of CDX2 and p53 in the tubular adenocarcinomatous and hepatoid components of hepatoid adenocarcinoma. Both components of hepatoid adenocarcinoma were classified into 4 phenotypic categories according to the immunohistochemical results for CD10, MUC2, MUC5AC, and MUC6. The complete intestinal phenotype (CD10+, MUC5AC-, MUC6-) was most frequently observed in the adenocarcinomatous and hepatoid components (61&#37; and 65&#37;, respectively). In contrast, no gastric phenotype (MUC5AC+, MUC6+, MUC2-, CD10-) was observed in any of the hepatoid adenocarcinoma components. The positivity for p53 protein in the adenocarcinomatous and hepatoid components was concordant. The expression of CDX2 with early differentiation and maintenance of intestinal epithelial cells was observed in all of the adenocarcinomatous components, whereas 9 of the 23 hepatoid components (39&#37;) were negative for CDX2. These findings suggest that hepatoid adenocarcinoma arises from an adenocarcinoma with an intestinal phenotype and that its hepatoid component is in some way related to reduced CDX2 expression.

DOI： 10.1016/j.humpath.2006.10.020

Language：English   Publishing type：Research paper (scientific journal)  

The morphologic characteristics and biologic behavior of small liver cancers with hepatic and biliary differentiation, and their histogenesis, remain unclear. In this study, 35 cases of hepatocellular carcinoma (HCC) smaller than 3 cm in diameter with biliary differentiation were divided into 3 groups, group 1 [cytokeratin (CK) 19-negative/mucin-negative], group 2 (CK 19-positive/mucin-negative), and group 3 (CK 19-positive/mucin-positive). Sixty-one HCCs without biliary differentiation were used as controls. We compared the histologic features of these tumors and the postoperative outcomes. Three morphologic features of HCCs with biliary differentiation were respectively observed in 40&#37; (14/35), 60&#37; (21/35), and 42.9&#37; (15/35) as follows: (1) cancer cells with intermediate morphology, (2) prominent inflammatory cell infiltrate, (3) desmoplastic stroma; neural cell adhesion molecule and c-kit expression were noted in 25.7&#37;(9/35) and 8.6&#37;(3/35), respectively. Extrahepatic tumor recurrence after surgery occurred in 0&#37; (0/16) of group 1, 33.3&#37; (3/9) of group 2, 40.0&#37; (4/10) of group 3, and 8.2&#37; (5/61) of the ordinary HCCs. The tumor-related survival of group 3 patients was worse than that of patients with ordinary HCCs, but there were no differences between the survival of group 1, or group 2 patients and those with ordinary HCCs. Our results suggest that the biliary differentiation does occur even in small HCC, and a mucin-producing cancer cells indicates aggressive tumor behavior. The combination of intermediate cancer cells, inflammatory cell infiltrate, and desmoplastic stroma is likely to be related to the biliary differentiation of HCC.

DOI： 10.1097/01.pas.0000213421.53750.0a

Language：Others   Publishing type：Research paper (scientific journal)  

BACKGROUND. Liver transplantation is an accepted treatment option for patients with otherwise untreatable hepatocellular carcinoma (HCC). The present study assessed the outcome of living donor liver transplantation (LDLT) under extended selection criteria based on a single-center experience. METHODS. A total of 60 patients who underwent LDLT for HCC were included. Our indication for LDLT included HCC without extrahepatic spread or macroscopic vascular invasion. The size and number of HCC nodules were not limited. Recurrence-free survival rates according to various factors were compared to identify risk factors for recurrence. RESULTS. Forty patients (67&#37;) preoperatively exceeded the Milan criteria. The median follow-up was 437 days (range: 23-1,385 days). The overall 1- and 3-year actuarial survival rates were 88.4 and 68.6&#37;, respectively. HCC recurred in eight patients (14.3&#37;) within a mean follow-up of 288 days; all were patients who exceeded the Milan criteria. The 1-, 2- and 3-year recurrence-free survival rates of patients who fulfilled the Milan criteria were 100&#37;, 100&#37;, and 100&#37;, respectively, whereas those of patients who exceeded the criteria were 83.0&#37;, 74.0&#37;, and 74.0&#37;, respectively. Tumor diameter >5 cm was significantly associated with worse prognosis, but the number of tumors was not. A preoperative des-gamma-carboxy prothrombin value >300 mAU/ml was strongly associated with the high recurrence rate. These two variables were significant in multivariate analysis. CONCLUSIONS. LDLT was shown to offer acceptable results in patients who exceeded the Milan criteria. The indication for LDLT can therefore be expanded beyond the Milan criteria, especially for patients with small multiple tumors <5 cm. © 2007 Lippincott Williams & Wilkins, Inc.

DOI： 10.1097/01.tp.0000259015.46798.ec

Language：English   Publishing type：Research paper (scientific journal)  

The microvascular invasion of cancer cells (mvi) is a good prognostic factor after orthotopic liver transplantation (OLT) for hepatocellular carcinoma (HCC). The aim of this study is to predict mvi in patients with HCC who were candidates for OLT. We studied 218 patients with HCC resections who had HCC without any extrahepatic metastases and vascular invasion detected during preoperative evaluation. We analyzed the clinico-pathological data of these patients to predict the mvi presence. The mvi prediction scoring system was made and the accuracy of this system was examined using independent clinico-pathologic factors. The size and histological grade of the tumor were significantly correlated with the mvi. The des-gamma-carboxy prothrombin (DCP) is a mvi predictor. The sensitivity of our mvi prediction system was 75&#37; and the specificity was 85&#37; in 32 patients who underwent living-donor liver transplantations for HCC. Our study shows that besides the tumor size and histological grade, a measurement of the serum DCP levels could be a good predictor for mvi. A tumor biopsy and a preoperative measurement of DCP could improve the selection of patients with HCC for OLT. Our scoring system for mvi provides us a precise prediction of the presence of mvi.

DOI： 10.1002/jso.20655

Language：English   Publishing type：Research paper (scientific journal)  

AIM: To study a more accurate quantification of hepatic fibrosis which would provide clinically useful information for monitoring the progression of chronic liver disease. METHODS: Using a cDNA microarray containing over 22000 clones, we analyzed the gene-expression profiles of non-cancerous liver in 74 patients who underwent hepatic resection. We calculated the ratio of azan-stained: total area, and determined the morphologic fibrosis index (MFI), as a mean of 9 section-images. We used the MFI as a reference standard to evaluate our method for assessing liver fibrosis. RESULTS: We identified 39 genes that collectively showed a good correlation (r > 0.50) between gene-expression and the severity of liver fibrosis. Many of the identified genes were involved in immune responses and cell signaling. To quantify the extent of liver fibrosis, we developed a new genetic fibrosis index (GFI) based on gene-expression profiling of 4 clones using a linear support vector regression analysis. This technique, based on a supervised learning analysis, correctly quantified the various degrees of fibrosis in both 74 training samples (r = 0.76, 2.2&#37; vs 2.8&#37;, P < 0.0001) and 12 independent additional test samples (r = 0.75, 9.8&#37; vs 8.6&#37;, P < 0.005). It was far better in assessing liver fibrosis than blood markers such as prothrombin time (r = -0.53), type IV collagen 7s (r = 0.48), hyaluronic acid (r = 0.41), and aspartate aminotransferase to platelets ratio index (APRI) (r = 0.38). CONCLUSION: Our cDNA microarray-based strategy may help clinicians to precisely and objectively monitor the severity of liver fibrosis.

DOI： 10.3748/wjg.v13.i3.383

Language：Others   Publishing type：Research paper (scientific journal)  

Aims: To define a new histological staging and grading system for primary biliary cirrhosis (PBC), to provide more information reflecting clinical laboratory data and the prognosis to hepatologists. Methods and results: First, 17 histological lesions of PBC were scored in 188 needle liver biopsy specimens. Factor analysis yielded three independent groups of factors: factor 1 (fibrosis, fibrous piecemeal necrosis, orcein-positive granules, bile plugs, Mallory bodies, feathery degeneration, bile duct loss and atypical ductular proliferation); factor 2 (portal inflammation, eosinophilic infiltration, lymphoid follicles, epithelioid granulomas, interface hepatitis and chronic cholangitis); and factor 3 (interface hepatitis, lobular hepatitis, acidophilic bodies and pigmented macrophages). The eight findings of factor 1, but not factors 2 and 3, were significantly correlated with clinical laboratory data and scores in the Mayo Clinic's prognostic model. Factor 1 lesions may reflect histological progression (staging), while factor 2 and 3 lesions may relate to necroinflammatory activity (grading). Then, we devised a staging and grading system using three lesions (bile duct loss, fibrosis and orcein-positive granules) from factor 1 and three from factors 2 and 3 (chronic cholangitis, interface hepatitis and lobular hepatitis). Conclusion: This new system might provide more pathological information on PBC patients for hepatologists. © 2006 The Authors.

DOI： 10.1111/j.1365-2559.2006.02537.x

Language：English   Publishing type：Research paper (scientific journal)  

It is important to evaluate advanced primary biliary cirrhosis (PBC) clinicopathologically to clarify its progressive mechanism. According to the cirrhotic pattern, 26 cases of explanted PBC were classified into non-cirrhotic (n=4), macronodular (n=4), mixed nodular (n=6), and micronodular cirrhosis (n=12), to compare their clinical and morphological features. In addition, the degree of preserved intrahepatic bile ducts and other histologic features were analyzed. Patients at living donor liver transplantation (LDLT) in the macronodular cirrhosis were significantly older than those in the micronodular cirrhosis. The mean duration between clinical presentation and LDLT in the macronodular cirrhosis was significantly longer than in the micronodular cirrhosis. The non-cirrhotic group showed a short duration between clinical presentation and LDLT. The ratio of explanted liver volume to standard liver volume (ELV/SLV) indicates that macronodular cirrhosis revealed more atrophic change than that in the other three types. The density of remnant intrahepatic bile ducts of less than 50mum per group in cases of macronodular cirrhosis was significantly higher than that in cases of micronodular cirrhosis. Therefore, different cirrhotic patterns of advanced PBC were correlated with the disease progression and the degree of bile duct disappearance. The macronodular cirrhotic patients were older, had a longer disease course, yet had less bile duct loss. We suggest that macronodular cirrhosis and micronodular cirrhosis of PBC are different type of PBC.

DOI： 10.1016/j.hepres.2006.07.008

Language：English   Publishing type：Research paper (scientific journal)  

Insulin-like growth factor binding protein-3 (IGFBP-3) modulates cell proliferation of various cancer cell types. However, it remains unclear how IGF-IGFBP-3-signaling is involved in growth and progression of hepatocellular carcinoma (HCC). The aim of the present study was to evaluate the role of IGFBP-3 in HCC. Type 1 receptor for IGF (IGF-1R) was expressed at various levels in the seven lines examined, but IGF-2R was not expressed. Of the seven lines, the growth of HAK-1B, KIM-1, KYN-2 and HepG2 cells was stimulated in a dose-dependent manner by the exogenous addition of IGF-I or IGF-II, but the HAK-1A, KYN-1 and KYN-3 cell lines showed no growth. Exogenous addition of IGFBP-3 markedly blocked IGF-I and IGF-II-stimulated cell growth of KYN-2 and HepG2 cells, and moderately stimulated that of KIM-1 and HAK-1B cells, but no growth of the KYN-1, KYN-3 and HAK-1A cell lines was observed. IGF-I enhanced the phosphorylation of IGF-1R, Akt and Erk1/2 in KYN-2 cells, and coadministration of IGFBP-3 blocked all types of activation by IGF-I investigated here. In contrast, no such activation by IGF-I was detected in KYN-3 cells. IGFBP-3 also suppressed IGF-I-induced cell invasion by KYN-2 cells. Moreover, we were able to observe the apparent expression of IGFBP-3 in KYN-3 cells, but not in the other six cell lines. Furthermore reduced expression of IGFBP-3, but not that of IGF-1R, was significantly correlated with tumor size, histological differentiation, capsular invasion and portal venous invasion. Low expression of IGFBP-3 was independently associated with poor survival. IGFBP-3 could be a molecular target of intrinsic importance for further development of novel therapeutic strategy against HCC.

DOI： 10.1111/j.1349-7006.2006.00322.x

Language：English   Publishing type：Research paper (scientific journal)  

We report herein a case of hepatocellular carcinoma (HCC) with a prominent central scar. Dynamic CT and MRI studies revealed a hypervascular liver mass and a washout of contrast material in the delayed phase. The tumor center showed particular hyperintensity on T2-weighted images and delayed or prolonged enhancement. The surgical specimen revealed moderately differentiated HCC with a central scar. The central scar consisted of prominent vascular channels and loose fibrous tissue, indicative of a vascular scar. We should understand MR imaging findings of this type of central scar in the HCC.

DOI： 10.1007/s11604-006-0052-z

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Aims: To identify the role of mucus core protein (MUC) in intrahepatic cholangiocarcinoma (ICC). Methods and results: We examined the expression profile of MUC2, MUC5AC and MUC6 by immunohistochemical staining in 100 ICCs and compared the clinicopathological factors and the immunohistochemical results. The expression frequency was: MUC2, 9&#37;; MUC5AC, 40&#37;; and MUC6, 21&#37;. According to the gastric mucin expression profile, ICCs were classified into the following groups: null type (n = 43), gastric foveolar type (n = 36), pyloric gland type (n = 11) and gastric combined type (n = 10). Half of the gastric foveolar type and the gastric combined type were located in the hilar region, but the other types were predominant at the periphery (P = 0.0004). Well-differentiated components were more often detected in the gastric combined type and the pyloric gland type (P = 0.0281). The gastric foveolar type was associated with a higher incidence of lymph node metastasis (P < 0.0001). The pyloric gland type was associated with better survival and the gastric foveolar type was associated with worse survival. The gastric mucin phenotype was an independent prognostic factor by multivariate survival analysis. Conclusion: The gastric foveolar type of ICC was more often associated with aggressive tumour development, whereas the pyloric gland type exhibited less aggressive behaviour. © 2006 Blackwell Publishing Limited.

DOI： 10.1111/j.1365-2559.2006.02414.x

Language：English   Publishing type：Research paper (scientific journal)  

Combined hepatocellular and cholangiocarcinoma (cHC-CC) is a rare type of liver cancer displaying both hepatocellular and cholangiocellular components. The cholangiocellular carcinoma (CC) in these tumors ranges from focal to prominent. Those cHC-CCs with sarcomatous features are reported to have a poor prognosis. To clarify whether the CC and sarcomatous component affects the prognosis, we classified 40 patients with cHC-CCs into 4 groups according to the presence of a sarcomatous component and the extent of the CC component. Seven (17.5&#37;) tumors showed areas with a sarcomatous component. The remaining tumors were divided into a low-CC group (CC occupying <30&#37; of the tumor, n = 12), a middle-CC group (30&#37;-60&#37;, n = 15), and a high-CC group (>60&#37;, n = 6). Vascular invasion was more frequently present in the high-CC and sarcomatous group than in the other groups (P = .0007). No lymph node metastasis occurred in either the low- or the middle-CC groups, but it was detected in 3 (50&#37;) cases of the high-CC group and in 2 (29&#37;) cases of the sarcomatous group (P < .0001). There was a tendency for tumor size to increase from the low- to the middle- to the high-CC group. The Ki-67 labeling index values for the hepatocellular carcinoma, CC, and sarcomatous components were 11.4&#37; +/- 12.9&#37;, 25.4&#37; +/- 18.3&#37;, and 46.0&#37; +/- 23.6&#37;, respectively. The overall survival of patients in the high-CC and sarcomatous group was significantly poorer than that of patients in the low- and middle-CC groups (P = .0048). By multivariate analysis of overall survival, lymph node metastasis, histological subgroup, and vascular invasion were significant independent prognostic factors. A cHC-CC with a large CC component is as aggressive as cHC-CC with sarcomatous features.

DOI： 10.1016/j.humpath.2005.08.019

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: To retrospectively determine whether the degree of contrast material enhancement at delayed-phase dynamic computed tomography (CT) for intrahepatic cholangiocarcinoma (ICC) is related to the patient's prognosis after surgery. MATERIALS AND METHODS: Neither institutional review board approval nor informed consent was required for this retrospective evaluation. Thirty-two patients (22 men, 10 women; mean age, 60.8 years; range, 33-80 years) with mass-forming ICC underwent dynamic CT. Delayed CT images obtained 4-6 minutes after the injection of contrast material were evaluated by two radiologists. Patients were classified in consensus into one of two groups: Group 1 included those in whom more than two-thirds of the tumor showed enhancement on delayed-phase scans. Group 2 included those in whom less than two-thirds of the tumor showed enhancement on delayed-phase scans. The imaging findings were correlated with pathologic findings. Survival curves were drawn by using the Kaplan-Meier method, and the differences between the groups were compared with the log-rank test. Multivariate analysis was performed to clarify prognostic factors. RESULTS: There were 13 patients in group 1 and 19 in group 2. The degree of enhancement on the delayed-phase images showed statistically significant correlation with the amount of fibrous stroma (P < .001) and the frequency of perineural invasion (P < .01). The survival rate in group 1 was significantly lower than that in group 2 (P = .016). Multivariate analysis revealed that enhancement of more than two-thirds of the ICC was a significant and independent prognostic factor. CONCLUSION: The degree of enhancement on delayed-phase CT scans is a useful indicator for prediction of the prognosis of patients with mass-forming ICC.

DOI： 10.1148/radiol.2381041765

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND AND OBJECTIVES: Irregular regeneration of hepatocytes has been reported as an important factor in the hepatocarcinogenesis, so we studied the relationship between irregular regeneration and two hepatocarcinogenic pathways, "de novo" and "dysplastic nodule-hepatocellular carcinoma sequence." METHODS: Liver tissue was obtained from surgically resected 112 specimens, early well differentiated hepatocellular carcinomas and non-cancerous tissue. Hepatocellular carcinomas were divided into two groups; carcinoma with dysplastic area (type A) and without dysplastic area (type B) and were compared with irregular regeneration of hepatocytes in the non-cancerous tissue. RESULTS: Eighty-eight of 112 cases were judged to have irregular regeneration, such as anisocytosis, pleomorphism, bulging and map-like distribution. The degree of irregular regeneration was not correlated to the type of early well differentiated hepatocellular carcinomas. However, the existence of pleomorphism, map-like distribution and bulging are significantly correlated with type A. CONCLUSION: Type A might be more frequently occurring in a carcinogenic liver showing some kinds of irregular regeneration.

DOI： 10.1002/jso.20293

Language：Japanese   Publishing type：Research paper (scientific journal)  

[A case of adult's still disease complicated with cytomegalovirus infection and hemorrhagic rectal ulcer].

DOI： 10.11405/nisshoshi.102.1281

Language：Others   Publishing type：Research paper (scientific journal)  

Aims: 'Scirrhous' hepatocellular carcinoma (scirrhous HCC) is extremely rare and its characteristics remain unclear. We investigated the clinicopathological and immunohistochemical features of scirrhous HCC, compared with those of ordinary hepatocellular carcinoma (ordinary HCC). Methods and results: We compared the clinicopathological and immunohistochemical features of 20 resected cases of scirrhous HCC with those of 69 resected cases of ordinary HCC. Scirrhous HCC was characterized by its gross and histological findings, such as a higher proportion of contiguous multinodular type tumours, the absence of a complete fibrous capsule around the tumour, the absence of tumour necrosis and highly preserved portal tracts in the tumour. The immunohistochemical results revealed a significantly higher expression of cytokeratin 7 and a significantly lower expression of hepatocyte paraffin 1 in scirrhous HCC than in ordinary HCC (P < 0.0001, respectively). There were no significant differences in proliferative activity and survival curves between the patients with scirrhous HCC and those with ordinary HCC. Conclusion: Scirrhous HCC has several particular gross, histological and immunohistochemical features. In particular, we would like to emphasize the greater immunohistochemical expression of cytokeratin 7 and lower expression of hepatocyte paraffin 1 in scirrhous HCC than in ordinary HCC. © 2005 Blackwell Publishing Limited.

DOI： 10.1111/j.1365-2559.2005.02230.x

Language：Others   Publishing type：Research paper (scientific journal)  

Background. The use of steatotic livers is associated with increased primary nonfunction in liver transplantation. To reduce the risk of liver injury, we applied a short-term combination therapy of diet, exercise and drugs for 11 living-donor liver transplantation (LDLT) candidates with steatosis. Methods. Subjects were treated with a protein-rich (1000 kcal/day) diet, exercise (600 kcal/day), and bezafibrate (400 mg/day) for 2-8 weeks. Results. The treatment significantly improved macrovesicular steatosis (30±4&#37; vs. 12±2&#37; [mean±SEM], P= 0.0028). Body weight and BMI were significantly reduced (73.7±3.2 kg vs. 66.9±2.9 kg, P=0.0033, 26.4±0.7 kg/m2 vs. 24.1±0.8 kg/m2, P=0.0033). The treatment completely normalized liver function tests and lipid metabolism. Seven treated liver grafts (left lobe) were transplanted to the recipients. We compared transplanted graft function and resected liver function of donors using parameters such as peak total bilirubin, prothrombin time at postoperative day 3, and peak alanine aminotransferase between treated liver (n=7) and donor liver without hepatic steotosis (n=37). The transplanted grafts showed good liver functions, and there was no difference between them with respect to functional parameters. The treated donors also showed good liver functions, and no significant differences in functional parameters. Conclusions. The results of this study indicate that our short-term treatment effectively reduced steatosis and contributed to safer LDLT. Our findings also suggest that even severely steatotic livers can be used for LDLT grafting subsequent to our short-term treatment regimen. Copyright © 2005 by Lippincott Williams & Wilkins.

DOI： 10.1097/01.tp.0000166009.77444.f3

Language：English   Publishing type：Research paper (scientific journal)  

Bronchiolitis obliterans organizing pneumonia (BOOP) is a rare complication of adult systemic lupus erythematosus (SLE). This is the first report of a pediatric patient with BOOP as an initial presentation of SLE. She had dyspnea, cough, arthralgia, and erythema on her face. Laboratory examinations revealed pancytopenia, low serum levels of complements, and positivity for anti-nuclear antibody, anti-double stranded DNA antibody, and anti-SM antibody. Her respiratory symptoms, pulmonary function tests, and radiologic findings showed significant improvement after treatment with oral prednisolone. Although it is a rare complication among the pleuro-pulmonary manifestations in SLE, BOOP can be the first presentation, even in pediatric patients.

DOI： 10.1002/ppul.20224

Language：English   Publishing type：Research paper (scientific journal)  

Biliary lining epithelia of the bile ducts in biliary diseases are known to have intraepithelial atypical/proliferative lesions related to the development of cholangiocarcinoma. The purpose of the present study was to determine the histological criteria for these lesions based on interobserver agreement. Digital images of 30 intraepithelial atypical/proliferative lesions in the stone-containing intrahepatic bile ducts of hepatolithiasis (30 cases) were sent to 10 pathologists. At first, 10 pathologists made a diagnosis (either of reactive/regenerative change, low-grade or high-grade biliary intraepithelial neoplasia (BilIN-1 and BilIN-2), or in situ carcinoma (BilIN-3)) based on their own criteria. The histological criteria for these four lesions were then determined, and the digital images of the same lesions with proposed criteria were re-distributed. Interobserver agreement on these four lesions was slightly improved (kappa = 0.44, first diagnosis; 0.49, second diagnosis) and intraobserver agreement was 'almost perfect' (kappa = 0.82 at both first and second diagnosis). Interobserver agreement between BilIN-1 and BilIN-2 and that between BilIN-2 and BilIN-3 were 'moderate', although the agreement between regenerative/reactive change and BilIN-1 was 'fair'. In this report, we propose histological criteria for reactive/regenerative change, BilIN-1, BilIN-2 and BilIN-3. Improvement of interobserver agreement suggests their applicability in diagnostic and research fields.

DOI： 10.1111/j.1440-1827.2005.01816.x

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: The purpose of this study was to evaluate the performance of enhanced CT in making a diagnosis of combined hepatocellular and cholangiocarcinomas (HCC-CCs) by comparing CT findings with histologic findings. CONCLUSION: One third (nine of 27 cases) of the combined HCC-CCs were correctly diagnosed on enhanced CT by detailed analysis of the enhancing pattern around or within the mass. Various factors such as an atypical enhancing pattern, the size of each component, and the presence of a mass composed of intermediate tumor cells-that is, cells with intermediate characteristics between HCC and CC-were found to be the causes of misdiagnosis of combined HCC-CC on enhanced CT.

DOI： 10.2214/ajr.184.4.01841157

Language：Japanese   Publishing type：Research paper (scientific journal)  

[A case of valproate-associated hyperammonemia with chronic hepatitis C].

DOI： 10.11405/nisshoshi.102.42, 10.2957/kanzo.59.421_references_DOI_7iqc9gI6LrFzakFaQecy4g2pG30

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: A recent report showed that heat shock protein (HSP)-27 expression was related to histological grade and survival of patients with hepatocellular carcinoma (HCC). AIMS: The aim of this study was to examine the effect of expression of HSP-27 on clinicopathological variables in Japanese patients with HCC. METHODS: An immunohistochemical study for HSP-27 was performed on 60 HCC cases using a monoclonal anti-HSP-27 antibody. We divided 60 patients into two groups, patients with a low expression of HSP-27 (n = 34) and those with a high expression of HSP-27 (n = 26). Forty patients tested positive for the hepatitis C virus (HCV) antibody and 20 tested positive for the hepatitis B surface antigen. RESULTS: There appeared to be no relationship between HSP expression and clinicopathologic factors and no differences were observed between the high expression group and the low expression group. In the hepatitis B virus (HBV) group (n = 20), HSP-27 expression correlated significantly with prognosis, disease-free survival (DFS) and overall survival. High expression was significantly associated with poor prognosis in the HBV group. In contrast, patients with a high expression tended to have a good prognosis in the HCV group (n = 40): DFS and overall survival. CONCLUSIONS: This study showed the possibility that HSP-27 plays different roles in HBV- and HCV-associated HCCs.

DOI： 10.1111/j.1478-3231.2004.0927.x

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: A recent report showed that heat shock protein (HSP)-27 expression was related to histological grade and survival of patients with hepatocellular carcinoma (HCC). AIMS: The aim of this study was to examine the effect of expression of HSP-27 on clinicopathological variables in Japanese patients with HCC. METHODS: An immunohistochemical study for HSP-27 was performed on 60 HCC cases using a monoclonal anti-HSP-27 antibody. We divided 60 patients into two groups, patients with a low expression of HSP-27 (n = 34) and those with a high expression of HSP-27 (n = 26). Forty patients tested positive for the hepatitis C virus (HCV) antibody and 20 tested positive for the hepatitis B surface antigen. RESULTS: There appeared to be no relationship between HSP expression and clinicopathologic factors and no differences were observed between the high expression group and the low expression group. In the hepatitis B virus (HBV) group (n = 20), HSP-27 expression correlated significantly with prognosis, disease-free survival (DFS) and overall survival. High expression was significantly associated with poor prognosis in the HBV group. In contrast, patients with a high expression tended to have a good prognosis in the HCV group (n = 40): DFS and overall survival. CONCLUSIONS: This study showed the possibility that HSP-27 plays different roles in HBV- and HCV-associated HCCs.

DOI： 10.1111/j.1478-3231.2004.0927.x

Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: Although hepatocellular carcinoma (HCC) is the most common cancer of the human liver, the mechanisms that regulate HCC development and progression remain unclear. The aim of this study was to investigate whether focal adhesion kinase (FAK) is involved in the progression of human HCC. EXPERIMENTAL DESIGN: Western blot analysis for FAK was performed on three HCC cell lines. We reviewed 64 consecutive patients who had undergone initial liver resection for HCC without preoperative treatment. Immunohistochemistry analysis for FAK was performed on paraffin-embedded tissues. FAK expression was confirmed by Western blot analysis in several clinical samples. We investigated the correlation between FAK expression and clinical outcome. RESULTS: FAK proteins were detected in all HCC cell lines. Hepatocytes in the normal liver and chronic hepatitis with or without cirrhosis were negative for immunohistochemical staining for FAK expression. Cytoplasmic FAK expression was observed in 18 of 64 patients (28.1&#37;), and this positive staining was correlated with gender (P < 0.05), a lower level of serum albumin (P < 0.05), and portal venous invasion (P < 0.01). Positive staining for FAK was associated with significantly poorer survival (P < 0.05). In multivariate analysis, FAK overexpression was an independent factor in determining the prognosis of patients. CONCLUSIONS: These data suggest that FAK plays an important role in promoting tumor progression, especially vascular invasion, in HCC. FAK could play an important role in HCC progression and would be a novel target for HCC therapeutics as well as a prognostic marker.

DOI： 10.1158/1078-0432.CCR-1046-03

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: The aim of this study was to clarify prognostic factors and recurrence patterns in patients with node-negative intrahepatic cholangiocarcinoma (IHCC). METHODS: A retrospective study was performed to review prognostic factors and recurrence patterns (1) in 22 patients with node-negative IHCC after curative hepatic resection and (2) in 49 patients who underwent resection and lymph node dissection for IHCC. In addition to determining the clinicopathologic factors, the investigators also performed immunohistochemical examination of microvessel counts using antihuman CD-31 and antibody. RESULTS: The significant poor prognostic factors in node-negative IHCC were the presence of intrahepatic metastasis, portal vein invasion of cancer cells, and high microvessel counts. After multivariate analysis was conducted, the independent poor prognostic factors were the presence of intrahepatic metastases and high microvessel counts. Of 9 patients who had postoperative recurrence of their disease, intrahepatic recurrence was observed in 7 (78 &#37;). CONCLUSIONS: The factors linked to poor prognosis in IHCC were tumor angiogenesis and the presence of intrahepatic metastasis. Because intrahepatic recurrence was common, regional and adjuvant chemotherapy to the liver may improve the outcome of patients with these risk factors and node-negative IHCC.

DOI： 10.1016/j.amjsurg.2003.12.044

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Osteopontin (OPN) is known to be a secreted adhesive glycoprotein. Recent studies have reported that the overexpression of OPN is correlated with tumorigenesis, tumor aggressiveness, and poor prognosis in several types of human cancer. The aim of this study was to determine whether the expression of OPN in cases of intrahepatic cholangiocarcinoma (ICC) indicates the clinical outcome. METHODS: The expression of OPN protein was investigated immunohistochemically in surgically resected specimens from 73 patients, and the level of OPN mRNA was also examined by quantitative real-time reverse transcription-polymerase chain reaction (real-time RT-PCR) in nine samples of ICC. We examined the correlation between the expression of OPN and the clinicopathological factors, including overall survival, in patients with ICC. RESULTS: We detected the positive expression of OPN protein in 31 of 73 (42.5&#37;) of the primary ICCs. Negative expression of OPN protein was significantly related to lymphatic permeation, perineural invasion, intrahepatic metastasis, and lymph node metastasis (P=0.0029, 0.0072, 0.0134, and 0.0101, respectively). Overall survival was significantly lower among the patients with a negative expression of OPN than it was among those with a positive expression of OPN. The negative expression of OPN protein and the lower levels of OPN mRNA were statistically significant (P=0.0139). CONCLUSIONS: Decreased expression of OPN is considered to be a reliable indicator of tumor aggressiveness and clinical outcome in patients with ICC.

DOI： 10.1111/j.1478-3231.2004.00886.x

Language：Others   Publishing type：Research paper (scientific journal)  

Aim: Angiopoietin 1 (Ang-1) and its antagonist, angiopoietin 2 (Ang-2), are novel ligands that regulate the Tie2 receptor. The Ang-2 gene is upregulated in the hypervascular type of human hepatocellular carcinoma (HCC). To gain a better understanding of the role of the Ang-Tie2 system in HCC the expression of these genes was investigated in a series of human HCCs. Methods: The expression of the angiopoietin and Tie2 proteins was investigated in nine normal liver tissues and 52 surgically resected HCCs. In addition, the effects of hypoxic stimuli on Ang-1, Ang-2, vascular endothelial growth factor (VEGF), and erythropoietin (EPO) expression was investigated in Hep3B cells. Results: Ang-1, rather than Ang-2, was more frequently expressed in the normal liver. Ang-1 was expressed in 68&#37; of HCCs, whereas Ang-2 was expressed in 81&#37;, and was significantly higher in poorly differentiated HCCs characterised by high vascularity (p = 0.02), and in tumours with a peliotic change (p = 0.02). Strong expression of Tie2 was seen in tumour vessels in accordance with Ang-2 expression. In Hep3B cells, hypoxic stimuli upregulated VEGF and EPO, but not Ang-1 or Ang-2. Conclusions: These data support the evidence that the reversal of Ang-1 and Ang-2 expression plays an important role in the angiogenic and dedifferentiation processes in HCC. The hypoxic stimuli were not responsible for Ang-2 upregulation, unlike that of VEGF, in human HCC cells.

DOI： 10.1136/jcp.56.11.854

Language：English   Publishing type：Research paper (scientific journal)  

Tenascin and decorin are components of the extracellular matrix (ECM) that are implicated in cell proliferation in tumors. Here, we propose that abnormal expression of stromal ECM may play an important role in the progression of intrahepatic cholangiocarcinoma, which is characterized by desmoplastic reaction. To explore this hypothesis, we performed immunohistochemical analysis in order to examine the expression and distribution of tenascin and decorin in 75 cases of intrahepatic cholangiocarcinoma. In the intratumoral stroma, positive staining for tenascin was observed in 51 (68&#37;) cases, and positive staining for decorin was observed in 61 (81&#37;) cases. However, at the invasive front, positive staining for tenascin was found in 23 (31&#37;) cases, and positive staining for decorin was found in 6 (8&#37;) cases. Decorin staining was not correlated with aggressive behavior of intrahepatic cholangiocarcinoma, whereas intratumoral tenascin staining was correlated with lymphatic permeation and proliferative activity measured by Ki67. Tenascin staining at the invasive front was associated with tumor size, lymphatic permeation, lymph node metastasis, and proliferative activity and appeared to be a useful prognostic factor by univariate analysis, although it was not an independent prognostic factor. These results indicate that tenascin plays a role in tumor progression in cases of intrahepatic cholangiocarcinoma and that tenascin expression, especially at the invasive front, may be a useful marker in evaluating an unfavorable prognosis in patients with intrahepatic cholangiocarcinoma.

DOI： 10.1097/01.MP.0000086860.65672.73

Language：English   Publishing type：Research paper (scientific journal)  

Tenascin and decorin are components of the extracellular matrix (ECM) that are implicated in cell proliferation in tumors. Here, we propose that abnormal expression of stromal ECM may play an important role in the progression of intrahepatic cholangiocarcinoma, which is characterized by desmoplastic reaction. To explore this hypothesis, we performed immunohistochemical analysis in order to examine the expression and distribution of tenascin and decorin in 75 cases of intrahepatic cholangiocarcinoma. In the intratumoral stroma, positive staining for tenascin was observed in 51 (68&#37;) cases, and positive staining for decorin was observed in 61 (81&#37;) cases. However, at the invasive front, positive staining for tenascin was found in 23 (31&#37;) cases, and positive staining for decorin was found in 6 (8&#37;) cases. Decorin staining was not correlated with aggressive behavior of intrahepatic cholangiocarcinoma, whereas intratumoral tenascin staining was correlated with lymphatic permeation and proliferative activity measured by Ki67. Tenascin staining at the invasive front was associated with tumor size, lymphatic permeation, lymph node metastasis, and proliferative activity and appeared to be a useful prognostic factor by univariate analysis, although it was not an independent prognostic factor. These results indicate that tenascin plays a role in tumor progression in cases of intrahepatic cholangiocarcinoma and that tenascin expression, especially at the invasive front, may be a useful marker in evaluating an unfavorable prognosis in patients with intrahepatic cholangiocarcinoma.

DOI： 10.1097/01.MP.0000086860.65672.73

Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: Snail protein is a suppressive transcriptional factor of E-cadherin that mediates cell-to-cell adhesion, tumor progression, and metastases. We explored the expression and function of Snail and its family member Slug in human hepatocellular carcinoma (HCC) to identify its role in tumor progression. EXPERIMENTAL DESIGN AND RESULTS: Transfection of Snail cDNA in Li-7, endogenous E-cadherin-positive human HCC cells, selectively induced the loss of E-cadherin protein expression. We then investigated the expression of Snail and Slug mRNA in 43 human tissue samples of HCC. Using in situ hybridization, Snail mRNA was determined to dominantly express in HCC cells, but not in bile duct cells, blood vessels or infiltrating leukocytes. The mRNA of Snail and Slug were quantified using real-time reverse transcriptase-PCR, and correlations with E-cadherin expression and clinicopathological factors were investigated. Snail mRNA was overexpressed in 7 cases (16&#37;) of HCC compared with adjacent noncancerous liver tissue. E-Cadherin protein expression determined in the same 43 cases by immunohistochemistry was significantly down-regulated in those cases with Snail mRNA overexpression (P = 0.04). The tumor and nontumor ratio of Snail mRNA independently correlated with tumor invasiveness (P = 0.04). However, Slug mRNA correlated with neither E-cadherin expression nor tumor invasiveness. CONCLUSIONS: The data indicate that Snail both down-regulates E-cadherin expression and promotes the invasion in human HCC.

Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: Snail protein is a suppressive transcriptional factor of E-cadherin that mediates cell-to-cell adhesion, tumor progression, and metastases. We explored the expression and function of Snail and its family member Slug in human hepatocellular carcinoma (HCC) to identify its role in tumor progression. EXPERIMENTAL DESIGN AND RESULTS: Transfection of Snail cDNA in Li-7, endogenous E-cadherin-positive human HCC cells, selectively induced the loss of E-cadherin protein expression. We then investigated the expression of Snail and Slug mRNA in 43 human tissue samples of HCC. Using in situ hybridization, Snail mRNA was determined to dominantly express in HCC cells, but not in bile duct cells, blood vessels or infiltrating leukocytes. The mRNA of Snail and Slug were quantified using real-time reverse transcriptase-PCR, and correlations with E-cadherin expression and clinicopathological factors were investigated. Snail mRNA was overexpressed in 7 cases (16&#37;) of HCC compared with adjacent noncancerous liver tissue. E-Cadherin protein expression determined in the same 43 cases by immunohistochemistry was significantly down-regulated in those cases with Snail mRNA overexpression (P = 0.04). The tumor and nontumor ratio of Snail mRNA independently correlated with tumor invasiveness (P = 0.04). However, Slug mRNA correlated with neither E-cadherin expression nor tumor invasiveness. CONCLUSIONS: The data indicate that Snail both down-regulates E-cadherin expression and promotes the invasion in human HCC.

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Sarcomatous hepatocellular carcinoma (HCC) has a worse prognosis than ordinary HCC. The relationship between the malignant potential of sarcomatous HCC and cell proliferation or cell adhesion is unknown. This study was undertaken to clarify this relationship. METHODS: In 21 cases of sarcomatous HCC, including 16 surgically resected and five autopsy cases, immunohistochemistry was used to compare the sarcomatous component (s-comp) and the ordinary component (o-comp) within each sarcomatous HCC. RESULTS: We found 15 epithelial-cadherin (E-cadherin)-positive cases in o-comp (79&#37;) and nine positive cases in s-comp (43&#37;). The difference between sarcomatous HCC and ordinary HCC in E-cadherin-positive tumor prevalence was significant (P < 0.05). The Ki-67 (MIB1) labeling index ratio was 127 +/- 40 in s-comp and 80 +/- 33 in o-comp, and there was a greater tendency to have an ability to multiply in s-comp than in o-comp (P = 0.096). CONCLUSION: This study indicated that the loss of E-cadherin related to a morphological alteration in sarcomatous HCC; however, no relationship in respect to the malignant potential was found.

DOI： 10.1046/j.1440-1746.2003.02888.x

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Sarcomatous hepatocellular carcinoma (HCC) has a worse prognosis than ordinary HCC. The relationship between the malignant potential of sarcomatous HCC and cell proliferation or cell adhesion is unknown. This study was undertaken to clarify this relationship. METHODS: In 21 cases of sarcomatous HCC, including 16 surgically resected and five autopsy cases, immunohistochemistry was used to compare the sarcomatous component (s-comp) and the ordinary component (o-comp) within each sarcomatous HCC. RESULTS: We found 15 epithelial-cadherin (E-cadherin)-positive cases in o-comp (79&#37;) and nine positive cases in s-comp (43&#37;). The difference between sarcomatous HCC and ordinary HCC in E-cadherin-positive tumor prevalence was significant (P < 0.05). The Ki-67 (MIB1) labeling index ratio was 127 +/- 40 in s-comp and 80 +/- 33 in o-comp, and there was a greater tendency to have an ability to multiply in s-comp than in o-comp (P = 0.096). CONCLUSION: This study indicated that the loss of E-cadherin related to a morphological alteration in sarcomatous HCC; however, no relationship in respect to the malignant potential was found.

DOI： 10.1046/j.1440-1746.2003.02888.x

Language：English   Publishing type：Research paper (scientific journal)  

The cytokeratins phenotype is largely preserved during neoplastic transformation and tumor development. We evaluated the immunoreactivity of biliary epithelial markers keratin 903 and cytokeratin 7 and 19 for intrahepatic cholangiocarcinoma, and compared the results with those for biliary dysplasia and hepatocellular carcinoma. Reactivity with keratin 903 was weakly expressed and increased after the expression of cytokeratin 7 and 19 during human intrahepatic bile duct development. More than 80&#37; of cases of biliary dysplasia showed positive reactivity with keratin 903. Of the 30 cases of hepatocellular carcinoma, 3 (10&#37;), 6 (20&#37;), and 1 (3&#37;) showed positive reactivity with Keratin 903 and cytokeratin 7 and 19, respectively. Among the 73 cases of intrahepatic cholangiocarcinoma, 54 (74&#37;), 66 (90&#37;), and 61 (84&#37;) showed positive reactivity with keratin 903 and cytokeratin 7 and 19, respectively. On clinicopathologic examination of intrahepatic cholangiocarcinomas, reduced keratin 903 reactivity was significantly higher in tumors with an expansive growth pattern (P <.0001), in those with medullary-type stromal reaction (P =.0327), in those without perineural invasion (P =.0001), and in those without lymph node metastasis (P =.0015). In addition, the reactivity with Keratin 903 was directly correlated with expression of cytokeratin 7 and 19 (P =.0153 and P <.0001, respectively). Cases showing reduced keratin 903 reactivity were characterized by a distinctive morphology indicating an hepatocellular carcinoma-like pattern. Multivariate analysis of overall survival revealed that keratin 903 reactivity was a significantly independent prognostic factor. In conclusion, patients with intrahepatic cholangiocarcinoma showing reduced keratin 903 reactivity had a favorable prognosis. Remarkably, the cytokeratin phenotype of intrahepatic cholangiocarcinoma was correlated with the morphologic appearance of intrahepatic cholangiocarcinoma.

DOI： 10.1097/01.MP.0000032537.82380.69

Language：English   Publishing type：Research paper (scientific journal)  

The cytokeratins phenotype is largely preserved during neoplastic transformation and tumor development. We evaluated the immunoreactivity of biliary epithelial markers keratin 903 and cytokeratin 7 and 19 for intrahepatic cholangiocarcinoma, and compared the results with those for biliary dysplasia and hepatocellular carcinoma. Reactivity with keratin 903 was weakly expressed and increased after the expression of cytokeratin 7 and 19 during human intrahepatic bile duct development. More than 80&#37; of cases of biliary dysplasia showed positive reactivity with keratin 903. Of the 30 cases of hepatocellular carcinoma, 3 (10&#37;), 6 (20&#37;), and 1 (3&#37;) showed positive reactivity with Keratin 903 and cytokeratin 7 and 19, respectively. Among the 73 cases of intrahepatic cholangiocarcinoma, 54 (74&#37;), 66 (90&#37;), and 61 (84&#37;) showed positive reactivity with keratin 903 and cytokeratin 7 and 19, respectively. On clinicopathologic examination of intrahepatic cholangiocarcinomas, reduced keratin 903 reactivity was significantly higher in tumors with an expansive growth pattern (P <.0001), in those with medullary-type stromal reaction (P =.0327), in those without perineural invasion (P =.0001), and in those without lymph node metastasis (P =.0015). In addition, the reactivity with Keratin 903 was directly correlated with expression of cytokeratin 7 and 19 (P =.0153 and P <.0001, respectively). Cases showing reduced keratin 903 reactivity were characterized by a distinctive morphology indicating an hepatocellular carcinoma-like pattern. Multivariate analysis of overall survival revealed that keratin 903 reactivity was a significantly independent prognostic factor. In conclusion, patients with intrahepatic cholangiocarcinoma showing reduced keratin 903 reactivity had a favorable prognosis. Remarkably, the cytokeratin phenotype of intrahepatic cholangiocarcinoma was correlated with the morphologic appearance of intrahepatic cholangiocarcinoma.

DOI： 10.1097/01.MP.0000032537.82380.69

Language：English   Publishing type：Research paper (scientific journal)  

It has been shown that atypical reactive bile ductules (ARBD) display positive immunoreactivity of neural cell adhesion molecules (NCAM) and bcl-2. We investigated the clinicopathological features of intrahepatic cholangiocarcinoma (CC) arising in cases of viral hepatitis B or C (VHBC) and examined their relation to ARBD by means of immunohistochemical analysis. Sixty-eight surgical cases with CC were included in this study. The cause of the background liver disease was hepatitis B surface antigen (HBsAg)(+) in eight cases, antihepatitis C virus antibody (HCVAb)(+) in 13 cases, both HBsAg(+) and HCVAb(+) in one case, and both HBsAg(-) and HCVAb(-) in 46 cases. The average age of patients with CC arising in the HBsAg(+) group was significantly less than that of patients with CC in the HCVAb(+) group (P = 0.0192). Immunohistochemically, CC arising in the HBsAg(+) and HCVAb(+) groups was correlated with coexpression of NCAM/bcl-2 in the tumor cells (P = 0.0068 and P = 0.0382, respectively). Among the 12 cases of CC coexpressing NCAM/bcl-2, 11 were of mass-forming and peripheral type (P = 0.0437), and lymph node metastasis was a rare finding compared with CC showing negative coexpression of NCAM/bcl-2 (P = 0.0213). The tumor cells of CCs arising in VHBC have some characteristics of ARBD. In such tumors, because lymph node metastases were rarely seen and lymph node dissection did not improve patient's survival, lymph node dissection can be limited.

DOI： 10.1046/j.1440-1827.2002.01349.x

Language：English   Publishing type：Research paper (scientific journal)  

It has been shown that atypical reactive bile ductules (ARBD) display positive immunoreactivity of neural cell adhesion molecules (NCAM) and bcl-2. We investigated the clinicopathological features of intrahepatic cholangiocarcinoma (CC) arising in cases of viral hepatitis B or C (VHBC) and examined their relation to ARBD by means of immunohistochemical analysis. Sixty-eight surgical cases with CC were included in this study. The cause of the background liver disease was hepatitis B surface antigen (HBsAg)(+) in eight cases, antihepatitis C virus antibody (HCVAb)(+) in 13 cases, both HBsAg(+) and HCVAb(+) in one case, and both HBsAg(-) and HCVAb(-) in 46 cases. The average age of patients with CC arising in the HBsAg(+) group was significantly less than that of patients with CC in the HCVAb(+) group (P = 0.0192). Immunohistochemically, CC arising in the HBsAg(+) and HCVAb(+) groups was correlated with coexpression of NCAM/bcl-2 in the tumor cells (P = 0.0068 and P = 0.0382, respectively). Among the 12 cases of CC coexpressing NCAM/bcl-2, 11 were of mass-forming and peripheral type (P = 0.0437), and lymph node metastasis was a rare finding compared with CC showing negative coexpression of NCAM/bcl-2 (P = 0.0213). The tumor cells of CCs arising in VHBC have some characteristics of ARBD. In such tumors, because lymph node metastases were rarely seen and lymph node dissection did not improve patient's survival, lymph node dissection can be limited.

DOI： 10.1046/j.1440-1827.2002.01349.x

Language：English   Publishing type：Research paper (scientific journal)  

Thymidine phosphorylase (TP), an important regulator of angiogenesis, is correlated with progression, metastasis, and prognosis in various types of tumor. In contrast, both positive and negative effects of thrombospondin-1 (TSP-1) on angiogenesis have been reported. In the present study, we examined the expression of TP and TSP-1 in carcinoma cells in 67 primary intrahepatic cholangiocarcinomas (ICCs) immunohistochemically and its correlation with angiogenesis, clinicopathological features, and prognosis. Twenty-six (38.8&#37;) cases were classified as exhibiting positive TP expression. TP expression showed a significant correlation with vascular invasion, lymphatic permeation, perineural invasion, and lymph node metastasis. Thirty-four (50.7&#37;) cases were classified as exhibiting positive TSP-1 expression. TSP-1 expression was significantly correlated with only lymphatic permeation. The microvessel count in positive TP expression cases was significantly higher than that in negative cases. In contrast, the microvessel count in negative TSP-1 expression cases was significantly higher than that in positive cases. Survival in patients who were positive for both TP and TSP-1 expression was significantly poor. Our results suggest that the increased TP expression and decreased TSP-1 expression contribute to angiogenesis, but that the role of angiogenesis in ICC is not closely related to tumor aggressiveness. The TP and TSP-1 expression in ICC may enhance tumor aggressiveness.

DOI： 10.1177/106689690201000108

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: The long-term prognosis after resection for patients with hepatocellular carcinoma is still unsatisfactory because of the high recurrence rate. The survival of patients with multiple intrahepatic or extrahepatic recurrence is especially poor. METHODS: Among the patients who underwent hepatic resection for hepatocellular carcinoma between 1981 and 2000, 216 patients with 3 or less than 3 intrahepatic recurrences (group B); 156 patients with more than 3 intrahepatic recurrences, extrahepatic recurrences, or both (group C); and 51 patients who survived more than 5 years without recurrence (group A) were clinicopathologically studied. RESULTS: The period to recurrence of group C was significantly earlier than that of group B and also showed a significantly poor prognosis after recurrence. Tumor factors, including size, portal venous invasion, intrahepatic metastasis, histologic grade, or the number of tumors at resection in group C was significantly worse than in groups A and B. Although no differences are recognized in the tumor factors between groups A and B, except for the alpha-fetoprotein level, liver function in group B was significantly worse than that in group A. In addition, the frequency of hepatitis B surface antigen in group B and that of hepatitis C virus in group B was significantly less and higher than that in group A, respectively. CONCLUSION: Similar to extrahepatic metastasis, multinodular recurrences are also mainly caused by metastatic recurrence from the main tumor by means of the portal system, and recurrences with up to 3 intrahepatic nodules are mainly caused by metachronous multicentric hepatocarcinogenesis. Because the mechanisms of recurrence differed, determining the patterns of recurrence on the basis of the clinicopathologic findings is important for selecting the optimal postoperative therapy for each individual patient.

DOI： 10.1067/msy.2002.119496

Language：English   Publishing type：Research paper (scientific journal)  

Intrahepatic cholangiocarcinoma (IHCC) is a primary adenocarcinoma of the liver, arising from the intrahepatic bile ducts. The prognosis is generally poor because locoregional extension is usually advanced at the time of diagnosis. Even after a resection, the outcome for patients with advanced IHCC is extremely poor, and the presence of lymph node metastasis has been reported in most previous studies to be the worst prognostic factor after a resection. There are no clear guidelines on lymph node dissection with IHCC. In this article, we review the mode of invasion and the therapeutic modalities: hepatic resection, lymph node dissection, liver transplantation, radiation, and chemotherapy for IHCC.

DOI： 10.1067/msy.2002.119498

Language：English   Publishing type：Research paper (scientific journal)  

Thymidine phosphorylase (TP), an important regulator of angiogenesis, is correlated with progression, metastasis, and prognosis in various types of tumor. In contrast, both positive and negative effects of thrombospondin-1 (TSP-1) on angiogenesis have been reported. In the present study, we examined the expression of TP and TSP-1 in carcinoma cells in 67 primary intrahepatic cholangiocarcinomas (ICCs) immunohistochemically and its correlation with angiogenesis, clinicopathological features, and prognosis. Twenty-six (38.8&#37;) cases were classified as exhibiting positive TP expression. TP expression showed a significant correlation with vascular invasion, lymphatic permeation, perineural invasion, and lymph node metastasis. Thirty-four (50.7&#37;) cases were classified as exhibiting positive TSP-1 expression. TSP-1 expression was significantly correlated with only lymphatic permeation. The microvessel count in positive TP expression cases was significantly higher than that in negative cases. In contrast, the microvessel count in negative TSP-1 expression cases was significantly higher than that in positive cases. Survival in patients who were positive for both TP and TSP-1 expression was significantly poor. Our results suggest that the increased TP expression and decreased TSP-1 expression contribute to angiogenesis, but that the role of angiogenesis in ICC is not closely related to tumor aggressiveness. The TP and TSP-1 expression in ICC may enhance tumor aggressiveness.

DOI： 10.1177/106689690201000108

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: The long-term prognosis after resection for patients with hepatocellular carcinoma is still unsatisfactory because of the high recurrence rate. The survival of patients with multiple intrahepatic or extrahepatic recurrence is especially poor. METHODS: Among the patients who underwent hepatic resection for hepatocellular carcinoma between 1981 and 2000, 216 patients with 3 or less than 3 intrahepatic recurrences (group B); 156 patients with more than 3 intrahepatic recurrences, extrahepatic recurrences, or both (group C); and 51 patients who survived more than 5 years without recurrence (group A) were clinicopathologically studied. RESULTS: The period to recurrence of group C was significantly earlier than that of group B and also showed a significantly poor prognosis after recurrence. Tumor factors, including size, portal venous invasion, intrahepatic metastasis, histologic grade, or the number of tumors at resection in group C was significantly worse than in groups A and B. Although no differences are recognized in the tumor factors between groups A and B, except for the alpha-fetoprotein level, liver function in group B was significantly worse than that in group A. In addition, the frequency of hepatitis B surface antigen in group B and that of hepatitis C virus in group B was significantly less and higher than that in group A, respectively. CONCLUSION: Similar to extrahepatic metastasis, multinodular recurrences are also mainly caused by metastatic recurrence from the main tumor by means of the portal system, and recurrences with up to 3 intrahepatic nodules are mainly caused by metachronous multicentric hepatocarcinogenesis. Because the mechanisms of recurrence differed, determining the patterns of recurrence on the basis of the clinicopathologic findings is important for selecting the optimal postoperative therapy for each individual patient.

DOI： 10.1067/msy.2002.119496

Language：English   Publishing type：Research paper (scientific journal)  

Intrahepatic cholangiocarcinoma (IHCC) is a primary adenocarcinoma of the liver, arising from the intrahepatic bile ducts. The prognosis is generally poor because locoregional extension is usually advanced at the time of diagnosis. Even after a resection, the outcome for patients with advanced IHCC is extremely poor, and the presence of lymph node metastasis has been reported in most previous studies to be the worst prognostic factor after a resection. There are no clear guidelines on lymph node dissection with IHCC. In this article, we review the mode of invasion and the therapeutic modalities: hepatic resection, lymph node dissection, liver transplantation, radiation, and chemotherapy for IHCC.

DOI： 10.1067/msy.2002.119498

Language：Japanese  

Language：Others   Publishing type：Research paper (scientific journal)  

We aimed to clarify the clinical significance of des-γ-carboxy prothrombin (DCP) levels in both hepatocellular carcinoma (HCC) and liver tissues with a special reference to the relationship between DCP level in non-cancerous parts of the liver and the multicentric occurrence of HCC. Twenty-eight patients with HCC, who underwent hepatectomy, were studied. Surgical specimens were obtained from both HCC and non-cancerous liver of each patient. After the preparation of the liver tissues, including tissues with HCC, the DCP levels both in HCC and non-cancerous liver tissue were measured using an electro-chemiluminescence immunoassay. The correlation was investigated between DCP levels and other clinicopathological factors. The DCP level of HCC ranged from 55 to 77 735 U/0.1 g tissue weight, with a median of 2801, while the DCP level of non-cancerous parts of the liver ranged from 24 to 721 U/0.1 g tissue weight, with a median of 86. The DCP level in the liver tissue in patients having a multicentric occurrence of HCC was significantly higher than that in patients without multicentric occurrence of HCC. The logarithm of the plasma DCP level correlated with that of the DCP level in HCC (correlation coefficient = 0.46; P < 0.05). No significant correlation was found between the DCP level in HCC and other clinicopathological parameters. The DCP level in non-cancerous parts of the liver with simultaneous multicentric occurrence of HCC was significantly higher than that in the liver without multicentric HCC. Furthermore, the DCP level in non-cancerous parts of the liver was one of the most important predictable factors of the multicentric occurrence of HCCs among various clinicopathological factors. Therefore, the DCP level may have an important role in hepatocarcinogenesis. (C) 2000 Elsevier Science Ireland Ltd.

DOI： 10.1016/S0304-3835(00)00539-5

Language：Others   Publishing type：Research paper (scientific journal)  

We aimed to clarify the clinical significance of des-γ-carboxy prothrombin (DCP) levels in both hepatocellular carcinoma (HCC) and liver tissues with a special reference to the relationship between DCP level in non-cancerous parts of the liver and the multicentric occurrence of HCC. Twenty-eight patients with HCC, who underwent hepatectomy, were studied. Surgical specimens were obtained from both HCC and non-cancerous liver of each patient. After the preparation of the liver tissues, including tissues with HCC, the DCP levels both in HCC and non-cancerous liver tissue were measured using an electro-chemiluminescence immunoassay. The correlation was investigated between DCP levels and other clinicopathological factors. The DCP level of HCC ranged from 55 to 77 735 U/0.1 g tissue weight, with a median of 2801, while the DCP level of non-cancerous parts of the liver ranged from 24 to 721 U/0.1 g tissue weight, with a median of 86. The DCP level in the liver tissue in patients having a multicentric occurrence of HCC was significantly higher than that in patients without multicentric occurrence of HCC. The logarithm of the plasma DCP level correlated with that of the DCP level in HCC (correlation coefficient = 0.46; P < 0.05). No significant correlation was found between the DCP level in HCC and other clinicopathological parameters. The DCP level in non-cancerous parts of the liver with simultaneous multicentric occurrence of HCC was significantly higher than that in the liver without multicentric HCC. Furthermore, the DCP level in non-cancerous parts of the liver was one of the most important predictable factors of the multicentric occurrence of HCCs among various clinicopathological factors. Therefore, the DCP level may have an important role in hepatocarcinogenesis. (C) 2000 Elsevier Science Ireland Ltd.

DOI： 10.1016/S0304-3835(00)00539-5

Language：Others   Publishing type：Research paper (scientific journal)  

Background: Assessment of clinicopathologic characteristics and postoperative prognoses for patients with multicentric hepatocellular carcinoma (HCC) is important to determine not only a need to operate, but also an appropriate treatment after hepatic resection. Study Design: Between May 1990 and April 1998, among 116 patients with an initial hepatectomy for HCC measuring 3 cm or less in maximum diameter, 34 patients had multicentric HCC (MC group), and 82 patients had single nodular HCC (SN group). To clarify the clinicopathologic features of patients in the MC group versus the SN group, we compared both the clinicopathologic parameters and the postoperative prognosis after curative hepatectomy between the two groups. Results: The percentages of patients positive for hepatitis B surface antigen and hepatitis C virus antibody were not significantly different between the two groups. No differences were noted in pathologic characteristics of the main tumor or tumor markers. On the other hand, in the MC group, the percentage of patients evaluated in a Child's classification as either B or C was significantly higher (p < 0.05) than that of patients in the SN group, indicating that patients with multicentric HCC have a poor hepatic functional reserve. Both survival and disease-free survival of patients in the MC group who underwent a curative hepatectomy did not differ statistically from those in the SN group. Conclusions: Our results indicate that hepatic resection is useful, even for patients with multicentric HCC, if a curative hepatectomy can be performed and liver function can be saved, despite their poor hepatic functional reserve. (C) 2000 by the American College of Surgeons.

DOI： 10.1016/S1072-7515(99)00268-9

Language：Others   Publishing type：Research paper (scientific journal)  

Background: Assessment of clinicopathologic characteristics and postoperative prognoses for patients with multicentric hepatocellular carcinoma (HCC) is important to determine not only a need to operate, but also an appropriate treatment after hepatic resection. Study Design: Between May 1990 and April 1998, among 116 patients with an initial hepatectomy for HCC measuring 3 cm or less in maximum diameter, 34 patients had multicentric HCC (MC group), and 82 patients had single nodular HCC (SN group). To clarify the clinicopathologic features of patients in the MC group versus the SN group, we compared both the clinicopathologic parameters and the postoperative prognosis after curative hepatectomy between the two groups. Results: The percentages of patients positive for hepatitis B surface antigen and hepatitis C virus antibody were not significantly different between the two groups. No differences were noted in pathologic characteristics of the main tumor or tumor markers. On the other hand, in the MC group, the percentage of patients evaluated in a Child's classification as either B or C was significantly higher (p < 0.05) than that of patients in the SN group, indicating that patients with multicentric HCC have a poor hepatic functional reserve. Both survival and disease-free survival of patients in the MC group who underwent a curative hepatectomy did not differ statistically from those in the SN group. Conclusions: Our results indicate that hepatic resection is useful, even for patients with multicentric HCC, if a curative hepatectomy can be performed and liver function can be saved, despite their poor hepatic functional reserve. (C) 2000 by the American College of Surgeons.

DOI： 10.1016/S1072-7515(99)00268-9

Event date： 2024.1

Language：Japanese  

Venue：ホテルニューオータニ博多   Country：Japan  

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Event date： 2023.11

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：福岡市   Country：Japan  

Event date： 2023.11

Language：Japanese  

Venue：福岡市   Country：Japan  

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Event date： 2023.7

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：大阪府   Country：Japan  

Event date： 2023.7

Language：Japanese  

Venue：大阪府   Country：Japan  

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