記述言語：英語   出版者・発行元：Wiley  

Background / Pancreatic neuroendocrine tumors (PanNETs) show heterogeneity, including temporal shifts in proliferation and hormone production; however, their clinical implications remain uncertain. / Methods / This retrospective study included 114 patients with metastatic or recurrent PanNETs at Kyushu University Hospital. Paired specimens from 46 patients (27 synchronous metastases and 19 recurrences) were evaluated for Ki-67 index and tumor grade. Proliferation change was defined as grade progression or a ≥ 10% absolute Ki-67 increase. Hormonal phenotype changes were assessed in all patients. / Results / In metastases, mean Ki-67 increased from 12.3% to 16.4% (p = 0.0043); 22.2% showed a ≥ 10% increase, and 33.3% progressed in grade. In recurrences, Ki-67 increased from 8.8% to 9.3% (p = 0.8256); 15.8% showed a ≥ 10% increase, and 21.1% progressed in grade. Median progression-free survival was 7.8 months in metastases and 17.1 months in recurrences. Median overall survival was significantly longer in the recurrence group (124.8 vs. 32.5 months, p = 0.003). Hormonal transformation occurred in six patients (5.3%), mostly during progressive hepatic disease. / Conclusion / A subset of PanNETs exhibited increased proliferation of metastases or recurrence without detrimental survival effects, possibly because of timely treatment adjustments. Rebiopsy may be useful for detecting proliferative changes, whereas hormonal shifts highlight tumor heterogeneity and warrant continued clinical and biochemical monitoring.

CiNii Research

記述言語：英語   出版者・発行元：American Journal of Surgical Pathology  

Gastric-type intraductal papillary neoplasm of the bile duct (G-type IPNB) remains an underexplored subtype of IPNBs, with limited molecular characterization. This study aimed to elucidate the clinicopathologic and genomic features of G-type IPNB to better understand its malignant potential and progression. Eighty-three IPNB cases, including 21 G-type IPNBs, were analyzed. The clinicopathologic features and prognosis of G-type IPNB were compared with those of other subtypes. Targeted sequencing was performed in 15 G-type cases, comprising 5 with high-grade dysplasia (HGD), 6 with invasive carcinoma (INV), and 4 with lymph node metastasis (LNM). The samples displayed varying histologic grades. The G-type frequently exhibited HGD; however, invasive G-type IPNBs showed significantly higher rates of lymph node metastasis compared with the other subtypes (P=0.044). Recurrent mutations were detected in KRAS (60%), STK11 (40%), KMT2C (40%), APC (20%), CTNNB1 (13%), and TP53 (13%). Mutational profiles remained highly concordant across histologic grades, with no significant new mutations accumulating during tumor progression. KRAS mutations were predominantly found in preinvasive lesions, supporting their role in early tumorigenesis. STK11 mutations were exclusive to INV and LNM cases, but not detected in HGD cases. Notably, identical mutations were uniformly carried over from preinvasive lesions to invasive carcinoma and metastatic lymph node lesions. Immunohistochemically, aberrant STK11 expression was specific to the G-type compared with other subtypes (P=0.030). These findings highlight the unique clinicopathologic and molecular features of G-type IPNB, including the association of STK11 mutations with invasive behavior and their potential as indicators of tumor progression.

DOI： 10.1097/PAS.0000000000002451

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記述言語：英語   出版者・発行元：一般社団法人 日本内科学会  

A 75-year-old man diagnosed with esophageal cancer and lung metastasis received a combination of fluorouracil, cisplatin, and pembrolizumab. During pembrolizumab maintenance therapy, lymphoproliferative lesions at the lips and mouth and multiple lymph node swellings appeared. Histologically, Epstein-Barr virus (EBV)-encoded RNA was positive, and EBV-DNA was detected in the blood. The patient was diagnosed with other iatrogenic immunodeficiency-associated lymph proliferative disorders (OIIA-LPDs) related to EBV activation induced by pembrolizumab. Rituximab was administered, resulting in the improvement of the OIIA-LPD. The emergence of an OIIA-LPD merits close attention in patients receiving immune checkpoint inhibitors.

DOI： 10.2169/internalmedicine.3743-24

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記述言語：英語   出版者・発行元：Cancer Research Communications  

Pancreatic ductal adenocarcinoma (PDA) arises from distinct precursor lesions, primarily pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasm (IPMN). Unlike PanIN, IPMN is a cystic lesion detectable by imaging, providing an opportunity for early intervention. However, the molecular determinants guiding the formation of PanIN versus IPMN remain poorly understood. In this study, we uncover a previously unrecognized role for nuclear factor erythroid 2–related factor 2 (NRF2), a master regulator of redox homeostasis, in dictating pancreatic precursor lesion fate. Although NRF2 is known to promote PanIN formation and sustain PDA, we found that active NRF2 levels are significantly lower in human IPMN compared with PanIN and PDA. Using a conditional NRF2 knockout mouse model, we demonstrate that NRF2 loss significantly increases IPMN-like cystic tumor formation in KRAS^G12Dmutant pancreatic epithelium, revealing an unexpected suppressive role of NRF2 in IPMN development. Mechanistically, NRF2 suppresses IPMN formation through redox-independent transcriptional repression of SAM pointed domain–containing Ets transcription factor and MUC6, key markers of IPMN. These findings establish NRF2 as a lesion-specific regulator of pancreatic tumorigenesis, providing new molecular insights into PDA progression and potential biomarkers for early detection and risk stratification.

DOI： 10.1158/2767-9764.CRC-25-0107

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記述言語：英語   出版者・発行元：Cancer Science  

Ovarian carcinosarcoma (OCS) is a rare and aggressive tumor, and the development of its sarcomatous component is believed to be due to epithelial–mesenchymal transition (EMT). The SWIch/sucrose nonfermentable chromatin remodeling factor (CRF) is closely related to EMT; however, the relationship between CRF and EMT in OCS remains unclear. In this study, we analyzed the protein expression of CRFs, including ARID1A and SMARCA4, and their downstream mRNA expression in 28 OCS cases, two fallopian tube CS cases, and one peritoneal CS case. ARID1A and SMARCA4 exhibited a histological type-specific loss of protein expression in 5 of 11 (45%) endometrioid cases and all 5 serous/homologous OCS cases, respectively. The mRNA analysis suggested that sarcomatogenesis is induced by the transforming growth factor-β and Hippo signaling pathways, both of which regulate YAP1. Immunostaining for YAP1 suggested YAP1-associated sarcomatogenesis in the CRF-retained group, whereas YAP1-unassociated sarcomatogenesis was suggested in the CRF-reduced group. High-grade serous carcinoma cell line experiments showed that the transcriptome of the SMARCA4-knockdown group showed lower expression of the epithelial gene CDH1 and higher expression of mesenchymal genes such as VIM, ZEB1, and SNAI1 than the control group. Moreover, cell adhesion disappeared and cell morphology changed to a spindle shape, indicating sarcomatogenesis. In conclusion, this study reveals a mechanism for sarcoma development in OCS and provides novel therapeutic possibilities.

DOI： 10.1111/cas.16423

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記述言語：英語   出版者・発行元：シュプリンガー・ジャパン(株)  

記述言語：英語   出版者・発行元：Gastric Cancer  

Background: Hepatoid adenocarcinoma of the stomach (HAS), a subtype of gastric cancer (GC), includes multiple tumor components, such as enteroblastic and tubular adenocarcinoma components. However, which component mostly contributes to the aggressive behavior of HAS remains unclear. Moreover, the role of tumor-associated macrophages (TAMs) has not been explored in HAS. This study evaluated the clinical significance of the proportion of the hepatoid component within the tumor, CD163 + macrophages, and macrophage colony-stimulating factor-1 (CSF-1) in HAS. Methods: In total, 56 cases of primary HAS were analyzed. In each case, hepatoid (HC), enteroblastic (EC), and tubular (TC) components were identified, and the ratio of HC to the entire tumor (hepatoid component ratio, HCR) was assessed to examine the correlation between HCR and clinicopathological features. Immunohistochemical staining for CD163 and CSF-1 was performed, and differences in immunohistochemical results among the three tumor components were analyzed. In each tumor component, the prognostic impact of CD163 and CSF-1 was examined. Results: A high HCR was associated with worse overall survival (OS). CD163 + TAMs and CSF-1 immunoreactivity score in HC were significantly higher than those in the other components. High infiltration of CD163 + TAMs and a high CSF-1 immunoreactivity score in HC were associated with an aggressive course and worse OS. Multivariate analysis revealed the proportion of HC in HAS as an independent prognostic factor (HR = 3.176, p = 0.006). Conclusions: The HCR and CD163 + TAMs may be useful prognostic predictors, and TAMs may be novel therapeutic targets of HAS.

DOI： 10.1007/s10120-024-01562-x

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記述言語：英語   出版者・発行元：シュプリンガー・ジャパン(株)  

膵管腺癌患者由来オルガノイド(PDO)を確立し、サブタイプ分類と臨床転帰予測におけるその応用を評価した。超音波内視鏡下穿刺吸引法(EUS-FNB)で採取した腫瘍検体を用いてPDOライブラリを構築し、形態学的評価、RNA-seq分析、in vitro薬物反応アッセイを行った。PDOを用いた分析による治療反応や予後予測可能性を前向き臨床研究で評価した。PDO確立の全体的成功率は71%で、EUS-FNB、肝生検、外科的切除で得た膵管腺癌検体での成功率はそれぞれ74%、44%、71%であった。PDOは形態学的には腺様構造(GL型)と高密度増殖構造(DP型)に分類され、RNA-seq解析では両形態学的サブタイプが古典的と基底様の分子的サブタイプに対応していた。形態学的分類は臨床治療反応と予後を予測可能で、GL型患者の全生存期間中央値はDP型患者よりも有意に長かった。GL型はDP型よりもin vitroでのゲムシタビンに対する反応が良好であったが、DP型の薬剤反応はERK阻害剤とクロロキンの併用で改善した。EUS-FNBは膵管腺癌PDOの確立に有用で、確立されたPDOは短期的には形態学的評価に基づくサブタイプ予測および最適な治療選択に使用可能であった。

記述言語：日本語   出版者・発行元：(一社)日本消化器外科学会  

記述言語：英語   出版者・発行元：Journal of Gastroenterology  

Background: Recently, two molecular subtypes of pancreatic ductal adenocarcinoma (PDAC) have been proposed: the “Classical” and “Basal-like” subtypes, with the former showing better clinical outcomes than the latter. However, the “molecular” classification has not been applied in real-world clinical practice. This study aimed to establish patient-derived organoids (PDOs) for PDAC and evaluate their application in subtype classification and clinical outcome prediction. Methods: We utilized tumor samples acquired through endoscopic ultrasound-guided fine-needle biopsy and established a PDO library for subsequent use in morphological assessments, RNA-seq analyses, and in vitro drug response assays. We also conducted a prospective clinical study to evaluate whether analysis using PDOs can predict treatment response and prognosis. Results: PDOs of PDAC were established at a high efficiency (> 70%) with at least 100,000 live cells. Morphologically, PDOs were classified as gland-like structures (GL type) and densely proliferating inside (DP type) less than 2 weeks after tissue sampling. RNA-seq analysis revealed that the “morphological” subtype (GL vs. DP) corresponded to the “molecular” subtype (“Classical” vs. “Basal-like”). The “morphological” classification predicted the clinical treatment response and prognosis; the median overall survival of patients with GL type was significantly longer than that with DP type (P < 0.005). The GL type showed a better response to gemcitabine than the DP type in vitro, whereas the drug response of the DP type was improved by the combination of ERK inhibitor and chloroquine. Conclusions: PDAC PDOs help in subtype determination and clinical outcome prediction, thereby facilitating the bench-to-bedside precision medicine for PDAC.

DOI： 10.1007/s00535-024-02103-0

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記述言語：英語   出版者・発行元：Journal of Experimental and Clinical Cancer Research  

Background: Although immune checkpoint blockade (ICB) therapy has proven to be extremely effective at managing certain cancers, its efficacy in treating pancreatic ductal adenocarcinoma (PDAC) has been limited. Therefore, enhancing the effect of ICB could improve the prognosis of PDAC. In this study, we focused on the histamine receptor H1 (HRH1) and investigated its impact on ICB therapy for PDAC. Methods: We assessed HRH1 expression in pancreatic cancer cell (PCC) specimens from PDAC patients through public data analysis and immunohistochemical (IHC) staining. The impact of HRH1 in PCCs was evaluated using HRH1 antagonists and small hairpin RNA (shRNA). Techniques including Western blot, flow cytometry, quantitative reverse transcription polymerase chain reaction (RT-PCR), and microarray analyses were performed to identify the relationships between HRH1 and major histocompatibility complex class I (MHC-I) expression in cancer cells. We combined HRH1 antagonism or knockdown with anti-programmed death receptor 1 (αPD-1) therapy in orthotopic models, employing IHC, immunofluorescence, and hematoxylin and eosin staining for assessment. Results: HRH1 expression in cancer cells was negatively correlated with HLA-ABC expression, CD8⁺ T cells, and cytotoxic CD8⁺ T cells. Our findings indicate that HRH1 blockade upregulates MHC-I expression in PCCs via cholesterol biosynthesis signaling. In the orthotopic model, the combined inhibition of HRH1 and αPD-1 blockade enhanced cytotoxic CD8⁺ T cell penetration and efficacy, overcoming resistance to ICB therapy. Conclusions: HRH1 plays an immunosuppressive role in cancer cells. Consequently, HRH1 intervention may be a promising method to amplify the responsiveness of PDAC to immunotherapy.

DOI： 10.1186/s13046-024-03060-5

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出版者・発行元：東京医学社  

DOI： 10.24479/endo.0000001409

CiNii Research

記述言語：英語   出版者・発行元：Clinical Journal of Gastroenterology  

Pancreatic neuroendocrine tumors (PanNETs) are rare malignant tumors that occur in the pancreas. They are divided into functioning and non-functioning tumors based on the presence or absence of their specific hormonal hyper-expression symptoms. Adrenocorticotropic hormone (ACTH)-producing PanNETs are rare, functional tumors, and their clinical characteristics and outcomes have not been well reported. Here, we report the cases of two patients with PanNETs who presented with ectopic ACTH syndrome (EAS) during the course of their disease. Case 1 involved a non-functioning PanNET at the time of surgery. During treatment for recurrent liver metastases, the patient presented with EAS and tumor-associated hypercalcemia, probably due to ACTH and parathyroid hormone-related peptide (PTHrP) production from the liver tumor. Case 2 was a gastrinoma, and similar to Case 1, this patient presented with EAS during the treatment of recurrent liver metastases. It is not uncommon for patients with PanNETs to have multiple hormones and develop secondary hormone secretion during their disease course, although tumor phenotypes differ between primary and metastatic sites. In patients with functioning PanNETs, symptom control with anti-hormonal therapy is essential, in addition to anti-tumor therapy, especially for EAS, which is an endocrine emergency disease that requires prompt diagnosis and treatment.

DOI： 10.1007/s12328-023-01908-5

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記述言語：日本語   出版者・発行元：(一社)日本病理学会  

症例は64歳,男性。腹痛を主訴として受診し,画像検査から胆嚢壁の肥厚および膵頭部に多発嚢胞性病変を指摘された。胆嚢癌およびintraductal papillary mucinous neoplasm(IPMN)の診断で膵頭十二指腸切除,肝床部切除を含む胆嚢摘出術を施行された。肉眼所見で膵頭部を中心に最大6mm程度の小嚢胞が多発,内部に粘液産生は認めなかった。組織学的に好酸性顆粒を有する細胞質をもつ異型に乏しい上皮で裏打ちされる様々なサイズの嚢胞性病変を認めた。免疫染色で同上皮細胞は腺房細胞のマーカーであるBCL10およびtrypsinが陽性であり,以上よりacinar cystic transformation(ACT)と診断した。(著者抄録)

記述言語：英語   出版者・発行元：シュプリンガー・ジャパン(株)  

膵神経内分泌腫瘍(PanNET)は膵臓の稀な腫瘍である。特異的ホルモンの高発現症状の有無により、機能性と非機能性腫瘍に分類される。副腎皮質刺激ホルモン(ACTH)-産生PanNETは稀な機能性腫瘍で、その臨床的特徴と治療成績は十分に明らかにされていない。疾患の経過中に異所性ACTH症候群(EAS)を認めたPanNETの2例を報告した。症例1は手術時には非機能性PanNETであった。再発肝転移の治療中、肝転移巣からのACTHおよび副甲状腺ホルモン関連ペプチド(PTHrP)産生によると考えられるEASおよび腫瘍関連高カルシウム血症が認められた。症例2はガストリノーマで、症例1と同様、再発肝転移の治療中にEASが認められた。原発巣と転移巣で腫瘍表現型が異なっているにも関わらず、PanNET症例が複数のホルモンを有し、疾患の経過中に続発性のホルモン分泌をきたすことは稀ではない。以上より、機能性PanNET症例では、特に迅速な診断と治療が必要な内分泌緊急事態であるEASが認められる場合、抗ホルモン治療による症状の制御が、抗腫瘍治療と共に重要であることが明らかとなった。

記述言語：英語   出版者・発行元：John Wiley & Sons Australia, Ltd  

膵管腺癌(PDAC)は、その診断の遅れと生物学的悪性度から死亡率が高い。PDACの早期診断のための低侵襲スクリーニング法は比較的限られており、本疾患のバイオマーカー同定の優先度は高い。近年の研究で、体液由来の細胞外小胞内microRNA(EV-miR)がPDACの診断に有用である可能性が示された。本研究では、PDAC診断のためのバイオマーカーとして、十二指腸液(DF)から抽出した癌EVと、その中にあるEV-miRの有用性を評価した。複数の膵癌細胞株(Panc-1、SUIT2、MIAPaca2)、ヒト膵管上皮細胞の培養上清、PDAC患者および対照健常者のDFのEV-miRを評価した。超遠心分離法でEVを抽出し、EV-miR-20aの相対的発現を定量した。34例(PDAC群27例、対照群7例)のDF検体を評価のため収集した。EV-miR-20aの相対的発現量は、PDAC群で対照群と比較して有意に高かった(P=0.0025)。さらに、EV-miR-20aの発現は腫瘍の部位に関わらず、それぞれ曲線下領域値0.88および0.88でPDAC群を対照群から識別した。本研究によりDF内にEVが存在することが確認され、これらの標本におけるEV-miR-20aの発現がPDACの診断バイオマーカーとして役立つ可能性が示唆された。

記述言語：英語   出版者・発行元：Den Open  

Background: Pancreatic ductal adenocarcinoma (PDAC) has a high mortality rate owing to its late diagnosis and aggression. In addition, there are relatively few minimally invasive screening methods for the early detection of PDAC, making the identification of biomarkers for this disease a critical priority. Recent studies have reported that microRNAs in extracellular vesicles (EV-miRs) from bodily fluids can be useful for the diagnosis of PDACs. Given this, we designed this study to evaluate the utility of cancer EVs extracted from duodenal fluid (DF) and their resident EV-miRs as potential biomarkers for the detection of PDAC. Methods: EV-miRs were evaluated and identified in the supernatants of various pancreatic cancer cell lines (Panc-1, SUIT2, and MIAPaca2), human pancreatic duct epithelial cells, and the DF from patients with PDAC and healthy controls. EVs were extracted using ultracentrifugation and the relative expression of EV-miR-20a was quantified. Results: We collected a total of 34 DF samples (27 PDAC patients and seven controls) for evaluation and our data suggest that the relative expression levels of EV-miR-20a were significantly higher in patients with PDAC than in controls (p = 0.0025). In addition, EV-miR-20a expression could discriminate PDAC from control patients regardless of the location of the tumor with an area under the curve values of 0.88 and 0.88, respectively. Conclusions: We confirmed the presence of EVs in the DF and suggest that the expression of EV-miR-20a in these samples may act as a potential diagnostic biomarker for PDAC.

DOI： 10.1002/deo2.333

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記述言語：英語   出版者・発行元：John Wiley & Sons Australia, Ltd  

膵管腺癌患者における術前補助化学療法の予後因子について検討し、組織学的検討と免疫学的微小環境因子に基づく膵癌患者のクラスタリングにより治療標的を探索した。術前化学療法としてゲムシタビン+ナブパクリタキセルを投与された患者103例(年齢34～85歳)を対象に、腫瘍への免疫細胞の浸潤に基づいて免疫プロファイルを作成し、患者の転帰および組織学的特徴との相関を解析した。その結果、多変量解析により、腫瘍浸潤好中球が手術先行群と術前化学療法群の両方において独立した予後不良因子として同定された。さらに、患者を腫瘍内への免疫細胞浸潤に基づいて4群に分類した。その結果、腫瘍内へのCD15陽性細胞の浸潤が多く、切除断端の間質が未熟な患者は、術前化学療法群で最も予後不良であった。さらに、mRNA発現と免疫組織化学的特徴の解析から、CXCL8の受容体であるCXCR2が無病生存率および全生存率と相関していることが明らかになった。以上より、断端に未熟な間質を有し、腫瘍内にCD15陽性好中球の浸潤が多い患者は予後が最も不良であり、CXCR2またはCXCL8を標的とする阻害剤による治療が有効であると推察された。

記述言語：英語   出版者・発行元：Cancer Science  

Preoperative treatment is commonly carried out for borderline resectable pancreatic ductal adenocarcinoma (PDAC). However, the relationship between the combination of immune cells in the tumor microenvironment and their intratumoral heterogeneity along with their association with histological findings remains unclear, especially in patients receiving preoperative chemotherapy. We aimed to explore the therapeutic strategies for patients with PDAC with poor prognosis after receiving chemotherapy based on histological and immunological microenvironmental classifications. We investigated the correlation between the prognosis and histological immune microenvironmental factors of patients who initially underwent surgery (n = 100) and were receiving gemcitabine plus nab-paclitaxel (GEM + nabPTX) as preoperative chemotherapy (n = 103). Immune profiles were generated based on immune cell infiltration into the tumor, and their correlation with patient outcomes and histological features was analyzed. Tumor-infiltrating neutrophils (TINs) were identified as independent poor prognostic factors using multivariate analysis in both surgery-first and preoperative chemotherapy groups. The patients were further classified into four groups based on immune cell infiltration into the tumor. Patients with high CD15 infiltration into the tumor and immature stroma at the cancer margins showed the worst prognosis in the preoperative chemotherapy group. The analysis of mRNA expression and immunohistochemical features revealed that CXCR2, the receptor for CXCL8, was correlated with disease-free and overall survival. We inferred that patients with immature stroma at the margins and high infiltration of CD15⁺ neutrophils within the tumor showed the worst prognosis and they could particularly benefit from treatment with inhibitors targeting CXCR2 or CXCL8.

DOI： 10.1111/cas.16060

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：日本語   出版者・発行元：(一社)日本病理学会  

記述言語：英語   出版者・発行元：Modern Pathology  

Mixed-type ampullary carcinoma is a subtype that combines intestinal-type (I-type) and pancreatobiliary-type (PB-type) lesions, but few studies have examined its clinicopathologic features and genetic alterations. The differences in genetic alterations between mixed type and other subtypes, as well as the genetic differences between I-type and PB-type lesions in the mixed type, remain unclear. In this study, we compared the clinicopathologic features and prognosis of 110 ampullary carcinomas classified by hematoxylin and eosin and immunohistochemical staining as follows: 63 PB-type, 35 I-type, and 12 mixed-type carcinomas. A comparative analysis of genetic mutations by targeted sequencing of 24 genes was also performed in 3 I-type cases, 9 PB-type cases, and I and PB-type lesions of 6 mixed-type cases. The mixed subtype had a poorer prognosis than the other subtypes, and there was also a similar tendency in the adjuvant group (n = 22). A total of 49 genetic mutations were detected in all 18 lesions for which genetic alteration was analyzed. No genetic mutations specific to the mixed type were found, and it was not possible to determine genetically whether the mixed type had originally been I or PB type. However, 5 of 6 cases had mutations common to both I and PB-type lesions, and additional mutations were found only in either I or PB-type lesions. In support of this, the mixed type more frequently exhibited genetic heterogeneity intratumorally than the other subtypes. Mixed-type tumors are histologically, immunohistochemically, and genetically heterogeneous, and this heterogeneity is associated with poor prognosis and may affect treatment resistance.

DOI： 10.1016/j.modpat.2023.100181

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記述言語：日本語   出版者・発行元：日本臨床細胞学会-九州連合会  

目的 肝外胆管癌と胆管内乳頭状腫瘍(高異型度)の細胞診断精度を評価すること,陰性・鑑別困難症例を再評価し偽陰性の原因を精査することを目的とする.方法 術前に胆汁細胞診,胆管擦過細胞診が実施され,術後の病理組織診断で診断確定された肝外胆管癌,肝管内乳頭状腫瘍(高異型度),合計178例を用いて検査感度を算出した.また,鑑別困難症例について細胞検査士8名が各人の任意の判定基準で細胞診判定後に,日本臨床細胞学会研究班の貯留胆汁細胞診の細胞判定基準に基づき再評価した.成績 術前細胞診の感度は,肝外胆管癌86.8%,胆管内乳頭状腫瘍88.5%であった.細胞診鑑別困難症例13例を細胞検査士8名が再判定すると,1名以上が陽性とした症例が3例あった.研究班判定基準を用いて評価すると,13例全例で基準上悪性とした検査士が1名以上いたが,各判定項目で所見ありとした検査士の割合は38-71%と低かった.結論 肝外胆管癌と胆管内乳頭状腫瘍の細胞診断は既報と比較し,高い感度であった.鑑別困難症例に対し研究班判定基準を用いると,偽陽性を誘発する危険性があり,判定は慎重になるべきである.診断精度向上には,適切な標本作製,判定トレーニングが重要である.(著者抄録)

記述言語：英語   掲載種別：研究論文（学術雑誌）  

記述言語：英語   出版者・発行元：John Wiley & Sons Australia, Ltd  

融合遺伝子の検出により裏付けられた粘液型脂肪肉腫(MLS)症例の核形態、細胞密度、遺伝的背景を調査し、MLSの予後予測においてより信頼性の高い評価法を検討した。MLS患者64例(年齢中央値48歳)について、核異型を評価するために確立された2つの等級付けシステム(腎細胞癌における世界保健機構/国際泌尿器科病理学会[WHO/ISUP]等級付けおよびフールマン等級付け)を修正し適用した。さらに、形態と細胞密度の詳細なソフトウェアによる評価を行い、DNA変異解析、包括的mRNA発現解析、免疫組織化学検査も行った。その結果、修正フールマン等級付けシステムによる高い核グレード群では、無病生存率が有意に不良であった。修正フールマン高悪性度群では細胞密度が有意に高かったが、それ自体は生存率解析における予後不良因子にはならなかった。修正フールマン高悪性度群では、細胞周期関連遺伝子(FOXM1、PLK1、CDK1など)が有意に発現していた。以上より、MLSの予後予測では、核形態に焦点を当てた評価がより信頼できることが示唆された。

記述言語：英語   出版者・発行元：European Journal of Radiology  

Purpose: To clarify the relationship between extracellular volume (ECV) measured by dual-energy CT (DECT) and efficacy of preoperative neoadjuvant chemotherapy (NAC) in patients with pancreatic ductal adenocarcinoma (PDAC), as compared with single-energy CT (SECT). Methods: We enrolled 67 patients with PDAC who underwent dynamic contrast-enhanced CT with a dual-energy CT system prior to NAC. Attenuation values were measured on unenhanced and the equilibrium-phase 120-kVp equivalent CT images for PDAC and the aorta. ΔHU-tumor, ΔHU-tumor/ΔHU-aorta, and SECT-ECV were calculated. Iodine densities of the tumor and aorta were measured in the equilibrium phase, and DECT-ECV of the tumor was calculated. Response to NAC was evaluated and the correlation between imaging parameters and response to NAC was statistically assessed. Results: Tumor DECT-ECVs were significantly lower in the response group (n = 7) than in the non-response group (n = 60), with most significant difference (p = 0.0104). DECT-ECV showed highest diagnostic value with an Az value of 0.798. When using the optimal cut off value of DECT-ECV (<26.0 %), sensitivity, specificity, accuracy, positive predictive value, and negative value for predicting response group were 71.4 %, 85.0 %, 83.6 %, 35.7 % and 96.2 %, respectively. Conclusion: PDAC with lower DECT-ECV can potentially show better response to NAC. DECT-ECV might be a useful biomarker for predicting response to NAC in patients with PDAC.

DOI： 10.1016/j.ejrad.2023.110756

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記述言語：英語   出版者・発行元：Digestive Diseases  

Background: Neuroendocrine neoplasms of the ampulla of Vater (ampullary NEN) have features of both gastrointestinal and pancreato-biliary (PB) NEN. However, the limited number of studies examining ampullary NEN makes it difficult to clarify their unique characteristics. This study aimed to elucidate the clinical characteristics of ampullary NEN. Methods: We enrolled 162 patients with PB-NEN diagnosed at Kyushu University Hospital between 2011 and 2020. Clinical features, pathological diagnoses, treatments, and prognoses were retrospectively analyzed. We also compared ampullary NEN with pancreatic NEN (PanNEN). Results: We analyzed 10 ampullary NEN cases and 149 PanNEN cases. The ampullary NEN cases consisted of 4 cases of neuroendocrine tumor Grade 1 (NET G1), 1 NET G2 (Grade 2), and 5 neuroendocrine carcinomas (NECs). The incidences of NEC and cholangitis were significantly higher in ampullary NEN than in PanNEN. All ampullary NETs had a submucosal tumor-like appearance, as identified by endoscopic ultrasound-guided fine needle aspiration. We treated small NET G1 (10 mm) with endoscopic papillectomy and large NET G1 with pancreaticoduodenectomy. There were no cases of recurrence after resection. All ampullary NECs presented with the characteristic endoscopic finding of a "crater sign"similar to deep-mining ulcers seen in gastric malignant lymphoma. Four cases underwent surgical resection, and 1 case was unresectable. Two patients who underwent multidisciplinary treatment were maintained without recurrence for over 2 years. Conclusions: Endoscopic findings showed identifiable distinctions between ampullary NETs and NECs.

DOI： 10.1159/000525013

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PubMed

記述言語：日本語   出版者・発行元：一般社団法人 日本消化器外科学会  

<p>症例は61歳の女性で，貧血の精査で行った経口ダブルバルーン内視鏡で空腸中部に頂部に潰瘍を伴う無茎性の隆起性病変を認めた．黒色便，貧血の改善のため腹腔鏡下小腸部分切除を施行した．病理診断で炎症細胞浸潤および一部小葉状の毛細血管増生の所見を認め，pyogenic granulomaと診断した．術後は貧血の改善を認めた．Pyogenic granulomaは皮膚や口腔内に好発する肉芽組織型血管腫であり，消化管での発生はまれである．易出血性であり消化管出血の原因となりうることから原因不明の消化管出血は本症が原因であることがある．</p>

DOI： 10.5833/jjgs.2021.0085

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CiNii Research

記述言語：日本語   出版者・発行元：(一社)日本消化器外科学会  

症例は61歳の女性で,貧血の精査で行った経口ダブルバルーン内視鏡で空腸中部に頂部に潰瘍を伴う無茎性の隆起性病変を認めた.黒色便,貧血の改善のため腹腔鏡下小腸部分切除を施行した.病理診断で炎症細胞浸潤および一部小葉状の毛細血管増生の所見を認め,pyogenic granulomaと診断した.術後は貧血の改善を認めた.Pyogenic granulomaは皮膚や口腔内に好発する肉芽組織型血管腫であり,消化管での発生はまれである.易出血性であり消化管出血の原因となりうることから原因不明の消化管出血は本症が原因であることがある.(著者抄録)

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記述言語：日本語   出版者・発行元：一般社団法人 日本消化器外科学会  

<p>症例は69歳の女性で，食道胃接合部癌に対する手術時に，肝被膜下に5 mm弱の白色結節が散在していた．術中迅速診断で腺癌と診断されたため，手術適応外と判断した．化学療法を施行し，その後の審査腹腔鏡時に再度切除した組織で胆管過誤腫と診断され，後日改めて根治術を施行した．本症例は，初回手術時に採取した組織片が小さく，超音波凝固切開装置による熱変性による細胞の変形が，病理診断の大きな障害になったと考えられる．加えて，原発の食道胃接合部癌が高分化型であり，異型が比較的弱い病変であったことも一因といえる．消化器癌に併存した肝腫瘍の診断において，当疾患の存在も念頭におき，微小な病変であってもその組織構築や細胞形態の維持が不十分となり病理診断に影響しないように，アーチファクトが加わらない美麗な標本を十分量採取するよう心がけるべきである．</p>

DOI： 10.5833/jjgs.2021.0101

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CiNii Research

記述言語：日本語   出版者・発行元：(一社)日本消化器外科学会  

症例は69歳の女性で,食道胃接合部癌に対する手術時に,肝被膜下に5mm弱の白色結節が散在していた.術中迅速診断で腺癌と診断されたため,手術適応外と判断した.化学療法を施行し,その後の審査腹腔鏡時に再度切除した組織で胆管過誤腫と診断され,後日改めて根治術を施行した.本症例は,初回手術時に採取した組織片が小さく,超音波凝固切開装置による熱変性による細胞の変形が,病理診断の大きな障害になったと考えられる.加えて,原発の食道胃接合部癌が高分化型であり,異型が比較的弱い病変であったことも一因といえる.消化器癌に併存した肝腫瘍の診断において,当疾患の存在も念頭におき,微小な病変であってもその組織構築や細胞形態の維持が不十分となり病理診断に影響しないように,アーチファクトが加わらない美麗な標本を十分量採取するよう心がけるべきである.(著者抄録)

記述言語：英語   出版者・発行元：Virchows Archiv  

Intimal sarcoma is one of the most common and well-known primary malignant neoplasms of the aorta and heart. The authors reviewed cases of intimal sarcoma from histological, immunohistochemical and genetic perspectives. Twenty cases of intimal sarcoma were retrieved. Immunohistochemistry and FISH of MDM2 and PDGFRA genes were performed. All 20 tumours were composed of spindle-shaped, stellate, oval or polygonal tumour cells with irregular hyperchromatic nuclei arranged in a haphazard pattern, accompanied by nuclear pleomorphism and frequent mitotic figures. Other histological findings were as follows: abnormal mitosis in 10 cases (50%), necrosis in 15 cases (75%), myxoid stroma in 12 cases (60%), cartilaginous formation in 1 case (5%), haemorrhage in 12 cases (60%) and fibrinous deposition in 14 cases (70%). The tumours were positive for MDM2 in 16 cases (80%), ERG in 4 cases (20%), alpha-smooth muscle actin in 6 cases (30%), desmin in 5 cases (25%) and AE1/AE3 in 4 cases (20%). Immunohistochemical positivity was focal in each case. Loss of H3K27me3 expression was noted in 2 cases (10%). MDM2 and PDGFRA gene amplifications were detected in 11 cases (55%) and 1 case (5%), respectively. Fisher’s exact test revealed a significant correlation between MDM2 gene amplification and myxoid stroma (p = 0.0194). No parameters showed any association with the anatomical location of the tumours. It was suggested that myxoid histology of intimal sarcoma may be associated with MDM2 gene amplification and that intimal sarcoma may be divided into myxoid and non-myxoid types.

DOI： 10.1007/s00428-022-03293-9

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Virchows Archiv  

Mucinous cystic neoplasm (MCN) of the pancreas rarely progresses to invasive carcinoma, but few studies have analyzed genomic alterations involved in its malignant transformation. The relationships of ring finger protein 43 (RNF43) mutations with cytological atypia, RNF43 protein expression, and Wnt signaling proteins in MCN remain unclear. This study included 106 MCN cases, classified into 89 low-grade dysplasia (LG), 9 high-grade dysplasia (HG), and 8 invasive carcinoma (INV). We analyzed HG/INV and LG lesions of 9 HG/INV cases and LG lesions of 9 LG cases using targeted sequencing and confirmed the protein expression of RNF43 and β-catenin. The frequency of RNF43 mutations was significantly higher in HG/INV cases than in LG cases. Furthermore, HG/INV lesions (56%) and LG lesions (33%) of HG/INV cases possessed RNF43 mutation, whereas no such mutation was detected in any LG cases. The expression of RNF43 was reduced in 71% of HG/INV cases and significantly correlated with histological grade and aberrant expression of β-catenin. In 3 of 5 RNF43-mutated cases, the expression of RNF43 was reduced, but there was no significant correlation between RNF43 mutation and protein expression. MCNs frequently harbored KRAS mutations, at rates of 100% in HG/INV lesions and 50% in LG lesions of HG/INV and LG cases. There was no significant difference in mutation frequency in LG lesions between HG/INV and LG cases. These results suggest that RNF43 mutations may be involved in and predictive of malignant transformation from an early stage of MCN.

DOI： 10.1007/s00428-022-03277-9

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Modern Pathology  

In rare cases, giant cell tumor of bone (GCTB) can undergo primary or secondary malignant transformation to malignant giant cell tumor of bone (MGCTB), but the details of the molecular alterations are still unclear. The present study aimed to elucidate the clinicopathologic and molecular features of MGCTBs based on immunohistochemistry, fluorescence in situ hybridization (FISH) and next generation sequencing (NGS) of nine MGCTBs (five primary and four secondary). Seven (78%) of 9 MGCTBs were immunohistochemically positive for H3.3 G34W. In two (22%) patients, although GCTB components were focally or diffusely positive for H3.3 G34W, their malignant components were entirely negative for H3.3 G34W, which was associated with heterozygous loss of H3F3A by FISH. NGS on four MGCTBs revealed pathogenic mutations in TP53 (n = 3), EZH2 (n = 1) and several other genes. Immunohistochemical analysis of the nine MGCTBs confirmed the p53 nuclear accumulation (n = 5) and loss of H3K27me3 expression (n = 3) and showed that they were mutually exclusive. In addition, four (80%) of five cases of pleomorphic or epithelioid cell-predominant MGCTBs were positive for p53, while three (75%) of four cases of spindle cell-predominant MGCTBs were negative for trimethylation at lysine 27 of histone 3 (H3K27me3). The results suggested that p53 alteration and dysfunction of histone methylation as evidenced by H3K27me3 loss may play an important role in the malignant progression of GCTB, and might contribute to the phenotype–genotype correlation in MGCTB. The combined histologic, immunohistochemical and molecular information may be helpful in part for the diagnosis of challenging cases.

DOI： 10.1038/s41379-021-00972-x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：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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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.humpath.2021.03.009

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s00428-020-02844-2

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1097/SLA.0000000000003060

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1111/1754-9485.12925

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.7150/jca.38399

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

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記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

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記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

記述言語：日本語  

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記述言語：日本語  

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記述言語：日本語