| 1. |
Yu J, Ohuchida K, Nakata K, Mizumoto K, Cui L, Fujita H, Yamaguchi H, Egami T, Kitada H, Tanaka M, LIM only 4 is overexpressed in late stage pancreas cancer., Mol Cancer, 22, 7, 93, 2008.04, BACKGROUND: LIM-only 4 (LMO4), a member of the LIM-only (LMO) subfamily of LIM domain-containing transcription factors, was initially reported to have an oncogenic role in breast cancer. We hypothesized that LMO4 may be related to pancreatic carcinogenesis as it is in breast carcinogenesis. If so, this could result in a better understanding of tumorigenesis in pancreatic cancer. METHODS: We measured LMO4 mRNA levels in cultured cells, pancreatic bulk tissues and microdissected target cells (normal ductal cells; pancreatic intraepithelial neoplasia-1B [PanIN-1B] cells; PanIN-2 cells; invasive ductal carcinoma [IDC] cells; intraductal papillary-mucinous adenoma [IPMA] cells; IPM borderline [IPMB] cells; and invasive and non-invasive IPM carcinoma [IPMC]) by quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR). RESULTS: 9 of 14 pancreatic cancer cell lines expressed higher levels of LMO4 mRNA than did the human pancreatic ductal epithelial cell line (HPDE). In bulk tissue samples, expression of LMO4 was higher in pancreatic carcinoma than in intraductal papillary-mucinous neoplasm (IPMN) or non-neoplastic pancreas (p
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| 2. |
Ikenaga N, Ohuchida K, Mizumoto K, Yu J, Fujita H, Nakata K, Ueda J, Sato N, Nagai E, Tanaka M, S100A4 mRNA is a diagnostic and prognostic marker in pancreatic carcinoma, J Gastrointest Surg, 13, 10, 1852-1858, 2009.04, OBJECTIVE: The aim of this study is to evaluate the clinical significance of S100A4 mRNA expression in pancreatic cancer. MATERIALS AND METHODS: We obtained invasive ductal carcinoma (IDC) cells from ten lesions, intraductal papillary mucinous neoplasm (IPMN) cells from 20 lesions, and normal ductal cells from 20 normal pancreatic tissues by laser microdissection of frozen tissues. S100A4 expression was examined in the microdissected cells and in formalin-fixed paraffin-embedded (FFPE) samples of 87 pancreatic cancers by quantitative reverse transcription-polymerase chain reaction. RESULTS: IDC cells expressed higher levels of S100A4 than IPMN cells (P = 0.002) and normal ductal cells (P |
| 3. |
Nakata K, Nagai E, Ohuchida K, Aishima S, Hayashi A, Miyasaka Y, Yu J, Mizumoto K, Tanaka M, Tsuneyoshi M, REG4 is associated with carcinogenesis in the 'intestinal' pathway of intraductal papillary mucinous neoplasms, Mod Pathol, 22, 3, 460-468, 2009.04, Subclassification of intraductal papillary mucinous neoplasms of the pancreas (IPMNs), based on morphological features and immunohistochemical profiles, has been proposed. Intestinal-type IPMNs frequently show moderate to severe dysplasia. Regenerating islet-derived family, member 4 (REG4) is associated with the adenoma-carcinoma sequence in colon cancer and it is also associated with intestinal phenotype. Therefore, to identify REG4 expression in IPMNs may be helpful to detect high-grade IPMNs. We also investigated REG4 expression and CDX2 expression in IPMNs. To investigate the expressions of REG4 and CDX2 in IPMNs and in invasive ductal adenocarcinoma derived from IPMN, we used immunohistochemical staining and microdissection-based quantitative real-time reverse transcription-polymerase chain reaction. Among 125 IPMNs, 43 (34%) were positive for REG4 and most of the intestinal-type IPMNs showed its expression (35/38). The positive ratio of REG4 expression in colloid carcinoma (5/7) was significantly higher than that in tubular carcinoma (1/17; P=0.003). Most of CDX2-positive cases (31/33) expressed REG4 protein, whereas only 12 of 92 CDX2-negative cases did (P
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| 4. |
Nakata K, Ohuchida K, Nagai E, Hayashi A, Miyasaka Y, Kayashima T, Yu J, Aishima S, Oda Y, Mizumoto K, Tanaka M, Tsuneyoshi M, LMO2 is a novel predictive marker for a better prognosis in pancreatic cancer, Neoplasia, 11, 7, 712-719, 2009.04, PURPOSE: LIM domain only 2 (LMO2) has been identified as a novel oncogene associated with carcinogenesisand 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 cellsfrom pancreatic cancers by quantitative reverse transcription朴olymerase chain reaction and immunohistochemistry.RESULTS: Of 164 pancreatic cancers, 98 (60%) were positive for LMO2 expression. LMO2 was more frequently detectedin 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 LMO2messenger RNA levels were significantly higher in invasive ductal carcinoma cells than in normal pancreatic cellsas evaluated by quantitative reverse transcription朴olymerase chain reaction
a!
nalyses of microdissected cells (P =.036). We also found higher incidence of LMO2 expression in histologic grade G1/G2 cancers than in grade G3cancers (P < .001). The median survival time of LMO2-positive patients was significantly longer than that ofLMO2-negative patients (P < .001), and multivariate analyses revealed that high LMO2 expression was an independentpredictor 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 furtherperformed a large cohort study (n = 113) to examine the LMO2 messenger RNA levels in formalin-fixed paraffinembeddedsamples and found similar results. CONCLUSIONS: LMO2 is a promising marker for predicting a betterprognosis in pancreatic cancer.Neoplasia (2009) 11, 712・19IntroductionPancreatic cancer is the fourth leading cause of cancer-related deathin Western countries and has the lowest pat
i!
ent survival rate of anysolid cancer [1・]. Recently, although the cancer death rates of mostmalignancies have decreased owing to improvements in early detectionand treatment, the overall 5-year survival of patients with pancreaticcancer has only slightly increased from 3% to 5% [1] becauseof difficulties in the diagnosis of pancreatic cancer at early stages. Surgicalresection is the only curative treatment of pancreatic cancer, andthe survival rate for patients with a negative operative margin status(R0) is significantly higher than that for patients with positive operativemargin status (R1 and R2) [4]. However, some patients with apositive operative. |
| 5. |
Fujita H, Ohuchida K, Mizumoto K, Nakata K, Yu J, Kayashima T, Cui L, Manabe T, Ohtsuka T, Tanaka M, α-Smooth Muscle Actin Expressing Stroma Promotes an Aggressive Tumor Biology in Pancreatic Ductal Adenocarcinoma, Pancreas, 39, 8, 1254-1262, 2010.04, OBJECTIVES:: Pancreatic ductal adenocarcinoma (PDAC) is often characterized by a prominent desmoplastic stroma that is induced partially by alpha-smooth muscle actin (SMA)-expressing activated pancreatic stellate cells (PSCs). This study aimed to investigate the significance of alpha-SMA expression in PDAC and the correlation between alpha-SMA mRNA levels and the patient prognosis. METHODS:: We obtained formalin-fixed, paraffin-embedded tissue samples from 109 patients with PDAC, who underwent pancreatectomy at our institution from 1992 to 2007. We measured alpha-SMA mRNA levels by quantitative real-time reverse transcription-polymerase chain reaction and investigated the association of alpha-SMA mRNA expression with clinicopathologic parameters and survival time. We also assessed the influence of activated PSCs on malignant behaviors of pancreatic cancer cells using in vitro experiments. RESULTS:: alpha-SMA immunoreactivity was detected exclusively in the stroma of PDAC. The group with high alpha-SMA expression showed a significantly shorter survival, as shown by univariate analysis (P = 0.005) and multivariate analysis (P |
| 6. |
Nakata K, Nagai E, Ohuchida K, Morimatsu K, Hayashi A, Miyasaka Y, Aishima S, Mizumoto K, Tanaka M, Tsuneyoshi M, S100P is a novel marker to identify intraductal papillary mucinous neoplasms, Hum Pathol, 41, 6, 824-831, 2010.04, Backgrounds: Intraductal papillary mucinous neoplasms of the pancreas (IPMNs) 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 IPMNs than in normal pancreatic ductal epithelium. However, there have been no reports on novel diagnostic markers to distinguish IPMN from non-neoplastic lesions. Materials and Methods: Surgical specimens of IPMN obtained from 105 patients were investigated using immunohistochemistry. Results: S100P expression was not detected in normal pancreatic ductal epithelium, but was detected in all IPMN cells (100%) with diffuse nuclear or nuclear/cytoplasmic staining. MUC5AC was also expressed in most of the IPMNs (102 of 105, 97%). S100P was clearly detected in minimally invasive area
s!
of IPMNs. Furthermore, S100P was diffusely expressed in the invasive component of IPMNs (32 of 32, 100%), including perineural and lymphatic invasion. On the other hand, MUC5AC was expressed in only 23 cases of 32 invasive components (P < 0.01). Conclusions: These data suggest that the S100P antibody may be a useful marker for detecting all types of IPMNs including invasive lesions.. |
| 7. |
Hayashi A, Aishima S, Miyasaka Y, Nakata K, Morimatsu K, Oda Y, Nagai E, Oda Y, Tanaka M, Tsuneyoshi M, Pdcd4 expression in intraductal papillary mucinous neoplasm of the pancreas: its association with tumor progression and proliferation
, Hum Pathol, 41, 11, 1507-1515, 2010.04, 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%, 43%, and 10% in adenoma, borderline, and carcinoma, respectively. The positive rate of programmed cell death 4 decreased from adenoma to carcinoma (P |
| 8. |
Yu J, Ohuchida K, Mizumoto K, Sato N, Kayashima T, Fujita H, Nakata K, Tanaka M, MicroRNA, hsa-miR-200c, is an independent prognostic factor in pancreatic cancer and its upregulation inhibits pancreatic cancer invasion but increases cell proliferation
, Mol Cancer, 28
, 9, 169, 2010.04, BACKGROUND: Recently, the microRNA-200 family was reported to affect cancer biology by regulating epithelial to mesenchymal transition (EMT). Especially, the expression of miR-200c has been shown to be associated with upregulating the expression of E-cadherin, a gene known to be involved in pancreatic cancer behavior. However, the significance of miR-200c in pancreatic cancer is unknown. METHODS: In the present study, we investigated the relationship between E-cadherin and miR-200c expression in a panel of 14 pancreatic cancer cell lines and in macro-dissected formalin-fixed paraffin-embedded (FFPE) tissue samples obtained from 99 patients who underwent pancreatectomy for pancreatic cancer. We also investigated the effects of miR-200c on the proliferation and invasion of pancreatic cancer cells. RESULTS: We found that patients with high levels of miR-200c expression had significantly better survival rates than those with low levels of miR-200c expression. We also found a remarkably strong correlation between the levels of miR-200c and E-cadherin expression. CONCLUSIONS: These data indicate that miR-200c may play a role in the pancreatic cancer biology and may be a novel marker for the prognosis of pancreatic cancer.
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| 9. |
Ikenaga N, Ohuchida K, Mizumoto K, Yu J, Kayashima T, Sakai H, Fujita H, Nakata K, Tanaka M
, MicroRNA-203 expression as a new prognostic marker of pancreatic adenocarcinoma
, Ann Surg Oncol, 17, 12, 3120-3128, 2010.04, BACKGROUND: Detection of aberrant microRNA (miR) expression may contribute to diagnosis and prognosis of various cancers. The aim of this study is to evaluate the correlation between miR-203 expression and prognosis of patients with pancreatic adenocarcinoma after curative resection.
METHODS: A total of 113 formalin-fixed paraffin-embedded tissue samples of pancreatic adenocarcinoma, 20 samples of chronic pancreatitis, and 8 samples of normal pancreas were obtained. We investigated the association of miR-203 expression measured by quantitative reverse-transcription polymerase chain reaction assays with clinicopathological parameters and survival times.
RESULTS: miR-203 was overexpressed in pancreatic adenocarcinoma samples compared with chronic pancreatitis (P
CONCLUSIONS: miR-203 expression is a new prognostic marker in pancreatic adenocarcinoma patients.
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| 10. |
Yu J, Ohuchida K, Mizumoto K, Fujita H, Nakata K, Tanaka M, MicroRNA miR-17-5p is overexpressed in pancreatic cancer, associated with a poor prognosis, and involved in cancer cell proliferation and invasion., Cancer Biol Ther, 10, 8, 748-757, 2010.04, The microRNA-17-92 cluster is an oncogene in human B cell lymphomas and lung cancers. Previous microRNA microarray data revealed that miR-17-5p, a member of the miR-17-92 cluster, is upregulated in pancreatic cancer. However, the involvement of miR-17-5p expression in pancreatic carcinogenesis has not well been studied. In the present study, we measured the miR-17-5p expression levels in pancreatic cancer cell lines, primary cultures of normal human pancreatic ductal cells, formalin-fixed paraffin-embedded (FFPE) tissue samples derived from 80 patients who underwent pancreatectomy for pancreatic cancer and microdissected cells (including normal ductal epithelial, pancreatic intraepithelial neoplasia-1B and invasive ductal carcinoma cells) by qRT-PCR. Furthermore, we investigated the effects of upregulation of miR-17-5p expression on the proliferation and invasion of pancreatic cancer cells. We found that pancreatic cancer cells expressed higher levels of miR-17-5p than primary cultured normal ductal cells. miR-17-5p was also overexpressed in pancreatic cancer in FFPE and microdissected samples. Furthermore, analysis of macrodissected FFPE samples revealed that high miR-17-5p expression was associated with a poor prognosis (p = 0.03). In addition, in vitro experiments revealed that SUIT-2 and KP-2 pancreatic cancer cells transfected with the miR-17-5p precursor showed significantly higher cell growth ratios than the corresponding control cells (p |
| 11. |
Sadakari Y, Ohuchida K, Nakata K, Ohtsuka T, Aishima S, Takahata S, Nakamura M, Mizumoto K, Tanaka M, Invasive carcinoma derived from the nonintestinal type intraductal papillary mucinous neoplasm of the pancreas has a poorer prognosis than that derived from the intestinal type, Surgery, 147, 6, 812-817, 2010.04, 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%) was as poor as that of patients with conventional IDC (19.9%; P = .67). The patients with the intestinal type (66.7%) had a more favorable prognosis than patients with conventional IDC (P
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| 12. |
Fujita H, Ohuchida K, Mizumoto K, Itaba S, Ito T, Nakata K, Yu J, Kayashima T, Souzaki R, Tajiri T, Manabe T, Ohtsuka T, Tanaka M, Gene Expression Levels as Predictive Markers of Outcome in Pancreatic Cancer after Gemcitabine-Based Adjuvant Chemotherapy, NEOPLASIA, 12, 10, 807-817, 2010.04, Abstract
BACKGROUND AND AIMS: The standard palliative chemotherapy for pancreatic ductal adenocarcinoma (PDAC) is gemcitabine-based chemotherapy; however, PDAC still presents a major therapeutic challenge. The aims of this study were to investigate the expression pattern of genes involved in gemcitabine sensitivity in resected PDAC tissues and to determine correlations of gene expression with treatment outcome.
MATERIALS AND METHODS: We obtained formalin-fixed paraffin-embedded (FFPE) tissue samples from 70 patients with PDAC. Of the 70 patients, 40 received gemcitabine-based adjuvant chemotherapy (AC). We measured hENT1, dCK, CDA, RRM1, and RRM2 messenger RNA (mRNA) levels by quantitative real-time reverse transcription-polymerase chain reaction and determined the combined score (GEM score), based on the expression levels of hENT1, dCK, RRM1, and RRM2, to investigate the association with survival time. By determining the expression levels of these genes in endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) cytologic specimens, we investigated the feasibility of individualized chemotherapy.
RESULTS: High dCK (P = .0067), low RRM2 (P = .003), and high GEM score (P = .0003) groups had a significantly longer disease-free survival in the gemcitabine-treated group. A low GEM score (
CONCLUSIONS: Quantitative analyses of hENT1, dCK, RRM1, and RRM2 mRNA levels using FFPE tissue samples and microdissected neoplastic cells from EUS-FNA cytologic specimens may be useful in predicting the gemcitabine sensitivity of patients with PDAC.
PMID: 20927319 [PubMed - in process]PMCID: PMC2950330Free PMC Article
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Figure 1
Quantitative analyses of mRNA associated with cellular uptake and metabolism of gemcitabine in gemcitabine-resistant cells. Quantitative analyses of hENT1 (A), dCK (B), RRM1 (C), RRM2 (D), and CDA (E) mRNA in gemcitabine-resistant cell lines (SUIT-2-GR and Capan-1-GR) and parental cells. SUIT-2-GR cells expressed sign...
Gene Expression Levels as Predictive Markers of Outcome in Pancreatic Cancer after Gemcitabine-Based Adjuvant Chemotherapy12
Neoplasia. 2010 October;12(10):807-817.Figure 2
Correlation between gemcitabine-based AC and survival time. The patients who received gemcitabine-based AC (GEMgroup) showed a significantly prolongedOStime compared with the non-AC group (P = .0017). *P Gene Expression Levels as Predictive Markers of Outcome in Pancreatic Cancer after Gemcitabine-Based Adjuvant Chemotherapy12
Neoplasia. 2010 October;12(10):807-817.Figure 3
Correlation between the expression of each mRNA and DFS. Low dCK (P= .0067) and high RRM2 (P=.003) levels, normalized to β-actin, were associated with a shorter DFS in the GEM group (A, C, E, G). In contrast, there was no significant correlation between these gene expression levels and DFS in the non-AC group (B, D...
Gene Expression Levels as Predictive Markers of Outcome in Pancreatic Cancer after Gemcitabine-Based Adjuvant Chemotherapy12
Neoplasia. 2010 October;12(10):807-817.Figure 4
Correlation between the expression of each mRNA and OS. Low hENT1 (P = .011), low dCK (P = .0095), high RRM1 (P = .041), and high RRM2 (P = .030) levels, normalized to β-actin, were associated with a shorterOSin theGEMgroup (A, C, E, G). In contrast, there was no significant correlation between these gene expression levels an...
Gene Expression Levels as Predictive Markers of Outcome in Pancreatic Cancer after Gemcitabine-Based Adjuvant Chemotherapy12
Neoplasia. 2010 October;12(10):807-817.Figure 5
Correlation between GEM score and survival time. DFS time (A) and OS time (B) after resection of PDAC categorized by combined GEM score (hENT1 score x dCK score x RRM1 score x RRM2 score) in GEM group patients. High GEM scores were well correlated with prolonged DFS time (A) and OS time (B). *P Gene Expression Levels as Predictive Markers of Outcome in Pancreatic Cancer after Gemcitabine-Based Adjuvant Chemotherapy12
Neoplasia. 2010 October;12(10):807-817.Figure 6
Quantitative analyses of mRNA associated with gemcitabine sensitivity in EUS-FNA cytologic specimens. Representative micrographs of cytologic specimens obtained from patients with PDAC who underwent EUS-FNA cytologic examination (A, B). Most samples consisted of a large amount of blood and inflammat...
Gene Expression Levels as Predictive Markers of Outcome in Pancreatic Cancer after Gemcitabine-Based Adjuvant Chemotherapy12
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| 13. |
Hayashi A, Aishima S, Inoue T, Nakata K, Morimatsu K, Nagai E, Oda Y, Tanaka M, Tsuneyoshi M, Decreased expression of focal adhesion kinase is associated with a poor prognosis in extrahepatic bile duct carcinoma
, Hum Pathol, 41, 6, 859-866, 2010.04, 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%). Most dysplastic epithelia also showed positive FAK expression except for 2 cases (92%), whereas EBD carcinomas showed positive FAK expression in 53 (77%) of 76 cases (P
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| 14. |
Ikenaga N, Ohuchida K, Mizumoto K, Yu J, Kayashima T, Hayashi A, Nakata K, Tanaka M
, Characterization of CD24 expression in intraductal papillary mucinous neoplasms and ductal carcinoma of the pancreas
, Hum Pathol, 41, 10, 1466-1474, 2010.04, CD24 is a molecule involved in cell adhesion and tumor metastasis. The aims of this study were (1) to evaluate the association between CD24 expression and the progression of intraductal papillary mucinous neoplasms of the pancreas and (2) to investigate the association between CD24 expression in pancreatic cancer and the prognosis of patients who underwent curative pancreatectomy. Immunohistochemical analysis of CD24 was performed for 95 intraductal papillary mucinous neoplasms of the pancreas and 83 pancreatic cancers. We investigated the association between CD24 expression and the histologic grade of intraductal papillary mucinous neoplasms of the pancreas, the clinicopathologic parameters of pancreatic cancers, and the survival time of pancreatic cancer patients who underwent pancreatectomy. The positive rates of CD24 expression in intraductal papillary mucinous adenoma, borderline intraductal papillary mucinous neoplasm, noninvasive intraductal papillary mucinous carcinoma, and invasive intraductal papillary mucinous carcinoma were 5 (20%) of 24, 12 (48%) of 25, 10 (43%) of 23, and 15 (65%) of 23, respectively. The CD24-positive rates were significantly higher in borderline intraductal papillary mucinous neoplasm and intraductal papillary mucinous carcinoma compared with intraductal papillary mucinous adenoma (P = .046 and P = .007, respectively). The staining scores, which were determined from the percentage of stained cells and the staining intensity, were significantly higher in invasive intraductal papillary mucinous carcinoma than in noninvasive intraductal papillary mucinous carcinoma (P = .043). In the pancreatic cancers, higher tumor stage (P = .007), nodal metastasis (P = .021), and higher-grade tumors (P
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| 15. |
Miyasaka Y, Nagai E, Ohuchida K, Nakata K, Hayashi A, Mizumoto K, Tsuneyoshi M, Tanaka M, CD44v6 expression in intraductal papillary mucinous neoplasms of the pancreas, Pancreas, 39, 1, 31-35, 2010.04, OBJECTIVES: The purpose of this study was to examine
CD44v6 expression in intraductal papillary mucinous neoplasms (IPMNs)
and clarify the role of CD44v6 in progression, invasion, metastasis, and
morphogenesis of IPMNs. METHODS: One hundred fifty-one samples of IPMNs
and 30 normal controls were subjected to immunohistochemical analysis
for CD44v6. The IPMNs were divided into 4 groups according to the grade
of atypia (adenoma, borderline IPMN, noninvasive carcinoma, and invasive
carcinoma) and 5 subtypes according to histological phenotype (gastric,
intestinal, pancreatobiliary, oncocytic, and unclassified). Correlations
were investigated between CD44v6 expression and clinicopathological
characteristics including grade of atypia, subtype, lymph node
metastasis, and invasion pattern. RESULTS: Whereas normal ductal
epithelium did not express CD44v6, CD44v6 expression was observed from
the early stage of IPMNs and up-regulated in the progression of IPMNs
to invasive carcinoma. CD44v6 expression in intestinal-type IPMNs was
significantly lower compared with that in other subtypes. Whereas no
correlation was observed between lymph node metastasis and CD44v6
expression in invasive IPM carcinomas, the invasion pattern was
significantly correlated to CD44v6 expression. CONCLUSIONS: The present
data indicate that CD44v6 expression determines the morphology and
aggressiveness of IPMNs and is involved in development and invasion of
IPMNs.. |
| 16. |
Ikenaga N, Ohuchida K, Mizumoto K, Cui L, Kayashima T, Morimatsu K, Moriyama T, Nakata K, Fujita H, Tanaka M, CD10+ pancreatic stellate cells enhance the progression of pancreatic cancer , Gastroenterology, 139, 3, 1041-1051, 2010.04, Abstract
BACKGROUND & AIMS: Pancreatic stellate cells (PSCs) promote the progression of pancreatic cancer by producing extracellular matrix and soluble factors. However, the functional heterogeneity of PSCs has not been identified until now. Detailed characterization of the PSCs in human pancreatic cancer would provide a set of potential targets for stroma-directed therapy.
METHODS: We isolated PSCs from fresh pancreatic ductal adenocarcinoma tissue and sorted them by flow cytometry according to cell surface expression of CD10, which is a stromal prognostic marker for various tumors. We analyzed the functional differences between CD10(+) PSCs and CD10(-) PSCs.
RESULTS: Immunohistochemical analysis showed that the frequency of CD10 expression by PSCs was markedly higher in tumor tissue than in normal tissue (33.7% vs 0%, respectively, P = .028). In pancreatic ductal adenocarcinoma, CD10 expression by PSCs was associated with positive nodal metastases (P = .011) and a shorter survival time (P
CONCLUSIONS: CD10(+) PSCs enhance the progression of pancreatic cancer cells. CD10(+) PSCs may be a candidate for selective therapeutic targeting in the treatment of pancreatic cancer.
Copyright © 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.
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| 17. |
Miyasaka Y, Nagai E, Ohuchida K, Fujita H, Nakata K, Hayashi A, Mizumoto K, Tsuneyoshi M, Tanaka M, Senescence in intraductal papillary mucinous neoplasm of the pancreas.
, Hum Pathol, 42, 12, 2010-2017, 2011.04, Abstract
CD24 is a molecule involved in cell adhesion and tumor metastasis. The aims of this study were (1) to evaluate the association between CD24 expression and the progression of intraductal papillary mucinous neoplasms of the pancreas and (2) to investigate the association between CD24 expression in pancreatic cancer and the prognosis of patients who underwent curative pancreatectomy. Immunohistochemical analysis of CD24 was performed for 95 intraductal papillary mucinous neoplasms of the pancreas and 83 pancreatic cancers. We investigated the association between CD24 expression and the histologic grade of intraductal papillary mucinous neoplasms of the pancreas, the clinicopathologic parameters of pancreatic cancers, and the survival time of pancreatic cancer patients who underwent pancreatectomy. The positive rates of CD24 expression in intraductal papillary mucinous adenoma, borderline intraductal papillary mucinous neoplasm, noninvasive intraductal papillary mucinous carcinoma, and invasive intraductal papillary mucinous carcinoma were 5 (20%) of 24, 12 (48%) of 25, 10 (43%) of 23, and 15 (65%) of 23, respectively. The CD24-positive rates were significantly higher in borderline intraductal papillary mucinous neoplasm and intraductal papillary mucinous carcinoma compared with intraductal papillary mucinous adenoma (P = .046 and P = .007, respectively). The staining scores, which were determined from the percentage of stained cells and the staining intensity, were significantly higher in invasive intraductal papillary mucinous carcinoma than in noninvasive intraductal papillary mucinous carcinoma (P = .043). In the pancreatic cancers, higher tumor stage (P = .007), nodal metastasis (P = .021), and higher-grade tumors (P
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| 18. |
Cui L, Ohuchida K, Mizumoto K, Moriyama T, Onimaru M, Nakata K, Nabae T, Ueki T, Sato N, Tominaga Y, Tanaka M, Prospectively isolated cancer-associated CD10(+) fibroblasts have stronger interactions with CD133(+) colon cancer cells than with CD133(-) cancer cells.
, PLoS One, 5, 8, e12121, 2011.04, Abstract
Although CD133 has been reported to be a promising colon cancer stem cell marker, the biological functions of CD133+ colon cancer cells remain controversial. In the present study, we investigated the biological differences between CD133+ and CD133- colon cancer cells, with a particular focus on their interactions with cancer-associated fibroblasts, especially CD10+ fibroblasts. We used 19 primary colon cancer tissues, 30 primary cultures of fibroblasts derived from colon cancer tissues and 6 colon cancer cell lines. We isolated CD133+ and CD133- subpopulations from the colon cancer tissues and cultured cells. In vitro analyses revealed that the two populations showed similar biological behaviors in their proliferation and chemosensitivity. In vivo analyses revealed that CD133+ cells showed significantly greater tumor growth than CD133- cells (P=0.007). Moreover, in cocultures with primary fibroblasts derived from colon cancer tissues, CD133+ cells exhibited significantly more invasive behaviors than CD133- cells (P
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| 19. |
Nakata K, Ohuchida K, Mizumoto K, Kayashima T, Ikenaga N, Sakai H, Lin C, Fujita H, Otsuka T, Aishima S, Nagai E, Oda Y, Tanaka M, MicroRNA-10b is overexpressed in pancreatic cancer, promotes its invasiveness, and correlates with a poor prognosis., Surgery, 150, 5, 916-922, 2011.04, 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
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.
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| 20. |
Nakata K, Ohuchida K, Aishima S, Sadakari Y, Kayashima T, Miyasaka Y, Nagai E, Mizumoto K, Tanaka M, Tsuneyoshi M, Oda Y, Invasive carcinoma derived from intestinal-type intraductal papillary mucinous neoplasm is associated with minimal invasion, colloid carcinoma, and less invasive behavior, leading to a better prognosis.
, Pancreas, 40, 4, 581-587, 2011.04, Abstract
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
CONCLUSIONS: Invasive carcinoma derived from intestinal-type IPMN is associated with MI, colloid carcinoma, and less invasive behavior.
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| 21. |
Kayashima T, Nakata K, Ohuchida K, Ueda J, Shirahane K, Fujita H, Cui L, Mizumoto K, Tanaka M, Insig2 is overexpressed in pancreatic cancer and its expression is induced by hypoxia.
, Cancer Sci, 102, 6, 1137-1143, 2011.04, Abstract
A hypoxic microenvironment is a characteristic feature of pancreatic cancer, and induces the expressions of various genes involved in malignant behaviors. Insulin-induced gene 2 (Insig2) has recently been shown to be correlated with cellular invasion in colon cancer. However, there have been no reports regarding its expression in pancreatic cancer. In this study, we evaluated Insig2 mRNA expression and the biological function of Insig2 in pancreatic cancer. We measured Insig2 mRNA expression in cultured pancreatic cancer cell lines and invasive ductal carcinoma (IDC) cells, normal pancreatic epithelial cells, and pancreatic intraepithelial neoplasia cells obtained by laser-capture microdissection. We also investigated the effects of Insig2-targeting siRNAs on the cell proliferation and cell invasion of pancreatic cancer cell lines. All pancreatic cancer cell lines expressed Insig2 mRNA. The PANC-1 and MIA PaCa-2 pancreatic cancer cell lines showed >2-fold higher Insig2 mRNA expression levels under hypoxic conditions (1% O2) than under normoxic conditions (21% O2 ). Cell proliferation was significantly decreased in SUIT-2 cells and cell invasion was significantly decreased in SUIT-2, Capan-2, and CFPAC-1 cells after transfection of the Insig2-targeting siRNAs. In analyses of microdissected cells, cells from IDC tissues expressed significantly higher levels of Insig2 mRNA than normal pancreatic cells (P
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| 22. |
Sakai H, Ohuchida K, Mizumoto K, Cui L, Nakata K, Toma H, Nagai E, Tanaka M, Inhibition of p600 expression suppresses both invasiveness and anoikis resistance of gastric cancer.
, Ann Surg Oncol, 18, 7, 2057-2065, 2011.04, Abstract
BACKGROUND: Advanced gastric cancers often metastasize to distant organs and the peritoneum, leading to a poor prognosis. Both invasiveness and resistance to anchorage-independent cell death (anoikis) are important factors in the process of metastasis. p600 (600-kDa protein), recently identified from a cervical cancer cell line, plays a role in both anoikis resistance and cell migration. In this study, we examined whether p600 is involved in the progression of gastric cancer.
METHODS: We used both normal gastric mucosal cells and cancer cells laser-microdissected from 42 gastric cancers and their normal counterparts, and compared their p600 mRNA expression levels with quantitative reverse transcriptase-polymerase chain reaction. We inhibited p600 expression in two gastric cancer cell lines with siRNA and examined its effect on the invasiveness and anoikis resistance both in vitro and in vivo.
RESULTS: Expression of p600 mRNA was significantly higher in gastric cancer cells than in normal mucosal cells (P = 0.027). The invasion assay revealed that invasiveness was significantly reduced by inhibition of p600 (P
CONCLUSIONS: Our results strongly suggest that p600 is involved in gastric cancer progression, and has a potential to be a new molecular target for gastric cancer therapy.
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| 23. |
Fujita H, Ohuchida K, Mizumoto K, Itaba S, Ito T, Nakata K, Yu J, Kayashima T, Hayashi A, Souzaki R, Tajiri T, Onimaru M, Manabe T, Ohtsuka T, Tanaka M
, High EGFR mRNA expression is a prognostic factor for reduced survival in pancreatic cancer after gemcitabine-based adjuvant chemotherapy.
, Int J Oncol, 38, 3, 629-641, 2011.04, Pancreatic ductal adenocarcinoma (PDAC) still presents a major therapeutic challenge and a phase III clinical trial has revealed that the combination of gemcitabine and a human epidermal growth factor receptor type I (HER1/EGFR) targeting agent presented a significant benefit compared to treatment with gemcitabine alone. The aim of this study was to investigate EGFR mRNA expression in resected PDAC tissues and its correlation with patient prognosis. We obtained formalin-fixed paraffin-embedded (FFPE) tissue samples from 88 patients with PDAC who underwent pancreatectomy, and measured EGFR mRNA levels by quantitative real-time reverse transcription-polymerase chain reaction. The high-level EGFR group had significantly shorter disease-free-survival (p=0.029) and overall-survival (p=0.014) as shown by univariate analyses, although these did not reach statistical significance, as shown by multivariate analyses. However, we found that high EGFR expression was an independent prognostic factor in patients receiving gemcitabine-based adjuvant chemotherapy (p=0.023). Furthermore, we measured EGFR mRNA levels in 20 endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) cytological specimens. Altered EGFR levels were distinguishable in microdissected neoplastic cells from EUS-FNA cytological specimens compared to those in whole cell pellets. In conclusion, quantitative analysis of EGFR mRNA expression using FFPE tissue samples and microdissected neoplastic cells from EUS-FNA cytological specimens could be useful in predicting prognosis and sensitivity to gemcitabine in PDAC patients.
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| 24. |
Nakata K, Nagai E, Miyasaka Y, Ohuchida K, Otsuka T, Toma H, Hirahashi M, Aishima S, Oda Y, Tanaka M, The risk of lymph node metastasis in mucosal gastric carcinoma: especially for a mixture of differentiated and undifferentiated adenocarcinoma., Hepatogastroenterology, 59, 118, 1855-1858, 2012.04, 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.
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| 25. |
Morimatsu K, Aishima S, Kayashima T, Hayashi A, Nakata K, Oda Y, Taguchi T, Tsuneyoshi M, Tanaka M, Oda Y, Liver-intestine cadherin expression is associated with intestinal differentiation and carcinogenesis in intraductal papillary mucinous neoplasm.
, Pathobiology, 79, 2, 107-114, 2012.04, Abstract
Objectives: Intraductal papillary mucinous neoplasms (IPMN) are classified into four phenotypes according to the WHO classification. Recently, intestinal-type IPMN has been suggested to grow with a distinct carcinogenetic pathway. Like mucin 2, oligomeric mucus/gel forming (MUC2) and caudal-related homeobox 2 (CDX2), liver-intestine cadherin (LI cadherin) is an intestine-specific marker. We aimed to investigate the roles of LI cadherin expression in IPMN. Methods: We examined LI cadherin expression in 135 cases of IPMN by immunohistochemical staining and the quantitative real-time reverse-transcription polymerase chain reaction. Results: LI cadherin protein and mRNA levels were significantly higher in intestinal-type IPMN than in nonintestinal-type IPMN (protein level, p
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| 26. |
Morimatsu K, Aishima S, Yamamoto H, Hayashi A, Nakata K, Oda Y, Shindo K, Fujino M, Tanaka M, Oda Y, Insulin-like growth factor II messenger RNA-binding protein-3 is a valuable diagnostic and prognostic marker of intraductal papillary mucinous neoplasm, Hum Pathol, 44, 9, 1714-1721, 2013.04, 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 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.. |
| 27. |
Nagai E, Ohuchida K, Nakata K, Miyasaka Y, Maeyama R, Toma H, Shimizu S, Tanaka M, Feasibility and safety of intracorporeal esophagojejunostomy after laparoscopic total gastrectomy: Inverted T-shaped anastomosis using linear staplers., Surgery, 153, 5, 732-738, 2013.04, BACKGROUND:
Although laparoscopic distal gastrectomy has been widely accepted in clinical practice, laparoscopic total gastrectomy (LTG) is not yet familiar because of the difficulty in esophagojejunostomy. The purpose of this study was to evaluate perioperative and short-term outcomes of our procedure of intracorporeal gastrojejunostomy using linear staplers after LTG.
METHODS:
Of 98 consecutive patients who underwent LTG for gastric cancer in our department between August 2002 and December 2010, 94 patients underwent esophagojejunostomy with a linear stapling device. After October 2007, we modified the esophagojejunostomy; ie, the most recent 57 patients underwent transection of the esophagus in the ventrodorsal direction and insertion of a linear stapler from the anterior wall of the Roux limb to the posterior wall so as to make an inverted T-shaped anastomosis. We evaluated the results in these 57 patients (recent group) and compared them with the results in the earlier 37 patients (early group).
RESULTS:
The mean operative time in the recent group was 368 to 94.6 min, and the mean estimated blood loss was 57 to 33 g; both were comparable with those in the early group. Neither open conversion nor intraoperative complications were encountered. Two patients experienced anastomotic leakage in the earlier group, but anastomotic leakage did not occur in the recent group. No mortality was encountered.
CONCLUSION:
We herein report our procedure of intracorporeal gastrojejunostomy using linear staplers after LTG. Our procedure of esophagojejunostomy using linear staplers is safe and feasible and has acceptable morbidity.
Copyright © 2013 Mosby, Inc. All rights reserved.
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| 28. |
Nakata K, Nagai E, Ohuchida K, Shimizu S, Tanaka M, Technical feasibility of laparoscopic total gastrectomy with splenectomy for gastric cancer: clinical short-term and long-term outcomes., Surg Endosc, 29, 7, 1817-22, 2014.04, BACKGROUND:
Since its widespread acceptance for the treatment of early gastric cancer, laparoscopic gastrectomy has been gaining popularity as a treatment option for advanced gastric cancer. However, laparoscopic total gastrectomy (LTG) with splenectomy is seldom performed, because of its difficulty of removal of station 10 lymph nodes; splenectomy is technically essential for complete removal of these lymph nodes. The purpose of this study was to describe the details of the LTG procedure and to evaluate the short- and long-term outcomes of LTG with splenectomy.
METHODS:
Of 725 consecutive patients with gastric cancer who underwent laparoscopic gastrectomy with lymph node dissection in our institution from January 1996 to December 2012, 18 consecutive patients who underwent LTG with splenectomy were enrolled in this study.
RESULTS:
No operative mortality occurred, and the pathological margins were free from cancer cells in all patients. The mean operation time was 388 min (range 324-566 min). The mean volume of blood loss was 45 ml (range 5-347 ml), and the mean number of dissected lymph nodes was 51 (range 40-105). Postoperative morbidity occurred in six patients (33.3 %) (each with grade B postoperative pancreatic fistula, postoperative bleeding, chylous ascites, atelectasis, ileus, and intra-abdominal infection). Five patients (27.8 %) developed recurrence (four in the peritoneum and one in the liver), and the overall 3- and 5-year survival rates were 83.0 and 72.6 %, respectively.
CONCLUSIONS:
Considering the 0 % mortality rate and low rates of postoperative morbidity and locoregional recurrence, LTG with splenectomy is technically and oncologically acceptable. This procedure can be expanded to include advanced gastric cancer, which generally requires splenectomy for lymph node dissection.
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| 29. |
Nakata K, Ohuchida K, Mizumoto K, Aishima S, Oda Y, Nagai E, Tanaka M, Micro RNA-373 is Down-regulated in Pancreatic Cancer and Inhibits Cancer Cell Invasion, Ann Surg Oncol, 21, suppl4, S564-S574, 2014.04, 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
CONCLUSIONS:
MiR-373 is down-regulated in pancreatic cancer, and its reexpression represses the invasiveness of pancreatic cancer cells.
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| 30. |
Nagai E, Nakata K, Ohuchida K, Miyasaka Y, Shimizu S, Tanaka M, Laparoscopic total gastrectomy for remnant gastric cancer: feasibility study, Surg Endosc, 28, 1, 289-296, 2014.04, BACKGROUND:
The benefits and feasibility of laparoscopic surgery for remnant gastric cancer are still unclear. The purpose of this study was to describe the detailed procedure and to evaluate the clinical short-term outcomes of laparoscopic total gastrectomy (LTG) compared with open total gastrectomy (OTG) for remnant gastric cancer (RGC).
METHODS:
Of 1,247 consecutive patients who underwent gastrectomy for gastric cancer in our department at Kyushu University Hospital from January 1996 to May 2012, 22 patients who underwent successful curative resection of RGC with precise nodal dissection were enrolled in this study. Twelve patients underwent LTG and the remaining ten patients underwent OTG. We analyzed the clinical short-term outcomes of LTG and compared the results between LTG and OTG groups to evaluate the safety and feasibility of LTG.
RESULTS:
Twelve patients with RGC successfully underwent LTG without open conversion and morbidity. The mean operation time of LTG, 362.3 ± 68.4 min, was significantly longer than that of OTG (p = 0.0176), but the mean blood loss of LTG, 65.8 ± 62 g, was smaller than that of OTG (p
CONCLUSIONS:
This study shows that LTG is a feasible and reliable procedure for the treatment of RGC in terms of short-term outcomes.
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| 31. |
Kasetsermwiriya W, Nagai E, Nakata K, Nagayoshi Y, Shimizu S, Tanaka M, Laparoscopic surgery for gastric gastrointestinal stromal tumor is feasible irrespective of tumor size, J Laparoendosc Adv Surg Tech A, 24, 3, 123-129, 2014.04, Abstract
PURPOSE:
To compare the outcomes of laparoscopic surgery and open surgery for gastric gastrointestinal stromal tumors (GISTs) by size-matched analysis and evaluate whether laparoscopic surgery for lesions of >5 cm is feasible.
PATIENTS AND METHODS:
Data of 44 consecutive patients with gastric GIST who underwent surgery from 1988 to 2011 were reviewed. Twenty-three patients who underwent successful laparoscopic surgery were compared with 10 patients with similar tumor sizes who underwent open surgery. Among the 23 patients in the laparoscopic group, we compared postoperative results between GISTs of ≤5 cm and >5 cm.
RESULTS:
There were no differences in clinicopathological characteristics between the laparoscopic surgery group (LG) and the open surgery group (OG). The operation time was not different, but the blood loss (5.5 mL [range, 0-425 mL] in LG and 125 mL [range, 0-676 mL] in OG) (P=.008) and postoperative hospital stay (21 days in OG and 8 days in LG) (P<.001 were significantly less in the lg. postoperative complications and recurrence not different. comparison between patients with lesions of>5 cm and patients with smaller lesions in the LG found that smaller lesions were associated with a shorter postoperative hospital stay (7.5 days versus 11 days) (P=.037).
CONCLUSIONS:
Laparoscopic resection of primary gastric GISTs is feasible even for tumors of >5 cm.. |
| 32. |
Kasetsermwiriya W, Nagai E, Nakata K, Nagayoshi Y, Shimizu S, Tanaka M, Surgery of GI gastrointestinal stromal tumors: Our experience, prognostic analysis, Hepatogastroenterology, 62, 87-92, 2015.04, Abstract
BACKGROUND/AIMS:
To review our treatment experience of gastrointestinal stromal tumors (GISTs) of the upper gastrointestinal tract and identify the prognostic factors that influence tumor recurrence.
METHODOLOGY:
Data of 46 consecutive patients with upper GI GISTs who underwent surgery from 1988 to 2011 were reviewed. The overall and disease-free survival rates and influence of clinicopathologic variables on disease-free survival rate were evaluated.
RESULTS:
The median age was 64 years (range, 20-86 years). R0 resections were performed in 43 (93.5%) patients. With a median follow-up time of 33 months (1-275 months), there were 5 (10.9%) recurrences and 2 mortalities in the high-risk group. The overall survival and recurrence-free survival rates at 5 years were 92.1% and 84.6%, respectively. Male gender, tumor size of >10 cm, high numbers of mitotic figures, R1 resection, high risk according to the Joensuu criteria, and a Ki-67 index of >10% were associated with a poor prognosis.
CONCLUSIONS:
Surgical resection of low- and intermediate-risk GISTs has excellent results. High counts of mitotic figures, male gender, incomplete resection, large tumor size, and a high Ki-67 index are associated with a poor prognosis.. |
| 33. |
Nakata K, Nagai E, Ohuchida K, Nakamura K, Tanaka M, Outcomes of Cervical End-to-Side Triangulating Esophagogastric Anastomosis with Minimally Invasive Esophagectomy, World J Surg, 10.1007/s00268-014-2925-0 , 39, 5, 1099-1104, 2015.04, BACKGROUND:
Esophagogastric anastomosis after esophagectomy has been performed with a variety of techniques during the past decade. However, anastomotic leakage and stricture are still important clinical problems after esophagogastric anastomosis, causing burdensome symptoms and poor quality of life. Herein, we describe a novel cervical end-to-side triangulating esophagogastric anastomoasis using linear stapler.
METHODS:
A total of 90 patients (85 % male; mean age 63 years) with thoracic esophageal cancer who underwent cervical end-to-side esophagogastric triangular anastomosis using a linear stapler after minimally invasive esophagectomy between November 2006 and April 2013 were retrospectively reviewed.
RESULTS:
The median operation time was 602 min (range 424-936 min). The volume of blood loss during the entire operative procedure was 127 ml (range 0-700 ml). There were no cases of anastomotic leakage in this study, although four patients (4.4 %) developed dysphagia associated with benign anastomotic stricture formation. All patients with a benign anastomotic stricture underwent balloon dilation, which resulted in improvement in their symptoms.
CONCLUSIONS:
Considering the absence of anastomotic leakage and low rate of anastomotic stricture formation in this study, our modified triangular esophagogastric anastomosis technique appears promising and may contribute to reduced morbidity and mortality rates following esophagectomy.
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| 34. |
Miyasaka Y, Mori Y, Nakata K, Ohtsuka T, Nakamura M, Prophylactic biliary and gastrointestinal bypass for unresectable pancreatic head cancer: A retrospective case series, JOP, 18, 6, 470-474, 2017.04. |
| 35. |
Okumura T, Ohuchida K, Sada M, Abe T, Endo S, Koikawa K, Iwamoto C, Miura D, Mizuuchi Y, Moriyama T, Nakata K, Miyasaka Y, Manabe T, Ohtsuka T, Nagai E, Mizumoto K, Oda Y, Hashizume M, Nakamura M, Extra-pancreatic invasion induces lipolytic and fibrotic changes in the adipose microenvironment, with released fatty acids enhancing the invasiveness of pancreatic cancer cells, Oncotarget, 10.18632/oncotarget.15430., 8, 11, 18280-18295, 2017.04, Abstract
Pancreatic cancer progression involves components of the tumor microenvironment, including stellate cells, immune cells, endothelial cells, and the extracellular matrix. Although peripancreatic fat is the main stromal component involved in extra-pancreatic invasion, its roles in local invasion and metastasis of pancreatic cancer remain unclear. This study investigated the role of adipose tissue in pancreatic cancer progression using genetically engineered mice (Pdx1-Cre; LSL-KrasG12D; Trp53R172H/+) and an in vitro model of organotypic fat invasion. Mice fed a high fat diet had significantly larger primary pancreatic tumors and a significantly higher rate of distant organ metastasis than mice fed a standard diet. In the organotypic fat invasion model, pancreatic cancer cell clusters were smaller and more elongated in shape and showed increased fibrosis. Adipose tissue-derived conditioned medium enhanced pancreatic cancer cell invasiveness and gemcitabine resistance, as well as inducing morphologic changes in cancer cells and increasing the numbers of lipid droplets in their cytoplasm. The concentrations of oleic, palmitoleic, and linoleic acids were higher in adipose tissue-derived conditioned medium than in normal medium, with these fatty acids significantly enhancing the migration of cancer cells. Mature adipocytes were smaller and the concentration of fatty acids in the medium higher when these cells were co-cultured with cancer cells. These findings indicate that lipolytic and fibrotic changes in peripancreatic adipose tissue enhance local invasiveness and metastasis via adipocyte-released fatty acids. Inhibition of fatty acid uptake by cancer cells may be a novel therapy targeting interactions between cancer and stromal cells.
KEYWORDS:
adipose microenvironment; extra-pancreatic invasion; fatty acids; lipolysis; pancreatic cancer. |
| 36. |
Nakayama H, Ohuchida K, Yoshida M, Miyazaki T, Takesue S, Abe T, Endo S, Koikawa K, Okumura T, Moriyama T, Nakata K, Miyasaka Y, Shirahane K, Manabe T, Ohtsuka T, Toma H, Tominaga Y, Nagai E, Mizumoto K, Oda Y, Nakamura M, Degree of desmoplasia in metastatic lymph node lesions is associated with lesion size and poor prognosis in pancreatic cancer patients, Oncol Lett, 10.3892/ol.2017.6549, 14, 3, 3141-3147, 2017.04, Abstract
Pancreatic cancer is characterized by increased hyperplasia of fibrotic tissue, termed desmoplasia, and lymph node metastasis is an independent prognostic factor in this disease. However, there are no reports focused on desmoplasia in pancreatic cancer lymph node metastases. The present study evaluated a range of factors and investigated their association with poor prognosis in pancreatic cancer cases with lymph node metastasis, including the degree of desmoplasia in lesions. To identify the poor prognostic factors associated with lymph node metastasis, the present study retrospectively reviewed the clinical data of 65 patients with lymph node metastases that underwent surgical pancreatic cancer resection between 2007 and 2012 at a single institution. The investigation focused on the degree of fibrosis in metastatic lesions in 216 lymph nodes, and investigated associations with prognosis or clinicopathological findings. The ratios of the fibrotic area in metastatic lymph node lesions were evaluated and classified into three categories, high (≥70%), moderate (10-70%) and low (KEYWORDS:
desmoplasia; locally extranodal invasion; lymph node metastasis; pancreatic cancer; prognostic factor. |
| 37. |
Ohtsuka T, Mori Y, Ishigami K, Fujimoto T, Miyasaka Y, Nakata K, Ohuchida K, Nagai E, Oda Y, Shimizu S, Nakamura M, Clinical significance of circumportal pancreas, a rare congenital anomaly, in pancreatectomy, Am J Surg, 214, 2, 267-272, 2017.04, Abstract
BACKGROUND:
Circumportal pancreas is a rare congenital pancreatic anomaly. The aim of this study was to clarify the clinical characteristics of patients with circumportal pancreases undergoing pancreatectomy.
METHODS:
The medical records of 508 patients who underwent pancreatectomy were retrospectively reviewed. The prevalence of circumportal pancreas and related anatomical variations were assessed. Surgical procedures and postoperative outcomes were compared in patients with and without circumportal pancreas.
RESULTS:
Circumportal pancreas was observed in 9 of the 508 patients (1.7%). In all nine patients, the portal vein was completely encircled by the pancreatic parenchyma above the level of the splenoportal junction, and the main pancreatic duct ran dorsal to the portal vein. The rate of variant hepatic artery did not differ significantly in patients with and without circumportal pancreas. Pancreatic fistula developed more frequently in patients with than without circumportal pancreas (44% vs. 14%, p = 0.03), but other clinical parameters did not differ significantly in these two groups.
CONCLUSIONS:
Despite being rare, circumportal pancreas may increase the risk of postoperative pancreatic fistula in patients undergoing pancreatectomy. However, a prospective, large-cohort study is necessary to determine the real incidence of relevant anatomical variations and the definitive clinical significance of this rare anomaly.. |
| 38. |
Abe T, Ohuchida K, Endo S, Ookubo F, Mori Y, Nakata K, Miyasaka Y, Manabe T, Ohtsuka T, Nagai E, Oda Y, Nakamura M, Clinical importance of intraoperative peritoneal cytology in patients with pancreatic cancer, Surgery, 161, 4, 951-958, 2017.04, BACKGROUND:The clinical importance of intraoperative peritoneal cytology in patients with pancreatic cancer remains incompletely understood.METHODS:Peritoneal washing samples were collected from 411 consecutive patients with pancreatic ductal adenocarcinoma from 1996 to 2014. Of the 411 patients, 335 underwent macroscopically curative resection and 76 with noncurative factors did not undergo resection. We compared long-term outcomes between patients with positive cytology (cytology+) and those with negative cytology (cytology-) and investigated the importance of clinicopathologic factors.RESULTS:Of 335 patients with curative resection, 300 (89.6%) were cytology- and 35 (10.4%) were cytology+. The median overall survival of cytology+ patients was less than that of cytology- patients (16 vs 31 months, respectively; P < .0001). The median overall survival of cytology+ patients with noncurative factors was significantly worse than that of cytology+ pat
ients with curative resection (6.9 vs 16.0 months, respectively; P = .0023). The median disease-free survival of cytology+ patients was less than that of cytology- patients (6.5 vs 16 months, respectively; P < .0001). In the multivariate analysis, cytology+ was an independent prognostic factor for overall survival and disease-free survival.CONCLUSION:Cytology+ without noncurative factors was a predictive factor for a poor prognosis. Therefore, it is important to regard patients with pancreatic cancer characterized by cytology+ as a special group that may warrant more aggressive adjuvant therapy.. |
| 39. |
Abe T, Ohuchida K, Koikawa K, Endo S, Okumura T, Sada M, Horioka K, Zheng B, Moriyama T, Nakata K, Miyasaka Y, Manabe T, Ohtsuka T, Nagai E, Mizumoto K, Hashizume M, Nakamura M, Cancer-associated peritoneal mesothelial cells lead the formation of pancreatic cancer peritoneal dissemination, Int J Oncol, 50, 2, 457-467, 2017.04, The interaction between the cancer cells and the peritoneal mesothelial cells (PMCs) plays an important role in the peritoneal dissemination in several types of cancer. However, the role of PMCs in the peritoneal dissemination of pancreatic cancer remains unclear. In the present study, we investigated the interaction between the pancreatic cancer cells (PCCs) and the PMCs in the formation of peritoneal dissemination in vitro and in vivo. The tumor-stromal interaction of PCCs and PMCs significantly enhanced their mobility and invasiveness and enhanced the proliferation and anoikis resistance of PCCs. In a 3D organotypic culture model of peritoneal dissemination, co-culture of PCCs and PMCs significantly increased the cells invading into the collagen gel layer compared with mono-culture of PCCs. PMCs pre-invaded into the collagen gel, remodeled collagen fibers, and increased parallel fiber orientation along the direction of cell invasion. In the tissues
of peritoneal dissemination of the KPC (LSL-KrasG12D/+; LSL-Trp53R172H/+;Pdx-1-Cre) transgenic mouse, the monolayer of PMCs was preserved in tumor-free areas, whereas PMCs around the invasive front of peritoneal dissemination proliferated and invaded into the muscle layer. In vivo, intraperitoneal injection of PCCs with PMCs significantly promoted peritoneal dissemination compared with PCCs alone. The present data suggest that the cancer-associated PMCs have important promoting roles in the peritoneal dissemination of PCCs. Therapy targeting cancer-associated PMCs may improve the prognosis of patients with pancreatic cancer.. |
| 40. |
Endo S, Nakata K, Ohuchida K, Takesue S, Nakayama H, Abe T, Koikawa K, Okumura T, Sada M, Horioka K, Zheng B, Mizuuchi Y, Iwamoto C, Murata M, Moriyama T, Miyasaka Y, Ohtsuka T, Mizumoto K, Oda Y, Hashizume M, Nakamura M, Autophagy Is Required for Activation of Pancreatic Stellate Cells, Associated With Pancreatic Cancer Progression and Promotes Growth of Pancreatic Tumors in Mice, Gastroenterology, 10.1053/j.gastro.2017.01.010, 152, 6, 1492-1506, 2017.04, BACKGROUND & AIMS: Pancreatic stellate cells (PSCs) changefrom a quiescent to activated state in the tumor environmentand secrete extracellular matrix (ECM) molecules and cytokinesto increase the aggressiveness of tumors. However, it is notclear how PSCs are activated to produce these factors, orwhether this process can be inhibited. PSCs have morphologicand functional similarities to hepatic stellate cells, whichundergo autophagy to promote fibrosis and tumor growth. Weinvestigated whether autophagy activates PSCs, which promotesdevelopment of the tumor stroma and growth ofpancreatic tumors in mice. METHODS: We used immunofluorescencemicroscopy and immunohistochemistry to analyzepancreatic tumor specimens from 133 patients who underwentpancreatectomy in Japan from 2000 to 2009. PSCs werecultured from pancreatic tumor tissues or tissues of patientswith chronic pancreatitis; these were analyzed by immunofluorescencemicroscopy, immunoblots, quantitative
reversetranscription polymerase chain reaction, and in assays forinvasiveness, proliferation, and lipid droplets. Autophagy wasinhibited in PSCs by administration of chloroquine or transfectionwith small interfering RNAs. Proteins were knockeddown in immortalized PSCs by expression of small hairpinRNAs. Cells were transplanted into pancreatic tails of nudemice, and tumor growth and metastasis were quantified. RESULTS:Based on immunohistochemical analyses, autophagywas significantly associated with tumor T category (P ｼ .018),histologic grade (P ｼ .001), lymph node metastases (P < .001),stage (P ｼ .009), perilymphatic invasion (P ｼ .001), and perivascularinvasion (P ｼ .003). Autophagy of PSCs was associatedwith shorter survival times of patients with pancreatic cancer.PSC expression of microtubule-associated protein 1 lightchain 3, a marker of autophagosomes, was associated with pooroutcomes (shorter survival time, disease recurrence) forpati
ents with pancreatic cancer (relative risk of shorter survivaltime, 1.56). Immunoblots showed that PSCs from pancreatictumor samples expressed higher levels of markers of autophagythan PSCs from chronic pancreatitis samples. Inhibitorsof autophagy increased the number of lipid droplets of PSCs,indicating a quiescent state of PSCs, and reduced their productionof ECM molecules and interleukin 6, as well as theirproliferation and invasiveness in culture. PSCs exposedto autophagy inhibitors formed smaller tumors in nude mice(P ｼ .001) and fewer liver metastases (P ｼ .018) with lessperitoneal dissemination (P ｼ .018) compared to PSCs notexposed to autophagy inhibitors. CONCLUSIONS: AutophagicPSCs produce ECM molecules and interleukin 6 and areassociated with shorter survival times and disease recurrencein patients with pancreatic cancer. Inhibitors of PSC autophagymight reduce pancreatic tumor invasiveness by altering thetumor stroma.. |
| 41. |
Endo S, Nakata K, Sagara A, Koikawa K, Ando Y, Kibe S, Takesue S, Nakayama H, Abe T, Okumura T, Moriyama T, Miyasaka Y, Ohuchida K, Ohtsuka T, Mizumoto K, Nakamura M, Autophagy inhibition enhances antiproliferative effect of salinomycin in pancreatic cancer cells, Pancreatology, 10.1016/j.pan.2017.08.009, 17, 6, 990-996, 2017.04, Background: Salinomycin has cytotoxic effects on various types of malignancy and induces autophagy.However, it has not been clarified whether autophagy induced by salinomycin treatment has a protectiveor cytotoxic role. We investigated whether salinomycin affects autophagy in pancreatic cancer cells andwhether autophagy induced by salinomycin treatment has a protective or cytotoxic role in these cells.Methods: We investigated the effect of salinomycin using three pancreatic cancer cell lines. We investigatedeffect on proliferation and the CD133 positive fraction using flow cytometry. In addition, wemonitored the change in autophagic activity after salinomycin treatment using fluorescent immunostaining,western blotting, and flow cytometry. Finally, knockdown of ATG5 or ATG7 by siRNA was usedto investigate the impact of autophagy inhibition on sensitivity to salinomycin.Results: Salinomycin suppressed the proliferation of pancreatic cancer cells in a co
ncentration dependentmanner, and reduced the CD133 positive fraction. Salinomycin enhanced autophagy activity in these cellsin a concentration dependent manner. Autophagy inhibition made pancreatic cancer cells more sensitiveto salinomycin.Conclusions: Our data provide the first evidence indicating that autophagy induced by salinomycin havea protective role in pancreatic cancer cells. A new therapeutic strategy of combining salinomycin,autophagy inhibitors, and anticancer drugs could hold promise for pancreatic cancer treatment.. |
| 42. |
Nakamura M, Nakata K, Matsumoto H, Ohtsuka T, Yoshida K, Tokunaga S, Hino K, Acyl/free carnitine ratio is a risk factor for hepatic steatosis after pancreatoduodenectomy and total pancreatectomy, Pancreatology, 17, 1, 135-138, 2017.04, Abstract
OBJECTIVES:
Hepatic steatosis, one of the most frequent long-term complications of pancreatectomy, influences not only hepatic function but also survival rate. However, its risk factors and pathogenesis have not been established. The purpose of this study was to clarify the risk factors for hepatic steatosis after pancreatectomy.
METHODS:
In this retrospective study of 21 patients who had undergone pancreatectomy (19 cases of pancreatoduodenectomy and 2 cases of total pancreatectomy), serum carnitine concentrations, fractions of carnitine, and hepatic attenuation on computed tomography images were analyzed with the aim of identifying risk factors for hepatic steatosis.
RESULTS:
Thirteen (61.9%) of the 21 patients were diagnosed as having hypocarnitinemia after pancreatectomy. Average hepatic attenuation was as low as 42.2HU (±21.3 SD). A high ratio of acyl/free carnitine was associated with less pronounced hepatic attenuation according to both univariate (P CONCLUSIONS:
The serum carnitine concentrations were low after pancreatectomy in some patients. The statistical analyses suggest that a high ratio of acyl/free carnitine is an independent risk factor for hepatic steatosis after pancreatectomy.. |
| 43. |
Ohtsuka T, Gotoh Y, Nakashima Y, Okayama Y, Nakamura S, Morita M, Aly MYF, Velasquez VVDM, Mori Y, Sadakari Y, Nakata K, Miyasaka Y, Ishigami K, Fujimori N, Mochidome N, Oda Y, Shimizu S, Nakamura M, Role of SpyGlass-DStm in the preoperative assessment of pancreatic intraductal papillary mucinous neoplasm involving the main pancreatic duct, Pancreatology, 10.1016/j.pan.2018.04.012, 18, 5, 566-571, 2018.04, Abstract
BACKGROUND/OBJECTIVES:
It is often difficult to determine an adequate resection line during pancreatectomy for intraductal papillary mucinous neoplasm involving the main pancreatic duct during partial pancreatectomy. The aim of this study was to evaluate the usefulness of improved peroral pancreatoscopy using SpyGlass-DStm in the preoperative assessment of intraductal papillary mucinous neoplasm involving the main pancreatic duct.
METHODS:
We collected and retrospectively analyzed clinicopathological data from seven consecutive patients who underwent preoperative assessment of intraductal papillary mucinous neoplasm involving the main duct using SpyGlass-DStm.
RESULTS:
Good imaging quality of the intraductal protruding lesion was obtained in all seven patients, and only one adverse event was noted wherein a patient had mild pancreatitis. Six patients underwent pancreatectomy. In one patient, masked-type concomitant pancreatic ductal adenocarcinoma and low-length dysplastic lesion was found near the surgical margin, which was not detected by preoperative imaging modalities including SpyGlass-DStm. The sensitivity of targeting biopsy during SpyGlass-DStm to diagnose high-grade dysplasia was 0%.
CONCLUSIONS:
SpyGlass-DStm can be safely performed in patients with intraductal papillary mucinous neoplasm involving the main duct, and has excellent visualization of the target lesion. However, challenges include poor diagnostic ability of targeting biopsy, and, therefore, intraoperative frozen section is still needed to obtain negative surgical margins
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| 44. |
Abe T, Nakata K, Kibe S, Mori Y, Miyasaka Y, Ohuchida K, Ohtsuka T, Oda Y, Nakamura M, Prognostic Value of Preoperative Nutritional and Immunological Factors in Patients with Pancreatic Ductal Adenocarcinoma, Ann Surg Oncol, 10.1245/s10434-018-6761-6, 25, 13, 3996-4003, 2018.04. |
| 45. |
Koikawa K, Ohuchida K, Takesue S, Ando Y, Kibe S, Nakayama H, Endo S, Abe T, Okumura T, Horioka H, Sada M, Iwamoto C, Moriyama T, Nakata K, Miyasaka Y, Ohuchida R, Manabe T, Ohtsuka T, Nagai E, Mizumoto K, Hashizume M, Nakamura M, Pancreatic stellate cells reorganize matrix components and lead pancreatic cancer invasion via the function of Endo180, Cancer lett, 10.1016/j.canlet.2017.10.010, 1, 412, 143-154, 2018.04, Specific cell populations leading the local invasion of cancer are called “leading cells”. However, the underlying mechanisms are unclear. Here, we identified leading cells in pancreatic cancer and deter- mined how these cells lead and promote cancer cell invasion in the extracellular matrix (ECM). Using three-dimensional matrix remodeling assay, we found that pancreatic stellate cells (PSCs) frequently invaded the collagen matrix with pancreatic cancer cells (PCCs), which invaded behind the invading PSCs. In addition, invading PSCs changed the alignment of collagen fibers, resulting in ECM remodeling and an increase in the parallel fibers along the direction of invading PSCs. Endo180 expression was higher in PSCs than in PCCs, Endo180 knockdown in PSCs attenuated the invasive abilities of PSCs and co- cultured PCCs, and decreased the expression level of phosphorylated myosin light chain 2 (MLC2). In mouse models, Endo180-knockdown PSCs
suppressed tumor growth and changes in collagen fiber orientation in co-transplantation with PCCs. Our findings suggest that PSCs lead the local invasion of PCCs by physically remodeling the ECM, possibly via the function of Endo180, which reconstructs the actin cell skeleton by phosphorylation of MLC2.. |
| 46. |
Nakata K, Shikata S, Ohtsuka T, Ukai T, Miyasaka Y, Mori Y, Velasquez VVDM, Gotoh Y, Ban D, Nakamura Y, Nagakawa Y, Tanabe M, Sahara Y, Takaori K, Honda G, Misawa T, Kawai M, Yamaue H, Morikawa T, Kuroki T, Mou Y, Lee WJ, Shrikhande SV, Tang CN, Conrad C, Han HS, Chinnusamy P, Asbun HJ, Kooby DA, Wakabayashi G, Takada T, Yamamoto M, Nakamura M, Minimally invasive preservation versus splenectomy during distal pancreatectomy: a systematic review and meta-analysis, J HepatoBiliary Pancreat Sci, 10.1002/jhbp.569 , 25, 11, 476-488, 2018.04, Abstract
BACKGROUND:
Minimally invasive distal pancreatectomy (MIDP) has gained in popularity recently. However, there is no consensus on whether to preserve the spleen or not. In this study, we compared MIDP outcomes between spleen-preserving distal pancreatectomy (SPDP) and distal pancreatectomy with splenectomy (DPS); as well as outcomes between splenic vessel preservation (SVP) and Warshaw's technique (WT).
METHODS:
A systematic search of PubMed (MEDLINE) and Cochrane Library was conducted and the reference lists of review articles were hand-searched.
RESULTS:
Fifteen relevant studies with 769 patients were selected for meta-analyses of DPS and SPDP, while another 15 studies with 841 patients were used for the analysis between SVP and WT. Compared with the DPS group, SPDP patients had significantly lower incidences of infectious complications (P = 0.006) and pancreatic fistula (P = 0.002), shorter operative time (P CONCLUSIONS:
Based on this study, SPDP has significantly superior outcomes compared to DPS. When a spleen is preserved, SVP has better outcomes over WT for reducing splenic complications.
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| 47. |
Nagakawa Y, Nakamura Y, Honda G, Gotoh Y, Ohtsuka T, Ban D, Nakata K, Sahara Y, Velasquez VVDM, Takaori K, Misawa T, Kuroki T, Kawai M, Morikawa T, Yamaue H, Tanabe M, Mou Y, Lee WJ, Shrikhande SV, Conrad C, Han HS, Tang CN, Palanivelu C, Kooby DA, Asbun HJ, Wakabayashi G, Tsuchida A, Takada T, Yamamoto M, Nakamura M, Learning curve and surgical factors influencing the surgical outcomes during the initial experience with laparoscopic pancreaticoduodenectomy, J HepatoBiliary Pancreat Sci, 10.1002/jhbp.586 , 25, 11, 498-507, 2018.04, Abstract
BACKGROUND:
Laparoscopic pancreaticoduodenectomy (LPD) requires sufficient laparoscopic training for optimal outcomes. Our aim is to determine the learning curve and investigate the factors influencing surgical outcomes during the learning curve.
METHODS:
We analyzed surgical results of 150 consecutive cases of LPD performed by three hepatopancreatobiliary surgeons during their 50 first cases. Learning curves were constructed by cumulative sum (CUSUM) analysis. Preoperative factors influencing resection time and blood loss were investigated in the introductory and stable periods. RESULTS : The learning curve could be divided into three phases: initial (1-20 cases), plateau (21-30), and stable (31-50). Resection time with lymph node dissection was significantly longer during the introductory period (initial and plateau periods) (P CONCLUSIONS:
Hepatopancreatobiliary surgeons need more than 30 cases until LPD becomes stable. Lymph node dissection and patients with high visceral fat area and concomitant pancreatitis should be avoided during the introductory period of the learning curve.. |
| 48. |
Aly MYF, Mori Y, Miyasaka Y, Ohtsuka T, Sadakari Y, Nakata K, Oda Y, Shimizu S, Nakamura M, Laparoscopic surgery for congenital biliary dilatation: a single-institution experience, Surg Today, 10.1007/s00595-017-1545-3, 48, 1, 44-50, 2018.04, Abstract
PURPOSE:
Laparoscopic surgery as a treatment for congenital biliary dilatation is uncommon. We herein present a series of laparoscopic surgeries for congenital biliary dilatation performed in our institution and review our experience with this approach over a long period of time.
METHODS:
Medical records of 36 consecutive patients who underwent laparoscopic surgery for congenital biliary dilatation from 1996 to 2015 were retrospectively reviewed. Data on patient demographics, operative time, blood loss, hospital stay, and complications were evaluated. A comparison between the former period (Group A, 1996-2005) and the latter period (Group B, 2006-2015) was performed.
RESULTS:
The patients comprised 23 females and 13 males with a median age of 34 years. The median operative time, blood loss, and hospital stay was 493 min, 154 g, and 11 days, respectively. Total early and late complications occurred in 7 (19%) and 2 (5%) patients, respectively. A comparison between Groups A and B revealed no significant difference in operative time or complications, but operative blood loss, open conversion, and hospital stay were significantly lower in Group B than in Group A (P
CONCLUSION:
Laparoscopic surgery for congenital biliary dilatation is feasible and provides acceptable results. Further prospective studies of larger numbers of patients are needed.. |
| 49. |
Ohtsuka T, Mori Y, Fujimoto T, Miyasaka Y, Nakata K, Ohuchida K, Nagai E, Oda Y, Shimizu S, Nakamura M, Feasibility of Prophylactic Pancreatojejunostomy in Possible High-Risk Patients for Prevention of Pancreatic Fistula during Enucleation or Limited Pancreatic Resection, Am Surg, 84, 1, 149-153, 2018.04, Abstract
The aim of this study was to assess the feasibility of prophylactic pancreatojejunostomy after enucleation or limited pancreatic resection regarding the risk of postoperative pancreatic fistula (PF). We retrospectively reviewed the medical records of 32 patients who underwent enucleation or limited pancreatic resection and compared the clinical parameters between patients with (n = 10) and without (n = 22) prophylactic pancreatojejunostomy. Prophylactic pancreatojejunostomy was performed in patients with a possible high risk ofPF. No operation-related mortality occurred. Operation time was significantly longer (P |
| 50. |
Fujimoto T, Mori Y, Nakashima Y, Ohtsuka T, Nakamura S, Gotoh Y, Date K, Sadakari Y, Nakata K, Miyasaka Y, Osoegawa T, Aso A, Ihara E, Nakamura K, Ogawa Y, Shimizu S, Nakamura M, Endoscopic Retrograde Cholangiopancreatography in Patients With Surgically Altered Gastrointestinal Anatomy: A Retrospective Study, Int Surg, 10.9738/INTSURG-D-17-00137.1 , 103, 3-4, 184-190, 2018.04, Article Citation:
Takaaki Fujimoto, Yasuhisa Mori, Yohei Nakashima, Takao Ohtsuka, So Nakamura, Yoshitaka Gotoh, Kenjiro Date, Yoshihiko Sadakari, Kohei Nakata, Yoshihiro Miyasaka, Takashi Osoegawa, Akira Aso, Eikichi Ihara, Kazuhiko Nakamura, Yoshihiro Ogawa, Shuji Shimizu, and Masafumi Nakamura (2019) Endoscopic Retrograde Cholangiopancreatography in Patients With Surgically Altered Gastrointestinal Anatomy:. |
| 51. |
Ohtsuka T, Ban D, Nakamura Y, Nagakawa Y, Tanabe M, Gotoh Y, Velasquez VVDM, Nakata K, Sahara Y, Takaori K, Honda G, Misawa T, Kawai M, Yamaue H, Morikawa T, Kuroki T, Mou Y, Lee WJ, Shrikhande SV, Tang CN, Conrad C, Han HS, Palanivelu C, Asbun HJ, Kooby DA, Wakabayashi G, Takada T, Yamamoto M, Nakamura M, Difficulty scoring system in laparoscopic distal pancreatectomy, J HepatoBiliary Pancreat Sci, 10.1002/jhbp.578, 25, 11, 489-497, 2018.04, Abstract
BACKGROUND:
Several factors affect the level of difficulty of laparoscopic distal pancreatectomy (LDP). The purpose of this study was to develop a difficulty scoring (DS) system to quantify the degree of difficulty in LDP.
METHODS:
We collected clinical data for 80 patients who underwent LDP. A 10-level difficulty index was developed and subcategorized into a three-level difficulty index; 1-3 as low, 4-6 as intermediate, and 7-10 as high index. The automatic linear modeling (LINEAR) statistical tool was used to identify factors that significantly increase level of difficulty in LDP.
RESULTS:
The operator's 10-level DS concordance between the 10-level DS by the reviewers, LINEAR index DS, and clinical index DS systems were analyzed, and the weighted Cohen's kappa statistic were at 0.869, 0.729, and 0.648, respectively, showing good to excellent inter-rater agreement. We identified five factors significantly affecting level of difficulty in LDP; type of operation, resection line, proximity of tumor to major vessel, tumor extension to peripancreatic tissue, and left-sided portal hypertension/splenomegaly.
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| 52. |
Koikawa K, Ohuchida K, Ando Y, Kibe S, Nakayama H, Takesue S, Endo S, Abe T, Okumura T, Iwamoto C, Moriyama T, Nakata K, Miyasaka Y, Ohtsuka T, Nagai E, Mizumoto K, Hashizume M, Nakamura M, Basement membrane destruction by pancreatic stellate cells leads to local invasion in pancreatic ductal adenocarcinoma, Cancer Lett, 10.1016/j.canlet.2018.03.031
, 1, 425, 65-77, 2018.04, Stroma invasion is an important step in pancreatic cancer progression. However, how pancreatic ductal adenocarcinoma (PDAC) with ductal structure invades the surrounding stroma has not been clear. Here, we elucidated the mechanism of stromal invasion of PDAC, using organoids. From resected PDAC specimens, we established human PDAC organoids, which developed ductal and basement membrane (BM) structures. When the organoids were co-cultured with pancreatic stellate cells (PSCs) in a collagen matrix, organoids lost their BM and ductal structures, and invaded collagen matrix more frequently than did mono-cultured organoids. Interestingly, direct contact by PSCs to PDAC organoids was observed before BM destruction. Matrix metalloproteinase (MMP) 2 or membrane type-1 MMP (MT1MMP) knockdown in PSCs significantly attenuated BM destruction by PSCs, and retained the ductal structures in organoids. Our results imply that direct contact by PSCs induces BM destruct
ion and stromal invasion of PDAC via MMP2 which binds to MT1MMP on PSCs.. |
| 53. |
Okumura T, Ohuchida K, Kibe S, Iwamoto C, Ando Y, Takesue S, Nakayama H, Abe T, Endo S, Koikawa K, Sada M, Horioka K, Mochidome N, Arita M, Moriyama T, Nakata K, Miyasaka Y, Ohtsuka T, Mizumoto K, Oda Y, Hashizume M, Nakamura M, Adipose tissue-derived stromal cells are sources of cancer-associated fibroblasts and enhance tumor progression by dense collagen matrix, Int J Cancer, 10.1002/ijc.31775 , 144, 6, 1401-1413, 2018.04, Abstract
Although recent studies revealed that adipose tissue accelerates pancreatic tumor progression with excessive extracellular matrix, key players for desmoplasia in the adipose microenvironment remains unknown. Here, we investigated the roles of adipose tissue-derived stromal cells (ASCs) in desmoplastic lesions and tumor progression by in vitro and in vivo experiments. In a three-dimensional (3-D) organotypic fat invasion model using visceral fat from CAG-EGFP mice, GFP-positive fibroblastic cells infiltrated toward cancer cells. When tumor cells were inoculated into transplanted visceral fat pads in vivo, tumor weights and stromal components were enhanced compared to subcutaneous and orthotopic tumor cells inoculated without fat pads. Expression of αSMA in established human ASCs was lower compared to cancer associated fibroblasts, and the 3-D collagen matrices produced by ASCs cultured in cancer cell-conditioned medium changed from loose to dense structures that affected the motility of cancer cells. Microarray analyses revealed upregulation of S100A4 in ASCs, while S100A4-positive stromal cells were observed at extrapancreatic invasion sites of human pancreatic cancer. The present findings indicate that ASCs are recruited to extrapancreatic invasion sites and produce dense collagen matrices that lead to enhanced tumor progression. Both inhibition of ASCs recruitment and activation could lead to a novel antistromal therapy.
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| 54. |
Nakayama H, Ohuchida K, Yonenaga A, Sagara A, Ando Y, Kibe S, Takesue S, Abe T, Endo S, Koikawa K, Okumura T, Shido K, Miyoshi K, Nakata K, Moriyama T, Miyasaka Y, Inoue S, Ohtsuka T, Mizumoto K, Nakamura M, S100P regulates the collective invasion of pancreatic cancer cells into the lymphatic endothelial monolayer, Int J Oncol, 10.3892/ijo.2019.4812, 55, 1, 211-222, 2019.04, Abstract
Lymph node metastasis is an independent prognostic factor in pancreatic cancer. However, the mechanisms of lymph node colonization are unknown. As a mechanism of lymphatic metastasis, it has been reported for other types of cancer that spheroids from tumor cells cause circular chemorepellent‑induced defects (CCIDs) in lymphatic endothelial monolayers. In pancreatic cancer, such mechanisms of metastasis have not been elucidated. The present study evaluated the involvement of this new mechanism of metastasis in pancreatic cancer and investigated the associated factors. In human pancreatic cancer tissue, it was observed that clusters of cancer cells penetrated the wall of lymphatic ducts around the primary tumor. An in vitro co‑culture system was then used to analyze the mechanisms of tumor cell‑mediated disruption of lymphatic vessels. Time‑lapse microscopic imaging revealed that spheroids from pancreatic cancer cells caused circular defects in lymphatic endothelial monolayers. CCID formation ability differed depending on the cell line. Neither aggregation of spheroids nor adhesion to lymphatic endothelial cells (LECs) exhibited a significant correlation with this phenomenon. The addition of supernatant from cultured cancer cells enhanced CCID formation. Microarray analysis revealed that the expression of S100 calcium binding protein P (S100P) was significantly increased when LECs were treated with supernatant from cultured cancer cells. Addition of a S100P antagonist significantly suppressed the migration of LECs and CCID formation. The present findings demonstrated that spheroids from pancreatic cancer cells caused circular defects in lymphatic endothelial monolayers. These CCIDs in pancreatic cancer were partly regulated by S100P, suggesting that S100P may be a promising target to inhibit lymph node metastasis.
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| 55. |
Nakamura S, Sadakari Y, Ohtsuka T, Okayama T, Nakashima Y, Gotoh Y, Saeki K, Mori Y, Nakata K, Miyasaka Y, Onishi H, Oda Y, Goggins M, Nakamura M, Pancreatic Juice Exosomal MicroRNAs as Biomarkers for Detection of Pancreatic Ductal Adenocarcinoma, Ann Surg Oncol, 10.1245/s10434-019-07269-z, 26, 7, 2104-2111, 2019.04, Abstract
BACKGROUND:
Pancreatic ductal adenocarcinoma (PDAC) is a lethal neoplasm because of difficulties in early detection. Several studies have recently suggested that exosomes may have potential as novel biomarkers. This study aimed to isolate exosomes from pancreatic juice and to investigate whether exosomal microRNAs (ex-miRs) could be used as biomarkers for PDAC.
METHODS:
Pancreatic juice was collected from patients with PDAC and chronic pancreatitis (CP) by endoscopic retrograde pancreatography. Exosomes were extracted by ultracentrifugation. The presence of exosomes was confirmed by electron microscopy and Western blotting using anti-CD63, -CD81, and -TSG101 antibodies. Relative levels of ex-miR-21 and ex-miR-155 were quantified and compared between PDAC and CP patients.
RESULTS:
A total of 35 pancreatic juice samples (27 PDAC and 8 CP) were collected. Relative levels of both ex-miR-21 and ex-miR-155 were significantly higher in PDAC patients compared with CP patients (p CONCLUSIONS:
We successfully extracted exosomes from pancreatic juice. Ex-miRs, including ex-miR-21 and ex-miR-155, in pancreatic juice may be developed as biomarkers for PDAC
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| 56. |
Miyasaka Y, Ohtsuka T, Kimura R, Matsuda R, Mori Y, Nakata K, Kakihara D, Fujimori N, Ohno T, Oda Y, Nakamura M, Neoadjuvant Chemotherapy with Gemcitabine Plus Nab-Paclitaxel for Borderline Resectable Pancreatic Cancer Potentially Improves Survival and Facilitates Surgery, Ann Surg Oncol, 10.1245/s10434-019-07309-8, 26, 5, 1528-1534, 2019.04. |
| 57. |
Yan Z, Ohuchida K, Fei S, Zheng B, Guan W, Feng H, Kibe S, Ando Y, Koikawa K, Abe T, Iwamoto C, Shindo K, Moriyama T, Nakata K, Miyasaka Y, Ohtsuka T, Mizumoto K, Hashizume M, Nakamura M, Inhibition of ERK1/2 in cancer-associated pancreatic stellate cells suppresses cancer-stromal interaction and metastasis, J Exp Clin Cancer Res, 10.1186/s13046-019-1226-8 , 38, 1, 221, 2019.04, Abstract
BACKGROUND:Extracellular signal-regulated kinases (ERKs) have been related to multiple cancers, including breast cancer, hepatocellular cancer, lung cancer and colorectal cancer. ERK1/2 inhibitor can suppress growth of KRAS-mutant pancreatic tumors by targeting cancer cell. However, no studies have shown the expression of ERK1/2 on pancreatic stromal and its effect on pancreatic cancer-stromal interaction.
METHODS:Immunohistochemistry and western blotting were performed to detect the expression of p-ERK1/2 in pancreatic tissues and cells. Cell viability assay was used to study IC50 of ERK inhibitor on pancreatic cancer cells (PCCs) and primary cancer-associated pancreatic stellate cells (PSCs). Transwell migration, invasion, cell viability assay, senescence β-galactosidase staining were performed to determine the effect of ERK inhibitor on PCCs and PSCs in vitro and in vivo. The expression of key factors involved in autophagy and epithelial-to-mesenchymal transition (EMT) process were evaluated by western blotting. The expression of key factors related to cell invasiveness and malignancy were confirmed by qRT-PCR. Co-transplantation of PCC Organoid and PSC using a splenic xenograft mouse model was used to evaluated combined treatment of ERK inhibitor and autophagy inhibitor.
RESULTS:Immunohistochemical staining in pancreatic tumor samples and transgenetic mice detected p-ERK1/2 expression in both cancer cells and stromal cells. In pancreatic tissues, p-ERK1/2 was strongly expressed in cancer-associated PSCs compared with cancer cells and normal PSCs. PSCs were also significantly more sensitive to ERK1/2 inhibitor treatment. Inhibition of ERK1/2 suppressed EMT transition in HMPCCs, upregulated cellular senescence markers, activated autophagy in cancer-associated PSCs; and suppressed cancer-stromal interaction, which enhanced invasiveness and viability of cancer cells. We also found that chloroquine, an autophagy inhibitor, suppressed ERK inhibition-induced autophagy and promoted PSC cellular senescence, leading to significantly decreased cell proliferation. The combination of an ERK inhibitor and autophagy inhibitor suppressed liver metastasis in a splenic pancreatic cancer organoid xenograft mouse model.
CONCLUSIONS: These data indicate that inhibition of ERK1/2 in cancer-associated pancreatic stellate cells suppresses cancer-stromal interaction and metastasis.
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| 58. |
Nakashima Y, Ohtsuka T, Nakamura S, Mori Y, Nakata K, Miyasaka Y, Ishigami K, Matsuda R, Oda Y, Nakamura M, Clinicopathological characteristics of non-functioning cystic pancreatic neuroendocrine tumors, Pancreatology, 10.1016/j.pan.2018.11.010, 19, 1, 50-56, 2019.04, Abstract
BACKGROUND/OBJECTIVES:
The biological features of cystic pancreatic neuroendocrine tumors (PNETs) remain unclear. The aim of this study was to clarify the clinicopathological characteristics of non-functioning PNETs (NF-PNETs) with a cystic component.
METHODS:
The medical records of 75 patients with NF-PNETs who had undergone resection in our institution were retrospectively reviewed. Clinicopathological factors were compared between PNETs with and without a cystic component. Expression of somatostatin 2 receptor (SSTR-2) was also analyzed.
RESULTS:
Cystic PNETs were diagnosed in 14 patients (19%). The proportion of men was significantly higher for cystic than solid PNETs (79% vs. 44%, P CONCLUSIONS:
Although cystic PNETs were larger upon diagnosis than solid PNETs in this study, prognosis after surgical resection did not differ significantly between these types of PNET. Somatostatin receptor scintigraphy and somatostatin analogues may be more useful for diagnosing and treating cystic PNETs, respectively.
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| 59. |
Yan Z, Ohuchida K, Zheng B, Okumura T, Takesue S, Nakayama H, Iwamoto C, Shindo K, Moriyama T, Nakata K, Miyasaka Y, Ohtsuka T, Mizumoto K, Oda Y, Hashizume M, Nakamura M, CD110 promotes pancreatic cancer progression and its expression is correlated with poor prognosis, J Cancer Res Clin Oncol, 10.1007/s00432-019-02860-z , 145, 5, 1147-1164, 2019.04, Abstract
PURPOSE:This study aimed at investigating the function and significance of CD110 expression in pancreatic cancer.
METHODS:We performed immunohistochemical staining for CD110 expression in tumor samples from 86 patients with pancreatic cancer. We evaluated clinical outcomes and other clinicopathological factors to determine the significance of CD110 on survival and liver metastasis. We examine thrombopoietin-CD110 signaling in cancer cell extravasation in vitro and in vivo. We investigated the effects of CD110 knockdown on liver metastasis in a splenic xenograft mouse model.
RESULTS:CD110 expression in cancer cells was associated with low-histological-grade invasive ductal carcinoma, and patients with high CD110 expression had poorer prognosis (P = 0.0003). High CD110 expression was an independent predictor of liver metastasis (P = 0.0422). Knockdown of CD110 expression significantly attenuated cell migration and invasion. Treatment with thrombopoietin promoted pancreatic cancer cell extravasation. In the presence of thrombopoietin, CD110 increased cell viability through the activation of the ERK-MYC signaling pathway. Knockdown of CD110 expression inhibited liver metastases in the mouse model.
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| 60. |
Kibe S, Ohuchida K, Ando Y, Takesue S, Nakayama H, Abe T, Endo S, Koikawa K, Okumura T, Iwamoto C, Shindo K, Moriyama T, Nakata K, Miyasaka Y, Shimamoto M, Ohtsuka T, Mizumoto K, Oda Y, Nakamura M, Cancer-associated acinar-to-ductal metaplasia within the invasive front of pancreatic cancer contributes to local invasion, Cancer Lett, 10.1016/j.canlet.2018.12.005, 1, 444, 70-81, 2019.04, Abstract
The pancreas is an organ prone to inflammation, fibrosis, and atrophy because of an abundance of acinar cells that produce digestive enzymes. A characteristic of pancreatic cancer is the presence of desmoplasia, inflammatory cell infiltration, and cancer-associated acinar atrophy (CAA) within the invasive front. CAA is characterized by a high frequency of small ducts and resembles acinar-to-ductal metaplasia (ADM). However, the clinical significance of changes in acinar morphology, such as ADM with acinar atrophy, within the tumor microenvironment remains unclear. Here, we find that ADM within the invasive front of tumors is associated with cell invasion and desmoplasia in an orthotopic mouse model of pancreatic cancer. An analysis of resected human tumors revealed that regions of cancer-associated ADM were positive for TGFα, and that this TGFα expression was associated with primary tumor size and shorter survival times. Gene expression analysis identified distinct phenotypic profiles for cancer-associated ADM, sporadic ADM and chronic pancreatitis ADM. These findings suggest that the mechanisms driving ADM differ according to the specific tissue microenvironment and that cancer-associated ADM and acinar atrophy contribute to tumor cell invasion of the local pancreatic parenchyma.
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| 61. |
Takesue S, Ohuchida K, Shinkawa T, Otsubo Y, Matsumoto S, Sagara A, Yonenaga A, Ando Y, Kibe S, Nakayama H, Iwamoto C, Shindo K, Moriyama T, Nakata K, Miyasaka Y, Ohtsuka T, Toma H, Tominaga Y, Mizumoto K, Hashizume M, Nakamura M, Neutrophil extracellular traps promote liver micrometastasis in pancreatic ductal adenocarcinoma via the activation of cancer‑associated fibroblasts, Int J Oncol, 10.3892/ijo.2019.4951, 56, 2, 596-605, 2020.04, Abstract
Cancer‑associated fibroblasts (CAFs) promote the progression of pancreatic ductal adenocarcinoma (PDAC) via tumor‑stromal interactions. Neutrophil extracellular traps (NETs) are extracellular DNA meshworks released from neutrophils together with proteolytic enzymes against foreign pathogens. Emerging studies suggest their contribution to liver metastasis in several types of cancer. Herein, in order to investigate the role of NETs in liver metastasis in PDAC, the effects of NET inhibitors on spontaneous PDAC mouse models were evaluated. It was demonstrated that DNase I, a NET inhibitor, suppressed liver metastasis. For further investigation, further attention was paid to liver micrometastasis and an experimental liver metastasis mouse model was used that was generated by intrasplenic tumor injection. Furthermore, DNase I also suppressed liver micrometastasis and notably, CAFs accumulated in metastatic foci were significantly decreased in number. In vitro experiments revealed that pancreatic cancer cells induced NET formation and consequently NETs enhanced the migration of hepatic stellate cells, which was the possible origin of CAFs in liver metastasis. On the whole, these results suggest that NETs promote liver micrometastasis in PDAC via the activation of CAFs.
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| 62. |
Ando Y, Ohuchida K, Otsubo Y, Kibe S, Takesue S, Abe T, Iwamoto C, Shindo K, Moriyama T, Nakata K, Miyasaka Y, Ohtsuka T, Oda Y, Nakamura M, Necroptosis in pancreatic cancer promotes cancer cell migration and invasion by release of CXCL5, Plos one, 10.1371/journal.pone.0228015, 15, 1, e0228015, 2020.04, Abstract
Background: Necroptosis is a form of programmed cell death that is accompanied by release of intracellular contents, and reportedly contributes to various diseases. Here, we investigate the significance of necroptosis in pancreatic cancer.
Methods: We used immunohistochemistry and western blot analysis to evaluate expression of the key mediators of necroptosis-receptor-interacting serine/threonine protein kinase 3 (RIP3) and mixed lineage kinase domain-like (MLKL)-in human pancreatic cancer. We also tested the effects of conditioned media (CM) from necroptotic cells on pancreatic cancer cells in Transwell migration and Matrigel invasion assays. Protein array analysis was used to investigate possible mediators derived from necroptotic cells.
Results: RIP3 and MLKL are highly expressed in human pancreatic cancer tissues compared with normal pancreas. MLKL expression was particularly intense at the tumor invasion front. CM derived from necroptotic cells promoted cancer cell migration and invasion, but not CM derived from apoptotic cells. C-X-C motif chemokine 5 (CXCL5) was upregulated in CM derived from necroptotic cells compared with CM derived from control or apoptotic cells. Moreover, expression of the receptor for CXCL5, C-X-C-motif chemokine receptor-2 (CXCR2), was upregulated in pancreatic cancer cells. Inhibition of CXCR2 suppressed cancer cell migratory and invasive behavior enhanced by necroptosis.
Conclusion: These findings indicate that necroptosis at the pancreatic cancer invasion front can promote cancer cell migration and invasion via the CXCL5-CXCR2 axis.. |
| 63. |
Miyasaka Y, Ohtsuka T, Kimura R, Matsuda R, Mori Y, Nakata K, Watanabe M, Oda Y, Nakamura M, Is remnant pancreatic cancer after pancreatic resection more frequent in early-stage pancreatic cancer than in advanced-stage cancer? , Ann Gastroenterol Surg, 10.1002/ags3.12340
, 4, 4, 448-454, 2020.04, Abstract
Aim: As the prognosis of patients who undergo resection for pancreatic cancer has improved, reports of remnant pancreatic cancer after pancreatic cancer resection have been increasing. Previous studies regarding early-stage pancreatic cancer showed a high incidence of remnant pancreatic cancer in these patients. The aim of this study was to investigate the incidence of remnant pancreatic cancer according to the degree of progression of the initial pancreatic cancer.
Methods: Patients who underwent partial pancreatic resection for primary pancreatic cancer were retrospectively reviewed and divided into an early-stage group and an advanced-stage group according to the stage of the initial cancer. Patient characteristics and long-term outcomes, including development of remnant pancreatic cancer, were compared between the two groups.
Results: This study included 321 patients who underwent partial pancreatectomy for pancreatic cancer; 32 patients in the early-stage group and 289 patients in the advanced-stage group. Remnant pancreatic cancer developed in 19 patients (5.9%); seven patients (21.9%) in the early-stage group and 12 patients (4.5%) in the advanced-stage group. The cumulative incidence of remnant pancreatic cancer according to the Kaplan-Meier method was comparable between the two groups (5-year cumulative incidence: 20.6% vs 9.9%, early-stage group vs advanced-stage group; P = .1827).
Conclusion: Our results suggested that the potential for developing remnant pancreatic cancer was comparable between the early-stage and the advanced-stage groups. Therefore, the incidence of remnant pancreatic cancer may increase along with improved pancreatic cancer treatment.
Keywords: neoplasm; neoplasm staging; pancreatectomy; pancreatic cancer; recurrence; second primary.
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| 64. |
Miyasaka Y, Ohtsuka T, Matsuda R, Mori Y, Nakata K, Ohuchida K, Nakamura M, High-risk lesions in the remnant pancreas: fate of the remnant pancreas after pancreatic resection for pancreatic cancer and intraductal papillary mucinous neoplasms, Surg Today, 10.1007/s00595-019-01852-3, 50, 8, 832-840, 2020.04, Abstract:Progress in diagnostic modalities, surgical procedures, and multidisciplinary treatment for pancreatic diseases has increased the number of long-term survivors after pancreatic resection. Several reports have focused on high-risk lesions (HRLs), including high-grade pancreatic intraepithelial neoplasia (PanIN), pancreatic ductal adenocarcinoma, high-grade intraductal papillary mucinous neoplasm (IPMN), and IPMN with an associated invasive carcinoma, in the remnant pancreas after partial pancreatic resection for pancreatic cancer or IPMN. The etiology of HRLs in the remnant pancreas is thought to be either isolated local recurrence of the initial lesion in the remnant pancreas or a newly developed primary lesion. Although it is difficult to distinguish between local recurrence and a new primary lesion, comparison of genetic alterations between two lesions may help with this distinction. Early detection of HRLs in the remnant pancreas may improve the prognosis of patients, and several investigators have proposed predictive factors for HRLs in the remnant pancreas after partial pancreatic resection for pancreatic cancer or IPMN. The reported short- and long-term outcomes of surgical resection of HRLs in the remnant pancreas are relatively favorable. Life-long surveillance of the remnant pancreas is recommended after partial pancreatic resection for pancreatic cancer or IPMN.
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| 65. |
Nakata K, Yamamoto H, Miyata H, Kakeji Y, Seto Y, Yamaue H, Yamamoto M, Nakamura M, Definition of the Objective Threshold of Pancreatoduodenectomy With Nationwide Data Systems , J Hepatobiliary Pancreat Sci, 10.1002/jhbp.704
, 27, 3, 107-113, 2020.04, Abstract
Background: This study aimed to define an objective evidence-based threshold of high-volume hospitals (HVHs) for pancreatoduodenectomy (PD) using nationwide data systems.
Methods: A total of 36,453 patients underwent PD in 1,499 hospitals from 2012 to 2015 were collected from the National Clinical Database in Japan. Restricted cubic spline model with risk adjustment was used for definition of an objective evidence-based threshold of HVHs.
Results: The restricted cubic spline curve of 30-day and in-hospital mortality showed a continuous decrease with an increase in hospital volume and plateau phase of mortality was detected between approximately 30 and 50 PDs/year. On the basis of this curve, we defined hospitals ≥30 PDs/year as HVHs and ≤29 PDs/year as non-HVHs. We also sub-classified hospitals Conclusions: We consider that this concept is applicable to other high-risk procedures for reducing mortality after these procedures, which could improve medical care and health services.
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| 66. |
Mori Y, Nakata K, Ideno N, Ikenaga N, Okabe Y, Ishigami K, Oda Y, Nakamura M, Congenital biliary dilatation in the era of laparoscopic surgery, focusing on the high incidence of anatomical variations of the right hepatic artery, J Hepatobiliary Pancreat Sci, 10.1002/JHBP.819, 27, 11, 870-876, 2020.04, Abstract
Background: The present study aimed to evaluate anatomical variations of the right hepatic artery (RHA) in patients with congenital biliary dilatation (CBD) and the appropriate approach in laparoscopic surgery for CBD.
Methods: The medical records of 36 patients who underwent laparoscopic or open surgery for CBD from 1996 to 2018 were retrospectively reviewed. Radiological evaluation of the origin and course of the RHA in these 36 patients were compared with 195 control patients without CBD.
Results: The incidence of the RHA crossing anterior to the common hepatic duct (CHD) was significantly higher in patients with CBD than in those without CBD (33% versus 10%, P = .0001). There was no intraoperative injury of the RHA, irrespective of the course of the RHA. The CHD was divided at the caudal side of the RHA in 11 of 12 patients (92%) with the anterior type of RHA, and in 13 of 24 patients (54%) with the posterior type of RHA (P = .03).
Conclusions: Patients with CBD had a higher incidence of the RHA crossing anterior to the CHD than patients without CBD. Preservation of the RHA in each situation is necessary during surgery for CBD in the era of laparoscopic surgery.
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| 67. |
Shigeru Ishida, Yoko Makihara, Hiroyuki Watanabe, Takafumi Nakashima, Kenichiro Nagata, Kimitaka Suetsugu, Toshikazu Tsuji, Kojiro Hata, Munehiko Ikeda, Mio Ikebe, Haruna Minami, Hitomi Watanabe, Kohei Nakata, Masafumi Nakamura, Nobuaki Egashira, Ichiro Ieiri, Risk Factors for Gemcitabine-Induced Vascular Pain in Patients With Pancreatic Cancer, The Annanls of Pharmacotheraphy
, 10.1177/1060028020969354 , 55, 6, 738-744, 2021.04, Objectives:
This study focused on identifying predictive factors for gemcitabine-induced vascular pain.
Methods:
We retrospectively analyzed risk factors for developing vascular pain in patients with pancreatic cancer receiving gemcitabine infusions at our institution. Infusions were divided into groups according to presence or absence of vascular pain symptoms, and variables were compared. Odds ratios for risk factors were calculated using logistic regression analyses.
Results:
Overall, 272 patients with pancreatic cancer were subjected to 725 gemcitabine infusions, and of these, 18.4% (n = 50) experienced vascular pain. There were significant differences in the gemcitabine dose (P = 0.025), dose of gemcitabine/body surface area (BSA; P = 0.004), concentration of gemcitabine (P = 0.025), and hot pack use (P = 0.011) between the vascular pain and no vascular pain groups. Multivariable analyses indicated that gemcitabine dose/BSA and lack of hot pack use were risk factors for developing vascular pain. Moreover, on administration of a higher dosage (>930 mg/m2), the incidence of vascular pain in patients using a hot pack (6.7%) was significantly lower than that in patients not provided a hot pack (16.2%).
Conclusions and Relevance:
High gemcitabine dosages and lack of hot pack use were predictive factors for gemcitabine-induced vascular pain in patients with pancreatic cancer. Patients receiving gemcitabine treatment should apply a hot pack to the injection site. Scrupulous clinical attention is required for patients presenting with these risk factors to improve pain management.
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| 68. |
Akiko Sagara, Kohei Nakata, Sokichi Matsumoto, Weiyu Guan, Tomohiko Shinkawa, Chika Iwamoto, Naoki Ikenaga, Kenoki Ohuchida, Masafumi Nakamura, Repositioning of duloxetine to target pancreatic stellate cells, Oncol Lett, 10.3892/ol.2021.13005, 22, 4, 744, 2021.04, Abstract
Pancreatic cancer cells (PCCs) are surrounded by an abundant stroma, which is produced by pancreatic stellate cells (PSCs). PSCs promote tumor cell proliferation and invasion. The objective of the current study was to identify compounds that suppress PSC activation. Gene expression profiles of cancer-derived fibroblasts and normal fibroblasts were used, and the pathway analysis suggested altered pathways that were chosen for validation. It was found that the 'neuroactive ligand-receptor interaction' pathway from the Kyoto Encyclopedia of Genes and Genomes pathway analysis was one of the altered pathways. Several compounds related with this pathway were chosen, and changes in PSC activity were investigated using fluorescence staining of lipid droplets, reverse transcription-quantitative PCR, western blotting, and invasion and migration assays. Among these candidates, duloxetine, a serotonin-noradrenaline reuptake inhibitor, was found to suppress PSC activation and disrupt tumor-stromal interaction. Thus, duloxetine may be a potential drug for suppressing PSC activation and pancreatic cancer growth.
Keywords: drug repositioning; duloxetine; pancreatic cancer; pancreatic stellate cells; tumor microenvironment.. |
| 69. |
Akiko Sagara, Kohei Nakata, Tomohiro Yamashita, Weiyu Guan, Pingshan Zhong, Sokichi Matsumoto, Sho Endo, Chika Iwamoto, Koji Shindo, Naoki Ikenaga, Taiki Moriyama, Kenoki Ohuchida, Kazuhiro Mizumoto, Masafumi Nakamura, New high-throughput screening detects compounds that suppress pancreatic stellate cell activation and attenuate pancreatic cancer growth, Pancreatology, 10.1016/j.pan.2021.04.002, 21, 6, 1071-1080, 2021.04, Abstract
Background/objectives: Pancreatic stellate cells (PSCs) are involved in abundant desmoplasia, which promotes cancer cell aggressiveness and resistance to anti-cancer drugs. Therefore, PSCs are suggested to be a promising therapeutic target by attenuating PSC activation to inhibit tumor-stromal interactions with pancreatic cancer cells. Here, we developed a screen to identify compounds that reduce the activity of PSCs and investigated the effect of candidates on pancreatic cancer.
Methods: Lipid droplet accumulation in PSCs was used to observe differences in PSC activity and a new high-throughput screening platform that quantified lipid droplets in PSCs was established. A library of 3398 Food and Drug Administration-approved drugs was screened by this platform. Validation assays were performed in vitro and in vivo.
Results: Thirty-two compounds were finally selected as candidate compounds by screening. These compounds decreased α-smooth muscle actin expression and inhibited autophagic flux in PSCs in vitro. Among the candidates, three drugs selected for validation assays inhibited the proliferation and migration of PSCs and invasion of cancer cells by disrupting tumor-stromal interactions. Production of extracellular matrix molecules was also decreased significantly by this treatment. In vivo testing in xenograft models showed that dopamine antagonist zuclopenthixol suppressed tumor growth; this suppression was significantly increased when combined with gemcitabine.
Conclusions: A new screening platform that focused on the morphological features of PSCs was developed. Candidate drugs from this screening suppressed PSC activation and tumor growth. This screening system may be useful to discover new compounds that attenuate PSC activation.
Keywords: Cell-based screen; Dopamine antagonist; Pancreatic cancer; Pancreatic stellate cell; Stromal targeting therapy.. |
| 70. |
Haimin Feng, Taiki Moriyama, Kenoki Ohuchida, Nan Sheng, Chika Iwamoto, Koji Shindo, Kengo Shirahane, Naoki Ikenaga, Shuntaro Nagai, Kohei Nakata, Kazuhiro Mizumoto, Masafumi Nakamura, N-acetyl cysteine induces quiescent-like pancreatic stellate cells from an active state and attenuates cancer-stroma interactions, J Exp Clin Cancer Res, 10.1186/s13046-021-01939-1, 40, 133, 1-19, 2021.04, Background: Pancreatic stellate cells (PSCs) occupy the majority of the pancreatic cancer microenvironment, contributing to aggressive behavior of pancreatic cancer cells (PCCs). Recently, anti-fibrotic agents have proven to be an effective strategy against cancer, but clinical trials have shown little efficacy, and the driving mechanism remains unknown. N-acetyl-cysteine (NAC) is often used for pulmonary cystic fibrosis. Pioglitazone, an agonist of peroxisome proliferator-activated receptor gamma, was habitually used for type II diabetes, but recently reported to inhibit metastasis of PCCs. However, few studies have focused on the effects of these two agents on cancer-stromal interactions.
Method: We evaluated the expression of α-smooth muscle actin (α-SMA) and the number of lipid droplets in PSCs cultured with or without NAC. We also evaluated changes in invasiveness, viability, and oxidative level in PSCs and PCCs after NAC treatment. Using an indirect co-culture system, we investigated changes in viability, invasiveness, and migration of PSCs and PCCs. Combined treatment effects of NAC and Pioglitazone were evaluated in PSCs and PCCs. In vivo, we co-transplanted KPC-derived organoids and PSCs to evaluate the effects of NAC and Pioglitazone's combination therapy on subcutaneous tumor formation and splenic xenografted mouse models.
Results: In vitro, NAC inhibited the viability, invasiveness, and migration of PSCs at a low concentration, but not those of PCCs. NAC treatment significantly reduced oxidative stress level and expression of α-SMA, collagen type I in PSCs, which apparently present a quiescent-like state with a high number of lipid droplets. Co-cultured PSCs and PCCs mutually promoted the viability, invasiveness, and migration of each other. However, these promotion effects were attenuated by NAC treatment. Pioglitazone maintained the NAC-induced quiescent-like state of PSCs, which were reactivated by PCC-supernatant, and enhanced chemosensitivity of PCCs. In vivo, NAC and Pioglitazone's combination suppressed tumor growth and liver metastasis with fewer stromal components and oxidative stress level.
Conclusion: NAC suppressed activated PSCs and attenuated cancer-stromal interactions. NAC induces quiescent-like PSCs that were maintained in this state by pioglitazone treatment.. |
| 71. |
Kohei Nakata, Yasuhisa Mori, Naoki Ikenaga, Noboru Ideno, Yusuke Watanabe, Yoshihiro Miyasaka, Takao Ohtsuka, Masafumi Nakamura, Management of postoperative pancreatic fistula after pancreatoduodenectomy: Analysis of 600 cases of pancreatoduodenectomy patients over a 10-year period at a single institution, Surgery., 10.1016/j.surg.2021.01.010, 169, 6, 1446-1453, 2021.04, Abstract
Background: Although postoperative pancreatic fistula (POPF) is a common and critical complication of pancreatoduodenectomy (PD), effective strategies to prevent POPF have not yet been completely developed. Because appropriate management of POPF is important to reduce the mortality rate after PD, in this study we aimed to evaluate our approach for the management of POPF after PD, including the postoperative course.
Methods: This retrospective study included 605 consecutive patients who underwent PD at our hospital between 2010 and 2020. All patients who developed POPF were first managed conservatively, with drainage tubes placed during surgery retained to manage POPF. In cases wherein conservative treatment was unsuccessful, open drainage, followed by continuous negative pressure and continuous irrigation, was used. For open drainage, the surgical wound was opened bluntly (approximate length, 5 cm) under local anesthesia, and the fluid was directly and completely drained.
Results: The prevalence of POPF of grades B and C was 15.4% (n = 93) and 0.33% (n = 2), respectively. Of these patients, 1 required reoperation, 43 recovered with conservative management only, 47 required open drainage, and 4 required image-guided percutaneous drainage. Postoperative hemorrhage with a pseudoaneurysm was identified in 3 (0.66%) patients. The postoperative in-hospital mortality rate was low (n = 1, 0.16%). The rate of successful POPF management was 98.9%.
Conclusion: Based on our high success rate in POPF management, we consider open drainage to be a safe primary management method for POPF.. |
| 72. |
Chikanori Tsutsumi, Kenoki Ohuchida, Koji Shindo, Taiki Moriyama, Shin Akagawa, Ryo Maeyama, Shuntaro Nagai, Kohei Nakata, Toshinaga Nabae, Nobuhiro Suehara, Kazuyoshi Nishihara, Akihiko Uchiyama, Toru Nakano, Masafumi Nakamura, High frequency of bone recurrence as an initial recurrence site after radical surgery in T1N3 gastric cancer: a propensity score matching analysis, Langenbecks Arch Surg, 10.1007/s00423-021-02231-8, 406, 7, 2305-2313, 2021.04, Purpose: T1 gastric cancer (GC) with seven or more metastatic lymph nodes is extremely rare, and very few clinical studies have been conducted to evaluate the clinicopathological features of their recurrence.
Methods: We retrospectively analyzed the outcomes of T1 GC and T2-4 GC patients who had multiple nodal metastases after radical surgery from 2006 to 2020. Propensity score matching was performed to compare the two groups of patients.
Results: After propensity score matching, 18 of 22 patients in the T1 group and 36 of 144 patients in the T2-4 group were selected. Recurrence occurred in six patients (33.3%) in the T1 group. In the T1 group, the most common site of initial recurrence was bone (15.0%). The prevalence of bone recurrence was significantly higher in the T1 group than in the T2-4 group (P = 0.02). The median interval time between radical surgery and bone recurrence was 24 months, and the median survival time after bone recurrence was 14 months.
Conclusion: Bone recurrence was more frequently identified as an initial recurrence site in T1 GC cases with multiple metastases after radical surgery compared with that in T2-4 GC cases. Careful attention should be paid to postoperative bone recurrence in the long-term postoperative course of these patients.. |
| 73. |
Ryuichiro Kimura, Takao Ohtsuka, Makoto Kubo, Atsuko Kajihara, Atsushi Fujii, Yusuke Watanabe, Yasuhisa Mori, Naoki Ikenaga, Kohei Nakata, Koji Shindo, Kenoki Ohuchida, Masafumi Nakamura, FoundationOne® CDx gene profiling in Japanese pancreatic ductal adenocarcinoma patients: a single-institution experience , Surgery Today, 10.1007/s00595-020-02123-2
, 51, 4, 619-626, 2021.04, Abstract
Purpose: The aim of this study was to investigate the genetic mutation profiles of Japanese pancreatic ductal adenocarcinoma (PDAC) patients.
Methods: Next-generation sequencing was performed using FoundationOne® CDx on 17 PDAC patients who were treated by surgical resection at Kyushu University Hospital between February 2016 and January 2019. The tumor mutational burden and microsatellite instability status were also assessed.
Results: There were 16 patients (94%) with KRAS mutations, 13 (76%) with TP53 mutations, three (18%) with SMAD4 mutations, and one (6%) with a CDKN2A mutation. All patients had at least one pathogenic variant or a likely pathogenic variant. No patient had targeted therapies that matched with any clinical benefit according to FoundationOne® CDx. An unresectable PDAC patient with BRCA2-mutant disease was successfully treated by conversion surgery using platinum-based neoadjuvant chemotherapy.
Conclusions: Currently, FoundationOne® CDx might be difficult to use on PDAC patients, although further investigations with larger study populations are called for.
Keywords: FoundationOne; Gene profiling; Next-generation sequencing; Pancreatic cancer; Pancreatic ductal adenocarcinoma.
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| 74. |
Kohei Nakata, Takao Ohtsuka, Yoshihiro Miyasaka, Yusuke Watanabe, Noboru Ideno, Yasuhisa Mori, Naoki Ikenaga, Masafumi Nakamura, Evaluation of relationship between splenic artery and pancreatic parenchyma using three-dimensional computed tomography for laparoscopic distal pancreatectomy, Langenbecks Arch Surg, 10.1007/s00423-021-02101-3, 406, 6, 1885-1895, 2021.04, Abstract
Aim: Isolating the root of the splenic artery (SPA) is a challenging procedure in laparoscopic distal pancreatectomy (LDP). We investigated the usefulness of evaluation of the relationship between the SPA and pancreatic parenchyma using three-dimensional computed tomography (3D-CT).
Methods: In total, 104 patients were evaluated. The relationship between the SPA and pancreatic parenchyma was classified into two types: buried and non-buried. Video clips of 50 patients who underwent LDP requiring isolation of the SPA root were reviewed to determine whether the classification is related to difficulty of LDP.
Results: Of the 50 assessed patients who underwent LDP, the relationship between the SPA and pancreatic parenchyma was the buried type in 30 (60.0%) and non-buried type in 20 (40.0%). The buried type was associated with a significantly longer median operative time than the non-buried type (285.0 vs. 235.5 min, respectively; P
Conclusion: Preoperative 3D-CT around the pancreas is practical for predicting the difficulty of SPA isolation and determining the safety of the procedure.. |
| 75. |
Sokichi Matsumoto, Kohei Nakata, Akiko Sagara, Weiyu Guan, Naoki Ikenaga, Kenoki Ohuchida, Masafumi Nakamura, Efficient pre-treatment for pancreatic cancer using chloroquine-loaded nanoparticles targeting pancreatic stellate cells, Oncol Lett, 10.3892/ol.2021.12894, 22, 2, 633-633, 2021.04, Abstract
Pancreatic stellate cells (PSCs) play a key role in desmoplastic stroma, which is a characteristic of pancreatic ductal adenocarcinoma (PDAC), and they also enhance the malignancy of pancreatic cancer cells. Our previous study reported chloroquine's mitigating effects on PSC activation; however, the drug is known to induce adverse effects in clinical practice. The present study aimed to reduce chloroquine doses and develop a useful pre-treatment that targets PSCs using nanoparticles. Poly lactic-co-glycolic acid (PLGA) nanoparticles were used as carriers and loaded with indocyanine green (Nano-ICG) or chloroquine (Nano-CQ). Tumor accumulation of Nano-ICG was evaluated using an in vivo imaging system. The effects of chloroquine, Nano-CQ and/or chemotherapy drug gemcitabine were investigated in an orthotopic xenograft mouse model. Nano-ICG selectively accumulated in pancreatic tumors and persisted therein for over 7 days after administration. Additionally, Nano-ICG accumulated in the peritoneal metastasized regions, but not in the liver, kidney and normal pancreatic tissues. Nano-CQ reduced the density of activated PSCs at lower chloroquine doses and significantly restrained tumor progression in combination with gemcitabine. In conclusion, the PLGA nanosystem successfully delivered the drug to pancreatic tumors. Nano-CQ efficiently reduced PSC activation and may be a promising novel pre-treatment strategy for PDAC.
Keywords: chloroquine; combination therapy; desmoplasia; nanoparticles; orthotopic xenograft; pancreatic cancer; pancreatic ductal adenocarcinoma; pre-treatment; stroma.. |
| 76. |
Naoki Ikenaga, Takao Ohtsuka, Kohei Nakata, Yusuke Watanabe, Yasuhisa Mori, Masafumi Nakamura, Clinical significance of postoperative acute pancreatitis after pancreatoduodenectomy and distal pancreatectomy, Surgery, 10.1016/j.surg.2020.06.040, 169, 4, 732-737, 2021.04, Abstract
Background: The definition of postoperative acute pancreatitis as a specific complication of pancreatic surgery was proposed in 2016. Its presence and relevance have not been established, especially after a distal pancreatectomy.
Methods: Medical records of 319 patients who underwent pancreatoduodenectomy or distal pancreatectomy were analyzed. Postoperative acute pancreatitis was defined as an increase in serum amylase activity greater than the upper normal limit on postoperative day 1, according to Connor's definition of postoperative acute pancreatitis.
Results: Postoperative acute pancreatitis occurred in 63.4% of 153 of the patients undergoing pancreatoduodenectomy and 65.7% of the 166 undergoing distal pancreatectomies. Patients who developed postoperative acute pancreatitis after pancreatoduodenectomy experienced an increase in the rate of morbidity (22.7% vs 7.1%; P = .0137), including postoperative pancreatic fistula (18.6% vs 1.8%; P = .024), resulting in greater postoperative stays (21 days vs 17 days; P = .0008). Postoperative acute pancreatitis in association with an increased serum C-reactive protein ≥18.0 mg/dL (which we defined as a clinically relevant postoperative acute pancreatitis) more strongly indicated the occurrence of severe complications (P = .0032) and was an independent predictor of postoperative pancreatic fistula after pancreatoduodenectomy (odds ratio, 3.03; P = .0448). Patients who developed postoperative acute pancreatitis after distal pancreatectomy experienced similar postoperative courses regarding morbidity and the duration of postoperative stay.
Conclusion: The clinical relevance of postoperative acute pancreatitis differs after a pancreatoduodenectomy versus a distal pancreatectomy. The development of effective strategies for preventing postoperative acute pancreatitis might improve surgical outcomes after pancreatoduodenectomy.. |
| 77. |
Chika Iwamoto, Kenoki Ohuchida, Tomohiko Shinkawa, Sho Okuda, Yoshiki Otsubo, Takashi Okumura, Akiko Sagara, Kazuhiro Koikawa, Yohei Ando, Koji Shindo, Naoki Ikenaga, Kohei Nakata, Taiki Moriyama, Yoshihiro Miyasaka, Takao Ohtsuka, Masatoshi Eto, Koichi Akashi, Masafumi Nakamura, Bone marrow-derived macrophages converted into cancer-associated fibroblast-like cells promote pancreatic cancer progression, Cancer Lett., 10.1016/j.canlet.2021.04.013, 1, 512, 15-27, 2021.04, Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterized by a desmoplastic reaction caused by cancer-associated fibroblasts (CAFs), which provokes treatment resistance. CAFs are newly proposed to be heterogeneous populations with different functions within the PDAC microenvironment. The most direct sources of CAFs are resident tissue fibroblasts and mesenchymal stem cells, however, the origins and functions of CAF subtypes remain unclear. Here, we established allogeneic bone marrow (BM) transplantation models using spontaneous PDAC mice, and then investigated what subtype cells derived from BM modulate the tumor microenvironment and affect the behavior of pancreatic cancer cells (PCCs). BM-derived multilineage hematopoietic cells were engrafted in recipient pancreas, and accumulated at the invasive front and central lesion of PDAC. We identified BM macrophages-derived CAFs in tumors. BM-derived macrophages treated with PCC-conditioned media expressed CAF markers. BM-derived macrophages led the local invasion of PCCs in vitro and enhanced the tumor invasive growth in vivo. Our data suggest that BM-derived cells are recruited to the pancreas during carcinogenesis and that the specific subpopulation of BM-derived macrophages partially converted into CAF-like cells, acted as leading cells, and facilitated pancreatic cancer progression. The control of the conversion of BM-derived macrophages into CAF-like cells may be a novel therapeutic strategy to suppress tumor growth.. |
| 78. |
Tomohiko Shinkawa, Kenoki Ohuchida, Yuki Mochida, Kukiko Sakihama, Chika Iwamoto, Toshiya Abe, Noboru Ideno, Yusuke Mizuuchi, Koji Shindo, Naoki Ikenaga, Taiki Moriyama, Kohei Nakata, Yoshinao Oda, Masafumi Nakamura, Subtypes in pancreatic ductal adenocarcinoma based on niche factor dependency show distinct drug treatment responses
, J Exp Clin Cancer Res, 10.1186/s13046-022-02301-9, 41, 89, 1-20, 2022.04, Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by abundant stroma in which microenvironmental (niche) factors promote PDAC progression. In mouse models, reduction of the stroma increased the proportion of poorly differentiated PDAC with a worse prognosis. Here, we aimed to clarify the effects of stroma on PDAC that may define the PDAC phenotype and induce distinct therapeutic responses.
Methods: The molecular features of PDAC based on differentiation grade were clarified by genome and transcriptome analysis using PDAC organoids (PDOs). We identified the dependency on niche factors that might regulate the differentiation grade. A three-dimensional co-culture model with cancer-associated fibroblasts (CAFs) was generated to determine whether CAFs provide niche factors essential for differentiated PDAC. PDOs were subtyped based on niche factor dependency, and the therapeutic responses for each subtype were compared.
Results: The expression profiles of PDOs differed depending on the differentiation grade. Consistent with the distinct profiles, well differentiated types showed high niche dependency, while poorly differentiated types showed low niche dependency. The three-dimensional co-culture model revealed that well differentiated PDOs were strongly dependent on CAFs for growth, and moderately differentiated PDOs showed plasticity to change morphology depending on CAFs. Differentiated PDOs upregulated the expression of mevalonate pathway-related genes correlated with the niche dependency and were more sensitive to simvastatin than poorly differentiated PDOs.
Conclusions: Our findings suggest that CAFs maintain the differentiated PDAC phenotype through secreting niche factors and induce distinct drug responses. These results may lead to the development of novel subtype-based therapeutic strategies.
Keywords: Cancer-associated fibroblast; Organoid; Statin; Stroma-targeting therapy; Subtype-based therapy; Tumor differentiation; Tumor microenvironment.. |
| 79. |
Masatoshi Murakami, Nao Fujimori, Akihisa Ohno, Kazuhide Matsumoto, Katsuhito Teramatsu, Yu Takamatsu, Ayumu Takeno, Takamasa Oono, Toshiya Abe, Noboru Ideno, Naoki Ikenaga, Kohei Nakata, Masafumi Nakamura, Kousei Ishigami, Yoshihiro Ogawa, Predictive factors of operability after neoadjuvant chemotherapy in resectable or borderline resectable pancreatic cancer: a single-center retrospective study, Discover Oncology, 10.1007/s12672-021-00462-1, 13, 1, 2022.04, Abstract
Background/aims: Recently neoadjuvant chemotherapy (NAC) for pancreatic cancer has been shown to be superior to upfront surgery, but it remains a matter of debate for resectable cases. In clinical practice, some resectable cases may become unresectable after NAC. This study aimed to reveal the outcomes after NAC and to clarify the characteristics of unresected cases.
Methods: The medical records of 142 patients who underwent NAC between 2016 and 2020 were retrospectively reviewed. Patient characteristics, effectiveness of NAC, and outcomes were compared between the surgical group and non-surgical group (NSG). Furthermore, the risk of recurrence limited to in the patients who received NAC with gemcitabine plus nab-paclitaxel, which were mostly administered in this cohort, following R0/R1 resection was assessed.
Results: The overall and R0 resection rates after NAC were 89.1% and 79.7%, respectively. The neutrophil to lymphocyte ratio (NLR) > 2.78 (p = 0.0120) and anatomical borderline resectable pancreatic cancer (p = 0.0044) revealed a statistically significantly correlation with the NSG. On the other hand, NAC week IIA (P = 0.0003) were significantly associated with recurrence. The tumor response rate was approximately 26.1%, and three patients with ≥ 30% reduction of primary tumor lost excision opportunities because of metastasis, interstitial pneumonia, and vascular invasion.
Conclusions: This study shows incomplete tumor shrinkage benefits, but pre-NAC NLR is a predictive factor for predicting operability after NAC. The NLR can be easily calculated by normal blood test, and can be considered as a suitable marker of operability.
Keywords: Neoadjuvant chemotherapy; Operability; Pancreatic cancer; Pancreatic neoplasms; Recurrence.. |
| 80. |
Yuichi Nagakawa, Kohei Nakata, Hitoe Nishino, Takao Ohtsuka, Daisuke Ban, Horacio J Asbun, Ugo Boggi, Jin He, Michael L Kendrick, Chinnusamy Palanivelu, Rong Liu, Shin-E Wang, Chung-Ngai Tang, Kyoichi Takaori, Mohammed Abu Hilal, Brian K P Goh, Goro Honda, Jin-Young Jang, Chang Moo Kang, David A Kooby, Yoshiharu Nakamura, Shailesh V Shrikhande, Christopher L Wolfgang, Anusak Yiengpruksawan, Yoo-Seok Yoon, Yusuke Watanabe, Shingo Kozono, Ruben Ciria, Giammauro Berardi, Giovanni Maria Garbarino, Ryota Higuchi, Naoki Ikenaga, Yoshiya Ishikawa, Aya Maekawa, Yoshiki Murase, Giuseppe Zimmitti, Filipe Kunzler, Zi-Zheng Wang, Leon Sakuma, Chie Takishita, Hiroaki Osakabe, Itaru Endo, Masao Tanaka, Hiroki Yamaue, Minoru Tanabe, Go Wakabayashi, Akihiko Tsuchida, Masafumi Nakamura, International expert consensus on precision anatomy for minimally invasive pancreatoduodenectomy: PAM-HBP surgery project, J Hepatobiliary Pancreat Sci, 10.1002/jhbp.1081, 29, 1, 124-135, 2022.04, Abstract
Background: The anatomical structure around the pancreatic head is very complex and it is important to understand its precise anatomy and corresponding anatomical approach to safely perform minimally invasive pancreatoduodenectomy (MIPD). This consensus statement aimed to develop recommendations for elucidating the anatomy and surgical approaches to MIPD.
Methods: Studies identified via a comprehensive literature search were classified using the Scottish Intercollegiate Guidelines Network method. Delphi voting was conducted after experts had drafted recommendations, with a goal of obtaining >75% consensus. Experts discussed the revised recommendations with the validation committee and an international audience of 384 attendees. Finalized recommendations were made after a second round of online Delphi voting.
Results: Three clinical questions were addressed, providing six recommendations. All recommendations reached at least a consensus of 75%. Preoperatively evaluating the presence of anatomical variations and superior mesenteric artery (SMA) and superior mesenteric vein (SMV) branching patterns was recommended. Moreover, it was recommended to fully understand the anatomical approach to SMA and intraoperatively confirm the SMA course based on each anatomical landmark before initiating dissection.
Conclusions: MIPD experts suggest that surgical trainees perform resection based on precise anatomical landmarks for safe and reliable MIPD.
Keywords: consensus; minimally invasive surgical procedures; pancreatoduodenectomy; robotic surgery; superior mesenteric artery.. |
| 81. |
Daisuke Ban, Hitoe Nishino, Takao Ohtsuka, Yuichi Nagakawa, Mohammed Abu Hilal, Horacio J Asbun, Ugo Boggi, Brian K P Goh, Jin He, Goro Honda, Jin-Young Jan, Chang Moo Kang, Michael L Kendrick, David A Kooby, Rong Liu, Yoshiharu Nakamura, Kohei Nakata, Chinnusamy Palanivelu, Shailesh V Shrikhande, Kyoichi Takaori, Chung-Ngai Tang, Shin-E Wan, Christopher L Wolfgang, Anusak Yiengpruksawan, Yoo-Seok Yoon, Ruben Ciria, Giammauro Berardi, Giovanni Maria Garbarino, Ryota Higuchi, Naoki Ikenaga, Yoshiya Ishikawa, Shingo Kozono, Aya Maekawa, Yoshiki Murase, Yusuke Watanabe, Giuseppe Zimmitti, Filipe Kunzler, Zi-Zheng Wang, Leon Sakuma, Hiroaki Osakabe, Chie Takishita, Itaru Endo, Masao Tanaka, Hiroki Yamaue, Minoru Tanabe, Go Wakabayashi, Akihiko Tsuchida, Masafumi Nakamura, International Expert Consensus on Precision Anatomy for minimally invasive distal pancreatectomy: PAM-HBP Surgery Project, J Hepatobiliary Pancreat Sci, 10.1002/jhbp.1071, 29, 1, 161-173, 2022.04, Background: Surgical views with high resolution and magnification have enabled us to recognize the precise anatomical structures that can be used as landmarks during minimally invasive distal pancreatectomy (MIDP). This study aimed to validate the usefulness of anatomy-based approaches for MIDP before and during the Expert Consensus Meeting: Precision Anatomy for Minimally Invasive HBP Surgery (February 24, 2021).
Methods: Twenty-five international MIDP experts developed clinical questions regarding surgical anatomy and approaches for MIDP. Studies identified via a comprehensive literature search were classified using Scottish Intercollegiate Guidelines Network methodology. Online Delphi voting was conducted after experts had drafted the recommendations, with the goal of obtaining >75% consensus. Experts discussed the revised recommendations in front of the validation committee and an international audience of 384 attendees. Finalized recommendations were made after a second round of online Delphi voting.
Results: Four clinical questions were addressed, resulting in 10 recommendations. All recommendations reached at least a 75% consensus among experts.. |
| 82. |
Yusuke Watanabe, Kohei Nakata, Yasuhisa Mori, Noboru Ideno, Naoki Ikenaga, Takao Ohtsuka, Masafumi Nakamura, Extensive (subtotal) distal pancreatectomy for pancreatic ductal adenocarcinoma: a propensity score matched cohort study of short- and long-term outcomes compared with those of conventional distal pancreatectomy, Langenbecks Arch Surg, 10.1007/s00423-022-02453-4, 407, 4, 1479-1488, 2022.04, Abstract
Purpose: Extensive distal pancreatectomy (ExDP) can transect the pancreatic parenchyma more from the right side than conventional distal pancreatectomy (CDP) can. This study aimed to evaluate the short- and long-term outcomes of ExDP for pancreatic ductal adenocarcinoma (PDAC) of the pancreatic body, located adjacent to the portal vein (PV).
Methods: Medical records of 98 patients who underwent ExDP (n = 15) or CDP (n = 83) for PDAC were retrospectively reviewed. Short- and long-term outcomes of the two groups were compared. Propensity score matched analysis was additionally performed to minimize the impact of treatment allocation bias.
Results: In the total cohort, the CDP group had a significantly higher proportion of pancreatic tail lesions (P Conclusions: Surgical and oncological outcomes after ExDP for PDAC were acceptable and comparable to those after CDP. ExDP is a feasible procedure, and could be an option for the treatment of PDAC of the pancreatic body near PV.
Keywords: Distal pancreatectomy; Extensive distal pancreatectomy; Pancreatic cancer; Pancreatic ductal adenocarcinoma; Subtotal distal pancreatectomy.. |
| 83. |
Weiyu Guan, Kohei Nakata, Akiko Sagara, Chika Iwamoto, Sho Endo, Ryota Matsuda, Sokichi Matsumoto, Naoki Ikenaga, Koji Shindo, Taiki Moriyama, Hideya Onishi, Kenoki Ohuchida, Yoshinao Oda, Masafumi Nakamura, ERAP2 is a novel target involved in autophagy and activation of pancreatic stellate cells via UPR signaling pathway, Pancreatology, 10.1016/j.pan.2021.09.012, 22, 1, 9-19, 2022.04, Abstract
Background/objectives: Pancreatic ductal adenocarcinoma (PDAC) is characterized by excessive desmoplasia and autophagy-dependent tumorigenic growth. Pancreatic stellate cells (PSCs) as a predominant stromal cell type play a critical role in PDAC biology. We have previously reported that autophagy facilitates PSC activation, however, the mechanism remains unknown. We investigated the mechanism of autophagy in PSC activation.
Methods: We compared gene expression profiles between patient-derived PSCs from pancreatic cancer and chronic pancreatitis using a microarray. The stromal expression of target gene in specimen of PDAC patients (n = 63) was analyzed. The effect of target gene on autophagy and activation of PSCs was investigated by small interfering RNAs transfection, and the relationship between autophagy and ER stress was investigated. We analyzed the growth and fibrosis of xenografted tumor by orthotopic models.
Results: In analysis of gene expression microarray, endoplasmic reticulum aminopeptidase 2 (ERAP2) upregulated in cancer-associated PSCs was identified as the target gene. High stromal ERAP2 expression is associated with a poor prognosis of PDAC patients. Knockdown of ERAP2 inhibited unfolded protein response mediated autophagy, and led to inactivation of PSCs, thereby attenuating tumor-stromal interactions by inhibiting production of IL-6 and fibronectin. In vivo, the promoting effect of PSCs on xenografted tumor growth and fibrosis was inhibited by ERAP2 knockdown.
Conclusions: Our findings demonstrate a novel mechanism of PSCs activation regulated by autophagy. ERAP2 as a promising therapeutic target may provide a novel strategy for the treatment of PDAC.
Keywords: Endoplasmic reticulum stress; Stromal remodeling; Tumor-stromal interaction; Tunicamycin.. |
| 84. |
Yasuhisa Mori, Kohei Nakata, Noboru Ideno, Naoki Ikenaga, Yasuhiro Okabe, Masafumi Nakamura, Efficacy of Distal Pancreatectomy Combined With Modified DuVal Procedure in Patients With a High Risk of Postoperative Pancreatic Fistula, The American Surgeon, 10.1177/0003134821995088, 88, 6, 1244-1249, 2022.04, Abstract
Background: The incidence of postoperative pancreatic fistula (POPF) after distal pancreatectomy (DP) remains high. The present study aimed to clarify the efficacy of our modified DuVal (mDuVal) pancreatojejunostomy following DP in patients with a high risk of POPF.
Methods: The medical records of 346 consecutive patients who underwent DP between 2006 and 2016 were retrospectively reviewed. Perioperative features were compared between 24 patients undergoing mDuVal (mDuVal group) and 322 patients undergoing standard DP (standard DP group).
Results: Preoperative American Society of Anesthesiologists physical status 1 was more frequent in the standard group than in the mDuVal group (P = .02). The start of a solid diet after operation was significantly earlier in the mDuVal group than in the standard DP group (P = .01), while there were no significant differences between the groups for clinically relevant POPF, amylase concentration in the drainage fluid on postoperative day 1 and days 3-5, time to drain removal, additional intervention for POPF, overall complications, or postoperative hospital stay.
Discussion: The mDuVal procedure could be an option for patients with a high risk of POPF to improve the outcomes after DP. Further investigation involving large study populations is necessary to clarify the efficacy of this procedure.
Keywords: pancreatectomy; pancreatic fistula; postoperative complications.. |
| 85. |
Yusuke Mizuuchi, Yoshitaka Tanabe, Masafumi Sada, Koji Tamura, Kinuko Nagayoshi, Shuntaro Nagai, Yusuke Watanabe, Sadafumi Tamiya, Kohei Nakata, Kenoki Ohuchida, Toru Nakano, Masafumi Nakamura, Cross-sectional area of psoas muscle as a predictive marker of anastomotic failure in male rectal cancer patients: Japanese single institutional retrospective observational study, Annals of Coloproctology, 10.3393/ac.2022.00122.0017, 38, 5, 353-361, 2022.04, Purpose: Preoperative sarcopenia worsens postoperative outcomes in various cancer types including colorectal cancer. However, we often experienced postoperative anastomotic leakage in muscular male patients such as Judo players, especially in rectal cancer surgery with lower anastomosis. It is controversial whether the whole skeletal muscle mass impacts the potential for anastomotic failure in male rectal cancer patients. Thus, the purpose of this study was to clarify whether skeletal muscle mass impacts anastomotic leakage in rectal cancer in men.
Methods: We reviewed the medical charts of male patients suffering from rectal cancer who underwent colo-procto anastomosis below the peritoneal reflection without a protective diverting stoma. We measured the psoas muscle area and calculated the psoas muscle index.
Results: One hundred ninety-seven male rectal cancer patients were enrolled in this study. The psoas muscle index was significantly higher in patients with anastomotic leakage (P<0.001). Receiver operating characteristic curve determined the optimal cut-off value of the psoas muscle index for predicting anastomotic leakage as 812.67 cm2/m2 (sensitivity of 60% and specificity of 74.3%). Multivariate analysis revealed that high psoas muscle index (risk ratio [RR], 3.933; P<0.001; 95% confidence interval [CI], 1.917-8.070) and super low anastomosis (RR, 2.792; P=0.015; 95% CI, 1.221-6.384) were independent predictive factors of anastomotic leakage.
Conclusion: This study showed that male rectal cancer patients with a large psoas muscle mass who underwent lower anastomosis had a higher rate of postoperative anastomotic leakage.
Keywords: Anastomotic leak; Lower colo-anorectal anastomosis; Psoas muscle index; ROC curve; Rectal neoplasms.. |
| 86. |
Kohei Nakata, Hiroyuki Yamamoto, Hiroaki Miyata, Yoshihiro Kakeji, Yuko Kitagawa, Masafumi Nakamura, Comparison of outcomes between laparoscopic and open pancreaticoduodenectomy without radical lymphadenectomy: Results of coarsened exact matching analysis using national database systems, Asian J Endosc Surg, 10.1111/ases.12948, 15, 1, 15-21
, 2022.04, Abstract
Introduction: Laparoscopic pancreaticoduodenectomy has recently been covered under Japan's insurance system for patients not requiring lymph node dissection. Only high-volume hospitals that meet specific criteria are permitted to perform laparoscopic pancreaticoduodenectomy. Although open and laparoscopic pancreaticoduodenectomy outcomes with lymph node dissection have been described previously, procedures performed without lymph node dissection have not been compared using a nationwide database. This study aimed to review the results of laparoscopic pancreaticoduodenectomy and compare them to those of open pancreaticoduodenectomy (OPD) using records from a nationwide database.
Methods: We collected patient demographic and medical data of 2900 patients who underwent pancreaticoduodenectomy (laparoscopic, n = 162; open, n = 2738) without lymph node dissection between 2016 and 2018 from the National Clinical Database in Japan. Coarsened exact matching was used to match patients in the laparoscopic and open pancreaticoduodenectomy groups.
Results: In-hospital mortality was not observed in the laparoscopic pancreaticoduodenectomy group. The rate of conversion to an open procedure was 6.8% (11 cases). After 1:1 matching, we obtained 141 pairs of patients for comparison. The mortality rate was comparable in the laparoscopic and open pancreaticoduodenectomy groups (0.0% vs 0.7%, respectively; P = 1.00). The laparoscopic approach showed more favorable results in terms of median blood loss. Postoperative pancreatic fistula formation and complications were comparable between the two groups.
Conclusions: Our results indicate that laparoscopic pancreaticoduodenectomy could be introduced successfully, and the outcomes achieved by the institutions included in our study were comparable to those of open pancreaticoduodenectomy.
Keywords: laparoscopic pancreaticoduodenectomy; mortality; registries.. |
| 87. |
Naoki Ikenaga, Kohei Nakata, Nobuhiro Fujita, Toshiya Abe, Noboru Ideno, Kousei Ishigami, Masafumi Nakamura, Clinical significance of postpancreatectomy acute pancreatitis defined by the International Study Group for Pancreatic Surgery, Ann Gastroenterol Surg, 10.1002/ags3.12587, 6, 6, 842-850, 2022.04. |
| 88. |
Sho Okuda, Kenoki Ohuchida, Koji Shindo, Taiki Moriyama, Jun Kawata, Koji Tamura, Masafumi Sada, Kinuko Nagayoshi, Yusuke Mizuuchi, Naoki Ikenaga, Kohei Nakata, Yoshinao Oda, Masafumi Nakamura, Clinical impact of remnant lymphatic invasion on the recurrence of esophageal squamous cell carcinoma after esophagectomy with neoadjuvant chemotherapy, Oncol Lett, 10.3892/ol.2022.13457, 24, 4, 337, 2022.04, For stage II and III esophageal squamous cell carcinoma (ESCC), neoadjuvant chemotherapy (NAC) followed by esophagectomy is recommended in the Japanese guidelines for the diagnosis and treatment of esophageal cancer. However, recurrence of ESCC is common regardless of the NAC regimen and surgical method, and NAC demonstrates limited efficacy against recurrence. Therefore, the present study was conducted to identify risk factors of recurrence of ESCC with surgery after NAC. The outcomes of 51 patients who underwent esophagectomy for ESCC after NAC from 2010 to 2017 at Kyushu University Hospital were retrospectively analyzed. A total of 52 patients with ESCC without NAC followed by esophagectomy from 2001 to 2017 were selected for comparison. Among patients who underwent NAC followed by surgery, only lymphatic invasion (LY; hazard ratio, 2.761; 95% CI, 1.86-6.43, P=0.018) was an independent factor significantly associated with 3-year recurrence-free survival in the multivariate analysis. In patients with pathologic lymph node metastasis (pN) and no LY after NAC, there was significantly less recurrence compared with patients with pN and LY (P=0.0085), whereas in patients without LY after NAC, the presence of pN was not significantly associated with recurrence (P=0.2401). There were significantly fewer LY (+) patients in the NAC (+) group (P=0.0158) compared with those in the NAC (-) group. The presence of LY was an independent risk factor for recurrence of ESCC after esophagectomy following NAC. Overall, adjuvant treatment after surgery may be required in cases with remnant LY after NAC.
Keywords: esophageal squamous cell carcinoma; lymphatic invasion; neoadjuvant chemotherapy; recurrence factor.. |
| 89. |
Katsuhito Teramatsu, Takamasa Oono, Koki Oyama, Nao Fujimori, Masatoshi Murakami, Sho Yasumori, Akihisa Ohno, Kazuhide Matsumoto, Ayumu Takeno, Kohei Nakata, Masafumi Nakamura, Yoshihiro Ogawa, Circulating CD8+CD122+ T cells as a prognostic indicator of pancreatic cancer, BMC cancer, 10.1186/s12885-022-10207-0, 22, 1, 1134, 2022.04, Purpose: The distribution of tissue infiltrating lymphocytes has been shown to affect the prognosis of patients with pancreatic cancer in some previous studies. However, the role of peripheral lymphocytes in pancreatic cancer remains debated. The purpose of this study was to analyze the peripheral subtypes of T lymphocytes, and establish their association with the prognosis of patients with pancreatic cancer.
Methods: Blood and tissue samples were collected from patients with metastatic pancreatic cancer (n = 54), resectable pancreatic cancer (n = 12), and benign pancreatic cysts (n = 52) between April 2019 and January 2022 and analyzed.
Results: Patients with metastatic pancreatic cancer had a larger proportion of both tumor-suppressive and tumor-promoting cells than those with benign pancreatic cysts. In addition, the proportion of peripheral CD4+ T cells positively correlated with the survival of patients with metastatic pancreatic cancer, and the proportion of peripheral CD8+CD122+ T cells was associated with early mortality (Conclusion: Circulating CD8+CD122+ T cells can be a prognostic indicator in patients with pancreatic cancer.
Keywords: Benign pancreatic cysts; CD4+ T cells; CD8+CD122+ T cells; Metastatic pancreatic cancer; Resectable pancreatic cancer.. |
| 90. |
Kinuko Nagayoshi, Yusuke Mizuuchi, Jinghui Zhang, Kyoko Hisano, Koji Tamura, Masafumi Sada, Kohei Nakata, Kenoki Ohuchida, Masafumi Nakamura, Strong impact of sarcopenic state defined by skeletal muscle mass index on postoperative complication of Crohn's disease patients, Surgery Open Science, 10.1016/j.sopen.2023.07.022, 6, 15, 54-59, 2023.04, Background: Malnutrition impacts the clinical course of Crohn's disease; however, there is little evidence of its influence on perioperative adverse events. We assessed whether nutritional indicators are associated with postoperative complications in surgical treatment of Crohn's disease.
Methods: 137 patients with Crohn's disease who underwent surgical treatment between January 2011 and December 2020 were included. Skeletal muscle index was calculated by a single CT slice. We analyzed the risk factors for adverse events.
Results: 37 % of patients had postoperative complications. Adverse events occurred more frequently in patients with high serum C-reactive protein, low serum albumin, prognostic nutritional index Conclusions: Skeletal muscle index is the most useful nutritional predictor of postoperative complications in Crohn's disease patients among other nutritional indices. We believe that these patients are at high risk of postoperative complications and need appropriate nutritional support in the perioperative period.
Keywords: Crohn's disease; Nutritional status; Postoperative complications; Sarcopenia; Skeletal muscle mass index.. |
| 91. |
Shoichi Nakamura, Kenoki Ohuchida, Yoshiki Ohtsubo. Yutaka Yamada, Chikanori Tsutsumi, Sho Okuda, Kyoko Hisano, Yuki Mochida, Tomohiko Shinkawa, Chika Iwamoto, Nobuhiro Torata, Yusuke Mizuuchi, Koji Shindo, Kohei Nakata, Taiki Moriyama, Takehiro Torisu, Eishi Nagai, Takashi Morisaki, Takanari Kitazono, Yoshinao Oda, Masafumi Nakamura, Single-cell transcriptome analysis reveals functional changes in tumour-infiltrating B lymphocytes after chemotherapy in oesophageal squamous cell carcinoma, Clin Transl Med, 10.1002/ctm2.1181., 13, 1
, e1181, 2023.04, Background: Tumour immune microenvironment is related with carcinogenesis and efficacy of immunotherapy. B cells play major roles in humoral immunity, but detailed functions of tumour-infiltrating B lymphocytes (TIL-Bs) are unknown. Therefore, our aim was to investigate the functional heterogeneity of TIL-Bs in oesophageal squamous cell carcinoma (ESCC) and lymph nodes (LNs) during chemotherapy.
Methods: Single-cell transcriptome analysis was performed on 23 specimens. We also performed immunohistochemical analysis of immunoglobulin κ C (IGKC), an antibody-secreting cell (ASC) marker, in 166 ESCC samples and evaluated the implication of IGKC in 2-year recurrence free survival (RFS) and 3-year overall survival (OS).
Results: A total of 81,246 cells were grouped into 24 clusters. We extracted B cell clusters based on canonical markers and identified 12 TIL-B subtypes in ESCC. We found that several functions, such as co-stimulation and CD40 signalling, were enhanced in TIL-Bs after chemotherapy. The proportion of naive B cells (NBCs) decreased and B cell activation genes were up-regulated in NBCs after chemotherapy. The proportion of ASCs in tumours increased with the loss of migratory abilities and antibody production in ASCs was promoted after chemotherapy. Differentially expressed genes up-regulated with chemotherapy in ASCs correlated with prolonged survival with oesophageal cancer (p = .028). In a metastatic LN, the ASC proportion increased and B cell differentiation was enhanced. In immunohistochemical analysis, RFS and OS of high IGKC expression cases were significantly better than those of low IGKC expression cases (RFS: p
Conclusions: Our findings provide novel insights for the heterogeneity of TIL-Bs during chemotherapy and will be useful to understand the clinical importance of TIL-Bs.
Keywords: neoadjuvant chemotherapy; oesophageal squamous cell carcinoma; single-cell transcriptome; tumour immune microenvironment; tumour infiltrating B lymphocytes.. |
| 92. |
Naoki Ikenaga, Kohei Nakata, Toshiya Abe, Noboru Ideno, Nao Fujimori, Takamasa Oono, Nobuhiro Fujita, Kousei Ishigami, Masafumi Nakamura, Risks and benefits of pancreaticoduodenectomy in patients aged 80 years and over, Langenbecks Arch Surg, 10.1007/s00423-023-02843-2., 408, 108, 108, 2023.04, Purpose: The frequency of pancreaticoduodenectomy is increasing in oldest old patients owing to population aging. We aimed to clarify the clinical significance of pancreaticoduodenectomy in patients aged ≥ 80 years with multiple underlying diseases.
Methods: A total of 649 consecutive patients who underwent pancreaticoduodenectomy from April 2010 to March 2021 in our institute were divided into two groups according to their age: ≥ 80 years (51) and ≤ 79 years (598). We compared mortality and morbidity between the groups. The age-related prognosis was analyzed in 302 patients who underwent pancreaticoduodenectomy for pancreatic ductal adenocarcinoma treatment.
Results: There were no significant differences in morbidity (Clavien-Dindo classification grade III or higher; P = 0.1300), mortality (P = 0.0786), or postoperative hospital stay (P = 0.5763) between the groups. Patients aged ≥ 80 years, who underwent pancreaticoduodenectomy for pancreatic ductal adenocarcinoma, had shorter overall survival than those aged ≤ 79 years (median survival time, 16.7 months vs. 32.7 months; P = 0.0206). However, the overall survival of patients aged ≥ 80 years who received perioperative chemotherapy was comparable to that of patients aged ≤ 79 years (P = 0.9795). In the multivariate analysis, the absence of perioperative chemotherapy was identified as an independent prognostic factor, while age ≥ 80 years was not. Perioperative chemotherapy was the sole independent prognostic factor in patients aged ≥ 80 years who underwent pancreaticoduodenectomy for pancreatic ductal adenocarcinoma.
Conclusions: Pancreaticoduodenectomy is safe for patients aged ≥ 80 years. The survival benefits of pancreaticoduodenectomy for patients with pancreatic ductal adenocarcinoma aged ≥ 80 years might be limited to those who can receive perioperative chemotherapy.
Keywords: Adenocarcinoma; Aged; Chemotherapy; Pancreaticoduodenectomy; Survival analysis.. |
| 93. |
Yusuke Mizuuchi, Yoshitaka Tanabe, Masafumi Sada, Koji Tamura, Kinuko Nagayoshi, Shuntaro Nagai, Yusuke Watanabe, Sadafumi Tamiya, Kenoki Ohuchida, Kohei Nakata, Toru Nakano, Masafumi Nakamura, Relationship between prognostic impact of N3 lymph node metastasis at the root of the feeding artery and location of colon cancer, Langenbecks Arch Surg, 10.1007/s00423-023-02778-8, 408, 1, 31, 2023.04, Purpose: To determine whether N3 nodal involvement predicts outcomes and whether its prognostic implications vary with tumor location in patients with Stage III colon cancer (CC).
Methods: We defined N3 as lymph node metastases near the bases of the major feeding arteries. We retrospectively examined recurrence rates and patterns by tumor location and sites of lymph node metastases in 57 patients with N3 CC who had undergone curative resections between January 2000 and March 2019. Survival analysis was performed to compare the prognoses of patients with and without N3 lymph node metastasis.
Results: Most N3 patients had large tumors (T ? 3); five had T2 disease. Recurrence occurred quickly in one patient with T2N3M0 disease. Multivariate survival analysis demonstrated that N3 lymph node metastasis is an independent predictor of poor prognosis in Stage III CC patients (P < 0.001). Categorizing N3 patients according to UICC-TNM staging system does not stratify risk of recurrence (P = 0.970). To investigate the impact of tumor location on recurrence risk, we classified N3 CC into two subtypes according to tumor location: metastasis at the base of the superior mesenteric artery in right-sided CC and inferior mesenteric artery in left-sided CC. The former was found to have a statistically significant poorer prognosis than the latter (P = 0.091).
Conclusion: N3 is a robust prognostic marker in CC patients. Recurrence risk varies by tumor location. N3 right-sided CCs with lymph node metastasis at the base of the superior mesenteric artery have poorer prognoses than do N3 left-sided CCs.
Keywords: Feeding artery; Inferior mesenteric artery; N3 colon cancer; Superior mesenteric artery; Tumor sidedness.. |
| 94. |
Toshiya Abe, Kohei Nakata, So Nakamur, Noboru Ideno, Naoki Ikenaga, Nobuhiro Fujita, Kousei Ishigami, Kazuyoshi Nishihara, Masafumi Nakamura, Prognostic Impact of Preoperative Osteosarcopenia for Patients with Pancreatic Ductal Adenocarcinoma After Curative Resection, Ann Surg Oncol, 10.1245/s10434-023-13936-z, 30, 11, 6673-6679, 2023.04, Backgrounds: The clinical significance of preoperative osteosarcopenia in pancreatic ductal adenocarcinoma (PDAC) has not been fully studied. The purpose of this study was to evaluate the role of preoperative osteosarcopenia in predicting the survival of patients with PDAC.
Methods: We retrospectively analyzed 265 patients who underwent curative surgical resection for PDAC between 2012 and 2018 in two Japanese institutes. The skeletal muscle index at the L3 vertebrae and the bone mineral density at the Th11 vertebra were calculated for the evaluation of osteosarcopenia before surgery. The relationship between perioperative osteosarcopenia and clinicopathological factors and prognosis was analyzed.
Results: The median overall survival (OS) and disease-free survival (DFS) of patients with osteosarcopenia were significantly shorter than those of patients without osteosarcopenia (OS: 23 and 48 months, respectively, P Conclusions: Preoperative osteosarcopenia may be a useful prognostic factor in patients with PDAC who undergo surgical resection. Further studies are needed to assess whether perioperative, nutritional interventions and rehabilitation contribute to improving the prognosis of these patients.. |
| 95. |
Sho Okuda, Kenoki Ohuchida, Shoichi Nakamura, Chikanori Tsutsumi, Kyoko Hisano, Yuki Mochida, Jun Kawata, Yoshiki Ohtsubo, Tomohiko Shinkawa, Chika Iwamoto, Nobuhiro Torata, Yusuke Mizuuchi, Koji Shindo, Taiki Moriyama, Kohei Nakata, Takehiro Torisu, Takashi Morisaki, Takanari Kitazono, Yoshinao Oda, Masafumi Nakamura, Neoadjuvant chemotherapy enhances anti-tumor immune response of tumor microenvironment in human esophageal squamous cell carcinoma, iScience.
, 10.1016/j.isci.2023.106480., 26, 4, 106480, 2023.04. |
| 96. |
Kohei Nakata, Toshiya Abe, Noboru Ideno, So Nakamura, Naoki Ikenaga, Kinuko Nagayoshi, Yusuke Mizuuchi, Taiki Moriyama, Kenoki Ohuchida, Masafumi Nakamura, Minimally invasive distal pancreatectomy for pancreatic cancer: cranial-to-caudal approach with identification of Gerota's fascia (with video), Surg Endosc, 10.1007/s00464-023-10438-7, 37, 11, 8901-8909, 2023.04, Background: Although radical antegrade modular pancreatosplenectomy for pancreatic ductal adenocarcinoma (PDAC) has become the gold standard procedure in open distal pancreatectomy, there has been no gold standardized procedure for PDAC in minimally invasive distal pancreatectomy (MIDP). In this study, we analyzed our novel cranial-to-caudal approach (CC approach) for patients undergoing MIDP and provide a video clip illustrating the details of the CC approach.
Methods: Ninety-four patients who underwent MIDP with splenectomy between 2016 and 2021 were included in this study. The CC approach was performed in 23 (24.5%) of the 94 patients. The concept of the CC approach is easy identification of Gerota's fascia from the cranial side of the pancreas and secure tumor removal (R0 resection) wrapped by Gerota's fascia. The short- and long-term outcomes were compared between the CC and non-CC approaches.
Results: The median operation time and blood loss were similar between the two groups. The ratios of grade ≥ B postoperative pancreatic fistula and Clavien-Dindo grade ≥ III complications were also comparable. All patients in the CC approach group achieved R0 resection, and the R0 ratio was similar in the two groups (p = 0.345). The 2-year survival rate in CC and non-CC approach groups was 87.5% and 83.6%, respectively (p = 0.903).
Conclusions: The details of the CC approach for MIDP were demonstrated based on an anatomical point of view. This approach has the potential to become a standardized approach for left-sided PDAC.
Keywords: Approach; Distal pancreatectomy; Minimally invasive pancreatectomy.. |
| 97. |
Masatoshi Murakami, Nao Fujimori, Kohei Nakata, Masafumi Nakamura, Shinichi Hashimoto, Hiroshi Kurahara, Kazuyoshi Nishihara, Toshiya Abe, Shunpei Hashigo, Naotaka Kugiyama, Eisuke Ozawa, Kazuhisa Okamoto, Yusuke Ishida, Keiichi Okano, Ryo Takaki, Yutaka Shimamatsu, Tetsuhide Ito, Masami Miki, Noriko Oza, Daisuke Yamaguchi, Hirofumi Yamamoto , Hironobu Takedomi, Ken Kawabe, Tetsuro Akashi , Koichi Miyahara, Jiro Ohuchid, Yasuhiro Ogura, Yohei Nakashima, Toshiharu Ueki, Kousei Ishigami, Hironobu Umakoshi, Keijiro Ueda, Takamasa Oono, Yoshihiro Ogawa, Machine learning-based model for prediction and feature analysis of recurrence in pancreatic neuroendocrine tumors G1/G2, J Gastroenterol, 10.1007/s00535-023-01987-8, 58, 6, 586-597, 2023.04, Background: Pancreatic neuroendocrine neoplasms (PanNENs) are a heterogeneous group of tumors. Although the prognosis of resected PanNENs is generally considered to be good, a relatively high recurrence rate has been reported. Given the scarcity of large-scale reports about PanNEN recurrence due to their rarity, we aimed to identify the predictors for recurrence in patients with resected PanNENs to improve prognosis.
Methods: We established a multicenter database of 573 patients with PanNENs, who underwent resection between January 1987 and July 2020 at 22 Japanese centers, mainly in the Kyushu region. We evaluated the clinical characteristics of 371 patients with localized non-functioning pancreatic neuroendocrine tumors (G1/G2). We also constructed a machine learning-based prediction model to analyze the important features to determine recurrence.
Results: Fifty-two patients experienced recurrence (14.0%) during the follow-up period, with the median time of recurrence being 33.7 months. The random survival forest (RSF) model showed better predictive performance than the Cox proportional hazards regression model in terms of the Harrell's C-index (0.841 vs. 0.820). The Ki-67 index, residual tumor, WHO grade, tumor size, and lymph node metastasis were the top five predictors in the RSF model; tumor size above 20 mm was the watershed with increased recurrence probability, whereas the 5-year disease-free survival rate decreased linearly as the Ki-67 index increased.
Conclusions: Our study revealed the characteristics of resected PanNENs in real-world clinical practice. Machine learning techniques can be powerful analytical tools that provide new insights into the relationship between the Ki-67 index or tumor size and recurrence.
Keywords: Machine learning; Pancreatic neuroendocrine tumor; Prediction model; Random survival forest; Recurrence.. |
| 98. |
Shuang Fei, Kenoki Ohuchida, Shin Kibe, Zilong Yan, Chika Iwamoto, Tomohiko Shinkawa, Bo Zhang, Jun Kawata, Toshiya Abe, Noboru Ideno, Naoki Ikenaga, Kohei Nakata, Yoshinao Oda, Masafumi Nakamura, Involvement of angiogenesis in cancer-associated acinar-to-ductal metaplasia lesion of pancreatic cancer invasive front, Gastric Cancer, 10.1007/s00432-022-04554-5., 149, 9, 5885-5899, 2023.04, Purpose: This study aimed to demonstrate the involvement of angiogenesis in cancer-associated acinar-to-ductal metaplasia (CA-ADM) lesion of invasive front pancreatic ductal adenocarcinoma (PDAC) and investigate the possible mechanism.
Methods: Tissue samples from 128 patients with PDAC and 36 LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre mice were analyzed. Immunohistochemical assay was performed using HE, anti-CK19 and anti-amylase to confirm the presence of CA-ADM lesions, using anti-CD34 and anti-CD31 to measure microvessel density (MVD), and using anti-CD68, anti-CD163, anti-iNOS, or anti-MMP9 to evaluate the immune microenvironment. We performed multiplex immunohistochemical assay to detect the co-expression of MMP9 and CD68 on macrophage. We examined clinical outcomes and other clinicopathological factors to determine the significance of high-level MVD of CA-ADM on survival and liver metastasis. We performed tube formation assay to evaluate the effect of macrophage on angiogenic capacity in vitro.
Results: Angiogenesis was significantly abundant in CA-ADM lesions compared with that in PDAC lesions in human and mouse tissues. High-level MVD in CA-ADM lesions was an independent predictor of poor prognosis (P = 0.0047) and the recurrence of liver metastasis (P = 0.0027). More CD68-positive and CD163-positive macrophages were detected in CA-ADM lesions than in PDAC. The percentage of CD68-positive macrophages was positively correlated with MVD in CA-ADM lesions. Multiplex-immunostaining revealed that MMP9 was expressed in CD68-positive macrophages of CA-ADM lesions. In CA-ADM lesions, the percentage of macrophages was positively correlated with MMP9 expression, which positively correlated with microvessel density.
Conclusion: CA-ADM related angiogenesis is a promising predictive marker for poor prognosis of PDAC and may provide an attractive therapeutic target for PDAC.
Keywords: Angiogenesis; Cancer-associated acinar-to-ductal metaplasia; Liver metastasis; Macrophages; Pancreatic cancer; Prognosis.. |
| 99. |
Masataka Hayashi, Naoki Ikenaga, Kohei Nakata, Haizhen Luo, PingShan Zhong, Satomi Date, Koki Oyama, Nobuhiro Higashijima, Akihiro Kubo, Chika Iwamoto, Nobuhiro Torata, Toshiya Abe, Yutaka Yamada, Kenoki Ohuchida, Yoshinao Oda, Masafumi Nakamura, Intratumor Fusobacterium nucleatum promotes the progression of pancreatic cancer via the CXCL1-CXCR2 axis, Cancer Science, 10.1111/cas.15901 , 114, 9, 3666-3678, 2023.04, Intratumor bacteria modify the tumor immune microenvironment and influence outcomes of various tumors. Periodontal pathogen Fusobacterium nucleatum has been detected in pancreatic cancer tissues and is associated with poor prognosis. However, it remains unclear how F. nucleatum affects pancreatic cancer. Here, we compared clinical features with F. nucleatum colonization in pancreatic cancer tissues. F. nucleatum was detected in 15.5% (13/84) of pancreatic cancer patients. The tumor size was significantly larger in the F. nucleatum-positive group than in the negative group. To clarify the biological effect of intratumor F. nucleatum on pancreatic cancer progression, we performed migration/invasion assays and cytokine array analysis of cancer cells cocultured with F. nucleatum. F. nucleatum promoted CXCL1 secretion from pancreatic cancer cells, leading to cancer progression through autocrine signaling. Intratumor F. nucleatum suppressed tumor-infiltrating CD8+ T cells by recruiting myeloid-derived suppressor cells (MDSCs) to the tumor in an F. nucleatum-injected subcutaneous pancreatic cancer mouse model, resulting in tumor progression. Furthermore, tumor growth accelerated by F. nucleatum was suppressed by MDSC depletion or cytokine inhibitors. Intratumor F. nucleatum promoted pancreatic cancer progression through autocrine and paracrine mechanisms of the CXCL1-CXCR2 axis. Blockade of the CXCL1-CXCR2 axis may be a novel therapeutic approach for patients with intratumor F. nucleatum-positive pancreatic cancer.
Keywords: Fusobacterium nucleatum; CXCL1; CXCR2; pancreatic cancer; tumor immune microenvironment.. |
| 100. |
Nobuhiro Fujita, Yasuhiro Ushijima, Masahiro Itoyama, Daisuke Okamoto, Keisuke Ishimatsu, Noriaki Wada, Seiichiro Takao, Ryo Murayama, Nao Fujimori, Kohei Nakata, Masafumi Nakamura, Takeo Yamamoto, Yoshinao Oda, Kousei Ishigami, Extracellular volume fraction determined by dual-layer spectral detector CT: Possible role in predicting the efficacy of preoperative neoadjuvant chemotherapy in pancreatic ductal adenocarcinoma, Eur J radiol
, 10.1016/j.ejrad.2023.110756, 162, 110756, 2023.04, 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 (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.
Keywords: Dual-energy CT; Extracellular volume; Neoadjuvant chemotherapy; Pancreatic ductal adenocarcinoma.. |
| 101. |
Woohyung Lee, Dae Wook Hwang, Ho-Seong Han, In Woong Han, Jin Seok Heo, Michiaki Unno, Masaharu Ishida, Hiroshi Tajima, Nobuyuki Nishizawa, Kohei Nakata, Yasuji Seyama, Yoshiya Isikawa, Ho Kyoung Hwang, Jin-Young Jang, Taeho Hong, Joon Seong Park, Hee Joon Kim, Chi-Young Jeong, Jeong-Ik Park, Ippei Matsumoto, Hiroki Yamaue, Manabu Kawai, Masayuki Ohtsuka,Shugo Mizuno, Mitsuhiro Asakuma, Yuji Soejima, Teijiro Hirashita, Masayuki Sho, Yutaka Takeda, Jeong-Ik Park, Yong Hoon Kim, Hwa Jung Kim, Hiroki Yamaue, Masakazu Yamamoto, Itaru Endo, Masafumi Nakamura, Yoo-Seok Yoon, Comparison of infectious complications after spleen preservation versus splenectomy during laparoscopic distal pancreatectomy for benign or low-grade malignant pancreatic tumors: A multicenter, propensity score-matched analysis, J Hepatobiliary Pancreat Sci, 10.1002/jhbp.1213, 30, 2, 252-262, 2023.04, Background
Previous studies reported contrasting results regarding the advantages of spleen preservation during laparoscopic distal pancreatectomy (LDP) for preventing infectious complications.
Methods
A total of 3,787 patients who underwent LDP for benign or low-grade malignant pancreatic disease in 92 centers across Korea and Japan were included in this retrospective study. Postoperative infectious complications and other complications were compared between LDP with splenectomy (LDPS) and LDP with spleen preservation (LSPDP) by propensity score matching (PSM) analysis.
Results
After PSM, the LSPDP group had a lower rate of overall infectious complications (P = 0.079) and a significantly lower rate of intraabdominal abscess (P = 0.014) compared with the LDPS group. Within the LSPDP group, the vessel preservation subgroup had a significantly higher rate of infectious complications (P = 0.002) compared with the vessel resection subgroup. Low-volume centers had a higher rate of intraabdominal abscess than did high-volume centers in the LSPDP group (P = 0.001) and the splenic vessel preservation subgroup (P = 0.043).
Conclusions
Spleen preservation in LDP for benign or borderline malignant pancreatic diseases was advantageous in lowering the risk of infectious complications, specifically intraabdominal abscess. However, the risk of intraabdominal abscess may differ according to the level of surgeon’s experience.. |
| 102. |
Kinuko Nagayoshi, Yusuke Mizuuchi, Koji Tamura, Masafumi Sada, Kohei Nakata, Kenoki Ohuchida, Masafumi Nakamura, Combination of robotic and transperineal techniques for total pelvic exenteration followed by a posterior-anterior approach to the supralevator space - a video vignette, Colorectal Dis, 10.1111/codi.16765, 25, 11, 2282-2283, 2023.04. |
| 103. |
Naoki Ikenaga, Kohei Nakata, Masataka Hayashi, So Nakamura, Toshiya Abe, Noboru Ideno, Masatoshi Murakami, Nao Fujimori, Nobuhiro Fujita, Takuro Isoda, Shingo Baba, Kousei Ishigami, Yoshinao Oda, Masafumi Nakamura, Clinical Implications of FDG-PET in Pancreatic Ductal Adenocarcinoma Patients Treated with Neoadjuvant Therapy, J Gastrointest Surg, 10.1007/s11605-023-05591-2, 27, 2, 337-346, 2023.04, urpose: To evaluate the clinical significance of 18F-fluorodeoxyglucose positron emission tomography/computed tomography in patients with pancreatic ductal adenocarcinoma who underwent neoadjuvant therapy.
Methods: Among 285 consecutive patients who underwent pancreatic resection for pancreatic ductal adenocarcinoma between 2015 and 2021, 86 who underwent preoperative 18F-fluorodeoxyglucose positron emission tomography/computed tomography after completion of neoadjuvant treatment were reviewed. Among preoperative factors, including post-treatment maximum standardized uptake value, predictors of early recurrence and poor prognosis were identified using multivariate analysis for decision making in surgery.
Results: Nineteen (22%) patients with pancreatic ductal adenocarcinoma demonstrated high maximum standardized uptake (≥ 4.5). High post-treatment maximum standardized uptake (≥ 4.5) predicted early recurrence within 6 months after surgery and correlated with shorter recurrence-free survival. Elevated post-treatment CA19-9 level (> 37 U/ml) and maximum standardized uptake ≥ 4.5 were independent prognostic factors. Post-treatment, a high maximum standardized uptake value indicated a poorer prognosis than a low maximum standardized uptake value in both patients with elevated CA19-9 and normal CA19-9 levels. The median overall survival in patients with elevated post-treatment CA19-9 and high maximum standardized uptake was only 17 months; 67% experienced early recurrence. Dynamic changes in maximum standardized uptake during neoadjuvant therapy were correlated with pathological response to neoadjuvant therapy, but not with radiological response or change in CA19-9 level.
Conclusions: Post-treatment assessment using maximum standardized uptake value is useful for stratifying patients with pancreatic ductal adenocarcinoma who will benefit from surgery. Instead of subsequent curative resection, additional neoadjuvant therapy should be considered in patients with a persistently high maximum standardized uptake value.
Keywords: 18F-fluorodeoxyglucose positron emission tomography/computed tomography; Neoadjuvant; Pancreatic ductal adenocarcinoma; Recurrence; Standardized uptake value.. |
| 104. |
Naoki Ikenaga, Yoshihiro Miyasaka, Takao Ohtsuka, Kohei Nakata, Tomohiko Adachi, Susumu Eguchi, Kazuyoshi Nishihara, Masafumi Inomata, Hiroshi Kurahara, Toru Hisaka, Hideo Baba, Hiroaki Nagano, Toshiharu Ueki, Hirokazu Noshiro, Shoji Tokunaga, Kousei Ishigami, Masafumi Nakamura, ASO Visual Abstract: A Prospective, Multicenter, Phase II, Trial of Neoadjuvant Chemotherapy with Gemcitabine Plus Nab-Paclitaxel for Borderline Resectable Pancreatic Cancer with Arterial Involvement, Clinical Trial, 10.1245/s10434-022-12611-z, 30, 1, 205-206, 2023.04. |
| 105. |
Kazuhide Matsumoto, Nao Fujimori, Yoshitaka Hata, Yosuke Minoda, Masatoshi Murakami, Katsuhito Teramatsu, Yu Takamatsu, Ayumu Taken, Takamasa Oono, Eikichi Ihara, Kohei Nakata, Masafumi Nakamura, Takeo Yamamoto, Yutaka Koga, Yoshinao Oda, Tetsuhide Ito, Yoshihiro Ogawa, Ampullary Neuroendocrine Neoplasm: Clinicopathological Characteristics and Novel Endoscopic Entity, Dig Dis, 10.1159/000525013, 41, 2, 316-324, 2023.04, 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 (Conclusions: Endoscopic findings showed identifiable distinctions between ampullary NETs and NECs.
Keywords: Crater sign; Endoscopic papillectomy; Neuroendocrine neoplasms of the ampulla of Vater; Pancreatic neuroendocrine neoplasms.. |
| 106. |
Naoki Ikenaga, Yoshihiro Miyasaka, Takao Ohtsuka, Kohei Nakata, Tomohiko Adachi, Susumu Eguchi, Kazuyoshi Nishihara, Masafumi Inomata, Hiroshi Kurahara, Toru Hisaka, Hideo Baba, Hiroaki Nagano, Toshiharu Ueki, Hirokazu Noshiro, Shoji Tokunaga, Kousei Ishigami, Masafumi Nakamura, A Prospective Multicenter Phase II Trial of Neoadjuvant Chemotherapy with Gemcitabine Plus Nab-Paclitaxel for Borderline Resectable Pancreatic Cancer with Arterial Involvement, Ann Surg Oncol, 10.1245/s10434-022-12566-1
Abstract, 30, 1, 193-202, 2023.04, Background: Only two clinical trials have shown the effects of neoadjuvant treatment for borderline resectable pancreatic cancer with arterial involvement (BRPC-A). Here, we aimed to analyze the efficacy and safety of neoadjuvant gemcitabine plus nab-paclitaxel (GnP) for BRPC-A.
Patients and methods: A prospective, single-arm, multicenter phase II trial was conducted. Patients who were radiologically and histologically diagnosed with BRPC-A were enrolled. A central review was conducted to confirm the presence of BRPC-A. Patients received two to four cycles of GnP before surgery. The primary endpoint of the study was the R0 resection rate. Overall survival (OS) was evaluated in an ancillary study.
Results: Thirty-five patients were enrolled, of whom 33 were subjected to central review and 28 were confirmed to have BRPC-A. All eligible patients with BRPC-A received neoadjuvant GnP. Nineteen patients underwent pancreatic resections. Postoperative complications of Clavien-Dindo IIIa or lower were observed in 11 patients. No treatment-related mortalities were observed. R0 resection was achieved in 17 patients (89%); the R0 resection rate was 61% in eligible patients. One patient underwent curative resection after termination of the treatment protocol, resulting in an overall R0 resection rate of 64%. The median overall survival (OS) and 2-year OS rate were 24.9 months [95% confidence interval (CI) 19.0 months to not estimatable] and 53.6%, respectively. OS in patients with BRPC-A who achieved overall R0 resection was significantly longer than that in the other patients (p = 0.0255).. |
| 107. |
kohei Nakata, Toshiya Abe, Noboru Ideno, So Nakamura, Naoki Ikenaga, Kinuko Nagayoshi, Yusuke Mizuuchi, Taiki Moriyama, Kenoki Ohuchida, Masafumi Nakamura, A left-sided approach for wide mobilization of the pancreas with complete dissection of the Treitz ligament(with video), Surgical Endoscopy, 10.1007/s00464-023-10065-2, 37, 6, 4982-4989, 2023.04. |
| 108. |
Chikanori Tsutsumi, Kenoki Ohuchida, Naoki Katayama, Yutaka Yamada, Shoichi Nakamura, Sho Okuda, Yoshiki Otsubo, Chika Iwamoto, Nobuhiro Torata, Kohei Horioka, Koji Shindo, Yusuke Mizuuchi, Naoki Ikenaga, Kohei Nakata, Eishi Nagai, Takashi Morisaki, Yoshinao Oda, Masafumi Nakamura, Tumor-infiltrating monocytic myeloid-derived suppressor cells contribute to the development of an immunosuppressive tumor microenvironment in gastric cancer, Gastric Cancer, 10.1007/s10120-023-01456-4, 2024.04, Background
Gastric cancer (GC) is characterized by an immunosuppressive and treatment-resistant tumor immune microenvironment (TIME). Here, we investigated the roles of different immunosuppressive cell types in the development of the GC TIME.
Methods
Single-cell RNA sequencing (scRNA-seq) and multiplex immunostaining of samples from untreated or immune checkpoint inhibitor (ICI)-resistant GC patients were used to examine the correlation between certain immunosuppressive cells and the prognosis of GC patients.
Results
The results of the scRNA-seq analysis revealed that tumor-infiltrating monocytic myeloid-derived suppressor cells (TI-M-MDSCs) expressed higher levels of genes with immunosuppressive functions than other immunosuppressive cell types. Additionally, among the immunosuppressive cell types assessed, M-MDSCs were most significantly enriched in GC tissues relative to adjacent normal tissues. The M-MDSCs in GC tissues expressed significantly higher levels of these markers than adjacent normal tissues; moreover, their presence was most strongly associated with a poor prognosis among the immunosuppressive cells. Immediate early response 3 (IER3), which we identified as a differentially expressed gene between M-MDSCs of GC and adjacent normal tissues, was an independent poor prognostic factor in GC patients (P=0.0003). IER3+ M-MDSCs expressed higher levels of genes with immunosuppressive functions than IER3－ M-MDSCs and were more abundant in treatment-resistant than -responsive GC patie
nts.
Conclusions
The present study suggests that TI-M-MDSCs, especially IER3+ ones, may play a predominant role in the development of the immunosuppressive and ICI-resistant GC TIME.
. |
| 109. |
Takashi Taniguchi, Noboru Ideno, Tomoyuki Araki, Shun Miura, Masahiro Yamamoto, Tomoki Nakafusa, Nobuhiro Higashijima, Takeo Yamamoto, Koji Tamura, So Nakamura, Toshiya Abe, Naoki Ikenaga, Kohei Nakata, Kenoki Ohuchida, Yoshinao Oda, Takao Ohtsuka, Masafumi Nakamura, MicroRNA-20a in extracellular vesicles derived from duodenal fluid is a possible biomarker for pancreatic ductal adenocarcinoma, DEN Open, 10.1002/deo2.333, 4, 1, e333, 2024.04, 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.
Keywords: duodenal fluid; early detection; extracellular vesicle; microRNA; pancreatic ductal adenocarcinoma.. |
| 110. |
Yutaka Yamada, Takeo Yamamoto, Chikanori Tsutsumi, Takashi Matsumoto, Shoko Noguchi, Yuki Shimada, Kohei Nakata, Kenoki Ohuchida, Masafumi Nakamura, Yoshinao Oda, Immature stroma and high infiltration of CD15+ cells are predictive markers of poor prognosis in different subsets of patients with pancreatic cancer, Cancer Sci, 10.1111/cas.16060, 115, 3, 1001-1013, 2024.04, 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.
Keywords: neoadjuvant chemotherapy; neutrophils; pancreatic cancer; receptors, chemokine; tumor microenvironment.. |
| 111. |
Taiki Moriyama, Kenoki Ohuchida, Takao Ohtsuka, Koji Shindo, Naoki Ikenaga, Kohei Nakata, Masafumi Nakamura, Higher incidence of cholelithiasis with Roux-en-Y reconstruction compared with Billroth-I after laparoscopic distal gastrectomy for gastric cancer: a retrospective cohort study, Langenbecks Arch Surg, 10.1007/s00423-024-03267-2, 409, 1, 75, 2024.04, Purpose: Cholelithiasis occurs often after gastrectomy. However, no consensus has been established regarding the difference in the incidence of postgastrectomy cholelithiasis with different reconstruction methods. In this study, we examined the frequency of cholelithiasis after two major reconstruction methods, namely Billroth-I (B-I) and Roux-en-Y (R-Y) following laparoscopic distal gastrectomy (LDG) for gastric cancer.
Methods: Among 696 gastric cancer patients who underwent LDG between April 2000 and March 2017, after applying the exclusion criteria, 284 patients who underwent B-I and 310 who underwent R-Y were examined retrospectively. The estimated incidence of cholelithiasis was compared between the methods, and factors associated with the development of cholelithiasis in the gallbladder and/or common bile duct were investigated.
Results: During the median follow-up of 61.2 months, 52 patients (8.8%) developed cholelithiasis postgastrectomy; 12 patients (4.2%) after B-I and 40 (12.9%) after R-Y (p = 0.0002). Among them, choledocholithiasis was more frequent in patients who underwent R-Y (n = 11, 27.5%) vs. B-I (n = 1, 8.3%) (p = 0.0056). Univariate and multivariate analyses revealed that male sex, body mass index > 22.5 kg/m2, and R-Y reconstruction were significant predictors of the development of postLDG cholelithiasis.
Conclusion: Regarding cholelithiasis development, B-I reconstruction should be preferred whenever possible during distal gastrectomy.
Keywords: Billroth-I; Cholelithiasis; Distal gastrectomy; Gastric cancer; Laparoscopy; Roux-en-Y.. |
| 112. |
Naoki Ikenaga, Tadayoshi Hashimoto, Junki Mizusawa, Ryo Kitabayashi, Yusuke Sano, Haruhiko Fukuda, Kohei Nakata, Kazuto Shibuya, Yuji Kitahata, Minoru Takada, Keiko Kamei, Hiroshi Kurahara, Daisuke Ban, Shogo Kobayashi, Hiroaki Nagano, Hajime Imamura, Michiaki Unno, Amane Takahashi, Shintaro Yagi, Hiroshi Wada, Hirofumi Shirakawa, Naoto Yamamoto, Seiko Hirono, Naoto Gotohda, Etsuro Hatano, Masafumi Nakamura, Makoto Ueno; on behalf of the Hepatobiliary and Pancreatic Oncology Group in Japan Clinical Oncology Group, A multi-institutional randomized phase III study comparing minimally invasive distal pancreatectomy versus open distal pancreatectomy for pancreatic cancer; Japan Clinical Oncology Group study JCOG2202 (LAPAN study), BMC cancer, 10.1186/s12885-024-11957-9, 24, 1, 231, 2024.04, Background: Minimally invasive distal pancreatectomy (MIDP), including laparoscopic and robotic distal pancreatectomy, has gained widespread acceptance over the last decade owing to its favorable short-term outcomes. However, evidence regarding its oncologic safety is insufficient. In March 2023, a randomized phase III study was launched in Japan to confirm the non-inferiority of overall survival in patients with resectable pancreatic cancer undergoing MIDP compared with that of patients undergoing open distal pancreatectomy (ODP).
Methods: This is a multi-institutional, randomized, phase III study. A total of 370 patients will be enrolled from 40 institutions within 4 years. The primary endpoint of this study is overall survival, and the secondary endpoints include relapse-free survival, proportion of patients undergoing radical resection, proportion of patients undergoing complete laparoscopic surgery, incidence of adverse surgical events, and length of postoperative hospital stay. Only a credentialed surgeon is eligible to perform both ODP and MIDP. All ODP and MIDP procedures will undergo centralized review using intraoperative photographs. The non-inferiority of MIDP to ODP in terms of overall survival will be statistically analyzed. Only if non-inferiority is confirmed will the analysis assess the superiority of MIDP over ODP.
Discussion: If our study demonstrates the non-inferiority of MIDP in terms of overall survival, it would validate its short-term advantages and establish its long-term clinical efficacy.
Trial registration: This trial is registered with the Japan Registry of Clinical Trials as jRCT 1,031,220,705 [ https://jrct.niph.go.jp/en-latest-detail/jRCT1031220705 ].
Keywords: Clinical trial; Laparoscopy; Minimally invasive surgical procedures; Pancreatectomy; Pancreatic neoplasm.. |
