Background: While recent research has shown that expression of ZEB-1 in a variety of tumors has a crucial impact on patient survival, there is little information regarding ZEB-1 expression in hepatocellular carcinoma (HCC). This study investigated the co-expression of ZEB-1 and E-cadherin in HCC by immunohistochemistry and evaluated its association with clinical factors, including patient prognosis. Methods: A total of 108 patients with primary HCC treated by curative hepatectomy were enrolled. ZEB-1 expression was immunohistochemically categorized as positive if at least 1% cancer cells exhibited nuclear staining. E-cadherin expression was divided into preserved and reduced expression groups and correlations between ZEB-1 and E-cadherin expression and clinical factors were then evaluated. Results: With respect to ZEB-1 expression, 23 patients were classified into the positive group and 85 into the negative group. Reduced E-cadherin expression was seen in 44 patients and preserved expression in the remaining 64 patients. ZEB-1 positivity was significantly associated with reduced expression of E-cadherin (p = 0.027). Moreover, significant associations were found between ZEB-1 expression and venous invasion and TNM stage. ZEB-1 positivity was associated with poorer prognosis (p = 0.025). Reduced E-cadherin expression was significantly associated with intrahepatic metastasis and poorer prognosis (p = 0.047). In particular, patients with both ZEB-1 positivity and reduced E-cadherin expression had a poorer prognosis (p = 0.005). Regardless of E-cadherin status, ZEB-1 was not a significant prognostic factor by multivariate analysis. There was no statistical difference in overall survival when E-cadherin expression was reduced in the ZEB-1 positive group (p = 0.24). Conclusions: Positive ZEB-1 expression and loss of E-cadherin expression are correlated with poor prognosis in HCC patients and malignancy of ZEB-1 positive tumors involves EMT.

The aggressive nature of intrahepatic cholangiocarcinoma (ICC) renders it a particularly lethal solid tumor. Searching for therapeutic targets for ICC is an essential challenge in the development of an effective treatment strategy. Our previous studies showed that the miR-29-3p-family members (miR-29a-3p, miR-29b-3p and miR-29c-3p) are key tumor-suppressive microRNAs that control many oncogenic genes/pathways in several cancers. In this study, we searched for therapeutic targets for ICC using the miR-29-3p-family as a starting point. Our functional studies of cell proliferation, migration and invasion confirmed that the miR-29-3p-family act as tumor-suppressors in ICC cells. Moreover, in silico analysis revealed that “focal adhesion”, “ECM-receptor”, “endocytosis”, “PI3K-Akt signaling” and “Hippo signaling” were involved in oncogenic pathways in ICC cells. Our analysis focused on the genes for integrin-α6 (ITGA6) and integrin-β1 (ITGB1), which are involved in multiple pathways. Overexpression of ITGA6 and ITGB1 enhanced malignant transformation of ICC cells. Both ITGA6 and ITGB1 were directly regulated by the miR-29-3p-family in ICC cells. Interestingly, expression of ITGA6/ITGB1 was positively controlled by the transcription factor SP1, and SP1 was negatively controlled by the miR-29-3p-family. Downregulation of the miR-29-3p-family enhanced SP1-mediated ITGA6/ITGB1 expression in ICC cells. MicroRNA-based exploration is an attractive strategy for identifying therapeutic targets for ICC.

The mesenteric approach is an artery-first approach to pancreaticoduodenectomy for pancreatic cancer, which starts with the dissection of connective tissues around the superior mesenteric artery. The procedure aims for early confirmation of resectability by checking the surgical margin around the superior mesenteric artery first during the operation. It also aims to decrease intraoperative blood loss by early ligation of the inferior pancreaticoduodenal artery and to increase R0 rate by complete clearance of the lymph nodes around the superior mesenteric artery and pancreatic head plexus II, the most favorable positive margin site for pancreatic ductal adenocarcinoma. Furthermore, it aims to avoid the spread of cancer cells during operation (nontouch isolation technique). The MAPLE-PD (Mesenteric Approach vs. Conventional Approach for Pancreatic Cancer during Pancreaticoduodenectomy) trial investigates whether the mesenteric approach can prolong the survival of patients with pancreatic ductal adenocarcinoma who undergo pancreaticoduodenectomy compared with the conventional approach. The MAPLE-PD trial is a Japanese multicenter randomized controlled trial that compares the surgical outcomes between the mesenteric and conventional approaches to pancreaticoduodenectomy. Patients with pancreatic ductal adenocarcinoma scheduled to undergo pancreaticoduodenectomy are randomized before operation to either a conventional approach (arm A) or a mesenteric approach (arm B). In arm A, the operation starts with Kocher’s maneuver. At the final step of the removal procedure, the connective tissues around the superior mesenteric artery are dissected. In arm B, the operation starts with dissection of the connective tissues around the superior mesenteric artery and ends with Kocher’s maneuver. In total, 354 patients from 15 Japanese high-volume centers will be randomized. The primary endpoint is overall survival by intention-to-treat analysis. Secondary endpoints include intraoperative blood loss, R0 rate, and recurrence-free survival. If the MAPLE-PD trial shows the oncological benefits of the mesenteric approach for patients with pancreatic ductal adenocarcinoma, this procedure may become a standard approach to pancreaticoduodenectomy. ClinicalTrials.gov, NCT03317886 . Registered on 23 October 2017. University Hospital Medical Information Network Clinical Trials Registry, UMIN000029615 . Registered on 15 January 2018.

Pancreatic hamartoma is an extremely rare benign disease of the pancreas. Only 30 cases have been reported to date. A 68-year-old man presented with an asymptomatic solid and multi-cystic lesion in the uncus of the pancreas, incidentally detected on abdominal enhanced computed tomography. The tumor was found to be a well-demarcated solid and multi-cystic lesion without any enhancement, measuring 4 cm in diameter. After 28 months of follow-up, the tumor enlarged. At 31 months after initial diagnosis, the patient underwent surgical resection because it was difficult to clinically determine whether the tumor was malignant or not. Macroscopically, the solid tumor consisted of yellow adipose tissue with a smooth thin capsule confined to the pancreatic uncus. The inner structure of the tumor consisted of multiple cysts with a white nodule between the cysts. Histologically, the solid part and the multi-cystic portion consisted of mature adipose tissue and colonization of dilated pancreatic ducts with mild fibrosis, respectively. Immunohistochemical findings revealed cytokeratin 7 and 19 positive staining in the epithelial cells of the ducts. Adipose tissue showed positive staining for S-100 protein and there were only a few MIB-1 positive cells. The tumor was then diagnosed as a pancreatic hamartoma. Beside on the above findings, we suggest that the term “well-demarcated solid and cystic lesion with chronological morphological changes” could be a clinical keyword to describe pancreatic hamartomas.

Background: Solid pseudopapillary neoplasm (SPN) is a rare pancreatic tumor that predominantly affects young females. Prognosis is excellent; however, 10–15% of patients show metastasis at the time of surgery or develop tumor recurrence after pancreatectomy. Case presentation: We reviewed the clinical course of three patients with advanced or recurrent SPN and subsequently underwent multidisciplinary treatment at our institution between 2002 and 2019. The primary tumor was resected in all three patients, and metastases were also resected if indicated. Intensive combined therapy, including re-resection, chemotherapy, ablation, arterial chemoembolization, and radiation therapy, allowed all patients to survive for a long time. The literature review showed that resection seems to be more effective than other treatments for metastatic SPN. Conclusions: Multidisciplinary treatment, including resection, may improve the prognosis of patients with SPN with recurrence or metastasis.

Previously, we established a microRNA (miRNA) expression signature in pancreatic ductal adenocarcinoma (PDAC) tissues using RNA sequencing and found significantly reduced expression of miR-204-5p. Here, we aimed to investigate the functional significance of miR-204-5p and to identify miR-204-5p target genes involved in PDAC pathogenesis. Cancer cell migration and invasion were significantly inhibited by ectopic expression of miR-204-5p in PDAC cells. Comprehensive gene expression analyses and in silico database searches revealed 25 putative targets regulated by miR-204-5p in PDAC cells. Among these target genes, high expression levels of RACGAP1, DHRS9, AP1S3, FOXC1, PRP11, RHBDL2 and MUC4 were significant predictors of a poor prognosis of patients with PDAC. In this study, we focused on RACGAP1 (Rac guanosine triphosphatase-activating protein 1) because its expression was most significantly predictive of PDAC pathogenesis (overall survival rate: p = 0.0000548; disease-free survival rate: p = 0.0014). Overexpression of RACGAP1 was detected in PDAC clinical specimens, and its expression enhanced the migration and invasion of PDAC cells. Moreover, downstream genes affected by RACGAP1 (e.g., MMP28, CEP55, CDK1, ANLN and S100A14) are involved in PDAC pathogenesis. Our strategy to identify antitumor miRNAs and their target genes will help elucidate the molecular pathogenesis of PDAC.