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Abstract Background Surgical resection is standard treatment for invasive intraductal papillary mucinous carcinoma (IPMC); however, impact of multidisciplinary treatment on survival including postoperative adjuvant therapy (AT), neoadjuvant therapy (NAT), and treatment for recurrent lesions is unclear. We investigated the effectiveness of multidisciplinary treatment in prolonging survival of patients with invasive IPMC. Methods This retrospective multi‐institutional study included 1183 patients with invasive IPMC undergoing surgery at 40 academic institutions. We analyzed the effects of AT, NAT, and treatment for recurrence on survival of patients with invasive IPMC. Results Completion of the planned postoperative AT for 6 months improved the overall survival (OS), disease‐specific survival (DSS), and recurrence‐free survival (RFS) of patients with stage IIB and stage III resected invasive IPMC, elevated preoperative carbohydrate antigen 19–9 level, lymphovascular invasion, perineural invasion, serosal invasion, and lymph node metastasis on un‐matched and matched analyses. Of the patients with borderline resectable (BR) invasive IPMC, the OS (p = 0.001), DSS (p = 0.001), and RFS (p = 0.001) of patients undergoing NAT was longer than that of those without on the matched analysis. Of the 484 invasive IPMC patients (40.9%) who developed recurrence after surgery, the OS of 365 patients who received any treatment for recurrence was longer than that of those without treatment (40.6 vs. 22.4 months, p

Abstract Background Locoregional recurrence and metastasis to the liver, peritoneum, and lung are the most common recurrent patterns of pancreatic ductal adenocarcinoma (PDAC) after radical resection. Recurrence in the abdominal wall is extremely rare. Herein, we report our experience with a patient who had recurrent PDAC in the abdominal wall with long-term survival by means of multidisciplinary therapy. Case presentation A 76-year-old Japanese woman was diagnosed with resectable pancreatic tail cancer. She underwent distal pancreatectomy with regional lymphadenectomy after two cycles of gemcitabine plus S-1 as neoadjuvant therapy. She also received eight cycles of S-1 as adjuvant chemotherapy. Approximately 14 months after the initial surgery, imaging examinations identified a mass suggesting recurrence in the abdominal wall at the middle wound that involved the transverse colon. After two cycles of gemcitabine plus nab-paclitaxel, chemoradiotherapy (S-1 plus 45 Gy) and seven cycles of modified FOLFIRINOX (5-fluorouracil/leucovorin, irinotecan, and oxaliplatin) were administered. The patient did not develop any new recurrent lesions during chemotherapy and chemoradiotherapy. Therefore, the recurrent lesion in the abdominal wall and the involved transverse colon were resected. We confirmed the lack of peritoneal dissemination during surgery. Pathological examination revealed that the resected lesion was metastasis of primary PDAC, and the surgical margin was 1 mm. However, re-recurrence localized in the abdominal wall was detected 9 months later. The re-recurrent lesion was diagnosed as local recurrence of the first recurrent lesion. We performed a second resection of the abdominal wall using a femoral myocutaneous flap to achieve sufficient surgical margin. The pathological findings of the resected specimen were the same as those of the previous specimens, and the resection margin was negative. The patient’s postoperative course was uneventful. Seven years after the initial surgery and 3 years and 7 months after the third surgery, the patient is alive with no signs of recurrence. Conclusions Long-term survival could be achieved by radical resection with sufficient surgical margins for recurrence of PDAC in the abdominal wall if new other recurrent lesions, including peritoneal dissemination, are prevented through chemotherapy.

Abstract 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.

Abstract Background Hepatocellular carcinoma (HCC) patients with metastases to the cervical lymph nodes are extremely rare, and its clinical course is characterized by rapidly progressive disease. Hence, there have been no reports of metastatic cervical lymph node recurrence indicated after a long postoperative surveillance period. Case presentation The patient was a 63-year-old male who underwent right hepatectomy for HCC of the right upper lobe. Three years after resection, metastatic lymph node recurrence was detected in the subdiaphragm, superior mediastinum, and right cervical lymph nodes. The patient underwent excisional biopsy of the cervical lymph node, followed by molecular-targeted therapy and radiation therapy. Lenvatinib reduced the size of all metastatic lymph nodes and the patient survived for a relatively long period of 43 months after the recurrence was detected. Conclusions After resection of HCC in the right upper lobe, there is the possibility of metastatic lymph node recurrence in unusual sites, including the cervical region, and lenvatinib may be effective in those recurrences.

Abstract Background Cholangiolocellular carcinoma (CoCC) is an extremely rare disease comprising less than 1% of all primary malignant liver tumors. No effective treatment other than resection has been established. Herein, we report a case of locally advanced CoCC diagnosed as unresectable, which was successfully treated with curative resection after downsizing chemotherapy. Case presentation A 59-year-old Japanese woman with chronic hepatitis B was diagnosed with locally advanced intrahepatic cholangiocellular carcinoma. As it was difficult to perform R0 resection in the local hospital, chemotherapy combined with gemcitabine plus cisplatin was administered every 3 weeks. After a total of 10 courses of chemotherapy over 10 months the tumor was shown to be reduced in size by computed tomography imaging, and she was referred to our department for surgical resection. The effect of chemotherapy was classified as a “partial response” in the response evaluation criteria of solid tumors. After adding one course of chemotherapy, an extended left hepatectomy with resection of the caudate lobe was performed. R0 resection was achieved. Based on the pathological findings, the final diagnosis of CoCC was determined and eight courses of S-1 adjuvant chemotherapy were administered. At 14 months after the operation, the patient was alive without tumor recurrence. Conclusions Downsizing chemotherapy with gemcitabine and cisplatin may be an effective treatment strategy in locally advanced CoCC. Further evidence is required to establish an optimal strategy for the treatment of locally advanced CoCC.

Abstract Background Mesenteric cysts have various histological forms, including mesenteric cystadenomas and borderline cystic neoplasms. Primary cystadenocarcinoma of the mesentery is extremely rare; therefore, the clinical and radiological features of this tumor have not been fully elucidated. Case presentation A 50-year-old Japanese woman had a complaint of a left-sided abdominal distention. Enhanced computed tomography and magnetic resonance imaging revealed a unilocular cystic lesion measuring approximately 10 cm located in the left side of the abdomen. 18F-fluorodeoxyglucose (FDG)-positron emission tomography/computed tomography (PET/CT) revealed mottled mild FDG uptake in the cyst wall and intense FDG uptake in several mural nodules. The cystic mass with the descending colon was completely removed. Pathological examination of the specimens revealed various histologic patterns of adenocarcinoma, including mucin production in the mural nodules. We eventually diagnosed a primary cystadenocarcinoma arising from the mesentery of the descending colon. Conclusions Malignancy should be suspected in mesenteric or retroperitoneal cystic tumors with high FDG uptake, and complete resection should be performed with adequate margins.

Aberrantly expressed microRNA (miRNA) are known to disrupt intracellular RNA networks in cancer cells. Exploring miRNA‐dependent molecular networks is a major challenge in cancer research. In this study, we performed RNA‐sequencing of breast cancer (BrCa) clinical specimens to identify tumor‐suppressive miRNA in BrCa. In total, 64 miRNA were identified as candidate tumor‐suppressive miRNA in BrCa cells. Analysis of our BrCa signature revealed that several miRNA duplexes (guide strand/passenger strand) derived from pre‐miRNA were downregulated in BrCa tissues (e.g. miR‐99a‐5p/‐3p, miR‐101‐5p/‐3p, miR‐126‐5p/‐3p, miR‐143‐5p/‐3p, and miR‐144‐5p/‐3p). Among these miRNA, we focused on miR‐101‐5p, the passenger strand of pre‐miR‐101, and investigated its tumor‐suppressive roles and oncogenic targets in BrCa cells. Low expression of miR‐101‐5p predicted poor prognosis in patients with BrCa (overall survival rate: P = 0.0316). Ectopic expression of miR‐101‐5p attenuated aggressive phenotypes, e.g. proliferation, migration, and invasion, in BrCa cells. Finally, we identified seven putative oncogenic genes (i.e. High Mobility Group Box 3, Epithelial splicing regulatory protein 1, GINS complex subunit 1 (GINS1), Tumor Protein D52, Serine/Arginine‐Rich Splicing Factor Kinase 1, Vang‐like protein 1, and Mago Homolog B) regulated by miR‐101‐5p in BrCa cells. The expression of these target genes was associated with the molecular pathogenesis of BrCa. Furthermore, we explored the oncogenic roles of GINS1, whose function had not been previously elucidated, in BrCa cells. Aberrant expression of GINS1 mRNA and protein was observed in BrCa clinical specimens, and high GINS1 expression significantly predicted poor prognosis in patients with BrCa (overall survival rate: P = 0.0126). Knockdown of GINS1 inhibited the malignant features of BrCa cells. Thus, identification of tumor‐suppressive miRNA and molecular networks controlled by these miRNA in BrCa cells may be an effective strategy for elucidation of the molecular pathogenesis of this disease.

We recently determined the RNA sequencing-based microRNA (miRNA) expression signature of colorectal cancer (CRC). Analysis of the signature showed that the expression of both strands of pre-miR-139 (miR-139-5p, the guide strand, and miR-139-3p, the passenger strand) was significantly reduced in CRC tissues. Transient transfection assays revealed that expression of miR-139-3p blocked cancer cell malignant transformation (e.g., cell proliferation, migration, and invasion). Notably, expression of miR-139-3p markedly blocked RAC-alpha serine/threonine-protein kinase (AKT) phosphorylation in CRC cells. A combination of in silico database and gene expression analyses of miR-139-3p-transfected cells revealed 29 putative targets regulated by miR-139-3p in CRC cells. RNA immunoprecipitation analysis using an Argonaute2 (AGO2) antibody revealed that KRT80 was efficiently incorporated into the RNA-induced silencing complex. Aberrant expression of Keratin 80 (KRT80) was detected in CRC clinical specimens by immunostaining. A knockdown assay using small interfering RNA (siRNA) targeting KRT80 showed that reducing KRT80 expression suppressed the malignant transformation (cancer cell migration and invasion) of CRC cells. Importantly, inhibiting KRT80 expression reduced AKT phosphorylation in CRC cells. Moreover, hexokinase-2 (HK2) expression was reduced in cells transfected with the KRT80 siRNAs or miR-139-3p. The involvement of miRNA passenger strands (e.g., miR-139-3p) in CRC cells is a new concept in miRNA studies. Our tumor-suppressive miRNA-based approach helps elucidate the molecular pathogenesis of CRC.

Lymphoepithelioma-like carcinoma (LELC) of the liver is extremely rare, and lymphoepithelioma-like hepatocellular carcinoma (LEL-HCC) is an uncommon variant form of HCC, exhibiting relatively good prognosis compared to conventional HCC. LELC is defined as a tumour composed of undifferentiated epithelial cells with densely infiltrating lymphoid stroma. LEL-HCC represents a unique immune response against tumour cells, which may contribute to the superior clinical outcomes. However, the exact aetiology remains unknown. We report a case of a 76-year-old man with a prior hepatitis B virus infection. A 20 mm tumour was detected in the liver. Microscopically, the tumour displayed characteristics of poorly differentiated HCC with a dense lymphocytic and plasma cell infiltration and was diagnosed as LEL-HCC. We describe a unique pathological finding with immunohistochemical data demonstrating T-cell dominant lymphocytic and polyclonal plasma cell infiltration, along with programmed death ligand 1 expression in the tumour cells and lymphocytes.

To elucidate novel aspects of the molecular pathogenesis of colorectal cancer (CRC), we have created a new microRNA (miRNA) expression signature based on RNA-sequencing. Analysis of the signature showed that 84 miRNAs were upregulated, and 70 were downregulated in CRC tissues. Interestingly, our signature indicated that both guide and passenger strands of some miRNAs were significantly dysregulated in CRC tissues. These findings support our earlier data demonstrating the involvement of miRNA passenger strands in cancer pathogenesis. Our study focused on downregulated miR-490-3p and investigated its tumor-suppressive function in CRC cells. We successfully identified a total of 38 putative oncogenic targets regulated by miR-490-3p in CRC cells. Among these targets, the expression of three genes (IRAK1: p = 0.0427, FUT1: p = 0.0468, and GPRIN2: p = 0.0080) significantly predicted 5-year overall survival of CRC patients. Moreover, we analyzed the direct regulation of IRAK1 by miR-490-3p, and its resultant oncogenic function in CRC cells. Thus, we have clarified a part of the molecular pathway of CRC based on the action of tumor-suppressive miR-490-3p. This new miRNA expression signature of CRC will be a useful tool for elucidating new molecular pathogenesis in this disease.

Our recent studies have implicated some passenger strands of miRNAs in the molecular pathogenesis of human cancers. Analysis of the microRNA (miRNA) expression signature in pancreatic ductal adenocarcinoma (PDAC) has shown that levels of miR-30a-3p, the passenger strand derived from pre-mir-30a, are significantly downregulated in PDAC tissues. This study aimed to identify the oncogenes closely involved in PDAC molecular pathogenesis under the regulation of miR-30a-3p. Ectopic expression assays showed that miR-30a-3p expression inhibited the aggressiveness of the PDAC cells, suggesting that miR-30a-3p acts as a tumor-suppressive miRNA in PDAC cells. We further identified 102 putative targets of miR-30a-3p regulation in PDAC cells by combining in silico analysis with gene expression data. Of these, ten genes (EPS8, HMGA2, ENDOD1, SLC39A10, TGM2, MGLL, SERPINE1, ITGA2, DTL, and UACA) were independent prognostic factors in multivariate analysis of survival of patients with PDAC (p < 0.01). We also investigated the oncogenic function of the integrin ITGA2 in PDAC cell lines. The integrin family comprises cell adhesion molecules expressed as heterodimeric, transmembrane proteins on the surface of various cells. Overexpression of ITGA2/ITGB1 (an ITGA2 binding partner) was detected in the PDAC clinical specimens. The knockdown of ITGA2 expression attenuated the malignant phenotypes of the PDAC cells. Together, results from these microRNA-based approaches can accelerate our understanding of PDAC molecular pathogenesis.

Laparoscopic distal pancreatectomy (LDP) is the standard surgery for malignant and premalignant tumors of the pancreatic body and tail. A stapler is commonly used to close the pancreatic stump due to its simplicity; however, the use of a stapler is associated with the risk of metal allergy and postoperative pancreatic fistula, especially in thick pancreases. Here, we present a case of LDP without metal instruments, including staplers and clips, in a 54-yearold woman with a metal allergy and a thick pancreas. The pancreatic stump was closed using the transpancreatic mattress suture method with a polyglycolic acid sheet (PGA) and fibrin glue. The postoperative course was uneventful. Metal-free LDP is useful and can be adopted regardless of the patient's background, such as a metal allergy or pancreatic thickness. [ABSTRACT FROM AUTHOR]