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Background: The aim of this study was to determine the optimal treatment for patients with pancreatic cancer (PaCa) having positive peritoneal cytology (PPC)., Methods: This multicenter retrospective study included patients with PPC treated at 78 high-volume centers between January 2012 and December 2020. Prognoses after resection (S-group) and initiation of nonsurgical treatment (N-group) were compared. Prognostic factors for survival in both groups were analyzed. Detailed characteristics of conversion surgery (CS) in the N-group were evaluated., Results: In total, 568 enrolled patients were classified into an S-group (n = 445) or an N-group (n = 123). Median survival times (MSTs) were 19.0 months and 19.3 months, respectively, with no significant difference in prognosis (p = .845). The intervenable prognostic factors for survival were adjuvant treatment in the S-group (p < .001) and CS in the N-group (p < .001). Following CS, the MST was prolonged to 45.6 months, and peritoneal or liver recurrence decreased considerably. CS can be expected if PPC is diagnosed before neoadjuvant treatment and when combination treatment is initiated., Conclusion: Surgical resection may not be beneficial for improving survival when PPC is evident. Chemotherapy aiming for CS may be the optimal treatment for such patients., (© 2024 The Author(s). Journal of Hepato‐Biliary‐Pancreatic Sciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Hepato‐Biliary‐Pancreatic Surgery.)

We present the case of a 54-year-old woman who was diagnosed with intraductal papillary neoplasm of the bile duct (IPNB) in the remnant intrapancreatic bile duct, 37 years after surgery for congenital biliary dilatation. Endoscopic ultrasonography revealed a papillary, low-echoic mass in the intrapancreatic bile duct, and peroral cholangioscopy revealed a papillary mucosa. A pancreaticoduodenectomy was performed, and the patient was pathologically diagnosed with type 1 pancreatobiliary-type IPNB with associated invasive carcinoma. As a similar atypical epithelium was identified in the pancreatic duct, it was suggested that the IPNB extended longitudinally to the pancreatic duct through the common channel.

Our previous studies revealed a novel link between gemcitabine (GEM) chemotherapy and elevated glutamine-fructose-6-phosphate transaminase 2 (GFPT2) expression in pancreatic cancer (PaCa) cells. GFPT2 is a rate-limiting enzyme in the hexosamine biosynthesis pathway (HBP). HBP can enhance metastatic potential by regulating epithelial-mesenchymal transition (EMT). The aim of this study was to further evaluate the effect of chemotherapy-induced GFPT2 expression on metastatic potential. GFPT2 expression was evaluated in a mouse xenograft model following GEM exposure and in clinical specimens of patients after chemotherapy using immunohistochemical analysis. The roles of GFPT2 in HBP activation, downstream pathways, and cellular functions in PaCa cells with regulated GFPT2 expression were investigated. GEM exposure increased GFPT2 expression in tumors resected from a mouse xenograft model and in patients treated with neoadjuvant chemotherapy (NAC). GFPT2 expression was correlated with post-operative liver metastasis after NAC. Its expression activated the HBP, promoting migration and invasion. Treatment with HBP inhibitors reversed these effects. Additionally, GFPT2 upregulated ZEB1 and vimentin expression and downregulated E-cadherin expression. GEM induction upregulated GFPT2 expression. Elevated GFPT2 levels promoted invasion by activating the HBP, suggesting the potential role of this mechanism in promoting chemotherapy-induced metastasis., (© 2024. The Author(s).)

Peritoneal washing cytology (CY) in patients with pancreatic cancer is mainly used for staging; however, it may also be used to evaluate the intraperitoneal status to predict a more accurate prognosis. Here, we investigated the potential of deep learning of CY specimen images for predicting the 1-year prognosis of pancreatic cancer in CY-positive patients. CY specimens from 88 patients with prognostic information were retrospectively analyzed. CY specimens scanned by the whole slide imaging device were segmented and subjected to deep learning with a Vision Transformer (ViT) and a Convolutional Neural Network (CNN). The results indicated that ViT and CNN predicted the 1-year prognosis from scanned images with accuracies of 0.8056 and 0.8009 in the area under the curve of the receiver operating characteristic curves, respectively. Patients predicted to survive 1 year or more by ViT showed significantly longer survivals by Kaplan-Meier analyses. The cell nuclei found to have a negative prognostic impact by ViT appeared to be neutrophils. Our results indicate that AI-mediated analysis of CY specimens can successfully predict the 1-year prognosis of patients with pancreatic cancer positive for CY. Intraperitoneal neutrophils may be a novel prognostic marker and therapeutic target for CY-positive patients with pancreatic cancer., (© 2024. The Author(s).)

Purpose: The intensity of adjuvant treatment for pancreatic ductal adenocarcinomas (PDACs) has not been stratified according to the risk after resection. This study was designed to identify patients with PDACs in whom the current S-1 adjuvant treatment is ineffective., Methods: This single-center, retrospective study included patients who underwent pancreatectomy for PDACs from 2009 to 2020 at Sendai Open Hospital and were receiving S-1 adjuvant treatment. The independent risk factors for recurrence and survival were determined by using a Cox proportional hazards regression model. The effects of S-1 adjuvant treatment and detailed patterns of recurrence were evaluated in patients with high-risk factors., Results: Overall, 118 patients with PDAC received S-1 adjuvant treatment. Postoperative nonnormalized carbohydrate antigen (CA19-9) was a predictive risk factor for recurrence (p < 0.010; hazard ratio [HR], 3.87; 95% confidence interval [CI], 2.26-6.62) and survival (p = 0.008; HR, 2.25; 95% CI, 1.24-4.11) after S-1 adjuvant treatment. In 24 patients with nonnormalized postoperative CA19-9, S-1 monotherapy was ineffective in preventing recurrence, even during the treatment period, compared with that noted in patients who did not receive adjuvant treatment. The recurrence rate during adjuvant treatment was 41.7%; in all cases, recurrence was caused by distant metastasis. The total recurrence rate was up to 95.8%, and distant recurrence was especially frequent., Conclusions: The current S-1 adjuvant treatment regimen is ineffective for patients with postoperative nonnormalized CA19-9. The postoperative CA19-9 level may be a good indicator for further aggressive treatment. This study may lead to further discussions on intensity stratification of adjuvant treatments for PDAC., (© 2023. Society of Surgical Oncology.)

Background: Loss of expression of the gene ataxia-telangiectasia mutated (ATM), occurring in patients with multiple primary malignancies, including pancreatic cancer, is associated with poor prognosis. In this study, we investigated the detailed molecular mechanism through which ATM expression affects the prognosis of patients with pancreatic cancer., Methods: The levels of expression of ATM and phosphorylated ATM in patients with pancreatic cancer who had undergone surgical resection were analyzed using immunohistochemistry staining. RNA sequencing was performed on ATM-knockdown pancreatic-cancer cells to elucidate the mechanism underlying the invlovement of ATM in pancreatic cancer., Results: Immunohistochemical analysis showed that 15.3% and 27.8% of clinical samples had low levels of ATM and phosphorylated ATM, respectively. Low expression of phosphorylated ATM substantially reduced overall and disease-free survival in patients with pancreatic cancer. In the pancreatic cancer cell lines with ATM low expression, resistance to gemcitabine was demonstrated. The RNA sequence demonstrated that ATM knockdown induced the expression of MET and NTN1. In ATM knockdown cells, it was also revealed that the protein expression levels of HIF-1α and antiapoptotic BCL-2/BAD were upregulated., Conclusions: These findings demonstrate that loss of ATM expression increases tumor development, suppresses apoptosis, and reduces gemcitabine sensitivity. Additionally, loss of phosphorylated ATM is associated with a poor prognosis in patients with pancreatic cancer. Thus, phosphorylated ATM could be a possible target for pancreatic cancer treatment as well as a molecular marker to track patient prognosis., (© 2023. BioMed Central Ltd., part of Springer Nature.)

The symposium "New criteria of resectability for pancreatic cancer" was held during the 33nd meeting of the Japanese Society of Hepato-Biliary-Pancreatic Surgery (JSHBPS) in 2021 to discuss the potential modifications that could be made in the current resectability classification. The meeting focused on setting the foundation for developing a new prognosis-based resectability classification that is based on the tumor biology and the response to neoadjuvant treatment (NAT). The symposium included selected experts from Western and Eastern high-volume centers who have discussed their concept of resectability status through published literature. During the symposium, presenters reported new resectability classifications from their respective institutions based on tumor biology, conditional status, pathology, and genetics, in addition to anatomical tumor involvement. Interestingly, experts from all the centers reached the agreement that anatomy alone is insufficient to define resectability in the current era of effective NAT. On behalf of the JSHBPS, we would like to summarize the content of the conference in this position paper. We also invite global experts as internal reviewers of this paper for intercontinental cooperation in creating an up-to-date, prognosis-based resectability classification that reflects the trends of contemporary clinical practice., (© 2021 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Background: The significance of surgical resection in pancreatic ductal adenocarcinoma (PDAC) with positive peritoneal cytology (PPC) is controversial. This study aimed to evaluate whether preceding chemotherapy could be beneficial for patients with PDAC with PPC., Methods: Between 2017 and 2019, 34 consecutive PDAC patients diagnosed with PPC without distant metastasis were retrospectively reviewed. Twenty-three patients did not receive neoadjuvant treatment (NAT) and 11 received NAT. All patients received systemic chemotherapy after PPC was confirmed, and they underwent surgical resection if PPC turned negative. The treatment course, ratio of conversion surgery (CS), and prognosis were evaluated. Moreover, the prognosis of PPC patients who underwent up-front surgery without NAT between 2003 and 2016 was analyzed as a comparative cohort., Results: The median survival time (MST) of the patients without NAT was 31.4 months. CS was performed in 52.2% of the patients. Patients who underwent CS had better prognoses than those who did not undergo CS (p = 0.005). The CS rate was significantly higher in resectable PDAC (78.5%) than in borderline/unresectable PDAC (11.1%) (p = 0.002). The prognosis of patients with resectable PDAC was improved with preceding chemotherapy compared with up-front surgery (MST 13.0 months; p = 0.016). After NAT, the CS rate was low (27.3%), and the MST was only 14.1 months., Conclusions: As an initial treatment for PDAC patients with PPC, chemotherapy may lead to a favorable prognosis. Especially, resectable PDAC is associated with a greater chance of improved prognosis. Future studies are required to ascertain whether up-front surgery or preceding chemotherapy should be performed for these patients., (© 2021. Society of Surgical Oncology.)

The small GTPases RalA and RalB are members of the Ras family and activated downstream of Ras. Ral proteins are found in GTP-bound active and GDP-bound inactive forms. The activation process is executed by guanine nucleotide exchange factors, while inactivation is mediated by GTPase-activating proteins (GAPs). RalGAPs are complexes that consist of a catalytic α1 or α2 subunit together with a common β subunit. Several reports implicate the importance of Ral in pancreatic ductal adenocarcinoma (PDAC). However, there are few reports on the relationship between levels of RalGAP expression and malignancy in PDAC. We generated RalGAPβ-deficient PDAC cells by CRISPR-Cas9 genome editing to investigate how increased Ral activity affects malignant phenotypes of PDAC cells. RalGAPβ-deficient PDAC cells exhibited several-fold higher Ral activity relative to control cells. They had a high migratory and invasive capacity. The RalGAPβ-deficient cells grew more rapidly than control cells when injected subcutaneously into nude mice. When injected into the spleen, the RalGAPβ-deficient cells formed larger splenic tumors with more liver metastases, and unlike controls, they disseminated into the abdominal cavity. These results indicate that RalGAPβ deficiency in PDAC cells contributes to high activities of RalA and RalB, leading to enhanced cell migration and invasion in vitro, and tumor growth and metastasis in vivo., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Probiotics have been reported to be beneficial for the prevention of postoperative complications and are often used during the perioperative period. Among the probiotic-related adverse events, bacteremia is rare. Here, we report two cases of probiotic-related bacteremia after major hepatectomy for biliary cancer. CASE PRESENTATION 1: A 74-year-old man was referred to our hospital to be treated for gallbladder cancer. Neoadjuvant chemotherapy, two courses of gemcitabine plus S-1 combination therapy, was administered. Extended right hepatectomy with caudate lobectomy, extrahepatic bile duct resection and biliary reconstruction were performed 3 weeks after chemotherapy. Probiotics, Clostridium butyricum (C. butyricum) MIYAIRI 588, were administered 6 days before surgery and continued after surgery. Sepsis of unknown origin occurred 17 days after surgery and developed into septic shock. C. butyricum was detected in blood cultures at postoperative day 26 and 45. After stopping the probiotic agent, C. butyricum was undetectable in the blood cultures. The patient died due to an uncontrollable sepsis 66 days after surgery. CASE PRESENTATION 2: A 63-year-old man with diabetes mellitus whose past history included total colectomy, papillectomy, and Frey's operation at the age of 19, 34 and 48, respectively, was referred to our hospital to be treated for perihilar cholangiocarcinoma. Extended left hepatectomy with caudate lobectomy, extrahepatic bile duct resection and reconstruction of bile duct were performed. Probiotics were administered during the perioperative period. Combined probiotics that included lactomin, amylolytic bacillus and C. butyricum, were given before surgery. C. butyricum MIYAIRI 588 was given after surgery. Sepsis occurred 16 days after surgery and developed to respiratory failure 8 days later. Blood culture at postoperative day 25 revealed Enterococcus faecalis and C. butyricum. After the probiotics were stopped at postoperative day 27, C. butyricum was not detected in the blood culture. The general condition improved with intensive care. The patient was transferred to another hospital for rehabilitation at postoperative day 156., Conclusion: It should be noted that the administration of probiotics in severe postoperative complications can lead to probiotic-related bacteremia.

Stomatin‑like protein 2 (SLP‑2) is associated with poor prognosis in several types of cancer, including pancreatic cancer (PC); however, the molecular mechanism of its involvement remains elusive. The present study aimed to elucidate the role of this protein in the development of PC. Human PC cell lines AsPC‑1 and PANC‑1 were transfected by a vector expressing SLP‑2 shRNA. Analyses of cell proliferation, migration, invasion, chemosensitivity, and glucose uptake were conducted, while a mouse xenograft model was used to evaluate the functional role of SLP‑2 in PC. Immunohistochemical analysis was retrospectively performed on human tissue samples to compare expression between the primary site (n=279) and the liver metastatic site (n=22). Furthermore, microarray analysis was conducted to identify the genes correlated with SLP‑2. In vitro analysis demonstrated that cells in which SLP‑2 was suppressed exhibited reduced cell motility and glucose uptake, while in vivo analysis revealed a marked decrease in the number of liver metastases. Immunohistochemistry revealed that SLP‑2 was increased in liver metastatic sites. Microarray analysis indicated that this protein regulated the expression of glutamine‑fructose‑6‑phosphate transaminase 2 (GFPT2), a rate‑limiting enzyme of the hexosamine biosynthesis pathway. SLP‑2 contributed to the malignant character of PC by inducing liver metastasis. Cell motility and glucose uptake may be induced via the hexosamine biosynthesis pathway through the expression of GFPT2. The present study revealed a new mechanism of liver metastasis and indicated that SLP‑2 and its downstream pathway could provide novel therapeutic targets for PC.

Background: The epithelial-mesenchymal transition (EMT) in cancer cells has been shown to closely associate with the survival and drug resistance of cancer cells. We recently provided evidence that Wnt signal activator leucine-rich repeat in flightless-1-interacting protein 1 (LRRFIP1) regulates EMT in pancreatic cancer. LRRFIP1 silencing inhibits the translocation of β-catenin to the nucleus, which led to reverse EMT in cancer cells. It was suggested that LRRFIP1 was implicated in gemcitabine sensitivity by regulating EMT signaling., Methods: Gemcitabine chemosensitivity was investigated in LRRFIP1-knockdown pancreatic cancer cells (PANC-1 and MIA Paca-2). In addition, the effects of LRRFIP1 knockdown on JNK/SAPK (stress activated-protein kinase) signaling and apoptosis were evaluated., Results: LRRFIP1 silencing accelerates gemcitabine-induced caspase activity and cell death in pancreatic cancer cells. It was also revealed that gemcitabine-induced phosphorylation of c-Jun N-terminal kinase (JNK) and c-Jun were increased in LRRFIP1 knockdown cells. The activation of JNK/c-Jun in LRRFIP1-knockdown cells was significantly diminished by the inhibition of Rac activity. It was confirmed that the acquisition of gemcitabine sensitivity by LRRFIP1 silencing largely depends on the stimulation of JNK/SAPK (stress activated-protein kinase) signaling., Conclusions: Our findings suggest that reversing EMT and transient activation of JNK might be essential for the gemcitabine sensitivity in LRRFIP1 knockdown pancreatic cancer cells. Our discoveries highlight the potential role of LRRFIP1 in the chemosensitivity related to the regulation of EMT signaling., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest with the contents of this article. To analyze the activation of JNK and c-Jun in LRRFIP1-knockdown PANC-1 cells, the expression of phosphorylated JNK and c-Jun was examined. (A) LRRFIP1-knockdown PANC-1 cells and control cells were treated with gemcitabine at the concentration of 1000 μM. Total protein was extracted and western blotting was performed. GAPDH was taken as the loading control. To quantify the phosphorylated JNK and c-Jun, the image data was scanned and analyzed using ImageJ software (National Institutes of Health, USA). The ratio of the phosphorylated JNK (B) and c-Jun (C) in gemcitabine treated cells to that in untreated cells were shown in the bar diagrams., (Copyright © 2021 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Purpose: Staging laparoscopy is considered useful for determining treatment plans for advanced pancreatic cancer. However, the indications for staging laparoscopy are not clear. This study aimed to evaluate the safety of staging laparoscopy and its usefulness for detecting distant metastases in patients with pancreatic cancer., Methods: A total of 146 patients with pancreatic cancer who underwent staging laparoscopy between 2013 and 2019 were analyzed. Staging laparoscopy was performed in all pancreatic cancer patients in whom surgery was considered possible., Results: In this cohort, 42 patients (29%) were diagnosed with malignant cells on peritoneal lavage cytology, 9 (6%) had peritoneal dissemination, and 11 (8%) had liver metastases. A total of 48 (33%) had radiologically negative metastases. On a multivariate analysis, body and tail cancer [odds ratio (OR) 5.00, 95% confidence interval (CI) 2.15-11.6, p < 0.001], high CA19-9 level [OR 4.04, 95% CI 1.74-9.38, p = 0.001], and a resectability status of unresectable (OR 2.31, 95% CI 1.03-5.20, p = 0.04) were independent risk factors for radiologically negative metastases., Conclusions: Staging laparoscopy can be safely performed and is useful for the diagnosis of radiologically negative metastases. Staging laparoscopy should be routinely performed for the accurate diagnosis of pancreatic cancer patients before pancreatectomy and/or local treatment, such as radiotherapy.

Background: The prognostic values of inflammation-based markers in well-differentiated pancreatic neuroendocrine neoplasms, diagnosed according to the new 2017 World Health Organization classification, have remained unclear. Therefore, we assessed the ability to predict the recurrence of such markers after curative resection in patients with these neoplasms., Methods: Circulating/systemic neutrophil-lymphocyte, monocyte-lymphocyte, platelet-lymphocyte, and platelet-white cell ratios were evaluated in 120 patients who underwent curative resection for well-differentiated pancreatic neuroendocrine neoplasms without synchronous distant metastasis between 2001 and 2018. Recurrence-free-survival and overall survival were compared using Kaplan-Meier analysis and log-rank tests. Univariate or multivariate analyses, using a Cox proportional hazards model, were used to calculate hazard ratios with 95% confidence intervals., Results: Univariate analysis demonstrated that preoperative neutrophil-lymphocyte ratio, tumor size, European Neuroendocrine Tumor Society TMN classification, 2017 World Health Organization classification, and venous invasion were associated with recurrence. The optimal preoperative neutrophil-lymphocyte ratio cut-off value was 2.62, based on receiver operating characteristic curve analysis. In multivariate analysis, a higher preoperative neutrophil-lymphocyte ratio (HR = 3.49 95% CI 1.05-11.7; P = 0.042) and 2017 World Health Organization classification (HR = 8.81, 95% CI 1.46-168.2; P = 0.015) were independent recurrence predictors., Conclusions: The circulating/systemic neutrophil-lymphocyte ratio is a useful and convenient preoperative prognostic marker of recurrence in patients with well-differentiated pancreatic neuroendocrine neoplasm based on the 2017 World Health Organization classification.

The collagen gel droplet-embedded drug sensitivity test (CD-DST) was revealed to be useful for predicting the effect of S-1 adjuvant chemotherapy for pancreatic ductal adenocarcinoma (PDAC). However, collection of an adequate number of PDAC cells is difficult due to the surrounding fibroblasts. Thus, the aim of this study was to discover novel biomarkers to predict chemosensitivity based on the CD-DST results. Proteomics analysis was performed using liquid chromatography tandem mass spectrometry (LC-MS/MS). Candidate proteins were validated in patients with 5-FU CD-DST results via immunohistochemistry (IHC). The relationships between the candidate proteins and the effect of the adjuvant S-1 were investigated via IHC. Among the 2696 proteins extracted by LC-MS/MS, C1TC and SAHH could accurately predict the CD-DST results. Recurrence-free survival (RFS) was significantly improved in the IHC-positive group compared with the IHC-negative group in both factors. The negative group did not show a significant difference from the group that did not receive S-1. The double-positive group was associated with significantly prolonged RFS compared to the no adjuvant chemotherapy group. C1TC and SAHH have been shown to be useful biomarkers for predicting 5-FU sensitivity as a substitute for the CD-DST in adjuvant chemotherapy for PDAC.

Objectives: Metabolic tumor volume (MTV) on 18 F-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) is a promising prognostic predictor in pancreatic ductal adenocarcinoma (PDAC). However, the optimal segmentation method and threshold value to determine MTV for PDAC are still unclear. We explored the optimal method and threshold value for the prognostic value of MTV measured on pre-treatment 18 F-FDG-PET/CT., Methods: Seventy-three patients with resected PDAC who underwent 18 F FDG-PET/CT before surgical resection were enrolled. MTV values of the tumor were measured on FDG-PET/CT by the two fixed-threshold methods using threshold values as 2.0, 2.5, 3.0, and 3.5 for the absolute method and 35%, 40%, 42%, 45%, and 50% for the relative method. Receiver operating characteristic curve analysis for prediction of 1-year survival rates was conducted for determining the optimal threshold values, and we selected the optimal method and threshold value considering area under the curve. The prognostic values of each FDG-PET/CT parameter for disease-specific survival and recurrence-free survival were assessed with Kaplan-Meier method and Cox proportional hazard models., Results: In receiver operating characteristic curve analysis, MTV by the fixed-absolute threshold method based on a threshold value of 3.5 (MTV3.5) performed best in our study with area under the curve 0.724, sensitivity of 65%, and specificity of 75%. In univariate and multivariate analyses, MTV3.5 was significantly associated with disease-specific and recurrence-free survival., Conclusions: MTV3.5 by absolute threshold on pre-treatment FDG-PET/CT was the best independent prognostic predictor in resectable PDAC compared with other absolute threshold values and relative threshold values., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Tatewaki, Terao, Ariake, Saito, Mutoh, Shimomura, Motoi, Mizuma, Odagiri, Unno and Taki.)

Background: Neoadjuvant therapy (NAT) is considered a potential approach to improve survival for patients with pancreatic adenocarcinoma (PA). The objective of this study was to identify the clinical implications of washing peritoneal cytology (CY) status after NAT., Methods: Between 2005 and 2016, 151 consecutive patients with resectable (R)/borderline resectable (BR) PA underwent NAT with intention of subsequent resection at our institution. Of them, 13 and 123 patients underwent pancreatectomies with positive (CY+) and negative (CY-) cytology, respectively, while the remaining 15 patients did not undergo resection due to gross metastases at laparotomy. The clinicopathological factors influencing overall survival were clarified by the uni- and multivariate analyses., Results: The postoperative overall survival (OS) and disease-free survival (DFS) were markedly worse in patients who underwent resection with CY+, compared with those who were CY- (median OS, 14.8 m vs 30.8 m, p = 0.026, and median DFS 6.0 m vs 15.1 m, p = 0.008). According to the resectability by NCCN guidelines, CY+ indicates worse prognosis than CY- in R-PA patients (mOS: 30.1 m vs 71.1 m: p = 0.080). Similarly, in BR-PA patients, CY+ showed the significantly worse prognosis than CY- (mOS: 13.8 m vs 24.5 m: p = 0.048), which prognosis is comparable with patients who did not undergo resection. The multivariate analysis revealed that resectability, CY status and the induction of adjuvant therapy were significant predictors of postoperative OS (p = 0.007: Hazard ratio 2.264, 0.040:2.094 and 0.002:3.246, respectively)., Conclusions: CY+ is a significant predictor of poorer prognosis in PA patients after NAT. The subsequent pancreatectomies with CY+ after NAT do not contribute to prolonged survival., (Copyright © 2020 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Purpose: This study aimed to elucidate the characteristics of biliary tract carcinoma (BTC) in young patients., Methods: This is a nationwide multicenter, retrospective cohort study supervised by the Japanese Society of Hepato-Biliary-Pancreatic Surgery (JSHBPS). Clinicopathological data of patients aged <50 years diagnosed with BTC from January 1997 to December 2011 were collected from 211 training institutes for highly advanced surgery registered by the JHBPS., Results: Data of 774 young patients aged <50 years were obtained from 102 institutes. Pancreaticobiliary maljunction (PBM) (10.6%) was most frequently associated with young BTC. However, organic solvents caused by printing or other occupations were only 2.5%. PBM was further associated with early onset of BTC and was noted in 38.9% of patients aged <30 years. Subgroup analysis revealed that the distributions of PBM, choledochal cysts, cholelithiasis, hepatitis B virus, and past history of cancer were significantly varied depending on the site of BTC. These results suggested that each site of BTC has a different mechanism for cancer development., Conclusion: Although the most frequent factor for young BTC patients was PBM, cancer-associated factors were dramatically different in each BTC site. These results might be useful to elucidate the etiology of young BTC patients., (© 2020 The Authors. Journal of Hepato-Biliary-Pancreatic Sciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Purpose: To evaluate the long-term outcomes of total pancreatectomy in a modern cohort of pancreatic cancer patients and to establish whether any factors identified prior to pancreatic resection were related to poor survival., Methods: We analyzed, retrospectively, patients who underwent total pancreatectomy for pancreatic cancer between 2007 and 2016. The short- and long-term outcomes were investigated and Cox regression analysis was used to evaluate the prognostic factors identified before resection., Results: The subjects were 49 patients with a mean age of 65 years, who underwent total pancreatectomy in our hospital during the study period. Peritoneal washing cytology was performed in 48 patients, with positive results in 4 (8.3%). There was no 30-day mortality. The median overall survival was 22.5 months, with a 5-year survival rate of 28.5%. Univariate analyses of the pre-resection variables revealed that overall survival was associated with tumor location, resectability classification, maximum standardized uptake value of positron emission tomography, the preoperative carbohydrate antigen 19-9 level, and peritoneal washing cytology status. Multivariate analysis revealed that positive peritoneal washing cytology status and the maximum standardized uptake value were independent predictors of poor survival., Conclusion: Total pancreatectomy for pancreatic cancer is appropriate for selected patients, but peritoneal washing cytology and positron emission tomography should be performed preoperatively.

Mixed adenoneuroendocrine carcinoma (MANEC) is defined as a tumor composed of both adenocarcinoma and neuroendocrine components. Here, we report the case of a 75-year-old woman with ampullary MANEC. She visited a physician with the chief complaint of dark urine and was diagnosed with advanced jaundice. Subsequently, she was referred to our hospital. Contrast-enhanced computed tomography scan revealed a neoplastic lesion measuring approximately 2 cm with a contrast effect at the duodenal papilla. Upper endoscopy showed a non-exposed tumor at the duodenal papilla. After biliary drainage, a subtotal stomach-preserving pancreaticoduodenectomy was performed. Histopathological examination revealed that the tumor components were composed of circular-to-oval atypical cells admixed with tubular adenocarcinoma tissue. These atypical cells were immunohistochemically positive for synaptophysin and diagnosed as neuroendocrine carcinoma with a Ki-67 labeling index of 63%. The patient was diagnosed with MANEC with a neuroendocrine carcinoma component of approximately 40%. The neuroendocrine carcinoma component had metastasized to the posterior pancreatic lymph nodes. Despite starting adjuvant chemotherapy with S-1, computed tomography revealed the presence of multiple liver metastases within 4 months after surgery. MANEC with neuroendocrine carcinoma is well known to have an extremely poor prognosis. Therefore, establishing a multidisciplinary therapy including chemotherapy is crucial.

A 43-year-old man was referred to our hospital for examination of a pancreatic tumor. Imaging revealed a mass-like lesion with a cyst in the pancreatic tail. Histological examination by EUS-FNA showed a low grade spindle cell lesion for which laparoscopic distal pancreatectomy was performed. The neoplasm was histologically diagnosed as pancreatic leiomyosarcoma. The postoperative course was uneventful and no signs of recurrence at 8 months after the surgery. Pancreatic leiomyosarcoma is very rare. Only 7 previous cases were reported in Japan. In tumors with diameters exceeding 50 mm, bleeding and necrosis occur inside the tumor and a cyst-like form often develops, which is considered a characteristic imaging finding. Therefore, imaging is important for preoperative differential diagnosis of the disease.

Purpose: We evaluated the clinical effectiveness of collagen gel droplet-embedded culture drug sensitivity tests (CD-DSTs) in predicting the efficacy of adjuvant chemo-therapeutic treatments for pancreatic cancer (PC)., Methods: The clinicopathological characteristics and prognoses of 22 PC patients who underwent CD-DST after pancreatectomy at Tohoku University between 2012 and 2016 were analyzed retrospectively. Eligibility criteria were resectable or borderline resectable PC, successful evaluation for 5-fluorouracil sensitivity by CD-DST, treatment with S-1 adjuvant chemotherapy, and no preoperative chemotherapy., Results: The rate of successful evaluation by CD-DST was 52.3% in PC. The optimal T/C ratio, defined as the ratio of the number of cancer cells in the treatment group (T) to that in the control group (C), for 5-fluorouracil was 85% using receiver operating characteristic curve analysis. The sensitive group (T/C ratio < 85%; n = 11) had a better recurrence-free survival rate than the resistant group (T/C ratio ≥ 85%; n = 11; P = 0.029). A Cox proportional hazards regression model demonstrated that sensitivity to 5-fluorouracil was an independent predictor of recurrence on multivariate analysis (hazard ratio 3.28; 95.0% CI 1.20-9.84; P = 0.020)., Conclusions: CD-DSTs helped to predict PC recurrence after S-1 adjuvant chemotherapy.

Positive peritoneal washing cytology (PPC) of pancreatic carcinoma is defined as distant metastasis in the American Joint Committee on Cancer or Union for International Cancer Control's tumour, node, metastases classification. However, surgical resection was believed to be the only method that prolong survival; thus, many institutions perform pancreatectomy for PPC, despite the unfavourable prognosis. Therefore, a more preferable alternative treatment for PPC is required. A 64-year-old man with resectable pancreatic tail cancer presented to our hospital. PPC was detected at first laparotomy; thus, pancreatectomy was avoided and gemcitabine with nabpaclitaxel (GnP) was administered. After four courses of GnP treatment, PPC converted to negative, as evaluated by abdominal port cytology. Thus, distal pancreatectomy was performed, and R0 resection was achieved. He has been healthy for more than 24 months since the first laparotomy. Initial chemotherapy with the intention of converting the cytological status followed by surgical treatment might become a useful treatment strategy for PPC., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Ovarian cancer typically spreads along the peritoneum or metastasizes through the blood or lymphatic stream. The bile duct is an extremely rare site of ovarian cancer-associated metastases., Case Presentation: A 55-year-old female underwent surgery for advanced left ovarian cancer 2 years ago. She was diagnosed with ovarian serous adenocarcinoma with multiple peritoneal metastases. She received chemotherapy for the residual peritoneal metastases. She achieved a clinical complete response and was followed up with imaging examinations for 1 year. She then complained of dark urine, yellowish discoloration of the eyes, and weight loss. Computed tomography showed an approximately 10-mm solid tumor at the hepatic hilum. Simultaneously, multiple peritoneal metastases were detected in the abdominal and pelvic cavity. Intraductal ultrasonography suggested that the hepatic hilum tumor was located in the bile duct wall. Tumor biopsy and brush cytology of the bile duct indicated atypical cells suspicious for carcinoma. After percutaneous transhepatic portal embolization, she underwent right hepatectomy and extrahepatic bile duct resection for the hepato-hilar tumor. The histopathological features were dysplastic cells with hyperchromatic nuclei and no dysplastic cells in the native biliary epithelium. Immunohistochemical staining revealed that the tumor cells were positive for CK-7 and WT-1 and negative for CK-20 and ER. These results suggested that the tumor was a metastasis of the ovarian serous adenocarcinoma., Conclusion: This may be the first case of ovarian cancer metastasis to the bile duct. While it is extremely rare, ovarian cancer may metastasize to the hepatic duct, mimicking hilar cholangiocarcinoma.

Here we report a case treated with conversion surgery combined with preoperative coil embolization of the hepatic artery after chemoradiation therapy for locally advanced unresectable pancreatic head cancer with hepatic artery invasion. A 63- year-old man was referred to our hospital for treatment of pancreatic cancer. Abdominal CT scan revealed a 30mm pancreatic head tumor with involvement of the common hepatic artery(CHA)and proper hepatic artery(PHA). The left hepatic artery diverged from the left gastric artery. Although S-1 with concurrent radiation therapy was performed, a follow-up CT scan revealed the progression of soft tissue shadow around the CHA. Subsequently, gemcitabine plus nab-paclitaxel(GnP)was administered 13 times. GnP helped achieve normalization of the tumor markers and long stable disease(SD)based on the Response Evaluation Criteria in Solid Tumors(RECIST). For the conversion surgery, embolization of the middle hepatic artery (MHA)was performed. Twelve days after, the right hepatic artery was embolized. Subtotal stomach-preserving pancreaticoduodenectomy was performed with resection of the CHA and PHA without arterial reconstruction 16 days after the hepatic arterial embolization. The patient was discharged from our hospital 33 days after surgery without complications related to hepatic ischemia. The patient is alive without recurrence 42 months after the initial diagnosis and 26 months after surgery.

The ubiquitin ligase F-box and WD repeat domain-containing 7 (FBXW7) is responsible for degrading diverse oncoproteins and is considered a tumor suppressor in many human cancers. Inhibiting FBXW7 enhances the malignant potential of several cancers. In this study, we aimed to investigate the role of FBXW7 in cholangiocarcinoma. We found that FBXW7 expression was associated with clinicopathological outcomes in cholangiocarcinoma patients. Both disease-free and overall survival were significantly worse in the low-FBXW7 group than in the high-FBXW7 group (P = .001 and P < .001, respectively). Multivariate analysis with the Cox proportional hazards model indicated that FBXW7 was the most important independent prognostic factor for disease-free (P = .006) and overall (P = .0004) survival. We also showed that the two FBXW7 substrates, NOTCH1 and myeloid cell leukemia sequence 1 (MCL1), regulate cholangiocarcinoma progression. Depletion of FBXW7 resulted in NOTCH1 accumulation and increased cholangiocarcinoma cell migration and self-renewal. Interestingly, when cells were stimulated with cis-diamminedichloridoplatinum(II) (cisplatin), FBXW7 suppression induced MCL1 upregulation, which reduced the sensitivity of cholangiocarcinoma cells to apoptosis, indicating that FBXW7-mediated ubiquitylation is context-dependent. These results indicate that FBXW7 modulates the malignant potential of cholangiocarcinoma through independent regulation of NOTCH1 and MCL1., (© 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Pancreatic cancer (PC) has poorer prognosis and higher surgical invasiveness than many other cancers, with associated psychiatric symptoms including depression and anxiety. Perioperative depression has not been investigated in PC patients regarding surgical stress and relevant interventions., Methods: We evaluated chronological depressive changes and subjective physical symptoms in surgically treated PC patients preoperatively and at 3 and 6 months postoperatively.Enrolled patients undergoing pancreatic tumor surgery completed questionnaires based on the Self-Rating Depression Scale (SDS) and Functional Assessment of Cancer Therapy for Patients with Hepatobiliary Cancer (FACT-Hep) preoperatively, and at 3 and 6 months postoperatively. Responses were analyzed with JMP® Pro using one-way and two-way ANOVA, Spearman's rank correlation coefficient, and multiple regression analysis., Results: Malignancy was diagnosed in 73 of 101 patients postoperatively; SDS score was significantly higher in these patients than in those with benign tumors at all timepoints: malignant/benign, 41.8/37.9 preoperatively ( p  = 0.004); 43.5/37.8 3 months postoperatively ( p  = 0.006); and 42.9/37.7 6 months postoperatively ( p  = 0.020). SDS scores were significantly higher in patients < 65 years old with malignancy at 3 months than at 6 months postoperatively (44.6/42.5, p  = 0.046) and in patients with malignancy who underwent pancreaticoduodenectomy at 3 months postoperatively than preoperatively (43.4/41.1; p  = 0.028). SDS scores moderately correlated with 8 physical symptom-related FACT-Hep items 3 months postoperatively ( p  < 0.05), showing low-to-moderate correlation with 16 physical symptom-related FACT-Hep items at 6 months postoperatively ( p  < 0.05). Multiple regression analysis of FACT-Hep symptoms significantly correlated with SDS scores revealed the following significant variables: "lack of energy" ( p  < 0.000) and "pain" ( p  = 0.018) preoperatively (R 2  = 0.43); "able to perform usual activities" ( p  = 0.031) and "lack of energy" ( p  < 0.000) at 3 months postoperatively (R 2  = 0.51); and "stomach swelling or cramps" ( p  = 0.034) and "bowel control" ( p  = 0.049) at 6 months postoperatively (R 2  = 0.52)., Conclusions: PC patients experience persistently high levels of depression preoperatively through 6 months postoperatively, with associated subjective symptoms including pain and gastrointestinal symptoms., Trial Registration: UMIN Clinical Trials Registry 000009592, Registered 20 December 2012., Competing Interests: This study was approved by the Ethics Committee of Tohoku University Graduate School of Medicine (IRB No.2012–1-403). A participant information statement and consent form were provided and verbally explained to each participant. Participation was voluntary, and participants were allowed time to read the forms prior to the commencement of the survey. Participation in the survey was anonymous and did not affect an employees’ relationship with the employer.Not applicable.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Background: We aimed to determine whether treatment should be stratified according to 18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) maximum standardized uptake values (SUV max ) in pancreatic ductal adenocarcinoma., Methods: Patients who underwent preoperative 18F-FDG PET/CT between 2006 and 2014 (n = 138) were stratified into high (≥ 4.85) and low (< 4.85) PET groups. The clinicopathological characteristics and prognostic outcomes were analyzed retrospectively., Results: The primary tumor SUV max was positively correlated with preoperative CA19-9 levels (P < 0.001). The high PET group failed to achieve postoperative CA19-9 normalization (P = 0.014). Disease-specific (P < 0.001), recurrence-free (P < 0.001), liver recurrence-free (P < 0.001), and peritoneal recurrence-free (P = 0.020) survivals were significantly shorter in the high PET group. The primary tumor SUV max was an independent predictive risk factor for liver metastasis (hazard ratio 3.46, 95% confidence interval 1.61-7.87; P = 0.001) and peritoneal recurrence (hazard ratio 3.36, 95% confidence interval 1.18-10.89; P = 0.023)., Conclusions: Surgical resection failed to achieve CA19-9 normalization in the high PET group and distant recurrence was frequent. This suggests the potential for residual cancer at distant sites, even after curative resection. Stronger preoperative systemic chemotherapy is preferred for the high PET group patients.

Background: Pancreatic cancer with distant metastases is classified as "unresectable," for which the standard treatment is systemic chemotherapy. The effectiveness of radical resection for pancreatic cancer with distant metastases is unknown. Here, we report a case of long term survival treated with conversion surgery following chemotherapy after diagnostic metastasectomy for pancreatic cancer with synchronous liver metastasis., Case Presentation: A 73-year-old man was referred to our hospital to examine and treat for cancer of the pancreatic body. Computed tomography (CT) scan revealed a 26-mm hypovascular tumor in contact with the common hepatic artery (CHA) (> 180°), the celiac artery (< 180°), and portal vein at the pancreatic body. Resectability was determined as "borderline resectable." Two courses of gemcitabine plus S-1 combination therapy (GS) were administered as neoadjuvant chemotherapy (NAC). CT scan showed tumor shrinkage (21 mm), determined as stable disease (SD) according to Response Evaluation Criteria in Solid Tumors (RECIST). Although the abdomen was opened for radical resection, a small nodule on the liver was detected and removed. Since the nodule was diagnosed as adenocarcinoma by intraoperative frozen section, resection of the primary tumor was not performed. After three subsequent courses of GS therapy, no distant metastases were detected under radiological findings. Distal pancreatectomy with celiac artery resection (DP-CAR) was performed as radical surgery 6 months after the initial diagnosis. Histological diagnosis was well-differentiated tubular adenocarcinoma, showing ypT1 ypN1 M1 stage IV, negative surgical margin (R0), and grade III in the Evans classification. S-1 was administered every other day from 6 months after resection up to the present. The patient has been alive with no recurrence for 5 years after the initial diagnosis and 4.5 years after the resection., Conclusion: There is a case that received survival benefits from conversion surgery following chemotherapy after diagnostic metastasectomy in pancreatic cancer with synchronous liver metastasis.

Purpose: To evaluate the risk factors for peritoneal recurrence (PR) of pancreatic adenocarcinoma and to discuss the appropriate management strategies., Methods: We reviewed the medical records of 236 patients who underwent pancreatectomy for pancreatic adenocarcinoma. We then compared the clinicopathological characteristics of patients with vs. those without PR. The independent risk factors for PR were defined using the Cox proportional hazards regression model., Results: The median survival of patients with PR was 13.3 months after surgical treatment. The PR group had a significantly higher incidence of portal vein resection, longer operative time (≥648 min), greater blood loss (≥2179 mL), blood transfusion, tumor size, portal vein invasion, artery invasion, pancreatic nerve plexus invasion, and histological grade. Multivariate analysis revealed that excessive blood loss (≥2179 mL; P = 0.010), artery invasion (P = 0.025), pancreatic nerve plexus invasion (P = 0.001), and histological grade 3 (P = 0.011) were independent risk factors for PR. Excessive blood loss was also strongly related to tumor size (P = 0.018)., Conclusions: Local invasion and tumor size-related factors suggested the possibility of intraoperative dissemination at the time of tumor resection. Preoperative treatment and an operative procedure to prevent tumor exposure may help prevent PR.

Background: The prognosis for pancreatic cancer remains dismal because many patients are diagnosed with unresectable cancer at the initial diagnosis. Recently, conversion surgery was reported as an effective treatment for initially unresectable pancreatic cancer with a favorable response to non-surgical treatment lasting over 240 days. Here, we describe a case of locally advanced pancreatic cancer (LAPC) successfully resected after treatment with S-1 and radiation followed by gemcitabine/nab-paclitaxel therapy., Case Presentation: A 73-year-old man with LAPC was referred to our hospital. Computed tomography findings revealed a 2.5-cm mass in the pancreatic body that had invaded the celiac artery, common hepatic artery, and splenic artery. Superior mesenteric artery (SMA) encasement was not observed, but tumor abutment over 180° with the main tumor was detected. Staging laparoscopy showed no findings of distant metastasis, and washing cytology revealed no malignancy. He was diagnosed with unresectable pancreatic cancer. Treatment with S-1 with radiation therapy followed by gemcitabine with nab-paclitaxel was performed. Six months after the initial treatment, the tumor size had decreased to 1.2 cm, and encasement of the main artery was diminished. Though abutment to the main artery, including the SMA, was still detected, distal pancreatectomy with celiac artery resection was performed. The histopathological findings around the celiac artery revealed fibrous changes with an Evans classification of grade IIb. There was no residual cancer at the periphery; thus, R0 resection was achieved. The patient has been healthy and without recurrence for more than 12 months since the initial treatment., Conclusions: Gemcitabine/nab-paclitaxel therapy revealed high response rate for metastasic pancreatic cancer (PC), but the effect for LAPC proposing conversion surgery was not well discussed. In this case, we achieve R0 resection combined with chemoradiation therapy and gemcitabine/nab-paclitaxel therapy. This regimen was also effective for LAPC and may be used to increase the population of conversion surgery by its high response rate.

Gemcitabine with nab-paclitaxel(GN)shows promisinganti -tumor effect and has been established standard regimen for metastatic pancreatic cancer(PC). Conversion surgery(CS), recently reported about initially unresectable PC with favorable response to non-surgical treatment, might provide long-term survival. The aim of this study is to evaluate the efficacy of multi-modal treatment includingCS after GN therapy for initially unresectable PC. From 2015 to 2016, 29 initially unresectable PC treated with chemotherapy includingGN were eligible for the retrospective analysis. Unresectability was defined over 180- degree abutment to major arteries(UR-LA)or suspicious small metastases(UR-M). CS was planed after clinical favorable response over 6 months of treatment duration. Median age of the patients was 62.5 years old, including 18 males and 11 females. Tumor in the pancreas head(n=20)was dominant. Eighteen patients were UR-LA and remaining1 1 were UR-M. CS was performed in 9 cases(31%)with no significant difference between UR-LA and UR-M. CS showed significant better survival with 67%of 2-year survival rate, compared to without CS(p=0.039). GN regimen effectively induced CS for initially unresectable PC. Multidisciplinary therapy includinginduction GN and CS might have survival impact on unresectable PC.

Background: von Hippel-Lindau disease is a dominantly inherited multi-system syndrome with neoplastic hallmarks. Pancreatic lesions associated with von Hippel-Lindau include serous cystic neoplasms, simple cysts, and neuroendocrine tumors. The combination of pancreatic neuroendocrine tumors and serous cystic neoplasms is relatively rare, and the surgical treatment of these lesions must consider both preservation of pancreatic function and oncological clearance. We report a patient with von Hippel-Lindau disease successfully treated with pancreas-sparing resection of a pancreatic neuroendocrine tumor where the pancreas had been completely replaced by serous cystic neoplasms, in which pancreatic function was preserved., Case Presentation: A 39-year-old female with von Hippel-Lindau disease was referred to our institution for treatment of a pancreatic neuroendocrine tumor. Abdominal computed tomography demonstrated a well-enhanced mass, 4 cm in diameter in the tail of the pancreas, and two multilocular tumors with several calcifications, 5 cm in diameter, in the head of the pancreas. There was complete replacement of the pancreas by multiple cystic lesions with diameters ranging from 1 to 3 cm. Magnetic resonance cholangiopancreatography showed innumerable cystic lesions on the whole pancreas and no detectable main pancreatic duct. Endoscopic ultrasound-guided fine-needle aspiration of the mass in the pancreatic tail showed characteristic features of a neuroendocrine tumor. A diagnosis of pancreatic neuroendocrine tumor in the tail of the pancreas and mixed-type serous cystic neoplasms replacing the whole pancreas was made and she underwent distal pancreatectomy while avoiding total pancreatectomy. The stump of the pancreas was sutured as firm as possible using a fish-mouth closure. The patient made a good recovery and was discharged on postoperative day 9. She is currently alive and well with no symptoms of endocrine or exocrine pancreatic insufficiency 8 months after surgery., Conclusions: A pancreas-sparing resection should be considered for patients with pancreatic neuroendocrine tumors and complete cystic replacement of the pancreas to preserve quality of life after surgery.

A 63-year-old man visited our hospital with pain on micturition and was found to have a large rectal tumor with urinary bladder invasion on enhanced abdominal computed tomography (CT). The tumor appeared to be unresectable at presentation; thus, sigmoid colostomy was performed and chemotherapy was initiated. The tumor was found to be EGFR-positive and contained a wild-type KRAS. The mFOLFOX6 plus cetuximab (c-mab) regimen was initiated. The follow-up CT scan showed good tumor shrinkage after 4 courses of chemotherapy; 4 additional courses were administered. The tumor eventually regressed by more than 60% and was judged to be resectable. High anterior resection of the rectum with partial resection of the bladder was performed. Abdominal wall metastasis was detected 8 months after surgery, and additional resection was performed. The patient remained well with no other recurrence 8 months after the high anterior resection. Although chemoradiotherapy is the standard preoperative treatment of locally advanced rectal cancer, systemic therapy is effective in certain cases such as substantial tumor invasion of adjacent organs or metastasis. Here, we present a case of rectal cancer that became curatively resectable after preoperative chemotherapy with mFOLFOX6 plus c-mab.

The canonical Wnt/β-catenin signaling pathway has been shown to promote the epithelial-mesenchymal transition (EMT), which is a crucial process in multiple embryonic developmental processes and the progression of carcinomas. We recently provided evidence that leucine-rich repeat flightless-1-interacting protein 1 (LRRFIP1) promotes cancer metastasis and invasion. In the present study, we identified the signaling elements targeted by LRRFIP1 for promotion of the EMT in pancreatic and lung cancer. LRRFIP1 silencing reversed the EMT, as shown by increased expression of E-cadherin (an epithelial marker) and decreased expression of vimentin (a mesenchymal marker). Silencing of LRRFIP1 up-regulated phosphorylation of β-catenin and decreased its nuclear localization by targeting the β-catenin destruction complex. The expression of β-catenin and E-cadherin in the plasma membrane fraction was increased in LRRFIP1 silenced cancer cells, and the migration and invasion capabilities were strongly inhibited. In addition, this protein was highly expressed at the invasion front of malignant tissue collected from pancreatic cancer patients. Consequently, our data strongly suggested that LRRFIP1 played an important role in the invasion of carcinoma cells. Our data provide experimental evidence that LRRFIP1 is an attractive candidate for targeted therapy in human cancers., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: Surgical treatment for adhesive small bowel obstructions (ASBOs) is the only way to release the obstructive structure; however, opening the peritoneal cavity may cause new adhesions, possibly leading to recurrent episodes of ASBO. The risk factors for recurrent ASBO, after surgical treatment, are not fully understood., Methods: The hospital records of 113 patients undergoing surgery for ASBO at Shirakawa Kousei (Japan) General Hospital, between 2002 and 2013, were studied. We compared the pre- and postoperative factors, intraoperative findings, and surgical histories of 18 patients with and 95 patients without recurrent ASBO. The risk factors for ASBO recurrence, after surgery, were determined using Cox-proportional hazard ratios., Results: The 5-year cumulative rate of overall recurrence was 20.8%. Among the 18 patients of recurrence, 11 (61.1%) were readmitted within 1 year of surgical treatment. Multivariate analysis revealed that a history of omentectomy was an independent risk factor for recurrence (hazard ratio, 2.98; p = 0.027). After omentectomy, the rate of adhesions to the peritoneum was significantly higher (with omentectomy, 54.5%; without omentectomy, 21.3%; p < 0.001), and the risk of adhesion or matted adhesion was increased (with omentectomy, 87.9%; without omentectomy, 53.8%; p < 0.001), compared with patients not undergoing omentectomy., Conclusion: Omentectomy significantly increases the likelihood of ASBO recurrence. Therefore, patients undergoing omentectomy may be candidates for prophylactic anti-adhesion agents, particularly when there is a risk of matted abdominal wall adhesions., (Copyright © 2014 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.)

Background and Objectives: The long-term prognosis of elderly gastric cancer patients is poor because of the cancer and unrelated comorbidities. We investigated the risk factors for mortality after gastrectomy to aid surgeons in deciding the correct operative procedure for elderly gastric cancer patients., Methods: A total of 414 gastric cancer patients surgically treated between 2002 and 2012 were divided into two groups A (≥75 years) and B (<75 years). Data were collected retrospectively and analyzed using the Estimation of Physiological Ability and Surgical Stress (E-PASS) scoring system as a predictor of postoperative complications., Results: Overall survival (P < 0.001), disease-specific survival (P = 0.029), and survival rate related to comorbid disease (P < 0.001) were significantly reduced in elderly patients compared with younger patients. Surgical treatment for Group A involved lesser extent of nodal resection (P < 0.001). Multivariate analysis revealed that a comprehensive risk score (CRS) ≥0.5 based on the E-PASS score (P = 0.022) and severe postoperative complication (P = 0.002) were independent risk factors for mortality from comorbid disease., Conclusions: Thus, E-PASS-based CRS was a good predictor of comorbidity-related mortality. CRS may help surgeons select elderly patients with gastric cancer for surgical or other therapies., (© 2013 Wiley Periodicals, Inc.)

A female in her 50s with a four-year history of myotonic dystrophy was admitted to our hospital with hematochezia. She was diagnosed with synchronous colonic cancer of the transverse and sigmoid colon, for which she underwent partial transverse and sigmoid colectomy, respectively. Postoperative respiratory failure resulted in prolonged stay in the intensive care unit. Her liver and renal function gradually deteriorated, and she eventually died from these sequelae on postoperative day 26. Intraoperative liver biopsy revealed cirrhosis arising from non-alcoholic steatohepatitis (NASH). Although myotonic dystrophy is believed to be a multisystem disease, its association with cirrhosis has not been reported in Japan. We therefore report this rare case of liver cirrhosis arising from NASH in a patient with myotonic dystrophy.

The precise relationship between GCF2 expression and carcinogenesis has not yet been established. To clarify the metastatic potential of GCF2 in colorectal cancer, HT-29 cells stably suppressing GCF2 expression were injected into the spleens of severe combined immunodeficient (SCID) mice. GCF2 suppression reduced the number of metastatic foci in the liver and reduced fibronectin-induced cell adhesion, migration, and invasion. Downstream from the integrin signaling pathways, GCF2 regulates RhoA interaction with the RGS domain of Leukemia associated RhoGEF (LARG). Altogether, our results suggest that GCF2 plays an important role in colorectal cancer metastasis by regulating RhoA-induced cell adhesion, migration, and invasion., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

GC-binding factor 2 (GCF2), a transcriptional repressor that decreases the activity of several genes is capable of binding directly to the GC-rich sequence of the EGFR promoter and repressing the transcriptional activity of EGFR. In addition to its function as a transcriptional repressor, GCF2 can directly interact with other proteins such as flightless-1 (Fli-1). Many previous findings pertaining to the function of Fli-1 have suggested a role for fli-1 in providing a direct link between molecules involved in signal transduction pathways and the actin cytoskeleton. We hypothesized that GCF2, together with Fli-1, plays a role in regulating cytoskeleton function, cell migration, and/or morphology. In our study, we observed that GCF2 is crucial for the activation of RhoA, a small GTPase that plays a key role in the regulation of the actin cytoskeleton. RhoA was markedly inactivated as a result of the decreased expression of GCF2. Co-immunoprecipitations were subsequently performed to further investigate the mechanism for the repressive function. We identified dishevelled (Dvl), which is the key mediator for the Wnt pathway, as a binding partner with GCF2. These results strongly suggest that GCF2 plays a role in the Wnt-noncanonical planar cell polarity (PCP) signaling pathway. Consequently, GCF2 may regulate the cytoskeleton or migration via Dvls and RhoA., (Copyright © 2010 UICC.)

Histamine H3 receptor (H3R), one of G protein-coupled receptors (GPCRs), has been known to regulate neurotransmitter release negatively in central and peripheral nervous systems. Recently, a variety of intracellular proteins have been identified to interact with carboxy (C)-termini of GPCRs, and control their intracellular trafficking and signal transduction efficiencies. Screening for such proteins that interact with the C-terminus of H3R resulted in identification of one of the chloride intracellular channel (CLIC) proteins, CLIC4. The association of CLIC4 with H3R was confirmed in in vitro pull-down assays, coimmunoprecipitation from rat brain lysate, and immunofluorescence microscopy of rat cerebellar neurons. The data from flowcytometric analysis, radioligand receptor binding assay, and cell-based ELISA indicated that CLIC4 enhanced cell surface expression of wild-type H3R, but not a mutant form of the receptor that failed to interact with CLIC4. These results indicate that, by binding to the C-terminus of H3R, CLIC4 plays a critical role in regulation of the receptor cell surface expression.

Intestines of mice with colitis caused by dextran sulfate sodium (DSS) contain more Bacteroidaceae cells than untreated controls. We investigated the roles of intestinal bacteria and succinic acid, a by-product of Bacteroidaceae metabolism, in this model of colitis. CBA/J mice were given 3% DSS in water for 14 days. After mice were anesthetized and killed, concentrations of organic acids in stools from the cecum and colon were measured. The resected rectum and colon were washed with sterile saline; some specimens were incubated with imipenem in saline for 1 h to kill bacteria on the surfaces and others were not. Their homogenates were cultured anaerobically and aerobically. Separately, 1 mL of 20 mM succinic acid was infused into the rectum of mice, whose anal verge was glued. Animals were anesthetized and killed the next day. The rectum and colon were examined histologically. Concentrations of succinate were higher everywhere in the colon of mice with colitis than in controls. Mice with colitis had more Bacteroidaceae cells, especially B. caccae, than controls. Mice given succinate enemas had focal erosions of the mucosa and edema of the submucosa. Succinic acid, produced abundantly by members of the family Bacteroidaceae, especially B. caccae, may be the ulcerogenic agent in DSS colitis.