Daisuke Hashimoto

Autophagy is needed for the growth of pancreatic adenocarcinoma and has a cytoprotective effect against anticancer drugs

BACKGROUND AND AIMnAutophagy is a regulated process of degradation and recycling of cellular constituents. The role of autophagy in pancreatic cancer is still not clear. Some studies indicate that in pancreatic cancer autophagy exerts cytoprotective effects, whereas others suggest that autophagy positively contributes to cell death by enhancing cytotoxicity of anticancer drugs. The aim of this study was to investigate the role of autophagy in pancreatic cancer, and to provide insights into new strategies for treatment.nnnMATERIALS AND METHODSnPancreatic cancer cell lines PANC-1 and BxPC-3 were treated with anticancer drugs (5-fluorouracil or gemcitabine) alone and in combination with autophagy inhibitors (chloroquine or wortmannin). Biopsy samples were retrieved from patients from pancreatic normal tissue and adenocarcinoma. Western blot of microtubule-associated protein 1 light chain 3 (LC3)-II was performed to investigate the degree of autophagy and cell proliferation was assessed by a crystal violet assay.nnnRESULTSnAutophagy was active in PANC-1 cells under basal conditions. Autophagy was significantly induced in pancreatic ductal adenocarcinoma compared to healthy pancreatic tissue in patients. Inhibition of autophagy by chloroquine suppressed the growth of PANC-1 and BxPC-3. Autophagy was markedly increased after treatment with 5-fluorouracil or gemcitabine. Inhibition of autophagy by chloroquine potentiated the inhibition of cell proliferation of PANC-1 and BxPC-3 by 5-fluorouracil and gemcitabine.nnnCONCLUSIONSnOur results with pancreatic cancer cell lines and human pancreatic adenocarcinoma suggest that autophagy contributes to pancreatic cancer cell growth. Autophagy has a cytoprotective effect against 5-fluorouracil and gemcitabine in pancreatic cancer cells. Combination therapy of these anticancer drugs and chloroquine should be investigated.

miR-9-3p plays a tumour-suppressor role by targeting TAZ (WWTR1) in hepatocellular carcinoma cells.

Background:The inactivation of the Hippo pathway lead to TAZ (PDZ-binding motif)/YAP (yes-associated protein) overexpression, and is associated with worse prognostic outcomes in various cancers including hepatocellular carcinoma (HCC). Although there are several reports of microRNA (miR) targeting for YAP, miR targeting for TAZ remains unclear. The aim of this study is to identify the miR targeting TAZ expression in HCC.Methods:MicroRNA expression was analysed using the Human miFinder 384HC miScript miR PCR array, and was compared between low and high TAZ expression cell lines. Then, we extracted miR-9-3p as a tumour-suppressor miR targeting TAZ. We examined the functional role of miR-9-3p using miR-9-3p mimic and inhibitor in HCC cell lines).Results:In HCC cell lines and HCC clinical samples, there was the inverse correlation between miR-9-3p and TAZ expressions. TAZ expression was induced by treatment of miR-9-3p inhibitor and was downregulated by treatment of miR-9-3p mimic. Treatment of miR-9-3p mimic inhibited cell proliferative ability with downregulated phosphorylations of Erk1/2, AKT, and β-catenin in HLF. Inversely, treatment of miR-9-3p inhibitor accelerated cell growth compared with control in HuH1.Conclusions:MicroRNA-9-3p was identified as the tumour-suppressor miR targetting TAZ expression in HCC cells.

Pancreatic cancer in the remnant pancreas following primary pancreatic resection

AbstractPurposeTo clarify the clinical features of cancer in the pancreatic remnant.MethodsnWe retrospectively reviewed the clinical and pathological findings of 10 patients who developed remnant pancreatic cancer in our hospital between 2002 and 2012. The KRAS sequences in both the initial pancreatic tumor and remnant pancreatic cancer were examined in two patients.ResultsEight patients underwent a second pancreatectomy for remnant pancreatic cancer (resected group), while two patients were not operated on and underwent chemotherapy (unresected group). The remnant pancreatic cancer developed at the cut end of the pancreas (pancreaticogastrostomy site) in four patients. In the resected group, four patients died 17xa0months after the emergence of the remnant pancreatic cancer and four patients survived during the median 40.5-month observation period. The median survival of the unresected group after the emergence of the remnant pancreatic cancer was 10xa0months. The findings of the KRAS sequencing and immunohistological staining of the remnant pancreatic cancer for MUC1 and MUC2 in the two patients were consistent with those of the initial pancreatic tumor in one patient, and not consistent in the other.ConclusionsOur results suggest that both local recurrence and a new primary cancer can develop in the pancreatic remnant, and repeated pancreatectomy can prolong survival.

Pancreaticodigestive anastomosis and the postoperative management strategies to prevent postoperative pancreatic fistula formation after pancreaticoduodenectomy

Over the past 100xa0years, advances in surgical techniques and perioperative management have reduced the morbidity and mortality after pancreaticoduodenectomy (PD). Many techniques have been proposed for the reconstruction of the pancreaticodigestive anastomosis to prevent the development of a postoperative pancreatic fistula (POPF), but which is the best approach is still highly debated. We carried out a systematic review to determine and compare the effectiveness of various methods of anastomosis after PD. A meta-analysis and most randomized controlled trials (RCTs) showed that the mortality, POPF rate and incidence of other postoperative complications were not statistically different between the pancreaticogastrostomy and pancreaticojejunostomy (PJ) groups. One RCT showed that a binding PJ significantly decreased the risk of POPF and other postoperative complications compared with conventional PJ. External duct stenting reduced the risk of clinically relevant POPF in a meta-analysis and RCTs. The prophylactic use of octreotide after PD does not result in a reduced incidence of POPF. In conclusion, our findings suggest that the successful management of pancreatic anastomoses may depend more on the meticulous surgical technique, surgical volume, and other management parameters than on the type of technique used. However, some new approaches, such as binding PJ, and the use of external stents should be considered in further RCTs.

Impact of Postoperative Weight Loss on Survival After Resection for Pancreatic Cancer

BACKGROUNDnThe aim of this study was to assess the effects of postoperative body weight loss on long-term survival after resection for pancreatic cancer.nnnMETHODSnA total of 93 patients with primary pancreatic cancer underwent pancreatic resection between April 2005 and December 2011. Patient characteristics, preoperative body mass index, and changes in postoperative body weight were evaluated retrospectively and correlated with long-term survival.nnnRESULTSnThere was no significant association between survival and preoperative body mass index. Body weight fell by 8.4% at 2 months after surgery and by 9.0% at 4 months after surgery. Severe postoperative body weight losses, both at 2 months (P = .033) and 4 months (P = .014) after surgery, were significantly associated with poor prognosis, especially among patients with stage IA-IIA pancreatic cancer (n = 43) (P = .005 at 2 months and P < .001 at 4 months). Additionally, severe body weight loss tended to be associated with shorter survival among patients with stage IIB-III pancreatic cancer (n = 50), although the difference was not significant. Multivariate analysis revealed that postoperative body weight loss was an independent prognostic factor.nnnCONCLUSIONSnThe results of this study demonstrated that pancreatic cancer patients with severe postoperative body weight loss have poorer postoperative outcomes.

Heterogeneity of KRAS Mutations in Pancreatic Ductal Adenocarcinoma

Objectives Activating Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are the most common and frequent changes observed in pancreatic cancer. This study aimed to determine the frequency and extent of intratumoral and metastatic lymph node KRAS mutation heterogeneity of resected pancreatic ductal adenocarcinoma. Methods Tumor tissues macrodissected from tumor centers, invasion fronts (n = 97), and lymph nodes (n = 11) were subjected to DNA extraction and mutation analysis of KRAS codons 12 and 13 by pyrosequencing. Results Activating mutations in codon 12 of KRAS were detected in 90 (92.8%) tumor centers. No mutations were detected in KRAS codon 13 in any patient. After a comparison of tumor centers and invasion fronts, intratumoral heterogeneity of KRAS was observed only in 4 (4.1%) cases. Additional invasion front tumor analysis revealed the same mutation status consistent with each tumor center. No heterogeneity was observed between primary tumors and metastatic lymph nodes. Conclusions Intratumoral heterogeneity of the KRAS mutational status is rare in pancreatic ductal adenocarcinoma. In addition, no KRAS heterogeneity between primary tumors and metastatic lymph nodes was detected in this study. This finding is consistent with the hypothesis that oncogenic activation of KRAS is the first driver mutation in pancreatic cancer.

The diagnostic role of the neutrophil-to-lymphocyte ratio in predicting pancreatic ductal adenocarcinoma in patients with pancreatic diseases

BackgroundAccurately diagnosing pancreatic ductal adenocarcinomas (PDACs) is challenging because of the loss of vascularity and poor imaging. The neutrophil-to-lymphocyte ratio (NLR) has been reported to predict poor prognosis in several types of malignancy including PDAC; however, the diagnostic role of NLR in PDAC has never been addressed.MethodsThis study retrospectively assessed 297 patients who underwent curative pancreatic resection for pancreatic tumors from 1995−2015, including 140 with PDACs, 58 with pancreatic neuroendocrine tumors (PNETs), 76 with intraductal papillary mucinous neoplasms (IPMNs), 13 with mucinous/serous cyst neoplasms, 7 with solid pseudopapillary neoplasms, and 3 with tumor-forming pancreatitis. The role of preoperative NLR in predicting PDACs was investigated.ResultsPreoperative NLR was significantly higher in patients with PDACs (2.52xa0±xa01.34) than in patients with PNETs (1.93xa0±xa00.68, Pxa0=xa00.0004) and IPMNs (2.17xa0±xa00.79, Pxa0=xa00.0253). Only eight patients with PDACs (5.7xa0%) had NLRxa0>5; of these, three had normal carcinoembyronic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) levels. Multivariate analysis revealed that abnormal CA19-9 levels, abnormal CEA levels, agexa0>67 years, and NLRxa0>5 were independent predictors of PDACs. Both the specificity and the positive predictive value of NLRxa0>5 for predicting PDACs were 100xa0%; however, the sensitivity was 4.6xa0% and the negative predictive value was 43.8xa0%.ConclusionsNLRxa0>5 could independently predict the occurrence of PDACs in pancreatic neoplastic disease irrespective of other tumor markers, CEA and CA19-9, in pancreatic disease.

Staging laparoscopy leads to rapid induction of chemotherapy for unresectable pancreatobiliary cancers

Preoperatively evaluating the resectability of pancreatobiliary cancers is difficult. The aim of this study was to investigate the benefit of staging laparoscopy in unresectable pancreatobiliary cancers. Between 2010 and 2013, 25 patients with pancreatobiliary cancers underwent staging laparoscopy after conventional tumor staging; they were compared with 10 patients who had unresectable or metastatic tumors that were found during laparotomy. Staging laparoscopy did not show unresectable factors in 11 patients, and resections were performed in these patients. Unresectable factors were found in other 14 patients who underwent staging laparoscopy. In these patients, chemotherapy was started after median postoperative dayu20093 (range, 2–10 days). This period was significantly longer in patients who received unnecessary laparotomy; chemotherapy was started after median postoperative day 11 (range, 6–15 days). These results suggest that staging laparoscopy, while avoiding laparotomy with unsuccessful resection, can lead to rapid induction of chemotherapy for unresectable pancreatobiliary cancers.

Recombinant soluble thrombomodulin for postoperative disseminated intravascular coagulation

BACKGROUNDnThrombomodulin is a thrombin receptor on the endothelial cell surface that plays an important role in the regulation of intravascular coagulation. The purpose of this study was to evaluate the efficacy and safety of treatment with recombinant human soluble thrombomodulin (rhTM) for patients with septic-disseminated intravascular coagulation (DIC) associated with gastroenterological surgery.nnnMATERIALS AND METHODSnFrom April 2011-September 2013, 201 patients with DIC associated with gastroenterological surgery were treated in 16 institutions in Kumamoto, Japan. The patients were diagnosed according to the Japanese Association for Acute Medicine DIC scoring system. The clinical course, mortality rate at 28 d, and adverse events were evaluated retrospectively.nnnRESULTSnForty-five patients were excluded because they did not meet the Japanese Association for Acute Medicine DIC criteria or had an insufficient duration of drug administration. Thus, 156 patients were analyzed. Of these patients, 107 received rhTM at the discretion of the attending surgeon and 49 did not. The most common reason for surgery in both groups was peritonitis due to perforation of the colon. Within 7 d, the platelet count, prothrombin time-international normalized ratio, DIC score, neutrophil count, and C-reactive protein level significantly improved in the rhTM group compared with those in the control. Treatment with rhTM was significantly associated with reduced inhospital mortality at 28 d. The incidence of adverse events did not differ between the two groups.nnnCONCLUSIONSnTherapy with rhTM may be associated with reduced inhospital mortality in patients with septic DIC associated with gastroenterological surgery without increasing adverse events.

Accessory right hepatic artery branched from gastroduodenal artery

The right hepatic artery usually branches from the common hepatic artery, however, there are cases showing anatomic variations. We present 41-year-old female patient with gallbladder cancer. In this case, the accessory right hepatic artery branched from the gastroduodenal artery, passed in front of the common bile duct and fed into the anterior segment of the liver. Cholecystectomy and resection of the extrahepatic bile duct with hepaticoenterostomy were performed successfully, preserving the accessory right hepatic artery. There are few reports presenting such an extremely rare anomaly of hepatic arteries in the English literature. Additionally, we herein present a review of the English literature regarding anatomic variations of right hepatic artery.