Impact of S-1 adjuvant chemotherapy longer than 6 months on survival in patients with resected pancreatic cancer: a nationwide survey by the Japan Pancreas Society based on real-world data.

BACKGROUND: Based on the Japan Adjuvant Study Group of Pancreatic Cancer 01 study, the standard duration of adjuvant chemotherapy with S-1 (an oral 5-fluorouracil prodrug consisting of tegafur, gimeracil, and oteracil) in patients with resected pancreatic ductal adenocarcinoma (PDAC) was considered to be 6 months, but the impact of increasing its duration on postoperative survival was unknown. Here, the authors investigated this question by reviewing real-world data from a large cohort of patients with PDAC. METHODS: In total, 3949 patients who underwent surgery for PDAC during the study period followed by S-1 adjuvant chemotherapy in board-certified institutions were included. Based on the duration of S-1 chemotherapy, two subgroups were defined: a standard-duration group that included patients who were treated for 180 ± 30 days and a longer duration group that included patients who received treatment for >210 days. RESULTS: The median duration of S-1 chemotherapy was 167 days, with a mean ± standard deviation of 200 ± 193 days. After excluding patients who had a recurrence within 210 days after the initiation of adjuvant chemotherapy, postoperative recurrence-free survival (RFS) and overall survival (OS) in the standard-duration group (n = 1473) and the longer duration group (n = 975) were compared. RFS and OS did not differ significantly between the standard-duration and longer duration groups (5-year RFS: 37.8% vs. 36.2% respectively; p = .6186; 5-year OS: 52.8% vs. 53.4%, respectively; p = .5850). The insignificant difference was verified by multivariate analysis and propensity-score matching analysis. CONCLUSIONS: The current findings suggest that extending S-1 adjuvant chemotherapy beyond 6 months has no significant additional effect on survival in patients with PDAC. This could be useful in determining whether to extend S-1 chemotherapy in patients who have completed the standard 6-month treatment.

[A case of biliary panperitonitis due to intrahepatic bile duct rupture with intrahepatic bile duct tumor].

An 87-year-old man visited his previous doctor because of jaundice, abdominal pain, and disturbance of consciousness. He was diagnosed with cholangitis and panperitonitis and was referred to our hospital. Emergency laparotomy revealed biliary peritonitis. However, the bile leak point was unclear. Two days after surgery, endoscopic retrograde cholangiopancreatography was performed and revealed hilar bile duct stenosis, slight dilation of the intrahepatic bile duct, and bile leakage from the peripheral left intrahepatic bile duct to the abdominal free space. Endoscopic nasobiliary drainage was performed, and bile leakage decreased. He was discharged from our hospital with improvement from jaundice and peritonitis. Intrahepatic bile duct rupture with neoplastic obstruction of the bile duct is extremely rare. To date, only two cases of intrahepatic bile duct rupture with intrahepatic cholangiocarcinoma have been published.

The rate of polymyalgia rheumatica (PMR) and remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome in a clinic where primary care physicians are working in Japan.

We analyzed the rate of polymyalgia rheumatica (PMR) and remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome, both characterized as seronegative inflammatory arthritis in elderly, in an outpatient unit where primary care physicians are working in Japan to better understand the epidemiological characteristics of the diseases in Japan. Consecutive outpatients who newly visited at Department of General Medicine, Asahikawa Medical University Hospital, Japan, between April 2004 and March 2010 were analyzed. Each parameter such as age, sex, diagnosis, and biochemical examination was investigated. During the 6 years, 10 or 3 patients were diagnosed as PMR or RS3PE syndrome, respectively. The patients with PMR were 7 women and 3 men, and the average age at diagnosis was 69. Out of all patients aged over 50 (n = 3,347), the rate of PMR was 0.22% in men or 0.36% in women, respectively. On the other hand, RS3PE syndrome was diagnosed in 3 men (76, 76, and 81 years old). The rate of patients with RS3PE syndrome was 0.09% among outpatients aged over 50 indicating that the rate of PMR in an outpatient clinic in Japan is not far from previous findings reported from western countries. When compared with PMR, the rate of RS3PE syndrome was approximately one-third, providing for the first time the rate of RS3PE syndrome when compared with PMR. These epidemilogical data might help us pick up the diseases in primary care setting in Japan.

Safety and long-term outcomes of endoscopic papillary balloon dilation in children with bile duct stones.

BACKGROUND: Although experience with diagnostic and therapeutic ERCP in children is growing, little is known about the safety and technical outcomes of endoscopic papillary balloon dilation (EPBD) in pediatric patients with bile duct stones (BDSs). OBJECTIVE: To assess the safety and long-term outcomes of EPBD in pediatric patients with BDSs. DESIGN: Case study. SETTING: Tertiary referral center. PATIENTS AND INTERVENTIONS: This study involved 5 children who had BDSs combined with gallstones who underwent EPBD. MAIN OUTCOME MEASUREMENTS: Successful EPBD, successful stone removal, procedure-related complications, and long-term outcomes. RESULTS: ERCP was successful in all cases, with cannulation and subsequent EPBD. Stone removal was performed in 1 session in all patients. No EPBD-related complications were observed in any patient. After EPBD, 1 patient subsequently underwent laparoscopic cholecystectomy for gallstones. The remaining 4 were followed without surgery. In 2 patients, gallstones were spontaneously passed from the bile duct into the duodenum. During the follow-up period, over a mean of 7.1 years (range 3.7-9.3 years), no recurrence of BDSs was observed in any patient. LIMITATIONS: Small number of patients. CONCLUSIONS: Although BDSs are rare in pediatric patients, EPBD may be a safe and effective technique for the management of such stones in some children.

Incidence of synchronous and metachronous pancreatic carcinoma in 168 patients with branch duct intraductal papillary mucinous neoplasm.

BACKGROUND/AIMS: Although branch duct intraductal papillary mucinous neoplasms of the pancreas (BD-IPMN) are being diagnosed with increasing frequency, the incidence of concomitant pancreatic carcinoma (PC) is not well known. We investigated the incidence and clinical features of synchronous and metachronous PC in patients with BD-IPMN. METHODS: We studied 168 BD-IPMN patients diagnosed by various imaging modalities, including endoscopic retrograde pancreatography, between 1990 and 2008. We reviewed the medical records and clinical features in both patients developing and not developing PC. The diagnosis of PC was histologically verified in all patients. RESULTS: PC was observed in 9 (5.4%) of 168 patients. Five were synchronously detected at the time of BD-IPMN diagnosis, whereas four were metachronously identified during the follow-up period. All PCs occurred in regions separate from the BD-IPMN lesion. All PCs represented histologically invasive ductal adenocarcinomas, whereas the BD-IPMN lesion was diagnosed as adenoma. Patients developing PC were significantly older than patients not developing PC (p = 0.017). The diameters of the BD-IPMN lesions and main pancreatic ducts were significantly smaller in patients developing PC than patients not developing PC (p = 0.013 and p < 0.001, respectively). CONCLUSIONS: It was not infrequent for PC to occur in the pancreas with BD-IPMN. Particular attention should therefore be paid to the development of PC, even in low-risk BD-IPMN, as well as to changes in BD-IPMN.

[A case of pancreatic carcinoma presenting as pancreaticopleural fistula with pancreatic pleural effusion].

A 63-year-old man was admitted with left pleural effusion, and an amylase level of 30994IU/l. A diagnosis of pancreaticopleural fistula was made, based on the findings of magnetic resonance cholangiopancreatography and endoscopic retrograde pancreatography (ERP). After the placement of an endoscopic naso-pancreatic drainage tube, the pleural effusion markedly reduced. When ERP was performed for internal drainage, the main pancreatic duct and stricture were biopsied and showed pancreatic ductal adenocarcinoma histologically. CT revealed a mass in the head of the pancreas. He underwent pylorus-preserving pancreaticoduodenectomy. To the best of our knowledge this is the first case of pancreatic carcinoma presenting as pancreaticopleural fistula with pancreatic pleural effusion. Clinicians should pay attention to the possible presence of cancer and pancreaticopleural fistula in patients with pancreatic pleural effusion.

Optimal Treatment for Octogenarians With Resectable and Borderline Resectable Pancreatic Ductal Adenocarcinoma: A Multicenter Retrospective Study.

OBJECTIVES: The objective of this study was to clarify the role of pancreatectomy for patients with resectable and borderline resectable pancreatic ductal adenocarcinoma aged 80 years or older using a nationwide audit by the Japan Pancreas Society. METHODS: Data were collected from 39 institutions from 2007 to 2014. The primary endpoint was overall survival, and secondary endpoints were surgical outcomes and predictive factors for prognosis. RESULTS: Data were obtained from 556 octogenarians who underwent pancreatectomy (n = 369, 66%), chemo(radio)therapy (n = 99, 18%), and palliative therapy (n = 88, 16%). Median survival times were 20.6, 18.6, and 8.8 months in each group, respectively. Even after propensity score matching, median survival time in the surgery group (22.8 months) was significantly higher than that in the chemotherapy group (18.5 months; hazard ratio, 0.64 [95% confidence interval, 0.44-0.93]; P = 0.020). Significant independent prognostic factors were body mass index, lymph node metastasis, and tumor diameter in the surgery group, and serum albumin level, American Society of Anesthesiologists classification, body mass index, modified Glasgow prognostic score, second-line chemotherapy, and tumor diameter in the chemotherapy group. CONCLUSIONS: Octogenarians with resectable/borderline resectable pancreatic ductal adenocarcinoma can be recommended for pancreatectomy according to mental and physical fitness for surgical procedures.

A Jak2 inhibitor, AG490, reverses lipin-1 suppression by TNF-alpha in 3T3-L1 adipocytes.

Lipin-1 is a multifunctional metabolic regulator, involving in triacylglycerol and bioactive glycerolipids synthesis as an enzyme, transcriptional regulation as a coactivator, and adipogenesis. In obesity, adipose lipin-1 expression is decreased. Although lipin-1 is implicated in the pathogenesis of obesity, the mechanism is still not clear. Since TNF-alpha is deeply involved in the pathogenesis of obesity, insulin resistance, and diabetes, here we investigated the role of TNF-alpha on lipin-1 expression in adipocytes. Quantitative PCR studies showed that TNF-alpha suppressed both lipin-1A and -1B isoform expression in time- and dose-dependent manners in mature 3T3-L1 adpocytes. A Jak2 inhibitor, AG490, reversed the suppressive effect of TNF-alpha on both lipin-1A and -1B. In contrast, NF-kappaB, MAPKs, ceramide, and beta-catenin pathway tested were not involved in the mechanism. These results suggest that TNF-alpha could be involved in obesity-induced lipin-1 suppression in adipocytes and Jak2 may play an important role in the mechanism.

Tumor doubling time in two cases of main duct intraductal papillary-mucinous neoplasms of the pancreas.

The present study reports the growth rate in two cases of main duct pancreatic intraductal papillary-mucinous neoplasms (MD-IPMNs) demonstrating significant changes over several years' observation. The first patient was a 74-year-old woman with an incidental finding of diffuse dilatation of the main pancreatic duct (MPD). Endoscopic retrograde pancreatography (ERP) identified a 5 mm filling defect. Three years later computed tomography (CT) revealed a 20 mm mass occupying the MPD. The second patient was a 67-year-old woman who presented with back pain. Abdominal CT revealed a 5 mm mass in the dilated MPD. Five years later, CT and ERP showed a 20 mm mass occupying the markedly dilated MPD. Both patients subsequently underwent pancreatectomy. Histologically, the tumors showed an intraductal papillary growth occupying the dilated MPD and comprised of mucin-containing columnar epithelial cells. The tumor volume doubling time of these MD-IPMNs was 141 and 304 days in patient 1 and 2, respectively, with a mean of 222.5 days. The present reports demonstrate the ability of benign MD-IPMNs to grow at a significant rate, supporting the current consensus guidelines that MD-IPMNs require surgical resection.

[Gemcitabine in combination with S-1 or UFT in patients with advanced pancreatic cancer].

The present retrospective study aimed to evaluate the anti-tumor activity and toxicity of combination chemotherapy with gemcitabine (GEM) and oral S-1 or UFT in patients with advanced or metastatic pancreatic cancer. Ninety-four patients received chemotherapy. Among them, sixty-three were treated with GEM alone, twenty-two with UFT and GEM (UFT/GEM), and nine with S-1 and GEM(S-1/GEM). The median survival time was 8.7 months with GEM, 7.3 months with UFT/GEM, and 23.3 months with S-1/GEM. The overall response rate was 11.1%, 10.0%, and 22.2%, respectively. The 1-year survival rate was 29.5%, 36.4%, and 85.7%, respectively. Although the treatment-related adverse effects were not infrequent in patients treated with S-1/GEM, they were moderate in intensity. The combination chemotherapy with S-1/GEM was well tolerated and yielded a high response rate in patients with pancreatic cancer.

Prognostic importance of peritoneal washing cytology in patients with otherwise resectable pancreatic ductal adenocarcinoma who underwent pancreatectomy: A nationwide, cancer registry-based study from the Japan Pancreas Society.

BACKGROUND: The importance of peritoneal washing cytology status both as a sign of irresectability and as a prognostic factor for pancreatic ductal adenocarcinoma remains controversial. The purpose of this nationwide, cancer registry-based study was to clarify the clinical implications of operative resection in patients who had positive cytology status. METHODS: Clinical data from 1,970 patients who underwent tumor resection were collected from the Pancreatic Cancer Registry in Japan. Clinicopathologic factors and overall survival curves were analyzed, and multivariate Cox proportional hazard models were evaluated. RESULTS: Among the 1,970 patients analyzed, positive cytology status was found in 106 patients and negative cytology status was found in 1,864 patients. The positive cytology status group had a greater frequency of pancreatic body and tail cancer and greater preoperative serum carbohydrate antigen 19-9 levels than the negative cytology status group (P < .001 each). The ratio of peritoneal recurrence tended to be greater in the positive cytology status group (14% vs 43%; P < .001). Overall median survival times were less in the positive cytology status group (17.5 months vs 29.4 months; P < .001). The 5-year survival rates were 13.7% and 31.1% in the positive cytology status and negative cytology status groups, respectively. Multivariate analysis of positive cytology status patients revealed that adjuvant chemotherapy was an independent prognostic factor. CONCLUSION: Positive cytology status was an adverse prognostic factor in patients who underwent resection for pancreatic ductal adenocarcinoma but did not preclude attempted curative resection. Curative resection followed by adjuvant chemotherapy may contribute to long-term prognosis in patients with positive cytology status.

Sonic hedgehog derived from human pancreatic cancer cells augments angiogenic function of endothelial progenitor cells.

Hedgehog signaling is important in the pathogenesis of pancreatic cancer. Several recent observations suggest the involvement of sonic hedgehog (SHH) in postnatal neovascularization. We identified a novel role for SHH in tumor-associated angiogenesis in pancreatic cancer. Immunohistochemical analysis revealed that patched homolog 1 (PTCH1), both a receptor for and transcriptional target of hedgehog signaling, was expressed in a small fraction of endothelial cells within pancreatic cancer, but not in normal pancreatic tissue. When endothelial progenitor cells (EPC) isolated from human peripheral blood were cultured with supernatant from SHH-transfected 293 cells or pancreatic cancer cells, mRNA levels of vascular endothelial growth factor (VEGF), stromal cell-derived factor-1 and angiopoietin-1 were significantly increased, whereas no such induction was observed in human umbilical vein endothelial cell (HUVEC) and human dermal microvascular endothelial cell (HMVEC). HUVEC tube formation was stimulated when cocultured with EPC, and preconditioning EPC with supernatant from KP-1 N pancreatic cancer cells highly expressing SHH significantly enhanced the effect. The effect was partially attenuated by specific inhibition of SHH with cyclopamine or a neutralizing antibody. These findings suggest that tumor-derived SHH can induce angiogenesis, and this is mediated by its effects on EPC specifically. Targeting SHH would be a novel therapeutic approach that can inhibit not only proliferation of cancer cells but also EPC-mediated angiogenesis.

[Milk-of-calcium in a pseudocyst of the pancreas].

A 59-year-old woman with a history of abdominal injury was admitted to our hospital for abdominal discomfort. CT revealed a cyst showing a fluid-calcium level in the pancreatic body. EUS-FNA was performed to aspirate the fluid in a cyst. Aspirated was milky-white odorless material. Chemical analysis showed high amylase level in the fluid. Spectroscopic analysis revealed that the fluid mainly consists of calcium phosphate. To the best of our knowledge, this is the first case of milk-of-calcium in a pancreatic pseudocyst with an analysis of cystic fluid obtained by EUS-FNA.

[Two cases of pancreatic tumor with von Hippel-Lindau disease].

Von Hippel-Lindau disease (VHL disease) is an inherited neoplasia syndrome. VHL disease which frequently complicates pancreatic lesions is rarely diagnosed by existence of pancreatic involvements. We report two cases of VHL disease with pancreatic lesions. The first patient was a 40-year-old woman. Adrenal pheochromocytoma, spinal hemangioblastoma and pancreatic endocrine tumor were resected. The second case was a 68-year-old woman with past surgical histories included cerebellar and spinal hemangioblastoma. Subtotal pancreatectomy was performed for multiple serous cystadenoma. IPMN which has been never reported as pancreatic involvement of VHL disease were documented by imaging diagnosis in the first case, and by histological examination in the second case. We considered VHL disease from coexistent multiple tumors include pancreatic involvements and finally diagnosed by genetic examination in both cases. Care should be taken regarding the patient's right for treatment against for the genetic disease. We hold a genetic conference composed of multidisciplinary team. Consequently we detected another VHL disease patient from patient's family.

Intracisternal injection of orexin-A prevents ethanol-induced gastric mucosal damage in rats.

BACKGROUND: Accumulating evidence indicates that orexin-A in the brain stimulates vagal flow projecting to the stomach. Since the vagal system plays an important role in gastric mucosal integrity, we hypothesized that orexin-A in the brain might have a gastroprotective action. METHODS: We examined the effect of centrally administered orexin-A on the development of gastric mucosal damage evoked by ethanol and its possible mechanism of action in rats. RESULTS: Intracisternal but not intraperitoneal injection of orexin-A significantly inhibited the severity of gastric mucosal damage by 70% ethanol in a dose-dependent manner, suggesting that orexin-A acts in the brain to prevent ethanol-induced gastric mucosal damage. The antiulcer action was observed in rats administered with orexin-A centrally but not orexin-B, indicating that the action is mediated through orexin 1 receptors. The gastroprotective action of centrally administered orexin-A was blocked by pretreatment with atropine, Nomega-nitro-L-arginine methylester, or indomethacin. CONCLUSIONS: These results suggest that orexin-A acts on orexin 1 receptors in the brain to exert a gastroprotective action against ethanol. The vagal muscarinic system, nitric oxide, and prostaglandins may mediate the cytoprotective action of centrally administered orexin-A.

Lipopolysaccharide induces adipose differentiation-related protein expression and lipid accumulation in the liver through inhibition of fatty acid oxidation in mice.

BACKGROUND: In the present study, we examined the effect of lipopolysaccharide (LPS) on liver histopathology with special reference to lipid metabolism in mice. METHODS: Mice were injected with LPS intraperitoneally, and its effect on the liver was investigated pathologically and biochemically. RESULTS: Oil-red O staining and adipose differentiation-related protein (ADRP) immunohistochemistry demonstrated that injection of LPS transiently induced lipid accumulation and ADRP expression in hepatocytes, especially around the portal vein. Microscopic observation revealed that lipid accumulation started 12 h after LPS injection. Time-course studies showed that LPS rapidly, within 2 h, decreased hepatic expression of nuclear hormone receptors, including peroxisome proliferator-activated receptor (PPAR) alpha. LPS inhibited the expression of PPARalpha-target genes involved in fatty acid oxidation in the liver such as those coding for enoyl-CoA hydratase, acyl-CoA dehydrogenase, and carnitine palmitoyl transferase-1, whereas LPS also suppressed the expression of genes related to fatty acid synthesis such as those for fatty acid synthase, stearoyl-CoA desaturase, and acetyl-CoA carboxylase alpha. CONCLUSIONS: LPS induces transient lipid accumulation and expression of ADRP in the liver through inhibition of fatty acid oxidation by downregulation of the PPARalpha-related transcriptional mechanism.

Serine/threonine kinase AKT is frequently activated in human bile duct cancer and is associated with increased radioresistance.

The prognosis for patients with bile duct cancer (BDC) remains poor. Although BDC cells are essentially radioresistant, recent reports have suggested that radiation therapy, in addition to its palliative role in the management of BDC, may improve patient survival. A better understanding of the mechanisms that lead to cellular radioresistance may assist in the development of more effective BDC therapies based on radiotherapy in combination with radiosensitizing agents. The serine/threonine kinase AKT/protein kinase B, a downstream effector of phosphatidylinositol 3'-kinase, is a well-characterized kinase that is known to play a critical role in antiapoptotic signaling pathways. In this investigation, we sought to clarify the role of AKT signaling in the radioresistance in BDC cells. First, to examine whether activated AKT is expressed in BDCs, tumor specimens were obtained from 19 consecutive BDC cases. Immunohistochemical staining using an anti-phosphorylated-AKT antibody showed that phosphorylated (activated) AKT was expressed in cancer cells but not in neighboring normal mucosa in 16 cases (84.2%). Next, to evaluate the role of AKT activation in the regulation of BDC cell radiosensitivity, clonogenic assays were performed using the phosphatidylinositol 3'-kinase inhibitor LY294002 with and without irradiation. LY294002 inhibited AKT activation in BDC cells and, on irradiation, decreased clonogenic survival in a radiation dose-dependent manner. Only a small decrease in cell viability was observed in cells exposed to LY294002. Expression of constitutively active AKT in BDC cells resulted in decreased radiosensitivity, whereas a dominant-negative AKT increased radiosensitivity. Furthermore, constitutively active AKT also inhibited radiation-induced apoptosis. Collectively, these results indicate that activated AKT in BDC cells is associated with radioresistance and suggest that pharmacological or genetic modulation of AKT activity may have important therapeutic implications in BDC patients treated with radiation.