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A patient in her 60s was referred to our hospital with pancreatic enlargement. Laboratory data and endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) revealed a nonfunctioning pancreatic neuroendocrine tumor (WHO classification 2010 G2). Resection was contraindicated because of portal vein invasion and extensive collateral vascularization. Everolimus (10 mg/day) was started after seven months of treatment with S-1 (an oral formulation of tegafur with the modulators gimeracil and oteracil) following its insurance approval in Japan. Four months later, the patient developed cough and fever, and there was radiological and clinical evidence of Grade 2 everolimus-associated interstitial pneumonia (according to the Everolimus Proper-Usage Guide). Everolimus was replaced with steroid therapy (30 mg/day), resulting in immediate symptomatic improvement. After conclusion of steroid therapy, everolimus was restarted. The patient has since remained on a dosage of 10 mg/day of everolimus, with the tumor in a state of partial response.

In contrast to pancreatic ductal adenocarcinomas (PDAs), intraductal papillary mucinous neoplasms (IPMNs) frequently harbour GNAS mutations. To characterise GNAS-mutated pancreatic carcinomas, we examined mutations of GNAS and KRAS in 290 pancreatic adenocarcinomas and 77 pancreatic intraepithelial neoplasias (PanINs). In 64 % (39/61) of IPMNs and 37 % (11/30) of IPMN-associated adenocarcinomas, a GNAS mutation was found. GNAS mutations were frequent (78 %, 7/9) in mucinous carcinomas, with or without associated IPMN. In contrast, GNAS mutations were rarely observed in PDAs (1 %, 1/88) and PanINs (3 %, 2/77), and not at all in mucinous cystic neoplasms (MCNs) (0/10), neuroendocrine neoplasms (0/52), acinar cell neoplasms (0/16), serous cystadenomas (0/10), and solid-pseudopapillary neoplasms (0/14). We found GNAS mutations in 55/91 IPMNs with or without associated invasive carcinoma, solely in intestinal-type (78 %, 21/27) and gastric-type (62 %, 34/55) IPMNs. Of the IPMN-associated adenocarcinomas, mucinous-subtype tumours harboured GNAS mutations more frequently (83 %, 5/6) than tubular-subtype tumours (25 %, 6/24) (p = 0.02). We separately analysed GNAS in the adenocarcinoma and the IPMN component in the IPMN-associated adenocarcinomas. In all mucinous-subtype tumours, the two components exhibited identical genotypes. In contrast, the two components in 8 of 24 tubular-subtype tumours exhibited different genotypes, indicating intratumour heterogeneity. In conclusion, mucinous carcinomas with or without associated IPMN as well as IPMNs frequently harbour a GNAS mutation, reinforcing the notion that these constitute a spectrum of pancreatic tumours. Clinically and pathologically, these tumours are associated, but GNAS mutation sheds further light on this spectrum.

Background/objectives Despite advances in imaging techniques, diagnosis and management of pancreatic cystic lesions still remains challenging. The objective of this study was to determine the utility of cyst fluid analysis (CEA, CA 19-9, CA 125, amylase, and cytology) in categorizing pancreatic cystic lesions, and in differentiating malignant from benign cystic lesions. Methods A retrospective analysis of 68 patients with histologically and clinically confirmed cystic lesions was performed. Cyst fluid was obtained by surgical resection ( n = 45) or endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) ( n = 23). Cyst fluid tumor markers and amylase were measured and compared between the cyst types. Results Receiver operating characteristic (ROC) curve analysis of the tumor markers demonstrated that cyst fluid CEA provided the greatest area under ROC curve (AUC) (0.884) for differentiating mucinous versus non-mucinous cystic lesions. When a CEA cutoff value was set at 67.3 ng/ml, the sensitivity, specificity and accuracy for diagnosing mucinous cysts were 89.2%, 77.8%, and 84.4%, respectively. The combination of cyst fluid CEA content >67.3 ng/ml and cyst fluid CA 125 content >10.0 U/ml segregated 77.8% (14/18) of mucinous cystic neoplasms (MCNs) from other cyst subtypes. On the other hand, no fluid marker was useful for differentiating malignant versus benign cystic lesions. Although cytology (accuracy 83.3%) more accurately diagnosed malignant cysts than CEA (accuracy 65.6%), it lacked sensitivity (35.3%). Conclusions Our results demonstrate that cyst fluid CEA can be a helpful marker in differentiating mucinous from non-mucinous, but not malignant from benign cystic lesions. A combined CEA and CA 125 approach may help segregate MCNs from IPMNs.

Background The WHO classified pancreatic neuroendocrine neoplasms in 2010 as G1, G2, and neuroendocrine carcinoma (NEC), according to the Ki67 labeling index (LI). However, the clinical behavior of NEC is still not fully studied. We aimed to clarify the clinicopathological and molecular characteristics of NECs. Methods We retrospectively evaluated the clinicopathological characteristics, KRAS mutation status, treatment response, and the overall survival of eleven pNEC patients diagnosed between 2001 and 2014 according to the WHO 2010. We subclassified WHO-NECs into well-differentiated NEC (WDNEC) and poorly differentiated NEC (PDNEC). The latter was further subdivided into large-cell and small-cell subtypes. Results The median Ki67 LI was 69.1 % (range 40–95 %). Eleven WHO-NECs were subclassified into 4 WDNECs and 7 PDNECs. The latter was further separated into 3 large-cell and 4 small-cell subtypes. Comparisons of WDNEC vs. PDNEC revealed the following traits: hypervascularity on CT, 50 % (2/4) vs. 0 % (0/7) (P = 0.109); median Ki67 LI, 46.3 % (40–53 %) vs. 85 % (54–95 %) (P = 0.001); Rb immunopositivity, 100 % (4/4) vs. 14 % (1/7) (P = 0.015); KRAS mutations, 0 % (0/4) vs. 86 % (6/7) (P = 0.015); response rates to platinum-based chemotherapy, 0 % (0/2) vs. 100 % (4/4) (P = 0.067), and median survival, 227 vs. 186 days (P = 0.227). Conclusions The WHO-NEC category may be composed of heterogeneous disease entities, namely WDNEC and PDNEC. These subgroups tended to exhibit differing profiles of Ki67 LI, Rb immunopositivity and KRAS mutation, and distinct response to chemotherapy. Further studies for the reevaluation of the current WHO 2010 classification are warranted. Electronic supplementary material The online version of this article (doi:10.1007/s00535-014-0987-2) contains supplementary material, which is available to authorized users.

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumor of the gastrointestinal tract. However, little is known about the clinical presentation of GIST, especially small lesions. The purpose of the present study was to clarify the efficacy of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) for the diagnosis of GIST and to determine its clinical course.Pathological and clinical records of GIST extracted from our institutional database between 1996 and 2012 were reviewed. All GIST cases were diagnosed pathologically by surgical specimen or EUS-FNA. To examine the efficacy of EUS-FNA for the diagnosis of GIST, the pathological findings of EUS-FNA were compared with the surgical findings from resected cases. Next, to clarify the clinical presentation of GIST, imaging findings and changes in tumor size over time were evaluated in follow up.Of 84 cases of GIST, 67 were resected surgically after EUS-FNA; tumor size was20 mm in 19 patients, and ≥20 mm in 48 patients. For the diagnosis of small GIST20 mm, sensitivity and positive predictive value of EUS-FNA were 81.3% and 100%, respectively. A total of 27 patients with GIST was follow up for more than 1 year. Tumor size increased significantly during follow up. However, generalized linear analysis showed that there was no significant relationship between tumor size and follow up period.The present results showed that even small GIST can be correctly identified by EUS-FNA. Moreover, size of small GIST increased significantly during follow up.

Self-expandable metallic stents have mainly been used for the palliation of malignant gastric outlet obstruction (GOO). However, their use in long-term survivors and the feasibility, safety and benefit of additional intervention for stent dysfunction remain controversial. The present study examined the long-term benefits of endoscopic gastroduodenal stenting.We reviewed 61 patients treated with Niti-S stents at several hospitals and estimated the efficacy of stent intervention, stent patency, eating period and factors related to poor effectiveness.All 61 first stent interventions and 14 additional stent interventions (11 second interventions and 3 third interventions) were successfully carried out. Clinical success rates were 83.6% and 85.7%, and median stent patency was 214 days and 146 days (P = 0.47), respectively. Fifty patients could be treated with a first stent only, and 11 patients received additional stents. At the time of study termination or death, 70.0% of the former group and 63.6% of the latter group maintained oral intake (P = 0.71), and each 86% and 100% among the group could maintain oral intake for a period exceeding half of their remaining lives after first stent intervention. Karnofsky performance status ≤50 (P = 0.03), ascites (P = 0.009), and peritoneal dissemination (P = 0.001) appeared to be factors related to poor effectiveness.Despite the presence of factors related to poor effectiveness, endoscopic gastroduodenal stenting would be the first treatment of choice for GOO and provide long-term benefits. If stent dysfunction occurs, additional stent intervention enables continued oral intake safely.

We analyzed clinical features and genetic alterations in the noncancerous and cancerous biliary lesions obtained from pancreaticobiliary maljunction (PBM) patients. Gallbladder (GB) and bile duct (BD) lesions were obtained surgically from 36 patients with PBM, and polymerase chain reaction (PCR) methods were used to examine for mutations of the K-ras gene and the p53 gene and for microsatellite instability (MSI). The 36 cases were clinically classified into two types according to whether extrahepatic bile duct dilatation was present: a congenital choledochal dilatation (CCD) group (n = 20) and a noncongenital choledochal dilatation (NCCD) group (n = 16). In the NCCD group, all 16 GB specimens exhibited hyperplastic, dysplastic, and cancerous (n = 9) lesions, but no pathological lesions were detected in the 12 BD specimens. On the other hand, in the CCD group, pathological examination revealed lesions, including 8 cancerous lesions, in 60% of the 20 GB specimens and lesions, and including 8 cancerous lesions, in 65% of the 20 BD specimens. K-ras mutations and MSI were detected in 33.3% and 0%, respectively, of 9 hyperplastic lesions, 28.6% and 85.7%, respectively, of 7 dysplastic lesions, and 60.0% and 80.0%, respectively, of 25 cancerous lesions (p

Associations between Helicobacter pylori (HP) infection and lifestyle factors have been reported by several authors, but little is known about the host factors associated with the infection. This study aims to examine the infection rate of HP according to gene polymorphisms of interleukin (IL)-1A, IL-1B, and IL-1RN, and to investigate the interactions with lifestyle factors. Subjects were 241 non-cancer outpatients who had participated in a HP eradication program. Polymorphisms at - 889 (T to C) of IL-1A, at - 31 (C to T; T allele makes a TATA box) and - 511 (C to T) of IL-1B, and at intron 2 (86-bp VNTR (variable number of tandem repeats)) of IL-1RN were genotyped by PCR (polymerase chain reaction), PCR-RFLP (restriction fragment length polymorphism) and PCR-CTPP (PCR with confronting two-pair primers). It was found that IL-1B polymorphisms at - 31 and - 511 were near-completely linked, but in the opposite way to that in Caucasians; - 31C / - 511T and - 31T / - 511C alleles were dominant in the present subjects. The HP infection rate was substantially different among the genotypes of IL-1B C - 31T; 45.2% (19 / 42) for the C / C, 67.7% (90 / 133) for the C / T, and 63.6% (42 / 66) for the T / T. The age-sex adjusted odds ratio (OR) relative to the C / C genotype was 2.32 (95%CI (confidence interval), 1.10 - 4.92) for the T / C genotype and 2.46 (1.06 - 5.74) for the T / T genotype. The OR for the T / T genotype was significantly modified by smoking status; interaction term = 14.6 (1.12 - 190). The polymorphisms of IL-1A and IL-1RN were not associated with the infection rate. The results suggested that the T allele of IL-1B C - 31T is associated with vulnerability to persistent HP infection, and that the vulnerability is modified by smoking.

Background: Endoscopic biopsy is routine in gastrointestinal disease; similarly, histopathologic diagnosis is desirable in gallbladder disease. In this study we examined the clinical usefulness and the problems associated with transpapillary gallbladder biopsy. Methods: Transpapillary gallbladder biopsy was attempted in 9 patients with gallbladder disease. After inserting a catheter sheath into the gallbladder using a guidewire via the transpapillary route without sphincterotomy, we inserted a biopsy forceps into the lumen of the sheath up to the gallbladder lumen and obtained specimens. Results: We could obtain sufficient specimens for histopathologic diagnosis in 8 of 9 cases (88.9%). Of the 8 successful cases, targeted specimens were obtained in 7 (87.5%). Diagnostic accuracy with respect to malignant versus benign disease was 100% (2 of 2) and 83.3% (5 of 6), respectively. There were no complications. Conclusion: Transpapillary gallbladder biopsy is a clinically useful technique because it facilitates histopathologic diagnosis and therefore guides the choice of therapy.

Dear Editor: Familial adenomatous polyposis (FAP) is an inherited disease characterized by the development of hundreds of colorectal adenomas, leading to a 100% lifetime risk of colorectal cancer. Thus, a prophylatic proctocolectomy is recommended for patients with FAP to prevent colorectal cancer. Four surgical strategies are available for patients with FAP: proctocolectomy with permanent ileostomy, proctocolectomy with Kock’s pouch continent ileostomy (Kock), colectomy with ileorectal anastomosis (IRA), and restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA). IRA produces good functional results, and this surgery is associated with less morbidity than the other procedures. However, continuing endoscopic surveillance for adenomas in the rectum is necessary, and there is a 13% to 25% cumulative risk of rectal cancer after 15 to 25 years, despite surveillance. On the other hand, both Kock’s pouch construction and IPAA (pouch patients) theoretically eliminate the risk of colorectal cancer and adenomas, and perhaps the need for further lower gastrointestinal surveillance. However, development of ileal adenomas in patients who undergo Kock or IPAA procedures is becoming evident. In a recent study, Parc et al. showed the risk of adenoma development in the ileal pouch was 7%, 35%, and 75% at 5, 10, and 15 years of follow-up, respectively. Furthermore, there are a few reports of the development of adenocarcinomas in the pouch of FAP patients. Although most of the cancers that develop in the pouch are likely from residual rectal or anal transitional epithelium, there are four reports of cancers arising from the ileal pouch mucosa in patients with FAP. The etiology of these true pouch cancers seem to be different from the cancers arising from residual rectal or anal transitional epithelium, and the risks associated with these true pouch are controversial. Here, we report two patients with adenocarcinoma developing in the ileal pouch mucosa. A 55-year-old female presented in 1989, at age 46 years, with gastric adenoma with high-grade dysplasia. A barium enema was performed as part of preoperative evaluation which showed a rectal tumor with multiple synchronous colorectal polyps, and a diagnosis of FAP was made. Her parents and four siblings were unaffected, and it seems that she had a de novo genetic mutation. Colonoscopy confirmed the presence of a rectal tumor and multiple colorectal polyps. Biopsy from the rectal tumor showed a well-differentiated adenocarcinoma. An IPAA was performed. The resected colon had an estimated 100 polyps, and the rectum had an estimated 150 polyps. Histology of the surgical specimen confirmed many tubular adenomas distributed throughout the colon and rectum, and a moderately differentiated rectal adenocarcinoma of 45 mm size M. Tajika (*) : T. Nakamura Department of Endoscopy, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan e-mail: mtajika@aichi-cc.jp

A case of carcinoid of the accessory papilla which is extremely rare is reported. A 52-year-old man consulted another a hospital for hematemesis and was diagnosed as gastric ulcer. During the treatment of gastric ulcer, a submucosal tumor of the duodenum was detected and he was sent to the hospital. The tumor was located on the anterior wall of the duodenal second portion, at 2.5cm oral side of Vater papilla, measuring about 10mm in diameter. Accessory papilla was not identified on examinations. Biopsy showed carcinoid cells invaded the smooth muscle. Pancreaticoduodenectomy with adjacent lymph node dissection was performed. Resected specimen showed the carcinoid tumor invaded submucosal layer in the accessory (papilla, measuring 12×12mm, with adjacent lymoh node metastasis. The careful choice of treatment is needed in treatment of carcinoid tumor near the accessory papilla, even if, it is small in size and not invaded to muscular layer. And the smooth muscle in biopsy specimen is a special bundle of smooth muscle in the accessory papilla like a sphincter of Oddi.

Endoscopic ultrasound-guided fine-needle tattooing (EUS-FNT) is an ideal technique for preoperative marking of lesions detected on preoperative examination. Although India ink has been used for endoscopic tattooing, there have been numerous reports of complications associated with its use. This is the first report of EUS-FNT using indocyanine green (ICG) and describes its use for preoperative marking of a tumor in a 78-year-old man with multiple pancreatic tumors. There were no complications associated with the EUS-FNT procedure and it is suggested that ICG is a more suitable dye for tattooing of pancreatic lesions than India ink, being far less frequently associated with side effects.

Three-dimensional (3D) intraductal ultrasonography (IDUS) is more useful than two-dimensional IDUS for the diagnosis of pancreatobiliary disease. We investigated the advantages and disadvantages of the transpapillary approach for 3D-IDUS using a newly developed system for pancreatobiliary application. In total 12 patients with a sufficiently wide orifice were examined, bile duct (BD) scanning being successful in 100% of attempted cases and main pancreatic duct (MPD) scanning in 85.7%. In all cases, acceptable radial and linear images were obtained and 3D diagnosis was accomplished. However, several primary problems were experienced; 1) The 3D probe is relatively inflexible, having a thick shaft and a long tip, such that insertion into the BD or MPD can be somewhat difficult; 2) Clear images of the BD or MPD wall were not always obtained because of artifacts produced by the 3D probe itself; 3) In some cases, linear images could not be reconstructed with BD or MPD scanning despite sufficiently clear radial scan images. In the future, development of new 3D probes with more flexible and thinner shafts, and shorter tips, should considerably enhance the diagnostic capacity of IDUS for the pancreatobiliary system.

Intraductal ultrasound (IDUS) probes mounted with 30 MHz or 20 MHz transducers were evaluated in the diagnosis of 239 patients with pancreatic disease (including 48 cancers, 90 mucin-producing tumors, seven islet-cell tumors, two metastatic pancreatic tumors, seven serous cystadenomas, one pancreatic teratoma, three solid cystic tumors, 49 cases of chronic pancreatitis, 25 cases of focal pancreatitis, and seven cases of pancreatolithiasis). The probe was inserted via the papilla into the main pancreatic duct. In terms of resolution, IDUS at 20 MHz was able to image cystic lesions of less than 30 mm in diameter and solid lesions of less than 20 mm in diameter. With regard to vessels, IDUS was able to image the entire cross-section of the portal vein and other large veins. IDUS was useful in detecting carcinoma in situ and small tumors, in assessing the intraductal spread of the tumor and its pancreatic parenchymal invasion in mucin-producing tumors of the main duct, and in assessing the indications for surgery by revealing mural nodules in mucin-producing tumors of the ductal branches. IDUS was also useful in evaluating the feasibility of partial resection of the tumor in mucin-producing tumors of the ductal branches and pancreatic islet-cell tumors, in accurately locating multiple lesions in pancreatic islet-cell cancer, and in differentiating benign from malignant cases of localized stenosis of the main pancreatic duct related to pancreatic stenting. With IDUS, the site of pancreatic stones could be identified in order to assess the need for endoscopic treatments such as stenting of the pancreatic duct and the bile duct, and the use of pulsed-dye laser treatment under pancreatoscopy for pancreatic stones. Acute pancreatitis as a complication occurred in one of the 239 patients who underwent IDUS (0.4%). An awareness of the limitations and usefulness of IDUS in evaluating pancreatic diseases can contribute to the treatment of these conditions.

閉塞性黄疸か否かは通常,体外式超音波検査で容易に診断されるが,原因疾患の究明には限界がある.閉塞性黄疸をきたす疾患の中でも特に中・下部胆管および乳頭部に発生する病変のEUSによる診断能は極めて高い.閉塞性黄疸が疑われた症例に対しては経皮的あるいは経乳頭的なドレナージなどの可及的な減黄処置が必要であるが,可能な限り早期にEUSを実施し治療法を決定すべきである.

Background: CD133 has been identified as a cancer stem cell marker for pancreatic ductal adenocarcinoma. Although leucine-rich-repeat-containing G-protein-coupled receptor 5 (LGR5), a marker of intestinal stem cells, has been shown to be on a higher level of the stem cell hierarchy than CD133, the expression and function of LGR5 in pancreatic cancer tissue remains unclear. This study investigated tissue expression of LGR5 and CD133 in resected pancreatic cancer tissue. Methods: LGR5 and CD133 expression was immunohistochemically examined in 9 patients with pancreatic ductal adenocarcinoma who underwent resection. Results: LGR5 was expressed in the cytoplasm of pancreatic cancer cells in 4 of 9 cases. CD133 was not detected in cancerous tissue. In non-neoplastic tissue, LGR5 was expressed in the basolateral membrane of a subset of endocrine cells. Conversely, CD133 was expressed in the apical membrane of small duct cells. Co-localization of LGR5 and CD133 was not found in either neoplastic or non-neoplastic tissue. LGR5 expression in pancreatic cancer cells showed no statistically significant correlation with survival after surgery. Conclusion: We have demonstrated that LGR5 is expressed in the cytoplasm of pancreatic adenocarcinoma cells, and the basolateral membrane of a subset of endocrine cells of the human pancreas. Further investigation is required to clarify any prognostic significance of LGR5 expression.

Background: Cigarette smoking is a well-established risk factor of pancreatic cancer (PC). Although an association between nicotine dependence phenotype, namely time to first cigarette (TTFC) after waking, and the risk of several smoking-related cancers has been reported, an association between TTFC and PC risk has not been reported. We assessed the impact of smoking behavior, particularly TTFC, on PC risk in a Japanese population. Materials and Methods: We conducted a case-control study using 341 PC and 1,705 non-cancer patients who visited Aichi Cancer Center in Nagoya, Japan. Exposure to risk factors, including smoking behavior, was assessed from the results of a self-administered questionnaire. The impact of smoking on PC risk was assessed with multivariate logistic regression analysis adjusted for potential confounders to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Results: Cigarettes per day (CPD) and/or smoking duration were significantly associated with PC risk, consistent with previous studies. For TTFC and PC risk, we found only a suggestive association: compared with a TTFC of more than 60 minutes, ORs were 1.15 (95%CI, 0.65- 2.04) for a TTFC of 30-60 minutes and 1.35 (95%CI, 0.85-2.15) for that of 0-30 minutes (p trend=0.139). After adjustment for CPD or smoking duration, no association was observed between TTFC and PC. Conclusions: In this study, we found no statistically significant association between TTFC and PC risk. Further studies concerning TTFC and PC risk are warranted.

Bile duct cancer (BDC) has a lower propensity for distant metastasis during the early part of its natural history, and local extension into adjacent vessels and longitudinal intraductal extension are of critical prognostic importance. Superficial intraductal spread (SIDS) is a characteristic feature of this tumor and is associated with a more-differentiated phenotype and a less-aggressive clinical course. However, the presence of SIDS correlates with positive resection margins after surgery. Hence, preoperative identification of the exact proximal and distal margins is important for deciding whether the surgical approach should comprise extrahepatic bile duct resection with or without pancreatoduodenectomy (PD) and whether rightor left-sided hepatectomy is needed. Direct cholangioscopic intraductal visualization, with or without narrow-band imaging, is important for evaluating SIDS. Despite these enhanced imaging techniques, stent-induced or cholangitis-induced mucosal changes are often difficult to differentiate from neoplastic involvement in a segment of bile duct, without tissue sampling. The use of intraductal biopsy specimens for diagnosing SIDS of BDC can be performed by percutaneous transhepatic cholangioscopy, but this technique is time consuming, invasive, and might result in cancer seeding. Hence, using an endoscopic route for obtaining transpapillary biopsy specimens may be preferable. Although the use of forceps biopsy in the diagnosis of stenotic bile duct lesions with fluoroscopic targeting or

Purpose The present phase III study was designed to investigate the noninferiority of S-1 alone and superiority of gemcitabine plus S-1 compared with gemcitabine alone with respect to overall survival. Patients and Methods The participants were chemotherapy-naive patients with locally advanced or metastatic pancreatic cancer. Patients were randomly assigned to receive only gemcitabine (1,000 mg/m2 on days 1, 8, and 15 of a 28-day cycle), only S-1 (80, 100, or 120 mg/d according to body-surface area on days 1 through 28 of a 42-day cycle), or gemcitabine plus S-1 (gemcitabine 1,000 mg/m2 on days 1 and 8 plus S-1 60, 80, or 100 mg/d according to body-surface area on days 1 through 14 of a 21-day cycle). Results In the total of 834 enrolled patients, median overall survival was 8.8 months in the gemcitabine group, 9.7 months in the S-1 group, and 10.1 months in the gemcitabine plus S-1 group. The noninferiority of S-1 to gemcitabine was demonstrated (hazard ratio, 0.96; 97.5% CI, 0.78 to 1.18; P < .001 for noninferiority), whereas the superiority of gemcitabine plus S-1 was not (hazard ratio, 0.88; 97.5% CI, 0.71 to 1.08; P = .15). All treatments were generally well tolerated, although hematologic and GI toxicities were more severe in the gemcitabine plus S-1 group than in the gemcitabine group. Conclusion Monotherapy with S-1 demonstrated noninferiority to gemcitabine in overall survival with good tolerability and presents a convenient oral alternative for locally advanced and metastatic pancreatic cancer.

It is controversial whether patients with gastric marginal zone lymphomas of mucosa associated lymphoid tissue (MALT) have higher risk of second malignancies. The aim of this study was to define the risk of second malignancies in these patients.We analyzed prospective follow-up data of 146 consecutive patients with gastric MALT lymphoma treated at Aichi Cancer Center Hospital and compared the incidence of second malignancies with that in the general population. We calculated the standardized incidence ratio (SIR), using age- and sex-specific incidence rates from the Aichi Cancer Registry.The median follow-up period was 74 months. A total of 27 tumors occurred in 22 patients (15.1%), including 19 solid tumors. Of these, nine tumors were detected concomitantly with, and 18 tumors following, the diagnosis of gastric MALT lymphoma. Four patients had two second malignancies each. For the entire group, the SIR of an additional malignancy was 3.39 (95% confidence interval [CI] 2.11-4.66). An increased incidence of solid tumors (SIR 2.91 [1.60-4.22]) and hematologic malignancies (SIR 5.54 [1.70-9.38]) were seen. In addition, there was increased risk for development of second malignancies during follow up (SIR 2.26 [1.21-3.30]). Chemotherapy for treatment of MALT was an independent risk factor for second malignancies (age-sex adjusted hazard ratio 3.98 [1.47-10.79].Compared with the general population, patients with gastric MALT lymphoma are at increased risk for second malignancies, including gastric cancer.

The impact of alcohol on the risk of stomach cancer is controversial. Although aldehyde dehydrogenase 2 (ALDH2) Glu504Lys (rs671) polymorphism has a strong effect on acetaldehyde metabolism, little is known about its impact on stomach cancer risk when combined with alcohol drinking. This case-control study included a total of 697 incident stomach cancer case subjects and 1372 non-cancer control subjects who visited Aichi Cancer Center between 2001 and 2005. We estimated odds ratios (OR) and 95% confidence intervals (CI) for ALDH2 genotypes and alcohol consumption using logistic regression models after adjustment for potential confounders, including Helicobacter pylori infection. The ALDH2 504Lys allele was associated with the risk of stomach cancer, with adjusted ORs of 1.40 (95% CI, 1.11-1.76) for Glu/Lys and 1.73 (1.12-2.68) for Lys/Lys compared with Glu/Glu. Heavy drinking was associated with risk (OR 1.72, 1.17-2.52) after adjustment for ALDH2 genotype and other confounders. Moreover, ORs for heavy drinking were 1.28 (0.77-2.12) for those with ALDH2 Glu/Glu and 3.93 (1.99-5.79) for those with the ALDH2 Lys allele relative to non-drinkers with the Glu/Glu genotype (P for interaction = 0.0054). In conclusion, ALDH2 and alcohol drinking showed interaction for risk factors of stomach cancer, indicating that acetaldehyde plays a role in stomach carcinogenesis.

Background & Aims Cells of tumors associated with chronic inflammation frequently have altered patterns of DNA methylation, including hepatocellular carcinomas. Chronic hepatitis has also been associated with aberrant DNA methylation, but little is known about their relationship. Methods Pyrosequencing was used to determine the methylation status of cultured Huh7.5.1 hepatoma cells after hepatitis C virus (HCV) infection. We also studied mice with severe combined immunodeficiency carrying the urokinase-type plasminogen activator transgene controlled by an albumin promoter (urokinase-type plasminogen activator/severe combined immunodeficient mice), in which up to 85% of hepatocytes were replaced by human hepatocytes (chimeric mice). Mice were given intravenous injections of hepatitis B virus (HBV) or HCV, liver tissues were collected, and DNA methylation profiles were determined at different time points after infection. We also compared methylation patterns between paired samples of hepatocellular carcinomas and adjacent nontumor liver tissues from patients. Results No reproducible changes in DNA methylation were observed after infection of Huh7.5.1 cells with HCV. Livers from HBV- and HCV-infected mice had genome-wide, time-dependent changes in DNA methylation, compared with uninfected urokinase-type plasminogen activator/severe combined immunodeficient mice. There were changes in 160 ± 63 genes in HBV-infected and 237 ± 110 genes in HCV-infected mice. Methylation of 149 common genes increased in HBV- and HCV-infected mice; methylation of some of these genes also increased in hepatocellular carcinoma samples from patients compared with nontumor tissues. Expression of Ifng , which is expressed by natural killer cells, increased significantly in chimeric livers, in concordance with induction of DNA methylation, after infection with HBV or HCV. Induction of Ifng was reduced after administration of an inhibitor of natural killer cell function (anti−asialo GM1). Conclusions In chimeric mice with humanized livers, infection with HBV and HCV appears to activate a natural kill cell−dependent innate immune response. This contributes to the induction and accumulation of aberrant DNA methylation in human hepatocytes.

A prospective clinical study was conducted to evaluate the safety, feasibility, and efficacy of endoscopic ultrasound (EUS)-guided choledochoduodenostomy (CDS) with direct metallic stent placement using a prototype forward-viewing echoendoscope. The indication for EUS – CDS in this study was lower biliary obstruction only, and not failed endoscopic biliary drainage, because the aim was to evaluate EUS – CDS for first-line biliary drainage therapy. The technical and functional success rates were 94 % (17 /18) and 94 % (16 /17), respectively. Early complications (focal peritonitis) were encountered in two patients (11 %). No patients developed late complications. EUS – CDS with direct metallic stent placement using a forward-viewing echoendoscope was generally feasible and effective for malignant distal biliary tract obstruction. The forward-viewing echoendoscope was useful, especially for deploying the metallic stent.

Acinar cell carcinomas (ACCs) of the pancreas are characterized by the histological and immunohistochemical features of acinar cell differentiation. Recently, BCL10, originally identified as a recurrent t(1;14)(p22;q32) translocation in MALT B-cell lymphoma, was found to be immunohistochemically positive in some solid tumors, including ACC. To evaluate its diagnostic efficacy, we performed BCL10 immunohistochemistry and evaluated molecular markers correlated to pancreatic tumor lineages (neuroendocrine markers and a mutation analysis of KRAS and GNAS) using samples from 126 pancreatic tumors (17 ACCs, 24 pancreatic ductal adenocarcinomas, 4 adenosquamous carcinomas, 9 intraductal papillary mucinous neoplasms, 10 mucinous cystic neoplasms, 44 neuroendocrine tumors, 9 serous cystic tumors and 10 solid-pseudopapillary neoplasms). BCL10 was exclusively expressed in normal acini. In pancreatic tumors, 14 of 17 (82%) ACCs and 2 of 4 (50%) adenosquamous carcinomas were positive, while the other subtypes were almost negative. We subsequently examined the diagnostic utility of BCL10 in endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) specimens using 57 pancreatic tumors. BLC10 correctly identified ACCs (9/13) and adenosquamous carcinomas (2/4) but none of the other subtypes (n = 41). Therefore, we suggested that BCL10 expression is a useful marker for acinar cell differentiation, particularly in the diagnosis of EUS-FNA specimens.

The development of pyloric mucosal metaplasia (PMM) with regard to cellular differentiation in the human gallbladder was studied by mucln staining (paradoxical concanavalin A (Con A), galactose oxidase-Schiff (GOS) and alcian blue (pH 2.5) PAS (AB-PAS) and immunohistochemistry (pepsino-gen II (Pgll) and SH-9, and proliferating cell nuclear antigen (PCNA). PMM was divided into three stages of development by three-dimensional (3D) computer graphic reconstruction analysis. In the early stage, a transitional zone of PCNA positive cells was observed between areas of SH-9 and/or GOS reactive cells and class III and/or Pg II positive cells in flat monolayered epithelium. In the middle stage, shallow pits became apparent as areas enlarged, with these becoming deeper in the advanced stage, whereby SH-9 and/or GOS reactive cells and class III and/or Pg II positive cells were observed at the upper and lower portion of the pits, respectively, with PCNA-positive cells forming a narrow zone between the two cell populations. Consequently, the structure of PMM gradually resembles that of the normal gastric pyloric mucosa.

Peptic ulcer is one of the most common gastrointestinal disorders with complex etiology. Recently we conducted the genome wide association study for duodenal ulcer and identified disease susceptibility variations at two genetic loci corresponding to the Prostate stem cell antigen (PSCA) gene and the ABO blood group (ABO) gene. Here we investigated the association of these variations with gastric ulcer in two Japanese case-control sample sets, a total of 4,291 gastric ulcer cases and 22,665 controls. As a result, a C-allele of rs2294008 at PSCA increased the risk of gastric ulcer with odds ratio (OR) of 1.13 (P value of 5.85×10(-7)) in an additive model. On the other hand, SNP rs505922 on ABO exhibited inconsistent result between two cohorts. Our finding implies presence of the common genetic variant in the pathogenesis of gastric and duodenal ulcers.

A patient with a cholecystocolic fistula, complicating cholecysto-choledocholithiasis, was treated endoscopically with gallbladder observation by peroral cholecystoscopy (POCCS). The patient was a 71-year-old female admitted to our hospital for investigation and treatment of biliary stones and a cholecystocolic fistula. Endoscopic lithotripsy and extracorporeal shock wave lithotripsy (ESWL) were performed after endoscopic sphincterotomy, and the gallbladder was subsequently investigated using a duodenoscope/ cholangioscope of the mother and baby type. Full distension of the gallbladder with saline solution allowed POCCS observation of the entire surface. The gallbladder mucosa was smooth, and neither stones nor tumors were observed. Though the cholecystocolic fistula itself could not be observed, we concluded that it had resulted from cholecystitis. Peroral cholecystoscopy is thus a useful method of investigating the gallbladder in such cases.

For the purpose of improving the ease and reliability of catheter insertion into the cystic duct and gallbladder, we developed a new combination method utilizing an ultrathin fiberscope (miniscope, 0.8 mm), a guidewire (0.25 inches) and a shape memory alloy, bendable, catheter (SMA catheter, 2.6 mm). The main feature of the SMA catheter, which incorporates a micro-actuator, is that its tip can be bent by remote control as desired. The SMA catheter could be inserted successfully into the cystic duct using a guide-wire under direct miniscope vision in two patients with gallbladder lesions. Moreover, after the miniscope had been inserted through the SMA catheter into the gallbladder, its maneuverability enhanced observation of the mucosa. This combination method should afford new diagnostic and therapeutic approaches to gallbladder disease.

Pancreatic cancer is highly lethal malignancy despite the recent clinical advancement. Since pancreatic cancer is often difficult to diagnose, there is an urgent need to develop minimally invasive biomarkers for detection. Epigenetic alterations have emerged as a common hallmark of many types of human cancers as well as pancreatic cancer. The presence of cell-free DNA (cfDNA) in blood stream has been known and cfDNA possesses tumor-related genetic alterations as well as epigenetic alterations. Therefore, invention of blood-based DNA methylation biomarkers and their high-sensitive detection system might be a promising diagnostic tool for pancreatic cancer. In order to establish the diagnostic biomarkers, first, we performed genome-wide DNA methylation analysis of 38 EUS-FNA specimens of pancreatic cancer with clinical stage III-IV using Illumina Infinium HumanMethylation450 BeadChip. We further analyzed the DNA methylation profiles of other types of tumors in the public database, TCGA (The Cancer Genome Atlas), and identified five marker genes, which were specifically methylated in pancreatic cancers. In addition, analysis of DNA methylation status of pancreas cancers comparing 10 normal tissues in TCGA data set revealed that 99% of tumors were methylated at least one of the five markers (sensitivity, 98.9%; specificity, 44%). We validated these methylation markers in different FNA sample set (n = 19) by bisulfite pyrosequencing or quantitative methylation specific PCR and found that 18/19 (95%) cases were methylated in at least one marker (AUC = 0.95). Finally, we performed methylation analysis in cfDNA from pancreatic cancer patients. From our preliminary data, we could detect aberrant DNA methylation in cfDNA from pancreatic cancer patients. We identified potential DNA methylation biomarkers for the diagnosis of pancreatic cancers and these markers might be applicable for detecting cancer in cfDNA. Citation Format: Keiko Shinjo, Keisuke Katsushima, Genta Nagae, Hiroyuki Aburatani, Kenji Yamao, Yutaka Kondo. Development of DNA methylation biomarkers for pancreatic cancer diagnosis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4448.

e14587Background: We conducted a multicenter phase II study using peptide vaccine cocktail named OCV-C01 containing epitope peptides derived from KIF20A, VEGFR1, and VEGFR2 combined with gemcitabin...

The recurrence rates of Hepatocellular carcinoma (HCC) are high, necessitating novel and effective adjuvant therapies. Therefore, we conducted a phase II study of glypican-3 (GPC3) peptide vaccine as an adjuvant therapy for HCC patients. Forty-one patients with initial HCC who had undergone surgery or radiofrequency ablation (RFA) were analyzed in this phase II, open-label, single-arm trial. Ten vaccinations were performed for 1 y after curative treatment. We also investigated case-control subjects, where selected patients treated surgically during the same period were analyzed. The expression of GPC3 in the available primary tumors was determined by immunohistochemical analysis. Six patients received RFA therapy while 35 received surgery. The recurrence rate tended to be lower in the 35 patients treated with surgery plus vaccination compared to 33 patients who underwent surgery alone (28.6% vs. 54.3% and 39.4% vs. 54.5% at 1 and 2 y, respectively; p = 0.346, 0.983). Twenty-five patients treated with surgery and vaccination had GPC3-positive tumors; the recurrence rate in this group was significantly lower compared to that in 21 GPC3-positive patients who received surgery only (24% vs. 48% and 52.4% vs. 61.9% at 1 and 2 y, respectively; p = 0.047, 0.387). The GPC3 peptide vaccine improved the 1-y recurrence rate in patients with GPC3-positive tumors. This study demonstrated that GPC3 expression by the primary tumor may be used as a biomarker in a putative larger randomized clinical trial to determine the efficacy of the GPC3-derived peptide vaccine.

Background: Intraoperative localization of polypectomy sites is critical for laparoscopic and open surgery, but conventional methods of marking the colorectum are sometimes unreliable. A new two-step method for marking polypectomy sites for identification during laparoscopic and open operations is described. Methods: Eighteen patients with postpolypectomy lesions necessitating preoperative marking were enrolled in this study. A physiologic saline solution was endoscopically injected into the submucosa to produce an artificial submucosal elevation (pseudopolyp). A small volume of India ink was then injected into the submucosal elevation (pseudopolyp) with a separate needle. Results: The two-step method was easily applied for all lesions without complication. At surgery, all lesions were immediately visualized. Conclusion: The two-step tattooing method proved to be easy, safe, and accurate for marking polypectomy sites.

AIM: To evaluate the possibility of reducing the volume of polyethylene glycol (PEG)-electrolyte solution using adjunctive mosapride citrate for colonoscopy preparation. METHODS: This was a single-center, prospective, randomized, investigator-blinded, non-inferiority study involving 252 patients of both sexes, aged from 20 to 80 years, scheduled for screening or diagnostic colonoscopy in our department. A total of 126 patients was randomized to receive 1.5 L PEG-electrolyte solution plus 15 mg of mosapride (1.5 L group), and 126 received 2 L PEG-electrolyte solution plus 15 mg of mosapride (2 L group). Patients completed a questionnaire on the acceptability and tolerability of the bowel preparation process. The efficacy of bowel preparation was assessed using a 5-point scale based on the Aronchick scale. The primary end point was adequate bowel preparation rates (score of excellent/good/fair) vs (poor/inadequate). Acceptability and tolerability, as well as disease detection, were secondary end points. RESULTS: A total of 244 patients was included in the analysis. There were no significant differences between the 2 L and 1.5 L groups in age, sex, body mass index, number of previous colonoscopies, and the preparation method used previously. The adequate bowel preparation rates were 88.5% in the 2 L group and 82.8% in the 1.5 L group [95% lower confidence limit (LCL) for the difference = -14.5%, non-inferiority P = 0.019] in the right colon. In the left colon, the adequate bowel preparation rates were 89.3% in the 2 L group and 81.1% in the 1.5 L group (95% LCL = -17.0%, non-inferiority P = 0.066). Compliance, defined as complete (100%) intake of the PEG solution, was significantly higher in the 1.5 L group than in the 2 L group (96.8% vs 85.7%, P = 0.002). The proportion of abdominal distension (none/mild/moderate/severe) was significantly lower in the 1.5 L group than in the 2 L group (36/65/22/3 vs 58/48/18/2, P = 0.040). Within the subgroup who had undergone colonoscopy previously, a significantly higher number of patients in the 1.5 L group than in the 2 L group felt that the current preparation was easier than the previous one (54.1% vs 28.0%, P = 0.001). The disease detection rate was not significantly different between the two groups. CONCLUSION: Although the 1.5 L group had better acceptability and tolerability, 15 mg of mosapride may be insufficient to compensate for a 0.5-L reduction of PEG solution.

BACKGROUND Although several reports have described a possible association between DNA repair genes and pancreatic cancer (PC) in smokers, this association has not been fully evaluated in an Asian population. We assessed the impact of genetic polymorphisms in the base excision repair (BER) pathway on PC risk among Japanese. METHODS This case-control study compared the frequency of 5 single-nucleotide polymorphisms (SNPs) of BER genes, namely rs1052133 in OGG1, rs1799782 and rs25487 in XRCC1, rs1130409 in APE1, and rs1136410 in PARP1. SNPs were investigated using the TaqMan assay in 185 PC cases and 1465 controls. Associations of PC risk with genetic polymorphisms and gene-environment interaction were examined with an unconditional logistic regression model. Exposure to risk factors was assessed from the results of a self-administered questionnaire. We also performed haplotype-based analysis. RESULTS We observed that the minor allele of rs25487 in XRCC1 was significantly associated with PC risk in the per-allele model (odds ratio = 1.29, CI = 1.01-1.65; trend P = 0.043). Haplotype analysis of XRCC1 also showed a statistically significant association with PC risk. No statistically significant interaction between XRCC1 polymorphisms and smoking status was seen. CONCLUSIONS Our findings suggest that XRCC1 polymorphisms affect PC risk in Japanese.

To evaluate the efficacy and safety of adjunctive mosapride citrate for bowel preparation before colonoscopy.We conducted a randomized, double-blind, placebo-controlled study with mosapride in addition to polyethylene glycol (PEG)-electrolyte solution. Of 250 patients undergoing colonoscopy, 124 were randomized to receive 2 L PEG plus 15 mg of mosapride citrate (mosapride group), and 126 received 2 L PEG plus placebo (placebo group). Patients completed a questionnaire reporting the acceptability and tolerability of the bowel preparation process. The efficacy of bowel preparation was assessed by colonoscopists using a 5-point scale based on Aronchick's criteria. The primary end point was optimal bowel preparation rates (scores of excellent/good/fair vs poor/inadequate).A total of 249 patients were included in the analysis. In the mosapride group, optimal bowel preparation rates were significantly higher in the left colon compared with the placebo group (78.2% vs 65.6%, P0.05), but not in the right colon (76.5% vs 66.4%, P = 0.08). After excluding patients with severe constipation, there was a significant difference in bowel preparation in both the left and right colon (82.4% vs 66.7%, 80.8% vs 67.5%, P0.05, P0.01). The incidence of adverse events was similar in both groups. Among the subgroup who had previous colonoscopy experience, a significantly higher number of patients in the mosapride group felt that the current preparation was easier compared with patients in the placebo group (34/72 patients vs 24/74 patients, P0.05).Mosapride citrate may be an effective and safe adjunct to PEG-electrolyte solution that leads to improved quality of bowel preparation, especially in patients without severe constipation.

Although recent reports indicate that K-ras mutation status is a biomarker that acts as a prognostic factor, only a few analyses of K-ras mutation subtypes have been published. In addition, there are no reports that analyze overall survival and prognostic factors according to K-ras mutation status and subtypes in only unresectable pancreatic cancer (PC) determined from tissues obtained by endoscopic ultrasound-guided fine-needle aspiration.We retrospectively analyzed 242 patients who were diagnosed as having unresectable PC with available histological diagnosis. Clinical data collected included sex, age, Eastern Cooperative Oncology Group performance status, carbohydrate antigen (CA) 19-9, primary tumor location, stage (local or metastatic) according to TNM staging, first-line chemotherapy, K-ras mutation status and subtypes (G12D, G12V, and G12R), and overall survival. We analyzed the negative prognostic factors for reduced overall survival in unresectable PC patients using these data.From multivariate analysis, CA19-9 ≥1000 U/ml (hazard ratio [HR] 1.78, 95 % confidence interval [CI] 1.28-2.46, P0.01), metastatic stage (HR 2.26, 95 % CI 1.58-3.24, P0.01), and mutant-K-ras (HR 1.76, 95 % CI 1.03-3.01, P = 0.04) were negative prognostic factors, indicating a reduced survival. Among the patients who had K-ras mutation subtypes, CA19-9 ≥1000 U/ml (HR 1.65, 95 % CI 1.12-2.37, P0.01), metastatic stage (HR 2.12, 95 % CI 1.44-3.14, P0.01), and the presence of the G12D or G12R mutations (HR 1.60, 95 % CI 1.11-2.28) were negative prognostic factors for overall survival.K-ras mutation status and subtypes may be associated with survival duration in pancreatic cancer patients.

Purpose: The carcinoembryonic antigen glypican-3 (GPC3) is an ideal target of anticancer immunotherapy against hepatocellular carcinoma (HCC). In this nonrandomized, open-label, phase I clinical trial, we analyzed the safety and efficacy of GPC3 peptide vaccination in patients with advanced HCC. Experimental Design: Thirty-three patients with advanced HCC underwent GPC3 peptide vaccination (intradermal injections on days 1, 15, and 29 with dose escalation). The primary endpoint was the safety of GPC3 peptide vaccination. The secondary endpoints were immune response, as measured by IFN-γ ELISPOT assay, and the clinical outcomes tumor response, time to tumor progression, and overall survival (OS). Results: GPC3 vaccination was well-tolerated. One patient showed a partial response, and 19 patients showed stable disease 2 months after initiation of treatment. Four of the 19 patients with stable disease had tumor necrosis or regression that did not meet the criteria for a partial response. Levels of the tumor markers α-fetoprotein and/or des-γ-carboxy prothrombin temporarily decreased in nine patients. The GPC3 peptide vaccine induced a GPC3-specific CTL response in 30 patients. Furthermore, GPC3-specific CTL frequency after vaccination correlated with OS. OS was significantly longer in patients with high GPC3-specific CTL frequencies (N = 15) than in those with low frequencies (N = 18; P = 0.033). Conclusions: GPC3-derived peptide vaccination was well-tolerated, and measurable immune responses and antitumor efficacy were noted. This is the first study to show that peptide-specific CTL frequency can be a predictive marker of OS in patients with HCC receiving peptide vaccination. Clin Cancer Res; 18(13); 3686–96. ©2012 AACR.

We examined the clinicopathological features of metastatic gastric tumor, using 9 tumors of 8 patients. Histological diagnosis with all biopsy specimens were adenocarcinoma. Most of the metastatic sites were located in the middle or upper gastric corpus. Endoscopic features of the lesion showed a submucosal tumor-like (5 cases) and primary gastric cancer-like (3 cases) appearance. Immunohistochemical staining of cytokeratins, TTF-1, surfactant protein, ER, or MGB1 identified the primary site; 6 in the lung and 2 in the breast. One case was diagnosed based on the EGFR mutation analysis. In conclusion, immunohistochemical staining and molecular method are useful tools to distinguish metastatic gastric tumor from primary gastric cancer.

There is urgent need for biomarkers that provide early detection of pancreatic ductal adenocarcinoma (PDAC) as well as discrimination of autoimmune pancreatitis, as current clinical approaches are not suitably accurate for precise diagnosis. We used mass spectrometry to analyze protein profiles of more than 300 plasma specimens obtained from PDAC, noncancerous pancreatic diseases including autoimmune pancreatitis patients and healthy subjects. We obtained 1063 proteomic signals from 160 plasma samples in the training cohort. A proteomic signature consisting of 7 mass spectrometry signals was used for construction of a proteomic model for detection of PDAC patients. Using the test cohort, we confirmed that this proteomic model had discrimination power equal to that observed with the training cohort. The overall sensitivity and specificity for detection of cancer patients were 82.6% and 90.9%, respectively. Notably, 62.5% of the stage I and II cases were detected by our proteomic model. We also found that 100% of autoimmune pancreatitis patients were correctly assigned as noncancerous individuals. In the present paper, we developed a proteomic model that was shown able to detect early-stage PDAC patients. In addition, our model appeared capable of discriminating patients with autoimmune pancreatitis from those with PDAC.

The international consensus guidelines for management of intraductal papillary mucinous neoplasm and mucinous cystic neoplasm of the pancreas established in 2006 have increased awareness and improved the management of these entities. During the subsequent 5 years, a considerable amount of information has been added to the literature. Based on a consensus symposium held during the 14th meeting of the International Association of Pancreatology in Fukuoka, Japan, in 2010, the working group has generated newguidelines. Since the levelsof evidence forallitemsaddressed in these guidelinesarelow,being4or5, we still have to designate them “consensus”, rather than “evidence-based”, guidelines. To simplify the entire guidelines, we have adopted a statement format that differs from the 2006 guidelines, although the headings are similar to the previous guidelines, i.e., classification, investigation, indications for and methods of resection and other treatments, histological aspects, and methods of follow-up. The present guidelines include recent information and recommendations based on our current understanding, and highlight issues that remain controversial and areas where further research is required. Copyright 2012, IAP and EPC. Published by Elsevier India, a division of Reed Elsevier India Pvt. Ltd. All rights reserved.

A new method for measuring distances using electrically charged jets of water is described, and its precision examined. When combined with endoscopy, this method can be utilized to measured the lengths and areas of objects inside human body cavities. The apparatus used consists of a catheter with three metal needles at the tip, a personal computer, and a commercially available videoendoscopy system. To test the system, a regulated voltage was passed between the catheter tip and a wooden board, and two salt solutions of different concentrations were ejected at three different angles from the catheter to the board. The coordinates of the board were then computed from the amperages of the currents passing through the three jets of saline, and optical distortion was corrected using the computer. The length and area of an object could be measured rapidly by setting electrically the coordinates to match the endoscopic image. Lengths ranging from 10 to 50 mm were measured while varying the distance between catheter tip and board (10, 20, and 30 mm), as well as the angle formed by the catheter and the board (45, 60, and 90 degrees). The mean measurement error was less than 5.6% and accuracy was relatively independent of the angle between catheter and target.

We describe a 54-year old woman with oxaliplatin-induced autoimmune hemolytic anemia and review the clinical features of similar published cases. The present patient had metastatic colon cancer and was admitted to our hospital with a floating sensation and general malaise on day 4 after undergoing the last of 4 cycles of a 7th round of chemotherapy with XELOX. Laboratory data revealed 4.6g/dl hemoglobin and 8.77 mg/dl creatinine. Direct and indirect Coombs tests of a blood sample for blood transfusion were both positive. We diagnosed immune hemolysis with acute renal failure based on the clinical course and blood samples showing haptoglobin10mg/dl. We treated her with hemodialysis, plasmapheresis and immune suppression with prednisolone, which improved the anemia and renal failure.

Although several reports have described a possible association between insulin-like growth factors-1 (IGF-1) and pancreatic cancer (PC) risk, this association has not been evaluated in the non-Caucasian population. To assess the impact of IGF-1 polymorphisms on PC risk in Japanese, we conducted a case-control study which compared the frequency of ten single nucleotide polymorphisms (SNPs) and haplotypes of IGF-1. SNPs were investigated using the TaqMan method in 176 patients with PC and 1402 control subjects. Exposure to risk factors was assessed from the results of a self-administered questionnaire. Associations and gene-environment interactions were examined using an unconditional logistic regression model. We did not observe any significant main effect of IGF-1 loci, but did find interactions between rs5742714 and past and/or current body-mass index (BMI) status. Among patients with BMI > 25 at age 20, an increased PC risk was observed with the addition of the minor allele for rs5742714 (trend P = 0.048) and rs6214 (P = 0.043). Among patients with current BMI > 25, an increased or decreased PC risk was observed with the addition of the minor allele for rs5742714 (trend P = 0.046), rs4764887 (P = 0.031) and rs5742612 (P = 0.038). Haplotype analysis of IGF-1 showed a significant association among patients who were either or both previously or currently overweight. These findings suggest that IGF-1 polymorphisms may affect the development of PC in the Japanese population in combination with obesity. Further studies to confirm these findings are warranted.

Objective: The aim of this multicenter Phase II study was to assess the efficacy and toxicity of gemcitabine and S-1 combination therapy for metastatic pancreatic cancer. Methods: Chemotherapy-naive patients with histologically or cytologically proven metastatic pancreatic adenocarcinoma were eligible for this study. Gemcitabine was administered at a dose of 1000 mg/m 2 over 30 min on days 1 and 8, and oral S-1 at a dose of 40 mg/m 2 twice daily from days 1 to 14, repeated every 3 weeks. Results: A total of 55 patients were included and the efficacy and toxicity were analyzed in 54 patients who received at least one dose of gemcitabine and S-1 combination therapy. Although no complete response was seen, a partial response was achieved in 24 patients, resulting in an overall response rate of 44.4% (95% confidence interval: 30.9-58.6%). The median progression-free survival was 5.9 months (95% confidence interval: 4.1-6.9 months) and the median overall survival was 10.1 months (95% confidence interval: 8.5-10.8 months) with a 1-year survival rate of 33.0%. The major Grade 3-4 toxicities were neutro- penia (80%), leucopenia (59%), thrombocytopenia (22%), anorexia (17%) and rash (7%). Hematological toxicity was mostly transient and there was only one episode of febrile neutro- penia Grade 3. Conclusions: Gemcitabine and S-1 combination therapy produced a high response rate with good survival in patients with metastatic pancreatic cancer. A randomized Phase III study to confirm the efficacy of gemcitabine and S-1 combination therapy is ongoing.