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Objective: In the treatment of advanced and recurrent colorectal cancer (ARCC), FOLFOXIRI regimens have been proven to be significantly superior to FOLFIRI in terms of the progression-free survival (PFS), response rate (RR), and overall survival (OS). Furthermore, the Tribe trial showed that the RR and PFS rates in patients who received bevacizumab (Bmab)+FOLFOXIRI were superior to those in patients treated with Bmab+FOLFIRI. A phase III trial of panitumumab (Pmab)+FOLFOXIRI is currently ongoing. A modified FOLFOXIRI regimen is also widely used to reduce adverse events. In our department, we introduced modified FOLFOXIRI+a (mFOLFOXIRI+a) in 2015. The present study reviewed the efficacy and safety of mFOLFOXIRI+a. Methods: Eligible patients were retrospectively reviewed, and their results were compared to those of patients treated with other regimens (OTHERS) (n=134) to demonstrate the efficacy of this treatment. Patients: Between February 2015 and November 2018, 12 patients with ARCC (male/female=6/6; average age, 60.7 years old) received mFOLFOXIRI+a (Bmab: 10, Pmab: 1, alone: 1). Results: The median PFS in the mFOLFOXIRI+a and OTHERS groups was 565 and 322 days, respectively (p=0.0544). The RR in the mFOLFOXIRI+a and OTHERS groups was 66.7% and 31.3%, respectively (p= 0.0135). The conversion rate (Conv R) in the mFOLFOXIRI+a and OTHERS groups was 50.0% and 12.7%, respectively (p=0.0007). While 58% of patients treated with FOLFOXIRI+a developed grade >3 leukopenia, the incidence of febrile neutropenia (FN) was only 17%. In all patients with symptoms due to the tumor burden, the symptoms subsided with mFOLFOXIRI+a treatment. Conclusion: Based on the RR, Conv R, and symptom palliation ability, mFOLFOXIRI+a was suggested to be a viable candidate for first-line treatment for patients with ARCC, especially those with a high tumor burden., Internal medicine, 59(10), pp.1239-1245; 2020

This multicenter phase II N-DOCC-F-C-1701 trial is being planned in order to investigate the efficacy and safety of CPT-11+S-1 +Ramucirumab (IRIS+Rmab), which is anticipated to have a stronger anti-tumor effect than IRIS+Bmab in patients with metastatic colorectal cancer (mCRC) previously treated with oxaliplatin (L-OHP) containing regimen, in consideration of the result of RAISE, FIRIS and some phase II trials of IRIS+Bevacicizumab (Bmab). The number of patients is set at 38 for the statistical analysis, assuming an expected median PFS of 5.0 months (threshold: 3.0 months). The primary endpoint of the study is the progression free survival (PFS), and the secondary endpoints are the overall response rate (ORR), overall survival (OS), adverse events (AE), quality of life (QOL) and review of nausea and vomiting. This trial is registered in the UMIN Clinical Trials Registry as UMIN000028170. We intend to start conducting the trial in September 1, 2017. If this trial meets the endpoint, IRIS+Rmab might be supported as a new optional standard regimen for mCRC.

Background Esophageal elongation by traction suture is used in pediatric patients to manage long-gap esophageal atresia (EA). There was no histological evidence of the esophageal elongation. Here, we sought to clarify the histologic effects of traction on the esophagus by using a rat EA model simulating Foker's method. Materials and methods Rats were randomly assigned into three groups (n = 5 each). The traction group underwent daily stretching of the distal segment of the esophagus. The nontraction group underwent a sham operation, and the normal group served as controls. Seven days after the operation, the distal segments of the esophagus were removed. The length and thickness were measured, and samples were stained with Ki-67, nNOS, and S-100. Results The whole length of the esophagus in the traction group was significantly longer than that in the nontraction group (P < 0.01). The thickness of esophageal mucosa and muscle tended to become thin by traction, but not significantly. The Ki-67-positive ratio of mucosa and muscle was significantly higher in the traction group (P < 0.05). There were no significant differences in Ki-67 between two segments (cardia-middle and middle-stump) in any group. Auerbach's plexus was identified at all sites of elongated esophagus by nNOS and S-100 staining. Conclusions By traction, the esophagus was elongated uniformly and cell proliferation activity was promoted in all parts of the elongated esophagus in the rat EA model., Journal of Surgical Research, 195(2), pp.495-501; 2015

Background In Japan, two courses of CDDP+5-FU (CF) therapy followed by surgery is accepted as a standard treatment for stage II/III esophageal cancer (EC) based on the results of the JCOG9907 trial. However, in some cases, especially stage III disease, the anti-tumor effect of CF is insufficient. Therefore, a three-arm phase III trial (neoadjuvant [NAC] setting: CF vs. CF+radiation vs. DOC+CF [DCF]) is on-going. We have aggressively performed DCF therapy mainly in NAC settings since October 2014. We herein review the outcomes of DCF therapy. Methods Twenty-three patients (20 men, 3 women; median age: 70.0 years) with stage III or IV EC who received DCF therapy (October 2014 to February 2018) were retrospectively reviewed. Results The response rate was 43.5%. Down-staging was achieved in 11 patients (47.8%) over the course of treatment. Twenty-one patients transited to surgery, and 20 of them underwent R0 resection. One patient with disease progression was converted to chemoradiation therapy. Histological efficacy was observed in 21 patients, including 7 cases of grade 2. Those treated with DCF therapy who achieved down-staging had a significantly longer relapse-free survival (RFS) than those without down-staging (median RFS: not reached vs. 167 days, p = 0.0011) and also tended to have a longer overall survival (OS) than those without down-staging (MST: not reached vs. 824 days, p = 0.0637). Patients receiving CF therapy with down-staging tended to show a better RFS and OS than those without down-staging, although not to a significant degree. Patients receiving DCF therapy with grade ≥1b histological efficacy tended to have a longer RFS than those with grade Conclusions These findings suggest that down-staging and the histological efficacy might be predictive factors for DCF therapy for EC.

BACKGROUND: The anatomical status of the pancreatic remnant after a pancreatic head resection varies greatly among patients. The aim of the present study was to improve management of the pancreatic remnant for reducing pancreatic fistula after pancreatic head resection. METHODS: Ninety-five consecutive patients who underwent an end-to-side, duct-to-mucosa pancreaticojejunostomy after pancreatic head resection were included in the study. To approximate the pancreatic stump to the jejunum, the transfixing and interrupted suture techniques were used in 51 and 44 patients, respectively. We modified the interrupted suture technique according to the anatomical status of the pancreatic remnant, i.e., the shape of the pancreatic stump and the location of the pancreatic duct. RESULTS: There was no operative mortality in this study. Overall, 14 patients (15%) developed a clinically relevant pancreatic fistula. Certain anatomical features, including a small pancreatic duct, a soft, nonfibrotic pancreatic gland, and a pancreatic duct adjacent to the posterior cut edge, were significantly associated with pancreatic fistula. The fistula rate in the interrupted suture group was 7%, lower than that (22%) in the transfixing suture group (P = 0.036), and it was not influenced by pancreatic anatomy. Multivariate analysis identified a nonfibrotic pancreas (versus fibrotic pancreas; odds ratio [OR] 12.58, 95% CI 1.2-23.9; P = 0.001), a soft pancreas (versus hard pancreas; OR 4.67, CI 1.2-51.1; P = 0.006), and the transfixing suture technique (versus interrupted suture technique; OR 9.91, CI 1.7-57.5; P = 0.003) as significant predictors of clinically relevant pancreatic fistula. CONCLUSIONS: Pancreatic anastomosis modified according to the pancreatic anatomy is effective in reducing the risk of pancreatic fistula formation with end-to-side, duct-to-mucosa pancreaticojejunostomy after pancreatic head resection., World journal of surgery, 33(10), pp.2166-2176; 2009

The present study was designed to investigate whether an inducible nitric oxide synthase (iNOS)-specific inhibitor, ONO-1714 [(1S, 5S, 6R, 7R)-7-chloro-3-imino-5-methyl-2-azabicyclo[4.1.0] heptane], could prevent inflammation-associated biliary carcinogenesis in bilioenterostomized hamsters. Syrian golden hamsters underwent choledochojejunostomy and then received subcutaneous injections of the chemical carcinogen N-nitrosobis(2-oxopropyl)amine every 2 weeks at a dose of 10 mg/kg body wt, starting 4 weeks after surgery and continuing for 18 weeks. The hamsters were divided into two groups according to their oral intake of either a standard pelleted diet containing ONO-1714 at 100 p.p.m. for 18 weeks (ONO group, n = 15) or an ordinary diet alone (control group, n = 15). The animals were killed 22 weeks after surgery, and the development of biliary tumors was examined histologically. The presence and degree of cholangitis, cell kinetic status of the biliary epithelium and iNOS expression were evaluated. Intrahepatic biliary adenomas developed in all control animals, whereas they developed in only seven (47%) hamsters treated with ONO-1714 (P < 0.05). Intrahepatic biliary carcinomas were present in 13 (87%) hamsters in the control group and in only 6 (40%) hamsters in the ONO groups (P < 0.05). Histological and immunohistochemical examinations demonstrated a significant decrease in the degree of cholangitis, biliary epithelial cell kinetics and the expression of iNOS in the biliary epithelium in the ONO group in comparison with the control (P < 0.05). These results indicate that ONO-1714 represses N-nitrosobis(2-oxopropyl)amine-induced biliary carcinogenesis in bilioenterostomized hamsters and inhibits iNOS expression in the biliary epithelium. ONO-1714 may therefore be a promising agent for the prevention of biliary carcinoma in various inflammation-associated biliary disorders., Carcinogenesis, 30(10), pp.1763-1767; 2009

A bifid pancreatic duct presenting a major bifurcation in the main pancreatic duct is one of the anatomical variations of the pancreatic ducts. We encountered a 71-year-old female with a 5-cm-diameter branch duct intraductal papillary mucinous neoplasm of the pancreas in whom preoperative endoscopic retrograde pancreatography demonstrated an anomalous bifurcation of the main pancreatic duct at the body of the pancreas. We performed a distal pancreatectomy, instead of a middle pancreatectomy, with a cutting line at the downstream pancreas to the duct bifurcation point. Intraoperative ultrasonography was useful to confirm the exact location of the pancreatic duct bifurcation as well as the tumor extension. The procedure resulted in a favorable outcome without any postoperative complications. Although a bifid pancreatic duct is an unusual anomalous condition, this case should alert surgeons to be aware of such anatomical variants when performing pancreatic resection, otherwise, incurable pancreatic complications may occur postoperatively., Journal of hepato-biliary-pancreatic surgery, 16(6), pp.865-868; 2009

BACKGROUND/PURPOSE: Laparoscopic cholecystectomy is difficult to perform in patients with a low-lying costal arch that entirely covers the liver. We conducted this study to clarify the factors related to a low-lying costal arch and establish countermeasures to circumvent this characteristic. METHODS: The study included 103 consecutive patients who underwent a laparoscopic cholecystectomy. The possible clinical factors associated with a low-lying costal arch restricting the operative working space were analyzed. The position of the liver against the costal arch and the presumed surgical visual angle for laparoscopic cholecystectomy, comprising the hepatic porta, umbilicus, and costal arch, were estimated with abdominal multidetector computed tomography (MDCT). RESULTS: Seven (7%) patients had a low-lying costal arch presenting an inadequate exposure of Calot's triangle and restricted instrument mobility during laparoscopic cholecystectomy, and three patients required conversion to a laparotomy. A low-lying costal arch was significantly associated with advanced age, shorter stature, lighter body weight, coexisting kyphoscoliosis, gallbladder pathology, laparotomy conversion, and most of all, the liver edge lying above the costal arch and a narrow surgical visual angle upon MDCT. Of the seven patients with a critical low-lying costal arch, four underwent a successful laparoscopic cholecystectomy, this being done by lifting the right costal arch to create a workable surgical field; the rib-lifting procedure was planned as part of the scheduled procedure in the other three patients because the preoperative MDCT examination indicated a poor working space for a laparoscopic cholecystectomy. CONCLUSIONS: A low-lying costal arch is a substantial risk factor for conversion to a laparotomy when performing a laparoscopic cholecystectomy. However, the operative difficulty related to a low-lying costal arch can be predicted by using preoperative MDCT images and can be managed with proper planning and the appropriate use of the rib-lifting technique., Journal of hepato-biliary-pancreatic sciences, 18(1), pp.60-66; 2011

Background Helicobacter bilis is considered to be a causative factor in the pathogenesis of biliary cancer. This study investigated the prevalence of H. bilis colonization of the biliary system of patients with pancreaticobiliary maljunction (PBM). Methods Bile juice and biliary tissue samples were collected from 17 patients with PBM and 27 controls who had benign biliary disease without PBM. DNA extracted from each biliary sample was subjected to polymerase chain reaction (PCR) analysis for H. bilis and Helicobacter pylori. Results PCR assays revealed that 12 of the 17 patients with PBM were positive for H. bilis DNA, compared with eight of 27 patients without PBM (P = 0·009). Among patients with PBM, H. bilis DNA was identified in six of eight children, including a 2-month-old infant, and in six of nine adults. The high prevalence of H. bilis DNA in the biliary system of patients with PBM was independent of age, sex, common bile duct dilatation, configuration of the pancreatic and bile ducts, and amylase activity in bile. Conclusion H. bilis colonization of the biliary system is extremely common in patients with PBM. This may point to a role in the pathogenesis of biliary cancer.

connecting to the huge pancreatic pseudocyst (Fig 2). These findings were consistent with a diagnosis of chronic calcifying pancreatitis with a huge pancreatic pseudocyst involving the psoas muscle and the groin owing to a pancreatic fistula arising from the distal pancreatic duct. The patient underwent laparotomy. After fenestration of the pancreatic pseudocyst, the migration of the pseudocyst into the psoas muscle and a short fistulous tract between the pseudocyst and the pancreatic duct in the tail of the pancreas were identified. A distal pancreatectomy and a longitudinal pancreaticojejunostomy were performed, resulting in a favorable outcome.

The appropriate management for patients with multifocal branch-duct intraductal papillary mucinous neoplasms (IPMNs) of the pancreas involving the entire pancreatic gland remains unclear. We present a 66-year-old woman who underwent pylorus-preserving pancreaticoduodenectomy for a branch-duct intraductal papillary mucinous carcinoma demonstrating a grape-like multilocular cyst, 35 mm in diameter, in the head of the pancreas along with numerous number of small branch-duct IPMNs in the whole pancreas. Histologically, the multifocal cystic lesions were lined by a single row of columnar mucin-containing epithelial cells without atypia. The patient has been doing well without any recurrence during 9-year follow-up after surgery. Surgical removal of the prominent lesions suspicious of malignancy and a close observation of the remaining lesions in the remnant pancreas may be a reasonable treatment plan for patients with multifocal branch-duct IPMNs involving the entire pancreatic gland., American Journal of Surgery, 196(5), pp.e50-e52; 2008

Background Rectal carcinoids comprise only about 1% of all anorectal neoplasms. In addition, ganglioneuroma of the gastrointestinal tract is a rare tumor composed ganglion cells, nerve fibers, and supporting cells. Multiple carcinoid tumors with diffuse ganglioneuromatosis limited to the rectum are quite unusual. Case presentation A 69-year-old man was referred to us because of about 100 small submucosal rectal tumors. He underwent abdominoperineal resection. Pathology revealed carcinoid tumors for about 30 submucosal nodules and diffuse ganglioneuromotosis. To date (6 months later) he remains well with no recurrence. Conclusion Although the optimal treatment for the multiple rectal carcinoids remains to be clearly established, it is believed that not all patients with multiple rectal carcinoids (measuring less than 1 cm in diameter) need to have a radical operation. However, the treatment plan for each case should be individualized and a careful follow-up is mandatory.

膵管内乳頭粘液性腫瘍（IPMN）の臨床研究は多岐に渡り進行している．疾患病態の更なる解明ならびに治療への展開にはIPMN動物モデルの確立が有用と思われる．我々は，主膵管内乳頭腺癌（IPC）を高率に誘発することが可能なハムスターモデルを作成した．このモデルの特徴は，下部共通管結紮及び胆嚢十二指腸吻合を施行することで膵管内へ胆汁が逆流し，胆汁刺激により主膵管上皮の細胞回転亢進をきたすことにある．このモデルに膵癌誘発剤を負荷すると，通常型浸潤膵癌のみならずIPCが高率に発生する．誘発されたIPCは著明な膵管内乳頭状増殖を示し，またslow growthであることが示唆され，これらの特徴はヒトIPMNと類似していた．今後このハムスターモデルを用いた種々の検討が，ヒトIPMNにおける臨床課題を克服する一助となり得ると考えられる．