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Neuroendocrine neoplasms (NENs) are rare neoplasms that occur in various organs and present with diverse clinical manifestations. Pathological classification is important in the diagnosis of NENs. Treatment strategies must be selected according to the status of differentiation and malignancy by accurately determining whether the neoplasm is functioning or nonfunctioning, degree of disease progression, and presence of metastasis. The newly revised Clinical Practice Guidelines for Gastroenteropancreatic Neuroendocrine Neoplasms (GEP-NENs) comprises 5 chapters—diagnosis, pathology, surgical treatment, medical and multidisciplinary treatment, and multiple endocrine neoplasia type 1 (MEN1)/von Hippel–Lindau (VHL) disease—and includes 51 clinical questions and 19 columns. These guidelines aim to provide direction and practical clinical content for the management of GEP-NEN preferentially based on clinically useful reports. These revised guidelines also refer to the new concept of “neuroendocrine tumor” (NET) grade 3, which is based on the 2017 and 2019 WHO criteria; this includes health insurance coverage of somatostatin receptor scintigraphy for NEN, everolimus for lung and gastrointestinal NET, and lanreotide for GEP-NET. The guidelines also newly refer to the diagnosis, treatment, and surveillance of NEN associated with VHL disease and MEN1. The accuracy of these guidelines has been improved by examining and adopting new evidence obtained after the first edition was published. Supplementary Information The online version contains supplementary material available at 10.1007/s00535-021-01827-7.

Published online: 25 March 2014, Article, JOURNAL OF GASTROENTEROLOGY. 49(5):765-784 (2014)

Pancreatobiliary reflux (PBR) can occur in individuals without pancreaticobiliary maljunction. The aim of this study was to elucidate the incidence of PBR in individuals with a normal pancreaticobiliary junction and its impact on the biliary tree.Data were prospectively collected from 15 centers on 420 patients with a morphologically normal pancreaticobiliary junction who had undergone bile sampling and measurement of the biliary amylase level. We investigated the incidence and predictive factors for high biliary amylase levels (HBAL), as well as the relationship of HBAL with biliary malignancy.Twenty-three patients (5.5%) showed HBAL (≥10,000 IU/L). Univariate analysis showed that risk factors for the elevation of biliary amylase levels were the existence of a relatively long common channel (≥5 mm), acute pancreatitis, and papillitis. Multivariate analysis revealed that only the existence of a relatively long common channel was a significant factor for PBR. Biliary amylase levels in patients with a relatively long common channel were significantly higher than in patients without a long common channel (12,333 vs. 2,070 IU/L, P = 0.001). The incidence of HBAL (P0.001), as well as the overall biliary amylase levels (P = 0.007) were significantly higher in patients with gallbladder cancer than in those without gallbladder cancer.The PBR was frequently observed in individuals with a relatively long common channel. Patients showing HBAL with normal pancreaticobiliary junction are at high risk for gallbladder cancer.

Because of the rarity and variety of pancreatic neuroendocrine tumors (PNETs), there have been few reports regarding the indication for lymph node dissection in patients with these tumors. This study aimed to evaluate the risk of lymph node metastasis of PNETs based on the tumor size and hormonal production.Data for a total of 66 patients who had PNETs resected at our department between 1987 and 2010 were retrospectively studied. The clinicopathological features, including the disease-specific survival rate, were assessed based on the status of lymph node metastasis at the time of initial surgical resection. Then the cut-off point of tumor size to predict lymph node metastasis was estimated.There were 12 patients (18%) with lymph node metastasis. The frequency of lymph node metastasis tended to be higher in gastrinomas than that in other tumors (43 vs. 15%; P = 0.08). The size of PNETs with lymph node metastasis was significantly larger than that of the PNETs without metastasis (P = 0.04). The postoperative survival rate in the PNET patients with lymph node metastasis was significantly lower than that in the patients without metastasis (P0.0001). Only 2 (8%) of 26 PNETs with a tumor size of15 mm had lymph node metastasis, and both of these were gastrinomas. On the other hand, 10 (25%) of the remaining 40 PNETs with a tumor size of ≥15 mm had lymph node metastasis. Notably, there were no PNETs with lymph node metastasis in 22 non-gastrinomas with a tumor size of15 mm.Non-gastrinomas with a tumor size of ≥15 mm and all gastrinomas would be an indication for pancreatectomy with lymph node dissection.

Although patients with cholecystocholedocholithiasis are generally referred to cholecystectomy after endoscopic sphincterotomy (ES) and common bile duct clearance, we often have a conflict whether cholecystectomy is necessary in very elderly patients with comorbid diseases. The aim of this study is to assess whether cholecystectomy in very elderly patients is justified after ES.Patients with cholecystocholedocholithiasis who underwent ES and stone extraction and were followed-up for more than 10 years were retrospectively reviewed. We divided these patients into two groups: the elderly group (equal to or more than 80 years old) and young group (less than 80 years old) and compared late biliary complications and mortality.The 10-year cumulative incidence of overall biliary complications was significantly lower in cholecystectomized patients than in patients with gallbladder in situ in the young group (7.5 vs. 21.7%, p = 0.0037), but not different in the elderly group (8.3 vs. 7.4%, p = 0.92). When each complication was evaluated separately, the rate of recurrent common bile duct stones (CBDS) was not different, but that of acute cholecystitis was significantly lower in the elderly group than in the young group (4.1 vs. 22.6%, p = 0.011).In very elderly patients the incidence of acute cholecystitis is low even when the gallbladder is preserved after endoscopic treatment of CBDS, with a similar risk of CBDS recurrence. Thus, it may not be necessary to recommend cholecystectomy after ES for CBDS in very elderly patients.

In Japan, we are now using the clinical diagnostic criteria for chronic pancreatitis (CP) that were revised in 2001 to add the findings of magnetic resonance cholangiopancreatography to the criteria compiled by the Japan Pancreas Society (JPS) in 1995. Because the current criteria are set for diagnosing advanced CP, they are unlikely to improve patients' prognoses. In addition, they seem unsuitable for current clinical practice because exocrine pancreatic function tests, which have become obsolete in Japan, are included in the diagnostic factors. For these reasons, the Research Committee on Intractable Pancreatic Diseases supported by the Ministry of Health, Labour and Welfare of Japan, the JPS and the Japanese Society of Gastroenterology have revised the criteria. The revised criteria are unique in that they contain an introduction to the concept of early CP. It is a challenge aimed at improvement of the long-term prognosis of CP patients by early diagnosis and therapeutic intervention in this disease. We need to determine and clarify the clinico-pathological outcome of early CP by a prospective long-term follow-up of the patients in this category.

Steroid therapy appeared to be a standard treatment for autoimmune pancreatitis (AIP), although some AIP patients improve spontaneously. The indications for steroid therapy in AIP patients are symptoms such as obstructive jaundice, abdominal pain, and back pain, and the presence of symptomatic extrapancreatic lesions. Before steroid therapy, jaundice should be managed by biliary drainage in patients with obstructive jaundice, and blood glucose levels should be controlled in patients with diabetes mellitus. For the initial oral prednisolone dose for induction of remission, 0.6 mg/kg/day is recommended. The initial dose is administered for 2-4 weeks, and the dose is tapered by 5 mg every 1-2 weeks, based on changes in the clinical manifestations, biochemical blood tests (such as liver enzymes and IgG or IgG4 levels), and repeated imaging findings (US, CT, MRCP, ERCP, etc.). The dose is tapered to a maintenance dose (2.5-5 mg/day) over a period of 2-3 months. Steroid therapy should be stopped based on the disease activity in each case. Stopping of maintenance therapy should be planned within at least 3 years in cases with radiological and serological improvement. Re-administration or dose-up of steroid is effective for treating AIP relapses. The prognosis of AIP appears to be good over the short-term with steroid therapy. It is unclear whether the long-term outcome is good because there are many unknown factors, such as relapse, pancreatic exocrine or endocrine dysfunction, and associated malignancy.

• A variety of extrapancreatic lesions are reported to be complicated with AIP. Among those cited are close association with lachrymal and salivary gland lesions, hilar lymphadenopathy, interstitial pneumonitis, sclerosing cholangitis, retroperitoneal fibrosis, and tubulointerstitial nephritis. Description A variety of extrapancreatic lesions are reported to be complicated with AIP, and close associations have been pointed out with lachrymal and salivary gland lesions (Fig. 1) [1], hilar lymphadenopathy [2], sclerosing cholangitis [3, 4], retroperitoneal fibrosis (Fig. 2) [5], and tubulointerstitial nephritis [6]. Associations were also reported with hypophysitis [7], chronic thyroiditis [8], and prostatitis [9]. Other extrapancreatic involvements have been reported in a few cases [10–12]. Though it is not certain that all of them have a relation with AIP, extrapancreatic lesions are prevalent in the systemic organs (Table 1) [7–12], suggesting that AIP may be a member of IgG4related diseases. The extrapancreatic lesions appear synchronously or metachronously with the pancreatic lesion(s), share the same pathological conditions, and show favorable response to corticosteroid therapy; these characteristics indicate a common pathophysiological background. The lesions are usually detected by image tests and blood tests (CT, MRI, gallium scintigraphy, FDG-PET, and hormone assay); however, these should be confirmed by histological findings. Extrapancreatic lesions sometimes mimic, or are misdiagnosed as, primary lesions of the corresponding organs: lachrymal and salivary gland lesions for Sjogren’s syndrome, respiratory lesions for sarcoidosis, and sclerosing cholangitis for primary sclerosing cholangitis (PSC). Therefore, it is necessary to differentiate between IgG4related diseases and inherent diseases of the corresponding organs. When the pancreatic lesion is obscured, it may be difficult to detect these presumably IgG4-related extrapancreatic lesions. However, recognition of these extrapancreatic lesions should also aid in the correct diagnosis of AIP.

As the number of patients with autoimmune pancreatitis (AIP) is increasing in Japan, practical guidelines for managing AIP need to be established. Three committees [the professional committee for developing clinical questions (CQs) and statements by Japanese specialists, the expert panelist committee for rating statements by the modified Delphi method, and the evaluating committee of moderators] were organized. Fifteen AIP specialists extracted specific clinical statements from a total of 871 articles in the literature using a PubMed search (1963–2008) and a secondary database, and developed the CQs and statements. The expert panelists individually rated these clinical statements using a modified Delphi approach in which a clinical statement receiving a median score greater than 7 on a 9-point scale from the panel was regarded as valid. The professional committee developed 13, 6, 6, and 11 CQs and statements for the concept and diagnosis, extra-pancreatic lesions, differential diagnosis and treatment, respectively. The expert panelists regarded them as valid after two-round modified Delphi approaches. After evaluation by the moderators, the Japanese clinical guidelines for AIP were established. The digest versions of the present guidelines have been published in the official journal of the Japan Pancreas Society, “Pancreas.” Full versions divided into three series are scheduled to be published in the present and followings two issues in the Journal of Gastroenterology with approval of Professor Go VLW, the Editor-in-Chief of "Pancreas.”

We investigated the role of the duodenum in the sphincter of Oddi response to cholecystokinin-octapeptide (CCK-OP), using conscious dogs.In controls, a cannula was inserted into the duodenum opposite the papilla for retrograde manometry. In the duodenectomy group, the entire duodenum was resected, while preserving the papilla, which was implanted into the jejunum, and the cannula was placed. Sphincter motility was recorded after bolus injections of 20 and 100 ng/kg of CCK-OP.CCK-OP at 20 ng/kg produced sphincter relaxation followed by contraction in the controls, but produced no changes after duodenectomy. CCK-OP at 100 ng/kg caused strong contractions followed by relaxation in the controls, but caused only contractions after duodenectomy.(1) Relaxation and delayed contraction of the sphincter induced by 20 ng/kg of CCK-OP require the presence of the duodenum; (2) early contractions of the sphincter induced by 100 ng/kg of CCK-OP do not require the duodenum; (3) the duodenum plays an important role in the actions of CCK-OP on sphincter motility.

Pancreas divisum is an embryologic anomaly of the pancreas that is characterized by a lack of fusion of the dorsal and ventral pancreatic ducts. It is rarely associated with pancreatic neoplasms. We report herein a rare association of pancreas divisum and serous cystadenoma of the pancreas. A 46-year-old Japanese woman presented with epigastralgia. Ultrasonography, computed tomography (CT) and magnetic resonance cholangiopancreatography revealed a multilocular cystic mass, measuring 7 cm in diameter, with a central stellate scar, in the body and tail of the pancreas. Angiography demonstrated a relatively hypervascular mass, suppressing the splenic vein. No arterial encasement was evident. Endoscopic retrograde pancreatography through the major papilla demonstrated only the duct of Wirsung; cannulation into the minor papilla was unsuccessful. In addition, CT showed a mildly dilated main pancreatic duct draining into the minor papilla. Distal pancreatectomy and splenectomy were performed, with the tentative diagnosis being serous cystic neoplasm of the pancreas, possibly malignant, and pancreas divisum. The cut surface of the resected specimen had a honeycomb-like appearance and the specimen consisted of multiple cysts of various sizes. Histopathological examination showed multiple cysts lined by a single layer of flat or cuboidal epithelial cells with glycogen in the cytoplasm. There was no evidence of malignancy. The histopathological diagnosis was serous cystadenoma of the pancreas. To the best of our knowledge, only three cases of serous cystadenoma of the pancreas associated with pancreas divisum have been reported. We report the fourth case of such an association, and briefly review the literature.

We report a 74-year-old Japanese woman with a spontaneously vanishing pseudocyst in the remnant pancreas after pylorus-preserving pancreatoduodenectomy for intraductal papillary-mucinous adenoma of the pancreas. A cystic lesion appeared in the remnant pancreas 6 months after the operation and had disappeared 3 months later. When a cystic lesion is encountered in the remnant pancreas after pancreatectomy for mucin-hypersecreting tumor of the pancreas, pseudocyst, as well as recurrence, should be considered in the differential diagnosis. Additional resection would likely cause considerable morbidity, with loss of endocrine and exocrine functions.

The standard treatment for autoimmune pancreatitis (AIP) is steroid therapy, although some patients improve spontaneously. Indications for steroid therapy in AIP patients are symptoms such as obstructive jaundice, abdominal pain, back pain, and the presence of symptomatic extrapancreatic lesions. Prior to steroid therapy, obstructive jaundice should be managed by biliary drainage, and blood glucose levels should be controlled in patients with diabetes mellitus. The recommended initial oral prednisolone dose for induction of remission is 0.6 mg/kg/day, which is administered for 2–4 weeks. The dose is then tapered by 5 mg every 1–2 weeks, based on changes in clinical manifestations, biochemical blood tests (such as liver enzymes and IgG or IgG4 levels), and repeated imaging findings (US, CT, MRCP, ERCP, etc.). The dose is tapered to a maintenance dose (2.5–5 mg/day) over a period of 2–3 months. Cessation of steroid therapy should be based on the disease activity in each case. Termination of maintenance therapy should be planned within 3 years in cases with radiological and serological improvement. Re-administration or dose-up of steroid is effective for treating AIP relapse. Application of immunomodulatory drugs is considered for AIP patients who prove resistant to steroid therapy. The prognosis of AIP appears to be good over the short-term with steroid therapy. The long-term outcome is less clear, as there are many unknown factors, such as relapse, pancreatic exocrine or endocrine dysfunction, and associated malignancy.

In response to the proposal of the international consensus diagnostic criteria (ICDC) for autoimmune pancreatitis (AIP) and the Japanese diagnostic criteria in 2011, the 2009 Japanese consensus guidelines for managing AIP required revision.Three committees [the professional committee for making clinical questions (CQs) and statements by Japanese specialists, the expert panelist committee for rating statements by the modified Delphi method, and the evaluating committee by moderators] were organized. Fifteen specialists for AIP extracted the specific clinical statements from 1,843 articles published between 1963 and 2012 (obtained from Pub Med and a secondary database, and developed the CQs and statements. The expert panel individually rated the clinical statements using a modified Delphi approach, in which a clinical statement receiving a median score greater than seven on a nine-point scale from the panel was regarded as valid.The professional committee created 13 CQs and statements for the current concept and diagnosis of AIP, 6 for extra-pancreatic lesions, 6 for differential diagnosis, and 11 for treatment.After evaluation by the moderators, amendments to the Japanese consensus guidelines for AIP have been proposed for 2013.

We previously reported significant changes in sphincter of Oddi cyclic motility after proximal duodenal transection and anastomosis. However, the role of intrinsic myoneural continuity between the antrum and duodenum in this respect is not understood. The aim of this study was to elucidate the effects of prepyloric gastric transection on sphincter of Oddi motility in animals in the conscious state. Methods. Pressures in the bile duct, duodenum, stomach, and sphincter of Oddi and their response to an injection of cholecystokinin-octapeptide were measured in four conscious dogs, with a duodenal cannula, before and after gastric transection and anastomosis 1.5 cm proximal to the pylorus. Results. Gastric transection did not affect the initiation and propagation of the gastroduodenal migration motor complex. Biliary pressure (5.7 ± 0.15 to 5.5 ± 0.2 mmHg; P = 0.91), sphincter of Oddi basal pressure (10.6 ± 0.3 to 10.7 ± 0.2 mmHg; P = 0.97), and amplitude (26.0 ± 1.2 to 32.9 ± 1.7 mmHg; P = 0.304) did not change after gastric transection. Biliary pressure decreased from phase II to phase III of the duodenal migrating motor complex. Cholecystokinin-octapeptide inhibited sphincter of Oddi phasic waves before and after gastric transection. Conclusions. Intrinsic myoneural transection at the prepyloric region does not influence sphincter of Oddi cyclic motility. Preservation of pyloroduodenal myoneural continuity in pylorus-preserving gastrectomy would be beneficial to maintain normal sphincter of Oddi motility.

A single institutional experience with endoscopic retrograde cholangiopancreatography (ERCP) in pediatric patients was reviewed, focusing on the method of anesthesia, choice of an endoscope, indications, and complications. The medical records of 50 ERCPs performed in 42 infants and children (14 male and 28 female) were reviewed retrospectively. The patients' ages ranged from 57 days to 15 years. Forty-four ERCPs were diagnostic and 6 were therapeutic, including incision of choledochocele, and sphincterotomy and extraction of pancreatic stones. All procedures were successful. The most common indication for ERCP was to evaluate congenital biliary dilatation, in 28 patients (67%). Mild cholangitis occurred as a complication in 1 patient, but was alleviated with medication. A conventional duodenoscope could be used in patients older than 10 years. A pediatric duodenoscope was always used in patients under 1 year of age. Either type was chosen individually for those aged 1 to 10 years depending on the purpose, diagnostic or therapeutic. It is noteworthy that ERCP and/or sphincterotomy in a 1-year-old infant and two 2-year-old children were safely performed with the conventional endoscope. General anesthesia was employed in those younger than 9 years and intravenous sedation and local anesthesia in those older than 11 years. For children aged 9 to 11 years, anesthesia was chosen individually. We concluded that ERCP is a relatively easy and safe technique even for infants and children when performed by skilled hands with an appropriate duodenoscope under suitable anesthesia. The minimum age for use of the conventional duodenoscope may be 1 year.

The relationship between sphincter of Oddi pressure and the morphological structure of the sphincter was studied in eight dogs prepared with a duodenal cannula. Sphincter of Oddi manometry was performed in awake animals in three directions, ventral, left dorsal, and right dorsal, using a catheter with three radial side holes for recording at one level. The pressure in the ventral direction (26.6+/-1.06 mmHg) (mean+/-SEM) was significantly lower than that in the left and right dorsal directions (30.6+/-1.42 and 31.2+/-1.23 mmHg, respectively). This functional manometric difference in the three directions correlated closely with the morphological structure of the sphincter of Oddi; the sum of the thickness of the sphincter of Oddi muscle and duodenal proper muscle was greater on the dorsal than on the ventral side. To our knowledge, this is the first report of axial asymmetry in sphincter of Oddi pressure.

A 16-year-old man who had been diagnosed with the Peutz-Jeghers syndrome at the age of 8 years presented with crampy abdominal pain. Thorough examinations revealed a large jejunal polyp causing intussusception, as well as multiple polyps in the small and large intestines. Preoperative proctoscopy demonstrated the coexistence of a submucosal tumor in the rectum. Proctoscopic mucosal resection was performed and histological and immunohistochemical examinations led to a diagnosis of carcinoid tumor. Additional transanal resection of the rectal wall showed no residual tumor and the patient has been well for 2 years to date. Although malignant tumors are increasingly reported in association with the Peutz-Jeghers syndrome, to our knowledge, there have been no previous reports of such an association in the English-language and Japanese literature.

Although neuroendocrine tumors (NETs) are rare, the number of patients with NET is increasing. However, in Japan, there have been no epidemiological studies on NET since 2005; thus, the prevalence of NET remains unknown. We reported the epidemiology of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) [pancreatic neuroendocrine tumors (PNETs) and gastrointestinal neuroendocrine tumors (GI-NETs)] in Japan in 2005. Here, we conducted the second nationwide survey on patients with GEP-NETs who received treatment in 2010. A total of 3,379 patients received treatment for PNETs in 2010, representing a 1.2-fold increase in the number of patients from 2005 to 2010. The prevalence was estimated to be 2.69/100,000, with an annual onset incidence of 1.27/100,000 in 2010. Non-functioning tumor (NF)-PNETs comprised 65.5 % of cases followed by insulinoma (20.9 %) and gastrinoma (8.2 %). Interestingly, the number of patients with NF-PNETs increased ~1.8 fold since 2005. A total of 19.9 % of patients exhibited distant metastasis at initial diagnosis; 4.3 % had complications with multiple endocrine neoplasia type 1 (MEN-1), and only 4.0 % had NF-PNETs associated with MEN-1. Meanwhile, an estimated 8,088 patients received treatment for GI-NETs, representing a ~1.8-fold increase since 2005. The prevalence was estimated to be 6.42/100,000, with an annual onset incidence of 3.51/100,000. The locations of GI-NETs varied: foregut, 26.1 %; midgut, 3.6 %; and hindgut, 70.3 %. Distant metastasis and complications with MEN-1 were observed in 6.0 and 0.42 % at initial diagnosis, respectively. The frequency of carcinoid syndrome in patients with GI-NETs was 3.2 %. We clarified the epidemiological changes in GEP-NETs from 2005 to 2010 in Japan.

We studied the effect of the order of ward rounds on nosocomial infection in gastroenterologic surgery patients. The subjects were patients with gastrointestinal diseases admitted between September 1992 and August 1994. During the 1st year, the round proceeded indiscriminately among recovery rooms and rooms with stable patients and isolated patients with methicillin-resistant Staphylococcus aureus (MRSA). In the subsequent year, the round started in the recovery rooms and moved into the general rooms with stable patients and finally into the isolation rooms. Against the time course, piecewise linear regression analyses were made with the number of culture-positive patients and the quantities of antibiotics and disinfectants used. Of a total of 1894 strains from 264 patients, isolates of MRSA (n = 200) decreased from 150 in the 1st year to 50 in the 2nd year. The number of MRSA-positive patients showed the point of inflexion in the analysis at the change of round order, with a later decrease. The trend was similar for Candida (n = 99) and Enterococcal (n = 225) species. The amount of antibiotics was unchanged while the amount of disinfectants used decreased in the 2nd year. Thus, the round re-ordering appeared to help prevent nosocomial infection. Ward rounds for patients who have had gastroenterologic surgery should proceed from compromised hosts to stable patients, and then isolated patients.

The frequency and prognosis of pancreatic endocrine tumors (PNET)/pancreatic cystic tumors (PCT) in Japanese patients with von Hippel-Lindau disease (VHL) are still open to question.We conducted the first nationwide epidemiological study of VHL disease in Japan to elucidate this question. Data on 377 VHL patients (PNET, 53; PCT, 152) were reported, and then their clinical characteristics were analyzed.PNET was found in 14.1 % and PCT in 40.3 %; 4.5 % had both. The onset of PNET and PCT mostly occurred at 30-39 years of age (median ages, 34 and 33 years, respectively). Metastasis was observed in 7.5 % of PNET patients at diagnosis, and 64.2 % underwent surgery including enucleation, partial and total pancreatectomy, and bypass surgery. Two patients received non-surgical therapies. No PNET-related deaths were observed. In PCT patients, no metastasis was observed at diagnosis, and 9.2 % underwent surgery or drainage. According to the classification system without or with adrenal pheochromocytoma, the VHL patients studied herein were subdivided into 313 (83 %) with VHL type 1 and 64 (17 %) with VHL type 2; 29 (9.3 %) and 24 (37.5 %) patients had PNET with VHL type 1 and 2, suggesting that patients with VHL type 2 were significantly more related to PNET than those with VHL type 1 (P0.01).This study showed no significant difference in the epidemiology of pancreatic involvement between Japanese and non-Japanese VHL patients. Concerning the prognosis, follow-up study is needed.

The hedgehog (Hh) signaling pathway is aberrantly activated in many cancers. Overproduction of sonic hedgehog (Shh), a ligand in the Hh pathway, increases Hh signaling activity by inhibiting Patched-1 (Ptch1), a suppressive receptor in the Hh pathway. The purpose of this study was to establish a novel strategy for treating pancreatic cancer and other Hh-dependent cancers through control of the tumor-suppressive function of Ptch1. We synthesized seven interacting peptides to the amino-acid sequence of the Ptch1 docking site for Shh. Human pancreatic cancer cell lines (AsPC-1, SUIT2) were cultured in the presence or absence of the peptides. Cell proliferation was assessed by cell counting and by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The activity of the Hh pathway was estimated by real-time polymerase chain reaction of the target gene product Gli1. To confirm their anti-tumor activity in vivo, the effect of the peptides in a mouse model of pancreatic cancer was determined. Finally, the Hh signaling activity of the xenograft was examined. Three of the interacting peptides to Ptch1 suppressed the proliferation of the two pancreatic cancer cell lines and decreased the expression of Gli1, both in vitro and in vivo. This study suggests that interacting peptides to Ptch1 may be a new tool for controlling the Hh-dependent growth of pancreatic cancer.

There have been few epidemiological studies on gastroenteropancreatic neuroendocrine tumors (GEP-NETs) in Japan.We examined the epidemiology of GEP-NETs [pancreatic endocrine tumors (PETs) and gastrointestinal neuroendocrine tumors (GI-NETs)] in Japan in 2005 using a nationwide stratified random sampling method.A total of 2,845 individuals received treatment for PETs. Prevalence was estimated as 2.23/100,000 with an annual onset incidence of 1.01/100,000. Non-functioning tumor (NF)-PET constituted 47.4%, followed by insulinoma (38.2%) and gastrinoma (7.9%). Distant metastases were reported in 21% patients with NF-PETs and occurred more frequently as tumor size increased (2 cm). Multiple endocrine neoplasia type 1 (MEN-1) was detected in 10% of PETs but only in 6.1% of NF-PETs. NF-PETs were detected incidentally by physical examination in 24% patients. In 2005, an estimated 4,406 patients received treatment for GI-NETs. Prevalence was estimated as 3.45/100,000, with an annual onset incidence of 2.10/100,000. The locations of GI-NETs varied: foregut, 30.4%; midgut, 9.6%; and hindgut, 60.0%. Distant metastases were observed in 6%. Lymph node metastases occurred more frequently as tumor size increased (1 cm). The frequency of MEN-1 complications was 1%. Physical examination revealed GI-NETs in 44% patients. The frequency of symptomatic GI-NETs was 3.4%. Interestingly, 77.1% of patients with foregut GI-NETs had type A gastritis.Our results show there are large differences in GEP-NETs between Japan and Western nations, primarily due to differences in the presence of MEN-1 in NF-PETs and the location, symptomatic status, and prevalence of malignancy in GI-NETs.

Ventral pancreatitis, pancreatitis localized in the embryologic ventral pancreas, is rare. To date, only three well documented reports of ventral pancreatitis have been reported in the English-language literature. All three were associated with pancreas divisum. This report presents a patient suspected to have ventral pancreatitis on endoscopic retrograde cholangiopancreatography, confirmed by magnetic resonance imaging.

We conducted a nationwide survey to estimate the incidence of neuroendocrine gastrointestinal tumors (NETs) newly diagnosed in Japan from 2002 through 2004.Data on 1541 patients, 514 pancreatic endocrine tumors (PETs) and 1027 gastrointestinal carcinoids (GICs), were collected and analyzed.Nonfunctioning tumors (NF-PET) constituted 47.7% of PETs. Next in frequency were insulinoma (31.7%) and gastrinoma (8.6%). Malignancy was frequent in NF-PETs (46.1%) and gastrinomas (45.5%), but only 7.4% of insulinomas were malignant. The incidence of multiple endocrine neoplasia type-1 associated with PETs was 7.4%. The incidence of GICs was 28.8%, 5.2%, and 66.0% in foregut, midgut, and hindgut, respectively. Carcinoid syndrome and metastases were observed in only 1.7% and 5.6% of GICs, respectively.The incidence of NETs in Japan was clarified by this preliminary study. Comparatively large differences in GICs between Japan and Western nations were present with regard to the location, symptomatic status, and prevalence of malignancy.

Intraductal papillary mucinous neoplasm (IPMN) is a spectrum of neoplasia in the pancreatic duct epithelium characterized by cystic dilation of the main and/or branch pancreatic duct. According to the site of involvement IPMNs are classified into three categories, i.e., main duct type, branch duct type, and combined type. Most branch duct IPMNs are benign, whereas the other two types are often malignant. A large size of branch duct IPMN and marked dilation of the main pancreatic duct indicate the presence of adenoma at least. The additional existence of large mural nodules increases the possibility of malignancy in all types. Of recent interest is the relatively high prevalence of synchronous and/or metachronous malignancy in various organs, including the pancreas. The prognosis is favorable after complete resection of benign and noninvasive malignant IPMNs. Malignant IPMNs acquiring aggressiveness after parenchymal invasion necessitate adequate lymph node dissection. On the other hand, asymptomatic branch duct IPMNs without mural nodules can be observed without resection for a considerably long time. This review addresses available data, current understanding, controversy, and future directions.

We herein report a 64-year-old Japanese woman with cystadenocarcinoma of the liver without mesenchymal stroma which had been followed up by imagings for 12 years. A samll round cyst grew from 1 cm to 4 cm in diameter during 10 years. Thereafter, solid components were first detected in the unilocular cystic mass, which showed very rapid growth. Extended right lobectomy with right caudate lobectomy was performed. The histopathological diagnosis was cystadenocarcinoma of the liver without mesenchymal stroma. In this communication, we describe the progressive morphologic changes, shown on imagings, from a benign hepatic cyst to cystadenocarcinoma of the liver without mesenchymal stroma, and we briefly discuss the carcinogenesis of cystadenocarcinoma of the liver.

Early gastric stasis is a frequent complication of pylorus-preserving pancreatoduodenectomy (PPPD). However, few reports have addressed this phenomenon in relation to the type of gastrointestinal reconstruction. We compared gastrointestinal motility and gastric juice output after two different types of gastrointestinal reconstruction following PPPD, end-to-side duodenojejunostomy after pancreaticojejunostomy and hepaticojejunostomy (group 1) and end-to-end duodenojejunostomy before pancreaticojejunostomy and hepaticojejunostomy (group 2).In a total of 25 patients, 10 in group 1 and 15 in group 2, who underwent PPPD, manometry was repeated to assess gastric and jejunal motility until the first occurrence of phase III activity of gastric cyclic motor activity (CMA). The plasma level of motilin was measured in each phase of the gastric CMA and compared between the two groups. The daily volume of gastric juice output through a gastrostomy tube was also recorded for comparison.There was no significant difference in the time period for recovery of gastric phase III activity and gastric juice output between the two groups. However, abnormal contractions with an increased basal pressure appeared frequently in the afferent jejunal loop only in group 1. The plasma motilin level after PPPD showed no apparent cyclic change even after the recovery of gastric phase III in either group.Gastrointestinal reconstructive procedures have almost no effect on the recovery of gastric CMA. The plasma motilin concentration does not play a major role in the recovery of gastric CMA in the early postoperative period after PPPD.

Autoimmune pancreatitis is a rare type of pancreatitis that is characterized by diffuse swelling of the pancreas and irregular stenosis of the pancreatic ductal system ("sclerosing" pantreatitis), caused by autoimmune processes. Previous reports have shown the complete form of the disease, but very few have presented follow-up imagings from the beginning to the complete form. We, herein, report a case of autoimmune pancreatitis starting as a localized form. A-56-year-old Japanese man developed obstructive jaundice. Ultrasonography showed a hypoechoic mass in the head of the pancreas, and endoscopic retrograde pancreatography (ERP) showed localized stenosis of the pancreatic duct in the head of the pancreas. Computed tomography (CT) showed enlargement, with a capsule-like rim, in the head of the pancreas. Internal biliary tube drainage was performed to relieve the obstructive jaundice. The patient was followed-up under the tentative diagnosis of localized "mass-forming" pancreatitis. Four months after the drainage, CT showed diffuse swelling of the pancreas, with a capsule-like rim, and ERP demonstrated diffuse irregular narrowing of the pancreatic duct. Glucose intolerance was noted for the first time. Steroid was given as a diagnostic treatment for autoimmune pancreatitis. Two months after initiation of the steroid treatment, the ERP findings were normal, and CT showed a normal pancreas. The biliary tube was removed, and the glucose intolerance was subsequently alleviated. To summarize, we report a case of autoimmune pancreatitis starting as localized "mass-forming" pancreatitis with a peripheral rim on imagings. It is very important to be well aware of the presence of the localized form of autoimmune pancreatitis.

An inflammatory polyp of the gallbladder is a rare variant of benign gallbladder polyp. Differentiation between an inflammatory polyp and polypoid gallbladder carcinoma is difficult when the polyp is more than 1 cm in diameter. We report a rare case of a large inflammatory polyp of the gallbladder masquerading as gallbladder carcinoma in a 37-year-old Japanese woman who was incidentally diagnosed with a large gallbladder polyp, measuring 1 cm in diameter, by ultrasonography. She was asymptomatic and physical examination was unremarkable. Abdominal ultrasonography and endoscopic ultrasonography revealed three polypoid lesions in the gallbladder. One lesion was an isoechoic polyp, measuring 15 x 8 mm, showing a nodular surface and located in the fundus of the gallbladder. The other two lesions were hyperechoic polyps, measuring 5 x 5 mm, in the body of the gallbladder. Computed tomography and magnetic resonance imaging revealed marked enhancement of the largest polypoid lesion by dynamic study, and no lymph node enlargement was noted. Endoscopic retrograde cholangiography revealed a 12 x 8 mm polyp with an irregular surface in the fundus of the gallbladder. Superselective angiography of the cystic artery revealed neovascularity and a tumor stain in the fundus of the gallbladder. Cholecystectomy with lymph node dissection was performed. Intraoperative frozen section diagnosis of the largest polyp was an inflammatory polyp of the gallbladder. The other two polyps were cholesterol polyps. Inflammatory polyp should be considered as a differential diagnosis of hypervascular gallbladder polyps that measure more than 1 cm in diameter.

Pseudocyst of the pancreas is sometimes difficult to distinguish from mucinous cystic neoplasm of the pancreas. A 37-year-old asymptomatic Japanese man was diagnosed with hypertension. He had a 20-years history of habitual drinking of alcohol, but no history of pancreatitis or abdominal trauma. During examinations to ascertain the cause of hypertension, ultrasonography and computed tomography incidentally demonstrated a huge cyst in the head of the pancreas. Laboratory data were within normal limits, including serum levels of amylase, carcinoembryonic antigen, and carbohydrate antigen 19-9. Imaging studies showed a huge unilocular cyst, measuring 7 cm, in the head-to-body of the pancreas, and two small unilocular cysts, measuring 1.4 and 1.5 cm, in the tail and head of the pancreas, respectively. A mural nodule was suspected in the largest cyst. Endoscopic retrograde cholangiopancreatography demonstrated communication of the main pancreatic duct with the two small cysts in the head and tail of the pancreas but not with the huge cyst. There were no ductal changes suggesting chronic pancreatitis. Laparotomy was performed under the tentative diagnosis of potentially malignant mucinous cystic neoplasms of the pancreas. However, inflammatory adhesion was dense around the pancreas and the mural nodule suspected preoperatively was found to be sludge aggregates in a pseudocyst. The diagnosis of an intraoperative frozen section of the cyst wall was pseudocyst of the pancreas. Cystojejunostomy was performed. We report this case because the pre-operative diagnosis was mucinous cystic neoplasm of the pancreas, but the diagnosis changed with careful intraoperative examinations, to pseudocyst of the pancreas. We discuss the differential diagnosis of the two conditions.

Using a polymerase chain reaction-based amplification assay, we measured telomerase activity in surgically resected pancreatic ductal carcinomas (n = 16 cases) and normal ducts (n = 6), comparing findings with the telomerase activity of a human pancreatic cancer cell line, MIA PaCa-2, as a standard, i.e., relative telomerase activity was determined. Telomerase activity was expressed as the equivalent telomerase intensity of the number of cells of MIA PaCa-2 per microgram protein of tissue samples. The median value for telomerase activity in normal pancreatic ducts was 0.13 and the 25th and 75th percentile were 0.01 and 0.76. The median value for telomerase activity in pancreatic ductal adenocarcinoma was 34.7 (25th percentile, 4.98; and 75th percentile, 296), significantly higher than that of normal ducts (P0.001). When the cut-off value was set at 1.0 and 3.0, the telomerase positivity rate of pancreatic ductal adenocarcinomas was 100% and 81.3%, respectively. Telomerase may be specific marker for pancreatic ductal carcinomas.

An ultrasonographic study of ten healthy volunteers was carried out to evaluate the effect of cisapride on gastric antral emptying. More than 1 week after the measurement of the baseline emptying rate, cisapride was given at a single oral dose of 5 mg 30 minutes before intake of a balanced liquid test meal (5 ml/kg body weight). To determine the time to half emptying (T1/2), an exponential curve was extrapolated for the elimination phase of the gastroantral sagittal cross-sectional area plotted against time. The T1/2 was reduced by 18.5% after cisapride, from 62.6 +/- 4.3 to 51.0 +/- 4.4 min (P = 0.0284). We conclude that a single oral dose of 5 mg of cisapride significantly accelerates the gastric antral emptying rate in healthy humans.