Yoshiaki Kawaguchi

Pharmacologic prophylaxis of post-endoscopic retrograde cholangiopancreatography pancreatitis: protease inhibitors and NSAIDs in a meta-analysis.

Post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis is the most frequent complication of ERCP. Several meta-analyses have examined the effects of protease inhibitors (gabexate mesilate, ulinastatin, and nafamostat mesilate) and non-steroidal anti-inflammatory drugs (NSAIDs) on post-ERCP pancreatitis, but the results have been confusing. Since the previous meta-analysis, several new studies have been published on this topic. To provide an updated quantitative assessment of the effectiveness of protease inhibitors and NSAIDs in preventing post-ERCP pancreatitis, we conducted a meta-analysis of randomized trials for patients at risk of post-ERCP pancreatitis. Twenty-six articles were included in this meta-analysis. Nafamostat mesilate (summary RRxa0=xa00.41; 95xa0%CI 0.28–0.59; nxa0=xa04 studies) and NSAIDs (summary RRxa0=xa00.58; 95xa0%CIxa0=xa00.44–0.76; nxa0=xa07 studies) were associated with decreased risk of post-ERCP pancreatitis in the high-quality studies. However, gabexate mesilate (summary RRxa0=xa00.64; 95xa0%CIxa0=xa00.36–1.13; nxa0=xa06 studies) and ulinastatin (summary RRxa0=xa00.65; 95xa0%CIxa0=xa00.33–1.30; nxa0=xa02 studies) were not associated with decreased risk of post-ERCP pancreatitis in the high-quality studies. This is the first meta-analysis to compare the effects of three protease inhibitors. Solid evidence supports the use of nafamostat mesilate and NSAIDs for preventing post-ERCP pancreatitis.

Randomized controlled trial of pancreatic stenting to prevent pancreatitis after endoscopic retrograde cholangiopancreatography

AIMnTo determine the effectiveness of pancreatic duct (PD) stent placement for the prevention of pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP) in high risk patients.nnnMETHODSnAuthors conducted a single-blind, randomized controlled trial to evaluate the effectiveness of a pancreatic spontaneous dislodgement stent against post-ERCP pancreatitis, including rates of spontaneous dislodgement and complications. Authors defined high risk patients as having any of the following: sphincter of Oddi dysfunction, difficult cannulation, prior history of post-ERCP pancreatitis, pre-cut sphincterotomy, pancreatic ductal biopsy, pancreatic sphincterotomy, intraductal ultrasonography, or a procedure time of more than 30 min. Patients were randomized to a stent group (n = 60) or to a non-stent group (n = 60). An abdominal radiograph was obtained daily to assess spontaneous stent dislodgement. Post-ERCP pancreatitis was diagnosed according to consensus criteria.nnnRESULTSnThe mean age (± standard deviation) was 67.4 ± 13.8 years and the male: female ratio was 68:52. In the stent group, the mean age was 66 ± 13 years and the male: female ratio was 33:27, and in the non-stent group, the mean age was 68 ± 14 years and the male: female ratio was 35:25. There were no significant differences between groups with respect to age, gender, final diagnosis, or type of endoscopic intervention. The frequency of post-ERCP pancreatitis in PD stent and non-stent groups was 1.7% (1/60) and 13.3% (8/60), respectively. The severity of pancreatitis was mild in all cases. The frequency of post-ERCP pancreatitis in the stent group was significantly lower than in the non-stent group (P = 0.032, Fishers exact test). The rate of hyperamylasemia were 30% (18/60) and 38.3% (23 of 60) in the stent and non-stent groups, respectively (P = 0.05, χ(2) test). The placement of a PD stent was successful in all 60 patients. The rate of spontaneous dislodgement by the third day was 96.7% (58/60), and the median (range) time to dislodgement was 2.1 (2-3) d. The rates of stent migration, hemorrhage, perforation, infection (cholangitis or cholecystitis) or other complications were 0% (0/60), 0% (0/60), 0% (0/60), 0% (0/60), 0% (0/60), respectively, in the stent group. Univariate analysis revealed no significant differences in high risk factors between the two groups. The pancreatic spontaneous dislodgement stent safely prevented post-ERCP pancreatitis in high risk patients.nnnCONCLUSIONnPancreatic stent placement is a safe and effective technique to prevent post-ERCP pancreatitis. Therefore authors recommend pancreatic stent placement after ERCP in high risk patients.

Perivascular epithelioid cell tumor (PEComa) of the pancreas: Immunoelectron microscopy and review of the literature

A perivascular epithelioid tumor (PEComa) is a rare tumor probably arising from the perivascular epithelioid cells. Only three cases of pancreatic PEComa have been reported in the English‐language literature. The present report describes an extremely rare case of pancreatic PEComa. A 47‐year‐old Japanese woman complained of lower abdominal pain and a well‐demarcated solid tumor was found in the pancreatic head. There was no history of tuberous sclerosis complexes. Pylorus‐preserving pancreaticoduodenectomy was thus performed. There was a well‐demarcated, solid tumor measuring 17u2003mm in the pancreatic head. The tumor was composed of a diffuse proliferation of epithelioid tumor cells with many blood vessels but no adipose tissue. The tumor cells expressed HMB45 and α‐smooth muscle actin. Ultrastructurally, the tumor cells possessed many membrane‐bound granules that were positive for HMB45 on immunoelectron microscopy. The results of immunoelectron microscopy show that some PEComas possess not only typical melanosomes or premelanosomes but also aberrant melanosomes.

Smoking and risk for acute pancreatitis: a systematic review and meta-analysis.

Abstract We aimed to better understand the relationship between smoking and a risk for acute pancreatitis (AP) in existing observational studies. We identified studies by searching the PubMed, Scopus, and Web of Science databases (from inception through August 31, 2013) and by searching bibliographies of relevant articles. Summary relative risks (RRs) with 95% confidence intervals (CIs) were calculated with fixed-effects and random-effects models. A total of 5 studies met inclusion criteria for analysis. Both current smoking (summary RR, 1.74; 95% CI, 1.39–2.17; n = 5 studies) and former smoking (summary RR, 1.32; 95% CI, 1.03–1.71; n = 4 studies) were associated with an increased risk for AP. The positive association of current smoking and risk for AP remained when we limited the meta-analysis to studies that controlled for alcohol intake and body mass index (summary RR, 1.76; 95% CI, 1.31–2.36; n = 4 studies). Both current and former smoking are associated with increased risk for AP. Further investigations, both epidemiological and mechanistic, are needed to establish the extent to which the association can be explained by a causal link and whether smoking cessation can prevent the occurrence and development of AP.

The distance of tumor spread in the main pancreatic duct of an intraductal papillary-mucinous neoplasm: where to resect and how to predict it

BackgroundThe surgical decision regarding where to resect the pancreas is an important judgement that is directly linked to the surgical procedure. An appropriate surgical margin to resect intraductal papillary-mucinous neoplasm (IPMN) of the pancreas based on the distance of tumor spread (DTS) in the main pancreatic duct has not been adequately documented. We analyzed the appropriate surgical margin based on the DTS in the main pancreatic duct of IPMN and the positive rate at the pancreatic cut end margin.MethodsForty patients with main duct- or mixed-type IPMN diagnosed histopathologically who underwent surgery at Tokai University Hospital between 1991 and 2008 were retrospectively analyzed. The resection line was determined to achieve a 2-cm surgical margin in patients with main duct- or mixed-type IPMN and as limited a resection as possible to remove the dilated branch duct in patients with branch duct-type IPMN according to macroscopic type. The dysplastic state of the epithelium was judged as positive for carcinoma in situ (high-grade dysplasia) or adenoma (very low to moderate dysplasia) and judged as negative for hyperplasia or normal.ResultsThe mean DTS in the main pancreatic duct was 41.6xa0±xa030.0xa0mm, and that of the distance of tumor absence was 13.6xa0±xa012.4xa0mm. The positive rate at the pancreatic cut end margin in frozen sections was 29.7%. The final positive rate at the pancreatic cut end margin was 26.2%. There has been no evidence of local recurrence in the remnant pancreas. DTS in the main pancreatic duct of IPMN was correlated with the maximum diameter of the duct (Rxa0=xa00.678).ConclusionDistance of tumor spread offered important insights about the appropriate site to resect the pancreas and the positive rate at the cut end margin in IPMN.

Eosinophilic gastroenteritis cured with Helicobacter pylori eradication.

To the Editor: Eosinophilic gastroenteritis is a rare disease characterized by eosinophilic infiltration of the gastrointestinal mucosa and various gastrointestinal symptoms including nausea, vomiting, diarrhea, and abdominal pain. Although the cause of eosinophilic gastroenteritis is unknown, it most likely represents a heterogeneous group of disorders. We present a patient with eosinophilic gastroenteritis coexistent with Helicobacter pylori gastritis, who was cured with H. pylori eradication, and review the literature. A 26-year-old man, who was a Japanese professional football player, presented with a 2-week history of abdominal pain and diarrhea. He denied any fever, bloody stools, loss of appetite, weight loss, or joint pain. There was no exposure to raw food. He had no past medical history of note and was not taking any medication. No food allergy or intolerance was reported. He did not smoke or drink alcohol, and was very healthy. Physical examination revealed only mild epigastric tenderness. Laboratory evaluation revealed a white blood cell count of 23,200 cells/mm (normal 3300 to 9400) with an eosinophil count of 16,704 cells/mm (normal 0 to 564), protein of 5.4 g/ dL (normal 6.9 to 8.3), and albumin of 3.6 g/dL (normal 4.3 to 5.4). C reactive protein was 0.1mg/dL (normal 0.0 to 0.2) and erythrocyte sedimentation rate 0mm/1 h (normal 2 to 10). Serum IgE was normal. Stool studies for ova and parasites and stool cultures were negative. Radioallergosorbent (RAST) test was within normal limits. Abdominal ultrasound and computed tomography revealed mild thickening of the small intestinal wall and bowel fluid collection. No findings of abdominal malignancy or ascites were evident. Colonoscopy with terminal ileoscopy showed only small erosions. Colonic biopsies showed eosinophilic infiltration of the colonic mucosal layer. Gastroscopy showed edema and erosions of the mucosa. Gastric biopsies showed eosinophilic infiltration of the gastric mucosal layer. Rapid urease test was positive for H. pylori. He was diagnosed as having coexistence of H. pylori gastritis and eosinophilic gastroenteritis, and was treated with lansoprazole (60mg/d), amoxycillin (1500mg/d), and clarithromycin (800mg/d) for 7 days. No treatment was given for eosinophilia. After treatment, he became asymptomatic, and the white blood cell count and eosinophil count decreased rapidly and normalized. Three months after eradication therapy, repeat gastroscopy showed marked improvement. Gastric biopsies showed only trivial eosinophilic infiltration, and gastric biopsy, rapid urease test, and urea breath test showed no H. pylori infection. Though H. pylori IgG antibody was negative on admission, 3 months after eradication therapy the antibody had become positive. We think he had first become infected with H. pylori during this time interval. He remained asymptomatic, with a normal white blood count of 6000 cells/mm and normal eosinophil count of 276 cells/mm. Protein and albumin also normalized gradually. There has been no admission for recurrence. Eosinophilic gastroenteritis is a rare disease that was first described by Kaijser in 1937. Klein et al classified this disease into 3 types: mucosal, muscle layer, and subserosal disease. Abdominal pain, nausea, vomiting, weight loss, diarrhea, iron-deficiency anemia, and protein-losing enteropathy characterize the mucosal type. Our patient had mucosal disease, and presented with a 2-week history of abdominal pain and diarrhea. Although the etiology is unknown, associations with various conditions, including allergies, connective tissue diseases, paraneoplastic syndromes, and parasitic infection, have been proposed. Though 50% to 70% of reported cases have a history of allergy, our patient did not. Serum IgE level and RAST test were also normal. Though steroid therapy is often given, 50% of patients have recurrent symptoms. Our patient also showed no evidence of connective tissue disease, paraneoplastic syndrome, or parasitic infection. Our patient seemed to have coexisting mucosal type eosinophilic gastroenteritis and H. pylori gastritis. A literature search to determine whether these 2 diseases are related revealed only 4 cases. Ours is the fifth reported case of coexistence of H. pylori infection and eosinophilic gastroenteritis, and is the second case in which blood and tissue eosinophilia resolved completely after successful eradication of H. pylori infection, and the first case of H. pylori first infection. In 3 of the previous cases, H. pylori gastritis persisted despite eradication, but blood and tissue eosinophilia resolved; however, as the symptoms recurred, in 2 cases a steroid was used, and in 1 case acid suppression was used. Successful eradication prevented recurrence in 1 case and in ours. We cannot confirm an association between H. pylori gastritis and eosinophilic gastroenteritis in the literature, but our case shows that H. pylori may play a pathogenic role in the development of blood eosinophilia and eosinophilic gastroenteritis, and that its eradication may be of value in treating certain cases of this disease. In future cases of eosinophilic gastroenteritis, attention should be paid to the possibility of H. pylori infection.

Rb loss and KRAS mutation are predictors of the response to platinum-based chemotherapy in pancreatic neuroendocrine neoplasm with grade 3: A Japanese multicenter pancreatic NEN-G3 study

Purpose: Patients with pancreatic neuroendocrine neoplasm grade-3 (PanNEN-G3) show variable responses to platinum-based chemotherapy. Recent studies indicated that PanNEN-G3 includes well-differentiated neuroendocrine tumor with G3 (NET-G3). Here, we examined the clinicopathologic and molecular features of PanNEN-G3 and assessed the responsiveness to chemotherapy and survival. Experimental Design: A total of 100 patients with PanNEN-G3 were collected from 31 institutions, and after central review characteristics of each histologic subtype [NET-G3 vs. pancreatic neuroendocrine carcinoma (NEC-G3)] were analyzed, including clinical, radiological, and molecular features. Factors that correlate with response to chemotherapy and survival were assessed. Results: Seventy patients analyzed included 21 NETs-G3 (30%) and 49 NECs-G3 (70%). NET-G3 showed lower Ki67-labeling index (LI; median 28.5%), no abnormal Rb expression (0%), and no mutated KRAS (0%), whereas NEC-G3 showed higher Ki67-LI (median 80.0%), Rb loss (54.5%), and KRAS mutations (48.7%). Chemotherapy response rate (RR), platinum-based chemotherapy RR, and prognosis differed significantly between NET-G3 and NEC-G3. Chemotherapeutic outcomes were worse in NET-G3 (P < 0.001). When we stratified PanNEN-G3 with Rb and KRAS, PanNENs-G3 with Rb loss and those with mutated KRAS showed significantly higher RRs to platinum-based chemotherapy than those without (Rb loss, 80% vs. normal Rb, 24%, P = 0.006; mutated KRAS, 77% versus wild type, 23%, P = 0.023). Rb was a predictive marker of response to platinum-based chemotherapy even in NEC-G3 (P = 0.035). Conclusions: NET-G3 and NEC-G3 showed distinct clinicopathologic characteristics. Notably, NET-G3 does not respond to platinum-based chemotherapy. Rb and KRAS are promising predictors of response to platinum-based chemotherapy for PanNEN-G3, and Rb for NEC-G3. Clin Cancer Res; 23(16); 4625–32. ©2017 AACR.

Isolated intrapancreatic IgG4-related sclerosing cholangitis

Immunoglobulin G4-related sclerosing cholangitis (IgG4-SC) is frequently associated with type 1 autoimmune pancreatitis (AIP). Association with AIP can be utilized in the diagnosis of IgG4-SC. However, some cases of IgG4-SC are isolated from AIP, which complicates the diagnosis. Most of the reported cases of isolated IgG4-SC displayed hilar biliary strictures, whereas isolated IgG4-SC with intrapancreatic biliary stricture is very rare. Recently, we have encountered 5 isolated intrapancreatic IgG4-SC cases that were not associated with AIP, three of which were pathologically investigated after surgical operation. They all were males with a mean age of 74.2 years. The pancreas was not enlarged in any of these cases. No irregular narrowing of the main pancreatic duct was found. Bile duct wall thickening in lesions without luminal stenosis was detected by abdominal computed tomography in all five cases, by endoscopic ultrasonography in two out of four cases and by intraductal ultrasonography in all three cases. In three cases, serum IgG4 levels were within the normal limits. The mean serum IgG4 level measured before surgery was 202.1 mg/dL (4 cases). Isolated intrapancreatic IgG4-SC is difficult to diagnose, especially if the IgG4 level remains normal. Thus, this type of IgG4-SC should be suspected in addition to cholangiocarcinoma and pancreatic cancer if stenosis of intrapancreatic bile duct is present.

Multicenter study of endoscopic preoperative biliary drainage for malignant distal biliary obstruction.

AIMnTo determine the optimal method of endoscopic preoperative biliary drainage for malignant distal biliary obstruction.nnnMETHODSnMulticenter retrospective study was conducted in patients who underwent plastic stent (PS) or nasobiliary catheter (NBC) placement for resectable malignant distal biliary obstruction followed by surgery between January 2010 and March 2012. Procedure-related adverse events, stent/catheter dysfunction (occlusion or migration of PS/NBC, development of cholangitis, or other conditions that required repeat endoscopic biliary intervention), and jaundice resolution (bilirubin level < 3.0 mg/dL) were evaluated. Cumulative incidence of jaundice resolution and dysfunction of PS/NBC were estimated using competing risk analysis. Patient characteristics and preoperative biliary drainage were also evaluated for association with the time to jaundice resolution and PS/NBC dysfunction using competing risk regression analysis.nnnRESULTSnIn total, 419 patients were included in the study (PS, 253 and NBC, 166). Primary cancers included pancreatic cancer in 194 patients (46%), bile duct cancer in 172 (41%), gallbladder cancer in three (1%), and ampullary cancer in 50 (12%). The median serum total bilirubin was 7.8 mg/dL and 324 patients (77%) had ≥ 3.0 mg/dL. During the median time to surgery of 29 d [interquartile range (IQR), 30-39 d]. PS/NBC dysfunction rate was 35% for PS and 18% for NBC [Subdistribution hazard ratio (SHR) = 4.76; 95%CI: 2.44-10.0, P < 0.001]; the pig-tailed tip was a risk factor for PS dysfunction. Jaundice resolution was achieved in 85% of patients and did not depend on the drainage method (PS or NBC).nnnCONCLUSIONnPS has insufficient patency for preoperative biliary drainage. Given the drawbacks of external drainage via NBC, an alternative method of internal drainage should be explored.

A case of successful placement of a fully covered metallic stent for hemobilia secondary to hepatocellular carcinoma with bile duct invasion.

Hemobilia represents gastrointestinal bleeding that develops as a result of communication between blood vessels and the biliary tract, which causes the blood to reach the duodenal papilla. It is characterized by biliary colic as the initial symptom, and the complications of cholangitis, obstructive jaundice and/or anemia. In general, definitive diagnosis is made by esophagogastroduodenoscopy which confirms bleeding from the duodenal papilla. Abdominal US and abdominal enhanced CT are performed to identify the source of the bleeding, as well as ERCP for biliary drainage to control the comorbid cholangitis. If active hemorrhage accompanied by worsening of the anemia is suspected, abdominal angiography is performed to selectively image the hepatic artery. Then, embolization of the culprit vessel is recommended. In our patients with difficult hemostasis, because of the direct compression hemostasis to the tumor site achieved with the fully covered metallic stent and secondary compression hemostasis due to blood clots, the bleeding could be controlled.