Pathogenicity of IgG in patients with IgG4-related disease.

OBJECTIVE: IgG4-related disease (IgG4-RD) is a systemic disease characterised by elevated serum IgG4 and IgG4-positive lymphoplasmacytic infiltration in the affected tissues. The pathogenic role of IgGs, including IgG4, in patients with IgG4-RD, however, is unknown. DESIGN: We examined the pathogenic activity of circulating IgGs in patients with IgG4-RD by injecting their IgGs into neonatal male Balb/c mice. Binding of patient IgGs to pancreatic tissue was also analysed in an ex vivo mouse organ culture model and in tissue samples from patients with autoimmune pancreatitis (AIP). RESULTS: Subcutaneous injection of patient IgG, but not control IgG, resulted in pancreatic and salivary gland injuries. Pancreatic injury was also induced by injecting patient IgG1 or IgG4, with more destructive changes induced by IgG1 than by IgG4. The potent pathogenic activity of patient IgG1 was significantly inhibited by simultaneous injection of patient IgG4. Binding of patient IgG, especially IgG1 and IgG4, to pancreatic tissue was confirmed in both the mouse model and AIP tissue samples. CONCLUSIONS: IgG1 and IgG4 from patients with IgG4-RD have pathogenic activities through binding affected tissues in neonatal mice.

Impact of EUS-FNA for preoperative para-aortic lymph node staging in patients with pancreatobiliary cancer.

BACKGROUND AND AIMS: In patients with pancreatobiliary cancer, para-aortic lymph node (PALN) metastasis is considered to be the involvement beyond the regional lymph nodes, namely, distant metastasis. Effective methods for preoperative PALN staging, however, are not established. This study aimed to compare the diagnostic capability for PALN metastasis between EUS-FNA and (18)F-fluorodeoxyglucose positron emission tomography with CT (PET/CT). METHODS: We performed a prospective, nonrandomized, single-center trial. Between December 2010 and March 2014, 208 patients with pancreatobiliary cancer without apparent distant metastasis except for PALNs were assessed for study eligibility before surgery. Among them, 52 consecutive patients with PALN enlargement were enrolled in the study. (18)F-Fluorodeoxyglucose PET/CT and EUS-FNA were performed sequentially as a single combined procedure to evaluate PALN metastases. The primary outcome was to compare the diagnostic capability of EUS-FNA and PET/CT for PALN metastasis. RESULTS: Of 71 enlarged PALNs in the 52 patients, 30 (42.3%) were finally diagnosed as metastases in 21 patients (40.4%). Of the 21 patients with PALN metastases, preoperative EUS-FNA or PET/CT made a correct diagnosis in 20 (95.2%) or 12 (57.1%), respectively. EUS-FNA had higher sensitivity and specificity for the diagnosis of PALN metastasis (sensitivity, 96.7% [29/30]; 95% confidence interval, 82.2%-99.9%; specificity, 100% [39/39]; 95% confidence interval, 91.0%-100%) than PET/CT. CONCLUSIONS: EUS-FNA is superior to PET/CT for preoperative PALN staging in patients with pancreatobiliary cancer. Because of the clinical benefit of EUS-FNA to reduce unnecessary surgery, it should be part of the standard preoperative examination for patients with pancreatobiliary cancer. (UMIN clinical trials registry number: 000006408.).

Late-onset acetaminophen-induced allergic hepatitis with progression to chronicity.

Acetaminophen (paracetamol), a widely used antipyretic/analgesic, is a well-known agent causing acute hepatic injury. Whereas most cases are caused by its intrinsic hepatotoxicity, idiosyncratic hepatitis by the allergic mechanism is extremely rare. We herein report a case of late-onset acetaminophen-induced allergic hepatitis with progression to chronicity. This unique case extends the spectrum of acetaminophen-induced liver injury. Clinicians should be aware of this unusual clinical manifestation. The mechanism underlying the immunological reaction to acetaminophen remains to be elucidated.

Pancreatic Neuroendocrine Neoplasm Concomitant with Branch-duct Intraductal Papillary Mucinous Neoplasm: A Case Report and Literature Review.

Reports of pancreatic neuroendocrine neoplasm (P-NEN) concomitant with intraductal papillary mucinous neoplasm (IPMN) are gradually increasing. However, many of these cases were diagnosed in the resected specimen incidentally. We herein report a case of minimal P-NEN concomitant with branch-duct IPMN that was successfully diagnosed preoperatively by contrast-enhanced endoscopic ultrasonography (EUS) and an EUS-guided fine-needle biopsy. These findings suggest that P-NEN as well as pancreatic ductal adenocarcinoma should be considered as concurrent tumors developing in patients with IPMNs. EUS is an essential modality when evaluating IPMN for detecting small lesions concomitant with IPMN.

Risk of cancer in patients with autoimmune pancreatitis.

OBJECTIVES: Although simultaneous occurrences of autoimmune pancreatitis (AIP) and cancer are occasionally observed, it remains largely unknown whether cancer and AIP occur independently or these disorders are interrelated. The aim of this study was to examine the relationship between AIP and cancer. METHODS: We conducted a multicenter, retrospective cohort study. One hundred and eight patients who met the Asian diagnostic criteria for AIP were included in the study. We calculated the proportion, standardized incidence ratio (SIR), relative risk, and time course of cancer development in patients with AIP. We also analyzed the clinicopathological characteristics of AIP patients with cancer in comparison with those without cancer. RESULTS: Of the 108 AIP patients, 18 cancers were found in 15 patients (13.9%) during the median follow-up period of 3.3 years. The SIR of cancer was 2.7 (95% confidence interval (CI) 1.4-3.9), which was stratified into the first year (6.1 (95% CI 2.3-9.9)) and subsequent years (1.5 (95% CI 0.3-2.8)) after AIP diagnosis. Relative risk of cancer among AIP patients at the time of AIP diagnosis was 4.9 (95% CI 1.7-14.9). In six of eight patients whose cancer lesions could be assessed before corticosteroid therapy for AIP, abundant IgG4-positive plasma cell infiltration was observed in the cancer stroma. These six patients experienced no AIP relapse after successful cancer treatment. CONCLUSIONS: Patients with AIP are at high risk of having various cancers. The highest risk for cancer in the first year after AIP diagnosis and absence of AIP relapse after successful treatment of the coexisting cancers suggest that AIP may develop as a paraneoplastic syndrome in some patients.

Reducing the risk of developing walled-off necrosis in patients with acute necrotic collection using recombinant human soluble thrombomodulin.

BACKGROUND/PURPOSE: The purpose of the present study was to investigate the possibility of reducing clinical impacts of acute necrotic collection (ANC) on patients with acute pancreatitis (AP) using recombinant human soluble thrombomodulin (rTM). METHODS: In this retrospective multicenter study, 233 consecutive AP patients with ANC and acute peripancreatic fluid collection (APFC) from 2012 to 2016 were enrolled. To assess clinical impacts of ANC, severity on admission (JPN score, JPN CT grade, and Modified CT severity index), development of walled-off necrosis (WON), imaging costs for follow-up, and mortality were recorded. Finally, we investigated whether rTM could reduce the clinical impacts, adjusting the severity using propensity analysis with Inverse probability of treatment weighting. RESULTS: Patients with ANC developed WON with higher ratio than APFC (58/98 [59.2%] vs 20/135 [14.8%], OR = 8.3, P < .01]. Severity on admission and imaging costs for follow-up in ANC patients were significantly higher than those in APFC (P < .01). However, regarding mortality, there was no significant difference between patients with ANC and APFC (P = .41). Adjusting severity, it was revealed that rTM administration significantly reduced the risk of ANC developed WON (OR = 0.23, P = .01). CONCLUSIONS: While ANC had a higher clinical impact than that of APFC, we found that early administration of rTM may reduce the impact.

Underwater endoscopic mucosal resection: a new endoscopic method for resection of rectal neuroendocrine tumor grade 1 (carcinoid) ≤ 10 mm in diameter.

Background and study aims Rectal neuroendocrine tumors grade 1 (NET G1; carcinoid) ≤ 10 mm in diameter often extend into the submucosa, making their complete histological resection difficult using endoscopic techniques. Endoscopic submucosal resection with a ligation device (ESMR-L) and endoscopic submucosal dissection (ESD) are commonly used to overcome these difficulties. We also previously reported that underwater endoscopic mucosal resection (UEMR) could facilitate resection of rectal NET G1. This study aimed to evaluate the safety and efficacy of UEMR for removing rectal NET G1 ≤ 10 mm in diameter. 6 consecutive patients with rectal NET G1 ≤ 10 mm in diameter underwent UEMR at our hospital. The rate of en bloc resection was 100 %, and the rate of R0 resection was 83 %. The median procedure time was 8 min (range 5 - 12 min). No perforations or delayed bleeding occurred in this study. In conclusion, UEMR allows the safe and reliable resection of rectal NET G1 ≤ 10 mm in diameter with comparable results to ESMR-L or ESD, including high en bloc and R0 resection rates with no increase in significant adverse events. A multicenter trial is required to confirm the validity of the present results.

Cold snare polypectomy reduced delayed postpolypectomy bleeding compared with conventional hot polypectomy: a propensity score-matching analysis.

BACKGROUND AND STUDY AIMS: Cold snare polypectomy (CSP) for small colorectal polyps has lower incidence of adverse events, especially delayed postpolypectomy bleeding (DPPB). However, few data are available on comparisons of the incidence of DPPB of CSP and hot polypectomy (HP). The aim of this study was to evaluate the incidence of DPPB after CSP and compare it with that of HP. A propensity score model was used as a secondary analysis. PATIENTS AND METHODS: This was a retrospective cohort study conducted in a single municipal hospital. We identified 539 patients with colorectal polyps from 2 mm to 11 mm in size who underwent CSP (804 polyps in 330 patients) or HP (530 polyps in 209 patients) between July 2013 and June 2015. RESULTS: There were no cases of DPPB in the CSP group. Conversely, DPPB occurred in 4 patients (1.9 %) after HP, resulting in a significant difference between the CSP and HP groups (0.008 % vs 0 %, P  = 0.02). Propensity score-matching analysis created 402 matched pairs, yielding a significantly higher DPPB rate in the HP group than CSP group (0.02 % vs 0 %, P  = 0.04). However, significantly more patients in the CSP group had unclear horizontal margins that precluded assessment (83 vs 38 cases, P  < 0.001). The retrieval failure rate was significantly higher in the CSP group than in the HP group (3 % vs 0.7 %, P  = 0.01). CONCLUSIONS: DPPB was less frequent with CSP than HP, as selected by the propensity score-matching model. Our findings indicate that CSP is recommended polypectomy in daily clinical setting. However, special care should be taken during polyp retrieval and horizontal margin assessment, and these issues could be taken into account in follow-up after CSP.

Activation-Induced Cytidine Deaminase Contributes to Pancreatic Tumorigenesis by Inducing Tumor-Related Gene Mutations.

Pancreatic ductal adenocarcinoma (PDAC) develops via an accumulation of various gene mutations. The mechanism underlying the mutations in PDAC development, however, is not fully understood. Recent insight into the close association between the mutation pattern of various cancers and specific mutagens led us to investigate the possible involvement of activation-induced cytidine deaminase (AID), a DNA editing enzyme, in pancreatic tumorigenesis. Our immunohistochemical findings revealed AID protein expression in human acinar ductal metaplasia, pancreatic intraepithelial neoplasia, and PDAC. Both the amount and intensity of the AID protein expression increased with the progression from precancerous to cancerous lesions in human PDAC tissues. To further assess the significance of ectopic epithelial AID expression in pancreatic tumorigenesis, we analyzed the phenotype of AID transgenic (AID Tg) mice. Consistent with our hypothesis that AID is involved in the mechanism of the mutations underlying pancreatic tumorigenesis, we found precancerous lesions developing in the pancreas of AID Tg mice. Using deep sequencing, we also detected Kras and c-Myc mutations in our analysis of the whole pancreas of AID Tg mice. In addition, Sanger sequencing confirmed the presence of Kras, c-Myc, and Smad4 mutations, with the typical mutational footprint of AID in precancerous lesions in AID Tg mice separated by laser capture microdissection. Taken together, our findings suggest that AID contributes to the development of pancreatic precancerous lesions by inducing tumor-related gene mutations. Our new mouse model without intentional manipulation of specific tumor-related genes provides a powerful system for analyzing the mutations involved in PDAC.

Endoscopic stent placement above the intact sphincter of Oddi for biliary strictures after living donor liver transplantation.

BACKGROUND AND STUDY AIMS: Biliary complications are one of the most serious morbidities after liver transplantation. Inside-stent is a plastic stent placed above the sphincter of Oddi without endoscopic sphincterotomy against biliary strictures. Our aims were to analyze the long-term efficacy of inside-stent placement in patients with biliary stricture after living donor liver transplantation. PATIENTS AND METHODS: Ninety-four patients who experienced biliary stricture that employed duct-to-duct reconstruction were treated with inside-stent placement. Treatment outcomes, including stricture resolution, recurrence, inside-stent patency, and morbidity rate were evaluated retrospectively. RESULTS: Ninety-two patients could be evaluated. Resolution of stricture was eventually observed in 81 of 92 patients with an average of 1.4 sessions of endoscopic retrograde cholangiography. Of the 81 patients who achieved the resolution of the stricture, recurrent biliary stricture that required intervention occurred in 8 patients. Conversely, stricture remission was achieved 73 patients (90.1 %) during 53 months follow-up after stent removal. Median duration of patency of the initial stent was 189 (range 2-1228) days. Stent dislocation occurred in 10 patients. Adverse event related to inside-stent placement was pancreatitis in 18 cases (mild 13, moderate 5). CONCLUSIONS: Inside-stent placement achieved long-term patency and high remission rate in patients with biliary stricture after liver transplantation.

Autoimmune pancreatitis exhibiting multiple mass lesions.

Our case is a first report of autoimmune pancreatitis with multiple masses within the pancreas which was pathologically diagnosed by endoscopic ultrasound-guided fine needle aspiration and treated by steroid. The masses disappeared by steroid therapy. Our case is informative to know that autoimmune pancreatitis sometimes exhibits multiple masses within the pancreas and to diagnose it without unnecessary surgery.

Spontaneous rupture of liver plasmacytoma mimicking hepatocellular carcinoma.

Extramedullary plasmacytoma of the liver is rare. Here, we report a case presenting with rupture of extramedullary plasmacytoma of the liver. She had a past history of multiple myeloma with IgA lambda type. Her serum was positive for hepatitis C virus infection and exhibited elevated levels of serum protein induced by vitamin K absence or antagonist-II. She was initially diagnosed as rupture of hepatocellular carcinoma (HCC) and then treated with transarterial chemoembolization (TACE) since bloody ascites and formation of hematoma were seen around hyper-vascular liver tumors on computed tomography. However, the clinical course of this case after TACE was atypical for HCC rupture, as shown by the development of a huge intra-abdominal abscess extending from the liver tumor. Immuno-histochemical analysis of the tumor biopsy specimen revealed massive infiltration of plasma cells expressing IgA and lambda chain. To our knowledge, this is the first case of rupture of extramedullary liver plasmacytoma.

Clinical impact of radiotherapy for locally advanced pancreatic cancer.

BACKGROUND: Although a randomized controlled trial for locally advanced pancreatic cancer (PC) has demonstrated a survival advantage for treatment with gemcitabine alone, chemoradiotherapy remains the treatment of choice for locally advanced disease in Japan. The aim of this study was to compare the survival benefits associated with gemcitabine and concurrent chemoradiotherapy in locally advanced unresectable PC. PATIENTS: Seventy-seven patients with locally advanced unresectable PC were retrospectively enrolled from April 2001 to December 2006. All cases were histologically proven, and patients received gemcitabine chemotherapy (n = 30) or concurrent chemoradiotherapy (based on 5-fluorouracil, n = 28, or gemcitabine, n = 19, as a radiosensitizer) at Aichi Cancer Center Hospital. RESULTS: Patients who received chemoradiotherapy had significantly better performance status than those who had chemotherapy. Tumor response was 0% for chemotherapy and 13% chemoradiotherapy, but survival benefit was similar among patients in the chemotherapy group (overall response (OS) 12 months; progression-free survival (PFS), 3 months) and those in the chemoradiotherapy group (OS, 13 months; PFS, 5 months). Two-year survival was 21% for chemotherapy patients and 19% for chemoradiotherapy patients. Severe toxicities (Grade 3-4 National Cancer Institute-Common Toxicity Criteria, version 3.0) were significantly more frequent for chemoradiotherapy than for chemotherapy. CONCLUSIONS: Gemcitabine chemotherapy showed similar survival benefit compared to 5-fluorouracil- and gemcitabine-based chemoradiotherapy.