Adverse events of self-expandable metal stent placement for malignant distal biliary obstruction: a large multicenter study.

BACKGROUND AND AIMS: Endoscopic placement of self-expandable metal stents (SEMSs) for malignant distal biliary obstruction (MDBO) may be accompanied by several types of adverse events. The present study analyzed the adverse events occurring after SEMS placement for MDBO. METHODS: The present study retrospectively investigated the incidence and types of adverse events in patients who underwent SEMS placement for MDBO between April 2018 and March 2021 at 26 hospitals. Risk factors for acute pancreatitis, cholecystitis, and recurrent biliary obstruction (RBO) were evaluated by univariate and multivariate analyses. RESULTS: Of the 1425 patients implanted with SEMSs for MDBO, 228 (16.0%) and 393 (27.6%) experienced early adverse events and RBO, respectively. Pancreatic duct without tumor involvement (P = .023), intact papilla (P = .025), and SEMS placement across the papilla (P = .037) were independent risk factors for acute pancreatitis. Tumor involvement in the orifice of the cystic duct was an independent risk factor for cholecystitis (P < .001). Use of fully and partially covered SEMSs was an independent risk factor for food impaction and/or sludge. Use of fully covered SEMSs was an independent risk factor for stent migration. Use of uncovered SEMSs and laser-cut SEMSs was an independent risk factor for tumor ingrowth. CONCLUSIONS: Pancreatic duct without tumor involvement, intact papilla, and SEMS placement across the papilla were independent risk factors for acute pancreatitis, and tumor involvement in the orifice of the cystic duct was an independent risk factor for cholecystitis. The risk factors for food impaction and/or sludge, stent migration, and tumor ingrowth differed among types of SEMSs.

Does endoscopic sphincterotomy contribute to the prevention of post-endoscopic retrograde cholangiopancreatography pancreatitis after endoscopic biliary stenting for malignant biliary obstruction? A multicenter prospective cohort study.

BACKGROUND: There is no consensus on the necessity of endoscopic sphincterotomy (ES) to prevent post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP) after endoscopic stenting in patients with malignant biliary obstruction. We investigated the incidence of PEP after endoscopic biliary stenting for malignant biliary obstruction with or without ES in a multicenter prospective cohort study. METHODS: We enrolled 807 patients who underwent endoscopic biliary stenting for malignant biliary obstruction with a native papilla at 36 hospitals between April 2017 and March 2018. The incidence of PEP in patients with or without ES was compared for subgroups based on stent type, placement method, and patient background. Univariate and multivariate analysis was performed to investigate the incidence of PEP in all stenting patients. RESULTS: Plastic and metal stents (MS) were inserted in 598 and 209 patients, respectively. The incidence of PEP in patients with or without ES was 7.9% and 7.4%, respectively among all stenting patients. The incidences of PEP with or without ES in plastic stent insertion patients, patients with MS insertion, stent insertions across the papilla, stent insertions across the papilla in patients without main pancreatic duct obstruction, and fully covered MS insertions across the papilla were compared. There was no overall significant difference in the incidence of PEP between those with or without ES. Multivariate logistic regression analysis for the incidence of PEP in all stenting patients revealed obstruction of the main pancreatic duct at the pancreatic head and epinephrine spraying on the papilla were significant factors; there was no significant difference in the incidence of PEP between patients with or without ES. CONCLUSION: Endoscopic sphincterotomy may not contribute to the prevention of PEP after endoscopic biliary stenting for malignant biliary obstruction, even in cases of insertion with a fully covered MS across the papilla.

Comparison of 22-gauge standard and Franseen needles in EUS-guided tissue acquisition for diagnosing solid pancreatic lesions: a multicenter randomized controlled trial.

BACKGROUND AND AIMS: This large multicenter randomized controlled trial compared the diagnostic yields of 22-gauge standard and 22-gauge Franseen needles for EUS-guided tissue acquisition (EUS-TA) of solid pancreatic lesions. METHODS: Consecutive patients with solid pancreatic lesions were prospectively randomized to EUS-TA using standard or Franseen needles. Samples obtained with the first needle pass and with second and subsequent passes were evaluated separately. The primary endpoint was the rate of accuracy for diagnosis of malignancy. Other endpoints were technical success rate, sample cellularity, adverse events, diagnostic accuracy in patient subgroups, and the diagnostic accuracy and numbers of second and subsequent needle passes. RESULTS: Of 523 patients undergoing EUS-TA, 260 were randomized to using standard 22-gauge needles and 263 to 22-gauge Franseen needles. The technical success rate in each group was 99.6%, with similar adverse event rates in the standard (1.5%) and Franseen (.8%) needle groups. First-pass EUS-TA using the Franseen needle resulted in significantly greater diagnostic accuracy (84.0% vs 71.2%, P < .001) and sensitivity (82.4% vs 66.7%, P < .001) than first-pass EUS-TA using a standard needle and also resulted in superior diagnostic accuracy in patients requiring immunostaining. Second and subsequent EUS-TA using Franseen needles showed significantly greater accuracy (94.7% vs 90.0%, P = .049) and sensitivity (94.0% vs 88.6%, P = .047) and required fewer needle passes (1.81 vs 2.03, P = .008) than using standard needles. CONCLUSIONS: EUS-TA with the Franseen needle is superior to EUS-TA with a standard needle with respect to diagnostic accuracy per pass, particularly in patients who require immunostaining, and number of passes when using macroscopic on-site evaluation. (Clinical trial registration numbers: UMIN000030634 and jRCTs052180062.).

Stent placement above the sphincter of Oddi is a useful option for patients with inoperable malignant hilar biliary obstruction.

BACKGROUND AND AIMS: Endoscopic biliary drainage (EBD) is essential for the management of malignant hilar biliary obstruction (MHBO). We prospectively evaluated the efficacy and safety of "inside-stent" therapy, where a plastic stent is placed above the sphincter of Oddi without endoscopic sphincterotomy, in patients with inoperable MHBO. METHODS: This study was a multicenter, single-blinded, randomized controlled trial at three centers. Patients with inoperable MHBO were enrolled in this study, and randomly assigned to receive an inside-stent or conventional-stent therapy. The primary endpoint was cumulative stent patency of the initial stent. The secondary endpoints were second stent patency, technical and clinical success rate, adverse events, re-intervention rate, and overall patient survival. RESULTS: Forty-three patients were randomly assigned to the inside-stent group (n = 21) or the conventional-stent group (n = 22). The median cumulative stent patency of the initial stent was 123 days in the inside-stent group and 51 days in the conventional-stent group (P = .031). For patients with the initial stent dysfunction in the conventional-stent group, the inside-stent was placed as a second stent, and its patency was significantly longer than that of the initial stent (P = .0001). The technical and clinical success rate, re-intervention rate, second stent patency, adverse events, and survival probability did not differ between the groups. CONCLUSIONS: Inside-stent therapy appears to be useful not only as an initial stent but also as a second stent for patients with inoperable MHBO. TRIAL REGISTRATION NUMBER: UMIN000004587.

Multicenter prospective cohort study of adverse events associated with biliary endoscopic retrograde cholangiopancreatography: Incidence of adverse events and preventive measures for post-endoscopic retrograde cholangiopancreatography pancreatitis.

OBJECTIVES: The reported incidence of adverse events (AEs) in endoscopic retrograde cholangiopancreatography (ERCP) varies between 2.5% and 14%. The aim of this study was to evaluate the incidence and severity of AEs in biliary ERCP and to specify the risk factors and preventive measures for post-ERCP pancreatitis (PEP). METHODS: Patients with biliary disease with intact papilla were prospectively enrolled at 36 hospitals between April 2017 and March 2018. The primary outcomes were the incidence and severity of AEs. RESULTS: A total of 16,032 ERCP procedures were performed at the 36 hospitals during the study period and 3739 patients were enrolled. The overall incidence of AEs was 10.1% and ERCP-related mortality was 0.08%. PEP developed in 258 cases (6.9%), bleeding in 33 (0.9%), instrumental AEs in 17 (0.5%), infections in 37 (1.0%), cardiovascular AEs in eight (0.2%), pulmonary AEs in eight (0.2%), drug reaction AE in one (0.03%), pain in 15 (0.4%), and other AEs in 15 (0.4%). Multivariable analysis showed significant risk factors for PEP were: female of younger age, pancreatic guidewire-assisted biliary cannulation, temporary guidewire insertion into the pancreatic duct, total procedure time >60 min, and post-ERCP administration of non-steroidal anti-inflammatory drugs. Effective preventive measures were prophylactic pancreatic stenting (PPS) and epinephrine spraying onto the papilla. CONCLUSIONS: In patients with intact papilla who underwent biliary ERCP, the incidence of AEs was 10.1% and the mortality was 0.08%. PPS and epinephrine spraying may prevent PEP. REGISTRATION: This study was registered in the University Hospital Medical Information Network (UMIN000024820).

Endoscopic placement of covered versus uncovered self-expandable metal stents for palliation of malignant gastric outlet obstruction.

OBJECTIVE: Stenting is an established endoscopic therapy for malignant gastric outlet obstruction (mGOO). The choice of stent (covered vs uncovered) has been examined in prior randomised studies without clear results. DESIGN: In a multicentre randomised prospective study, we compared covered (CSEMS) with uncovered self-expandable metal stents (UCSEMS) in patients with mGOO; main outcomes were stent dysfunction and patient survival, with subgroup analyses of patients with extrinsic and intrinsic tumours. RESULTS: Overall survival was poor with no difference between groups (probability at 3 months 49.7% for covered vs 48.4% for uncovered stents; log-rank for overall survival p=0.26). Within that setting of short survival, the proportion of stent dysfunction was significantly higher for uncovered stents (35.2% vs 23.4%, p=0.01) with significantly shorter time to stent dysfunction. This was mainly relevant for patients with extrinsic tumours (stent dysfunction rates for uncovered stents 35.6% vs 17.5%, p<0.01). Subgrouping was also relevant with respect to tumour ingrowth (lower with covered stents for intrinsic tumours; 1.6% vs 27.7%, p<0.01) and stent migration (higher with covered stents for extrinsic tumours: 15.3% vs 2.5%, p<0.01). CONCLUSIONS: Due to poor patient survival, minor differences between covered and uncovered stents may be less relevant even if statistically significant; however, subgroup analysis would suggest to use covered stents for intrinsic and uncovered stents for extrinsic malignancies.

Histological diagnosis and grading of pancreatic neuroendocrine tumor by endoscopic ultrasound-guided fine needle biopsy using a 25-gauge needle with a core trap: A multicenter prospective trial.

OBJECTIVES: Preoperative grading of pancreatic neuroendocrine tumors (PanNET) is challenging. The aim of this study was to prospectively evaluate the use of a 25-gauge needle with a core trap for diagnosis and grading of PanNET. METHODS: This multicenter prospective trial was registered with the University Hospital Medical Information Network (UMIN000021409). Consecutive patients with suspected PanNET between June 2016 and November 2017 were enrolled. All patients underwent endoscopic ultrasound-guided fine needle biopsy (EUS-FNB) using a 25-gauge needle with a core trap. Samples obtained after the first needle pass were used for central pathological review. EUS-FNB was evaluated in terms of (i) technical success rate, (ii) adequacy for histological evaluation, (iii) complication rate during the procedure, and (iv) concordance between PanNET grading on EUS-FNB and that after analysis of the resected tumor. RESULTS: Fifty-two patients were enrolled. Of the 36/52 patients who underwent surgical resection, 31 were finally diagnosed with PanNET and were eligible for analysis. The technical success rate of EUS-FNB was 100%. The rate of adequacy for histological evaluation was 90.3%. There were no complications related to EUS-FNB. The concordance rate between PanNET grading on EUS-FNB and that after analysis of the resected tumor was 82.6% (95% confidence interval = 61.22-95.05, P = 0.579). CONCLUSIONS: EUS-FNB using a 25-gauge needle with a core trap is feasible, providing histological samples are of sufficient quality for diagnosis and grading of PanNET.

Comparison of a 22-gauge Franseen-tip needle with a 20-gauge forward-bevel needle for the diagnosis of type 1 autoimmune pancreatitis: a prospective, randomized, controlled, multicenter study (COMPAS study).

BACKGROUND AND AIMS: Histologic diagnosis of autoimmune pancreatitis (AIP) using EUS-guided FNA (EUS-FNA) is difficult. To address this issue, new fine-needle biopsy (FNB) needles were recently developed. Here, we prospectively evaluated 2 newly designed EUS-FNB needles for histologic evaluation in patients with type 1 AIP. METHODS: This was a prospective, randomized, multicenter trial comparing biopsy specimens obtained with a 22-gauge Franseen needle or a 20-gauge forward-bevel needle in patients with suspected type 1 AIP. AIP was diagnosed according to international consensus diagnostic criteria. The primary endpoint was the sensitivity of EUS-FNB needles, and secondary endpoints were the amount of specimen obtained, histology of the pancreas based on evaluation of lymphoplasmacytic sclerosing pancreatitis (LPSP), and contribution of histologic findings to the diagnosis of AIP. RESULTS: One hundred ten patients were randomly assigned to the Franseen group (22-gauge Franseen needle) or the forward-bevel group (20-gauge forward-bevel needle). EUS-FNB sampling was successful in all patients. Nine patients were excluded because of diagnoses other than AIP. Compared with the forward-bevel needle, the Franseen needle obtained a significantly greater number of high-power fields. Of 101 patients, 39 patients (78%) in the Franseen group and 23 patients (45%) in the Forward-bevel group were diagnosed with level 1 or 2 LPSP (P = .001). Thirty-six patients could not be diagnosed with type 1 AIP without EUS-FNB specimen results. CONCLUSIONS: The 22-gauge Franseen needle should be routinely used for histologic diagnosis of type 1 AIP. (Clinical trial registration number: UMIN 000027668.).

Outcomes of endoscopic biliary drainage in pancreatic cancer patients with an indwelling gastroduodenal stent: a multicenter cohort study in West Japan.

BACKGROUND AND AIMS: Gastroduodenal and biliary obstruction may occur synchronously or asynchronously in advanced pancreatic cancer, and endoscopic double stent placement may be required. EUS-guided biliary drainage (EUS-BD) often is performed after unsuccessful placement of an endoscopic transpapillary stent (ETS), and EUS-BD may be beneficial in double stent placement. This retrospective multicenter cohort study compared the outcomes of ETS placement and EUS-BD in patients with an indwelling gastroduodenal stent (GDS). METHODS: We recorded the clinical outcomes of patients at 5 tertiary-care medical centers who required biliary drainage after GDS placement between March 2009 and March 2014. RESULTS: Thirty-nine patients were included in this study. Patients' mean age was 68.5 years; 23 (59.0%) were men. The GDS overlay the papilla in 23 patients (59.0%). The overall technical success rate was significantly higher with EUS-BD (95.2%) than with ETS placement (56.0%; P < .01). Furthermore, the technical success rate was significantly higher with EUS-BD (93.3%) than with ETS placement (22.2%; P < .01) when the GDS overlies the papilla. The overall clinical success rate of EUS-BD also was significantly higher than for ETS placement (90.5% vs 52.0%, respectively; P = .01), and there was no significant difference in the incidence of adverse events (ETS, 32.0% vs EUS-BD, 42.9%; P = .65). CONCLUSION: Endoscopic double stent placement with EUS-BD is technically and clinically superior to ETS placement in patients with an indwelling GDS. EUS-BD should be considered the first-line treatment option for patients with an indwelling GDS that overlies the papilla. ETS placement remains a reasonable alternative when the papilla is not covered by the GDS.

Factors predicting through-the-scope gastroduodenal stenting outcomes in patients with gastric outlet obstruction: a large multicenter retrospective study in West Japan.

BACKGROUND AND AIMS: Endoscopic gastroduodenal stenting for malignant gastric outlet obstruction recently has become more effective, but the factors that predict gastroduodenal stenting outcomes are poorly defined. This multicenter retrospective cohort study evaluated the clinical outcomes of gastroduodenal stenting in malignant gastroduodenal obstruction and identified factors predicting clinical ineffectiveness, stent dysfunction, and adverse events. METHODS: All consecutive patients with malignant gastroduodenal obstruction who underwent through-the-scope gastroduodenal stenting from 2009 to 2014 at 4 tertiary-care medical centers were identified. Clinically ineffective stenting was defined as symptom recurrence and a gastric outlet obstruction scoring system (GOOSS) score <2. RESULTS: Of the 278 patients (mean age ± standard deviation [SD] 71.7 ± 11.4 years), 121 (43.5%) and 87 (31.3%) had pancreatic and gastric cancer, respectively. Technical success was achieved in 277 patients (99.6%). GOOSS scores rose from 0.5 ± 0.6 to 2.6 ± 0.8. Stenting was ineffective in 32 patients (12.6%). Stent dysfunction that caused symptom recurrence during follow-up developed in 46 patients (16.6%). Adverse events occurred in 49 patients (17.7%). Three or more stenosis sites (odds ratio [OR] = 6.11; P < .01) and Karnofsky performance scores ≤50 (OR = 6.63; P < .01) predicted clinical ineffectiveness. Karnofsky performance scores ≤50 predicted stent dysfunction (hazard ratio [HR] = 3.63; P < .01). Bile duct stenosis (HR = 9.55; P = .02) and liver metastasis (HR = 9.42; P < .01) predicted stent overgrowth. Covered stent predicted stent migration (HR = 12.63; P < .01). Deployment of 2 stents predicted perforation (HR = 854.88; P < .01). CONCLUSIONS: Through-the-scope gastroduodenal stenting tended to be ineffective in patients with poor performance status and long stenosis sites. Stent dysfunction occurred more frequently in patients with poorer performance status. Deployment of 2 stents was a risk factor for perforation. Identification of these risk variables may help yield better gastroduodenal stenting outcomes.

Histologic diagnosis of pancreatic masses using 25-gauge endoscopic ultrasound needles with and without a core trap: a multicenter randomized trial.

BACKGROUND AND STUDY AIMS: Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) with 25-gauge needles yields small volume samples that are mainly processed for cytology. Using 25-gauge needles with a core trap may overcome this limitation. This trial compared 25-gauge needles with and without a core trap in terms of their ability to obtain histologic samples from solid pancreatic masses. PATIENTS AND METHODS: Consecutive patients with solid pancreatic masses who presented to eight Japanese referral centers for EUS-FNA in April - September 2013 were randomized to undergo sampling with a 25-gauge needle with a core trap (ProCore) or a standard 25-gauge needle. Tissue samples were fixed in formalin and processed for histologic evaluation. For the purpose of this study only samples obtained with the first needle pass were used for comparison of: (i) accuracy for the diagnosis of malignancy, (ii) rate of samples with preserved tissue architecture adequate for histologic evaluation, and (iii) sample cellularity. RESULTS: A total of 214 patients were enrolled. Compared to the first pass with a standard needle (n = 108), the first pass with the ProCore needle (n = 106) provided samples that were more often adequate for histologic evaluation (81.1 % vs. 69.4 %; P = 0.048) and had superior cellularity (rich/moderate/poor, 36 %/27 %/37 % vs. 19 %/26 %/55 %; P = 0.003). There were no significant differences between the two needles in sensitivity (75.6 % vs. 69.0 %, P = 0.337) and accuracy (79.2 % vs. 75.9 %, P = 0.561) for the diagnosis of malignancy. CONCLUSIONS: In patients with solid pancreatic masses, a 25-gauge EUS-FNA needle with a core trap provides histologic samples of better quality than a standard 25-gauge needle. There was no difference in accuracy for the diagnosis of malignancy between the needles. CLINICAL TRIAL NUMBER: UMIN000010021.

Prognostic model for survival based on readily available pretreatment factors in patients with advanced pancreatic cancer receiving palliative chemotherapy.

BACKGROUND: We aimed to construct a prognostic model to predict survival in patients with advanced pancreatic cancer (APC) receiving palliative chemotherapy using readily available pretreatment factors. METHODS: The model was constructed using data from 306 consecutive patients with APC who received palliative chemotherapy between January 2006 and March 2013. The predictive accuracy of the model was assessed using a concordance index (c-index) and calibration curves. RESULTS: Among the 12 potential prognostic factors investigated, multivariate analysis identified the following six independent negative prognostic factors-performance status (PS), the presence of distant metastatic disease, the status of initially unresectable disease, carcinoembryonic antigen (CEA) level, carbohydrate antigen 19-9 (CA19-9) level, and neutrophil-lymphocyte ratio (NLR). A prognostic index (PI) based on the coefficients of these factors was constructed as follows-PI = 2 (if PS 2-3) + 1 (if distant metastatic disease) + 1 (if initially unresectable disease) + 1 (if CEA level ≥5.0 ng/ml) + 1 (if CA 19-9 level ≥1,000 U/ml) + 2 (if NLR ≥5). The patients were classified into three prognostic groups-favorable (PI 0-1, n = 73), intermediate (PI 2-3, n = 145), and poor (PI 4-8, n = 88). The median overall survival times for each prognostic group were 16.5, 12.3, and 6.2 months, respectively (P < 0.001). Bootstrapping verified the good fitness of this model for predicting 1-year survival, and the c-index was 0.658. CONCLUSIONS: This simple prognostic model could help clinicians to estimate survival in patients with APC who receive palliative chemotherapy.

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.

Prognostic Factors for Severe-to-Fatal Post-Endoscopic Retrograde Cholangiopancreatography Pancreatitis: A Multicenter Prospective Cohort Study.

The prognostic factors associated with severe-to-fatal post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) remain unclear despite the extensive number of studies on PEP. In total, 3739 ERCP patients with biliary disease with an intact papilla and indicated for ERCP were prospectively enrolled at 36 centers from April 2017 to March 2018. Those with acute pancreatitis diagnosed before ERCP, altered gastrointestinal anatomy, and an American Society of Anesthesiologists (ASA) physical status > 4 were excluded. Univariate and multivariate logistic regression analyses were performed on patient-related factors, operator-related factors, procedure-related factors, and preventive measures to identify potential prognostic factors for severe-to-fatal PEP. Multivariate analyses revealed pancreatic guidewire-assisted biliary cannulation (OR 13.59, 95% CI 4.21-43.83, p < 0.001), post-ERCP non-steroidal anti-inflammatory drug (NSAID) administration (OR 11.54, 95% CI 3.83-34.81, p < 0.001), and previous pancreatitis (OR 6.94, 95% CI 1.45-33.33, p = 0.015) as significant risk factors for severe-to-fatal PEP. Preventive measures included endoscopic biliary sphincterotomy (EST; OR 0.29, 95% CI, 0.11-0.79, p = 0.015) and prophylactic pancreatic stents (PPSs; OR 0.11, 95% CI, 0.01-0.87, p = 0.036). In biliary ERCP, pancreatic guidewire-assisted biliary cannulation, NSAID administration after ERCP, and previous pancreatitis were risk factors for severe-to-fatal PEP, whereas EST and PPS were significant preventive measures for severe-to-fatal PEP.

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.

Adiponectin pathway attenuates malignant mesothelioma cell growth.

Malignant mesothelioma (MM) is caused by exposure to asbestos. Because MM has a latency period, short survival time, and has a poor response to current therapeutic regimes, long-term preventive strategies are required to suppress the advance of pathological states after asbestos exposure. Accumulating evidence suggests that adiponectin plays a crucial role in the regulation of energy metabolism by increasing AMP-activated protein kinase (AMPK) activation. Several studies have indicated that the activation of AMPK decreases cyclooxygenase (COX)-2 expression. Because high COX-2 levels correlated with a worse prognosis and survival rate in MM, we examined whether the adiponectin pathway suppresses MM cell growth through the AMPK/COX-2 pathway. In vivo, dietary fish oil (a potential promoter of adiponectin) decreased the growth rate of MM, which was accompanied by an increase in adiponectin and phospho-AMPK levels, and a decrease in COX-2 level. In vitro, adiponectin significantly impaired the cell proliferation rate of MM cell lines. These effects partly involved induction of growth arrest and apoptosis to MM cells. MM cells expressed both adiponectin receptors 1 and 2 (AdipoR1 and -R2) at mRNA and proteins levels. These receptors were functional, because adiponectin activated AMPK. Adiponectin treatment also significantly down-regulated protein levels of COX-2 and its downstream prostaglandin E(2). Finally, inhibitory analysis of AdipoR1/R2 by small interfering RNA knockdown suggests that adiponectin enhances AMPK activity and impairs the cell proliferation rate of MM cells, mainly via AdipoR1. These findings suggest that the induction or supplementation of adiponectin is an important tactic for developing therapeutic strategies against MM.

Role of ephrinB2 in nonproductive angiogenesis induced by Delta-like 4 blockade.

Delta-like 4 (DLL4) is one of the Notch ligands and plays an important role in vascular development. DLL4 blockade inhibits tumor growth by promoting nonproductive angiogenesis, which is characterized by an increase in vascular density and decrease in tissue perfusion. However, a detailed mechanism remains unclear. In this study, newly developed neutralizing antibodies against mouse and human DLL4 were used to investigate the possible involvement of VEGF-DLL4-ephrinB2 cascade in nonproductive angiogenesis caused by DLL4 blockade. DLL4 blockade and soluble ephrinB2 treatment suppressed tumor growth and induced nonproductive angiogenesis. DLL4 was expressed in subcutaneous tumors, and DLL4 blockade suppressed ephrinB2 expression in the tumors. DLL4 blockade significantly promoted human umbilical vein endothelial cell (HUVEC) proliferation in vitro, and the effect was additive to that of VEGF. Both DLL4 blockade and VEGF significantly increased cord length and branch points in a tubular formation assay. Expression of ephrinB2 in HUVECs was enhanced by VEGF alone, and the enhancement was inhibited by DLL4 blockade. Moreover, when we studied the effect of ephrinB2 RNA interference on HUVEC tubular formation, knockdown of ephrinB2 mimicked the effect of DLL4. These results suggest that ephrinB2 plays a crucial role in nonproductive angiogenesis caused by DLL4 blockade.

[Severe community-acquired pneumonia due to Acinetobacter baumannii].

A 78-year-old man with COPD was admitted in August 2010 complaining of productive cough and fever of 38 degrees C for 2 days. He was admitted with septic shock and pneumonia of the right upper lobe. Despite antibiotic administration, infiltration progressed to the right lung and lower left lung after 24 hours, and he developed acute respiratory distress syndrome (ARDS) and disseminated intravascular coagulation. All cultures from both sputum and blood grew Acinetobacter baumannii. He recovered following intensive care. Although some community-acquired pneumonias by A. baumannii are reported in Japan, this is the first report concerning a successfully treated patient.

Utility of a 20G needle with a core trap in EUS-guided fine-needle biopsy for gastric submucosal tumors: A multicentric prospective trial.

BACKGROUND AND OBJECTIVES: Differential diagnosis to estimate the malignant potential of gastric submucosal tumor (g-SMT) is important for decision-making. This study evaluated the use of a 20G needle with a core trap for EUS-guided fine-needle biopsy (EUS-FNB) for g-SMT. METHODS: This multicentric prospective trial was registered in the University Hospital Medical Information Network (UMIN000021410). Consecutive patients with g-SMT who presented at one of the nine Japanese Referral Centers between June 2017 and November 2018 were enrolled. All patients underwent EUS-FNB using a 20G needle with a core trap. Samples obtained with the first-needle pass were used for central pathological review. EUS-FNB was evaluated in terms of (i) technical success rate, (ii) adequacy for histological evaluation, (iii) rate of complications, (iv) accuracy for histological diagnosis of gastrointestinal stromal tumor (GIST), and (v) concordance between GIST mitotic index determined by EUS-FNB and after tumor resection. RESULTS: The study included 52 patients. The technical success rate of EUS-FNB was 100%. The adequacy rate for histological evaluation was 90.4% (P < 0.001). There were no complications related to EUS-FNB. Of the 38/52 patients who underwent surgical resection, 36 were finally diagnosed with GIST. The sensitivity, specificity, and accuracy of EUS-FNB for the histological diagnosis of g-SMT were 80.6%, 100%, and 81.6%, respectively. The concordance rate between the mitotic index on EUS-FNB and that after analysis of the resected tumor was 89.7%. CONCLUSIONS: EUS-FNB using a 20G needle with a core trap is feasible, providing histological samples of sufficient quality for diagnosing g-SMT.