Risk model for severe postoperative complications after total pancreatectomy based on a nationwide clinical database.

BACKGROUND: Total pancreatectomy is required to completely clear tumours that are locally advanced or located in the centre of the pancreas. However, reports describing clinical outcomes after total pancreatectomy are rare. The aim of this retrospective observational study was to assess clinical outcomes following total pancreatectomy using a nationwide registry and to create a risk model for severe postoperative complications. METHODS: Patients who underwent total pancreatectomy from 2013 to 2017, and who were recorded in the Japan Society of Gastroenterological Surgery and Japanese Society of Hepato-Biliary-Pancreatic Surgery database, were included. Severe complications at 30 days were defined as those with a Clavien-Dindo grade III needing reoperation, or grade IV-V. Occurrence of severe complications was modelled using data from patients treated from 2013 to 2016, and the accuracy of the model tested among patients from 2017 using c-statistics and a calibration plot. RESULTS: A total of 2167 patients undergoing total pancreatectomy were included. Postoperative 30-day and in-hospital mortality rates were 1·0 per cent (22 of 2167 patients) and 2·7 per cent (58 of 167) respectively, and severe complications developed in 6·0 per cent (131 of 2167). Factors showing a strong positive association with outcome in this risk model were the ASA performance status grade and combined arterial resection. In the test cohort, the c-statistic of the model was 0·70 (95 per cent c.i. 0·59 to 0·81). CONCLUSION: The risk model may be used to predict severe complications after total pancreatectomy.

ANTECEDENTES: La pancreatectomía total está indicada cuando se requiere la resección completa de tumores localmente avanzados o ubicados en el centro del páncreas. Sin embargo, existen pocos artículos que describan los resultados clínicos después de una pancreatectomía total. El objetivo de este estudio observacional retrospectivo fue evaluar los resultados clínicos después de una pancreatectomía total utilizando un registro nacional y crear un modelo de riesgo de complicaciones postoperatorias graves. MÉTODOS: Se incluyeron aquellos pacientes que se sometieron a una pancreatectomía total entre 2013 y 2017 y que fueron registrados en la base de datos de la Sociedad Japonesa de Cirugía Gastrointestinal y de la Sociedad Japonesa de Cirugía Hepato-Bilio-Pancreática. Las complicaciones graves a los 30 días se definieron como Clavien-Dindo grado III con reintervención o grado IV/V. Se analizó la aparición de complicaciones graves de los pacientes desde 2013 a 2016 y se evaluó la precisión del modelo entre los pacientes operados desde 2017 usando estadísticos c y un gráfico de calibración. RESULTADOS: Se incluyeron 2.167 pacientes sometidos a una pancreatectomía total. La mortalidad postoperatoria a los 30 días y la mortalidad hospitalaria fueron del 1,0% (22/2167) y del 2,7% (58/2167), respectivamente, y las complicaciones graves ocurrieron en el 6,0% (131/2167) de los pacientes. Los factores que mostraron una fuerte asociación positiva con los resultados en este modelo de riesgo fueron el estado funcional según la Sociedad Americana de Anestesiología y la resección arterial combinada. En la cohorte de prueba, el estadístico c del modelo fue de 0,70 (i.c. del 95% 0,59-0,81). CONCLUSIÓN: El modelo de riesgo puede usarse para predecir las complicaciones graves después de una pancreatectomía total.

Review article: Asia-Pacific consensus recommendations on endoscopic tissue acquisition for biliary strictures.

BACKGROUND: Pre-operative tissue diagnosis for suspected malignant biliary strictures remains challenging. AIM: To develop evidence-based consensus statements on endoscopic tissue acquisition for biliary strictures. METHODS: The initial draft of statements was prepared following a systematic literature review. A committee of 20 experts from Asia-Pacific region then reviewed, discussed, and modified the statements. Two rounds of independent voting were conducted to reach a final version. Consensus was considered to be achieved when 80% or more of voting members voted "agree completely" or "agree with some reservation." RESULTS: Eleven statements achieved consensus. The choice of tissue sampling modalities for biliary strictures depends on the clinical setting, the location of lesion, and availability of expertise. Detailed radiological and endoscopic evaluation is useful to guide the selection of appropriate tissue acquisition technique. Standard intraductal biliary brushing and/or forceps biopsy is the first option when endoscopic biliary drainage is required with an overall (range) sensitivity and specificity of 45% (26%-72%) and 99% (98%-100%), and 48% (15%-100%) and 99% (97%-100%), respectively, in diagnosing malignant biliary strictures. Probe-based confocal laser endomicroscopy and fluorescence in situ hybridisation using 4 fluorescent-labelled probes targeting chromosomes 3, 7, 17 and 9p21 locus may be added to improve the diagnostic yield. Cholangioscopy-guided biopsy and EUS-guided tissue acquisition can be considered after prior negative conventional tissue sampling with an overall (range) sensitivity and specificity of 60% (38%-88%) and 98% (83%-100%), and 80% (46%-100%) and 97% (92%-100%), respectively, in diagnosing malignant biliary strictures. CONCLUSION: These consensus statements provide evidence-based recommendations for endoscopic tissue acquisition of biliary strictures.

Randomised phase II trial of irinotecan plus S-1 in patients with gemcitabine-refractory pancreatic cancer.

BACKGROUND: We aimed to compare the efficacy and safety of irinotecan/S-1 (IRIS) therapy with S-1 monotherapy in patients with gemcitabine-refractory pancreatic cancer. METHODS: Patients were treated with oral S-1 (80-120 mg for 14 days every 4 weeks) plus intravenous irinotecan (100 mg m-2 on days 1 and 15 every 4 weeks; IRIS group) or oral S-1 group (80-120 mg daily for 28 days every 6 weeks). The primary endpoint was progression-free survival (PFS). RESULTS: Of 137 patients enrolled, 127 were eligible for efficacy. The median PFS in the IRIS group and S-1 monotherapy group were 3.5 and 1.9 months, respectively (hazard ratio (HR)=0.77; 95% confidence interval (CI), 0.53-1.11; P=0.18), while the median overall survival (OS) were 6.8 and 5.8 months, respectively (HR=0.75; 95% CI, 0.51-1.09; P=0.13). Response rate was significantly higher in the IRIS group than in the S-1 monotherapy group (18.3% vs 6.0%, P=0.03). Grade 3 or higher neutropenia and anorexia occurred more frequently in the IRIS group. CONCLUSIONS: There was a trend for better PFS and OS in the IRIS group that could be a treatment arm in the clinical trials for gemcitabine-refractory pancreatic cancer.

Peroral video cholangioscopy to evaluate indeterminate bile duct lesions and preoperative mucosal cancerous extension: a prospective multicenter study.

BACKGROUND AND STUDY AIMS: Despite the development of peroral video cholangioscopy (PVCS), no prospective multicenter studies have been undertaken to investigate the diagnostic accuracy of PVCS in biliary tract diseases. Therefore, the aim of this study was to clarify the accuracy of PVCS in evaluating biliary tract lesions. PATIENTS AND METHODS: This study was a prospective multicenter study at five tertiary referral centers in Japan and included 87 eligible patients with biliary tract diseases who underwent PVCS. The study evaluated the ability of PVCS to diagnose indeterminate biliary tract diseases, detect mucosal cancerous extension preoperatively in extrahepatic bile duct cancers, and predict adverse events. RESULTS: The use of PVCS appearance alone correctly distinguished benign from malignant indeterminate biliary lesions in 92.1 % of patients whereas biopsy alone was accurate in 85.7 %. In extrahepatic bile duct cancer, mucosal cancer extended histologically at least 20 mm in 34.7 % (17/49) of patients. The accuracy rate of PVCS to evaluate the presence or absence of mucosal cancerous extension by endoscopic retrograde cholangiography (ERC) alone, ERC with PVCS, and ERC with PVCS + biopsy were 73.5 %, 83.7 %, and 92.9 %, respectively. Adverse events were seen in 6.9 % of PVCS patients, but no serious complications were observed. CONCLUSION: PVCS enhanced the accurate diagnosis of biliary tract lesions by providing excellent resolution in combination with biopsy.

Japanese multicenter experience of endoscopic necrosectomy for infected walled-off pancreatic necrosis: The JENIPaN study.

BACKGROUND AND STUDY AIMS: Only a few large cohort studies have evaluated the efficacy and safety of endoscopic necrosectomy for infected walled-off pancreatic necrosis (WOPN). Therefore, a multicenter, large cohort study was conducted to evaluate the efficacy and safety of endoscopic necrosectomy and to examine the procedural details and follow-up after successful endoscopic necrosectomy. PATIENTS AND METHODS: A retrospective review was conducted in 16 leading Japanese institutions for patients who underwent endoscopic necrosectomy for infected WOPN between August 2005 and July 2011. The follow-up data were also reviewed to determine the long-term outcomes of the procedures. RESULTS: Of 57 patients, 43 (75 %) experienced successful resolution after a median of 5 sessions of endoscopic necrosectomy and 21 days of treatment. Complications occurred in 19 patients (33 %) during the treatment period. Six patients died (11 %): two due to multiple organ failure and one patient each from air embolism, splenic aneurysm, hemorrhage from a Mallory - Weiss tear, and an unknown cause. Of 43 patients with successful endoscopic necrosectomy, recurrent cavity formation was observed in three patients during a median follow-up period of 27 months. CONCLUSIONS: Endoscopic necrosectomy can be an effective technique for infected WOPN and requires a relatively short treatment period. However, serious complications can arise, including death. Therefore, patients should be carefully selected, and knowledgeable, skilled, and experienced operators should perform the procedure. Further research into safer technologies is required in order to reduce the associated morbidity and mortality.

Endoscopic ultrasound-guided celiac ganglia neurolysis vs. celiac plexus neurolysis: a randomized multicenter trial.

BACKGROUND AND STUDY AIMS: No prospective comparison of endoscopic ultrasonography-guided direct celiac ganglia neurolysis (EUS - CGN) vs. EUS-guided celiac plexus neurolysis (EUS - CPN) has been reported. The aim of the current study was to compare the effectiveness of EUS - CGN and EUS - CPN in providing pain relief from upper abdominal cancer pain in a multicenter randomized controlled trial. PATIENTS AND METHODS: Patients with upper abdominal cancer pain were randomly assigned to treatment using either EUS - CGN or EUS - CPN. Evaluation was performed at Day 7 postoperatively using a pain scale of 0 to 10. Patients for whom pain decreased to ≤ 3 were considered to have a positive response, and those experiencing a decrease in pain to ≤ 1 were considered to be completely responsive. Comparison between the two groups was performed using intention-to-treat analysis. The primary endpoint was the difference in treatment response rates between EUS - CGN and EUS - CPN at postoperative Day 7. Secondary endpoints included differences in complete response rates, pain scores, duration of pain relief, and incidence of adverse effects. RESULTS: A total of 34 patients were assigned to each group. Visualization of ganglia was possible in 30 cases (88 %) in the EUS - CGN group. The positive response rate was significantly higher in the EUS - CGN group (73.5 %) than in the EUS - CPN group (45.5 %; P = 0.026). The complete response rate was also significantly higher in the EUS - CGN group (50.0 %) than in the EUS - CPN group (18.2 %; P = 0.010). There was no difference in adverse events or duration of pain relief between the two groups. CONCLUSIONS: EUS - CGN is significantly superior to conventional EUS - CPN in cancer pain relief. CLINICAL TRIAL REGISTRATION: http://www.umin.ac.jp/ctr/index.htm (ID: UMIN-000002536).

Carbon dioxide insufflation vs. conventional saline irrigation for peroral video cholangioscopy.

BACKGROUND AND STUDY AIMS: Recent studies have evaluated the efficacy of peroral cholangioscopy (POCS) for diagnosis of biliary diseases. In order to obtain clear images with POCS, saline irrigation, which is performed to replace yellow bile, is carried out for an extended duration. The aim of this study was to evaluate the feasibility of replacing saline irrigation with CO2 insufflation during POCS. PATIENTS AND METHODS: A total of 36 patients who had bile duct lesions and were due to undergo POCS were enrolled in the study. Of these patients, 18 underwent POCS using saline irrigation followed by CO2 insufflation, and 18 patients underwent the reverse approach. The two methods were compared with regard to the time required to obtain a clear endoscopic image and the quality of the images. RESULTS: The median time required to obtain a clear endoscopic image using CO2 insufflation (5.0 min) was significantly shorter than that required for saline irrigation (22.5 min; P < 0.001). The quality of the endoscopic images obtained was similar in 27 cases. However, CO2 insufflation provided better images in four cases that showed an abundance of mucin or biliary sludge, and saline irrigation was superior to CO2 insufflation in five cases that showed severe stricture with bleeding and tall papillary lesions. CONCLUSIONS: CO2 insufflation during POCS can reduce procedure time and simplify cholangioscopy. The overall image quality was similar to that obtained with conventional saline irrigation.

Endoscopic hemostasis using covered metallic stent placement for uncontrolled post-endoscopic sphincterotomy bleeding.

Severe bleeding following endoscopic biliary sphincterotomy (EBS) can sometimes be difficult to manage, resulting in the need for an invasive intervention. The aim of this study was to retrospectively evaluate the feasibility and efficacy of endoscopic hemostasis using covered self-expandable metallic stents (SEMSs) for severe post- EBS bleeding. Eleven patients with bile duct stones underwent standard EBS using a standard sphincterotome-based technique at 4 endoscopic units of a university-affiliated hospital and a general hospital. Monotherapy or combined therapy were used to achieve hemostasis with either balloon tamponade, hypertonic saline epinephrine injection, or endoclip placement. When active bleeding could not be controlled, covered SEMSs were placed across the major papilla. Emergency endoscopy was performed on the day of admission or the subsequent day (ranging from 6 to 35 h after admission). Bleeding was classified as mild in 6 cases (54.5 %) and moderate in 5 (45.5 %). A covered SEMS 10mm in diameter and 6 cm long was placed across the papilla. After placement, complete hemostasis was achieved. The mean duration of stent placement was 8.2 days (range 5­10 days), and the SEMS was successfully removed in all cases. Although the present study has the limitations of a small sample size and lack of control patients, covered SEMS placement for endoscopic hemostasis may be useful in selected patients with uncontrolled post-EBS bleeding.

Double inhibition of XIAP and Bcl-2 axis is beneficial for retrieving sensitivity of renal cell cancer to apoptosis.

Renal cell carcinoma (RCC) is known to be resistant to chemo- and radiotherapy due to a high apoptotic threshold. Smac and XIAP (X-linked inhibitor of apoptosis protein) proteins were detected in all RCC cell lines and tissue samples examined. We modulated the function of XIAP, either through its constitutional downregulation with an shRNA vector or by applying a Smac-mimicking peptide. Among RCC cell lines, Caki1 expresses the highest levels of XIAP. We transfected Caki1 with XIAP-targeting shRNA vector and generated stable clones. XIAP was knocked down by RNA interference in clone no. 14 by 81.6% and in clone no. 19 by 85.3%. Compared to the parental and mock-transfected cells, neither clone was more sensitive to conventional chemotherapeutic agents, but both clones were more susceptible to Fas stimulation (P<0.0001) and to pharmacological Bcl-2 inhibition (P<0.0001), as well as to a combination of the two (P<0.0001). Mature Smac binds to XIAP via the N-terminal residues, disrupting its interaction with caspases and promoting their activity. We determined that exposure of Caki1 cells to Smac-N7 peptide (AVPIAQK) resulted in a slight but significant decrease in viability (P=0.0031) and potentiated cisplatin's effect (P=0.0027). In contrast with point targeting of XIAP by shRNA, Smac-N7 peptide is active against several IAP (inhibitor of apoptosis protein) family members, which can explain its role in sensitising cells to cisplatin. Our results suggest that multiple targeting of both Bcl-2 and XIAP or, alternatively, of several IAP family members by the Smac-N7 peptide is a potent way to overcome resistance of RCC to apoptosis-triggering treatment modalities, and might be a new tool for molecular targeted therapy.

Severe hypoglycaemia in a person with insulin autoimmune syndrome accompanied by insulin receptor anomaly type B.

AIMS: A rare case of the insulin autoimmune syndrome (IAS) accompanied by insulin receptor anomaly is reported. METHODS: Antibodies to insulin and insulin receptor were determined in the patient with severe hypoglycaemia before and after the treatment with prednisolone. RESULTS: Titers of antibody to insulin and insulin receptors were 73.0% and 41.5%, respectively. Drug-induced lymphocyte stimulation tests were all negative for the suspicious drugs. Her HLA-DR was DRB1*0403/04051. Following steroid therapy, the formation of antibodies was suppressed and alleviated her symptoms. Scatchard analysis yielded findings specific to polyclonal antibodies. CONCLUSIONS: The changes in autoantibodies resulted in alleviation of the hypoglycemic symptoms as a result of steroid therapy.

Changes in evaluation of the pepsinogen test result following Helicobacter pylori eradication therapy in Japan.

AIMS: The pepsinogen (PG) test result is used in Japan for screening for gastric cancer. In this study, we investigated the changes in evaluation of the PG test result following H. pylori eradication. METHODS: The subjects were 120 consecutive H. pylori-positive patients with upper gastrointestinal symptoms. Subjects underwent endoscopy prior to, and at 2 months after the eradication therapy, at which time blood was taken for determination of changes in PG levels. RESULTS: The overall eradication rate was 79.3% (per protocol). Following eradication therapy, the evaluation of PG test result converted from positive to negative in 80.4% (37/46) of cases of successful eradication, and in 0% (0/6) of cases of eradication failure. CONCLUSIONS: These results suggest that the evaluation of PG test result should be used after the definitive confirmation of the success or failure of H. pylori eradication therapy.

Absence of Bcl-2 and Fas/CD95/APO-1 predicts the response to immunotherapy in metastatic renal cell carcinoma.

Immunotherapy is the only available treatment for metastatic renal cell cancer (RCC), but the response rate is only about 20% and the treatment is occasionally associated with severe adverse effects. Thus, the selection of patients with a high susceptibility to immunotherapy is needed; however, there is no promising molecular marker that can predict the response to immunotherapy for RCC. This study was carried out to elucidate the potential role of apoptosis-related molecules Bcl-2 and Fas, as well as apoptotic and proliferating indexes (AI, PI) as predictors of the susceptibility of metastatic RCC to immunotherapy. Immunohistochemical examination of tumour tissues from 40 patients with metastatic RCC undergoing postoperative immunotherapy after radical nephrectomy was performed. Patients with progressive disease (PD) after immunotherapy presented with decreased survival (P=0.006). Progressive disease correlated with higher PI in the primary lesion (P=0.0087). All primary tumours of CR or PR patients were negative for Bcl-2, whereas among NC+PD patients, 40.6% were positive for Bcl-2 (P=0.0373). Patients in whom the primary tumours were both Bcl-2- and Fas-negative showed significantly better responses to immunotherapy in comparison with the remaining group (P=0.0022). The Bcl-2 and Fas status of the primary lesion may become useful criteria for the selection of patients with metastatic RCC for immunotherapy.