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.

Fucosylated haptoglobin is a novel predictive marker of hepatocellular carcinoma after hepatitis C virus elimination in patients with advanced liver fibrosis.

BACKGROUND: Patients with advanced fibrosis are at risk for developing hepatocellular carcinoma (HCC) even after hepatitis C virus (HCV) elimination. We previously reported that serum fucosylated haptoglobin (Fuc-Hp) levels increase as the disease progresses from chronic hepatitis to cirrhosis and then HCC. However, it remains unclear whether serum Fuc-Hp levels can stratify the risk of HCC occurrence after a sustained virological response (SVR) is achieved with direct-acting antivirals (DAAs) in patients with advanced liver fibrosis. METHODS: Among 3,550 patients with chronic hepatitis C treated with DAAs at Osaka University Hospital and related hospitals, the stored sera of 140 patients who were diagnosed with F3 or F4 by liver biopsy before DAA treatment, achieved SVR, and had no history of HCC were available at both baseline and the end of treatment (EOT). We measured the Fuc-Hp levels in these samples. RESULTS: The median serum levels of Fuc-Hp at EOT were significantly lower than those at baseline. During the 54.4-month follow-up period, 16 of 140 patients developed HCC. Multivariate Cox proportional hazards analysis revealed that high Fuc-Hp at EOT, high body mass index (BMI), and low albumin at EOT were independent risk factors for HCC occurrence. Patients with all three factors-high Fuc-Hp, high BMI, and low albumin-had a higher incidence of HCC than patients without these factors. CONCLUSIONS: High serum Fuc-Hp levels at EOT were an independent risk factor for HCC occurrence after SVR. Combined with BMI and albumin, Fuc-Hp can stratify the risk of HCC occurrence among those with advanced fibrosis.

Prognostic impact of worsening of esophageal varices after balloon-occluded retrograde transvenous obliteration.

BACKGROUND AND AIM: Balloon-occluded retrograde transvenous obliteration (BRTO) is widely performed for treating gastric varices (GVs). However, worsening of esophageal varices (EVs) can be observed after BRTO. This study aimed to investigate the impact of EV worsening on prognosis after BRTO. METHODS: Overall, 258 patients who underwent initial BRTO for GV treatment between January 2004 and May 2019 at 12 institutions were retrospectively registered. RESULTS: Technical success was achieved in 235 patients (91.1%). Based on the exclusion criteria, 37 patients were excluded, and 198 were evaluated. The cumulative worsening rates of EVs at 1, 2, and 3 years were 39.0%, 59.4%, and 68.4%, respectively. In the univariate Cox proportional hazards model, sex, EV size, history of EV treatment, left gastric vein dilatation, platelet count, aspartate transaminase (AST), alanine aminotransferase (ALT), total bilirubin, albumin, albumin-bilirubin score, prothrombin time-international normalized ratio, fibrosis-4 index, AST to platelet ratio index, and spleen width were significantly associated with worsening of EV after BRTO. Multivariate analysis showed that sex (adjusted hazard ratio [aHR] 1.72; 95% confidence interval [CI] 1.03-2.86; P = 0.04), left gastric vein dilatation (aHR 1.90; 95% CI 1.17-3.10; P = 0.01), ALT (aHR 1.01; 95% CI 1.00-1.03; P = 0.02), albumin (aHR 0.61; 95% CI 0.43-0.87; P < 0.01), and spleen width (aHR 1.02; 95% CI 1.01-1.03; P < 0.01) were independent risk factors for worsening of EV after BRTO. Patients with EV worsening within 1 year after BRTO had a significantly worse prognosis than the other patients (P = 0.007). CONCLUSIONS: Early worsening of EV after BRTO was associated with poor prognosis after BRTO.

Helicobacter pylori eradication prevents secondary gastric cancer in patients with mild-to-moderate atrophic gastritis.

BACKGROUND AND AIM: Whether Helicobacter pylori eradication prevents metachronous recurrence after endoscopic resection (ER) of early gastric cancer remains controversial. This multicenter retrospective study aimed to evaluate the long-term (> 5 years) effects of H. pylori eradication by stratifying patients' baseline degrees of atrophic gastritis. METHODS: A total of 483 H. pylori-positive patients who had undergone ER for early gastric cancer were divided into two groups-(i) those having undergone successful H. pylori eradication within 1 year after ER (eradicated group, n = 294) and (ii) those with failed or not attempted H. pylori eradication (non-eradicated group, n = 189). The cumulative incidences of metachronous gastric cancer between the two groups were compared for all patients, for patients with mild-to-moderate atrophic gastritis (n = 182), and for patients with severe atrophic gastritis (n = 301). RESULTS: During a median follow-up of 5.2 years (range 1.1-14.8), metachronous cancer developed in 52 (17.7%) patients in the eradicated group and in 35 (18.5%) patients in the non-eradicated group (P = 0.11, log-rank test). In patients with mild-to-moderate atrophic gastritis (111 and 71 in the eradicated and non-eradicated groups, respectively), the cumulative incidence of metachronous cancer was significantly lower in the eradicated group than that in the non-eradicated group (P = 0.03, log-rank test). However, no significant intergroup difference was observed in patients with severe atrophic gastritis (P = 0.69, log-rank test). CONCLUSIONS: Helicobacter pylori eradication had a preventive effect on the development of metachronous gastric cancer in patients with mild-to-moderate atrophic gastritis.

Impact of branched-chain amino acid supplementation on survival in patients with advanced hepatocellular carcinoma treated with sorafenib: A multicenter retrospective cohort study.

AIM: The therapeutic efficacy of branched-chain amino acid (BCAA) when added to sorafenib has not been fully assessed in patients with advanced hepatocellular carcinoma (HCC). This multicenter study investigated whether BCAA supplementation improves prognosis in patients with advanced HCC who underwent sorafenib treatment. METHODS: This retrospective analysis included 256 patients with advanced HCC treated with sorafenib, including 55 who did and 201 who did not receive BCAA supplementation. Clinical characteristics and outcomes in relation to Child-Pugh classification were compared in the two groups. Statistical analyses of univariate, multivariate and propensity score-based procedures were used for this study. RESULTS: Assessment of 216 Child-Pugh A patients showed that median overall survival was significantly longer in patients with BCAA supplementation than in those without it (440 vs 299 days, P = 0.023). Multivariate analysis showed that BCAA supplementation (P = 0.023), low α-fetoprotein (<100 ng/mL) (P < 0.001), less progressive Barcelona Clinic Liver Cancer stage (A and B) (P = 0.007) and male sex (P = 0.018) were significant independent contributors to better overall survival. The significantly longer overall survival by BCAA supplementation was verified in the analysis using the propensity score in combination with the inverse probability of treatment weighted adjustment (P = 0.026). Assessment of the 40 Child-Pugh B patients showed no significant differences in overall survival between patients with and without BCAA supplementation. CONCLUSION: BCAA supplementation may be a valuable adjunctive therapy for improving prognosis in sorafenib-treated Child-Pugh A patients with advanced HCC.

Scheduled endoscopic surveillance controls secondary cancer after curative endoscopic resection for early gastric cancer: a multicentre retrospective cohort study by Osaka University ESD study group.

BACKGROUND: After endoscopic submucosal dissection (ESD) of early gastric cancer (EGC), patients are at high risk for synchronous or metachronous multiple gastric cancers. OBJECTIVE: To elucidate the time at which multiple cancers develop and to determine whether scheduled endoscopic surveillance might control their development. DESIGN: A multicentre retrospective cohort study from 12 hospitals was conducted. Patients with EGC who underwent ESD with en bloc margin-negative curative resection were included. Synchronous cancer was classified as concomitant cancer or missed cancer. The cumulative incidence of metachronous cancers and overall survival rate were calculated using the Kaplan-Meier method. RESULTS: From April 1999 to December 2010, 1258 patients met the inclusion criteria. Synchronous or metachronous multiple cancers were detected in 175 patients (13.9%) during a mean of 26.8 months. Among the 110 synchronous cancers, 21 were missed at the time of the initial ESD. Many of the missed lesions existed in the upper third of the stomach and the miss rate was associated with the endoscopist's inexperience (<500 oesophagogastroduodenoscopy cases). The cumulative incidence of metachronous cancers increased linearly and the mean annual incidence rate was 3.5%. The incidence rate did not differ between patients with or without Helicobacter pylori eradication. Four lesions (0.32%) were detected as massively invading cancers during the follow-up. CONCLUSIONS: Nineteen per cent of synchronous cancers were not detected until the initial ESD. The incidence rate of metachronous cancer after ESD was constant. Scheduled endoscopic surveillance showed that almost all recurrent lesions were treatable by endoscopic resection.

Short-term outcomes of endoscopic submucosal dissection (ESD) for early gastric neoplasm: multicenter survey by osaka university ESD study group.

BACKGROUND: Endoscopic submucosal dissection (ESD) was developed for en bloc removal of large and flat gastrointestinal tract neoplasms. In Japan, ESD is performed under conscious sedation. The risks for sedation-related complications of ESD, such as postoperative pneumonia, have not been evaluated. The aim of this study was to evaluate the incidence of postoperative pneumonia after ESD in a multicenter survey. PATIENTS AND METHODS: A total of 1188 patients with upper gastric neoplasms treated with ESD in nine hospitals were enrolled from May 2003 to September 2008. The en bloc resection rates and complications (bleeding, perforation, and postoperative pneumonia) were assessed. The correlations between the clinical variables and complications were investigated using logistic regression models. RESULTS: The en bloc resection rate was 95.3%. Bleeding, perforation, and pneumonia occurred in 37 (3.1%), 49 (4.1%), and 19 (1.6%) patients, respectively. Univariate analysis indicated that procedure time, but not specimen size, or patient age, or sex, was significantly related to bleeding and perforation. The incidence of pneumonia was higher in patients with ulceration, older patients (≥75years), and those with a long procedure duration (≥5h). CONCLUSION: The incidence of pneumonia, but not perforation and bleeding, after ESD, is high in older patients (≥75years). Special care should be taken with older patients undergoing ESD to minimize the risk of postoperative pneumonia.

Endoscopic submucosal dissection as a treatment for gastric noninvasive neoplasia: a multicenter study by Osaka University ESD Study Group.

BACKGROUND: Treatment with endoscopic submucosal dissection (ESD) for gastric noninvasive neoplasia (NIN) diagnosed by endoscopic forceps biopsy specimen, whether as a follow-up or "total incisional biopsy", is controversial. To validate the use of ESD for total incisional biopsy in NIN, we examined the underdiagnosis rate of NIN and the rates of complication associated with ESD. METHODS: This is a cross-sectional multicenter retrospective study from 10 hospitals. Subjects diagnosed with NIN (equivalent to category 3 or 4.1 of the Vienna classification) by endoscopic forceps biopsy and treated with ESD were included. From March 2003 to December 2009, a total of 468 subjects were included and analyzed. The underdiagnosis rate was defined as the proportion of lesions diagnosed with adenocarcinoma after ESD. We assessed the complete en-bloc resection rate and the complication rate of ESD. RESULTS: Among the 468 subjects with NIN, 205 were diagnosed with adenocarcinoma after ESD, with an underdiagnosis rate of 44% (95% confidence interval: 39-49%). Two submucosal cancer lesions had invaded beyond 500 µm and one had lymphatic involvement. The complete en-bloc resection rate was 97%. The incidences of post-ESD bleeding, perforation, and serious complications were 5.5, 4.7, and 0.43%, respectively. There were no procedure-related deaths. CONCLUSIONS: In this large-scale, multicenter cross-sectional study, over 40% of the noninvasive gastric neoplasia specimens were determined to have adenocarcinoma, and the ESD-related complication rate was relatively low. Therefore, ESD was useful and may be a therapeutic option for gastric NIN.

[An imported Japanese case of cyclosporiasis].

A 42-year-old Japanese woman, who resided in Indonesia suffered from watery diarrhea. As soon as she returned to Japan, she had a medical examination at our hospital. Oocysts of Cyclospora cayetanensis were isolated from her stool on the 14th day. Treatment with 1.6g/day sulfamethoxazole/trimethoprim combination for 1 week was effective. Cyclosporiasis is a of newly-emerging infection and causes group infection or traveler's diarrhea. Cyclosporiasis should be suspected in patients with diarrhea who have returned from the endemic areas to Japan.

[Palliative care team in National Hospital Organization Osaka Minami Medical Center].

Preparation of a system of palliative care support is called for by The Basic Act on Anti-Cancer Measures and The Basic Plans for National Cancer Strategy. The Organization of Hospitals for Cancer Treatment should play a very important role in the regional palliative care network. The palliative care team in the Organization of Hospitals for Cancer Treatment should promote palliative care support throughout regional hospitals. In 2007, we established a palliative care team at the National Hospital Organization Osaka Minami Medical Center. We have drawn up a detailed report on the activities of palliative care team in our medical center.

A new prognostic system for hepatocellular carcinoma including recurrent cases: a study of 861 patients in a single institution.

OBJECTIVE: To manage hepatocellular carcinoma (HCC) patients surviving for a long term, the treatment strategy for recurrent cancer is as important as that for the initial treatment. However, no prognostic scoring system has been available for patients with HCC recurrence. The purpose of this study was to develop a new staging system for deciding the treatment strategy not only for first-time diagnosed patients but also for recurrent patients. METHODS: A total of 861 cases diagnosed at our single institution from 1993 to 2003 were included. Overall survival was the only end point. The Cox model was used for multivariate analyses. RESULTS: As of August 2004, 344 cases (59%) had died. Overall median survival time was 41 months. For multivariate Cox regression analysis, independent predictive factors of survival were the number of recurrences, the Child-Pugh score, 3 nodules less than 3 cm and none of vascular invasion, and the alpha-fetoprotein level. A simple scoring system was thus developed, assigning scores (0/1) to the 4 covariates of the final model. Compared with the other scoring systems, the new scoring system has a greater discriminant ability. CONCLUSIONS: We concluded that our scoring system can serve as a new prognostic system that reflects the spread of HCC, treatment response, and liver function. It should be very useful as the only method which can be applied for patients with recurrence.

Alteration in gene expression profile by full-length hepatitis B virus genome.

Persistent expression of hepatitis B virus (HBV) proteins is thought to be involved in virus-related hepatocarcinogenesis. Here, we compared the gene expression profile of cells persistently expressing the full-length HBV with that of negative control cells to comprehensively investigate virus-mediated changes in the gene expression of the host cells. RNA samples from both virus-expressing and negative control cells were used for the DNA array assay. DNA array assay and subsequent corroboration assays revealed that expression of 14 of 1,176 genes (1.2%) was altered in response to virus expression. The upregulated genes included CD44, high mobility group protein-I, thymosin beta-10 and 27-kD heat shock protein, while the downregulated genes included NM23-H1, all of which are thought to be associated with the development or progression of carcinoma in the liver or other organs. Furthermore, virus expression resulted in the decrease of two apoptosis-inducing molecules, caspase-3 and BAX, which may also contribute to carcinogenesis through prolonged survival of the host cell. Thus, expression of the virus genome caused carcinogenesis-related changes in host cell gene expression. HBV expression may change the host cell to a malignant phenotype through alterations in the expression levels of a set of genes.

Juvenile hepatocellular carcinoma with congestive liver cirrhosis.

A case of juvenile hepatocellular carcinoma (HCC) with congestive liver cirrhosis is reported. The patient was a 21-year-old woman. She had been diagnosed as having transposition of the great arteries, type 2, in 1978. She underwent the Mustard operation, but suffered from chronic heart failure. In 1995, she experienced abdominal pain and underwent examination. The laboratory data were normal, except for elevated total bilirubin (5.2 mg/dl). Blood examinations were performed at frequent intervals, and the total bilirubin level fluctuated between 0.9 and 8.1 mg/dl over the next 4 years, but the transaminase level remained normal. In 1999, she experienced abdominal pain again and was admitted to our hospital. Computed tomography showed four space-occupying lesions in the liver; 45 mm, 20 mm, 12 mm, and 10 mm in size. She was diagnosed as having HCC, and transcatheter arterial chemoembolization and percutaneous ethanol injection therapy were performed. Histology of the cancerous and the noncancerous liver tissue revealed HCC, moderately differentiated type, in cirrhotic liver with congestion. This patient had no background factors of liver disease, except for liver congestion, associated with the chronic heart failure. Because most patients with cardiac cirrhosis die of cardiac disease, only a small number of these patients develop liver failure. However, the incidence of HCC in patients with congestive liver disease is likely to increase in the future, as survival time is prolonged with the advances in treatment for chronic heart failure. Therefore, patients with congestive liver disease should be followed, taking into account the possibility of HCC.

The significance of interferon and ribavirin combination therapy followed by interferon monotherapy for patients with chronic hepatitis C in Japan.

One hundred seventy-one patients with chronic hepatitis C were included in this study (genotype1 and high viral loads (1H), [Formula: see text]; non-1H, [Formula: see text]; N.D., [Formula: see text] ). The combination therapy of interferon and ribavirin for 24 weeks with an additional 24 weeks of interferon monotherapy (48-week treatment) was undergone by 42 1H patients and 5 non-1H patients. The combination therapy of interferon and ribavirin was administered for 24 weeks in 67 1H patients and 22 non-1H patients. Among the 1H patients, the HCV relapse rate was significantly higher in those receiving 24-week combination treatment than in those receiving 48-week treatment (78% versus 42%, [Formula: see text] ). Among the non-1H patients, no significant difference was found between them. Sustained virological response (SVR) rates were observed to decrease as the timing of HCV RNA disappearance was delayed. In spite of the small rate (16%), SVR was obtained from the patients who became negative for HCV RNA by week 24 (beyond week 12) only in those receiving 48-week treatment. In 1H patients, 24-week combination treatment followed by interferon monotherapy for 24 weeks was concluded to be the treatment offering the most hope among those that the medical insurance can be applied in Japan.

Hepatitis C virus core functions as a suppressor of cyclin-dependent kinase-activating kinase and impairs cell cycle progression.

We investigated how the hepatitis C virus (HCV) core protein affects the cell cycle profile and cell cycle-related molecules by using the HCV core-expressing stable transfectant. Analysis of the cell cycle profile showed that HCV core impaired G(1) to S transition. The E2F-mediated transcription, phosphorylation of the retinoblastoma protein, and cyclin-dependent kinase (CDK) 4 and CDK2 activities were suppressed in HCV core-expressing cells. The expression levels of G(1) phase-related CDKs/cyclins and various CDK inhibitors were not substantially affected by expression of HCV core. When influences of HCV core on CDK-activating kinase (CAK) were examined, the expression levels of the CAK components, CDK7, cyclin H, and MAT1, were not affected. However, formation of the ternary CAK complex, CAK activity, and the CDK2 level with activating phosphorylation were inhibited by expression of the HCV core. The direct effect of HCV core on CAK was further assessed in the cell-free system by adding the in vitro translated HCV core protein to the anti-CDK7 immunoprecipitate from the cell. The results showed that HCV core led to dissociation of MAT1 from the CAK complex and suppressed the CAK activity. Furthermore, the binding assay revealed that the HCV core was directed against CDK7. Their interaction occurred mainly in the nucleus by the immunostaining. In conclusion, the HCV core protein interacts with CAK and functions as an extrinsic suppressor of CAK. This may be the molecular basis of HCV core-mediated suppression of cell cycle progression. Our findings suggest a novel mechanism concerning HCV core-mediated alteration in the cell cycle machinery.

Hepatitis C virus core protein differently regulates the JAK-STAT signaling pathway under interleukin-6 and interferon-gamma stimuli.

We established hepatitis C virus (HCV) core-expressing cells and investigated whether HCV core would modify the Janus kinase (JAK)-signal transducer and activator transcription factor (STAT) pathway under interleukin-6 (IL-6) and interferon (IFN)-gamma stimuli. Phosphorylation of JAK1/2 and STAT3, and STAT3-mediated transcription, were prevented by HCV core under IL-6 stimulation. In contrast, HCV core increased phosphorylation of JAK1/2 and STAT1 and STAT1-mediated transcription under IFN-gamma stimulation. Immunoprecipitation/Western blot analysis showed that HCV core could bind to JAK1/2. The PGYPWP sequences at codons 79-84 within HCV core were important for interaction with JAKs by in vitro binding analysis. In the reporter gene assay, HCV core-mediated suppression of JAK-STAT pathway under IL-6 stimulation was not observed by abrogation of PGYPWP sequence, suggesting that HCV core/JAK interaction may directly affect the signal transduction. In contrast, augmentation of JAK-STAT pathway was still seen by HCV core without functional PGYPWP sequence under IFN-gamma stimulation. Flow cytometric analysis revealed that HCV core up-regulated of IFN-gamma receptor 2 expression, which may be responsible for HCV core-mediated enhancement of JAK-STAT pathway under IFN-gamma stimulation. In conclusion, HCV core has different effects on the JAK-STAT pathway under IL-6 and IFN-gamma stimuli. This may be exerted by these two independent mechanisms.

Changes in gene expression profile by HCV core protein in cultured liver cells: analysis by DNA array assay.

In this study, we established hepatitis C virus (HCV) core-expressing mouse liver cells and investigated changes occurring in the gene expression profile accompanied by expression of the viral core protein using DNA array analysis. Both non-transformed and transformed mouse liver cells constitutively expressing the viral core protein were established by DNA transfection, and subjected to DNA array analysis. For the genes judged positive by DNA array, Northern blot analysis was done for corroboration. DNA array analysis revealed one up-regulated gene and three down-regulated genes by expression of the viral core protein in non-transformed liver cells. For the transformed liver cells, four enhanced and five suppressed genes were observed. The Northern blot corroboration analysis clarified two genes, osteopontin precursor and activating transcription factor 4, as being down-regulated by the viral core protein in both non-transformed and transformed liver cells, and three genes, cathepsin D, matrix metalloproteinase 14 and anti-proliferative B-cell translocation gene 2, as being up-regulated by the viral core protein in only transformed liver cells. In conclusion, a total of five genes were identified as viral core protein-responsive ones in the DNA array analysis. Alterations in the expression levels of these genes may be relevant to the viral core-mediated pathogenesis.

Power spectrum analysis of compound muscle action potential in carpal tunnel syndrome patients.

The objective of using wave-form analysis to assess compound muscle action potential (CMAP) in entrapment neuropathy had not been fully developed. We applied the power spectrum analysis to patients with carpal tunnel syndrome (CTS) for this purpose. 24 patients with CTS were divided into three stages according to Mackinnon s classification, and 50 normal volunteers were examined. CMAP was obtained from the abductor pollicis brevis with supramaximal stimulation to median nerve. Mean and peak frequencies were measured by power spectrum analysis. The distal latencies of CMAP and the sensory nerve conduction velocities showed some prolongation in CTS patients. Integral values of CMAP were also decreased in CTS patients. Mean and peak frequencies of power spectrum of CMAP in volunteers were 134 Hz and 98 Hz, respectively. These values shifted into lower frequencies in CTS patients, namely 102 Hz and 61 Hz. Regardless of clinical stage, distal latency of CTS patients correlated with mean frequency.