Endoscopic treatment of bile duct stones with benign choledochojejunal anastomotic stenosis.

[BACKGROUND AND AIMS]: Endoscopic interventions for bile duct stones (BDS) with benign choledochojejunal anastomotic stenosis (bCJS) are challenging. Therefore, we investigated endoscopic interventions for BDS with bCJS. [METHODS]: Seventeen patients with BDS with bCJS were retrospectively analyzed. Patient characteristics, technical success, adverse events (AEs), and recurrence were evaluated. [RESULTS]: In 17 patients, the median diameters of the bile duct and BDS were both 8 mm. The median number of BDS was 3. The technical success rate was 94% (16/17). Ten patients underwent balloon dilation at the choledochojejunal anastomotic site (CAS), the median diameter of balloon dilation was 10.5 mm, and waist disappearance was achieved in 2. Six patients had fully covered self-expandable metal stents (FCSEMS) with a diameter of 10 mm placed at the CAS. BDS were removed after balloon dilation or FCSEMS removal, and 6 out of 16 patients were treated with a combination of lithotripsy and 5 with peroral direct cholangioscopy (PDCS). Regarding AEs, perforation at the CAS by balloon dilation occurred in 1 patient. The median follow-up was 3701 days. Nine out of 16 patients (56%) had recurrence. The patients treated with combination of PDCS at BDS removal (p=0.022) and waist disappearance at the CAS by balloon dilation (p=0.035) had significantly fewer recurrences. [CONCLUSIONS]: Endoscopic interventions for BDS with bCJS are useful and relatively safe; however, long-term follow-ups showed frequent recurrences. Recurrence was common in patients not treated with the combination of PDCS at BDS removal and those without waist disappearance at the CAS by balloon dilation.

The declining insulinogenic index correlates with inflammation and metabolic dysregulation in non-obese individuals assessed by blood gene expression.

AIMS: Diabetes onset is difficult to predict. Since decreased insulinogenic index (IGI) is observed in prediabetes, and blood gene expression correlates with insulin secretion, candidate biomarkers can be identified. METHODS: We collected blood from 96 participants (54 males, 42 females) in 2008 (age: 52.5 years) and 2016 for clinical and gene expression analyses. IGI was derived from values of insulin and glucose at fasting and at 30 min post-OGTT. Two subgroups were identified based on IGI variation: "Minor change in IGI" group with absolute value variation between -0.05 and +0.05, and "Decrease in IGI" group with a variation between -20 and -0.05. RESULTS: Following the comparison of "Minor change in IGI" and "Decrease in IGI" groups at time 0 (2008), we identified 77 genes correlating with declining IGI, related to response to lipid, carbohydrate, and hormone metabolism, response to stress and DNA metabolic processes. Over the eight years, genes correlating to declining IGI were related to inflammation, metabolic and hormonal dysregulation. Individuals with minor change in IGI, instead, featured homeostatic and regenerative responses. CONCLUSIONS: By blood gene expression analysis of non-obese individuals, we identified potential gene biomarkers correlating to declining IGI, associated to a pathophysiology of inflammation and metabolic dysregulation.

Effects of adoptive T-cell immunotherapy on immune cell profiles and prognosis of patients with unresectable or recurrent cholangiocarcinoma.

The identification of immune cell profiles (ICP) involved in anti-tumor immunity is crucial for immunotherapy. Therefore, we herein investigated cholangiocarcinoma patients (CCA) who received adoptive T-cell immunotherapy (ATI). Eighteen unresectable or recurrent CCA received ATI of αß T cells alone or combined with chemotherapy. ICP were evaluated by flow cytometry. There were 14 patients with intrahepatic cholangiocarcinoma (iCCA) and four with distal cholangiocarcinoma (dCCA). After one course of treatment, nine iCCA and four dCCA had progressive disease (PD), while five iCCA had stable disease (SD). Median overall survival (OS) was prolonged to 21.9 months. No significant differences were observed in OS between the PD and SD groups of iCCA. The frequency of helper T cells (HT) in iCCA decreased from 70.3% to 65.5% (P = .008), while that of killer T cells (KT) increased from 27.0% to 30.6% (P = .005). dCCA showed no significant changes of immune cells. OS was prolonged in iCCA with increased frequencies of CD3+ T cells (CD3) (P = .039) and αß T cells (αß) (P = .039). dCCA showed no immune cells associated with OS. The frequencies of CD3+ T cells and αß T cells in the PD group for iCCA decreased from 63.5% to 53% (P = .038) and from 61.6% to 52.2% (P = .028), respectively. In the SD group, the frequency of HT decreased from 65.8% to 56.9% (P = .043), whereas that of KT increased from 30.1% to 38.3% (P = .043). In conclusions, ATI affected ICP and prolonged OS. Immune cells involved in treatment effects differed according to the site of cholangiocarcinoma.

Biliary stones or ulcers at the choledochojejunal anastomotic site involving the jejunal mucosa at stent removal may be recurrent factors in patients with benign choledochojejunal anastomotic stenosis undergoing endoscopic biliary stenting using fully covered self-expandable metal stents.

BACKGROUND: Temporary fully covered self-expandable metal stent (FCSEMS) placement is performed for benign choledochojejunal anastomotic stenosis (bCJS). However, recurrence may develop after stricture resolution. We investigated endoscopic biliary stenting using FCSEMS for bCJS. METHODS: Sixteen bCJS patients with FCSEMS placement were retrospectively analyzed. FCSEMS was removed endoscopically after 2 months. Technical success, stricture resolution, recurrence, and adverse events were evaluated. RESULTS: The technical success rate for FCSEMS placement was 94% (15/16). Biliary stones were detected and extracted in four patients. FCSEMS removal was successfully performed on 14 patients, excluding one with stent migration. At FCSEMS removal, stricture resolution was noted in 14 patients; however, four had anastomotic ulcers. The median follow-up was 319 days. Three patients with a history of repeated plastic stent placement had no recurrence. Four out of 15 patients (27%) had recurrence, and three had no recurrence after additional interventions. Biliary stones before first FCSEMS placement (P = .003) or anastomotic ulcers at FCSEMS removal (P = .018) were associated with recurrence. CONCLUSIONS: Although FCSEMS placement was useful for stricture resolution, recurrence was detected in patients with biliary stones before first FCSEMS placement or anastomotic ulcers at FCSEMS removal. Anastomotic ulcers are a risk factor for recurrence and only detected by endoscopy.

Management of biliary stricture in patients with IgG4-related sclerosing cholangitis.

BACKGROUND: We aimed to determine the optimal approach with endoscopic biliary drainage (EBD) and corticosteroid (CS) for the treatment of IgG4-related sclerosing cholangitis (ISC). METHODS: To evaluate the safety of EBD for treatment of biliary stricture caused by ISC, we assessed the risk of stent dislodgement and sought to determine the most appropriate time for stent removal. We also assessed the safety of treatment with CS alone for patients with obstructive jaundice, and the rate of and risk factors for biliary tract complications. RESULTS: Sixty-nine patients with ISC treated with CS were enrolled. Twenty-eight patients (40.6%) were treated with EBD for biliary stricture before CS initiation. Intentional stent removal was performed in thirteen (46.4%) after confirming CS-induced improvement. Eleven of thirteen patients (84.6%) underwent stent removal within 1 month after CS initiation and all their stent removals were safely carried out without early (within two weeks) recurrence of obstructive jaundice. Ten of twenty-eight patients (35.7%) experienced spontaneous stent dislodgement after CS initiation, and seven (70%) of them developed stent dislodgement two weeks to two months after CS initiation. Among forty-one patients treated with CS alone without EBD, 10 patients had obstructive jaundice at the time of CS initiation and all of them achieved clinical improvement without biliary tract infection. During the follow-up, three patients (4.3%), all of whom had undergone EBD, developed bile-duct stones, while none of those treated with CS alone developed bile-duct stones (p = 0.032). Long-term biliary stenting was a risk factor for bile-duct stones. CONCLUSIONS: Biliary stent removal should be carried out within 2 weeks after CS initiation if biliary stricture improves to prevent stent dislodgement. Obstructive jaundice can be treated safely with CS alone in patients without infection. Clinicians should be aware of the possibility of bile-duct stones in patients treated with EBD.

Induction of Selenoprotein P mRNA during Hepatitis C Virus Infection Inhibits RIG-I-Mediated Antiviral Immunity.

Patients infected with hepatitis C virus (HCV) have an increased risk of developing type 2 diabetes. HCV infection is linked to various liver abnormalities, potentially contributing to this association. We show that HCV infection increases the levels of hepatic selenoprotein P (SeP) mRNA (SEPP1 mRNA) and serum SeP, a hepatokine linked to insulin resistance. SEPP1 mRNA inhibits type I interferon responses by limiting the function of retinoic-acid-inducible gene I (RIG-I), a sensor of viral RNA. SEPP1 mRNA binds directly to RIG-I and inhibits its activity. SEPP1 mRNA knockdown in hepatocytes causes a robust induction of interferon-stimulated genes and decreases HCV replication. Clinically, high SeP serum levels are significantly associated with treatment failure of direct-acting antivirals in HCV-infected patients. Thus, SeP regulates insulin resistance and innate immunity, possibly inducing immune tolerance in the liver, and its upregulation may explain the increased risk of type 2 diabetes in HCV-infected patients.

Serum selenoprotein P, but not selenium, predicts future hyperglycemia in a general Japanese population.

We aimed to test the hypothesis that selenoprotein P (SELENOP), a hepatokine involved in the development of both insulin resistance and impaired insulin production in mice, is related to future onset of hyperglycemia in humans. 76 healthy non-pregnant human subjects without diabetes underwent oral glucose tolerance test (OGTT) at baseline and 4-years follow-up. Nine subjects developed either impaired glucose tolerance or type 2 diabetes at follow-up. At baseline, SELENOP concentrations correlated negatively with insulinogenic index, but not with homeostasis model assessment-estimated insulin resistance (HOMA-IR). Multivariate analysis showed that baseline SELENOP predicted fasting plasma glucose at follow-up independently of the other parameters. The receiver operating characteristic (ROC) curve analysis showed that baseline concentrations of serum SELENOP, but not of selenium, were a reliable test to predict future onset of glucose intolerance. In conclusion, elevation of circulating SELENOP, but not of circulating selenium, was positively and independently associated with future onset of glucose intolerance in a general Japanese population.

Treatment patterns and outcomes of unresectable pancreatic cancer patients in real-life practice: a region-wide analysis.

BACKGROUND: FOLFIRINOX (FFX) and gemcitabine (GEM) plus nab-paclitaxel (GnP) have recently been available for treating pancreatic ductal adenocarcinoma (PDAC). We investigated trends in characteristics, treatment and outcomes of unselected patients with unresectable PDAC in real-life practice in Japan. METHODS: We retrospectively reviewed the medical records of 1085 patients diagnosed as having unresectable or recurrent PDAC in multiple centers in the Hokuriku area between January 2009 and July 2015. RESULTS: The incidence of pathologically proven PDAC had increased from 18.7% in 2009 to 56.2% in 2015. Oncological therapy was administered to 779 patients (71.8%): chemotherapy (n = 675), chemo-radiotherapy (n = 92) or radiotherapy (n = 12); the remaining patients were treated with best supportive care. Of 100 patients diagnosed in 2009, 62.0% received GEM as first-line chemotherapy; whereas 30.7% of the 75 patients diagnosed in 2015 received FFX, 25.3% GnP, 22.7% GEM and 17.3% S-1. The objective response rates of patients treated with FFX, GnP and GEM were 14.9%, 35.0% and 5.5%, respectively and the OS 10.3, 9.9 and 7.5 months after FFX, GnP and GEM, respectively. Grade 3 or greater any hematological toxicity occurred in 70.2%, 70.0% and 18.8% of the patients treated with FFX, GnP and GEM, respectively. The reasons for treatment discontinuation were adverse events in 9.8%, 26.7% and 24.1% of the patients treated with FFX, GnP and GEM, respectively. CONCLUSION: Chemotherapeutic protocols changed dramatically between 2009 and 2015. Continuous collection and analysis for our cohort with longer follow-up provides useful information about treatment selection and prediction of outcome.

Prognosis of type 1 autoimmune pancreatitis after corticosteroid therapy-induced remission in terms of relapse and diabetes mellitus.

BACKGROUND AND AIM: Relapse and diabetes mellitus (DM) are major problems for the prognosis of autoimmune pancreatitis (AIP). We examined the prognosis of type 1 AIP after corticosteroid therapy (CST)-induced remission in terms of relapse and DM. METHODS: The study enrolled 82 patients diagnosed with type 1 AIP who achieved remission with CST. We retrospectively evaluated the relapse rate in terms of the administration period of CST, clinical factors associated with relapse, and the temporal change in glucose tolerance. RESULTS: During follow-up, 32 patients (39.0%) experienced relapse. There was no significant clinical factor that could predict relapse before beginning CST. AIP patients who ceased CST within 2 or 3 years experienced significantly earlier relapse than those who had the continuance of CST (p = 0.050 or p = 0.020). Of the 37 DM patients, 15 patients (40.5%) had pre-existing DM, 17 (45.9%) showed new-onset DM, and 5 (13.5%) developed CST-induced DM. Patients with new-onset DM were significantly more likely to show improvement (p = 0.008) than those with pre-existing DM. CONCLUSIONS: It was difficult to predict relapse of AIP based on clinical parameters before beginning CST. Relapse was likely to occur within 3 years after the beginning of CST and maintenance of CST for at least 3 years reduced the risk of relapse. The early initiation of CST for AIP with impaired glucose tolerance is desirable because pre-existing DM is refractory to CST.

Corrigendum to 'Weight-adjusted lean body mass and calf circumference are protective against obesity-associated insulin resistance and metabolic abnormalities'.

[This corrects the article DOI: 10.1016/j.heliyon.2017.e00347.].

Weight-adjusted lean body mass and calf circumference are protective against obesity-associated insulin resistance and metabolic abnormalities.

BACKGROUND: To test the hypothesis that preserved muscle mass is protective against obesity-associated insulin resistance and metabolic abnormalities, we analyzed the relationship of lean body mass and computed tomography-assessed sectional areas of specific skeletal muscles with insulin resistance and metabolic abnormalities in a healthy cohort. METHODS: A total of 195 subjects without diabetes who had completed a medical examination were included in this study. Various anthropometric indices such as circumferences of the arm, waist, hip, thigh, and calf were measured. Body composition (fat and lean body mass) was determined by bioelectrical impedance analysis. Sectional areas of specific skeletal muscles (iliopsoas, erector spinae, gluteus, femoris, and rectus abdominis muscles) were measured using computed tomography. FINDINGS: Fat and lean body mass were significantly correlated with metabolic abnormalities and insulin resistance indices. When adjusted by weight, relationships of fat and lean body mass with metabolic parameters were mirror images of each other. The weight-adjusted lean body mass negatively correlated with systolic and diastolic blood pressures; fasting plasma glucose, HbA1c, alanine aminotransferase, and triglyceride, and insulin levels; and hepatic insulin resistance indices, and positively correlated with HDL-cholesterol levels and muscle insulin sensitivity indices. Compared with weight-adjusted lean body mass, weight-adjusted sectional areas of specific skeletal muscles showed similar, but not as strong, correlations with metabolic parameters. Among anthropometric measures, the calf circumference best reflected lean body mass, and weight-adjusted calf circumference negatively correlated with metabolic abnormalities and insulin resistance indices. INTERPRETATION: Weight-adjusted lean body mass and skeletal muscle area are protective against weight-associated insulin resistance and metabolic abnormalities. The calf circumference reflects lean body mass and may be useful as a protective marker against obesity-associated metabolic abnormalities.

Development of a Sol Particle Homogeneous Immunoassay for Measuring Full-Length Selenoprotein P in Human Serum.

BACKGROUND: Selenoprotein P (SeP), a selenium-rich extracellular glycoprotein, is the primary selenoprotein in the plasma. SeP plays an important role in the maintenance of selenium levels in the peripheral tissues. We developed a new sol particle homogeneous immunoassay (SPIA) for measuring full-length SeP (FL-SeP) levels in the human serum. METHODS: We used colloidal gold particles coated with two types of anti-SeP monoclonal antibodies, one recognizing the N-terminal side domain of SeP and the other recognizing the C-terminal side domain. RESULTS: The assay range was 0.2-9 mg/l, and the linearity was excellent. The within-day and between-day coefficients of variation ranged from 0.73% to 2.24% and 0.45% to 1.11%, respectively. Serum samples (n = 200) were examined using the newly developed assay system (employing a Model 7070 Hitachi automatic clinical analyzer) and the conventional enzyme-linked immunosorbent assay. These two methods were compared using the Passing-Bablok regression analysis; the resulting regression equation and correlation coefficient were y = 0.940x + 0.165 and r = 0.954, respectively. CONCLUSIONS: Our new SPIA assay is a fully automated homogeneous immunoassay that can be used in conjunction with various commercial analyzers. The assay was sensitive, precise, and suitable for clinical measurement of the FL-SeP in the human serum.

[A case of definitive type 2 autoimmune pancreatitis diagnosed using endoscopic ultrasound-guided fine needle aspiration biopsy].

A 29-year-old man with ulcerative colitis presented to the hospital complaining of persistent back pain. Pancreatic enzymes and tumor markers were elevated; imaging showed diffuse narrowing of the main pancreatic duct associated with diffuse pancreatic enlargement. We therefore performed an endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) biopsy of the pancreas using a 19-gauge needle. Histopathology revealed interlobular fibrosis, neutrophil infiltration in the intralobular ducts and acini, and very few immunoglobulin G4-positive cells. The patient was diagnosed with type 2 autoimmune pancreatitis and started on oral steroids; subsequently, we observed an improvement in the pancreatic enlargement and duct narrowing. Histologically proven type 2 autoimmune pancreatitis is rare in Japan.

A fatal case of progressive steatohepatitis, possibly chemotherapy-associated steatohepatitis related to gemcitabine.

We report the case of an 80-year-old female suffering from pancreatic cancer who developed severe non-alcoholic steatohepatitis (NASH) resulting in fatal hepatic failure after anti-cancer chemotherapy with gemcitabine. Hepatic encephalopathy appeared 1 year after the chemotherapy, and the patient developed progressive liver failure and eventually died. Radiological examination showed severe fatty liver. Histopathological examination of a liver needle necropsy showed almost panlobular macrovesicular fatty change. Ballooning degeneration and necrosis of hepatocytes accompanying neutrophil infiltration, Mallory bodies, and a few bile plugs were found in zone 3. Marked perivenular and pericellular/perisinusoidal fibrosis and extensive bridging fibrosis were also found. Together, these findings indicated steatohepatitis at a precirrhotic stage. Because the patient had no history of drinking in excess, we made a diagnosis of NASH, in particular, chemotherapy-associated steatohepatitis (CASH). Gemcitabine is a pyrimidine nucleoside antimetabolite with anti-cancer activity. A few reports have mentioned fatal hepatotoxicity caused by gemcitabine, but, to our knowledge, this is the first report of steatohepatitis, possibly associated with gemcitabine. Physicians treating patients with this drug should be aware of the possibility of steatohepatitis.

Duct-narrowing chronic pancreatitis without immunoserologic abnormality: comparison with duct-narrowing chronic pancreatitis with positive serological evidence and its clinical management.

We reviewed the clinical features and clinical course of patients with duct-narrowing chronic pancreatitis who were negative for immunoserologic test results (n = 16) in comparison with the findings for serological test-positive patients (n = 20) in order to determine an adequate treatment for those who had typical morphology of autoimmune pancreatitis in the absence of immunoserologic abnormality. No significant differences were found between the two groups of patients in clinical profiles including associated autoimmune-related diseases, pancreatic histology, and response to steroid therapy. Of the seronegative patients, eight who showed an improvement in narrowing of the main pancreatic duct with steroid therapy and three who did no show an improvement or who relapsed after surgical resection without this therapy had stenosis of the common bile duct with increased levels of serum hepatobiliary enzymes, except for two patients with affected sites limited to the body or tail of the gland. For the remaining five patients, who showed an improvement in pancreatic duct changes or long-term remission after surgery without steroid administration, normal biochemistry test results for liver functions were obtained, with no abnormal cholangiographic findings in the three patients examined. Duct-narrowing chronic pancreatitis without immunoserologic abnormality overlaps in clinical features with that fulfilling the immunoserologic criteria for a diagnosis of autoimmune pancreatitis. In particular, the disease with bile duct involvement should be treated clinically as autoimmune pancreatitis, for which steroid therapy is recommended, even if an autoimmune mechanism is not demonstrated serologically.

[Recurrent ovarian cancer with cancer peritonitis treated with weekly paclitaxel infusion--a clinicopharmacological study].

We treated a patient with recurrent ovarian cancer with cancerous peritonitis by weekly paclitaxel (w-TXL) therapy (65 mg/m2). Abdominocentesis was not performed to eliminate ascites, in order to maintain higher quality of life (QOL), and critical adverse reaction was not seen for 12 months. We measured the TXL concentration in blood plasma and ascites after TXL infusion by HPLC method. The TXL titer in plasma was 427 ng/ml after infusion, 23 ng/ml after 24 hours and under 10 ng/ml after 48 hours. The TXL titer in ascites was 41 ng/ml after infusion, 37 ng/ml after 6 hours, 18 ng/ml after 12 hours, 10 ng/ml after 24 hours and under 10 ng/ml after 48 hours. TXL transportation from blood to ascites was good. This result suggested that intravenous infusion of TXL was effective for cancerous peritonitis treatment.

[A case of ovarian cancer with Parkinson's disease treated by combined chemotherapy with paclitaxel and carboplatin followed by surgery].

It is well known that neuropathy, myelopathy, and arthropathy are specific adverse effects induced by paclitaxel administration. Parkinson's disease is neural degenerative disease, and the influence of paclitaxel administration on patients with Parkinson's disease is unknown. We have successfully treated an ovarian cancer patient with Parkinson's disease by paclitaxel/CBDCA combined chemotherapy after surgery. The patient was a 57-year-old woman with solid and cystic ovarian tumor. Among the tumor markers CA125, CA19-9, and SLX, only SLX was elevated. We operated and made a pathological diagnosis of the ovarian tumor as clear cell adenocarcinoma (FIGO stage Ic). After surgery, the patient was treated with paclitaxel (260 mg [175 mg/m2]) and CBDCA (600 mg [AUC = 5]) combined chemotherapy for 5 courses. Her status is complete remission. During chemotherapy, she had felt the decreased efficacy of her Parkinson's disease medication. We could continue chemotherapy by increasing the dose of the Parkinson's drug. There is only one case report on the influence of paclitaxel on Parkinson's disease, in which the course was similar to the present case.

Combination chemotherapy for advanced hepatocellular carcinoma complicated by major portal vein thrombosis.

Patients with advanced hepatocellular carcinoma (HCC) have a poor prognosis, and the development of new therapeutic strategies is necessary. Here we report the efficacy of combination chemotherapy in our biochemical modulation. Synergistic effects of interferon-alpha-2b on 5-fluorouracil or cisplatin were demonstrated in Huh7 cells. The efficacy of methotrexate-5-fluorouracil, cisplatin, and interferon-alpha-2b combination therapy was demonstrated in 34 patients with HCC complicated by major portal vein thrombosis. Among the 29 patients eligible for the study, there were 3 complete responders and 10 partial responders with an overall response rate of 45%. The 2-year survival of the 34 patients was 15%, and the median survival of complete and partial responders was 11 months. There was severe transient hematological toxicity. Eight patients suffered from renal insufficiency, and 4 of them underwent hemodialysis. Although a control study is clearly necessary, our combination therapy induced a good response in the patients with advanced HCC. On the basis of our results, intensive chemotherapy should be attempted in advanced HCC complicated by major portal vein invasion.