Efficacy and safety of modified fluorouracil/leucovorin plus irinotecan and oxaliplatin (mFOLFIRINOX) compared with S-1 as second-line chemotherapy in metastatic pancreatic cancer.

BACKGROUND AND AIM: The optimal standard second-line chemotherapy for metastatic pancreatic cancer (MPC) remains unclear. Here, we evaluated the efficacy and safety of modified fluorouracil/leucovorin plus irinotecan and oxaliplatin (mFOLFIRINOX) compared with oral fluoropyrimidine S-1 as a second-line chemotherapy in patients with MPC. METHODS: We retrospectively reviewed 76 consecutive patients with metastatic pancreatic adenocarcinoma who underwent mFOLFIRINOX or S-1 treatment as a second-line chemotherapy after gemcitabine plus nab-paclitaxel (GnP) failure at our department between December 2014 and February 2019. RESULTS: Patients who underwent mFOLFIRINOX treatment exhibited significantly better objective response rates (ORRs) and progression-free survival (PFS) than S-1 (ORR, 20.0% vs 0%, P = 0.003; PFS, 3.7 vs 2.1 months, P = 0.010). Although baseline patient characteristics of age, performance status, and serum albumin levels differed significantly between the two groups, mFOLFIRINOX was identified as an independent factor of favorable PFS on multivariate analyses. Grade 3-4 neutropenia and peripheral sensory neuropathy occurred more frequently in the mFOLFIRINOX group. The median overall survival from the initiation of second-line chemotherapy was not significantly longer in the mFOLFIRINOX group than in the S1 group (8.5 vs 5.8 months, respectively; P = 0.213); however, the 8-month survival rate was significantly higher in the mFOLFIRINOX group (56.0% vs 27.5%, respectively; P = 0.030). CONCLUSIONS: mFOLFIRINOX as a second-line regimen contributed to favorable treatment outcomes, but induced more frequent adverse events than S-1. On multivariate analyses, mFOLFIRINOX was identified as an independent factor with favorable PFS, suggesting that mFOLFIRINOX could be a promising treatment option for patients with GnP failure.

Environmental factors affecting Edwardsiella ictaluri-induced mortality of riverine ayu, Plecoglossus altivelis (Temminck & Schlegel).

We analysed the predisposing factors for Edwardsiella ictaluri infection in the riverine ayu Plecoglossus altivelis on the basis of environmental and epidemiological data obtained in a tributary to and the lower reaches of the Tama River, Japan, in July and August 2011-2015. Mortality of ayu due to E. ictaluri infection was observed only in the tributary in August 2012 and 2013; both periods were unusually hot. During these mortality events, daily average water temperatures rose approximately 3-4°C over 4-8 days, reaching the optimum temperature for E. ictaluri infection (>25°C) and approaching the upper tolerable limit for ayu (30°C). Diurnal water temperature ranges (DWTRs) in the tributary during the mortality events exceeded 6°C, which was 1-2°C greater than in the lower reaches. Experimental infection of ayu with E. ictaluri resulted in higher mortality when exposed to 6°C DWTR than to 4°C DWTR. Furthermore, water levels in the tributary were generally low in August 2012 and 2013 because of low rainfall. From these results, we conclude that unusually high-water temperatures combined with high DWTRs and low water levels drove riverine ayu mortality from E. ictaluri infection.

Adverse reactions to 1% cyclopentolate eye drops in children: an analysis using logistic regression models.

PURPOSE: To determine the frequency, symptoms and risk factors for adverse reactions to two-times instillation of 1% cyclopentolate in children. STUDY DESIGN: Prospective, observational study. METHODS: The subjects were 646 patients who underwent cycloplegic refraction with cyclopentolate (mean age; 7.0 ± 3.5 years, age range; 0-15 years). Five minutes after instillation of 0.4% oxybuprocaine hydrochloride, a 1% cyclopentolate eye drop was instilled twice, with an interval of 10 min. Fifty minutes later, two certified orthoptists evaluated adverse reactions using a questionnaire and interviewed the patients' guardians. The relationship between the adverse reaction rates and age, gender, additional instillation, complications of the central nervous system (CNS), time of day and season were analysed using binominal and polytomous logistic regression models. RESULTS: The overall frequency of adverse reactions was 18.3% (118/646 patients). The main symptoms included conjunctival injection (10.5%, 68/646), drowsiness (6.8%, 44/646) and facial flush (2.2%, 14/646). The odds ratio (OR) of conjunctival injection increased with patient's age (p < 0.05), in boys (p < 0.01) and in winter (p < 0.001). In contrast, the OR of drowsiness decreased with age (p < 0.001). Facial flush was observed mostly in children younger than 4 years. CNS complications were not a significant risk factor for any of the symptoms. CONCLUSIONS: Adverse reactions to 1% cyclopentolate eye drops were more frequent than previously expected, but all were mild and transient. The probability of each symptom was associated with a clear age-specific trend.

Self-expandable metallic stent placement above the papilla without endoscopic sphincterotomy in patients with distal malignant biliary obstruction.

Background and study aims The best method for endoscopic placement of self-expandable metallic stents (SEMS) for distal malignant biliary obstruction (MBO) has not yet been determined. The aim of this study was to evaluate how SEMS placement above the papilla and without endoscopic sphincterotomy (EST) impacts the time to recurrent biliary obstruction (RBO) in patients with distal MBO. Patients and methods We retrospectively reviewed data for 73 consecutive patients with unresectable distal MBO who underwent endoscopic SEMS placement for the first time at our institution between April 2014 and March 2016. We compared time to RBO of SEMS placement above the papilla (intraductal placement) with SEMS placement across the papilla (transpapillary placement). In the intraductal placement group, we also compared time to RBO of placement without EST with placement with EST. Results Endoscopic SEMS placement was performed in 30 patients with intraductal placement and in 43 patients with transpapillary placement. The median time to RBO was significantly longer with intraductal placement (307 days) than with transpapillary placement (161 days) ( P  = 0.022). Complication rates did not differ between the two groups. In both univariate and multivariate analysis, intraductal placement was an independent factor contributing to prolonged time to RBO. In intraductal placement, time to RBO was significantly longer in SEMS placement without EST than with EST (363 days vs. 227 days, respectively; P  = 0.026). Conclusions Intraductal SEMS placement, especially without EST for distal MBO contributed to longer time to RBO.

Prognostic Factors for Patients With a Large Number of Hepatocellular Carcinoma Nodules.

BACKGROUND: The prognostic factors and treatment strategies for hepatocellular carcinoma (HCC) patients with a large number of tumor nodules have not been fully elucidated. Clinical factors influencing prognosis were investigated in HCC patients with 30 or more tumor nodules. METHODS: Forty-six HCC patients with 30 or more tumor nodules participated in this study. None of them had vascular invasion and extrahepatic metastasis. Kaplan-Meier curve and Cox proportional hazard model were used for analysis. RESULTS: The median survival time of our patients was no more than 15 months, suggesting that patients with 30 or more tumor nodules may be regarded as a progressive subgroup showing poorer prognosis. In multivariate analysis, presence of between 30 and 59 tumor nodules (P = 0.002), male gender (P = 0.002), lower total bilirubin (total bilirubin < 1.0 mg/dL) (P = 0.011), transarterial chemoembolization (TACE) as an initial therapy (P = 0.027) and higher prothrombin time (P = 0.049) were significant independent factors for better overall survival. Among 39 patients who underwent TACE as an initial therapy, patients who received sorafenib therapy during follow-up showed better overall survival than those who did not (P = 0.026). Efficacy of sorafenib appeared to be more evident in patients who needed repeated transarterial treatment. CONCLUSIONS: In HCC patients with 30 or more tumor nodules, TACE as an initial therapy may be correlated with better prognosis. Sorafenib administration after the prior transarterial treatment may improve antitumor efficacy.

Development of a thrombus in the superior mesenteric artery associated with sequential therapy with tyrosine kinase inhibitors for hepatocellular carcinoma.

Tyrosine kinase inhibitors (TKIs) are widely used for systemic chemotherapy of hepatocellular carcinoma (HCC). Arterial thromboembolism (ATE) has been reported to be an adverse event associated with TKI therapy, but its incidence is rare. Here, we report a case of an HCC patient who developed a thrombus in the superior mesenteric artery (SMA) while on TKI therapy. The patient was a 78-year-old Japanese man with hepatitis C virus-associated HCC with multiple nodules. Several sessions of transarterial chemoembolization therapy caused him to become refractory to the treatment. Sorafenib and regorafenib therapy had also been previously performed, but his disease continued to progress gradually. Therefore, we started lenvatinib therapy. When a contrast-enhanced computed tomography (CT) examination was performed 2 months later, we found a thrombus in the SMA. Retrospective analysis of the CT images revealed that the thrombus formed during the sorafenib-regorafenib sequential therapy and it developed rapidly, especially during the lenvatinib therapy. An HCC patient developed a thrombus in the SMA during TKI therapy. The incidence of ATE is rare in TKI treatment; however, long-term or sequential TKI therapy may increase the frequency of ATE. Further study is needed.

Chemotherapy-Induced Sclerosing Cholangitis Caused by Systemic Chemotherapy.

A 61-year-old woman diagnosed with cervical cancer received systemic chemotherapy using paclitaxel and bevacizumab. Marked elevation of liver enzyme levels was observed. Ultrasonography and computed tomography showed wall thickening of the extrahepatic and intrahepatic bile ducts accompanied by stricture and dilatation. According to these, she was diagnosed as chemotherapy-induced sclerosing cholangitis (CISC), a form of secondary sclerosing cholangitis. Although CISC triggered by systemic chemotherapy is rare, CISC should be considered as a clinically important adverse event of chemotherapy because it causes rapid deterioration of liver function and necessitates interruption of chemotherapy.

Factors Affecting Therapeutic Effects in 17 Patients with Advanced Hepatocellular Carcinoma Who Were Treated with Sorafenib for More than 12 Months.

BACKGROUND AND OBJECTIVE: Sorafenib is recommended for treating advanced hepatocellular carcinoma. However, it is frequently discontinued because of adverse events, which greatly affects its therapeutic effects. Furthermore, because patients treated with sorafenib for a long period can presumably tolerate adverse events, this study aimed to identify their characteristics and analyze factors affecting the therapeutic effects of the drug. SUBJECTS AND METHODS: Seventeen patients with hepatocellular carcinoma who received sorafenib for 12 months or longer at our hospital between January 2009 and October 2015 were included. In these 17 patients, factors affecting the time to untreatable progression were analyzed using a Cox proportional hazards model, Kaplan-Meier curve, and log-rank test. RESULTS: In the 17 patients, the mean sorafenib dose was 433 mg/day. The drug was discontinued in 12 patients, 9 (75%) of whom discontinued it because of progressive disease. The median time to untreatable progression was 23.1 months. The contributors to favorable therapeutic effects included administration of at least two sessions of concomitant therapy after initiating sorafenib therapy, a low neutrophil-to-lymphocyte ratio, and a decreased total bilirubin level. CONCLUSION: Achieving favorable therapeutic effects of sorafenib requires strict dose adjustment that allows better control of adverse events and long-term administration of the drug. Furthermore, combining sorafenib with other therapies, a low neutrophil-to-lymphocyte ratio, and a decreased total bilirubin level are useful predictors of favorable effects.

Number of Nodules but not Size of Hepatocellular Carcinoma Can Predict Refractoriness to Transarterial Chemoembolization and Poor Prognosis.

BACKGROUND: To determine whether response to transarterial chemoembolization (TACE) predicts survival and to identify pretreatment factors associated with TACE response and prognosis. METHODS: Between April and September 2010, 50 patients underwent TACE for hepatocellular carcinoma. Response to TACE was assessed using post-treatment computed tomography (CT) and magnetic resonance imaging (MRI) scans and tumor marker levels and classified as Response Poor (P) and Non-poor (NP). Time zero was set to September 30, 2010, and survival rates were analyzed by landmarking. Cumulative survival rates were calculated using the Kaplan-Meier method and compared according to grades using the log-rank test; contributing factors to survival were analyzed using a Cox proportional hazards model. Pretreatment factors were analyzed for 109 TACE sessions performed until October 2017, using a multiple logistic regression model. Receiver operating characteristic (ROC) curves were generated to determine the best tumor number for predicting response P. RESULTS: Response P patients showed significantly lower cumulative survival rates than Response NP patients (P < 0.001). On multivariate analysis, tumor number (hazard ratio (HR), 1.475), protein-induced vitamin-K absence-II (HR, 4.539), and the number of previous TACE sessions (HR, 1.472) were identified as pretreatment factors contributing to Response P. Further, pre-treatment platelet count (HR, 0.876) and tumor number (HR, 1.330) were factors contributing to survival in multivariate analysis. ROC curve analysis revealed that the optimal cut-off value to discriminate Response P was 7.5. CONCLUSIONS: Response to TACE can predict survival. Pretreatment tumor number is a useful factor for predicting both TACE response and prognosis.

Two-step progression of varenicline-induced autoimmune hepatitis.

We describe a rare case of drug-induced hepatitis due to the smoking cessation agent varenicline in a 46-year-old Asian woman. The liver injury progressed in two steps. First, the liver injury started in the absence of viral/autoimmune responses, and withdrawal of varenicline lowered the increase in the levels of liver enzymes immediately. Such findings suggested varenicline-induced liver injury. Second, hepatitis recurred in association with conversion of antinuclear antibody from negative to positive about 8 weeks after the initial episode. Histology upon recurrence of liver injury revealed interface hepatitis with lymphocytic and lymphoplasmacytic portal inflammatory infiltrates extending into lobules. Such findings suggested autoimmune hepatitis. Corticosteroid treatment was effective for recurrent hepatitis. The clinical course suggests that varenicline caused drug-induced liver injury and subsequent autoimmune hepatitis. Some autoimmune changes were probably involved in the mechanism of varenicline-induced liver injury.

Determination of glycated hemoglobin in clinically silent hemoglobin variants.

BACKGROUND: Evaluation of glycated hemoglobin determination methods in patients with clinically silent hemoglobin variants. METHODS: HbA1c results were determined with various methods, including a new enzymatic assay, a boronate affinity HPLC, immunoassays and ion-exchange HPLC in patients with the clinically silent hemoglobin variants Hb Graz, Hb Sherwood Forest, Hb D and Hb O Padova. RESULTS: The effect of hemoglobin variants on glycated hemoglobin determination was method-dependent. The enzymatic and boronate affinity HPLC method did not interfere with any of the variants evaluated. In contrast, Hb Graz interfered with all immunoassay and ion-exchange HPLC methods evaluated. The Tosoh ion-exchange HPLC method HLC-723 did not detect the late migrating Hb O Padova in the chromatogram, but this hemoglobin variant still interfered causing artificially low HbA1c results. CONCLUSIONS: Our study underscores the need for clinical laboratories and physicians to be aware of the limitations of their HbA1c assay methods as well as the importance of visual inspection of ion-exchange chromatograms to detect abnormalities caused by the hemoglobin variants. Samples with clinically silent Hb variants should be analyzed by a second method with a different assay principle, preferably a boronate affinity HPLC or an enzymatic assay.