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No adjuvant treatment has been established for patients who remain at high risk for hepatocellular carcinoma recurrence after curative-intent resection or ablation. We aimed to assess the efficacy of adjuvant atezolizumab plus bevacizumab versus active surveillance in patients with high-risk hepatocellular carcinoma.

We examined whether Mac-2-binding protein glycosylation isomer (M2BPGi) levels could be a predictive marker for the presence of esophagogastric varices (EGV) in cirrhotic patients after hepatitis C virus (HCV) eradication with direct-acting antivirals (DAAs).

Background Interferon-free, direct-acting antiviral treatments can result in a sustained virologic response in nearly 100% of patients with chronic hepatitis C virus infection.Aims The purpose of this study was to evaluate histological improvement after achieving a sustained virologic response to direct-acting antiviral treatments in patients with chronic hepatitis C.Methods Among 691 patients with chronic hepatitis C who achieved a sustained virologic response to direct-acting antivirals, 51 underwent liver biopsy 41 ± 20 weeks after the end of treatment despite normal transaminase levels. In 20 patients, liver biopsy specimens obtained a median of 1.2 years before the start of treatment were available.Results Among the 51 patients who underwent post-sustained virologic response biopsies, the grade of inflammation was A0 in 18 patients, A1 in 24, A2 in eight, and A3 in one; the stage of fibrosis was F0 in three patients, F1 in 20, F2 in 15, F3 in nine, and F4 in four. Among the nine post-sustained virologic response biopsy specimens with moderate-to-severe inflammation (≥A2), four showed S1-to-S3 steatosis (>5% of hepatocytes affected). In the 20 paired biopsy specimens, the inflammation grade significantly regressed (p= 0.0043), but the fibrosis stage did not (p= 0.45). Histological improvement, defined as a ≥ 2-point decrease in the Knodell inflammatory score and no worsening of the fibrosis, was found in 11 (55%) patients. The iron accumulation had significantly regressed (p= 0.0093), but the steatosis had not (p= 0.10).Conclusions Even if transaminases become normal after obtaining a sustained virologic response, significant histological inflammation of unknown cause was found in some patients. Additionally, improvement in liver fibrosis was not evident in the short term.

Interferon-free, direct-acting antiviral treatments can result in a sustained virologic response in nearly 100% of patients with chronic hepatitis C virus infection. The purpose of this study was to evaluate histological improvement after achieving a sustained virologic response to direct-acting antiviral treatments in patients with chronic hepatitis C. Among 691 patients with chronic hepatitis C who achieved a sustained virologic response to direct-acting antivirals, 51 underwent liver biopsy 41?±?20 weeks after the end of treatment despite normal transaminase levels. In 20 patients, liver biopsy specimens obtained a median of 1.2 years before the start of treatment were available. Among the 51 patients who underwent post-sustained virologic response biopsies, the grade of inflammation was A0 in 18 patients, A1 in 24, A2 in eight, and A3 in one; the stage of fibrosis was F0 in three patients, F1 in 20, F2 in 15, F3 in nine, and F4 in four. Among the nine post-sustained virologic response biopsy specimens with moderate-to-severe inflammation (=A2), four showed S1-to-S3 steatosis (>5% of hepatocytes affected). In the 20 paired biopsy specimens, the inflammation grade significantly regressed (p?=?0.0043), but the fibrosis stage did not (p?=?0.45). Histological improvement, defined as a?=?2-point decrease in the Knodell inflammatory score and no worsening of the fibrosis, was found in 11 (55%) patients. The iron accumulation had significantly regressed (p?=?0.0093), but the steatosis had not (p?=?0.10). Even if transaminases become normal after obtaining a sustained virologic response, significant histological inflammation of unknown cause was found in some patients. Additionally, improvement in liver fibrosis was not evident in the short term.

Endoscopic biliary drainage is the recommended 1st-line treatment for malignant biliary obstruction. Although a high incidence of febrile neutropenia has been reported in patients treated with FOLFIRINOX and a biliary stent, it remains unknown whether the biliary stent contributes to patient survival. Thus, we aimed to elucidate the effects of biliary stents on the survival of patients with advanced pancreatic cancer treated with modified FOLFIRINOX (mFFX). We retrospectively reviewed medical charts of patients with advanced pancreatic cancer treated with mFFX between January 2014 and April 2020. We compared the overall survival (OS) of patients with and without biliary stent during mFFX treatment and examined the independent effect on mortality using propensity score matching. Overall, we included 89 patients (stent group, n = 24; non-stent group, n = 65). The proportion of patients with pancreatic head cancer was significantly higher in the stent group than in the non-stent group (P < .01). Stratification analysis in patients with pancreatic head cancer revealed that OS was significantly shorter in the stent group than in the non-stent group (P = .03). After propensity score matching, 19 pairs of patients in each group were analyzed. The stent group revealed a significantly shorter survival than the non-stent group (median OS, 10.3 vs 24.9 months; P < .01). The incidences of febrile neutropenia (P = .01) and biliary tract-related events that required biliary stenting or stent replacement (P < .01) were significantly higher in the stent group than in the non-stent group. Stent insertion was an independent risk factor for overall mortality. Biliary stents may reduce survival in patients with advanced pancreatic cancer. The rate of febrile neutropenia was higher in the stent group than in the non-stent group. There is a need to assess the patient’s condition with discretion and develop a treatment strategy with short prognosis in mind after stent insertion.

The possible mechanisms of cardiac adverse effects of astemizole were studied using a halothane-anesthetizedin vivocanine model under the cardiohemodynamic and monophasic action potential monitoring. A dose of 0.3 mg/kg of iv astemizole (n= 7), which is close to the recommended dose for clinical use, showed a bradycardic effect and a reversed use-dependent lengthening of repolarization. The increase in the repolarization was greater than in the effective refractory period. These effects persisted even when the plasma drug concentration became undetectable. Additional administration of 3.0 mg/kg of iv astemizole (n= 7) decreased the mean blood pressure, suppressed the cardiac contraction and conduction, and induced early after depolarization-like potential in addition to the qualitatively similar effects compared to those observed by the lower dose. The decrease of the plasma concentration of astemizole followed the pattern predicted by the two-compartment theory of pharmacokinetics, but the drug concentration in the cardiac muscle was estimated to be more than 100 times greater than that in plasma. Our study emphasizes that each cardiac consequence of astemizole overdose may be related to proarrhythmic effects and the monitoring of plasma drug concentration will be less helpful in predicting the cardiac adverse effects of astemizole. The results provide some insights into the clinical cardiotoxicity of astemizole. Drugs or interventions inducing positive chronotropic, inotropic, and dromotropic effects can become good candidates for the treatment of astemizole intoxication, which may attenuate the cardiac effects of astemizole including the lengthening of repolarization.

Polymorphic ventricular arrhythmias induced by astemizole overdose have been reported to be successfully managed with intravenous magnesium sulfate. This study was designed to assess the effects of magnesium sulfate on the cardiovascular system, complicating astemizole overdose, the better to understand the therapeutic utility and undesirable effects of magnesium sulfate. Beagle dogs were anesthetized with halothane inhalation (n = 6). Monophasic action potential of the right ventricle, electrocardiogram, and systemic and left ventricular pressure were continuously monitored. Cardiac output was measured by a thermodilution method. Effective refractory period of the right ventricle was assessed by programed electrical stimulation. An intentionally high dose of astemizole (3 mg/kg, i.v.) prolonged the repolarization and refractory period, while it decreased the sinus automaticity, ventricular contraction, and conduction. A canine antiarrhythmic dose of magnesium sulfate (100 mg/kg, i.v.) was additionally injected 1 h after i.v. astemizole. Magnesium sulfate increased the atrioventricular conduction time, electrical vulnerability, and preload of the left ventricle, while it decreased the blood pressure and cardiac output, besides the effects similar to those observed after i.v. astemizole. The plasma concentration of astemizole was at least 10 times higher than its therapeutic concentration during the experimental period. Magnesium sulfate could be expected to act as a calcium channel blocker during astemizole overdose; however, it may not antagonize the proarrhythmic effects of astemizole.

Time courses of β-adrenoceptor-blocking actions of ONO-1101, a new cardioselective β-blocker, were compared with those of esmolol and propranolol by using the isolated, blood-perfused sinoatrial node (SAN) and papillary muscle (PM) preparations of dogs. ONO-1101 per se given intraarterially (i.a.) in each nutrient artery did not affect basal sinoatrial rates (SARs; 99 ± 2 beats/min, n = 7) in the SAN and developed tension (DT; 3.2 ± 0.7 g, n = 7) of the PM preparations. Norepinephrine (NE) injected i.a. into the each artery induced increases in SAR (42 ± 6 beats/min at 0.051 ± 0.014 μg) and PMDT (2.9 ± 0.4 g at 0.048 ± 0.011 μg). The i.a. injections of NE were repeated every 3 min after i.v. bolus injections of ONO-1101 into the support dog. NE-induced increases in SAR and PMDT were maximally inhibited 3 to 6 min after the i.v. injections of ONO-1101. Maximal percentage inhibitions by ONO-1101 of NE-induced increases in SAR were 54 ± 6, 78 ± 3, and 96 ± 2% at 0.01, 0.1, and 1 mg/kg of the drug, respectively. Similarly, maximal percentage inhibitions by ONO-1101 of NE-induced increases in PMDT were 50 ± 12, 93 ± 2, and 100% ± 0, respectively. The inhibition was quickly recovered; times required for 50% recovery (RT1/2) were 12 ± 3, 17 ± 3, and 32 ± 10 min in the SAN preparation, and 13 ± 3, 16 ± 2, and 39 ± 11 min in the PM preparations, after i.v. injections of 0.01, 0.1, and 1 mg/kg of ONO-1101, respectively. In comparison, maximal percentage inhibitions by esmolol of NE-induced increases in SAR were 45 ± 5, 79 ± 6, and 96 ± 2%, and those in PMDT were 34 ± 4, 75 ± 5, and 97 ± 1%, whereas the RT1/2values were 11 ± 2, 15 ± 4, and 40 ± 12 min in the SAN preparation, and 10 ± 2, 16 ± 7, and 27 ± 6 min in the PM preparations, after i.v. injections of 0.01, 0.1, and 1 mg/kg of esmolol, respectively. In contrast, the maximal percentage inhibitions by an i.v. bolus injection of 0.1 mg/kg of propranolol of NE-induced increases in SAR and PMDT were 77 ± 18% and 87 ± 13% (n = 4). respectively. The maximal inhibitions were obtained 6-15 min after injections of propranolol and then slowly recovered only by 21% in the SAN and 8% in the PM preparations, even after 60 min. These results clearly demonstrate that ONO-1101 is an ultrashort-acting β-blocker, but the recovery time is dose dependent, and that the β-blocking action of ONO-1101 is almost similar to or slightly more potent (or both) than esmolol.

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