Risk of serious adverse events and fatal adverse events with sorafenib in patients with solid cancer: a meta-analysis of phase 3 randomized controlled trials†.

Background: Sorafenib is a multikinase-tyrosine kinase inhibitor commonly used in a variety of cancers. There are concerns about the increased risk of serious adverse events (SAEs) and fatal adverse events (FAEs) with sorafenib. We performed an up-to-date meta-analysis of all phase 3 randomized controlled trials (RCTs) of sorafenib to quantify the increased risk of SAEs and FAEs. Patients and methods: We carried out a systematic search of electronic databases for studies published from inception to February 2016 without any restrictions. Eligibility criteria included phase 3 RCTs of solid tumors comparing sorafenib, alone or in combination with nontargeted chemotherapy (Sorafenib arm) versus placebo or nontargeted chemotherapy (control arm). Data on SAEs and FAEs for both the arms were extracted from each study and pooled to determine the overall incidence, relative risks (RRs) and 95% Confidence Intervals (CIs). Results: Of 471 studies identified, a total of 12 phase 3 RCTs involving 6797 solid cancer patients comparing sorafenib with control met the eligibility criteria and were included. The overall incidence of SAEs and FAEs with sorafenib were 26.4% (95% CI, 18.0-36.9%) and 1.3% (95% CI: 0.8-2.2%), respectively. Compared with control, sorafenib use significantly increased the risk of both SAEs (RR: 1.49, 95% CI: 1.18-1.89, P = 0.001) and FAEs (RR: 1.82, 95% CI: 1.05-3.14, P = 0.033). This association varied significantly with cancer types (P < 0.001) and approval status (P = 0.012) for SAEs but no evidence of heterogeneity was found for FAEs. Conclusions: This meta-analysis of phase 3 RCTs demonstrates an increased risk of both SAEs and FAEs with sorafenib use in adult patients with solid cancers. This quantification of increased risks of SAEs and FAEs will be important in considering the trade-off of sorafenib treatment during shared decision-making.

A phase I study of binimetinib (MEK162) in Japanese patients with advanced solid tumors.

PURPOSE: Binimetinib is a potent, selective MEK1/2 inhibitor with demonstrated efficacy against BRAF- and RAS-mutant tumors. Retinal adverse events associated with MEK inhibitors have been reported in some cases. The aim of this study was to assess single-agent binimetinib, with detailed ophthalmologic monitoring, in Japanese patients with advanced solid tumors. METHODS: This was an open-label phase I dose-escalation and dose-expansion study (NCT01469130). Adult patients with histologically confirmed, evaluable, advanced solid tumors were enrolled and treated with binimetinib 30 or 45 mg twice daily (BID). The primary objective was to determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) of single-agent binimetinib in Japanese patients. RESULTS: Twenty-one patients were enrolled; 3 and 8 patients had documented BRAF and KRAS mutations, respectively. Two of 6 patients (33 %) receiving binimetinib 45 mg BID in dose-escalation experienced recurrent grade 2 retinal adverse events (AEs) which were reversible, and this dose was declared the MTD and RP2D. All patients experienced ≥1 AE suspected to be treatment related; the most common (>50 %) were blood creatine phosphokinase increase (76 %), retinal detachment and aspartate aminotransferase increase (62 % each), and diarrhea (52 %). There were no complete or partial responses; 14 patients (67 %) had stable disease, which lasted >180 days in 5 patients. Expression of phospho-ERK decreased in the skin following binimetinib treatment at both dose levels, indicating target inhibition. CONCLUSIONS: Binimetinib demonstrated efficacy and acceptable safety in Japanese patients with solid tumors, supporting the 45 mg BID dose of binimetinib as the RP2D.

Novel thin bronchoscope with a 1.7-mm working channel for peripheral pulmonary lesions.

In the present study, the authors evaluated the diagnostic utility of a novel thin bronchoscope with a 1.7-mm working channel for peripheral pulmonary lesions. A total of 118 patients were included in this prospective study. Bronchoscopic examination was performed using a 5.9-mm standard bronchoscope. If no visible endobronchial lesion was found, transbronchial biopsies were performed with 1.5-mm biopsy forceps under fluoroscopic guidance and the bronchus were washed with 10-20 mL of saline solution, using a prototype 3.5-mm thin bronchoscope with a 1.7-mm working channel. Endobronchial lesion was visualised with the standard bronchoscope in 16 patients, and the other 102 patients underwent biopsies with the thin bronchoscope. The mean bronchus levels reached with the standard bronchoscope and the thin bronchoscope were 2.3 and 4.3 generations, respectively. Endobronchial abnormality was revealed with the thin bronchoscope in a further 14 patients. Diagnostic material was obtained in 50 of 68 (74%) patients with malignant disease and 18 of 30 (60%) patients with benign disease. Four patients did not return to follow-up. The diagnostic yield was 57%, even in lesions <20 mm. There were no major complications. In conclusion, bronchoscopy using a 3.5-mm thin bronchoscope with a 1.7-mm working channel is useful and safe for the diagnosis of peripheral pulmonary lesions.

Murine model of IgE production with a predominant Th2-response by feeding protein antigen without adjuvants.

Stimulation of systemic antigen-specific IgE production plays an important role in the mediation of food allergy; however, the mechanism of IgE production against food antigens is not fully understood. The development of relevant animal models may help to elucidate the pathogenesis of food allergy. We here show that DBA/2 mice receiving a casein diet without any adjuvant produced high levels of IgE specific for casein, accompanied by predominant Th2-like responses in liver lymphocytes, mesenteric lymph node cells and spleen cells. This model of IgE production produced by feeding protein antigen as a constituent of the diet can be applied to investigate the mechanism of IgE production and to develop reagents for controlling food allergy.

[Assessment of interaction between the left and right ventricles using pressure-volume loops in various heart diseases].

To assess the interaction and interdependence of left and right ventricular function, ECG-gated radionuclide angiocardiography was performed immediately after cardiac catheterization during right atrial pacing for 11 patients with old myocardial infarction (MI), two with non-obstructive hypertrophic cardiomyopathy, one with aortic stenosis (AS), two with pulmonary infarction (PI), and one with neurocirculatory asthenia (NCA). Absolute left ventricular (LV) volume curves were obtained by the count-based method with attenuation factor corrections. Biventricular pressure and volume curves were digitized and synchronized to end-diastole, and pressure-volume (P-V) loops were constructed throughout a cardiac cycle. The stroke work index (SWI), the work index per min (WI/M) and the contractility index (CNTI) were calculated from the P-V loops. In a patient with NCA, LV end-diastolic volume decreased during rapid pacing, but no significant change in the LV end-systolic P-V relation was recognized. However, the entire right ventricular (RV) P-V loop was shifted toward the left during rapid pacing. In a patient with AS, the LV P-V loop was markedly enlarged and every parameter of LV function was much greater than that of the right ventricle due to increased LV afterload. The areas of RV P-V loops in two patients with PI were larger than those of other patients, because RV pressure was relatively high, and RV volume was increased. It is suggested that RV pressure and volume overloads prevail in patients with PI. In four MI patients with three vessel disease and having collateral circulation, the LV end-systolic P-V relationship was shifted toward the lower right, and every parameter (SWI, WI/M, CNTI) of LV function decreased by rapid pacing. Myocardial ischemia may be induced by rapid pacing stress, causing decreased LV contractility. It was concluded that the P-V loops obtained by RNA and catheterization are clinically useful for estimating the interaction and interdependence between right and left ventricular hemodynamics.