BRAF and MEK Inhibitors and Their Toxicities: A Meta-Analysis

Purpose: This meta-analysis summarizes the incidence of treatment-related adverse events (AE) of BRAFi and MEKi. Methods: A systematic search of Medline/PubMed was conducted to identify suitable articles published in English up to 31 December 2021. The primary outcomes were profiles for all-grade and grade 3 or higher treatment-related AEs, and the analysis of single side effects belonging to both categories. Results: The overall incidence of treatment-related all-grade Aes was 99% for Encorafenib (95% CI: 0.97–1.00) and 97% for Trametinib (95% CI: 0.92–0.99; I2 = 66%) and Binimetinib (95% CI: 0.94–0.99; I2 = 0%). In combined therapies, the rate was 98% for both Vemurafenib + Cobimetinib (95% CI: 0.96–0.99; I2 = 77%) and Encorafenib + Binimetinib (95% CI: 0.96–1.00). Grade 3 or higher adverse events were reported in 69% of cases for Binimetinib (95% CI: 0.50–0.84; I2 = 71%), 68% for Encorafenib (95% CI: 0.61–0.74), and 72% for Vemurafenib + Cobimetinib (95% CI: 0.65–0.79; I2 = 84%). The most common grade 1–2 AEs were pyrexia (43%) and fatigue (28%) for Dabrafenib + Trametinib and diarrhea for both Vemurafenib + Cobimetinib (52%) and Encorafenib + Binimetinib (34%). The most common AEs of grade 3 or higher were pyrexia, rash, and hypertension for Dabrafenib + Trametinib (6%), rash and hypertension for Encorafenib + Binimetinib (6%), and increased AST and ALT for Vemurafenib + Cobimetinib (10%). Conclusions: Our study provides comprehensive data on treatment-related adverse events of BRAFi and MEKi combination therapies, showing related toxicity profiles to offer a helpful tool for clinicians in the choice of therapy

CDK4/6 Inhibitors in Melanoma: A Comprehensive Review

Historically, metastatic melanoma was considered a highly lethal disease. However, recent advances in drug development have allowed a significative improvement in prognosis. In particular, BRAF/MEK inhibitors and anti-PD1 antibodies have completely revolutionized the management of this disease. Nonetheless, not all patients derive a benefit or a durable benefit from these therapies. To overtake this challenges, new clinically active compounds are being tested in the context of clinical trials. CDK4/6 inhibitors are drugs already available in clinical practice and preliminary evidence showed a promising activity also in melanoma. Herein we review the available literature to depict a comprehensive landscape about CDK4/6 inhibitors in melanoma. We present the molecular and genetic background that might justify the usage of these drugs, the preclinical evidence, the clinical available data, and the most promising ongoing clinical trials

Chronic exertional compartment syndrome of the forearm: a systematic review

The aim of this systematic review is to understand which surgical procedure provides better results in terms of pain relief and function in the treatment of chronic exertional compartment syndrome (CECS) of the forearm. We searched Medline (PubMed), Web of Science, Embase and Scopus databases on 8 July 2020. Twelve studies were included in this review. We assessed the quality of the studies using the Coleman Methodological Score. Data on demographic features, operative readings, diagnostic methods, follow-up periods, type and rates of complications, survivorship of the procedure, return to sport activity, and outcome measures were recorded. In conclusion, compared to the other techniques, endoscopic fasciotomy delivers similar success rates and lower incidence of complications

Enabling Technologies for Silicon Microstrip Tracking Detectors at the HL-LHC

While the tracking detectors of the ATLAS and CMS experiments have shown excellent performance in Run 1 of LHC data taking, and are expected to continue to do so during LHC operation at design luminosity, both experiments will have to exchange their tracking systems when the LHC is upgraded to the high-luminosity LHC (HL-LHC) around the year 2024. The new tracking systems need to operate in an environment in which both the hit densities and the radiation damage will be about an order of magnitude higher than today. In addition, the new trackers need to contribute to the first level trigger in order to maintain a high data-taking efficiency for the interesting processes. Novel detector technologies have to be developed to meet these very challenging goals. The German groups active in the upgrades of the ATLAS and CMS tracking systems have formed a collaborative "Project on Enabling Technologies for Silicon Microstrip Tracking Detectors at the HL-LHC" (PETTL), which was supported by the Helmholtz Alliance "Physics at the Terascale" during the years 2013 and 2014. The aim of the project was to share experience and to work together on key areas of mutual interest during the R&D phase of these upgrades. The project concentrated on five areas, namely exchange of experience, radiation hardness of silicon sensors, low mass system design, automated precision assembly procedures, and irradiations. This report summarizes the main achievements

Definition of High-Risk Early Hormone-Positive HER2 12Negative Breast Cancer: A Consensus Review

Breast cancer is one of the major causes of cancer-related morbidity and mortality in women worldwide. During the past three decades, several improvements in the adjuvant treatment of hormone receptor-positive/HER2 12negative breast cancer have been achieved with the introduction of optimized adjuvant chemotherapy and endocrine treatment. However, estimating the risk of relapse of breast cancer on an individual basis is still challenging. The IRIDE (hIGh Risk DEfinition in breast cancer) working group was established with the aim of reviewing evidence from the literature to synthesize the current relevant features that predict hormonepositive/HER2 12negative early breast cancer relapse. A panel of experts in breast cancer was involved in identifying clinical, pathological, morphological, and genetic factors. A RAND consensus method was used to define the relevance of each risk factor. Among the 21 features included, 12 were considered relevant risk factors for relapse. For each of these, we provided a consensus statement and relevant comments on the supporting scientific evidence. This work may guide clinicians in the practical management of hormone-positive/HER2 12negative early breast cancers

Pion and proton showers in the CALICE scintillator-steel analogue hadron calorimeter

Showers produced by positive hadrons in the highly granular CALICE scintillator-steel analogue hadron calorimeter were studied. The experimental data were collected at CERN and FNAL for single particles with initial momenta from 10 to 80 GeV/c. The calorimeter response and resolution and spatial characteristics of shower development for proton- and pion-induced showers for test beam data and simulations using Geant4 version 9.6 are compared.Comment: 26 pages, 16 figures, JINST style, changes in the author list, typos corrected, new section added, figures regrouped. Accepted for publication in JINS

Infrastructure for Detector Research and Development towards the International Linear Collider

The EUDET-project was launched to create an infrastructure for developing and testing new and advanced detector technologies to be used at a future linear collider. The aim was to make possible experimentation and analysis of data for institutes, which otherwise could not be realized due to lack of resources. The infrastructure comprised an analysis and software network, and instrumentation infrastructures for tracking detectors as well as for calorimetry.Comment: 54 pages, 48 picture