Citations

Abstract This international guideline proposes improving clozapine package inserts worldwide by using ancestry-based dosing and titration. Adverse drug reaction (ADR) databases suggest that clozapine is the third most toxic drug in the United States (US), and it produces four times higher worldwide pneumonia mortality than that by agranulocytosis or myocarditis. For trough steady-state clozapine serum concentrations, the therapeutic reference range is narrow, from 350 to 600 ng/mL with the potential for toxicity and ADRs as concentrations increase. Clozapine is mainly metabolized by CYP1A2 (female non-smokers, the lowest dose; male smokers, the highest dose). Poor metabolizer status through phenotypic conversion is associated with co-prescription of inhibitors (including oral contraceptives and valproate), obesity, or inflammation with C-reactive protein (CRP) elevations. The Asian population (Pakistan to Japan) or the Americas’ original inhabitants have lower CYP1A2 activity and require lower clozapine doses to reach concentrations of 350 ng/mL. In the US, daily doses of 300–600 mg/day are recommended. Slow personalized titration may prevent early ADRs (including syncope, myocarditis, and pneumonia). This guideline defines six personalized titration schedules for inpatients: 1) ancestry from Asia or the original people from the Americas with lower metabolism (obesity or valproate) needing minimum therapeutic dosages of 75–150 mg/day, 2) ancestry from Asia or the original people from the Americas with average metabolism needing 175–300 mg/day, 3) European/Western Asian ancestry with lower metabolism (obesity or valproate) needing 100–200 mg/day, 4) European/Western Asian ancestry with average metabolism needing 250–400 mg/day, 5) in the US with ancestries other than from Asia or the original people from the Americas with lower clozapine metabolism (obesity or valproate) needing 150–300 mg/day, and 6) in the US with ancestries other than from Asia or the original people from the Americas with average clozapine metabolism needing 300–600 mg/day. Baseline and weekly CRP monitoring for at least four weeks is required to identify any inflammation, including inflammation secondary to clozapine rapid titration.

The NCCN Guidelines for Breast Cancer include up-to-date guidelines for clinical management of patients with carcinoma in situ, invasive breast cancer, Paget disease, phyllodes tumor, inflammatory breast cancer, male breast cancer, and breast cancer during pregnancy. These guidelines are developed by a multidisciplinary panel of representatives from NCCN Member Institutions with breast cancer–focused expertise in the fields of medical oncology, surgical oncology, radiation oncology, pathology, reconstructive surgery, and patient advocacy. These NCCN Guidelines Insights focus on the most recent updates to recommendations for adjuvant systemic therapy in patients with nonmetastatic, early-stage, hormone receptor–positive, HER2-negative breast cancer.

INTRODUCTION: Functional luminal imaging probe (FLIP) panometry can evaluate esophageal motility in response to sustained esophageal distension at the time of sedated endoscopy. This study aimed to describe a classification of esophageal motility using FLIP panometry and evaluate it against high-resolution manometry (HRM) and Chicago Classification v4.0 (CCv4.0). METHODS: Five hundred thirty-nine adult patients who completed FLIP and HRM with a conclusive CCv4.0 diagnosis were included in the primary analysis. Thirty-five asymptomatic volunteers (“controls”) and 148 patients with an inconclusive CCv4.0 diagnosis or systemic sclerosis were also described. Esophagogastric junction (EGJ) opening and the contractile response (CR) to distension (i.e., secondary peristalsis) were evaluated with a 16-cm FLIP during sedated endoscopy and analyzed using a customized software program. HRM was classified according to CCv4.0. RESULTS: In the primary analysis, 156 patients (29%) had normal motility on FLIP panometry, defined by normal EGJ opening and a normal or borderline CR; 95% of these patients had normal motility or ineffective esophageal motility on HRM. Two hundred two patients (37%) had obstruction with weak CR, defined as reduced EGJ opening and absent CR or impaired/disordered CR, on FLIP panometry; 92% of these patients had a disorder of EGJ outflow per CCv4.0. DISCUSSION: Classifying esophageal motility in response to sustained distension with FLIP panometry parallels the swallow-associated motility evaluation provided with HRM and CCv4.0. Thus, FLIP panometry serves as a well-tolerated method that can complement, or in some cases be an alternative to HRM, for evaluating esophageal motility disorders.

Abstract Background The aim of the Subcutaneous ICD Combined with Ventricular Tachycardia Ablation (SICD-VTAbl) Study is to provide preliminary data on the safety and efficacy of a management strategy that incorporates S-ICD implantation and VT ablation among patients with a secondary prevention indication for an ICD. We hypothesize that VT ablation for the prevention of monomorphic VT recurrence combined with S-ICD implantation for termination of life-threatening VT/VF is safe, while reducing the need for device interventions and systemic complications associated with conventional transvenous ICD implantation for secondary prevention. Methods SICD-VTAbl is an uncontrolled, prospective, multinational observational study, conducted in France, Germany, US (Rochester NY, and Rochester MN) and coordinated in Israel. We aim to prospectively enroll 30 patients presenting with scar-related VT/VF who will undergo VT ablation/substrate modification followed by S-ICD implantation. The primary endpoint is the first occurrence of S-ICD therapy (appropriate and inappropriate). Secondary endpoints include separate occurrence of appropriate and inappropriate ICD therapies, peri-procedural complications, and adverse clinical outcomes. Results We provide clinical, arrhythmia, and outcome data on the first 15 patients enrolled in the SICD-VTAbl Study through February 2021. Mean age was 59±12 years, 78% were males, 60% had New York Heart Association (NYHA) Class ≥II symptoms, 20% had renal insufficiency, and 33% were treated with an antiarrhythmic medication (all amiodarone). Periprocedural, arrhythmia, and long-term outcome data are provided in Table 1. There were no major complications associated with the VT ablation and the S-ICD implantation procedures. During a median follow-up of 6 months (interquartile range: 2–12 months), 2 patients (13%) received S-ICD therapy: one patient (7%) experienced VF terminated by the S-ICD and one patient experienced a single episode of inappropriate S-ICD therapy. Adverse events during follow-up, unrelated to study procedures, occurred in 3 patients (20%): hospitalization for heart failure exacerbation (N=1) and non-cardiovascular hospitalizations (N=2). None of the patients died during follow-up (Table 1). Conclusions Our preliminary data from the SICD-VTAbl Study suggest that a management approach that incorporates VT ablation followed by S-ICD implantation is safe and may lead to improved arrhythmia and clinical outcomes in patients presenting with a secondary prevention indication for an ICD. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Research grant to Sheba Medical Center from Boston Scientific

Abstract The discipline of Cardio-Oncology has seen tremendous growth over the past decade. It is devoted to the cardiovascular (CV) care of the cancer patient, especially to the mitigation and management of CV complications or toxicities of cancer therapies, which can have profound implications on prognosis. To that effect, many studies have assessed CV toxicities in patients undergoing various types of cancer therapies; however, direct comparisons have proven difficult due to lack of uniformity in CV toxicity endpoints. Similarly, in clinical practice, there can be substantial differences in the understanding of what constitutes CV toxicity, which can lead to significant variation in patient management and outcomes. This document addresses these issues and provides consensus definitions for the most commonly reported CV toxicities, including cardiomyopathy/heart failure and myocarditis, vascular toxicity, and hypertension, as well as arrhythmias and QTc prolongation. The current document reflects a harmonizing review of the current landscape in CV toxicities and the definitions used to define these. This consensus effort aims to provide a structure for definitions of CV toxicity in the clinic and for future research. It will be important to link the definitions outlined herein to outcomes in clinical practice and CV endpoints in clinical trials. It should facilitate communication across various disciplines to improve clinical outcomes for cancer patients with CV diseases.

AbstractBackgroundDue to a substantial decline in pancreas transplantation (PT) across the United States over the past 15 years, we sought to understand the perceptions and practices of US PT programs.MethodsSurveys were sent to members of the American Society of Transplantation Surgeons and the American Society of Transplantation by email and professional society postings between August 2019 and November 2019.ResultsOne hundred twenty three responses were recorded from 56 unique programs. Program characteristics were obtained from the Scientific Registry of Transplant Recipients. Respondents were transplant surgeons (71%), transplant nephrologists (17%), trainees (9%), and allied professionals (3%). Programs were defined according to annual volume as: low (<5 PT/year), intermediate (6–20), or high (>20). High‐volume programs reported that these factors were most important for increased PT: expansion of recipient selection, more aggressive donor utilization, and hiring of PT program‐specific personnel. At both the program and national level, the vast majority (82% and 79%, respectively) felt the number of PTs currently performed are not in balance with patients' needs.ConclusionsOverall, programs reported that the option of PT is not offered adequately to diabetic patients and that strategies to maintain higher PT volume are most evident at intermediate, and especially, high‐volume programs.

Sex differences have been well identified in many brain tumors. Even though glioblastoma (GBM) is the most common primary malignant brain tumor in adults and has the worst outcome, well-established differences between men and women are limited to incidence and outcome. Little is known about sex differences in GBM at the disease phenotype and genetical/molecular level. This review focuses on a deep understanding of the pathophysiology of GBM, including hormones, metabolic pathways, the immune system, and molecular changes, along with differences between men and women and how these dimorphisms affect disease outcome. The information analyzed in this review shows a greater incidence and worse outcome in male patients with GBM compared with female patients. We highlight the protective role of estrogen and the upregulation of androgen receptors and testosterone having detrimental effects on GBM. Moreover, hormones and the immune system work in synergy to directly affect the GBM microenvironment. Genetic and molecular differences have also recently been identified. Specific genes and molecular pathways, either upregulated or downregulated depending on sex, could potentially directly dictate GBM outcome differences. It appears that sexual dimorphism in GBM affects patient outcome and requires an individualized approach to management considering the sex of the patient, especially in relation to differences at the molecular level.