Phase I Study of Paclitaxel by Three-hour Infusion: Hypotension Just after Infusion Is One of the Major Dose-limiting Toxicities

The primary objectives of this study were to determine the maximum tolerated dose (MTD) of paclitaxel administered by 3-h infusion to patients with solid tumors, and to characterize the pharmacokinetics of a 3-h infusion in comparison with those of a 24-h infusion. Twenty-seven patients each received one of six levels of paclitaxel, 105, 135, 180, 210, 240 and 270 mg/m², with premedication. Two patients given 240 mg/m² and one patient given 270 mg/m² unexpectedly had grade 3/4 hypotension just after finishing the paclitaxel infusion. Peripheral neuropathy was also dose-limiting at 270 mg/m². Although granulocytopenia was significantly less severe than with a 24-h infusion, more than half of the patients experienced grade 4 toxicity at doses of 240 or 270 mg/m². Severe hypersensitivity reactions (HSRs) were not observed. Pharmacokinetic studies using high performance liquid chromatography demonstrated proportionally greater increases in the peak plasma concentration and area under the curve, and decreases in clearance and volume of distribution with increasing dose, suggesting non-linear pharmacokinetics of paclitaxel when given by 3-h infusion. The MTD of paclitaxel given as a 3-h infusion was determined to be 240 mg/m² with dose-limiting toxicities of granulocytopenia, peripheral neuropathy and hypotension. Hypotension just after infusion, induced by 3-h infusion of paclitaxel, is a new observation which has not been reported previously. The recommended dose for phase II study is 210 mg/m². Although hypotension was observed as an unexpected toxic effect, paclitaxel could be administered safely over 3 h with premedication and proper monitoring, resulting in reduced myelotoxicity and with no increase in the incidence of HSRs as compared with a 24-h infusion.     

Advancing RAS/RASopathy therapies: An NCI‐sponsored intramural and extramural collaboration for the study of RASopathies

RASopathies caused by germline pathogenic variants in genes that encode RAS pathway proteins. These disorders include neurofibromatosis type 1 (NF1), Noonan syndrome (NS), cardiofaciocutaneous syndrome (CFC), and Costello syndrome (CS), and others. RASopathies are characterized by heterogenous manifestations, including congenital heart disease, failure to thrive, and increased risk of cancers. Previous work led by the NCI Pediatric Oncology Branch has altered the natural course of one of the key manifestations of the RASopathy NF1. Through the conduct of a longitudinal cohort study and early phase clinical trials, the MEK inhibitor selumetinib was identified as the first active therapy for the NF1‐related peripheral nerve sheath tumors called plexiform neurofibromas (PNs). As a result, selumetinib was granted breakthrough therapy designation by the FDA for the treatment of PN. Other RASopathy manifestations may also benefit from RAS targeted therapies. The overall goal of Advancing RAS/RASopathy Therapies (ART), a new NCI initiative, is to develop effective therapies and prevention strategies for the clinical manifestations of the non‐NF1 RASopathies and for tumors characterized by somatic RAS mutations. This report reflects discussions from a February 2019 initiation meeting for this project, which had broad international collaboration from basic and clinical researchers and patient advocates.     

Ectodermal dysplasias: Classification and organization by phenotype,genotype and molecular pathway

An international advisory group met at the National Institutes of Health in Bethesda, Maryland in 2017, to discuss a new classification system for the ectodermal dysplasias (EDs) that would integrate both clinical and molecular information. We propose the following, a working definition of the EDs building on previous classification systems and incorporating current approaches to diagnosis: EDs are genetic conditions affecting the development and/or homeostasis of two or more ectodermal derivatives, including hair, teeth, nails, and certain glands. Genetic variations in genes known to be associated with EDs that affect only one derivative of the ectoderm (attenuated phenotype) will be grouped as non‐syndromic traits of the causative gene (e.g., non‐syndromic hypodontia or missing teeth associated with pathogenic variants of EDA “ectodysplasin”). Information for categorization and cataloging includes the phenotypic features, Online Mendelian Inheritance in Man number, mode of inheritance, genetic alteration, major developmental pathways involved (e.g., EDA, WNT “wingless‐type,” TP63 “tumor protein p63”) or the components of complex molecular structures (e.g., connexins, keratins, cadherins).     

Accounting for Intergenerational Cascade Testing in Economic Evaluations of Clinical Genomics: A Scoping Review

ObjectivesClinical genomics is emerging as a diagnostic tool in the identification of blood relatives at risk of developing heritable diseases. Our objective was to identify how genetic cascade screening has been incorporated into health economic evaluations.MethodsA scoping review was conducted to identify how multiple generations of a family were included in economic evaluations of clinical genomic sequencing, how many and which relatives were included, and uptake rates. Databases were searched for full economic evaluations of genetic interventions that screened multiple generations of families and were in English language, and no restrictions were made for disease or publication type. Data were synthesized using a narrative approach.ResultsTwenty-five studies were included covering a range of diseases in various countries. Markov cohort models were mostly used with hypothetical populations and unsupported by clinical evidence. Cascade testing was either the primary intervention or secondary to the index cases. The number and type of relatives were based on assumptions or identified through population or family records, clinical registry data, or clinical literature. Studies included only immediate family members and the uptake of testing ranged between 20% and 100%. All interventions were reported as cost-effective, and a higher number of relatives was a key driver.ConclusionsSeveral economic evaluations have considered the impacts of cascade testing interventions within clinical genomics. Ideally, models supported with high-quality clinical data are needed and, in their absence, transparent and justifiable assumptions of uptake rates and choices about including relatives. Consideration of more appropriate modeling types is required.     

US Food and Drug Administration Analysis of Patient-Reported Diarrhea and Its Impact on Function and Quality of Life in Patients Receiving Treatment for Breast Cancer

ObjectivesMany trials conclude “no clinically meaningful detriment” to health-related quality of life (HRQL) or function between arms, even when notable differential toxicity is observed. Mean change from baseline analyses of function or HRQL can possibly obscure important change in subgroups experiencing symptomatic toxicity. We evaluate the impact of diarrhea, a key treatment arm toxicity, on patient-reported HRQL and functioning in clinical trials submitted to US Food and Drug Administration.MethodsThis study used 4 randomized, breast cancer trials (adjuvant to late-line metastatic) as case examples. Diarrhea, physical functioning (PF), and global health status and quality of life (GHS/QoL) from the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 were analyzed at baseline and approximately 3 and 6 months.ResultsGenerally, patients reporting very much diarrhea at months 3 and 6 had worse PF (9-19 points lower) and GHS/QoL (16-19 points lower) than patients reporting no diarrhea regardless of treatment arm. In the change from baseline analysis, patients reporting very much diarrhea also experienced a greater decrease in PF (6-13 points) and GHS/QoL (6-16 points) versus patients reporting no diarrhea in both arms.ConclusionsIn trials with moderate to large differences in symptomatic toxicity by arm, reporting “no meaningful difference in functioning and HRQL between arms” based on mean change from baseline analysis is insufficient and may obscure important impacts on subgroups experiencing symptomatic adverse events. Additional exploratory analyses with simple data visualizations evaluating functioning or HRQL in patient subgroups experiencing expected symptomatic toxicities can further inform the safety and tolerability of an investigational agent.     

基于住院病案首页数据的全国部分医院心血管临床专科评估探索

目的运用“基于住院病案首页数据的心血管临床专科评估框架”,对全国部分医院的心血管临床专科进行评估。方法梳理112所医院心血管专科重点疾病和重点手术操作的编码情况,计算评估框架中的各个指标,根据医院纳入标准,运用基于数据的多指标综合评价方法,对医院进行打分排序。结果112所医院2010—2012年心血管疾病患者出院人次、重点疾病和重点手术/操作缺失数量均呈偏态分布。按照综合评价医院的纳入标准共56所医院纳入排序,前十位是YN05、SD04、BJ14、SH02、ZJ01、HN01、SX09、YN08、SD01、SX08。重点疾病和重点手术操作均完整的医院共12所,其排序是:BJ14、SH02、HN02、BJ01、TJ01、SH05、SC01、NA03、GD02、SH08、YN03、HL01。本研究综合评价的56所医院中,有30所在国家公布的名单之内,26所不在国家公布的名单之内。结论运用“基于住院病案首页数据的心血管临床专科评估框架”进行心血管临床专科评估是科学、可行的,为专科评估方法提供了新的思路,为专科对口支援建设提供了数据支持。