Variation in Toxicity Reporting Methods for Early Phase Lung Cancer Treatment Trials at Oncology Conferences.

INTRODUCTION: Phase I and II trials provide the initial human safety and tolerability data for new drugs. Nevertheless, the methods for presenting toxicity data are not standardized. Clinicians often first encounter these data at professional conferences. We sought to characterize how the burden of adverse events (AEs) is reported at the largest professional conference in clinical oncology. METHODS: We collected toxicity data from all lung cancer-associated phase I and II trial presentations and posters at the American Society for Clinical Oncology annual meetings from 2017 to 2019. We captured the various AE features, including the minimum incidence used for reporting; whether AEs found were treatment emergent or treatment related, grouped by organ system or separated by individual descriptors; whether combined or separated across dose levels when a dose-escalation component was included; and whether dose-limiting toxicities, serious AE, dose-reduction rules, and denominators for laboratory tests were described. RESULTS: A total of 209 trials were analyzed. There was wide variability in toxicity reporting practices. Six different thresholds for reporting AEs of any grade were used. Treatment-related AEs were reported twice as frequently as treatment-emergent AEs. Toxicities were as likely to be reported across dose levels as by dose level. Terms such as dose-limiting toxicity and serious AE were rarely defined. Dose-reduction rules and denominators for laboratory tests were never defined. CONCLUSIONS: Standardization of methods for reporting toxicities could improve the quality and ease of comparability of data on adverse effects in early phase therapeutic trials. A minimal AE data disclosure template is proposed.

Congenital melanocytic nevi in young children: Histopathologic features and clinical outcomes.

BACKGROUND: Although only large congenital melanocytic nevi (CMN) are associated with a significantly high risk for malignant transformation, CMN of all sizes are prone to changes in clinical appearance in early childhood and thus are often biopsied or excised. While CMNs typically exhibit benign behavior, atypical histopathologic findings might be common and may prompt additional unnecessary procedures. OBJECTIVE: To assess the prevalence and associated clinical outcomes of atypical histopathologic features in CMN in children. METHODS: A single center retrospective study was conducted with patients 0-35 months of age with CMN diagnosed by histopathology between 1993-2013. RESULTS: One hundred seventy-nine patients with a total of 197 CMNs were identified. Cytologic atypia, architectural disorder, or pagetoid spread were present in 73% of CMN. With a mean follow up of 7.3 years, no cases of melanoma or CMN-related deaths were identified. LIMITATIONS: Our findings were based on a largely Caucasian population and might not apply to darker skin types. Our findings might not apply to older children or adults with CMN. CONCLUSION: Atypical histopathologic features of cytologic atypia, architectural disorder, and pagetoid spread are common in benign CMN of young children.

Characterization of the Risks of Adverse Outcomes Following Rubella Infection in Pregnancy.

Although most infections with the rubella virus result in relatively minor sequelae, rubella infection in early pregnancy may lead to severe adverse outcomes for the fetus. First recognized in 1941, congenital rubella syndrome (CRS) can manifest with a diverse range of symptoms, including congenital cataracts, glaucoma, and cardiac defects, as well as hearing and intellectual disability. The gestational age of the fetus at the time of the maternal rubella infection impacts the probability and severity of outcomes, with infection in early pregnancy increasing the risks of spontaneous termination (miscarriage), fetal death (stillbirth), birth defects, and reduced survival for live-born infants. Rubella vaccination continues to change the epidemiology of rubella and CRS globally, but no models currently exist to evaluate the economic benefits of rubella management. This systematic review provides an overall assessment of the weight of the evidence for the outcomes associated with rubella infections in the first 20 weeks of pregnancy. We identified, evaluated, and graded 31 studies (all from developed countries) that reported on the pregnancy outcomes of at least 30 maternal rubella infections. We used the available evidence to estimate the increased risks of spontaneous termination, fetal death, infant death, and CRS as a function of the timing of rubella infection in pregnancy and decisions about induced termination. These data support the characterization of the disability-adjusted life years for outcomes associated with rubella infection in pregnancy. We find significant impacts associated with maternal rubella infections in early pregnancy, which economic analyses will miss if they only focus on live births of CRS cases. Our estimates of fetal loss from increased induced terminations due to maternal rubella infections provide context that may help to explain the relatively low numbers of observed CRS cases per year despite potentially large burdens of disease. Our comprehensive review of the weight of the evidence of all pregnancy outcomes demonstrates the importance of including all outcomes in models that characterize rubella-related disease burdens and costs.

Systematic Review of the Manifestations of Congenital Rubella Syndrome in Infants and Characterization of Disability-Adjusted Life Years (DALYs).

Congenital rubella syndrome (CRS) continues to cause disability among unvaccinated populations in countries with no or insufficient rubella vaccine coverage to prevent transmission. We systematically reviewed the literature on birth outcomes associated with CRS to estimate the duration, severity, and frequency of combinations of morbidities. We searched PubMed, the Science Citation Index, and references from relevant articles for studies in English with primary data on the frequency of CRS manifestations for ≥20 cases and identified 65 studies representing 66 study populations that met our inclusion criteria. We abstracted available data on CRS cases with one or more hearing, heart, and/or eye defect following maternal rubella infection during the period of 0-20 weeks since the last menstrual period. We assessed the quality and weight of the available evidence using a modified Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Most of the evidence originates from studies in developed countries of cohorts of infants identified with CRS in the 1960s and 1970s, prior to the development of standardized definitions for CRS and widespread use of vaccine. We developed estimates of undiscounted disability-adjusted life years (DALYs) lost per CRS case for countries of different income levels. The estimates ranged from approximately 19 to 39 for high-income countries assuming optimal treatment and from approximately 29 to 39 DALYs lost per CRS case in low- and lower- middle-income countries assuming minimal treatment, with the lower bound based on 2010 general global burden of disease disability weights and the upper bound based on 1990 age-specific and treatment-specific global burden of disease disability weights. Policymakers and analysts should appreciate the significant burden of disability caused by CRS as they evaluate opportunities to manage rubella.