MGMT promoter methylation in 1p19q-intact gliomas.

OBJECTIVE: Standard-of-care for 1p19q-intact anaplastic gliomas is defined by the international randomized phase III CATNON trial, which found an overall survival (OS) benefit for adjuvant temozolomide (TMZ) when added to radiotherapy. Paradoxically, TMZ did not appear to benefit patients with IDH-wildtype gliomas, regardless of MGMT promoter status. The authors concluded that well-powered prospective study on the clinical efficacy of TMZ for patients with IDH-wildtype anaplastic gliomas (meeting criteria for glioblastoma) is warranted. Given that the prognostic and predictive role of MGMT status for grade 2-3 gliomas is unresolved, we determined the effect of MGMT status on OS in patients with 1p19q-intact gliomas in the National Cancer Database (NCDB). METHODS: We queried the NCDB from 2018 to 2019 for patients with diffuse (grade 2) and anaplastic (grade 3) IDH-wildtype or -mutant astrocytomas who received chemotherapy with follow-up through 2022. The Kaplan-Meier method and Cox proportional hazards regressions models were used to determine the association of MGMT with OS. RESULTS: We identified 1514 patients who were newly diagnosed with IDH-wildtype (n = 802, 33% methylated) or -mutant astrocytomas (n = 712, 48% methylated) and received chemotherapy during initial management. An unmethylated promoter was associated with poorer survival in patients with IDH-wildtype (3-year OS 34% [95%CI 29-39%] vs. 46% [95%CI 39-54%], p < .001, adjusted HR 1.53 [95%CI 1.24-1.89]) but not IDH-mutant astrocytomas (3-year OS 79% [95%CI 74-84%] vs. 80% [95%CI 75-86%], p =0 .81, HR 1.04 [95%CI 0.73-1.50]). CONCLUSIONS: This ancillary analysis supports conclusions from the CATNON trial for adjuvant TMZ as standard-of-care for anaplastic astrocytomas (IDH-mutant and 1p19q-intact), irrespective of MGMT status. Determining the optimal strategy for diffuse gliomas that are IDH-wildtype will be particularly important. MGMT promoter methylation should be considered as a stratification factor in future clinical trials for these patients.

The statistical significance revolution.

Statistical significance has long relied on the criterion of P less than or equal to .05. Although this threshold has generally functioned well, it has engendered some negative practices to circumvent it and been criticized as too inflexible. We concur with the statisticians and methodologists who are currently arguing for more flexibility to the P value and more reliance on the 95% confidence interval, a shift that is likely to change future practice in data analysis and interpretation for oncology.

Site-specific patterns of early-stage cancer diagnosis during the COVID-19 pandemic.

The COVID-19 pandemic caused widespread disruptions in cancer care. We hypothesized that the greatest disruptions in diagnosis occurred in screen-detected cancers. We identified patients (≥18 years of age) with newly diagnosed cancer from 2019 to 2020 in the US National Cancer Database and calculated the change in proportion of early-stage to late-stage cancers using a weighted linear regression. Disruptions in early-stage diagnosis were greater than in late-stage diagnosis (17% vs 12.5%). Melanoma demonstrated the greatest relative decrease in early-stage vs late-stage diagnosis (22.9% vs 9.2%), whereas the decrease was similar for pancreatic cancer. Compared with breast cancer, cervical, melanoma, prostate, colorectal, and lung cancers showed the greatest disruptions in early-stage diagnosis. Uninsured patients experienced greater disruptions than privately insured patients. Disruptions in cancer diagnosis in 2020 had a larger impact on early-stage disease, particularly screen-detected cancers. Our study supports emerging evidence that primary care visits may play a critical role in early melanoma detection.

Use of Recommended Neurodiagnostic Evaluation Among Patients With Drug-Resistant Epilepsy.

Importance: Interdisciplinary practice parameters recommend that patients with drug-resistant epilepsy (DRE) undergo comprehensive neurodiagnostic evaluation, including presurgical assessment. Reporting from specialized centers suggests long delays to referral and underuse of surgery; however, longitudinal data are limited to characterize neurodiagnostic evaluation among patients with DRE in more diverse US settings and populations. Objective: To examine the rate and factors associated with neurodiagnostic studies and comprehensive evaluation among patients with DRE within 3 US cohorts. Design, Setting, and Participants: A retrospective cross-sectional study was conducted using the Observational Medical Outcomes Partnership Common Data Model including US multistate Medicaid data, commercial claims data, and Columbia University Medical Center (CUMC) electronic health record data. Patients meeting a validated computable phenotype algorithm for DRE between January 1, 2015, and April 1, 2020, were included. No eligible participants were excluded. Exposure: Demographic and clinical variables were queried. Main Outcomes and Measures: The proportion of patients receiving a composite proxy for comprehensive neurodiagnostic evaluation, including (1) magnetic resonance or other advanced brain imaging, (2) video electroencephalography, and (3) neuropsychological evaluation within 2 years of meeting the inclusion criteria. Results: A total of 33 542 patients with DRE were included in the Medicaid cohort, 22 496 in the commercial insurance cohort, and 2741 in the CUMC database. A total of 31 516 patients (53.6%) were women. The proportion of patients meeting the comprehensive evaluation main outcome in the Medicaid cohort was 4.5% (n = 1520); in the commercial insurance cohort, 8.0% (n = 1796); and in the CUMC cohort, 14.3% (n = 393). Video electroencephalography (24.9% Medicaid, 28.4% commercial, 63.2% CUMC) and magnetic resonance imaging of the brain (35.6% Medicaid, 43.4% commercial, 52.6% CUMC) were performed more regularly than neuropsychological evaluation (13.0% Medicaid, 16.6% commercial, 19.2% CUMC) or advanced imaging (3.2% Medicaid, 5.4% commercial, 13.1% CUMC). Factors independently associated with greater odds of evaluation across all 3 data sets included the number of inpatient and outpatient nonemergency epilepsy visits and focal rather than generalized epilepsy. Conclusions and Relevance: The findings of this study suggest there is a gap in the use of diagnostic studies to evaluate patients with DRE. Care setting, insurance type, frequency of nonemergency visits, and epilepsy type are all associated with evaluation. A common data model can be used to measure adherence with best practices across a variety of observational data sources.

Biochemical progression free and overall survival among Black men with stage IV prostate cancer in South Africa: Results from a prospective cohort study.

BACKGROUND: Men of African descent are disproportionately affected by prostate cancer (PCa), and many have metastatic disease at presentation. In South Africa (SA), androgen deprivation therapy (ADT) is the first-line treatment for stage IV PCa. OBJECTIVE: To identify predictors of overall survival (OS) in Black South African men with stage IV PCa treated with ADT. DESIGN, SETTING, AND PARTICIPANTS: Men diagnosed with prostate cancer (3/22/2016-10/30/2020) at Chris Hani Baragwanath Academic Hospital in Soweto, Johannesburg, were recruited for the Men of African Descent with Cancer of the Prostate study. We included men with newly diagnosed stage IV PCa treated with ADT who had a prostate-specific antigen (PSA) level drawn prior to initiation of ADT and had ≥1 PSA drawn ≥12 weeks after ADT start. OUTCOMES MEASURES AND STATISTICAL ANALYSIS: We used Kaplan-Meier statistics to estimate OS and Cox regression models to identify predictors of OS. RESULTS AND LIMITATIONS: Of the 1097 men diagnosed with prostate cancer, we included 153 men with stage IV PCa who received ADT and met PSA requirements. The median age was 68.0 years (interquartile range 64-73 years). Median OS from time of ADT initiation was 3.39 years (95% confidence interval (CI): 3.14%-noncalculable), while biochemical progression-free survival was 2.36 years (95% CI: 2.03%-3.73%). Biochemical progression (HR 3.52, 95% CI: 1.85%-6.70%), PSA nadir level >4 ng/mL (HR 3.77, 95% CI: 1.86%-7.62%), alkaline phosphatase level at diagnosis >150 IU/dL (HR 3.09, 95% CI: 1.64%-5.83%), and hemoglobin at diagnosis <13.5 g/dL (HR 2.90, 95% CI: 1.28%-6.56%) were associated with worse OS. CONCLUSIONS: In this study, we identified factors associated with poor OS among Black South African men with stage IV PCa treated with ADT. These factors may be useful in identifying patients for upfront treatment escalation, including the use of docetaxel chemotherapy or escalation of therapy at the time of biochemical progression. PATIENT SUMMARY: In this study, we found that high alkaline phosphatase level, anemia at diagnosis, and high PSA nadir after initiation of androgen deprivation therapy are associated with worse overall survival among Black South African men treated with androgen deprivation therapy for metastatic prostate cancer.

Systematic under-ascertainment of anaplastic large cell lymphoma cases in cancer registries: report from a comprehensive cancer center.

INTRODUCTION: Breast implant-associated anaplastic large cell lymphoma (ALCL) has been rapidly rising in the US and around the world, leading to a mandated "black-box" label on all silicone- and saline-filled implants by the Food and Drug Administration (FDA). Because regulatory decisions in the US and around the world have been influenced primarily by risk estimates derived from cancer registries, it is important to determine their validity in identifying cases of ALCL. METHOD: We reviewed all cases of ALCL submitted to the New York State Cancer Registry from a large comprehensive cancer center in New York City from 2007 to 2019. To determine the possibility of misdiagnosis or under-diagnosis of ALCL cases reported to cancer registries, we accessed the sensitivity and specificity of the ICD-O-3 codes 9714 (ALCL) and 9702 (Mature T-cell lymphoma, not otherwise specified [T-NOS]) to identify pathologically-proven ALCL. RESULTS: We reviewed 2286,164 pathology reports from 47,466 unique patients with primary cancers. Twenty-eight cases of histologically-proven ALCL were identified. The sensitivity and specificity of the ICD-O-3 code 9714 (ALCL) were 82% and 100%, respectively. The sensitivity of the combined codes 9714/9702 (ALCL/T-NOS) was 96% and the specificity was 44%. CONCLUSION: Previous epidemiological studies that influenced regulatory decisions by the FDA may have systematically underestimated the risk of ALCL by at least 20%. We encourage updated global risk estimates of breast ALCL using methods that ensure adequate case ascertainment.

The IDH paradox: Meta-analysis of alkylating chemotherapy in IDH-wildtype and -mutant lower grade gliomas.

BACKGROUND: IDH-wildtype (-wt) status is a pre-requisite for the diagnosis of glioblastoma (GBM); however, IDH-wt gliomas with low grade or anaplastic morphology have historically been excluded from GBM trials and may represent a distinct prognostic entity. While alkylating agent chemotherapy improves overall survival (OS) and progression-free survival (PFS) for IDH-wt GBM and also IDH-mutant gliomas, irrespective of grade, the benefit for IDH-wt diffuse histologic lower grade gliomas is unclear. METHODS: We performed a meta-analysis of randomized clinical trials for World Health Organization (WHO) grade 2-3 gliomas (2009 to present) to determine the effect of alkylating chemotherapy on IDH-wt and -mutant gliomas using a random-effects model with inverse-variance pooling. RESULTS: We identified six trials with 1,204 patients (430 IDH-wt, 774 IDH-mutant) that evaluated alkylating chemoradiotherapy versus radiotherapy alone, allowing us to perform an analysis focused on the value of adding alkylating chemotherapy to radiotherapy. For patients with IDH-wt tumors, alkylating chemotherapy added to radiotherapy was associated with improved PFS (HR:0.77 [95%CI 0.62-0.97], P=.03) but not OS (HR:0.87 [95%CI 0.64-1.18], P=.17). For patients with IDH-mutant tumors, alkylating chemotherapy added to radiotherapy improved both OS (HR:0.52 [95%CI 0.42-0.64], P<.001) and PFS (HR=0.47 [95%CI 0.39-0.57], P<.001) compared to radiotherapy alone. The magnitude of benefit was similar for IDH-mutant gliomas with or without 1p19q-codeletion. CONCLUSIONS: Alkylating chemotherapy reduces mortality by 48% and progression by 53% for patients with IDH-mutant gliomas. Optimal management of IDH-wt diffuse histologic lower grade gliomas remains to be determined, as there is little evidence supporting an OS benefit from alkylating chemotherapy.

Prevalence of monoclonal gammopathy of undetermined significance in Eswatini: a population-based study in Africa.

BACKGROUND: Although monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma disproportionately affect Black individuals, few epidemiological studies have been conducted on these plasma cell disorders in Africa. Here we describe the prevalence of MGUS in Eswatini and compare our results to the landmark Olmsted County, Minnesota study. METHODS: Between 2016 and 2017, 13 339 residents of Eswatini participated in the Swaziland HIV Incidence Measurement Survey, from which a nationally representative biorepository was created. Plasma samples were then randomly selected and analyzed for MGUS. MGUS prevalence in Eswatini was compared with that of Olmsted County. In addition, demographic and HIV-related associations with MGUS were assessed. RESULTS: Of the 515 samples randomly selected, the median age was 50 years (range = 35-80 years); 60% were female; and 38.6% were HIV positive, of whom 82.4% were on antiretroviral therapy. We found that 68 participants had evidence of MGUS, for a prevalence of 13.2%. HIV status was not significantly associated with MGUS (odds ratio = 1.05, 95% confidence interval = 0.62 to 1.77), but among HIV-positive individuals, MGUS was less frequent for patients on antiretroviral therapy (adjusted odds ratio = 0.31, 95% confidence interval = 0.11 to 0.82). The prevalence of conventional MGUS was similar between Eswatini and Olmsted County (3.4% vs 3.2%-3.4%), whereas the incidence of light-chain MGUS was significantly greater in Eswatini (12.3% vs 0.8%). CONCLUSION: Our study suggests that the incidence of MGUS is similar between ethnicities and raises the question of whether the current definition of light-chain MGUS reliably reflects a true monoclonal protein precursor state. Perhaps the current definition of light-chain MGUS may be capturing alternate etiologies, such as untreated HIV infection.

Cancer genetic mutation prevalence in sub-Saharan Africa: A review of existing data.

BACKGROUND: Cancer represents a leading cause of death worldwide. Germline mutations in several genes increase the risk of developing several cancers, including cancers of the breast, ovary, pancreas, colorectum, and melanoma. An understanding of the population prevalence of pathogenic germline variants can be helpful in the design of public health interventions, such as genetic testing, which has downstream implications for cancer screening, prevention, and treatment. While population-based studies of pathogenic germline variants exist, most such studies have been conducted in White populations. Limited data exist regarding the prevalence of germline mutations within sub-Saharan African populations. MATERIALS AND METHODS: We identified countries defined as sub-Saharan Africa by the World Bank and conducted a scoping literature review using PubMed. For each country, we identified and summarized studies that focused on the prevalence of germline genetic mutations with sample sizes >10 and in a population directly from sub-Saharan Africa, either with or without diseases associated with the relevant genetic mutations. Studies that evaluated the prevalence of somatic or likely benign variants were excluded. RESULTS: Within the 48 countries in sub-Saharan Africa, we identified 34 studies which meet the inclusion criteria. Twenty studies were conducted in South Africa, Nigeria, or Burkina Faso; four countries had more than two published papers. We found that 33 of 48 countries in sub-Saharan Africa lacked any genetic studies. Notably, there has been an increase in relevant studies starting in 2020. Importantly, of the 34 studies identified, 29 included data on BRCA1 or BRCA2. Data on the prevalence of mutations contributing to familial cancer syndromes other than BRCA1 and BRCA2 was limited. CONCLUSIONS: While some progress has been made towards understanding the prevalence of germline mutations in cancer susceptibility genes, the characterization of genetic mutations among sub-Saharan African populations remains strikingly incomplete. Given the genetic diversity in the region, there remains a great need for large-scale, population-based studies to understand the prevalence of germline pathogenic variants and adequately capture all the subpopulations in this part of the world.