Prevalence of lung cysts in adolescents and adults with a germline DICER1 pathogenic/likely pathogenic variant: a report from the National Institutes of Health and International Pleuropulmonary Blastoma/DICER1 Registry.

BACKGROUND: Pleuropulmonary blastoma (PPB), the hallmark tumour associated with DICER1-related tumour predisposition, is characterised by an age-related progression from a cystic lesion (type I) to a high-grade sarcoma with mixed cystic and solid features (type II) or purely solid lesion (type III). Not all cystic PPBs progress; type Ir (regressed), hypothesised to represent regressed or non-progressed type I PPB, is an air-filled, cystic lesion lacking a primitive sarcomatous component. This study aims to evaluate the prevalence of non-progressed lung cysts detected by CT scan in adolescents and adults with germline DICER1 pathogenic/likely pathogenic (P/LP) variants. METHODS: Individuals were enrolled in the National Cancer Institute Natural History of DICER1 Syndrome study, the International PPB/DICER1 Registry and/or the International Ovarian and Testicular Stromal Tumor Registry. Individuals with a germline DICER1 P/LP variant with first chest CT at 12 years of age or older were selected for this analysis. RESULTS: In the combined databases, 110 individuals with a germline DICER1 P/LP variant who underwent first chest CT at or after the age of 12 were identified. Cystic lung lesions were identified in 38% (42/110) with a total of 72 cystic lesions detected. No demographic differences were noted between those with lung cysts and those without lung cysts. Five cysts were resected with four centrally reviewed as type Ir PPB. CONCLUSION: Lung cysts are common in adolescents and adults with germline DICER1 variation. Further study is needed to understand the mechanism of non-progression or regression of lung cysts in childhood to guide judicious intervention.

Survival Modelling For Data From Combined Cohorts: Opening the Door to Meta Survival Analyses and Survival Analysis using Electronic Health Records.

Non-parametric estimation of the survival function using observed failure time data depends on the underlying data generating mechanism, including the ways in which the data may be censored and/or truncated. For data arising from a single source or collected from a single cohort, a wide range of estimators have been proposed and compared in the literature. Often, however, it may be possible, and indeed advantageous, to combine and then analyze survival data that have been collected under different study designs. We review non-parametric survival analysis for data obtained by combining the most common types of cohort. We have two main goals: (i) To clarify the differences in the model assumptions, and (ii) to provide a single lens through which some of the proposed estimators may be viewed. Our discussion is relevant to the meta analysis of survival data obtained from different types of study, and to the modern era of electronic health records.

Enrollment of adolescent and young adult patients newly diagnosed with cancer in NCI CTEP-sponsored clinical trials before and after launch of the NCI National Clinical Trials Network.

BACKGROUND: Participation of adolescents and young adults (AYAs) in oncology clinical trials is important to ensure adequate opportunities for AYA patients to contribute to, and benefit from, advances in cancer treatment. METHODS: Accrual data for National Cancer Institute (NCI) Cancer Therapy Evaluation Program (CTEP) cooperative group-led treatment trials were examined to assess enrollment of newly diagnosed AYA patients (15-39 years) during the period 2004-2019, with particular interest in comparing enrollment before launch of the NCI National Clinical Trials Network (NCTN) to after. All phase 2, 2/3, and 3 trials activated during the period between January 1, 2004, and December 31, 2019, were identified (n = 1568) and reduced to a set of 304 that met predetermined criteria to focus on cooperative group-led trials that involved therapy for newly diagnosed cancer and had age eligibility overlapping the AYA range. The proportion of AYA patients relative to total accrual, along with 95% bootstrapped CI was calculated for patients enrolled pre-NCTN and post-NCTN. RESULTS: AYA accrual comprised 9.5% (95% CI, 7.6-11.8) pre-NCTN compared with 14.0% (95% CI, 9.9-18.3) post-NCTN. The mean difference in proportions post-NCTN compared with pre-NCTN was 4.4% (0.7%-8.3%). CONCLUSIONS: These results indicate an increase in AYA participation in trials conducted within the NCTN relative to the pre-NCTN period. This suggests an awareness and utilization of NCTN trials for AYAs with cancer.

Cancer incidence, patterns, and genotype-phenotype associations in individuals with pathogenic or likely pathogenic germline TP53 variants: an observational cohort study.

BACKGROUND: Li-Fraumeni syndrome, caused primarily by pathogenic or likely pathogenic germline TP53 variants, is a rare, variably penetrant, cancer predisposition syndrome with very high risks of cancer starting in childhood, including the risk of multiple primary malignancies over an individual's lifespan. We aimed to characterise and quantify cancer incidence, patterns, and genotype-phenotype associations in individuals with pathogenic or likely pathogenic germline TP53 variants. METHODS: This observational cohort study was done in 480 carriers of pathogenic or likely pathogenic germline TP53 variants enrolled in the National Cancer Institute's referral-based longitudinal Li-Fraumeni syndrome study between Aug 1, 2011, and March 24, 2020. Data on personal and family history of cancer were obtained through study questionnaires and validated by medical records. Variants were categorised on the basis of both loss-of-function (LOF) and dominant-negative effect (DNE) properties. Cancer incidence associated with Li-Fraumeni syndrome was compared with that of the general population using the Surveillance, Epidemiology, and End Results (SEER) 1975-2017 registry. Cancer incidence was evaluated with family-clustered Cox regression models and competing risk methods. This study is registered with ClinicalTrials.gov, NCT01443468. FINDINGS: Individuals with Li-Fraumeni syndrome had a nearly 24 times higher incidence of any cancer than the general population (standardised incidence ratio 23·9; 95% CI 21·9-26·0), with the highest comparative incidence from childhood to 30 years of age. The overall cancer incidence remained 10·3 (95% CI 7·9-13·2) times higher than that of the general population after age 50 years. In women, when considering breast cancer as a competing risk, the probability of a first diagnosis of a non-breast cancer malignancy was substantially lower than that of any first cancer (24·4% [95% CI 19·6-30·5] vs 50·4% [43·5-56·5] by age 33·7 years). Overall, DNE_LOF and notDNE_LOF variants were associated with earlier age at first and second cancer compared with notDNE_notLOF and DNE_notLOF variants. The time interval from first to second cancer was shorter among carriers whose first cancer diagnoses were later in life. Multiple cancers were diagnosed within a short timeframe in some individuals, regardless of the order of cancer occurrence. INTERPRETATION: This study adds granularity to the understanding of cancer incidence and patterns in individuals with pathogenic or likely pathogenic germline TP53 variants. Integration of age range-specific cancer incidence estimates, cancer-free survival by functional variant group, the potential impact of risk-reducing mastectomy on female cancer incidence, and data on subsequent malignancies will be important for the development of strategies to optimise cancer screening and management for these individuals. FUNDING: Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Institutes of Health.

Frequency of heterozygous germline pathogenic variants in genes for Fanconi anemia in patients with non-BRCA1/BRCA2 breast cancer: a meta-analysis.

PURPOSE: Germline pathogenic variants in BRCA1 (FANCD1) and BRCA2 (FANCS) do not explain all familial or sporadic cases with breast cancer. Several reports indicate a role for pathogenic variants in other genes in the Fanconi anemia/breast cancer DNA repair pathway; the strengths of these associations vary widely. Publications from 2006 through 2017 were reviewed to provide a better estimate of the role of pathogenic variants in genes in this pathway in breast cancer. METHODS: We identified cohorts and case-control reports describing heterozygous pathogenic variants in Fanconi anemia genes in breast cancer cases with high risk of a germline pathogenic variant in a non-BRCA1/2 breast cancer susceptibility gene ("familial"), and cases unselected for family history ("unselected"). Meta-analysis and meta-regression were used to estimate the frequencies of pathogenic variants in cohorts and the odds ratios (OR) in case-control studies. RESULTS: Meta-analysis of more than 100 reports of FANCN/PALB2 in familial breast cancer cases provided an overall pathogenic variant prevalence of 1.29% and an OR of 8.45. The prevalence in unselected cohorts was 0.64%, and the OR was 4.76. Pathogenic variants in FANCJ/BRIP1 had a prevalence of 0.5% in familial cases, and an OR of 1.62; their prevalence in unselected cases was 0.39%. FANCO/RAD51C, FANCP/SLX4, FANCU/XRCC2, FANCD2, and other FA-related genes all had prevalences of ≤ 0.5% among familial cases, and even lower in unselected cases. CONCLUSIONS: Heterozygous pathogenic variants in FANCN/PALB2 and possibly FANCJ/BRIP1 may account for 1-2% of familial non-BRCA1/2 breast cancer cases and 0.5-1% of unselected cases. Genetic counseling and testing may be suggested for unaffected relatives.

Correction to: Frequency of heterozygous germline pathogenic variants in genes for Fanconi anemia in patients with non-BRCA1/BRCA2 breast cancer: a meta-analysis.

In the original publication of the article, the first sentence in the abstract was published incorrectly.

Trends in premature mortality in the USA by sex, race, and ethnicity from 1999 to 2014: an analysis of death certificate data.

BACKGROUND: Reduction of premature mortality is a UN Sustainable Development Goal. Unlike other high-income countries, age-adjusted mortality in the USA plateaued in 2010 and increased slightly in 2015, possibly because of rising premature mortality. We aimed to analyse trends in mortality in the USA between 1999 and 2014 in people aged 25-64 years by age group, sex, and race and ethnicity, and to identify specific causes of death underlying the temporal trends. METHODS: For this analysis, we used cause-of-death and demographic data from death certificates from the US National Center for Health Statistics, and population estimates from the US Census Bureau. We estimated annual percentage changes in mortality using age-period-cohort models. Age-standardised excess deaths were estimated for 2000 to 2014 as observed deaths minus expected deaths (estimated from 1999 mortality rates). FINDINGS: Between 1999 and 2014, premature mortality increased in white individuals and in American Indians and Alaska Natives. Increases were highest in women and those aged 25-30 years. Among 30-year-olds, annual mortality increases were 2·3% (95% CI 2·1-2·4) for white women, 0·6% (0·5-0·7) for white men, and 4·3% (3·5-5·0) and 1·9% (1·3-2·5), respectively, for American Indian and Alaska Native women and men. These increases were mainly attributable to accidental deaths (primarily drug poisonings), chronic liver disease and cirrhosis, and suicide. Among individuals aged 25-49 years, an estimated 111 000 excess premature deaths occurred in white individuals and 6600 in American Indians and Alaska Natives during 2000-14. By contrast, premature mortality decreased substantially across all age groups in Hispanic individuals (up to 3·2% per year), black individuals (up to 3·9% per year), and Asians and Pacific Islanders (up to 2·6% per year), mainly because of declines in HIV, cancer, and heart disease deaths, resulting in an estimated 112 000 fewer deaths in Hispanic individuals, 311 000 fewer deaths in black individuals, and 34 000 fewer deaths in Asians and Pacific Islanders aged 25-64 years. During 2011-14, American Indians and Alaska Natives had the highest premature mortality, followed by black individuals. INTERPRETATION: Important public health successes, including HIV treatment and smoking cessation, have contributed to declining premature mortality in Hispanic individuals, black individuals, and Asians and Pacific Islanders. However, this progress has largely been negated in young and middle-aged (25-49 years) white individuals, and American Indians and Alaska Natives, primarily because of potentially avoidable causes such as drug poisonings, suicide, and chronic liver disease and cirrhosis. The magnitude of annual mortality increases in the USA is extremely unusual in high-income countries, and a rapid public health response is needed to avert further premature deaths. FUNDING: US National Cancer Institute Intramural Research Program.

Family history of cancer in first-degree relatives and risk of gastric cancer and its precursors in a Western population.

BACKGROUND: Family history may inform risks of gastric cancer and preneoplastic lesions. METHODS: We examined associations with history of cancer in first-degree relatives for 307 incident gastric cancer cases among 20,720 male smokers in a prospective study in Finland. Cox regression was used to calculate gastric cancer hazard ratios (HR) and 95% confidence intervals (95% CI). Logistic regression was used to estimate odds ratios (OR) and 95% CIs for low serum pepsinogen, a marker of gastric atrophy. RESULTS: Gastric cancer risk was associated with gastric cancer history in first-degree relatives overall (HR 1.56, 95% CI 1.15-2.12), in fathers (HR 1.67, 95% CI 1.09-2.55) and in siblings (HR 2.05, 95% CI 1.25-3.38). Associations were significant for noncardia (HR 1.83, 95% CI 1.30-2.57) but not cardia (HR 0.93, 95% CI 0.46-1.87) cancers, and marginal for both intestinal-(HR 1.53, 95% CI 0.92-2.55) and diffuse-type (HR 1.47, 95% CI 0.72-3.03) histologies. Family history of other cancer types was not associated with gastric cancer risk. Family history of gastric cancer was associated with low pepsinogen (OR 1.29, 95% CI 1.11-1.50). CONCLUSIONS: Family history of gastric cancer is strongly associated with specific subtypes of gastric cancer as well as with gastric atrophy, a risk factor for developing this malignancy.

Murine MTHFD1-synthetase deficiency, a model for the human MTHFD1 R653Q polymorphism, decreases growth of colorectal tumors.

The common R653Q variant (∼20% homozygosity in Caucasians) in the synthetase domain of the folate-metabolizing enzyme MTHFD1 reduces purine synthesis. Although this variant does not appear to affect risk for colorectal cancer, we questioned whether it would affect growth of colorectal tumors. We induced tumor formation in a mouse model for MTHFD1-synthetase deficiency (Mthfd1S+/- ) using combined administration of azoxymethane (AOM) and dextran sodium sulfate (DSS) in male and female wild-type and Mthfd1S+/- mice. Tumor size was significantly smaller in MthfdS+/- mice, particularly in males. A reduction in the proliferation of MthfdS+/- mouse embryonic fibroblast cell lines, compared with wild-type lines, was also observed. Tumor number was not influenced by genotype. The amount of inflammation observed within tumors from male Mthfd1S+/- mice was lower than that in wild-type mice. Gene expression analysis in tumor adjacent normal (pre-neoplastic) tissue identified several genes involved in proliferation (Fosb, Fos, Ptk6, Esr2, Atf3) and inflammation (Atf3, Saa1, TNF-α) that were downregulated in MthfdS+/- males. In females, MthfdS+/- genotype was not associated with these gene expression changes, or with differences in tumor inflammation. These findings suggest that the mechanisms directing tumor growth differ significantly between males and females. We suggest that restriction of purine synthesis, reduced expression of genes involved in proliferation, and/or reduced inflammation lead to slower tumor growth in MTHFD1-synthetase deficiency. These findings may have implications for CRC tumor growth and prognosis in individuals with the R653Q variant. © 2016 Wiley Periodicals, Inc.

Nested case-control study designs for left-truncated survival data.

The determination of risk factors for disease incidence has been the subject of much epidemiologic research. With this goal a common study design entails the follow-up of an initially disease-free cohort, keeping track of the dates of disease incidence (onset) and ascertaining covariate (putative risk factor) information on the full cohort. However, the collection of certain covariate information on all study subjects may be prohibitively expensive and, therefore, the nested case-control study has commonly been used. The high cost of full covariate information on all subjects also arises when determining risk factors for "failure," death say, "following" disease onset, in particular, in a prevalent cohort study with follow-up; in such a study a cohort of subjects with existing disease is followed. We here adapt nested case-control designs to the setting of a prevalent cohort study with follow-up, a topic previously not addressed in the literature. We provide the partial likelihood under risk set sampling and state the asymptotic properties of the estimated covariate effects and baseline cumulative hazard. We address the following design questions in the context of prevalent cohort studies with follow-up: How many subjects should be included in the sampled risk sets for efficient estimation? In what way is the proportion of censored subjects associated with the benefit of a nested case-control design? What proportion of overall variance is attributable to risk set sampling? This work is motivated by the anticipated analysis of data on survival with Parkinson's Disease, being collected as part of the ongoing Canadian Longitudinal Study on Aging.

La détermination des facteurs de risque pour l'incidence d'une maladie est le sujet de nombreuses études épidémiologiques. À cet effet, un plan d'expérience commun consiste à suivre une cohorte initialement en santé en prenant note de la date à laquelle la maladie se manifeste (début) et en évaluant les covariables (facteurs de risque présumés) pour la cohorte en entier. Lorsque la collecte de certaines covariables pour tous les individus s'avère trop onéreuse, une étude cas-témoins peut eˆtre considérée. Un problème similaire de couˆts élevés pour la collecte d'information sur tous les sujets peut également se présenter lorsque les facteurs de risque pour un « échec ¼, disons le décès, doivent eˆtre déterminés après le début de la maladie. Une telle situation peut survenir dans une étude sur une cohorte prévalente avec suivi, mais la question n'a pas encore été traitée dans la littérature. Les auteurs développent la vraisemblance partielle pour un échantillonnage dans l'ensemble à risque et décrivent les propriétés asymptotiques des estimés de l'effet des covariables et de la fonction cumulative du risque de base. Ils répondent à certaines questions émergeant d'un plan d'expérience pour une cohorte prévalente avec suivi, notamment le nombre de sujets à inclure dans l'ensemble de risque pour obtenir une estimation efficace, les façons dont la proportion de sujets censurés est liée aux bénéfices d'un plan cas-témoin imbriqué, et la proportion de variance globale attribuable à l'échantillonnage dans l'ensemble à risque. Le développement de ces méthodes est motivé par l'analyse imminente de données de survie de patients atteints de la maladie de Parkinson dont la collecte est en cours dans le cadre de l'é tude longitudinale canadienne sur le vieillissement.

Risks of first and subsequent cancers among TP53 mutation carriers in the National Cancer Institute Li-Fraumeni syndrome cohort.

BACKGROUND: Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer predisposition syndrome characterized by a very high lifetime cancer risk and an early age at diagnosis of a wide cancer spectrum. Precise estimates for the risk of first and subsequent cancers are lacking. METHODS: The National Cancer Institute's Li-Fraumeni Syndrome Study includes families meeting the diagnostic criteria for LFS or Li-Fraumeni-like syndrome, and individuals with a germline TP53 mutation, choroid plexus carcinoma, adrenocortical carcinoma, or ≥3 cancers. Herein, we estimated the cumulative risk and annual hazards for first and second cancers among TP53 mutation carriers (TP53 positive [TP53+]) using MATLAB statistical software. RESULTS: This study evaluated 286 TP53+ individuals from 107 families. The cumulative cancer incidence was 50% by age 31 years among TP53+ females and 46 years among males, and nearly 100% by age 70 years for both sexes. Cancer risk was highest after age 20 years for females, mostly due to breast cancer, whereas among males the risk was higher in childhood and later adulthood. Among females, the cumulative incidence rates by age 70 years for breast cancer, soft tissue sarcoma, brain cancer, and osteosarcoma were 54%, 15%, 6%, and 5%, respectively. Among males, the incidence rates were 22%, 19%, and 11%, respectively, for soft tissue sarcoma, brain cancer, and osteosarcoma. Approximately 49% of those with 1 cancer developed at least another cancer after a median of 10 years. The average age-specific risk of developing a second cancer was comparable to that of developing a first cancer. CONCLUSIONS: The cumulative cancer risk in TP53 + individuals was very high and varied by sex, age, and cancer type. Additional work, including prospective risk estimates, is needed to better inform personalized risk management. Cancer 2016;122:3673-81. © 2016 American Cancer Society.

Race, Ethnicity, and Pediatric Postsurgical Mortality: Current Trends and Future Projections.

BACKGROUND: No study has contextualized the aggregate human costs attributable to disparities in pediatric postsurgical mortalities in the United States, a critical step needed to convey the scale of racial inequalities to clinicians, policymakers, and the public. METHODS: We conducted a population-based study of 673 677 children from US hospitals undergoing intermediate to high-risk surgery between 2000 and 2019. We estimated the excess deaths that could be avoided if Black and Hispanic children had comparable mortality rates to white children. We estimated the mortality reduction required to eliminate disparities within the next decade. We finally evaluated the impact of policy changes targeting a modest annual 2.5% reduction in disparity-attributable mortality. RESULTS: During 2000 to 2019, risk-adjusted postoperative mortality trended consistently higher for both Black (adjusted RR [aRR]: 1.42, 95% confidence interval [CI]: 1.36-1.49) and Hispanic children (aRR: 1.22, 95% CI: 1.17-1.27) than for white children. These disparity gaps were driven by higher mortality in Black and Hispanic children receiving surgery in nonteaching hospitals (Black versus white aRR: 1.63, 95% CI: 1.38-1.93; Hispanic versus white aRR: 1.50, 95% CI: 1.33-1.70). There were 4700 excess deaths among Black children and 5500 among Hispanic children, representing. 10 200 (average: 536 per year) excess deaths among minoritized children. Policy changes achieving an annual 2.5% reduction in postoperative mortality would prevent approximately 1100 deaths among Black children in the next decade. CONCLUSIONS: By exploring the solution, and not just the problem, our study provides a framework to reduce disparities in pediatric postoperative mortality over the next decade.

The efficient design of Nested Group Testing algorithms for disease identification in clustered data.

Group testing study designs have been used since the 1940s to reduce screening costs for uncommon diseases; for rare diseases, all cases are identifiable with substantially fewer tests than the population size. Substantial research has identified efficient designs under this paradigm. However, little work has focused on the important problem of disease screening among clustered data, such as geographic heterogeneity in HIV prevalence. We evaluated designs where we first estimate disease prevalence and then apply efficient group testing algorithms using these estimates. Specifically, we evaluate prevalence using individual testing on a fixed-size subset of each cluster and use these prevalence estimates to choose group sizes that minimize the corresponding estimated average number of tests per subject. We compare designs where we estimate cluster-specific prevalences as well as a common prevalence across clusters, use different group testing algorithms, construct groups from individuals within and in different clusters, and consider misclassification. For diseases with low prevalence, our results suggest that accounting for clustering is unnecessary. However, for diseases with higher prevalence and sizeable between-cluster heterogeneity, accounting for clustering in study design and implementation improves efficiency. We consider the practical aspects of our design recommendations with two examples with strong clustering effects: (1) Identification of HIV carriers in the US population and (2) Laboratory screening of anti-cancer compounds using cell lines.

Smoothing Lexis diagrams using kernel functions: A contemporary approach.

Lexis diagrams are rectangular arrays of event rates indexed by age and period. Analysis of Lexis diagrams is a cornerstone of cancer surveillance research. Typically, population-based descriptive studies analyze multiple Lexis diagrams defined by sex, tumor characteristics, race/ethnicity, geographic region, etc. Inevitably the amount of information per Lexis diminishes with increasing stratification. Several methods have been proposed to smooth observed Lexis diagrams up front to clarify salient patterns and improve summary estimates of averages, gradients, and trends. In this article, we develop a novel bivariate kernel-based smoother that incorporates two key innovations. First, for any given kernel, we calculate its singular values decomposition, and select an optimal truncation point-the number of leading singular vectors to retain-based on the bias-corrected Akaike information criterion. Second, we model-average over a panel of candidate kernels with diverse shapes and bandwidths. The truncated model averaging approach is fast, automatic, has excellent performance, and provides a variance-covariance matrix that takes model selection into account. We present an in-depth case study (invasive estrogen receptor-negative breast cancer incidence among non-Hispanic white women in the United States) and simulate operating characteristics for 20 representative cancers. The truncated model averaging approach consistently outperforms any fixed kernel. Our results support the routine use of the truncated model averaging approach in descriptive studies of cancer.

COVID-19 severity by vaccination status in the NCI COVID-19 and Cancer Patients Study (NCCAPS).

We investigated the association of SARS CoV-2 vaccination with COVID-19 severity in a longitudinal study of adult cancer patients with COVID-19. A total of 1610 patients who were within 14 days of an initial positive SARS CoV-2 test and had received recent anticancer treatment or had a history of stem cell transplant or CAR-T cell therapy were enrolled between May 21, 2020, and February 1, 2022. Patients were considered fully vaccinated if they were 2 weeks past their second dose of mRNA vaccine (BNT162b2 or mRNA-1273) or a single dose of adenovirus vector vaccine (Ad26.COV2.S) at the time of positive SARS CoV-2 test. We defined severe COVID-19 disease as hospitalization for COVID-19 or death within 30 days. Vaccinated patients were significantly less likely to develop severe disease compared with those who were unvaccinated (odds ratio = 0.44, 95% confidence interval = 0.28 to 0.72, P < .001). These results support COVID-19 vaccination among cancer patients receiving active immunosuppressive treatment.

Current Trends in Mortality Attributable to Racial or Ethnic Disparities in Post-Surgical Population in The United States: A Population-Based Study.

Background: No study has contextualized the excess mortality attributable to racial and ethnic disparities in surgical outcomes. Further, not much effort has been made to quantify the effort needed to eliminate these disparities. Objective: We examined the current trends in mortality attributable to racial or ethnic disparities in the US postsurgical population. We then identified the target for mortality reduction that would be necessary to eliminate these disparities by 2030. Methods: We performed a population-based study of 1,512,974 high-risk surgical procedures among adults (18-64 years) performed across US hospitals between 2000 and 2020. Results: Between 2000 and 2020, the risk-adjusted mortality rates declined for all groups. Nonetheless, Black patients were more likely to die following surgery (adjusted relative risk 1.42; 95% CI, 1.39-1.46) driven by higher Black mortality in the northeast (1.60; 95% CI, 1.52-1.68), as well as the West (1.53; 95% CI, 1.43-1.62). Similarly, mortality risk remained consistently higher for Hispanics compared with White patients (1.21; 95% CI, 1.19-1.24), driven by higher mortality in the West (1.26; 95% CI, 1.21-1.31). Overall, 8364 fewer deaths are required for Black patients to experience mortality on the same scale as White patients. Similar figures for Hispanic patients are 4388. To eliminate the disparity between Black and White patients by 2030, we need a 2.7% annualized reduction in the projected mortality among Black patients. For Hispanics, the annualized reduction needed is 0.8%. Conclusions: Our data provides a framework for incorporating population and health systems measures for eliminating disparity in surgical mortality within the next decade.

Standardized Definitions for Efficacy End Points in Neoadjuvant Breast Cancer Clinical Trials: NeoSTEEP.

PURPOSE: The Standardized Definitions for Efficacy End Points (STEEP) criteria, established in 2007 and updated in 2021 (STEEP 2.0), provide standardized definitions of adjuvant breast cancer (BC) end points. STEEP 2.0 identified a need to separately address end points for neoadjuvant clinical trials. The multidisciplinary NeoSTEEP working group of experts was convened to critically evaluate and align neoadjuvant BC trial end points. METHODS: The NeoSTEEP working group concentrated on neoadjuvant systemic therapy end points in clinical trials with efficacy outcomes-both pathologic and time-to-event survival end points-particularly for registrational intent. Special considerations for subtypes and therapeutic approaches, imaging, nodal staging at surgery, bilateral and multifocal diseases, correlative tissue collection, and US Food and Drug Administration regulatory considerations were contemplated. RESULTS: The working group recommends a preferred definition of pathologic complete response (pCR) as the absence of residual invasive cancer in the complete resected breast specimen and all sampled regional lymph nodes (ypT0/Tis ypN0 per AJCC staging). Residual cancer burden should be a secondary end point to facilitate future assessment of its utility. Alternative end points are needed for hormone receptor-positive disease. Time-to-event survival end point definitions should pay particular attention to the measurement starting point. Trials should include end points originating at random assignment (event-free survival and overall survival) to capture presurgery progression and deaths as events. Secondary end points adapted from STEEP 2.0, which are defined from starting at curative-intent surgery, may also be appropriate. Specification and standardization of biopsy protocols, imaging, and pathologic nodal evaluation are also crucial. CONCLUSION: End points in addition to pCR should be selected on the basis of clinical and biologic aspects of the tumor and the therapeutic agent investigated. Consistent prespecified definitions and interventions are paramount for clinically meaningful trial results and cross-trial comparison.

Update on Enrollment of Older Adults Onto National Cancer Institute National Clinical Trials Network Trials.

BACKGROUND: Older adults are a large and growing proportion of cancer cases in the United States, but concerns persist about whether older adults are adequately represented in the cancer clinical trials that test new options for treatment and cancer care. METHODS: This paper describes adult patient enrollments by age group to the National Cancer Institute's National Clinical Trials Network (NCTN) from 2016 to 2021, compares patient enrollment by age with the estimated incident cancer population across cancer types, and explores possible associations between patient age and patient race, ethnicity, and sex. RESULTS: This analysis found that patients aged 18 to 69 years were overrepresented in NCTN trials, whereas patients aged 70 years and older were underrepresented compared with the estimated incident cancer population. Underrepresentation of older patients was seen across cancer types. Older patients who enrolled to NCTN trials were more likely to be non-Hispanic White than the estimated incident cancer population. CONCLUSIONS: Compared with earlier analyses, NCTN trials are enrolling greater proportions of older adults, primarily driven by higher enrollment among patients aged 65 to 74 years. There is still significant room for improvement, however, especially among patients aged 75 years and older. Additionally, patient demographics should not be viewed in isolation: older Hispanic patients, for instance, were particularly underrepresented among patients enrolled to NCTN trials. The intersection between trial enrollment and age, race, and ethnicity warrants further study so that more targeted enrollment enhancement efforts can be developed that enhance trial diversity across demographic groups.

Utility of interim blood tests for cancer screening in Li-Fraumeni syndrome.

Comprehensive annual screening reduces cancer-related mortality in Li-Fraumeni syndrome (LFS), a cancer-prone disorder caused by pathogenic germline TP53 variants. Blood tests at months 4 and 8 between annual screening are recommended but their effectiveness in early cancer detection has not been established. Interim blood counts and inflammatory biomarkers were evaluated in 132 individuals with LFS (112 adults, 87 female, median age 36 years [range 3-68], median follow-up 37 months [range 2-70]) and test abnormalities were observed in 225 (35%). Thirteen cancers in 12 individuals were diagnosed between annual screenings but only one cancer (colorectal adenocarcinoma) was diagnosed due to an abnormal interim blood test. Fisher's exact test and generalized estimating equation models found no statistical associations between cancer diagnoses and any test abnormality. Four- and 8-monthly interim screening blood tests may not be of independent benefit for cancer detection in LFS, but annual cancer screening and personalized follow-up remain essential.

Geographic Inequalities in Cardiovascular Mortality in the United States: 1999 to 2018.

OBJECTIVE: To evaluate the trends in cardiovascular, ischemic heart disease (IHD), stroke, and heart failure mortality in the stroke belt in comparison with the rest of the United States. PATIENTS AND METHODS: We evaluated the nationwide mortality data of all Americans from the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research database from 1999 to 2018. Cause-specific deaths were identified in the stroke belt and nonstroke belt populations using International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes. The relative percentage gap was estimated as the absolute difference computed relative to nonstroke belt mortality. Piecewise linear regression and age-period-cohort modeling were used to assess, respectively, the trends and to forecast mortality across the 2 regions. RESULTS: The cardiovascular mortality rate (per 100,000 persons) was 288.3 (95% CI, 288.0 to 288.6; 3,684,273 deaths) in the stroke belt region and 251.2 (95% CI, 251.0 to 251.3; 13,296,164 deaths) in the nonstroke belt region. In the stroke belt region, age-adjusted mortality rates due to all cardiovascular causes (average annual percentage change [AAPC] in mortality rates, -2.4; 95% CI, -2.8 to -2.0), IHD (AAPC, -3.8; 95% CI, -4.2 to -3.5), and stroke (AAPC, -2.8; 95% CI, -3.4 to -2.1) declined from 1999 to 2018. A similar decline in cardiovascular (AAPC, -2.5; 95% CI, -3.0 to -2.0), IHD (AAPC, -4.0; 95% CI, -4.3 to -3.7), and stroke (AAPC, -2.9; 95% CI, -3.2 to -2.2) mortality was seen in the nonstroke belt region. There was no overall change in heart failure mortality in both regions (PAAPC>.05). The cardiovascular mortality gap was 11.8% in 1999 and 15.9% in 2018, with a modest reduction in absolute mortality rate difference (~7 deaths per 100,000 persons). These patterns were consistent across subgroups of age, sex, race, and urbanization status. An estimated 101,953 additional cardiovascular deaths need to be prevented from 2020 to 2025 in the stroke belt to ameliorate the gap between the 2 regions. CONCLUSION: Despite the overall decline, substantial geographic disparities in cardiovascular mortality persist. Novel approaches are needed to attenuate the long-standing geographic inequalities in cardiovascular mortality in the United States, which are projected to increase.