Search

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.

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.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.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%).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.

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.

PURPOSEThe Standardized Definitions for Efficacy End Points (STEEP) criteria, established in 2007, provide standardized definitions of adjuvant breast cancer clinical trial end points. Given the evolution of breast cancer clinical trials and improvements in outcomes, a panel of experts reviewed the STEEP criteria to determine whether modifications are needed.METHODSWe conducted systematic searches of ClinicalTrials.gov for adjuvant systemic and local-regional therapy trials for breast cancer to investigate if the primary end points reported met STEEP criteria. On the basis of common STEEP deviations, we performed a series of simulations to evaluate the effect of excluding non–breast cancer deaths and new nonbreast primary cancers from the invasive disease–free survival end point.RESULTSAmong 11 phase III breast cancer trials with primary efficacy end points, three had primary end points that followed STEEP criteria, four used STEEP definitions but not the corresponding end point names, and four used end points that were not included in the original STEEP manuscript. Simulation modeling demonstrated that inclusion of second nonbreast primary cancer can increase the probability of incorrect inferences, can decrease power to detect clinically relevant efficacy effects, and may mask differences in recurrence rates, especially when recurrence rates are low.CONCLUSIONWe recommend an additional end point, invasive breast cancer–free survival, which includes all invasive disease–free survival events except second nonbreast primary cancers. This end point should be considered for trials in which the toxicities of agents are well-known and where the risk of second primary cancer is small. Additionally, we provide end point recommendations for local therapy trials, low-risk populations, noninferiority trials, and trials incorporating patient-reported outcomes.

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.

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.

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.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.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.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.

Background: Nasal chondromesenchymal hamartomas are benign, rare nasal tumors associated with DICER1 pathogenic germ-line variation. They can be locally destructive and recurrent if not completely resected. Methodology: In this single-center, case-control study, otorhinolaryngology evaluations and review of systems questionnaires of DICER1-carriers and controls enrolled in the DICER1 Natural History Study at the National Cancer Institute were collected. Review of these medical records were analyzed to determine if DICER1-carriers experienced different sinonasal clinical manifestations compared to controls. Additionally, the number of diagnoses of nasal chondromesenchymal hamartoma cases in the NCI DICER1 study was compared against the total person years of observation of DICER1-carriers in the study to determine the total number of cases per person-years of observation. Lastly, both the NCI DICER1 study and the International Pleuropulmonary Blastoma/DICER1 Registry were queried for unpublished cases of nasal chondromesenchymal hamartomas. Results: There were no clinical differences in sinonasal symptomatology between DICER1-carriers and control patients seen in the ENT clinic. We observed of two cases of nasal chondromesenchymal hamartoma in a total of 555 person-years of monitoring DICER1-carriers. We include six unpublished nasal chondromesenchymal hamartoma cases. When combined with a comprehensive literature review, 38% of nasal chondromesenchymal hamartoma cases had at least one additional DICER1-associated tumor and 24% of the NCMH were found in the ethmoid sinus, the most commonly involved paranasal sinus. Conclusions: We quantify the risk of developing nasal chondromesenchymal hamartomas in our cohort of 236 DICER1-carriers, report six unpublished cases, and provide an updated review of the literature.

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.

BACKGROUND: Nasal chondromesenchymal hamartomas are benign, rare nasal tumors associated with DICER1 pathogenic germline variation. They can be locally destructive and recurrent if not completely resected. METHODOLOGY: In this single-center, case-control study, otorhinolaryngology evaluations and review of systems questionnaires of DICER1-carriers and controls enrolled in the DICER1 Natural History Study at the National Cancer Institute were collected. Review of these medical records were analyzed to determine if DICER1-carriers experienced different sinonasal clinical manifestations compared to controls. Additionally, the number of diagnoses of nasal chondromesenchymal hamartoma cases in the NCI DICER1 study was compared against the total person years of observation of DICER1-carriers in the study to determine the total number of cases per person-years of observation. Lastly, both the NCI DICER1 study and the International Pleuropulmonary Blastoma/DICER1 Registry were queried for unpublished cases of nasal chondromesenchymal hamartomas. RESULTS: There were no clinical differences in sinonasal symptomatology between DICER1-carriers and control patients seen in the ENT clinic. We observed of two cases of nasal chondromesenchymal hamartoma in a total of 555 person-years of monitoring DICER1-carriers. We include six unpublished nasal chondromesenchymal hamartoma cases. When combined with a comprehensive literature review, 38% of nasal chondromesenchymal hamartoma cases had at least one additional DICER1-associated tumor and 24% of the NCMH were found in the ethmoid sinus, the most commonly involved paranasal sinus. CONCLUSIONS: We quantify the risk of developing nasal chondromesenchymal hamartomas in our cohort of 236 DICER1-carriers, report six unpublished cases, and provide an updated review of the literature.

Li–Fraumeni syndrome (LFS) is a rare autosomal dominant cancer predisposition syndrome with exceptionally high lifetime cancer risks, caused primarily by germline TP53 variants. Early-onset breast cancer is the most common cancer in women with LFS. Associations between female reproductive factors and breast cancer risk have been widely studied in the general population and BRCA1/2 mutation carriers but not in LFS. We evaluated whether reproductive factors are associated with breast cancer in LFS. Questionnaire data were collected for 152 women with confirmed germline TP53 variants enrolled in the National Cancer Institute's LFS study (NCT01443468); of which, 85 had breast cancer, confirmed by pathology/medical reports. Fisher's exact test and Cox proportional hazards were used to calculate the effect of reproductive factors on breast cancer risk. Lifetime breastfeeding for at least 7 months was associated with lower breast cancer risk (hazard ratio [HR] 0.57, p = 0.05). Parity did not independently change breast cancer risk (HR 1.08, p = 0.8) but suggested an increased risk with older age at first live birth (HR 2.14, p = 0.05). Age at menarche (HR 1.09, p = 0.24) and use of oral contraceptives (HR 0.88; p = 0.7) did not significantly affect breast cancer risk. In this first study of reproductive factors and breast cancer in women with LFS, breastfeeding was observed to be protective against breast cancer risk, especially with at least 7 months of lifetime breastfeeding. Older age at first live birth was suggested to slightly increase breast cancer risk. Larger prospective studies of reproductive factors are warranted in women with LFS before making definitive clinical recommendations.

Disparities in cancer mortality by county-level income have increased. It is unclear whether these widening disparities have affected older and younger adults equally. National death certificate data were utilized to ascertain cancer deaths during 1999–2015. Average annual percent changes in mortality rates and mortality rate ratios (RRs) were estimated by county-level income quintile and age (25–64 vs ≥65 years). Among 25- to 64-year-olds, cancer mortality rates were 30% higher (RR = 1.30, 95% confidence interval [CI] = 1.29 to 1.31) in the lowest-vs the highest-income counties in 1999–2001 and 56% higher (RR = 1.56, 95% CI = 1.55 to 1.57) in 2013–2015; the disparities among those 65 years and older were smaller but also widened over time (RR1999–2001 = 1.04, 95% CI = 1.03 to 1.05; RR2013–2015 = 1.14, 95% CI = 1.13 to 1.14). Widening disparities occurred across cancer sites. If all counties had the mortality rates of the highest-income counties, 21.5% of cancer deaths among 25- to 64-year-olds and 7.3% of cancer deaths in those 65 years and older would have been avoided in 2015. These results highlight an ongoing need for equity-focused interventions, particularly among younger adults.

Purpose DICER1 syndrome is an autosomal-dominant, pleiotropic tumor-predisposition disorder caused by pathogenic germline variants in DICER1. We sought to quantify risk, hazard rates, and the probability of neoplasm incidence accounting for competing risks (“cumulative incidence”) of neoplasms (benign and malignant) and standardized incidence ratios for malignant tumors in individuals with DICER1 pathogenic variation. Patients and Methods We combined data from three large cohorts of patients who carry germline pathogenic variation in DICER1. To reduce ascertainment bias, we distinguished probands from nonprobands. Neoplasm diagnoses were confirmed by review of pathology reports and/or central review of surgical pathology materials. Standardized cancer incidence ratios were determined relative to the SEER program, which does not capture all DICER1-associated neoplasms. For all malignancies and benign tumors (“neoplasms,” excluding type Ir pleuropulmonary blastoma and thyroid nodules), we used the Kaplan-Meier method and nonparametric cumulative incidence curves to estimate neoplasm-free survival. Results We calculated the age at first neoplasm diagnosis (systematically ascertained cancers plus DICER1-associated neoplasms pleuropulmonary blastoma, cystic nephroma, and nasal chondromesenchymal hamartoma) in 102 female and male nonproband DICER1 carriers. By age 10 years, 5.3% (95% CI, 0.6% to 9.7%) of nonproband DICER1 carriers had developed a neoplasm (females, 4.0%; males, 6.6%). By age 50 years, 19.3% (95% CI, 8.4% to 29.0%) of nonprobands had developed a neoplasm (females, 26.5%; males, 10.2%). After age 10 years, female risk was elevated compared with male risk. Standardized cancer incidence ratio analysis of 102 nonproband DICER1 carriers, which represented 3,344 person-years of observation, showed significant cancer excesses overall, particularly of gynecologic and thyroid cancers. Conclusion This work provides the first quantitative analysis of site-specific neoplasm risk and excess malignancy risk in 102 systematically characterized nonproband DICER1 carriers. Our findings inform DICER1 syndrome phenotype, natural history, and genetic counseling.

Background: Eligibility guidelines for genetic testing may be revisited, given technological advances, plummeting costs, and proposals for population mutation screening. A key property of eligibility criteria is the tradeoff between the number of mutation carriers identified versus population members tested. We assess the fractions of mutation carriers identified, versus women undergoing mutation testing, for BRCA1/2 founder mutation screening in U.S. Ashkenazi-Jewish women. Methods: BRCA1/2 carrier probabilities, based on personal/family history, were calculated using the risk-prediction tool BRCAPRO for 4,589 volunteers (102 mutation carriers) in the population-based Washington Ashkenazi Study. For each carrier-probability threshold between 0% and 10%, we compared the percentage of founder mutations detected versus the percentage of women requiring mutation testing. PCR mutation testing was conducted at the NIH for the 3 Ashkenazi-Jewish founder mutations (5382insC and 185delAG in BRCA1, and 6174delT in BRCA2). Results: Identifying 90% of BRCA1/2 founder mutations required testing the 60% of Ashkenazi-Jewish women with carrier probabilities exceeding 0.56%, potentially avoiding mutation testing for approximately 0.7 to 1.1 million U.S. Ashkenazi-Jewish women. Alternatively, testing the 44% whose carrier probability exceeded 0.78% identified 80% of mutation carriers, increasing to 89% of mutation carriers when accounting for cascade testing triggered after mutation-positive daughters were identified by screening. We present data on all carrier-probability thresholds, e.g., a 5% threshold identified 46% of mutation carriers while testing 10% of women. Conclusions: Different carrier-probability thresholds offered diverse tradeoffs between numbers of identified mutation carriers versus women tested. Low carrier-probability thresholds identified 90% of BRCA1/2 founder mutation carriers, without testing approximately 1 million U.S. Ashkenazi-Jewish women with lowest carrier probabilities. Impact: In general, this risk-based framework could provide useful new options to consider during eligibility-criteria development for population mutation screening.

e17617 Background: NCI-MATCH, a signal-finding precision medicine trial, centrally screened tumors from ̃6000 patients age > 18 with refractory/relapsed cancer using Oncomine Comprehensive Assay (OCA) targeted gene panel. Screened cohort included a subset of patients with ovarian cancer age 18-39 yrs, overlapping adolescent and young adult (AYA) range (NCI consensus definition: 15-39 yrs). Objective of this study was to compare tumor genomic features of AYA to non-AYA ovarian cancers. Methods: Patient clinicopathologic, demographic, and tumor mutation (SNVs, Indels, CNVs by central OCA) data from NCI-MATCH were available. Analyses were restricted to mutation profiles generated by OCA version 2 (OCA v2), which assessed 143 genes and was used for most samples. Proportions of cases with mutations in each gene were compared for AYA and non-AYA groups by 2-sided Fisher’s exact tests. For each gene, association between age (continuous independent variable) and presence of mutation (binary dependent variable) was assessed using logistic regression. Benjamini-Hochberg adjusted p-values were computed; false discovery rate (FDR) was controlled at 10%. Results: Data from 455 ovarian cancers (437 epithelial, 18 stromal), including 21 AYA and 434 non-AYA cases, were included in this analysis. Among the 28 genes most frequently (in > 6 patient tumors) mutated and altered, CTNNB1 was mutated in 9.5% of AYA patients compared to 0.9% in non-AYA (unadj. p=0.027) but failed to meet 10% FDR criterion (FDR-adj. p=0.7). KRAS mutation was more frequent in AYA than non-AYA but not significantly after adjustment (FDR-adj. p=0.7). Logistic regression results showed TP53 mutation was significantly associated with older age (FDR-adj. p

Summary 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.

Background Benign meningiomas are the most frequently reported central nervous system tumors in the United States, with increasing incidence in past decades. However, the future trajectory of this neoplasm remains unclear. Methods We analyzed benign meningioma incidence of cases identified by any means (eg, radiographically with or without microscopic confirmation) in US Surveillance, Epidemiology, and End Results cancer registries among groups aged 35 to 84 years during 2004-2017 by sex and race and ethnicity using age-period-cohort models. We employed age-period-cohort forecasting models to glean insights regarding the etiology, distribution, and anticipated future (2018-2027) public health impact of this neoplasm. Results In all groups, meningioma incidence overall increased through 2010, then stabilized. Temporal declines were statistically significant overall and in most groups. JoinPoint analysis of cohort rate-ratios identified substantial acceleration in White men born after 1963 (from 1.1% to 3.2% per birth year); cohort rate-ratios were stable or increasing in all groups and all birth cohorts. We forecast that meningioma incidence through 2027 will remain stable or decrease among groups aged 55-84 years but remain similar to current levels among groups aged 35-54 years. The case count of total meningioma burden in 2027 is expected to be approximately 30 470, similar to the expected case count of 27 830 in 2018. Conclusions Between 2004 and 2017, overall incidence of benign meningioma increased and then stabilized or declined. For 2018-2027, our forecast is incidence will remain generally stable in younger age groups but decrease in older age groups. Nonetheless, the total future burden will remain similar to current levels because the population is aging.

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.

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

Summary Background Although life expectancy has been projected to increase across high-income countries, gains for the USA are anticipated to be among the smallest, and overall US death rates actually increased from 2014 to 2015, with divergence for specific US populations. Therefore, projecting future premature mortality is essential for clinical and public health service planning, curbing rapidly increasing causes of death, and sustaining progress in declining causes of death. We aimed to project premature mortality (here defined as deaths of individuals aged 25–64 years) trends through 2030, and to estimate the total number of projected deaths, the projected number of potential years of life lost due to premature mortality, and the effect of reducing projected accidental death rates by 2% per year. Methods We obtained death certificate data for the US population aged 25–64 years for 1990–2015 from the US Centers for Disease Control and Prevention (CDC) National Center for Health Statistics. We obtained US mortality data for 2016 for non-American Indian or Alaska native groups from CDC WONDER; data for 2016 were not available for American Indians or Alaska natives. Our analysis focused on all-cause premature mortality and the commonest causes of premature death (cancer, heart disease, accidents, suicide, and chronic liver disease or cirrhosis) among white, black, Hispanic, Asian or Pacific islanders, and American Indian or Alaska native men and women. We estimated age-standardised premature mortality and corresponding annual percentage changes for 2017–30 by sex and race or ethnic origin by use of age–period–cohort forecasting models. We also did a sensitivity analysis projecting future mortality from cross-sectional mortality and a JoinPoint of the (log) period rate ratio curve. We calculated absolute death counts by use of corresponding age-specific and year-specific US census population projections, and estimated years of potential life lost. Findings During 2017–30, all-cause deaths are projected to increase among white women and American Indians or Alaska natives, resulting in 239 700 excess premature deaths relative to 2017 rates (a 10% increase). Mortality declines in white men and black, Hispanic, and Asian or Pacific islander men and women will result in 945 900 fewer deaths (a 14% reduction). Cancer mortality rates are projected to decline among white, black, Hispanic, and Asian or Pacific islander women and men, with the largest declines among black women (age-standardised premature mortality rate 2016: 104·5 deaths per 100 000 woman-years; 2030: 77·1 per 100 000 woman-years) and men (2016: 116·8 per 100 000 man-years; 2030: 81·6 per 100 000 man-years). Heart disease death rates are projected to increase in American Indian or Alaska native men (2015: 150·9 per 100 000 man-years; 2030: 175·9 per 100 000 man-years) and decline in other groups, albeit only slightly in white (2016: 35·6 per 100 000 woman-years; 2030: 31·1 per 100 000 woman-years) and American Indian or Alaska native women (2015: 64·4 per 100 000 woman-years; 2030: 62·8 per 100 000 woman-years). Accidental death rates are projected to increase in all US populations except Asian or Pacific islander women, and will increase most rapidly among white women (2030: 60·5 per 100 000 woman-years) and men (2030: 101·9 per 100 000 man-years) and American Indian or Alaska native women (2030: 97·5 per 100 000 woman-years) and men (2030: 298·7 per 100 000 man-years). Suicide rates are projected to increase for all groups, and chronic liver disease and cirrhosis deaths are projected to increase for all groups except black men. A 2% per year reduction in projected accidental deaths would eliminate an estimated 178 700 deaths during 2017–30. Interpretation To reduce future premature mortality, effective interventions are needed to address rapidly rising mortality rates due to accidents, suicides, and chronic liver disease and cirrhosis. Funding National Cancer Institute Intramural Research Program.

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.

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. The Canadian Journal of Statistics 45: 4–28; 2017 © 2017 Statistical Society of Canada

PURPOSE Human papillomavirus–positive oropharynx cancer incidence has increased rapidly in cohorts of US white men born during the 1930s to 1950s. It is unknown how the trajectory of the oropharynx cancer epidemic may be changing in the United States. METHODS Using US cancer registry information, we investigated whether increases in oropharynx cancer have continued into recent birth cohorts and forecasted the future burden across age, sex, and race/ethnicity subgroups. Log-linear Joinpoint regression and age-period-cohort models were used to evaluate incidence trends during 1992 to 2015 and projections through 2029. RESULTS Among white men, oropharynx cancer incidence increased rapidly in individuals born during 1939 to 1955 (5.3% per 2-year birth cohort; 95% CI, 4.8% to 5.7%), but this rate of increase significantly moderated in individuals born during 1955 to 1969 (1.7% per 2-year birth cohort; 95% CI, 1.0% to 2.4%). Should these birth-cohort trends continue, from 2016 to 2029 we forecast that incidence will increase dramatically in older white men 65 to 74 years of age (from 40.7 to 71.2 per 100,000) and 75 to 84 years of age (from 25.7 to 50.1 per 100,000), moderately in white men 55 to 64 years of age (from 40.3 to 52.0 per 100,000), and remain stable in white men 45 to 54 years of age (approximately 18 per 100,000). Accounting for population growth, we project an increase in annual number of cases in the United States from 20,124 (95% CI, 19,779 to 20,469) in 2016 to 30,629 (95% CI, 29,413 to 31,845) in 2029, primarily driven by older individuals (age ≥ 65 years; from 7,976 [95% CI, 7,782 to 8,172] to 18,072 [95% CI, 17,271 to 18,895]) and white men (from 14,453 [95% CI, 14,142 to 14,764] to 22,241 [95% CI, 21,119 to 23,364]). CONCLUSION The exponential increase in oropharynx cancer incidence in young white US men has ebbed, and modest increases are occurring/anticipated in cohorts born after 1955. Continued strong increases in incidence in cohorts born before 1955, and an approximate 50% increase in size of the US population age 65 years or older through 2029, portend a substantial shift in burden to elderly white men.

Myotonic dystrophy type I (DM1) is an autosomal dominant disease of which clinical manifestations resemble premature aging. We evaluated the contribution of telomere length in pathogenesis in 361 DM1 patients (12 with serial measurements) and 223 unaffected relative controls using qPCR assay. While no differences in baseline leukocyte relative telomere length (RTL) was noted, the data suggested an accelerated RTL attrition in DM1 (discovery cohort: T/S change/year = -0.013 in DM1 vs. -0.005 in controls, P = 0.04); similar trend was noted in validation cohort. Further investigations are needed to examine the role of TL in the pathophysiology of DM1. The study was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health.

6565 Background: Patients (pts) with cancer are at increased risk of SARS-CoV-2 infection and severe COVID-19 disease. Longitudinal follow-up is needed to characterize the severity, sequelae and outcomes in pts with cancer who develop COVID-19. Methods: NCCAPS is a prospective, longitudinal study (NCT04387656) aiming to accrue 2,000 pts with cancer undergoing active treatment or prior stem cell transplant for hematologic or solid tumor malignancy. Adult patients are eligible to enroll within 14 days of their first positive SARS-CoV-2 test; pediatric patients may also enroll retrospectively. Clinical data, patient-reported outcomes, blood specimens, and imaging are collected for up to 2 years. This abstract provides initial baseline and 2-month follow-up data. Results: As of Jan 22, 2021, 585 pts (552 adults and 33 pediatric pts) had complete baseline data and of these pts, 215 adults had 2 months of complete follow-up data. 23.4% of adults and 42.4% of pediatric pts were of non-White race and/or Hispanic/Latinx ethnicity. The most common cancer diagnoses were breast (19.6%), lung (9.9%) and multiple myeloma (8.9%) in adults and acute leukemia (AML/ALL; 63.6%) in children. The most recent treatment was chemotherapy in 38.2%, immunotherapy in 9.6%, and radiation in 5.4%. Median time from positive SARS-CoV-2 test to study enrollment was 10.5 days in adults and 18 days in pediatric pts. Preliminary analysis of plasma cytokines will be presented. At enrollment, 84.6% of adults had COVID-19 symptoms. 55.9% reported symptoms 2 weeks after their positive SARS-CoV-2 test; this fell to 39.0% at 1 month and 28.8% at 2 months (see Table). Of the 215 adults with complete data at 2 months, sequelae included pulmonary (n=22, 10%), cardiovascular (n=12, 6%) thromboembolic (n=9, 4%), bleeding (n=9, 4%) and gastrointestinal (n=11, 5%). 144 (67%) reported at least one cancer treatment disruption in the first 2 months, most commonly delayed therapy (n=98; 46%).Of the 348 adults with baseline data and SARS-CoV-2 test date prior to Nov 23, 2020, 6.3% had died (median time from SARS-CoV-2 test to death: 27 days), and 22.1% reported at least one hospitalization for COVID-19. No deaths were reported in the pediatric population. Conclusion: Cancer pts with COVID-19 report ongoing symptoms after acute infection and a substantial number develop sequelae. Cancer treatment disruptions are common in the initial months following SARS-CoV-2 infection. Longer follow-up will inform whether these treatment disruptions are associated with adverse outcomes. Clinical trial information: NCT04387656. [Table: see text]

Key Points Question What are the prevalence, risk, and phenotypic spectrum of individuals with a germline putative loss-of-function (pLOF) variant in DICER1 according to a genome-first approach in a population-scale cohort? Findings In this cohort study, DICER1 pLOF variants were more than twice as common (even after adjustment for relatedness) than previously observed. Malignant tumors were observed in 16% of participants with a DICER1 pLOF variant, which is comparable to the frequency of neoplasms in the largest phenotype-first DICER1 studies published to date. Meaning The genome-first approach complements more traditional approaches to syndrome delineation and may be an efficient approach for risk estimation in monogenic disorders., Importance Genetic disorders are historically defined through phenotype-first approaches. However, risk estimates derived from phenotype-linked ascertainment may overestimate severity and penetrance. Pathogenic variants in DICER1 are associated with increased risks of rare and common neoplasms and thyroid disease in adults and children. This study explored how effectively a genome-first approach could characterize the clinical traits associated with germline DICER1 putative loss-of-function (pLOF) variants in an unselected clinical cohort. Objective To examine the prevalence, penetrance, and phenotypic characteristics of carriers of germline DICER1 pLOF variants via genome-first ascertainment. Design, Setting, and Participants This cohort study classifies DICER1 variants in germline exome sequence data from 92 296 participants of the Geisinger MyCode Community Health Initiative. Data for each MyCode participant were used from the start of the Geisinger electronic health record to February 1, 2018. Main Outcomes and Measures Prevalence of germline DICER1 variation; penetrance of malignant tumors and thyroid disease in carriers of germline DICER1 variation; structured, manual review of electronic health records; and DICER1 sequencing of available tumors from an associated cancer registry. Results A total of 92 296 adults (mean [SD] age, 59 [18] years; 98% white; 60% female) participated in the study. Germline DICER1 pLOF variants were observed in 1 in 3700 to 1 in 4600 participants, more than double the expected prevalence. Malignant tumors (primarily thyroid carcinoma) were observed in 4 of 25 participants (16%) with DICER1 pLOF variants, which is comparable (by 50 years of age) to the frequency of neoplasms in the largest registry- and clinic-based (phenotype-first) DICER1 studies published to date. DICER1 pLOF variants were significantly associated with risks of thyroidectomy (odds ratio [OR], 6.0; 95% CI, 2.2-16.3; P = .007) and thyroid cancer (OR, 9.2; 95% CI, 2.1-34.7; P = .02) compared with controls, but there was not a significant increase in the risk of goiter (OR, 1.8; 95% CI, 0.7-4.9). A female patient in her 80s who was a carrier of a germline DICER1 hotspot variant was apparently healthy on electronic health record review. The term DICER1 did not appear in any of the medical records of the 25 participants with a pLOF DICER1 variant, even in those affected with a known DICER1-associated tumor or thyroid phenotype. Conclusions and Relevance This cohort study was able to ascertain individuals with germline DICER1 variants based on a genome-first approach rather than through a previously established DICER1-related phenotype. Use of the genome-first approach may complement more traditional approaches to syndrome delineation and may be an efficient approach for risk estimation., This cohort study examines the prevalence and penetrance of germline DICER1 putative loss-of-function variants via genome-first ascertainment.

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.

Importance Notable increases in mortality from alcohol-induced causes over the past 2 decades in the United States have been reported. However, comprehensive assessments of trends in alcohol-induced mortality by sex, age, race/ethnicity, and social and geographic factors are lacking. Objective To examine trends in alcohol-induced mortality rates from 2000 to 2016, comparing results by demographic characteristics including sex, race/ethnicity, age, county-level socioeconomic status, and geographic location. Design, Setting, and Participants This serial cross-sectional study used US national vital statistics data for years 2000 to 2016 for all US residents older than 15 years. Data analysis was conducted from January to September 2019. Exposures Trends in alcohol-induced mortality by sex, race/ethnicity, age, county-level socioeconomic status (ie, median income, percentage of unemployed residents, percentage of residents with a bachelor’s degree), rurality level, and US state. Main Outcomes and Measures Alcohol-induced mortality, ie, deaths for which alcohol holds a population-attributable fraction of 1. Deaths were expressed per 100 000 residents as absolute and age-standardized rates. Mortality trends were measured as average annual percentage changes (AAPCs) for the entire period (ie, 2000-2016) and annual percentage changes (APCs) for individual periods of change within the study period. Results A total of 425 045 alcohol-induced deaths were identified from 2000 to 2016 (2000: 19 627 deaths; 14 979 [76.3%] men; 2016: 34 857 deaths; 25 213 [73.3%] men). The rate of alcohol-induced deaths increased substantially among men (AAPC, 1.4%; 95% CI, 1.0% to 1.8%) and women (AAPC, 3.1%; 95% CI, 2.6% to 3.6%) and accelerated recently (men, 2012-2016: APC, 4.2%; 95% CI, 3.1% to 5.3%; women, 2013-2016: APC, 7.1%; 95% CI, 5.1% to 9.1%). The largest increases by race/ethnicity were observed among American Indian and Alaska Native men (AAPC, 3.3%; 95% CI, 2.6% to 4.0%), American Indian and Alaska Native women (AAPC, 4.2%; 95% CI, 3.8% to 4.6%), and white women (AAPC, 4.1%; 95% CI, 3.6% to 4.7%). Despite initial declines among black women, black men, and Latino men (eg, Latino men, 2000-2003: APC, −5.1%; 95% CI, −9.8% to −0.1%; 2003-2013: APC, −0.6%; 95% CI, −1.4% to 0.2%), increases occurred later in the study period (eg, Latino men, 2013-2016: APC, 4.1%; 95% CI, 0.3% to 8.1%). The rates of increase varied by age group and in turn by racial/ethnic group. Among white individuals, large absolute increases occurred in midlife (eg, men aged 55-59 years, 2000-2003: 25.5 deaths per 100 000 residents; 2013-2016: 43.3 deaths per 100 000 residents; women aged 50-54 years, 2000-2003: 7.4 deaths per 100 000 residents; 2013-2016: 16.5 deaths per 100 000 residents), although APCs were also large for ages 25 to 34 years, ranging from 4.6% to 6.9% per year among men and from 7.3% to 12.0% among women. Among American Indian and Alaska Native individuals, increases throughout the age range were observed, with the largest absolute increase occurring for ages 45 to 49 years among men (2000-2013: 113.6 deaths per 100 000 residents; 2013-2016: 193.1 deaths per 100 000 residents) and for ages 50 to 54 among women (2000-2013: from 56.1 deaths per 100 000 residents; 2013-2016: 105.1 deaths per 100 000 residents). Conclusions and Relevance This study found large increases in alcohol-induced death rates across age and racial/ethnic subgroups of the US population, which have accelerated over recent years. Large increases in alcohol-induced deaths among younger age groups may be associated with future increases in alcohol-related disease.

Summary Background Increasing premature mortality among some groups of Americans has been largely driven by increases in drug poisoning deaths. However, to our knowledge, a formal descriptive study by race and ethnicity, socioeconomic status, rurality, and geography has not been done. In this study, we examined US trends in premature all-cause and drug poisoning mortality between 2000 and 2015 at the county level among white, black, and Latino people. Methods We used US mortality data for the period Jan 1, 2000, to Dec 31, 2015, including underlying cause of death and demographic data, collected from death certificates by the Centers for Disease Control and Prevention National Center for Health Statistics, and ascertained county attributes from the 2011–15 Census American Community Survey. We categorised counties into quintiles on the basis of the percentage of people unemployed, the percentage of people with a bachelor's degree, median income, and rurality. We estimated premature (ie, deaths in those aged 25–64 years) age-standardised mortality for all causes (by race and ethnicity) and drug poisoning, by county, for the periods of 2000–03 and 2012–15. We estimated annual percentage changes in mortality (2000–15) by county-level characteristics. Findings Premature mortality declined from 2000–03 to 2012–15 among black and Latino people, but increased among white people in many US counties. Drug poisoning mortality increased in counties throughout the country. Significant increases between 2000 and 2015 occurred across low and high socioeconomic status and urban and rural counties among white people aged 25–64 years (annual percentage change range 4·56% per year [95% CI 3·56–5·57] to 11·51% per year [9·41–13·65]), black people aged 50–64 years (2·27% per year [0·42–4·16] to 9·46% per year [7·02–11·96]), Latino women aged 25–49 years (2·43% per year [1·18–3·71] to 5·01% per year [3·80–6·23]), and Latino men aged 50–64 years (2·42% per year [0·53–4·34] to 5·96% per year [3·86–8·11]). Although drug poisoning mortality increased rapidly in counties with the lowest socioeconomic status and in rural counties, most deaths during 2012–15 occurred in the largest metropolitan counties (121 395 [76%] in metropolitan counties with ≥250 000 people vs 2175 [1%] in the most rural counties), reflecting population size. Interpretation Premature mortality has declined among black and Latino people in the USA, and increased among white people, particularly in less affluent and rural counties. Increasing drug poisoning mortality was not limited to poor white people in rural areas. Rapid increases have occurred in communities throughout the USA regardless of race and ethnicity, socioeconomic status, or rurality. Widespread public health interventions are needed to addess this public health emergency. Funding National Institutes of Health.

BACKGROUND: Eligibility guidelines for genetic testing may be revisited, given technological advances, plummeting costs, and proposals for population mutation-screening. A key property of eligibility criteria is the tradeoff between the number of mutation-carriers identified versus population-members tested. We assess the fractions of mutation-carriers identified, versus women undergoing mutation-testing, for BRCA1/2 founder-mutation-screening in US Ashkenazi-Jewish women. METHODS: BRCA1/2 carrier-probabilities, based on personal/family history, were calculated using the risk-prediction tool BRCAPRO for 4,589 volunteers (102 mutation-carriers) in the population-based Washington Ashkenazi Study. For each carrier-probability threshold between 0%-10%, we compared the percent of founder-mutations detected vs. the percent of women requiring mutation-testing. PCR mutation-testing was conducted at the NIH for the 3 Ashkenazi-Jewish founder mutations (5382insC and 185delAG in BRCA1, and 6174delT in BRCA2). RESULTS: Identifying 90% of BRCA1/2 founder-mutations required testing the 60% of Ashkenazi-Jewish women with carrier-probabilities exceeding 0.56%, potentially avoiding mutation-testing for approximately 0.7-1.1 million US Ashkenazi-Jewish women. Alternatively, testing the 44% whose carrier-probability exceeded 0.78% identified 80% of mutation-carriers, increasing to 89% of mutation-carriers when accounting for cascade-testing triggered after mutation-positive daughters were identified by screening. We present data on all carrier-probability thresholds; e.g., a 5% threshold identified 46% of mutation-carriers while testing 10% of women. CONCLUSIONS: Different carrier-probability thresholds offered diverse tradeoffs between numbers of identified mutation-carriers versus women tested. Low carrier-probability thresholds identified 90% of BRCA1/2 founder-mutation-carriers, without testing ~1 million US Ashkenazi-Jewish women with lowest carrier-probabilities. IMPACT: In general, this risk-based framework could provide useful new options to consider during eligibility-criteria development for population mutation-screening.

ImportanceThere are limited guidelines for clinical management in Li-Fraumeni syndrome, a multi-organ cancer predisposition condition. Whole body magnetic resonance imaging may play a role in surveillance of this high risk population.ObjectiveTo assess the clinical utility of whole body magnetic resonance imaging in germline TP53 mutation carriers at baseline.Data SourcesClinical and research surveillance cohorts were identified through the Li-Fraumeni Exploration Research Consortium.Study selectionCohorts that incorporated whole body magnetic resonance imaging for individuals with germline TP53 mutations were included.Data extraction and synthesisData was extracted by investigators from each cohort independently and synthesized by two investigators. Random effects meta-analysis methods were used to estimate proportions. Main outcomes and measuresThe proportion of participants at baseline in whom a lesion was detected that required follow up and in whom a new primary malignancy was detected. ResultsA total 578 participants from 13 cohorts were included in the analysis. Two hundred twenty-five lesions requiring clinical follow up were detected by whole body magnetic resonance imaging in 173 participants. Sixty-one lesions were diagnosed in 54 individuals as either benign or malignant neoplasms. Overall, 42 cancers were identified in 39 individuals, with 35 new localized cancers treated with curative intent. The overall detection rate for new localized primary cancers was 7% (95% Confidence Interval 5-9%).Conclusions and relevanceThese data suggest clinical utility in baseline whole body magnetic resonance imaging in TP53 germline mutation carriers, and may form an integral part of baseline clinical risk management in this high-risk population.

PURPOSE: To characterize the spectrum of germline muta-tions in BRCA1, BRCA2, and PALB2 in population-based unselected breast cancer cases in an Asian population. Methods Germline DNA from 467 breast cancer patients in Sarawak General Hospital, Malaysia, where 93% of the breast cancer patients in Sarawak are treated, was sequenced for the entire coding region of BRCA1; BRCA2; PALB2; Exons 6, 7, and 8 of TP53; and Exons 7 and 8 of PTEN. Pathogenic variants included known pathogenic variants in ClinVar, loss of function variants, and variants that disrupt splice site. RESULTS: We found 27 pathogenic variants (11 BRCA1, 10 BRCA2, 4 PALB2, and 2 TP53) in 34 patients, which gave a prevalence of germline mutations of 2.8, 3.23, and 0.86%for BRCA1, BRCA2, and PALB2, respectively. Compared to mutation non-carriers, BRCA1 mutation carriers were more likely to have an earlier age at onset, triple-negative subtype, and lower body mass index, whereas BRCA2 mutation carriers were more likely to have a positive family history. Mutation carrier cases had worse survival compared to non-carriers; however, the association was mostly driven by stage and tumor subtype. We also iden-tified 19 variants of unknown significance, and some of them were predicted to alter splicing or transcription factor binding sites. CONCLUSION: Our data provide insight into the genetics of breast cancer in this understudied group and suggest the need for modifying genetic testing guidelines for this population with a much younger age at diagnosis and more limited resources compared with Caucasian populations.

ObjectiveWe systematically evaluated CNS manifestations in patients with inherited telomere biology disorders (TBDs) to better understand the clinical and biological consequences of germline aberrations in telomere biology.MethodsForty-four participants with TBDs (31 dyskeratosis congenita, 12 Hoyeraal-Hreidarsson syndrome, and 1 Revesz syndrome) enrolled in an institutional review board–approved longitudinal cohort study underwent detailed clinical assessments, brain MRI, and genetic testing. Lymphocyte telomere length Z-scores were calculated to adjust for age.ResultsIn this cohort, 25/44 (57%) patients with a TBD had at least 1 structural brain abnormality or variant, most commonly cerebellar hypoplasia (39%). Twenty-one patients (48%) had neurodevelopmental disorder or psychomotor abnormality. Twelve had psychiatric diagnoses, including depression and/or anxiety disorders. Other findings such as hypomyelination, prominent cisterna magna, and cavum septum pellucidum were more frequent than in the general population (p < 0.001). Shorter lymphocyte telomere length was associated with an increased number of MRI findings (p = 0.02) and neurodevelopmental abnormalities (p < 0.001). Patients with autosomal recessive or X-linked TBDs had more neurologic findings than those with autosomal dominant disease.ConclusionsStructural brain abnormalities and variants are common in TBDs, as are neurologic and psychiatric symptoms. The connection between neurodevelopment and telomere biology warrants future study.

Fanconi anemia (FA) is a genomic instability syndrome with predisposition to congenital abnormalities, bone marrow failure, and cancer. Classical and most frequent congenital abnormalities include all those seen in VACTERL-H association and those described under the PHENOS acronym. Pathogenic variants in at least 22 genes are associated with FA, which code for proteins that comprise the FA/BRCA DNA repair pathway. We reviewed 187 publications and 1101 cases of FA in which the gene or complementation group was identified and analyzed those in whom physical findings were sought. We conducted genotype-phenotype analyses considering the specific gene, the location in the FA/BRCA DNA repair pathway, and the type of variant (null or hypomorphic) as exposures. The outcomes were the presence of any physical abnormality or specific categories of abnormalities. Seventy-nine percent of the patients had at least one physical abnormality. Pathogenic variants in FANCB, FANCD2, the ID complex and downstream genes were associated with several specific anomalies. Patients with biallelic or hemizygous null variants had a higher proportion of at least one abnormality, renal malformations, microcephaly, short stature and the combination of VACTERL-H compared with those with hypomorphic genotypes. VACTERL-H alone or in combination with PHENOS is highly associated with FA, but the absence of those features does not rule out the diagnosis of FA.

Importance The United States has higher infant and youth mortality rates than other high-income countries, with striking disparities by racial/ethnic group. Understanding changing trends by age and race/ethnicity for leading causes of death is imperative for focused intervention. Objective To estimate trends in US infant and youth mortality rates from 1999 to 2015 by age group and race/ethnicity, identify leading causes of death, and compare mortality rates with Canada and England/Wales. Design, Setting, and Participants This descriptive study analyzed death certificate data from the US National Center for Health Statistics, Statistics Canada, and the UK Office of National Statistics for all deaths among individuals younger than 25 years. The study took place from January 1, 1999, to December 31, 2015, and analyses started in September 2017. Exposures Race/ethnicity. Main Outcomes and Measures Average annual percent changes in mortality rates from 1999 to 2015 and absolute rate change between 1999 to 2002 and 2012 to 2015 for each age group, race/ethnicity, and cause of death. Results Among individuals from birth to age 24 years, 1 169 537 deaths occurred in the United States, 80 540 in Canada, and 121 183 in England/Wales from 1999 to 2015. In the United States, 64% of deaths occurred in male individuals and 52.6% occurred in white individuals (25.1% deaths occurred in black individuals and 17.9% in Latino individuals). All-cause mortality declined for all age groups (infants younger than 1 year [38.5% of deaths], children aged 1-9 years [10.6%], early adolescents aged 10-14 years [5%], late adolescents aged 15-19 years [17.7%], and young adults aged 20-24 years [28.1%]) in the United States, Canada, and England/Wales from 1999 to 2015. However, rates were highest in the United States. Within the United States, annual declines in all-cause mortality rates occurred among all age groups of black, Latino, and white individuals, except for white individuals aged 20 to 24 years, whose rates remained stable. Mortality rates declined across most major causes of death from 1999 to 2002 and 2012 to 2015, with notable declines observed for sudden infant death syndrome, unintentional injury death, and homicides. Among infants, unintentional suffocation and strangulation in bed increased (difference between 2012-2015 and 1999-2002 range, 6.11-29.03 per 100 000). Further, suicide rates among Latino and white individuals aged 10 to 24 years (range, 0.21-2.63 per 100 000) and black individuals aged 10 to 19 years (range, 0.10-0.45 per 100 000) increased, as did unintentional injury deaths in white young adults (0.79 per 100 000). The rise in unintentional injury deaths is attributed to increases in drug poisonings and was also observed in black and Latino young adults. Conclusions and Relevance Mortality rates in the United States have generally declined for infants and youths from 1999 to 2015 owing to reductions in sudden infant death syndrome, unintentional injury death, and homicides. However, US mortality rates remain higher than Canada and England/Wales, with particularly elevated rates among black and American Indian/Alaskan Native youth. Further, there is a concerning increase in suicide and drug poisoning death rates among US adolescents and young adults.

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

1530Background: Li-Fraumeni syndrome (LFS) is an autosomal dominant inherited cancer predisposition syndrome associated with germline pathogenic variants in TP53. It is characterized by early-onset...

We study continuous-time quantum walks on graphs which generalize the hypercube. The only known family of graphs whose quantum walk instantaneously mixes to uniform is the Hamming graphs with small arities. We show that quantum uniform mixing on the hypercube is robust under the addition of perfect matchings but not much else. Our specific results include: (1) The graph obtained by augmenting the hypercube with an additive matching is instantaneous uniform mixing whenever the parity of the matching is even, but with a slower mixing time. This strictly includes Moore-Russell's result on the hypercube. (2) The class of Hamming graphs is not uniform mixing if and only if its arity is greater than 5. This is a tight characterization of quantum uniform mixing on Hamming graphs; previously, only the status of arity less than 5 was known. (3) The bunkbed graph B(A[f]), defined by a hypercube-circulant matrix A and a Boolean function f, is not uniform mixing if the Fourier transform of f has small support. This explains why the hypercube is uniform mixing and why the join of two hypercubes is not., Comment: 13 pages, 4 figures

Malaria is a significant global health issue, with nearly 200 million cases in 2013 alone. Parasites obtain folate from the host or synthesize it de novo. Folate consumption has increased in many populations, prompting concerns regarding potential deleterious consequences of higher intake. The impact of high dietary folate on the host's immune function and response to malaria has not been examined. Our goal was to determine whether high dietary folate would affect response to malarial infection in a murine model of cerebral malaria. Mice were fed control diets (CD, recommended folate level for rodents) or folic acid-supplemented diets (FASD, 10x recommended level) for 5 weeks before infection with Plasmodium berghei ANKA. Survival, parasitemia, numbers of immune cells and other infection parameters were assessed. FASD mice had reduced survival (p

Background: Currently, women are referred for BRCA1/2 mutation testing if their family history of breast and ovarian cancer indicates they have sufficient probability of carrying mutations. In contrast, calls have intensified for population-wide testing for BRCA1/2 founder mutations among Ashkenazi Jews, due to relatively high mutation prevalence (2.5%) and decreasing genotyping costs. However, population-wide testing would strain genetic counseling resources and incur costs from testing mostly mutation-negative women. We compared the performance of population-wide vs. carrier-probability-based BRCA1/2 testing in the community-based Washington Ashkenazi Study (WAS). Methods: BRCA1/2 carrier-probabilities based on reported family histories were calculated using BRCAPRO for 4589 probands (102 BRCA1/2 mutation-carriers) in WAS. For each carrier-probability threshold, we compared the percent of mutations found (sensitivity) vs. the percent of women requiring mutation testing, overall and by proband age. At example carrier-probability thresholds, undetected and detected carriers’ attributes were compared using nonparametric tests. Results: A 1.2% carrier-probability threshold identified 80% of BRCA1/2 mutations in the 35% of women with highest carrier-probability. For women under age 40, 94% of BRCA1/2 mutations were identified in the 50% of women with highest carrier-probability. Compared to identified mutation-carriers, missed mutation-carriers had no personal cancer history, no affected first- and second-degree relatives (p Conclusion: Carrier-probability-based BRCA1/2 mutation testing identified large majorities of mutation-carriers and would have avoided testing for many mutation-negative women. Missed mutation-carriers were older and cancer-free and would gain minimal benefit from risk-reducing interventions. A cost-effective carrier-probability threshold could acceptably tradeoff identifying BRCA1/2 mutation carriers before they get cancer while testing as few women as possible. Citation Format: Ana F. Best, Margaret A. Tucker, Hormuzd A. Katki. Population-wide vs. carrier-probability-based BRCA1/2 mutation testing in the Washington Ashkenazi Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4271. doi:10.1158/1538-7445.AM2017-4271