The number of cancer survivors who develop new cancers is projected to increase, but comprehensive data on the risk of subsequent primary cancers (SPCs) among survivors of adult-onset cancers are limited.OBJECTIVE To quantify the overall and cancer type-specific risks of SPCs among adult-onset cancer survivors by first primary cancer (FPC) types and sex. DESIGN, SETTING, AND PARTICIPANTSA retrospective cohort study from 12 Surveillance, Epidemiology, and End Results registries in the United States, that included 1 537 101 persons aged 20 to 84 years diagnosed with FPCs from 1992-2011 (followed up until December 31, 2017) and who survived at least 5 years.EXPOSURES First primary cancer. MAIN OUTCOMES AND MEASURESIncidence and mortality of SPCs per 10 000 person-years; standardized incidence ratio (SIR) and standardized mortality ratio (SMR) compared with those expected in the general population.RESULTS Among 1 537 101 survivors (mean age, 60.4 years; 48.8% women), 156 442 SPC cases and 88 818 SPC deaths occurred during 11 197 890 person-years of follow-up (mean, 7.3 years). Among men, the overall risk of developing any SPCs was statistically significantly higher for 18 of the 30 FPC types, and risk of dying from any SPCs was statistically significantly higher for 27 of 30 FPC types as compared with risks in the general population. Among women, the overall risk of developing any SPCs was statistically significantly higher for 21 of the 31 FPC types, and risk of dying from any SPCs was statistically significantly higher for 28 of 31 FPC types as compared with risks in the general population. The highest overall SIR and SMR were estimated among survivors of laryngeal cancer (SIR, 1.75 [95% CI, 1.68-1.83]; incidence, 373 per 10 000 person-years) and gallbladder cancer (SMR, 3.82 [95% CI,; mortality, 341 per 10 000 person-years) among men, and among survivors of laryngeal cancer (SIR, 2.48 [95% CI, 2.27-2.72]; incidence, 336 per 10 000 person-years; SMR, 4.56 [95% CI,; mortality, 268 per 10 000 person-years) among women. Substantial variation existed in the associations of specific types of FPCs with specific types of SPC risk; however, only a few smoking-or obesity-associated SPCs, such as lung, urinary bladder, oral cavity/pharynx, colorectal, pancreatic, uterine corpus, and liver cancers constituted considerable proportions of the total incidence and mortality, with lung cancer alone accounting for 31% to 33% of mortality from all SPCs.CONCLUSIONS AND RELEVANCE Among survivors of adult-onset cancers in the United States, several types of primary cancer were significantly associated with greater risk of developing and dying from an SPC, compared with the general population. Cancers associated with smoking or obesity comprised substantial proportions of overall SPC incidence and mortality among all survivors and highlight the importance of ongoing surveillance and efforts to prevent new cancers among survivors.

Background: HPV testing is replacing cytology for cervical cancer screening because of greater sensitivity and superior reassurance following negative tests for the dozen HPV genotypes that cause cervical cancer. Management of women testing positive is unresolved. The need for identification of individual HPV genotypes for clinical use is debated. Also, it is unclear how long to observe persistent infections when precancer is not initially found. Methods: In the longitudinal NCI-Kaiser Permanente Northern California Persistence and Progression (PaP) Study, we observed the clinical outcomes (clearance, progression to CIN3+, or persistence without progression) of 11,573 HPV-positive women aged 30À65 yielding 14,158 type-specific infections. Findings: Risks of CIN3+ progression differed substantially by type, with HPV16 conveying uniquely elevated risk (26% of infections with seven-year CIN3+ risk of 22%). The other carcinogenic HPV types fell into 3 distinct seven-year CIN3+ risk groups: HPV18, 45 (13% of infections, risks >5%, with known elevated cancer risk); HPV31, 33, 35, 52, 58 (39%, risks >5%); and HPV39, 51, 56, 59, 68 (23%, risks <5%). In the absence of progression, HPV clearance rates were similar by type, with 80% of infections no longer detected within three years; persistence to seven years without progression was uncommon. The predictive value of abnormal cytology was most evident for prevalent CIN3+, but less evident in follow-up. A woman's age did not modify risk; rather it was the duration of persistence that was important.

HPV testing is more sensitive than cytology for cervical screening. However, to incorporate HPV tests into screening, risk-stratification ("triage") of HPV-positive women is needed to avoid excessive colposcopy and overtreatment. We prospectively evaluated combinations of partial HPV typing (Onclarity, BD) and cytology triage, and explored whether management could be simplified, based on grouping combinations yielding similar 3-year or 18-month CIN3+ risks. We typed ∼9,000 archived specimens, taken at enrollment (2007-2011) into the NCI-Kaiser Permanente Northern California (KPNC) HPV Persistence and Progression (PaP) cohort. Stratified sampling, with reweighting in the statistical analysis, permitted risk estimation of HPV/cytology combinations for the 700,000+-woman KPNC screening population. Based on 3-year CIN3+ risks, Onclarity results could be combined into five groups (HPV16, else HPV18/45, else HPV31/33/58/52, else HPV51/35/39/68/56/66/68, else HPV negative); cytology results fell into three risk groups ("high-grade," ASC-US/LSIL, NILM). For the resultant 15 HPV group-cytology combinations, 3-year CIN3+ risks ranged 1,000-fold from 60.6% to 0.06%. To guide management, we compared the risks to established "benchmark" risk/management thresholds in this same population (e.g., LSIL predicted 3-year CIN3+ risk of 5.8% in the screening population, providing the benchmark for colposcopic referral). By benchmarking to 3-year risk thresholds (supplemented by 18-month estimates), the widely varying risk strata could be condensed into four action bands (very high risk of CIN3+ mandating consideration of cone biopsy if colposcopy did not find precancer; moderate risk justifying colposcopy; low risk managed by intensified follow-up to permit HPV "clearance"; and very low risk permitting routine screening.) Overall, the results support primary HPV testing, with management of HPV-positive women using partial HPV typing and cytology.

OBJECTIVETo identify novel metabolic markers for diabetes development in American Indians.RESEARCH DESIGN AND METHODSUsing an untargeted high-resolution liquid chromatography–mass spectrometry, we conducted metabolomics analysis of study participants who developed incident diabetes (n = 133) and those who did not (n = 298) from 2,117 normoglycemic American Indians followed for an average of 5.5 years in the Strong Heart Family Study. Relative abundances of metabolites were quantified in baseline fasting plasma of all 431 participants. Prospective association of each metabolite with risk of developing type 2 diabetes (T2D) was examined using logistic regression adjusting for established diabetes risk factors.RESULTSSeven metabolites (five known and two unknown) significantly predict the risk of T2D. Notably, one metabolite matching 2-hydroxybiphenyl was significantly associated with an increased risk of diabetes, whereas four metabolites matching PC (22:6/20:4), (3S)-7-hydroxy-2′,3′,4′,5′,8-pentamethoxyisoflavan, or tetrapeptides were significantly associated with decreased risk of diabetes. A multimarker score comprising all seven metabolites significantly improved risk prediction beyond established diabetes risk factors including BMI, fasting glucose, and insulin resistance.CONCLUSIONSThe findings suggest that these newly detected metabolites may represent novel prognostic markers of T2D in American Indians, a group suffering from a disproportionately high rate of T2D.

BACKGROUND: Cancer incidence is higher in men than in women at most shared anatomic sites for currently unknown reasons. The authors quantified the extent to which behaviors (smoking and alcohol use), anthropometrics (body mass index and height), lifestyles (physical activity, diet, medications), and medical history collectively explain the male predominance of risk at 21 shared cancer sites. METHODS: Prospective cohort analyses (n = 171,274 male and n = 122,826 female participants; age range, 50-71 years) in the National Institutes of Health-AARP Diet and Health Study (1995-2011). Cancer-specific Cox regression models were used to estimate male-to-female hazard ratios (HRs). The degree to which risk factors explained the observed male-female risk disparity was quantified using the Peters-Belson method. RESULTS: There were 26,693 incident cancers (17,951 in men and 8742 in women). Incidence was significantly lower in men than in women only for thyroid and gallbladder cancers. At most other anatomic sites, the risks were higher in men than in women (adjusted HR range, 1.3-10.8), with the strongest increases for bladder cancer (

IMPORTANCETelemedicine provides patients access to episodic and longitudinal care. Policy discussions surrounding future support for telemedicine require an understanding of factors associated with successful video visits. OBJECTIVE To assess patient and clinician factors associated with successful and with failed video visits. DESIGN, SETTING, AND PARTICIPANTS This was a quality improvement study of 137 846 scheduled video visits at a single academic health system in southeastern Wisconsin between March 1 and December 31, 2020, supplemented with patient experience survey data. Patient information was gathered using demographic information abstracted from the electronic health record and linked with block-level socioeconomic data from the US Census Bureau. Data on perceived clinician experience with technology was obtained using the survey. MAIN OUTCOMES AND MEASURES The primary outcome of interest was the successful completion of a scheduled video visit or the conversion of the video visit to a telephone-based service. Visit types and administrative data were used to categorize visits. Mixed-effects modeling with pseudo R 2 values was performed to compare the relative associations of patient and clinician factors with video visit failures. RESULTS In total, 75 947 patients and 1155 clinicians participated in 137 846 scheduled video encounters, 17 190 patients (23%) were 65 years or older, and 61 223 (81%) patients were of White race and ethnicity. Of the scheduled video encounters, 123 473 (90%) were successful, and 14 373 (10%) were converted to telephone services. A total of 16 776 patients (22%) completed a patient experience survey. Lower clinician comfort with technology (odds ratio [OR], 0.15; 95% CI, 0.08-0.28), advanced patient age (66-80 years: OR, 0.28; 95% CI, 0.26-0.30), lower patient socioeconomic status (including low high-speed internet availability) (OR, 0.85; 95% CI, 0.77-0.92), and patient racial and ethnic minority group status (Black or African American: OR, 0.75; 95% CI, 0.69-0.81) were associated with conversion to telephone visits. Patient characteristics accounted for systematic components for success; marginal pseudo R 2 values decreased from 23% (95% CI, 21.1%-26.1%) to 7.8% (95% CI, 6.3%-9.4%) with exclusion of patient factors. CONCLUSIONS AND RELEVANCEAs policy makers consider expanding telehealth coverage and hospital systems focus on investments, consideration of patient support, equity, and friction should guide decisions. In particular, this quality improvement study suggests that underserved patients may become disproportionately vulnerable by cuts in coverage for telephone-based services.

For cost-effectiveness and efficiency, many large-scale general-purpose cohort studies are being assembled within large health-care providers who use electronic health records. Two key features of such data are that incident disease is interval-censored between irregular visits and there can be pre-existing (prevalent) disease. Because prevalent disease is not always immediately diagnosed, some disease diagnosed at later visits are actually undiagnosed prevalent disease. We consider prevalent disease as a point mass at time zero for clinical applications where there is no interest in time of prevalent disease onset. We demonstrate that the naive Kaplan-Meier cumulative risk estimator underestimates risks at early time points and overestimates later risks. We propose a general family of mixture models for undiagnosed prevalent disease and interval-censored incident disease that we call prevalence-incidence models. Parameters for parametric prevalence-incidence models, such as the logistic regression and Weibull survival (logistic-Weibull) model, are estimated by direct likelihood maximization or by EM algorithm. Non-parametric methods are proposed to calculate cumulative risks for cases without covariates. We compare naive Kaplan-Meier, logistic-Weibull, and non-parametric estimates of cumulative risk in the cervical cancer screening program at Kaiser Permanente Northern California. Kaplan-Meier provided poor estimates while the logistic-Weibull model was a close fit to the non-parametric. Our findings support our use of logistic-Weibull models to develop the risk estimates that underlie current U.S. risk-based cervical cancer screening guidelines.

Background This study was aimed at examining the risks of subsequent primary cancers (SPCs) among breast cancer survivors by hormone receptor (HR) status and age at diagnosis. Methods Data from 12 Surveillance, Epidemiology, and End Results registries were used to identify 431,222 breast cancer survivors (at least 1 year) diagnosed between the ages of 20 and 84 years from 1992 to 2015. Risks of SPCs were measured as the standardized incidence ratio (SIR) and the excess absolute risk (EAR) per 10,000 person‐years. Poisson regression was used to test the difference in SIRs by HR status. Results In comparison with the general population, the risk of new cancer diagnoses among survivors was 20% higher for those with HR‐positive cancers (SIR, 1.20; 95% confidence interval [CI], 1.19‐1.21; EAR, 23.3/10,000 person‐years) and 44% higher for those with HR‐negative cancers (SIR, 1.44; 95% CI, 1.41‐1.47; EAR, 45.2/10,000 person‐years), with the risk difference between HR statuses statistically significant. The higher risk after HR‐negative cancer was driven by acute nonlymphocytic leukemia and breast, ovarian, peritoneal, and lung cancers. By age at diagnosis, the total EAR per 10,000 person‐years ranged from 15.8 (95% CI, 14.1‐17.5; SIR, 1.11) among late‐onset (age, 50‐84 years) HR‐positive survivors to 69.4 (95% CI, 65.1‐73.7; SIR, 2.24) among early‐onset (age, 20‐49 years) HR‐negative survivors, with subsequent breast cancer representing 73% to 80% of the total EAR. After breast cancer, the greatest EARs were for ovarian cancer among early‐onset HR‐negative survivors, lung cancer among early‐ and late‐onset HR‐negative survivors, and uterine corpus cancer among late‐onset HR‐positive survivors. Conclusions Risks of SPCs after breast cancer differ substantially by subtype and age. This suggests that more targeted approaches for cancer prevention and early‐detection strategies are needed in survivorship care planning.