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Purpose: Although patients' function, symptoms, and supportive care needs are obviously related, a better understanding of these relationships could improve patient management.Methods: In this cross-sectional, observational study, 117 cancer patients completed the Supportive Care Needs Survey-34 and EORTC-QLQ-C30. Each symptom and function domain from the EORTC-QLQ-C30 was dichotomized (high vs. low) using a cut-off of reference sample mean scores. Each need domain was dichotomized using a cut-off of an average score representing an unmet need. We explored within-patient patterns of function, symptom, and need domains using latent class analysis. Based on these patterns, patients were categorized as high versus low function; high versus low symptom; and high versus low need. We examined the concordance between categorizations of patients' function, symptoms, and needs.Results: The categorizations of function, symptoms, and needs were concordant for 66 patients (56%). Among patients with deficits in at least one area (n = 68), categorizations for 51 patients (75%) were discordant.Conclusions: About 50% of patients have similar classifications of their level of function, symptoms, and needs, but discordance was common among patients with deficits in at least one area, emphasizing the importance of assessing all of these outcomes as part of patient evaluations. [ABSTRACT FROM AUTHOR]

Background: Continuous oxygen therapy is not recommended for emphysema patients who are not hypoxemic at rest, although it is often prescribed. Little is known regarding the clinical characteristics and survival of nonhypoxemic emphysema patients using continuous oxygen. Analysis of data from the National Emphysema Treatment Trial (NETT) offers insight into this population.Methods: We analyzed demographic and clinical characteristics of 1,215 participants of NETT, stratifying by resting PaO(2) and reported oxygen use. Eight-year survival was evaluated in individuals randomized to medical therapy.Results: At enrollment, 33.8% (n = 260) of participants nonhypoxemic at rest reported continuous oxygen use. When compared to nonhypoxemic individuals not using oxygen (n = 226), those using continuous oxygen had worse dyspnea, lower quality of life, more frequent exercise desaturation, and higher case-fatality rate. After adjusting for age, body mass index, and FEV(1) percentage of predicted, the presence of exercise desaturation accounted for the differential mortality seen between these groups.Conclusions: In the NETT, the use of continuous oxygen in resting nonhypoxemic emphysema patients was associated with worse disease severity and survival. The differential survival observed could nearly all be accounted for by the higher prevalence of exercise desaturation in those using continuous oxygen, suggesting that it is not a harmful effect of oxygen therapy contributing to mortality. It remains unclear whether continuous oxygen therapy improves survival in normoxic patients with exercise desaturation. [ABSTRACT FROM AUTHOR]

Purpose: As patient-reported outcome measures (PROMs) are increasingly used in clinical practice for screening, monitoring, and management, the potential for response bias has been raised (e.g., over-reporting problems for attention, under-reporting to avoid treatment changes/discontinuation). We investigated whether patients systematically bias their responses when they know clinicians will review their PROM results., Methods: We conducted secondary analyses of three experimental studies evaluating PROMs in adult and pediatric care. Prior to PROM completion, intervention group patients were informed that the results would be shown to their clinicians ("feedback" arm), whereas control group patients were told that their clinicians would not see their responses ("no feedback" arm). Independent sample t-tests compared the "feedback" and "no feedback" arms' PROM scores at baseline. Effect sizes and 95% confidence intervals were estimated using Cohen's d statistics with Hedges' g correction, and effect sizes > 0.50 were considered clinically relevant., Results: Across the 29 domains assessed in the three studies, no between-arm differences reached an effect size of ± 0.50. Only 3/29 effect sizes exceeded ± 0.30. The confidence intervals for 14 domains included ± 0.50, with 4 favoring the "no feedback" arm and 10 favoring the "feedback" arm. Two domains reached statistical significance, one favoring the "no feedback" arm and one favoring the "feedback" arm., Conclusion: This study does not support the hypothesis that patients systematically bias their PROM responses if they know that clinicians will see their results. These findings support using PROMs in clinical practice as a valid mechanism to promote patient-centered care., (© 2024. The Author(s).)

Purpose: Weight gain after breast cancer poses health risks. We aimed to identify factors associated with weight gain during adjuvant endocrine therapy (AET)., Methods: Women initiating AET enrolled in a prospective cohort. Participants completed FACT-ES plus PROMIS pain interference, depression, anxiety, fatigue, sleep disturbance and physical function measures at baseline, 3, 6, 12, 24, 36, 48 and 60 months. Treatment-emergent symptoms were defined as changes in scores in the direction indicative of worsening symptoms that exceeded the minimal important difference at 3 and/or 6 months compared to baseline. We used logistic regression to evaluate associations of clinicodemographic features and treatment-emergent symptoms with clinically significant weight gain over 60 months (defined as ≥ 5% compared to baseline) in pre- and post-menopausal participants., Results: Of 309 participants, 99 (32%) were pre-menopausal. The 60 months cumulative incidence of clinically significant weight gain was greater in pre- than post-menopausal participants (67% vs 43%, p < 0.001). Among pre-menopausal participants, treatment-emergent pain interference (OR 2.49), aromatase inhibitor receipt (OR 2.8), mastectomy, (OR 2.06) and White race (OR 7.13) were associated with weight gain. Among post-menopausal participants, treatment-emergent endocrine symptoms (OR 2.86), higher stage (OR 2.25) and White race (OR 2.29) were associated with weight gain while treatment-emergent physical function decline (OR 0.30) was associated with lower likelihood of weight gain., Conclusions: Weight gain during AET is common, especially for pre-menopausal women. Clinicodemographic features and early treatment-emergent symptoms may identify at risk individuals., Implications for Cancer Survivors: Patients at risk for weight gain can be identified early during AET., Gov Identifier: NCT01937052, registered September 3, 2013., (© 2023. The Author(s).)

Importance: Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with increasing incidence. The majority of PDACs are incurable at presentation, but population-based screening is not recommended. Surveillance of high-risk individuals for PDAC may lead to early detection, but the survival benefit is unproven., Objective: To compare the survival of patients with surveillance-detected PDAC with US national data., Design, Setting, and Participants: This comparative cohort study was conducted in multiple US academic medical centers participating in the Cancer of the Pancreas Screening program, which screens high-risk individuals with a familial or genetic predisposition for PDAC. The comparison cohort comprised patients with PDAC matched for age, sex, and year of diagnosis from the Surveillance, Epidemiology, and End Results (SEER) program. The Cancer of the Pancreas Screening program originated in 1998, and data collection was done through 2021. The data analysis was performed from April 29, 2022, through April 10, 2023., Exposures: Endoscopic ultrasonography or magnetic resonance imaging performed annually and standard-of-care surgical and/or oncologic treatment., Main Outcomes and Measures: Stage of PDAC at diagnosis, overall survival (OS), and PDAC mortality were compared using descriptive statistics and conditional logistic regression, Cox proportional hazards regression, and competing risk regression models. Sensitivity analyses and adjustment for lead-time bias were also conducted., Results: A total of 26 high-risk individuals (mean [SD] age at diagnosis, 65.8 [9.5] years; 15 female [57.7%]) with PDAC were compared with 1504 SEER control patients with PDAC (mean [SD] age at diagnosis, 66.8 [7.9] years; 771 female [51.3%]). The median primary tumor diameter of the 26 high-risk individuals was smaller than in the control patients (2.5 [range, 0.6-5.0] vs 3.6 [range, 0.2-8.0] cm, respectively; P < .001). The high-risk individuals were more likely to be diagnosed with a lower stage (stage I, 10 [38.5%]; stage II, 8 [30.8%]) than matched control patients (stage I, 155 [10.3%]; stage II, 377 [25.1%]; P < .001). The PDAC mortality rate at 5 years was lower for high-risk individuals than control patients (43% vs 86%; hazard ratio, 3.58; 95% CI, 2.01-6.39; P < .001), and high-risk individuals lived longer than matched control patients (median OS, 61.7 [range, 1.9-147.3] vs 8.0 [range, 1.0-131.0] months; 5-year OS rate, 50% [95% CI, 32%-80%] vs 9% [95% CI, 7%-11%])., Conclusions and Relevance: These findings suggest that surveillance of high-risk individuals may lead to detection of smaller, lower-stage PDACs and improved survival.

Background: Lack of stable, affordable housing is an important social determinant of health. Federal housing assistance may buffer against housing vulnerabilities among low-income households, but research examining the association of housing assistance and cancer care has been limited. We introduce a new linkage of Surveillance, Epidemiology, and End Results (SEER) program-Medicare and US Department of Housing and Urban Development (HUD) administrative data., Methods: Individuals enrolled in HUD public and assisted housing programs between 2006 and 2021 were linked with cancer diagnoses between 2006 and 2019 identified in the SEER-Medicare data from 16 states using Match*Pro (National Institutes of Health, Bethesda, MD) probabilistic linkage software. HUD administrative data include timing and type of housing assistance as well as verified household income. Medicare administrative data are available through 2020., Results: A total of 335 490 unique individuals who received housing assistance at any time point, including 156 794 who received housing assistance around the time of their diagnosis (at least 6 months before diagnosis until 6 months after diagnosis or death), were matched to SEER-Medicare data. A total of 63 251 individuals receiving housing assistance at the time of their diagnosis were aged 66 years and older and continuously enrolled in Medicare parts A and B fee for service; 12 035 had a diagnosis of lung cancer, 8866 of breast cancer, 7261 of colorectal cancer, and 4703 of prostate cancer., Conclusions: This novel data linkage will be available through the National Cancer Institute and can be used to explore the ways in which housing assistance is associated with cancer diagnosis, care, and outcomes, including the role of housing assistance status in potentially reducing or contributing to inequities across racialized and ethnic groups., (Published by Oxford University Press 2024.)

Purpose: Circulating carbohydrate antigen 19-9 (CA19-9) levels reflect FUT3 and FUT2 fucosyltransferase activity. Measuring the related glycan, DUPAN-2, can be useful in individuals unable to synthesize CA19-9. We hypothesized that similar to CA19-9, FUT functional groups determined by variants in FUT3 and FUT2 influence DUPAN-2 levels, and having tumor marker reference ranges for each functional group would improve diagnostic performance., Materials and Methods: Using a training/validation study design, FUT2 / FUT3 genotypes were determined in 938 individuals from Johns Hopkins Hospital: 607 Cancer of the Pancreas Screening (CAPS) study subjects with unremarkable pancreata and 331 with pancreatic ductal adenocarcinoma (PDAC). Serum DUPAN-2 and CA19-9 levels were measured by immunoassay., Results: In controls, three functional FUT groups were identified with significant differences in DUPAN-2 levels: FUT3-intact, FUT3-null/FUT2-intact, and FUT3-null/FUT2-null. DUPAN-2 training set diagnostic cutoffs for each FUT group yielded higher diagnostic sensitivity in the validation set for patients with stage I/II PDAC than uniform cutoffs (60.4% [95% CI, 50.2 to 70.0] v 39.8% [30.0 to 49.8]), at approximately 99% (96.7 to 99.6) specificity. Combining FUT/CA19-9 and FUT/DUPAN-2 tests yielded 78.4% (72.3 to 83.7) sensitivity for stage I/II PDAC, at 97.7% (95.3 to 99.1) specificity in the combined sets, with higher AUC (stage I/II: 0.960 v 0.935 for CA19-9 + DUPAN-2 without the FUT test; P < .001); for stage I PDAC, sensitivity was 62.0% (49.1 to 73.2; AUC, 0.919 v 0.883; P = .03). CA19-9 levels in FUT3-null/FUT2-null PDAC subjects were higher than in FUT3-null/FUT2-intact subjects (median/IQR; 24.9/57.4 v <1/2.3 U/mL; P = .0044). In a simulated CAPS cohort, AUC precision recall (AUC PR ) scores were 0.51 for CA19-9 alone, 0.64 for FUT/CA19-9, 0.73 for CA19-9/DUPAN-2, and 0.84 for FUT/CA19-9/DUPAN-2., Conclusion: Using a tumor marker gene test to individualize CA19-9 and DUPAN-2 reference ranges achieves high diagnostic performance for stage I/II pancreatic cancer.

Background and Aims: Liver fibrosis is common in children with NAFLD and is an important determinant of outcomes. High-performing noninvasive models to assess fibrosis in children are needed. The objectives of this study were to evaluate the performance of existing pediatric and adult fibrosis prediction models and to develop a clinical prediction rule for identifying moderate-to-severe fibrosis in children with NAFLD., Approach and Results: We enrolled children with biopsy-proven NAFLD in the Nonalcoholic Steatohepatitis Clinical Research Network within 90 days of liver biopsy. We staged liver fibrosis in consensus using the Nonalcoholic Steatohepatitis Clinical Research Network scoring system. We evaluated existing pediatric and adult models for fibrosis and developed a new pediatric model using the least absolute shrinkage and selection operator with linear and spline terms for discriminating moderate-to-severe fibrosis from none or mild fibrosis. The model was internally validated with 10-fold cross-validation. We evaluated 1055 children with NAFLD, of whom 26% had moderate-to-severe fibrosis. Existing models performed poorly in classifying fibrosis in children, with area under the receiver operator curves (AUC) ranging from 0.57 to 0.64. In contrast, our new model, fibrosis in pediatric NAFLD was derived from fourteen common clinical variables and had an AUC of 0.79 (95% CI: 0.77-0.81) with 72% sensitivity and 76% specificity for identifying moderate-to-severe fibrosis., Conclusion: Existing fibrosis prediction models have limited clinical utility in children with NAFLD. Fibrosis in pediatric NAFLD offers improved performance characteristics for risk stratification by identifying moderate-to-severe fibrosis in children with NAFLD., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Advances in biomedical research require a robust physician scientist workforce. Despite being equally successful at securing early career awards from the NIH as men, women MD-PhD physician scientists are less likely to serve as principal investigators on mid- and later careers awards. Here, we discuss the causes of gender disparities in academic medicine, the implications of losing highly trained women physician scientists, and the institutional and systemic changes needed to sustain this pool of talented investigators., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Cancer antigen 19-9 (CA19-9) is widely used as a marker of pancreatic cancer tumor burden and response to therapy. Synthesis of CA19-9 and its circulating levels are determined by variants encoding the fucosyltransferases, FUT2 and FUT3. Individuals can be grouped into one of four functional FUT groups (FUT3-null, FUT-low, FUT-intermediate, FUT-high), each with its own CA19-9 reference range based on its predicted capacity to produce CA19-9. The authors hypothesized that a FUT variant-based CA19-9 tumor marker gene test could improve the prognostic performance of CA19-9., Methods: Preoperative and pre-treatment CA19-9 levels were measured, and FUT variants were determined in 449 patients who underwent surgery for pancreatic ductal adenocarcinoma (PDAC) at Johns Hopkins Hospital between 2010 and 2020, including 270 patients who underwent neoadjuvant therapy. Factors associated with recurrence-free and overall survival were determined in Cox proportional hazards models., Results: Higher preoperative CA19-9 levels were associated with recurrence and mortality for patients in the higher-FUT groups (FUT-intermediate, FUT-high for mortality, with adjustment for other prognostic factors; hazard ratio [HR], 1.34 and 1.58, respectively; P < 0.001), but not for those in the lower-FUT groups (FUT3-null, FUT-low). As a tumor marker, CA19-9 levels of 100 U/ml or lower after neoadjuvant therapy and normalization of CA19-9 based on FUT group were more sensitive but less specific predictors of evidence for a major pathologic response to therapy (little/no residual tumor) and of early recurrence (within 6 months)., Conclusion: Among patients undergoing pancreatic cancer resection, a CA19-9 tumor marker gene test modestly improved the prognostic performance of CA19-9., (© 2024. Society of Surgical Oncology.)

Objectives: Early discontinuation is common among breast cancer patients taking aromatase inhibitors (AIs). Although several predictors have been identified, it is unclear how to simultaneously consider multiple risk factors for an individual. We sought to develop a tool for prediction of AI discontinuation and to explore how predictive value of risk factors changes with time., Materials and Methods: Survival machine learning was used to predict time-to-discontinuation of AIs in 181 women who enrolled in a prospective cohort. Models were evaluated via time-dependent area under the curve (AUC), c-index, and integrated Brier score. Feature importance was analysis was conducted via Shapley Additive Explanations (SHAP) and time-dependence of their predictive value was analyzed by time-dependent AUC. Personalized survival curves were constructed for risk communication., Results: The best-performing model incorporated genetic risk factors and changes in patient-reported outcomes, achieving mean time-dependent AUC of 0.66, and AUC of 0.72 and 0.67 at 6- and 12-month cutoffs, respectively. The most significant features included variants in ESR1 and emergent symptoms. Predictive value of genetic risk factors was highest in the first year of treatment. Decrease in physical function was the strongest independent predictor at follow-up., Discussion and Conclusion: Incorporation of genomic and 3-month follow-up data improved the ability of the models to identify the individuals at risk of AI discontinuation. Genetic risk factors were particularly important for predicting early discontinuers. This study provides insight into the complex nature of AI discontinuation and highlights the importance of incorporating genetic risk factors and emergent symptoms into prediction models., Competing Interests: The authors declare no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Medical Informatics Association.)

Purpose: CA19-9 synthesis is influenced by common variants in the fucosyltransferase (FUT) enzymes FUT3 and FUT2. We developed a clinical test to detect FUT variants, and evaluated its diagnostic performance for pancreatic ductal adenocarcinoma (PDAC)., Experimental Design: A representative set of controls from the Cancer of the Pancreas Screening study was identified for each FUT functional group. Diagnostic sensitivity was determined first in a testing set of 234 PDAC cases, followed by a 134-case validation set, all of whom had undergone resection with curative intent without neoadjuvant therapy. Tumor marker gene testing was performed in the Johns Hopkins Molecular Diagnostics Laboratory. CA19-9 levels were measured in the Hopkins Clinical Chemistry lab. Receiver operating characteristic (ROC) curve analysis was used to evaluate the discriminative ability of CA19-9 alone versus with the gene test., Results: Applying the CA19-9 standard cutoff (<36 U/mL) to all 716 subjects yielded a 68.8% sensitivity in the test set of cases, 67.2% in the validation set, at 91.4% specificity. Applying 99th percentile cutoffs according to each individual's FUT group (3, 34.9, 41.8, and 89.2, for the FUT3-null, FUT-low, FUT-intermediate, and FUT-high groups, respectively) yielded a diagnostic sensitivity for CA19-9 in the first set of cases of 66.7%, 65.7% in the validation set, at 98.9% specificity. ROC analysis for CA19-9 alone yielded an AUC of 0.84; with the tumor marker gene test, AUC improved to 0.92 (P < 0.001)., Conclusions: Using a tumor marker gene test to personalize an individual's CA19-9 reference range significantly improves diagnostic accuracy., (©2023 The Authors; Published by the American Association for Cancer Research.)

Substantial gaps in national healthcare spending and disparities in cancer mortality rates are noted across counties in the US. In this cross-sectional analysis, we investigated whether differences in local county-level social vulnerability impacts cancer-related mortality. We linked county-level age-adjusted mortality rates (AAMR) from the Centers for Disease Control and Prevention (CDC) Wide-ranging Online Data for Epidemiologic Research database, to county-level Social Vulnerability Index (SVI) from the CDC Agency for Toxic Substances and Disease Registry. SVI is a metric comprising 15 social factors including socioeconomic status, household composition and disability, minority status and language, and housing type and transportation. AAMRs were compared between least and most vulnerable counties using robust linear regression models. There were 4 107 273 deaths with an overall AAMR of 173 per 100 000 individuals. Highest AAMRs were noted in older adults, men, non-Hispanic Black individuals, and rural and Southern counties. Highest mortality risk increases between least and most vulnerable counties were noted in Southern and rural counties, individuals aged 45-65, and lung and colorectal cancers, suggesting that these groups may face highest risk for health inequity. These findings inform ongoing deliberations in public health policy at the state and federal level and encourage increased investment into socially disadvantaged counties., (© The Author(s) 2023. Published by Oxford University Press.)

Background: Patients with gastroparesis (Gp) may need enteral nutrition (EN) or exclusive parenteral nutrition (PN). Among patients with Gp, we aimed to (1) identify the frequency of EN and exclusive PN use and (2) explore characteristics of patients using EN and/or exclusive PN compared with those using oral nutrition (ON), including changes over 48 weeks., Methods: Patients with Gp underwent history and physical examination, gastric emptying scintigraphy, water load satiety testing (WLST), and questionnaires assessing gastrointestinal symptoms and quality of life (QOL). Patients were observed 48 weeks., Results: Of 971 patients with Gp (idiopathic, 579; diabetic, 336; post-Nissen fundoplication, 51), 939 (96.7%) were using ON only, 14 (1.4%) using exclusive PN, and 18 (1.9%) using EN. Compared with patients receiving ON, patients receiving exclusive PN and/or EN were younger, had lower body mass index, and had greater symptom severity. Patients receiving exclusive PN and/or EN had lower physical QOL but not mental QOL or Gp-related QOL scores. Patients receiving exclusive PN and/or EN ingested less water during WLST but did not have worse gastric emptying. Of those who had been receiving exclusive PN and/or EN, 50% and 25%, respectively, resumed ON at 48-week follow-up., Conclusions: This study describes patients with Gp requiring exclusive PN and/or EN for nutrition support, who represent a small (3.3%) but important subset of patients with Gp. Unique clinical and physiological parameters are associated with this subset and provide insight into the use of nutrition support in Gp., (© 2023 American Society for Parenteral and Enteral Nutrition.)

Patients with short telomere syndromes (STS) are predisposed to developing cancer, believed to stem from chromosome instability in neoplastic cells. We tested this hypothesis in a large cohort assembled over the last 20 years. We found that the only solid cancers to which patients with STS are predisposed are squamous cell carcinomas of the head and neck, anus, or skin, a spectrum reminiscent of cancers seen in patients with immunodeficiency. Whole-genome sequencing showed no increase in chromosome instability, such as translocations or chromothripsis. Moreover, STS-associated cancers acquired telomere maintenance mechanisms, including telomerase reverse transcriptase (TERT) promoter mutations. A detailed study of the immune status of patients with STS revealed a striking T cell immunodeficiency at the time of cancer diagnosis. A similar immunodeficiency that impaired tumor surveillance was documented in mice with short telomeres. We conclude that STS patients’ predisposition to solid cancers is due to T cell exhaustion rather than autonomous defects in the neoplastic cells themselves., Competing Interests: Declaration of interests R.H.V. is an inventor on licensed patents related to cancer cellular immunotherapy and cancer vaccines, receives royalties from Boston Children’s Hospital for a licensed research-only monoclonal antibody, and has received consulting fees from Bristol Myers Squibb., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Survivorship care plans (SCPs) communicate cancer-related information from oncology providers to patients and primary care providers. SCPs may limit overuse testing by specifying necessary follow-up care. From a randomized, controlled trial of SCP delivery, we examined whether cancer-related tests not specified in SCPs, but conducted after SCP receipt, were appropriate or consistent with overuse., Methods: Survivors of breast, colorectal, or prostate cancer treated at urban-academic or rural-community health systems were randomized to one of three SCP delivery arms. Tests during 18 months after SCP receipt were classified as consistent with overuse if they were (1) not included in SCPs and (2) on a guideline-based predetermined list of "not recommended surveillance." After chart abstraction, physicians performed review and adjudication of potential overuse. Descriptive analyses were conducted of tests consistent with overuse. Negative binomial regression models determined if testing consistent with overuse differed across study arms., Results: Among 316 patients (137 breast, 67 colorectal, 112 prostate), 140 individual tests were identified as potential overuse. Upon review, 98 were deemed to be consistent with overuse: 78 tumor markers and 20 imaging tests. The majority of overuse testing was breast cancer-related (95%). Across sites, 27 patients (9%) received ≥1 test consistent with overuse; most were breast cancer patients (22/27). Exploratory analyses of overuse test frequency by study arm showed no significant difference., Conclusions: This analysis identified practice patterns consistent with overuse of surveillance testing and can inform efforts to improve guideline-concordant care. Future interventions may include individual practice patterns and provider education., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

We performed a secondary analysis of the Moving To Opportunity (MTO) social experiment to investigate the impact of different types of housing assistance and neighborhood environments on long-term patterns of health care use for specific conditions and across different types of health care services. MTO participants, who were randomized at baseline, were linked to up to 21 years of all-payer hospital discharge and Medicaid data. Among the 9,170 children at the time of randomization, those who received a voucher had subsequent hospital admissions rates that were 36% lower for asthma and 30% lower for mental health disorders compared to the control group; rates of psychiatric services, outpatient hospital services, clinic services and durable medical equipment were also lower among the voucher groups. Findings for adults were not statistically significant. The results suggest that housing policies that reduce neighborhood poverty exposure as a child are associated with lower subsequent healthcare use for specific clinical conditions and types of services.

Purpose: Sexual function problems are common but under-reported among women receiving adjuvant endocrine therapy for breast cancer. Worsening scores on patient-reported outcomes (PROs) may identify those at risk for sexual function problems during treatment. We performed a secondary analysis of prospectively collected PROs in women receiving adjuvant endocrine therapy to identify factors associated with worsening sexual function., Methods: Women with stage 0-III breast cancer initiating adjuvant endocrine therapy participating in a prospective cohort completed PROs at baseline, 3, 6, 12, 24, 36, 48, and 60 months. Sexual function was evaluated by the MOS-SP measure. Other measures included PROMIS pain interference, fatigue, depression, anxiety, physical function, and sleep disturbance and the Endocrine Symptom Subscale of the FACT-ES. We evaluated associations between score worsening of at least the minimal important difference (MID) in PROMIS T-scores (4 points) and FACT-ES scores (5 points) with score worsening of at least the MID in MOS-SP scores (8 points) using logistic regression., Results: Among 300 participants, 45.7% experienced ≥ 8-point worsening of MOS-SP score at any time point compared to baseline. Worsening endocrine symptoms (OR 1.34, 95% CI 1.22-1.49, p < 0.001), worsening physical function (OR 1.09, 95% CI 1.00-1.18, p = 0.06), and prior mastectomy (OR 1.45, 95% CI 0.94-2.23, p = 0.09) were associated with MOS-SP score worsening by at least the MID., Conclusion: Worsening endocrine symptoms and physical function identified on PROs are associated with worsening sexual function during adjuvant endocrine therapy. Routine assessment of these domains with PROs may identify women at risk for sexual function problems., Trial Registration Number: NCT01937052; Date of Registration: 09/09/2013., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background and Aims: Serum diagnostic markers of early-stage pancreatic ductal adenocarcinoma (PDAC) are needed, especially for stage I disease. As tumors grow and cause pancreatic atrophy, markers derived from pancreatic parenchyma such as serum carboxypeptidase A (CPA) activity lose diagnostic performance. We evaluated, with CA19-9, serum CPA as a marker of early pancreatic cancer., Methods: Serum CPA activity levels were measured in 345 controls undergoing pancreatic surveillance, divided into 2 sets, set 1 being used to establish a reference range. Variants within the CPA1 locus were sought for their association with pancreatic CPA1 expression to determine if such variants associated with serum CPA levels. A total of 190 patients with resectable PDAC were evaluated., Results: Among controls, those having 1 or more minor alleles of CPA1 variants rs6955723 or rs2284682 had significantly higher serum CPA levels than did those without (P = .001). None of the PDAC cases with pancreatic atrophy had an elevated CPA. Among 122 PDAC cases without atrophy, defining serum CPA diagnostic cutoffs by a subject's CPA1 variants yielded a diagnostic sensitivity of 18% at 99% specificity (95% confidence interval [CI], 11.7-26) (vs 11.1% sensitivity using a uniform diagnostic cutoff); combining CPA with variant-stratified CA19-9 yielded a sensitivity of 68.0% (95% CI, 59.0-76.2) vs 63.1% (95% CI, 53.9- 71.7) for CA19-9 alone; and among stage I PDAC cases, diagnostic sensitivity was 51.9% (95% CI, 31.9-71.3) vs 37.0% (95% CI, 19.4-57.6) for CA19-9 alone. In the validation control set, the variant-stratified diagnostic cutoff yielded a specificity of 98.2%., Conclusion: Serum CPA activity has diagnostic utility before the emergence of pancreatic atrophy as a marker of localized PDAC, including stage I disease., (Copyright © 2022 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Purpose: Models used to predict the probability of an individual having a pathogenic homozygous or heterozygous variant in a mismatch repair gene, such as MMRpro, are widely used. Recently, MMRpro was updated with new colorectal cancer penetrance estimates. The purpose of this study was to evaluate the predictive performance of MMRpro and other models for individuals with a family history of colorectal cancer., Methods: We performed a validation study of 4 models, Leiden, MMRpredict, PREMM 5 , and MMRpro, using 784 members of clinic-based families from the United States. Predicted probabilities were compared with germline testing results and evaluated for discrimination, calibration, and predictive accuracy. We analyzed several strategies to combine models and improve predictive performance., Results: MMRpro with additional tumor information (MMRpro+) and PREMM 5 outperformed the other models in discrimination and predictive accuracy. MMRpro+ was the best calibrated with an observed to expected ratio of 0.98 (95% CI = 0.89-1.08). The combination models showed improvement over PREMM 5 and performed similar to MMRpro+., Conclusion: MMRpro+ and PREMM 5 performed well in predicting the probability of having a pathogenic homozygous or heterozygous variant in a mismatch repair gene. They serve as useful clinical decision tools for identifying individuals who would benefit greatly from screening and prevention strategies., Competing Interests: Conflict of Interest G.P. is a cofounder and equity holder in Phaeno Inc., a member of the Scientific Advisory Board of Konica Minolta Precision Medicine, Inc (which includes Ambry Genetics and Invicro), and a consultant for Delfi Diagnostics and Foundation Medicine, Inc. D.B. and G.P. colead the BayesMendel lab, which develops and maintains the BayesMendel software package. This includes a variety of risk assessment tools including BRCAPRO, PancPRO, MelaPRO, MMRpro, and PanelPRO and is licensed for commercial use. All licensing revenues are used for software maintenance and upgrades. Neither BayesMendel lab leaders nor members derive personal income from BayesMendel licenses. D.B. and G.P. are coinventor of the Ask2me tool, which is commercially licensed. D.B.’s conflicts of interest are managed by Harvard T.H. Chan School of Public Health. S.S. has been a consultant for Myriad Genetics, Inc and has rights to the inventor portion of licensing revenues for the PREMM model. Z.K.S.’s immediate family member serves as a consultant in Ophthalmology for Alcon, Adverum Biotechnologies, Gyroscope Therapeutics Limited, Neurogene Inc, and REGENXBIO Inc, outside the submitted work. All other authors declare no conflicts of interest., (Copyright © 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Purpose: To report pancreas surveillance outcomes of high-risk individuals within the multicenter Cancer of Pancreas Screening-5 (CAPS5) study and to update outcomes of patients enrolled in prior CAPS studies., Methods: Individuals recommended for pancreas surveillance were prospectively enrolled into one of eight CAPS5 study centers between 2014 and 2021. The primary end point was the stage distribution of pancreatic ductal adenocarcinoma (PDAC) detected (stage I v higher-stage). Overall survival was determined using the Kaplan-Meier method., Results: Of 1,461 high-risk individuals enrolled into CAPS5, 48.5% had a pathogenic variant in a PDAC-susceptibility gene. Ten patients were diagnosed with PDAC, one of whom was diagnosed with metastatic PDAC 4 years after dropping out of surveillance. Of the remaining nine, seven (77.8%) had a stage I PDAC (by surgical pathology) detected during surveillance; one had stage II, and one had stage III disease. Seven of these nine patients with PDAC were alive after a median follow-up of 2.6 years. Eight additional patients underwent surgical resection for worrisome lesions; three had high-grade and five had low-grade dysplasia in their resected specimens. In the entire CAPS cohort (CAPS1-5 studies, 1,731 patients), 26 PDAC cases have been diagnosed, 19 within surveillance, 57.9% of whom had stage I and 5.2% had stage IV disease. By contrast, six of the seven PDACs (85.7%) detected outside surveillance were stage IV. Five-year survival to date of the patients with a screen-detected PDAC is 73.3%, and median overall survival is 9.8 years, compared with 1.5 years for patients diagnosed with PDAC outside surveillance (hazard ratio [95% CI]; 0.13 [0.03 to 0.50], P = .003)., Conclusion: Most pancreatic cancers diagnosed within the CAPS high-risk cohort in the recent years have had stage I disease with long-term survival.

Background: Studies of the relationship between vitamin D and physical functioning have had inconsistent results., Methods: Physical functioning measures were collected for up to 2 years during a 2-stage, Bayesian, response-adaptive, randomized trial of 4 doses of vitamin D3 supplementation (200 [control], 1 000, 2 000, and 4 000 IU/day) to prevent falls. Two community-based research units enrolled adults aged ≥70 years, with elevated fall risk and serum 25-hydroxyvitamin D level of 10-29 ng/mL. The Pooled Higher Doses (PHD) group (≥1 000 IU/day, n = 349) was compared to the control group (n = 339) on changes in Short Physical Performance Battery (SPPB) score and its component tests, Timed Up-and-Go (TUG) test, 6-minute walk distance, and grip strength., Results: The trial enrolled 688 participants. Mean age was 77.2 years, 56.4% were male, 79.7% White, and 18.2% Black. While the PHD and control groups both lost function over time on most outcomes, the 2 groups did not show differential change overall on any outcome. Incidence of transitioning to poor functioning on gait speed, SPPB score, or TUG test did not differ by dose group., Conclusion: In older persons with low serum 25-hydroxyvitamin D level and elevated fall risk, high-dose vitamin D supplementation, ≥1 000 IU/day, did not improve measures of physical function compared to 200 IU/day., Clinical Trial Registration: NCT02166333., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Orthostatic hypotension (OH) based on a change from seated-to-standing blood pressure (BP) is often used interchangeably with supine-to-standing BP., Methods: The Study to Understand Fall Reduction and Vitamin D in You (STURDY) was a randomized trial of vitamin D3 supplementation and fall in adults aged ≥70 years at high risk of falls. OH was defined as a drop in systolic or diastolic BP of at least 20 or 10 mmHg, measured at pre-randomization, 3-, 12-, and 24-month visits with each of 2 protocols: seated-to-standing and supine-to-standing. Participants were asked about orthostatic symptoms, and falls were ascertained via daily fall calendar, ad hoc reporting, and scheduled interviews., Results: Among 534 participants with 993 paired supine and seated assessments (mean age 76 ± 5 years, 42% women, 18% Black), mean baseline BP was 130 ± 19/68 ± 11 mmHg; 62% had a history of high BP or hypertension. Mean BP increased 3.5 (SE, 0.4)/2.6 (SE, 0.2) mmHg from sitting to standing, but decreased with supine to standing (mean change: -3.7 [SE, 0.5]/-0.8 [SE, 0.3] mmHg; P-value < 0.001). OH was detected in 2.1% (SE, 0.5) of seated versus 15.0% (SE, 1.4) of supine assessments (P < 0.001). While supine and seated OH were not associated with falls (HR: 1.55 [0.95, 2.52] vs 0.69 [0.30, 1.58]), supine systolic OH was associated with higher fall risk (HR: 1.77 [1.02, 3.05]). Supine OH was associated with self-reported fainting, blacking out, seeing spots and room spinning in the prior month (P-values < 0.03), while sitting OH was not associated with any symptoms (P-values ≥ 0.40)., Conclusion: Supine OH was more frequent, associated with orthostatic symptoms, and potentially more predictive of falls than seated OH., (© 2022 The American Geriatrics Society.)

Purpose: Hospice utilization metrics are essential for any serious effort to improve end-of-life care in oncology. However, oncologists do not routinely receive these personalized reports. We evaluated whether a behavioral science intervention, using peer comparisons coupled with social norms, was associated with improvements in hospice use., Methods: Oncologists at two academic practices of Johns Hopkins Medicine were randomly assigned to receive a peer comparison report by e-mail displaying individual hospice utilization metrics compared with top-performing peers or to receive no report. The data accrued for the intervention represented hospice utilization for the previous calendar year. The intervention period was from June 1, 2020, to December 30, 2020, and included oncologists from both the solid and hematologic malignancies programs. The primary outcome was the proportion of patients between groups with short hospice length of stay (LOS; defined as ≤ 7 days) after 6 months. Secondary outcomes included hospice referral rate, enrollment rate, and median LOS., Results: Forty-seven oncologists participated. The percent of patients with a short hospice stay in the intervention group was lower (17.4%) compared with patients treated by physicians in the usual care group (46.3%, difference = 21.8%; 95% CI, 16.0 to 41.6; P < .001). Receipt of peer comparisons was associated with a greater likelihood of enrolling in hospice (73.7% v 42.8%; difference = 31.1%; 95% CI, 20.4 to 41.7; P < .001) and a longer hospice LOS (37.2 v 18.3 days; difference = 17.2; 95% CI, 8.8 to 25.7 days; P < .001)., Conclusion: Peer comparisons improved hospice utilization metrics among a group of academic oncologists. Behavioral science offers one pragmatic strategy to overcome suboptimal oncologist decision-making biases related to hospice use.

Purpose: In pre-planned observational analysis of the POWER-remote trial, we examined the impact of weight loss on patient-reported outcomes (PROs). We hypothesized a priori that survivors with ≥ 5% weight loss would have improved physical function (PF) at 6 months vs. those who did not., Methods: Patients with stage 0-III breast cancer who completed local therapy and chemotherapy with BMI ≥ 25 kg/m 2 were randomized to POWER-remote (telephone coaching; diet/activity tracking) or self-directed weight loss (booklet). Participants completed PROs at baseline, 6, and 12 months: PROMIS PF, pain, fatigue, anxiety, depression, sleep; FACT-endocrine symptoms; MOS-sexual function. Changes in PROs among those with ≥ 5% weight loss vs. those with < 5% were tested with multivariable mixed effect models, across randomized groups., Results: Of 94 women who completed PROs, 84 and 69 participants were evaluable at 6 and 12 months, respectively. Regardless of intervention, PF improved in those with ≥ 5% weight loss vs. those with < 5% at 6 months (4.4 vs. 0.3 points; p = 0.02) and 12 months (3.6 vs. 0 points; p = 0.04). While endocrine symptoms, fatigue, and anxiety improved at 6 months in those who lost ≥ 5%, differences were not significant vs. those who lost < 5%. There was no significant change within or between groups in sexual function, depression, or sleep. Findings at 12 months were similar, except pain improved in those losing ≥ 5%., Conclusions: These results support the benefits of weight loss in overweight/obese breast cancer survivors., Implications for Cancer Survivors: Weight management in breast cancer survivors may improve PF., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Many patients discontinue endocrine therapy for breast cancer due to intolerance. Identification of patients at risk for discontinuation is challenging. The minimal important difference (MID) is the smallest change in a score on a patient-reported outcome (PRO) that is clinically significant. We evaluated the association between treatment-emergent symptoms detected by worsening PRO scores in units equal to the MID with discontinuation. We enrolled females with stage 0-III breast cancer initiating endocrine therapy in a prospective cohort. Participants completed PROs at baseline, 3, 6, 12, 24, 36, 48, and 60 months. Measures included PROMIS pain interference, fatigue, depression, anxiety, physical function, and sleep disturbance; Endocrine Subscale of the FACT-ES; and MOS-Sexual Problems (MOS-SP). We evaluated associations between continuous PRO scores in units corresponding to MIDs (PROMIS: 4-points; FACT-ES: 5-points; MOS-SP: 8-points) with time to endocrine therapy discontinuation using Cox proportional hazards models. Among 321 participants, 140 (43.6%) initiated tamoxifen and 181 (56.4%) initiated aromatase inhibitor (AI). The cumulative probability of discontinuation was 23% (95% CI 18-27%) at 48 months. For every 5- and 4-point worsening in endocrine symptoms and sleep disturbance respectively, participants were 13 and 14% more likely to discontinue endocrine therapy respectively (endocrine symptoms HR 1.13, 95% CI 1.02-1.25, p = 0.02; sleep disturbance HR 1.14, 95% CI 1.01-1.29, p = 0.03). AI treatment was associated with greater likelihood of discontinuation than tamoxifen. Treatment-emergent endocrine symptoms and sleep disturbance are associated with endocrine therapy discontinuation. Monitoring for worsening scores meeting or exceeding the MID on PROs may identify patients at risk for discontinuation., (© 2022. The Author(s).)

Context: The Study to Understand Fall Reduction and Vitamin D in You (STURDY), a randomized trial enrolling older adults with low 25-hydroxyvitamin D [25(OH)D], demonstrated vitamin D supplementation ≥ 1000 IU/day did not prevent falls compared with 200 IU/day, with doses ≥ 2000 IU/day potentially showing safety concerns., Objective: To examine associations of achieved and change in 25(OH)D concentrations after 3 months of vitamin D supplementation with fall risk., Design: Observational analysis of trial data., Setting: General community., Participants: A total of 637 adults aged ≥ 70 with baseline 25(OH)D concentrations 10 to 29 ng/mL and elevated fall risk. Three-month on-treatment absolute 25(OH)D; absolute and relative changes from baseline., Main Outcome Measures: Incident first fall (primary) and first consequential fall (injury or sought medical care) up to 24 months. Cox models were adjusted for sociodemographics, season, Short Physical Performance Battery, and body mass index., Results: At baseline, mean (SD) age was 77.1 (5.4) years and 25(OH)D was 22.1 (5.1) ng/mL; 43.0% were women and 21.5% non-White. A total of 395 participants experienced ≥ 1 fall; 294 experienced ≥ 1 consequential fall. There was no association between absolute achieved 25(OH)D and incident first fall (30-39 vs < 30 ng/mL hazard ratio [HR], 0.93; 95% CI, 0.74-1.16; ≥40 vs < 30 ng/mL HR, 1.09; 95% CI, 0.82-1.46; adjusted overall P  = 0.67), nor absolute or relative change in 25(OH)D. For incident consequential first fall, the HR (95% CI) comparing absolute 25(OH)D ≥ 40 vs < 30 ng/mL was 1.38 (0.99-1.90)., Conclusion: Achieved 25(OH)D concentration after supplementation was not associated with reduction in falls. Risk of consequential falls may be increased with achieved concentrations ≥ 40 ng/mL., Trial Registration: ClinicalTrials.gov: NCT02166333., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: Survivorship care plans (SCP) should outline pertinent information about cancer treatment and follow-up., Methods: We descriptively analyzed the content of 74 colorectal cancer SCPs completed as part of a randomized, controlled trial of SCPs at an academic and community cancer center. Surveillance recommendations were compared with American Cancer Society, American Society of Clinical Oncology and National Comprehensive Cancer Network guidelines., Results: SCP information provided in >80% of the plans included participant age, cancer diagnosis, details, and side-effects of treatment (surgery, chemotherapy, radiation) and health promotion recommendations. SCP content documented less frequently included predisposing conditions, genetic counseling/testing information and staging. Posttreatment surveillance recommendations were documented in >90% SCPs. For stage 2-3 cancer, rates of guideline concordant recommendations were 100% for colonoscopy surveillance (Year 1 only), 87% for imaging surveillance, 65% for carcinoembryonic antigen surveillance, and 33% for follow-up visits. Excluding colonoscopy, >15 unique recommendations were listed for each modality across stages and sites, with more variation at the academic site., Conclusions: SCPs consistently recorded information about cancer diagnosis and treatment but omitted critical information about cancer-specific details denoting risk. Surveillance recommendations varied considerably between cancer centers. Future work to improve the consistency of surveillance recommendations documented in SCPs may be needed., (© 2021 Wiley Periodicals LLC.)

Background: Survivorship care plans seek to improve the transition to survivorship, but the required resources present implementation barriers. This randomized controlled trial aimed to identify the simplest, most effective approach for survivorship care planning., Methods: Stage 1-3 breast, colorectal, and prostate cancer patients aged 21 years or older completing treatment were recruited from an urban-academic and rural-community cancer center. Participants were randomly assigned, stratified by recruitment site and cancer type 1:1:1 to a mailed plan, plan delivered during a 1-time transition visit, or plan delivered during a transition visit plus 6-month follow-up visit. Health service use data were collected from participants and medical records for 18 months. The primary outcome, receipt of all plan-recommended care, was compared across intervention arms using logistic regression adjusting for cancer type and recruitment site, with P less than .05 considered statistically significant., Results: Of 378 participants randomly assigned, 159 (42.1%) were breast, 142 (37.6%) prostate, and 77 (20.4%) colorectal cancer survivors; 207 (54.8%) from the academic site and 171 (45.2%) from the community site; 316 were analyzable for the primary outcome. There was no difference across arms in the proportion of participants receiving all plan-recommended care: 45.2% mail, 50.5% 1-visit, 42.7% 2-visit (2-sided P = .60). Adherence by cancer type for mail, 1-visit, and 2-visit, respectively, was 52.2%, 53.3%, and 40.0% for breast cancer; 48.6%, 64.1%, and 57.1% for prostate cancer; and 23.8%, 19.0%, and 26.1% for colorectal cancer. There were no statistically significant interactions by recruitment site or cancer type., Conclusions: This study did not find differences in receipt of recommended follow-up care by plan delivery approach. Feasibility and other factors may determine the best approach for survivorship care planning., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Long-term prognostication is important to inform preventive care in older adults. Existing prediction indices incorporate age and comorbidities. Frailty is another important factor in prognostication. In this project, we aimed at developing life expectancy estimates that incorporate both comorbidities and frailty., Methods: In this retrospective cohort study, we used data from a 5% sample of Medicare beneficiaries with and without history of cancer from Surveillance, Epidemiology, and End Results (SEER) cancer registry areas. We included adults aged 66-95 years who were continuously enrolled in fee-for-service Medicare for ≥1 year from 1998 to 2014. Participants were followed for survival until 12/31/2015, death, or disenrollment. Comorbidity (none, low/medium, high) and frailty categories (low, high) were defined using established methods for claims. We estimated 5- and 10-year survival probabilities and median life expectancies by age, sex, comorbidities, and frailty., Results: The study included 479,646 individuals (4,128,316 person-years), of whom most were women (58.7%). Frailty scores varied widely among participants in the same comorbidity category. In Cox models, both comorbidities and frailty were independent predictors of mortality. Individuals with high comorbidities (HR, 3.24; 95% CI, 3.20-3.28) and low/medium comorbidities (HR, 1.36; 95% CI, 1.34-1.39) had higher risks of death than those with no comorbidities. Compared to low frailty, high frailty was associated with higher risk of death (HR, 1.55; 95% CI, 1.52-1.58). Frailty affected life expectancy estimates in ways relevant to preventive care (i.e., distinguishing <10-year versus >10-year life expectancy) in multiple subgroups., Conclusion: Incorporating both comorbidities and frailty may be important in estimating long-term life expectancies of older adults. Our life expectancy tables can aid clinicians' prognostication and inform simulation models and population health management., (© 2021 The American Geriatrics Society.)

Introduction: Identifying families with an underlying inherited cancer predisposition is a major goal of cancer prevention efforts. Mendelian risk models have been developed to better predict the risk associated with a pathogenic variant of developing breast/ovarian cancer (with BRCAPRO) and the risk of developing pancreatic cancer (PANCPRO). Given that pathogenic variants involving BRCA2 and BRCA1 predispose to all three of these cancers, we developed a joint risk model to capture shared susceptibility., Methods: We expanded the existing framework for PANCPRO and BRCAPRO to jointly model risk of pancreatic, breast, and ovarian cancer and validated this new model, BRCAPANCPRO on three data sets each reflecting the common target populations., Results: BRCAPANCPRO outperformed the prior BRCAPRO and PANCPRO models and yielded good discrimination for differentiating BRCA1 and BRCA2 carriers from non-carriers (AUCs 0.79, 95% CI: 0.73-0.84 and 0.70, 95% CI: 0.60-0.80) in families seen in high-risk clinics and pancreatic cancer family registries, respectively. In addition, BRCAPANCPRO was reasonably well calibrated for predicting future risk of pancreatic cancer (observed-to-expected (O/E) ratio = 0.81 [0.69, 0.94])., Discussion: The BRCAPANCPRO model provides improved risk assessment over our previous risk models, particularly for pedigrees with a co-occurrence of pancreatic cancer and breast and/or ovarian cancer., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Purpose: Chronic myeloid leukemia (CP-CML) patients can achieve undetectable minimal residual disease (UMRD) and discontinue tyrosine kinase inhibitors (TKIs). Cellular immunity plays an important role in CML disease control. We conducted a randomized, non-blinded phase II trial of adjuvant immunotherapy with TKIs to facilitate TKI discontinuation., Methods: TKI-treated patients with CP-CML were randomized to receive the K562/GM-CSF vaccine (vaccine) OR Interferon-α + Sargramostim (IFN). If UMRD was achieved, then all treatment was stopped. Patients who did not achieve UMRD within one year, had a molecular relapse, or discontinued therapy for toxicity could crossover., Results: Thirty-four patients were randomized to IFN (n = 18) or vaccine (n = 16), and 21 patients crossed over (IFN⟶vaccine: n = 9, vaccine⟶IFN, n = 12). TKIs at enrollment included imatinib (n = 31), nilotinib (n = 2), and dasatinib (n = 1). No patients discontinued vaccine due to side effects, while 33 % of IFN-treated patients discontinued treatment. More patients randomized to IFN (47.4 %, 95 % CI: 16.7-66.7 %) versus vaccine (25.0 %, 95 % CI: 0.5-43.5 %) achieved UMRD within one year. Seven patients randomized to IFN discontinued treatment with 28.6 % (95 % CI: 8.9-92.2 %) sustaining treatment-free remission (TFR) at 1 year, while three patients randomized to vaccine discontinued treatment with none sustaining TFR. Including crossover, there was a cumulative discontinuation success rate of 36.4 % (95 % CI: 16.6 %-79.5 %) after adjuvant IFN. Patients who sustained TFR received a median of 29 months of imatinib prior to discontinuation., Conclusion: Adjuvant IFN led to durable TFRs with limited prior TKI exposure with comparable success to prior discontinuation trials, but many patients stopped IFN early., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: Despite advances in immunotherapies, the prognosis for adults with Philadelphia chromosome-negative, newly diagnosed (ND) or relapsed/refractory (R/R) acute lymphoblastic leukemia/acute biphenotypic leukemia (ALL/ABL) remains poor. The benzamide derivative entinostat inhibits histone deacetylase and induces histone hyperacetylation. The purine nucleoside analogue clofarabine is FDA-approved for R/R ALL in children 1-21 years of age. Low doses of clofarabine have been reported to induce DNA hypomethylation. We conducted a phase 1 study of low dose clofarabine with escalating doses of entinostat in adults with ND or R/R ALL/ABL., Experimental Design: Adults ≥60 years with ND ALL/ABL or ≥21 years with R/R ALL/ABL received repeated cycles every 3 weeks of entinostat (4 mg, 6 mg or 8 mg orally days 1 and 8) and clofarabine (10 mg/m 2 /day IV for 5 days, days 3-7) (Arm A). Adults aged 40-59 years with ND ALL/ABL or age ≥21 years in first relapse received entinostat and clofarabine prior to traditional chemotherapy on day 11 (Arm B). Changes in DNA damage, global protein lysine acetylation, myeloid-derived suppressor cells and monocytes were measured in PBMCs before and during therapy., Results: Twenty-eight patients were treated at three entinostat dose levels with the maximum administered dose being entinostat 8 mg. The regimen was well tolerated with infectious and metabolic derangements more common in the older population versus the younger cohort. There was no severe hyperglycemia and no peripheral neuropathy in this small study. There were 2 deaths (1 sepsis, 1 intracranial bleed). Overall response rate was 32 %; it was 50 % for ND ALL/ABL. Entinostat increased global protein acetylation and inhibited immunosuppressive monocyte subpopulations, while clofarabine induced DNA damage in all cell subsets examined., Conclusion: Entinostat plus clofarabine appears to be tolerable and active in older adults with ND ALL/ABL, but less active in R/R patients. Further evaluation of this regimen in ND ALL/ABL appears warranted., (Copyright © 2021. Published by Elsevier Ltd.)

PET with small molecules targeting prostate-specific membrane antigen (PSMA) is being adopted as a clinical standard for prostate cancer imaging. In this study, we evaluated changes in uptake on PSMA-targeted PET in men starting abiraterone or enzalutamide. Methods: This prospective, single-arm, 2-center, exploratory clinical trial enrolled men with metastatic castration-resistant prostate cancer initiating abiraterone or enzalutamide. Each patient was imaged with 18 F-DCFPyL at baseline and within 2-4 mo after starting therapy. Patients were followed for up to 48 mo from enrollment. A central review evaluated baseline and follow-up PET scans, recording change in SUV max at all disease sites and classifying the pattern of change. Two parameters were derived: the δ-percent SUV max (DPSM) of all lesions and the δ-absolute SUV max (DASM) of all lesions. Kaplan-Meier curves were used to estimate time to therapy change (TTTC) and overall survival (OS). Results: Sixteen evaluable patients were accrued to the study. Median TTTC was 9.6 mo (95% CI, 6.9-14.2), and median OS was 28.6 mo (95% CI, 18.3-not available [NA]). Patients with a mixed-but-predominantly-increased pattern of radiotracer uptake had a shorter TTTC and OS. Men with a low DPSM had a median TTTC of 12.2 mo (95% CI, 11.3-NA) and a median OS of 37.2 mo (95% CI, 28.9-NA), whereas those with a high DPSM had a median TTTC of 6.5 mo (95% CI, 4.6-NA, P = 0.0001) and a median OS of 17.8 mo (95% CI, 13.9-NA, P = 0.02). Men with a low DASM had a median TTTC of 12.2 mo (95% CI, 11.3-NA) and a median OS of NA (95% CI, 37.2 mo-NA), whereas those with a high DASM had a median TTTC of 6.9 mo (95% CI, 6.1-NA, P = 0.003) and a median OS of 17.8 mo (95% CI, 13.9-NA, P = 0.002). Conclusion: Findings on PSMA-targeted PET 2-4 mo after initiation of abiraterone or enzalutamide are associated with TTTC and OS. Development of new lesions or increasing intensity of radiotracer uptake at sites of baseline disease are poor prognostic findings suggesting shorter TTTC and OS., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

Background/objectives: To assess whether vitamin D supplementation prevents specific fall subtypes and sequelae (e.g., fracture)., Design: Secondary analyses of STURDY (Study to Understand Fall Reduction and Vitamin D in You)-a response-adaptive, randomized clinical trial., Setting: Two community-based research units., Participants: Six hundred and eighty-eight participants ≥70 years old with elevated fall risk and baseline serum 25-hydroxyvitamin D levels of 10-29 ng/ml., Intervention: 200 IU/day (control), 1000 IU/day, 2000 IU/day, or 4000 IU/day of vitamin D3., Measurements: Outcomes included repeat falls and falls that were consequential, were injurious, resulted in emergency care, resulted in fracture, and occurred either indoors or outdoors., Results: After adjustment for multiple comparisons, the risk of fall-related fracture was greater in the pooled higher doses (≥1000 IU/day) group compared with the control (hazard ratio [HR] = 2.66; 95% confidence interval [CI]:1.18-6.00). Although not statistically significant after multiple comparisons adjustment, time to first outdoor fall appeared to differ between the four dose groups (unadjusted p for overall difference = 0.013; adjusted p = 0.222), with risk of a first-time outdoor fall 39% lower in the 1000 IU/day group (HR = 0.61; 95% CI: 0.38-0.97; unadjusted p = 0.036; adjusted p = 0.222) and 40% lower in the 2000 IU/day group (HR = 0.60; 95%CI 0.38-0.97; p = 0.037; adjusted p = 0.222), each versus control., Conclusion: Vitamin D supplementation doses ≥1000 IU/day might have differential effects on fall risk based on fall location and fracture risk, with the most robust finding that vitamin D doses between 1000 and 4000 IU/day might increase the risk of first time falls with fractures. Replication is warranted, given the possibility of type 1 error., (© 2021 The Authors. Journal of the American Geriatrics Society published by Wiley Periodicals LLC on behalf of The American Geriatrics Society.)

Background: Aromatase inhibitors (AI) reduce recurrence and death in patients with early-stage hormone receptor-positive (HR +) breast cancer. Treatment-related toxicities, including AI-induced musculoskeletal symptoms (AIMSS), are common and may lead to early AI discontinuation. The objective of this study was to replicate previously reported associations for candidate germline genetic polymorphisms with AIMSS., Methods: Women with stage 0-III HR + breast cancer initiating adjuvant AI were enrolled in a prospective clinic-based observational cohort. AIMSS were assessed by patient-reported outcomes (PRO) including the PROMIS pain interference and physical function measures plus the FACT-ES joint pain question at baseline and after 3 and 6 months. For the primary analysis, AIMSS were defined as ≥ 4-point increase in the pain interference T-score from baseline. Secondary AIMSS endpoints were defined as ≥ 4-point decrease in the physical function T-score from baseline and as ≥ 1-point increase on the FACT-ES joint pain question from baseline. The primary hypothesis was that TCL1A rs11849538 would be associated with AIMSS. Twelve other germline variants in CYP19A1 , VDR , PIRC66 , OPG , ESR1 , CYP27B1 , CYP17A1 , and RANKL were also analyzed assuming a dominant genetic effect and prespecified direction of effect on AIMSS using univariate logistic regression with an unadjusted α = 0.05. Significant univariate associations in the expected direction were adjusted for age, race, body mass index (BMI), prior taxane, and the type of AI using multivariable logistic regression., Results: A total of 143 participants with PRO and genetic data were included in this analysis, most of whom were treated with anastrozole (78%) or letrozole (20%). On primary analysis, participants carrying TCL1A rs11849538 were not more likely to develop AIMSS (odds ratio = 1.29, 95% confidence interval: 0.55-3.07, p = 0.56). In the statistically uncorrected secondary analysis, OPG rs2073618 was associated with AIMSS defined by worsening on the FACT-ES joint pain question (OR = 3.33, p = 0.004), and this association maintained significance after covariate adjustment (OR = 3.98, p = 0.003)., Conclusion: Carriers of OPG rs2073618 may be at increased risk of AIMSS. If confirmed in other cohorts, OPG genotyping can be used to identify individuals with HR + early breast cancer in whom alternate endocrine therapy or interventions to enhance symptom detection and implement strategies to reduce musculoskeletal symptoms may be needed., Competing Interests: KS research funding from Pfizer. Spouse with stock in Abbvie and ABT Labs. NH received research grants to institution from Pfizer. VS received research grants to institution from Abbvie, Biocept, Pfizer, Novartis, and Puma Biotechnology. Member, Data Safety Monitoring Board, Immunomedics, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Hertz, Smith, Zong, Gersch, Pesch, Lehman, Blackford, Henry, Kidwell, Rae and Stearns.)

Germline variation and smoking are independently associated with pancreatic ductal adenocarcinoma (PDAC). We conducted genome-wide smoking interaction analysis of PDAC using genotype data from four previous genome-wide association studies in individuals of European ancestry (7,937 cases and 11,774 controls). Examination of expression quantitative trait loci data from the Genotype-Tissue Expression Project followed by colocalization analysis was conducted to determine whether there was support for common SNP(s) underlying the observed associations. Statistical tests were two sided and P < 5 × 10 -8 was considered statistically significant. Genome-wide significant evidence of qualitative interaction was identified on chr2q21.3 in intron 5 of the transmembrane protein 163 (TMEM163) and upstream of the cyclin T2 (CCNT2). The most significant SNP using the Empirical Bayes method, in this region that included 45 significantly associated SNPs, was rs1818613 [per allele OR in never smokers 0.87, 95% confidence interval (CI), 0.82-0.93; former smokers 1.00, 95% CI, 0.91-1.07; current smokers 1.25, 95% CI 1.12-1.40, P interaction = 3.08 × 10 -9 ). Examination of the Genotype-Tissue Expression Project data demonstrated an expression quantitative trait locus in this region for TMEM163 and CCNT2 in several tissue types. Colocalization analysis supported a shared SNP, rs842357, in high linkage disequilibrium with rs1818613 ( r 2 = 0. 94) driving both the observed interaction and the expression quantitative trait loci signals. Future studies are needed to confirm and understand the differential biologic mechanisms by smoking status that contribute to our PDAC findings. SIGNIFICANCE: This large genome-wide interaction study identifies a susceptibility locus on 2q21.3 that significantly modified PDAC risk by smoking status, providing insight into smoking-associated PDAC, with implications for prevention., (©2021 American Association for Cancer Research.)

Background: Survivorship care plans contain important information for patients and primary care physicians regarding appropriate care for cancer survivors after treatment. We describe the completeness of prostate cancer survivorship care plans and evaluate the concordance of follow-up recommendations with guidelines., Methods: We analyzed 119 prostate cancer survivorship care plans from one academic and one community cancer center, abstracting demographics, cancer/treatment details, and follow-up recommendations. Follow-up recommendations were compared with the American Cancer Society (ACS), American Society of Clinical Oncology (ASCO), and National Comprehensive Cancer Network (NCCN) guidelines., Results: Content in >90% of plans included cancer TNM stage; prostate-specific antigen (PSA) at diagnosis; radiation treatment details (98% of men received radiation); and PSA monitoring recommendations. Potential treatment-specific side effects were listed for 82% of men who had surgery, 86% who received androgen deprivation therapy (ADT), and 97% who underwent radiation. The presence of posttreatment symptoms was noted in 71% of plans. Regarding surveillance follow-up, all guidelines recommend an annual digital rectal exam (DRE). No plans specified DRE. However, all 71 plans at the community site recommended at least annual follow-up visits with urology, radiation oncology, and primary care. Only 2/48 plans at the academic site specified follow-up visits. All guidelines recommend PSA testing every 6-12 months for 5 years, then annually. For the first 5 years, 90% of plans were guideline-concordant, 8% suggested oversurveillance, and 2% were incomplete. In men receiving ADT, ACS and ASCO recommend bone density imaging and NCCN recommends testosterone levels. Of 77 men on ADT, 1% were recommended bone density imaging and 16% testosterone level testing., Conclusions: While care plan content is more complete for demographic and treatment summary information, both sites had gaps in reporting posttreatment symptoms and ADT-related testing recommendations. These findings highlight the need to improve the quality of information in care plans, which are important in communicating appropriate follow-up recommendations to patients and primary care physicians., (© 2021 Wiley Periodicals LLC.)

We examined the effects of a communication intervention to engage family care partners on patient portal (MyChart) use, illness understanding, satisfaction with cancer care, and symptoms of anxiety in a single-blind randomized trial of patients in treatment for breast cancer. Patient-family dyads were recruited and randomly assigned a self-administered checklist to clarify the care partner role, establish a shared visit agenda, and facilitate MyChart access (n = 63) or usual care (n = 55). Interviews administered at baseline, 3, 9 (primary endpoint), and 12 months assessed anxiety (GAD-2), mean FAMCARE satisfaction, and complete illness understanding (4 of 4 items correct). Time-stamped electronic interactions measured MyChart use. By 9 months, more intervention than control care partners registered for MyChart (77.8 % vs 1.8%; p < 0.001) and logged into the patient's account (61.2% vs 0% of those registered; p < 0.001), but few sent messages to clinicians (6.1% vs 0%; p = 0.247). More intervention than control patients viewed clinical notes (60.3% vs 32.7%; p = 0.003). No pre-post group differences in patient or care partner symptoms of anxiety, satisfaction, or complete illness understanding were found. Intervention patients whose care partners logged into MyChart were more likely to have complete illness understanding at 9 months (changed 70.0% to 80.0% vs 69.7% to 54.6%; p = 0.03); symptoms of anxiety were numerically lower (16.7% to 6.7% vs 15.2% to 15.2%; p = 0.24) and satisfaction numerically higher (15.8-16.2 vs 18.0-17.4; p = 0.25). A brief, scalable communication intervention led to greater care partner MyChart use and increased illness understanding among patients with more engaged care partners (NCT03283553).

Background: Vitamin D supplementation may prevent falls in older persons, but evidence is inconsistent, possibly because of dosage differences., Objective: To compare the effects of 4 doses of vitamin D 3 supplements on falls., Design: 2-stage Bayesian, response-adaptive, randomized trial. (ClinicalTrials.gov: NCT02166333)., Setting: 2 community-based research units., Participants: 688 participants, aged 70 years and older, with elevated fall risk and a serum 25-hydroxyvitamin D [25-(OH)D] level of 25 to 72.5 nmol/L., Intervention: 200 (control), 1000, 2000, or 4000 IU of vitamin D 3 per day. During the dose-finding stage, participants were randomly assigned to 1 of the 4 vitamin D 3 doses, and the best noncontrol dose for preventing falls was determined. After dose finding, participants previously assigned to receive noncontrol doses received the best dose, and new enrollees were randomly assigned to receive 200 IU/d or the best dose., Measurements: Time to first fall or death over 2 years (primary outcome)., Results: During the dose-finding stage, the primary outcome rates were higher for the 2000- and 4000-IU/d doses than for the 1000-IU/d dose, which was selected as the best dose (posterior probability of being best, 0.90). In the confirmatory stage, event rates were not significantly different between participants with experience receiving the best dose (events and observation time limited to the period they were receiving 1000 IU/d; n  = 308) and those randomly assigned to receive 200 IU/d ( n  = 339) (hazard ratio [HR], 0.94 [95% CI, 0.76 to 1.15]; P  = 0.54). Analysis of falls with adverse outcomes suggested greater risk in the experience-with-best-dose group versus the 200-IU/d group (serious fall: HR, 1.87 [CI, 1.03 to 3.41]; fall with hospitalization: HR, 2.48 [CI, 1.13 to 5.46])., Limitations: The control group received 200 IU of vitamin D 3 per day, not a placebo. Dose finding ended before the prespecified thresholds for dose suspension and dose selection were reached., Conclusion: In older persons with elevated fall risk and low serum 25-(OH)D levels, vitamin D 3 supplementation at doses of 1000 IU/d or higher did not prevent falls compared with 200 IU/d. Several analyses raised safety concerns about vitamin D 3 doses of 1000 IU/d or higher., Primary Funding Source: National Institute on Aging.

Background: Patients participating in phase I trials represent a population with advanced cancer and symptoms, with quality-of-life implications arising from both disease and treatment. Transitions to end-of-life care for these patients have received little attention. Good empirical data are needed to better understand the role of advance care planning and palliative care during phase I trial transitions. We investigated how physician-patient communication at the time of disease progression, patient characteristics, and patterns of care were associated with end-of-life care., Methods: We conducted a retrospective chart review of all patients with solid tumors enrolled in phase I trials at a comprehensive cancer center from January 2015 to December 2017. We captured physician-patient communication during disease progression. Among patients who died, we assessed palliative care referral, advance care planning, place of death, healthcare use in the final month of life, hospice enrollment, and hospice length of stay (LOS). Factors independently associated with a short hospice LOS (defined as ≤3 days) were estimated from a multivariable model building approach., Results: Among 207 participants enrolled in phase I intervention studies at Johns Hopkins Hospital, the median age was 61 years (range, 31-91 years), 48% were women, 21% were members of racial minority groups, and 41.5% were referred from an outside institution. At the time of disease progression, 53% had goals of care documented, 47% were previously referred to palliative care, and 41% discussed hospice with their oncologist. A total of 82% of decedents died within 1 year of study enrollment, and 85% enrolled in hospice. Among the 147 participants who enrolled in hospice, 22 (15%) had a short LOS (≤3 days). Factors independently associated with an increased risk of short hospice LOS in the multivariable model included age >65 years (odds ratio [OR], 1.12; 95% CI, 1.01-1.24; P=.04), whereas remaining at the same institution (OR, 0.72; 95% CI, 0.65-0.80; P<.001) and referral to palliative care before progression (OR, 0.83; 95% CI, 0.75-0.92; P<.001) were associated with a decreased risk of short hospice LOS., Conclusions: Reported data support the benefit of palliative care for patients in phase I trials and the risks associated with healthcare transitions for all patients, particularly older adults, regardless of care received. Leaving a clinical trial is a time when clear communication is paramount. Phase I studies will continue to be vital in advancing cancer treatment. It is equally important to advance the support provided to patients who transition off these trials.