Risk of anthracycline-induced cardiac dysfunction in adolescent and young adult (AYA) cancer survivors: role of genetic susceptibility loci.

There is a known genetic susceptibility to anthracycline-induced cardiac dysfunction in childhood cancer survivors, but this has not been adequately shown in adolescent and young adult (AYA) patients. Our aim was to determine if the previously identified variants associated with cardiac dysfunction in childhood cancer patients affect AYA cancer patients similarly. Forty-five variants were selected for analysis in 253 AYAs previously treated with anthracyclines. We identified four variants that were associated with cardiac dysfunction: SLC10A2:rs7319981 (p = 0.017), SLC22A17:rs4982753 (p = 0.019), HAS3:rs2232228 (p = 0.023), and RARG:rs2229774 (p = 0.050). HAS3:rs2232228 and SLC10A2:rs7319981 displayed significant effects in our AYA cancer survivor population that were in the opposite direction than that reported in childhood cancer survivors. Genetic variants in the host genes were further analyzed for additional associations with cardiotoxicity in AYA cancer survivors. The host genes were then evaluated in a panel of induced pluripotent stem cell-derived cardiomyocytes to assess changes in levels of expression when treated with doxorubicin. Significant upregulation of HAS3 and SLC22A17 expression was observed (p < 0.05), with non-significant anthracycline-responsivity observed for RARG. Our study demonstrates that there is a genetic influence on cardiac dysfunction in AYA cancer patients, but there may be a difference in the role of genetics between childhood and AYA cancer survivors.

Patient-Reported Quality of Life at Diagnosis in Adolescent and Young Adults With Cancer.

BACKGROUND: The overall landscape of health-related quality of life (HRQoL) has not been thoroughly investigated in adolescents and young adults (AYAs) with cancer. Data are also lacking on how well HRQoL at the time of cancer diagnosis can prognosticate long-term survival in AYA survivors. PATIENTS AND METHODS: We included 3,497 survivors of AYA cancer (age 15-39 years at diagnosis) who completed the Short-Form 12 Health Survey (SF-12) HRQoL questionnaire at diagnosis. Physical component summary (PCS) and mental component summary (MCS) scores were generated, with scores <50 representing poor HRQoL. Differences in HRQoL by patient characteristics and tumor type were investigated using violin plots and t tests/analysis of variance. The effect of HRQoL on overall survival was assessed using Kaplan-Meier plots and Cox proportional hazards models. RESULTS: Overall mean PCS and MCS scores in this racially/ethnically diverse cohort (64% White, 19% Hispanic, 10% Black, and 7% other race/ethnicity) were 43.6 and 46.7, respectively. Women with breast cancer reported the most favorable PCS (50.8), and those with cervical cancer reported the lowest MCS (42.8). Age at diagnosis was associated positively with PCS (P<.001) and inversely with MCS (P<.001). Females had higher PCS yet lower MCS than males (both P<.001). Marginalized racial and ethnic populations reported lower PCS than White patients (P<.001). Physical and mental HRQoL were prognostic and associated with increased risk of poor survival (hazard ratio, 1.95; 95% CI, 1.72-2.21 for physical HRQoL, and 1.26; 95% CI, 1.13-1.40 for mental HRQoL). CONCLUSIONS: Physical and mental HRQoL at diagnosis vary across patient characteristics in AYA cancer survivors. Poor HRQoL at diagnosis may be a prognosticator of diminished overall survival among AYA cancer survivors.

Neighborhood-level Social Determinants of Health Burden among AYA Cancer Patients and Impact on Overall Survival.

PURPOSE: Neighborhood socioeconomic deprivation has been linked to adverse health outcomes, yet it is unclear if neighborhood-level social determinants of health (SDOH) measures impact overall survival in adolescent and young adult (AYA) cancer patients. METHODS: This study utilized a diverse cohort of AYA cancer patients (N = 10,261) seen at MD Anderson Cancer Center. Zip codes were linked to Area Deprivation Index (ADI) values, a validated neighborhood-level SDOH measure, with higher ADI representing worse SDOH. RESULTS: ADI was significantly worse (p < .05) for Black (61.7) and Hispanic (65.3), compared to White (51.2) patients. Analysis of ADI by cancer type showed significant differences, mainly driven by worse ADI in patients with cervical cancer (62.3) than other cancers. In multivariable models including sex, age at diagnosis, cancer diagnosis, and race/ethnicity, risk of shorter survival for people residing in neighborhoods with the least favorable ADI quartile was greater than those in the most favorable ADI quartile (HR: 1.09, 95% CI: 1.00-1.19, p = .043). CONCLUSION: AYA cancer patients with the worst ADI experienced a nearly 10% increase in risk of dying compared to those with more favorable ADI and this effect was strongest among White AYA survivors. Although the magnitude of the effect of ADI on survival was moderate, the presence of a relationship between neighborhood-level SDOH and survival among patients who received care at a tertiary cancer center suggests ADI is a meaningful predictor of survival. These findings provide intriguing evidence for potential interventions aimed at supporting AYA cancer patients from disadvantaged neighborhoods.

Clinical Outcomes After Idecabtagene Vicleucel in Older Multiple Myeloma Patients: A Multicenter Real-world Experience.

The safety and efficacy of CAR T-cell therapy is not well described in older patients, a population that has higher frailty and co-morbidities. In this multicenter retrospective study, we evaluated clinical outcomes along with frailty and geriatric characteristics such as comorbidities, polypharmacy, falls, neuropathy, organ dysfunction, and performance status in younger (<65 years) versus older (≥65 years) patients who received commercial idecabtagene vicleucel (ide-cel). A total of 156 patients (n=75, ≥65 years) were infused with ide-cel by data cut-off. In older patients (median age: 69 years, range: 65-83 years; 66.7% frail; 77.3% did not meet KarMMa eligibility criteria), with a median follow-up duration of 14.2 months, best overall response rate (ORR) was 86.7%, which was comparable to pivotal KarMMa study results (ORR: 73%). Median progression-free survival (PFS) and overall survival (OS) in older patients were 9.1 months and 26.5 months, respectively. Grade 3 or higher cytokine-release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were observed in 1% and 4% of older patients, respectively. Compared to younger patients, the older patients had significantly higher prevalence of frailty, geriatric characteristics such as polypharmacy (5+ drugs; 97%), 4+ comorbidities (69%), and organ dysfunction (35%) (p<0.05). The safety and efficacy of ide-cel therapy were similar in younger and older patients. Frailty and geriatric characteristics such as polypharmacy, comorbidities, and organ dysfunction in older patients did not confer an inferior overall outcome.

Psychological distress and mental health care utilization among Black survivors of adolescent and young adult cancer.

BACKGROUND: Survivors of adolescent and young adult (AYA) cancer experience significant psychological distress and encounter barriers to accessing mental health care. Few studies have investigated racial/ethnic disparities in psychological health outcomes among AYA survivors, and none have compared outcomes within a racially minoritized population. METHODS: National Health Interview Survey data (2010-2018) were analyzed that identified non-Hispanic Black (hereafter, Black) survivors of AYA cancer and age- and sex-matched Black noncancer controls. Sociodemographic factors, chronic health conditions, modifiable behaviors (smoking and alcohol use), and psychological outcomes were assessed with χ2 tests. Logistic regression models, adjusted for survey weights, were used to evaluate the odds of psychological distress by cancer status after adjusting for covariates. Interactions between variables and cancer status were investigated. RESULTS: The study included 334 Black survivors of AYA cancer and 3340 Black controls. Compared to controls, survivors were more likely to report moderate/severe distress (odds ratio [OR], 1.64; p < .001), use mental health care (OR, 1.53; p = .027), report an inability to afford mental health care (OR, 3.82; p < .001), and use medication for anxiety and/or depression (OR, 2.16; p = .001). Forty-one percent of survivors reported moderate/severe distress, and only 15% used mental health care. Among survivors, ages 18-39 years (vs. 40-64 years) and current smoking (vs. never smoking) were associated with the presence of moderate/severe distress. Among survivors with distress, high poverty status was associated with reduced utilization of mental health care. CONCLUSIONS: A cancer diagnosis for a Black AYA is associated with greater psychological distress within an already vulnerable population.

Obesity Predisposes Anthracycline-Treated Survivors of Childhood and Adolescent Cancers to Subclinical Cardiac Dysfunction.

Anthracyclines are effective chemotherapeutics used in approximately 60% of pediatric cancer cases but have a well-documented risk of cardiotoxicity. Existing cardiotoxicity risk calculators do not include cardiovascular risk factors present at the time of diagnosis. The goal of this study is to leverage the advanced sensitivity of strain echocardiography to identify pre-existing risk factors for early subclinical cardiac dysfunction among anthracycline-exposed pediatric patients. We identified 115 pediatric patients with cancer who were treated with an anthracycline between 2013 and 2019. Peak longitudinal left ventricular strain was retroactively calculated on 495 surveillance echocardiograms via the TOMTEC AutoSTRAIN software. Cox proportional hazards models were employed to identify risk factors for abnormal longitudinal strain (> - 16%) following anthracycline treatment. High anthracycline dose (≥ 250 mg/m2 doxorubicin equivalents) and obesity at the time of diagnosis (BMI > 95th percentile-for-age) were both significant predictors of abnormal strain with hazard ratios of 2.79, 95% CI (1.07-7.25), and 3.85, 95% CI (1.42-10.48), respectively. Among pediatric cancer survivors, patients who are obese at the time of diagnosis are at an increased risk of sub-clinical cardiac dysfunction following anthracycline exposure. Future studies should explore the incidence of symptomatic cardiomyopathy 10-15 years post-treatment among patients with early subclinical cardiac dysfunction.

Cardiovascular Disease in Childhood, Adolescent, and Young Adult Cancer Survivors: The Impact of Family History of Premature Heart Disease.

Purpose: Childhood, adolescent, and young adult (CAYA) cancer survivors (age 0-39 years at diagnosis) are at increased risk of cardiovascular disease (CVD). Family history of early heart disease increases the risk of CVD in the general population; however, it is unknown whether this association is seen in CAYA cancer survivors. Methods: Self-report data from the National Health and Nutrition Examination Survey (2005-2018) were used to identify CAYA survivors (>5 years post-diagnosis). The risk of CVD based on family history status (parent or sibling with a diagnosis of heart attack or angina before age 50 years), personal sociodemographic factors, personal medical history factors, and personal behavioral risk factors was determined using logistic regression models. Results: Included were 95 CAYA survivors with CVD and 491 CAYA survivors without CVD. The odds of CVD were significantly higher in survivors with a first-degree family history of early heart disease (odds ratio [OR]: 2.06, 95% confidence interval [CI]: 1.14-3.74). A history of diabetes (OR: 2.61, 95% CI: 1.41-4.84), hypertension (OR: 1.81, 95% CI: 1.04-3.16), and any smoking (OR: 2.19, 95% CI: 1.19-4.02) was also associated with higher odds of CVD in CAYA survivors. Reporting any physical activity in the past month was associated with lower odds (OR: 0.54, 95% CI: 0.30-0.97) of CVD. Conclusions: Family history of early heart disease was associated with increased odds of CVD in CAYA cancer survivors. Obtaining complete and accurate family history information is important both at time of diagnosis and throughout follow-up.

Socioeconomic Status and Chronic Health Conditions in Asian Survivors of Adolescent and Young Adult Cancers.

Purpose: While there are known disparities in socioeconomic status (SES) and health outcomes among racially and ethnically minoritized adolescent and young adult (AYA; ages 15-39 years at diagnosis) cancer survivors compared with White survivors, outcomes in the Asian survivor population are understudied. To better understand the association of an AYA cancer diagnosis with SES and health outcomes within a minoritized population, the current study makes comparisons between individuals of the same race or ethnicity with and without a history of AYA cancer. Methods: Non-Hispanic, Asian AYA cancer survivors and non-Hispanic, Asian age- and sex-matched controls were identified from self-reported data in the National Health Interview Survey (2009-2020). Prevalence of chronic health conditions and socioeconomic factors were compared between groups using chi-square tests. Odds of chronic conditions by SES factors were determined within and between survivors and controls using logistic regression methods. Results: One hundred and thirty-one survivors and 1310 controls were included. Survivors were less likely to be married compared with controls; however, there were no differences in other SES factors examined. Survivors had higher odds of at least one chronic condition diagnosis (odds ratio = 4.17, p < 0.001) compared with controls. Of the chronic conditions assessed, survivors had higher odds of arthritis, pulmonary disease, and hypertension compared with controls. Conclusions: Asian AYA cancer survivors are at increased risk of chronic health conditions compared with Asian individuals without a cancer history. Culturally adapted targeted interventions are needed to improve health outcomes for this population.

Adolescent and young adult Hodgkin lymphoma patients at risk for subcutaneous fat gain during early cancer treatment: a brief report.

Computed tomography scans were assessed for subcutaneous fat area and density at thoracic vertebra 4 in 65 adolescent and young adult (AYA) patients with Hodgkin lymphoma. Subcutaneous fat was quantified over 3 timepoints; (1) baseline, (2) end of initial anthracycline treatment (EOT) and (3) 1 year. Fat area increased at EOT (62.3 ± 5.4 cm/m2 vs 53.5 ± 5.0 cm/m2, p < 0.01) and 1 year (65.8 ± 5.6 cm/m2 vs 53.5 ± 5.0 cm/m2, p < 0.01) compared to baseline. Fat density significantly decreased at EOT (-91.2 ± 1.4 HU vs -86.5 ± 1.4 HU, p < 0.01) and at 1 year (-90.3 ± 1.6 HU vs -86.5 ± 1.4 HU, p = 0.01) compared to baseline. Female, radiation receiving, and anthracycline dosage >250mg/m2subgroups experienced significant fat gain (p < 0.05 for all). Female AYA Hodgkin lymphoma patients receiving radiation, and/or high-dose anthracyclines may be at higher risk of subcutaneous fat gain during therapy.

Risk of chronic health conditions in lesbian, gay, and bisexual survivors of adolescent and young adult cancers.

BACKGROUND: In the general population, individuals with minoritized sexual orientation and gender identity have a higher burden of chronic health conditions than heterosexual individuals. However, the extent to which sexual orientation is associated with excess burden of chronic conditions in adolescent and young adult cancer survivors (AYACS) is unknown. METHODS: Lesbian, gay, and bisexual (LGB) AYACSs, LGB individuals without a history of cancer, and heterosexual AYACSs were identified by self-reported data from the cross-sectional National Health Interview Survey (2013-2020). Socioeconomic factors and the prevalence of chronic health conditions were compared between groups using χ2 tests. Logistic regression methods were used to determine the odds of chronic conditions by socioeconomic factors within and between survivor and comparison groups. RESULTS: One hundred seventy LGB cancer survivors, 1700 LGB individuals without a history of cancer, and 1700 heterosexual cancer survivors were included. Compared with heterosexual survivors, LGB survivors were less likely to be married (p = .001) and more likely to have never been married (p < .001). LGB survivors were more likely to have incomes between 100% and 200% of the federal poverty level than LGB individuals without a history of cancer (p = .012) and heterosexual survivors (p = .021) and were less likely to report incomes >200% the federal poverty level. LGB survivors had higher odds of chronic health conditions than LGB individuals without a history of cancer (odds ratio, 2.45; p < .001) and heterosexual survivors (odds ratio, 2.16; p = .003). CONCLUSIONS: LGB AYACSs are at increased risk of having chronic health conditions compared with both LGB individuals without a history of cancer and heterosexual AYACSs.

Psychological distress and mental health care utilization among Hispanic/Latino survivors of adolescent and young adult cancer.

PURPOSE: Survivors of adolescent and young adult (AYA) cancer experience psychological distress and insufficient access to mental health care. Few studies have investigated racial/ethnic disparities in psychological health outcomes in this population. This study compared psychological distress, mental health care use, and inability to afford mental health care between Hispanic/Latino survivors of AYA cancer and Hispanic/Latino controls. METHODS: The National Health Interview Survey data (2010-2018) were analyzed to identify Hispanic/Latino survivors of AYA cancer and Hispanic/Latino age- and sex-matched non-cancer controls. Sociodemographic, chronic health, modifiable factors, and psychological outcomes were compared using chi-square tests. Logistic regression models with survey weights were used to assess the log-odds of psychological distress in relation to covariates, along with the cancer group. Interactions were evaluated between each variable and cancer group. RESULTS: The study included 370 Hispanic/Latino survivors of AYA cancer (mean time since diagnosis = 12.34 years) and 3700 Hispanic/Latino controls. Compared to controls, survivors were more likely to report moderate/severe distress (OR = 2.23, p < 0.001), use of mental health care (OR = 2.11, p < 0.001) and inability to afford mental health care (OR = 3.05, p < 0.001). Forty-one percent of survivors reported moderate/severe distress and only 16% utilized mental health care. Among survivors, having more than two chronic health conditions and public insurance (compared to private insurance) were associated with the presence of moderate/severe distress. Among survivors experiencing moderate/severe distress, lack of insurance was associated with decreased utilization of mental health care. CONCLUSIONS: Having cancer as an AYA may exacerbate disparities in psychological health within the Hispanic/Latino population.

Early skeletal muscle loss in adolescent and young adult cancer patients treated with anthracycline chemotherapy.

BACKGROUND: Early skeletal muscle loss has been observed in adolescent and young adult (AYA) sarcoma patients undergoing treatment. Identification of individuals within the AYA populace that are at greatest risk of anthracycline-induced skeletal muscle loss is unknown. Moreover, investigations which seek out underlying causes of skeletal muscle degradation during chemotherapy are critical for understanding, preventing, and reducing chronic health conditions associated with poor skeletal muscle status. METHODS: Computed tomography (CT) scans were used to investigate changes in skeletal muscle of 153 AYA sarcoma and Hodgkin lymphoma patients at thoracic vertebra 4 after anthracycline treatment. Images were examined at three time points during the first year of treatment. In parallel, we used translational juvenile mouse models to assess the impact of doxorubicin (DOX) in the soleus and gastrocnemius on muscle wasting. RESULTS: Significant reductions in total skeletal muscle index and density were seen after chemotherapy in AYA cancer patients (p < 0.01 & p = 0.04, respectively). The severity of skeletal muscle loss varied by subgroup (i.e., cancer type, sex, and treatment). Murine models demonstrated a reduction in skeletal muscle fiber cross-sectional area, increased apoptosis and collagen volume for both the soleus and gastrocnemius after DOX treatment (all p < 0.05). After DOX, hindlimb skeletal muscle blood flow was significantly reduced (p < 0.01). CONCLUSION: Significant skeletal muscle loss is experienced early during treatment in AYA cancer patients. Reductions in skeletal muscle blood flow may be a key contributing factor to anthracycline doxorubicin induced skeletal muscle loss.

Circulating microRNAs and Cytokines as Prognostic Biomarkers for Doxorubicin-Induced Cardiac Injury and for Evaluating the Effectiveness of an Exercise Intervention.

PURPOSE: To define a set of biomarkers that can be used to identify patients at high risk of developing late doxorubicin (DOX)-induced cardiac morbidity with the goal of focused monitoring and early interventions. EXPERIMENTAL DESIGN: Mice received phosphate buffered saline or DOX 2.5 mg/kg 2x/week for 2 weeks. Blood samples were obtained before and after therapy for quantification of miRNAs (6 and 24 hours), cytokines (24 hours), and troponin (24 hours, 4 and 6 weeks). Cardiac function was evaluated using echocardiography before and 24 hours after therapy. To assess the effectiveness of exercise intervention in preventing DOX-induced cardiotoxicity blood samples were collected from mice treated with DOX or DOX + exercise. Plasma samples from 13 DOX-treated patients with sarcoma were also evaluated before and 24 hours after therapy. RESULTS: Elevations in plasma miRNA-1, miRNA-499 and IL1α, IL1ß, and IL6 were seen in DOX-treated mice with decreased ejection fraction and fractional shortening 24 hours after DOX therapy. Troponin levels were not elevated until 4 weeks after therapy. In mice treated with exercise during DOX, there was no elevation in these biomarkers and no change in cardiac function. Elevations in these biomarkers were seen in 12 of 13 patients with sarcoma treated with DOX. CONCLUSIONS: These findings define a potential set of biomarkers to identify and predict patients at risk for developing acute and late cardiovascular diseases with the goal of focused monitoring and early intervention. Further studies are needed to confirm the predictive value of these biomarkers in late cardiotoxicity.

Real-world experience of patients with multiple myeloma receiving ide-cel after a prior BCMA-targeted therapy.

Most patients with multiple myeloma experience disease relapse after treatment with a B-cell maturation antigen-targeted therapy (BCMA-TT), and data describing outcomes for patients treated with sequential BCMA-TT are limited. We analyzed clinical outcomes for patients infused with standard-of-care idecabtagene vicleucel, an anti-BCMA chimeric antigen receptor (CAR) T-cell therapy, at 11 US medical centers. A total of 50 patients with prior BCMA-TT exposure (38 antibody-drug conjugate, 7 bispecific, 5 CAR T) and 153 patients with no prior BCMA-TT were infused with ide-cel, with a median follow-up duration of 4.5 and 6.0 months, respectively. Safety outcomes between cohorts were comparable. The prior BCMA-TT cohort had a lower overall response rate (74% versus 88%; p = 0.021), median duration of response (7.4 versus 9.6 months; p = 0.03), and median progression-free survival (3.2 months versus 9.0 months; p = 0.0002) compared to the cohort without prior BCMA-TT. All five patients who received a prior anti-BCMA CAR T responded to ide-cel, and survival outcomes were best for this subgroup. In conclusion, treatment with ide-cel yielded meaningful clinical responses in real-world patients exposed to a prior BCMA-TT, though response rates and durability were suboptimal compared to those not treated with a prior BCMA-TT.

Excess risk of chronic health conditions in Black adolescent and young adult cancer survivors.

BACKGROUND: The US population of adolescent and young adult (age 15-39 years at diagnosis) cancer survivors is growing. Previous studies have identified racial and ethnic disparities in survival and health outcomes in racially minoritized survivors, including Black survivors, compared with White survivors. However, comparisons should be made between those of the same race or ethnicity with and without a history of AYA cancer to fully understand the association of a cancer diagnosis with socioeconomic status (SES) and health outcomes within a minoritized population. METHODS: Non-Hispanic Black AYA cancer survivors and non-Hispanic Black age- and sex-matched controls were identified from self-reported data from the National Health Interview Survey (2009-2018). SES factors and chronic health conditions prevalence were compared between survivors and controls using chi-square tests. Survey-weighted logistic regression models were used to determine odds of chronic conditions by SES factors within and between survivors and controls. Interactions between each variable and cancer group were assessed. RESULTS: A total of 445 survivors and 4450 controls were included. Survivors were less likely than controls to be married, have family income >45K/year, have completed a bachelor's degree or higher, and have private insurance. Survivors had higher odds than controls of having at least one (odds ratio (OR): 7.02, p<0.001) and ≥3 (OR: 4.44, p<0.001) chronic conditions. Survivors had higher odds of each chronic condition assessed including cardiovascular disease, diabetes, and hypertension. Survivors had higher odds of having chronic health conditions compared with controls across all SES variables. CONCLUSIONS: A cancer diagnosis during adolescence and young adulthood is associated with poor SES outcomes and increased odds of comorbidities within the Black population, thus further exacerbating existing disparities. IMPLICATIONS FOR CANCER SURVIVORS: Black AYA cancer survivors have a very high risk of developing chronic health conditions after cancer treatment and interventions are needed to improve long-term health outcomes for this population.

Polymorphisms within Autophagy-Related Genes as Susceptibility Biomarkers for Multiple Myeloma: A Meta-Analysis of Three Large Cohorts and Functional Characterization.

Multiple myeloma (MM) arises following malignant proliferation of plasma cells in the bone marrow, that secrete high amounts of specific monoclonal immunoglobulins or light chains, resulting in the massive production of unfolded or misfolded proteins. Autophagy can have a dual role in tumorigenesis, by eliminating these abnormal proteins to avoid cancer development, but also ensuring MM cell survival and promoting resistance to treatments. To date no studies have determined the impact of genetic variation in autophagy-related genes on MM risk. We performed meta-analysis of germline genetic data on 234 autophagy-related genes from three independent study populations including 13,387 subjects of European ancestry (6863 MM patients and 6524 controls) and examined correlations of statistically significant single nucleotide polymorphisms (SNPs; p < 1 × 10-9) with immune responses in whole blood, peripheral blood mononuclear cells (PBMCs), and monocyte-derived macrophages (MDM) from a large population of healthy donors from the Human Functional Genomic Project (HFGP). We identified SNPs in six loci, CD46, IKBKE, PARK2, ULK4, ATG5, and CDKN2A associated with MM risk (p = 4.47 × 10-4-5.79 × 10-14). Mechanistically, we found that the ULK4rs6599175 SNP correlated with circulating concentrations of vitamin D3 (p = 4.0 × 10-4), whereas the IKBKErs17433804 SNP correlated with the number of transitional CD24+CD38+ B cells (p = 4.8 × 10-4) and circulating serum concentrations of Monocyte Chemoattractant Protein (MCP)-2 (p = 3.6 × 10-4). We also found that the CD46rs1142469 SNP correlated with numbers of CD19+ B cells, CD19+CD3- B cells, CD5+IgD- cells, IgM- cells, IgD-IgM- cells, and CD4-CD8- PBMCs (p = 4.9 × 10-4-8.6 × 10-4) and circulating concentrations of interleukin (IL)-20 (p = 0.00082). Finally, we observed that the CDKN2Ars2811710 SNP correlated with levels of CD4+EMCD45RO+CD27- cells (p = 9.3 × 10-4). These results suggest that genetic variants within these six loci influence MM risk through the modulation of specific subsets of immune cells, as well as vitamin D3-, MCP-2-, and IL20-dependent pathways.

Genome-wide Association Study of Bladder Cancer Reveals New Biological and Translational Insights.

BACKGROUND: Genomic regions identified by genome-wide association studies (GWAS) for bladder cancer risk provide new insights into etiology. OBJECTIVE: To identify new susceptibility variants for bladder cancer in a meta-analysis of new and existing genome-wide genotype data. DESIGN, SETTING, AND PARTICIPANTS: Data from 32 studies that includes 13,790 bladder cancer cases and 343,502 controls of European ancestry were used for meta-analysis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSES: Log-additive associations of genetic variants were assessed using logistic regression models. A fixed-effects model was used for meta-analysis of the results. Stratified analyses were conducted to evaluate effect modification by sex and smoking status. A polygenic risk score (PRS) was generated on the basis of known and novel susceptibility variants and tested for interaction with smoking. RESULTS AND LIMITATIONS: Multiple novel bladder cancer susceptibility loci (6p.22.3, 7q36.3, 8q21.13, 9p21.3, 10q22.1, 19q13.33) as well as improved signals in three known regions (4p16.3, 5p15.33, 11p15.5) were identified, bringing the number of independent markers at genome-wide significance (p < 5 × 10-8) to 24. The 4p16.3 (FGFR3/TACC3) locus was associated with a stronger risk for women than for men (p-interaction = 0.002). Bladder cancer risk was increased by interactions between smoking status and genetic variants at 8p22 (NAT2; multiplicative p value for interaction [pM-I] = 0.004), 8q21.13 (PAG1; pM-I = 0.01), and 9p21.3 (LOC107987026/MTAP/CDKN2A; pM-I = 0.02). The PRS based on the 24 independent GWAS markers (odds ratio per standard deviation increase 1.49, 95% confidence interval 1.44-1.53), which also showed comparable results in two prospective cohorts (UK Biobank, PLCO trial), revealed an approximately fourfold difference in the lifetime risk of bladder cancer according to the PRS (e.g., 1st vs 10th decile) for both smokers and nonsmokers. CONCLUSIONS: We report novel loci associated with risk of bladder cancer that provide clues to its biological underpinnings. Using 24 independent markers, we constructed a PRS to stratify lifetime risk. The PRS combined with smoking history, and other established risk factors, has the potential to inform future screening efforts for bladder cancer. PATIENT SUMMARY: We identified new genetic markers that provide biological insights into the genetic causes of bladder cancer. These genetic risk factors combined with lifestyle risk factors, such as smoking, may inform future preventive and screening strategies for bladder cancer.

Poor Sit-to-Stand Performance in Adolescent and Young Adult Patients with Sarcoma.

Background: Adolescents and young adult (AYA) patients with sarcoma are at heightened risk of reduced physical capacity and disease-related weakness. Sit-to-stand (STS) performance correlates with lower extremity functionality and activities of daily living; however, little is known regarding the relationship between muscular status and STS performance in patients with sarcoma. This study assessed STS performance in patients with sarcoma and the association between STS performance and the skeletal muscle index (SMI) and skeletal muscle density (SMD). Methods: This study included 30 patients with sarcoma (15-39 years old) treated with high-dose doxorubicin. Patients performed the five-times-STS test before starting treatment and 1 year after the baseline test. STS performance was correlated with SMI and SMD. SMI and SMD were quantified using computed tomography scans taken at the level of the 4th thoracic vertebra (T4). Results: Mean performance on the STS test at baseline and 1 year was 2.2-fold and 1.8-fold slower than the age-matched general population, respectively. A lower SMI was associated with worse performance on the STS test (p = 0.01). Similarly, lower SMD at baseline was also associated with poorer STS performance (p < 0.01). Conclusion: Patients with sarcoma have very poor STS performance at baseline and 1 year, which was accompanied by low SMI and SMD at T4.The inability for AYAs to return to healthy age normative STS standards by 1 year may indicate a need for early interventions to enhance skeletal muscle recovery and promote physical activity during and after treatment.

Excess risk of chronic health conditions in Hispanic survivors of adolescent and young adult cancers.

PURPOSE: There is a growing population of survivors of adolescent and young adult (AYA) cancers (age 15-39 years at diagnosis). Studies in AYA cancer survivors have identified racial and ethnic disparities in long-term outcomes. To understand the extent to which a cancer diagnosis exacerbates pre-existent health disparities within a minoritized population, comparisons should be made to those of the same race or ethnicity without a cancer history. METHODS: Self-reported data from the National Health Interview Survey (2009-2018) were used to identify Hispanic AYA cancer survivors and Hispanic age- and sex-matched controls. SES factors (marital status, income, education, insurance) and prevalence of chronic health conditions were compared between groups using chi-square tests. The log-odds of chronic conditions were modeled by survey-weighted logistic regression with relation to age at survey, sex, marital status, education, family income, and cancer group (control versus cancer), together with interactions between each variable and cancer group (survivors vs. controls). RESULTS: Five hundred thirty-nine survivors and 5390 controls were included. Compared with controls, survivors were less likely to be married and have family income > 45 K/year, and more likely to be insured and have completed some college. Survivors had higher odds than controls of chronic health conditions (odds ratio (OR): 7.39, p < 0.001 for at least 1 and OR: 4.78, p < 0.001 for 3 or more) including cardiovascular disease, diabetes, and hypertension. Female sex, higher educational attainment, and public insurance were each associated with increased odds of chronic conditions in Hispanic AYA survivors. CONCLUSIONS: An AYA cancer diagnosis is associated with poor SES outcomes and increased odds of comorbidities within the Hispanic population. IMPLICATIONS FOR CANCER SURVIVORS: Cancer history can exacerbate underlying health disparities. Screening for chronic conditions is especially important in minoritized populations.