Relationships Among Physical Activity, Sleep, and Cancer-related Fatigue: Results From the International ColoCare Study.

BACKGROUND: Risk factors for cancer-related fatigue are understudied in colorectal cancer. PURPOSE: This study aimed to address this critical gap in the literature by (a) describing changes in colorectal cancer-related fatigue and health behavior (physical activity, sleep problems) and (b) examining if physical activity and sleep problems predict fatigue trajectories from baseline (approximately at the time of diagnosis), to 6- and 12 months after enrollment. METHODS: Patients participating in the international ColoCare Study completed self-report measures at baseline (approximately time of diagnosis), 6-, and 12 months assessing physical activity using the International Physical Activity Questionnaire (IPAQ) and fatigue and sleep using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-C30). Mixed-effect models examined changes in physical activity, sleep problems, and fatigue. Cross-lagged panel models examined bidirectional relationships between physical activity or sleep and fatigue across time. RESULTS: Colorectal cancer patients (n = 649) had a mean age of 61 ± 13 years. Most were male (59%), non-Hispanic White (91%), diagnosed with Stages III-IV (56%) colon cancer (58%), and treated with surgery (98%). Within-person cross-lagged models indicated higher physical activity at Month 6 was associated with higher fatigue at Month 12 (ß = 0.26, p = .016). When stratified by cancer stage (I-II vs. III-IV), the relationship between physical activity at Month 6 and fatigue at Month 12 existed only for patients with advanced cancer (Stages III and IV, ß = 0.43, p = .035). Cross-lagged associations for sleep and fatigue from baseline to Month 6 were only observed in patients with Stages III or IV cancer, however, there was a clear cross-sectional association between sleep problems and fatigue at baseline and Month 6. CONCLUSIONS: Within-person and cross-lagged association models suggest fatiguability may become increasingly problematic for patients with advanced colorectal cancer the first year after diagnosis. In addition, sleep problems were consistently associated with higher fatigue in the first year, regardless of cancer stage. TRIAL REGISTRATION: The international ColoCare Study was registered on clinicaltrials.gov, NCT02328677, in December 2014.

Within-person and cross-lagged association models suggest fatiguability may become increasingly problematic for patients with advanced (Stages III and IV) colorectal cancer the first year after diagnosis.

Functional quality of life among newly diagnosed young adult colorectal cancer survivors compared to older adults: results from the ColoCare Study.

PURPOSE: Colorectal cancer (CRC) incidence and mortality are increasing among young adults (YAs) aged 18-39. This study compared quality of life (QOL) between YA and older adult CRC survivors in the ColoCare Study. METHODS: Participants were grouped by age (years) as follows: 18-39 (YA), 40-49, 50-64, and 65 + . Functional QOL (physical, social, role, emotional, cognitive) and global QOL were assessed with the EORTC-QLQ-C30 at enrollment, 3, 6, and 12 months. Average scores were compared between groups over time using longitudinal mixed-effect modeling. Proportions with clinically meaningful QOL impairment were calculated using age-relevant thresholds and compared between groups over time using logistic regression with mixed effects. RESULTS: Participants (N = 1590) were n = 81 YAs, n = 196 aged 40-49, n = 627 aged 50-64, and n = 686 aged 65 + . Average physical function was better among YAs than participants aged 50-64 (p = 0.010) and 65 + (p < 0.001), and average social function was worse among YAs than aged 65 + (p = 0.046). Relative to YAs, all age groups were less likely to report clinically meaningful social dysfunction (aged 40-49 OR = 0.13, 95%CI = 0.06-0.29; aged 50-64 OR = 0.10, 95%CI = 0.05-0.21; aged 65 + OR = 0.07, 95%CI = 0.04-0.15) and role dysfunction (aged 40-49 OR = 0.36, 95%CI = 0.18-0.75; aged 50-64 OR = 0.41, 95%CI = 0.22-0.78; aged 65 + OR = 0.32, 95%CI = 0.17-0.61). Participants aged 40-49 were also less likely to report physical dysfunction (OR = 0.42, 95%CI = 0.19-0.93). CONCLUSION: YA CRC survivors reported better physical and worse social function compared to older CRC survivors, and YA CRC survivors were more likely to report clinically meaningful social, role, and physical disfunction. Future work should further investigate QOL using age-relevant benchmarks to inform best practices for CRC survivorship care. TRIAL REGISTRATION: NCT02328677, registered December 2014.

Risk factors and health behaviors associated with loneliness among cancer survivors during the COVID-19 pandemic.

Loneliness may exacerbate poor health outcomes particularly among cancer survivors during the COVID-19 pandemic. Little is known about the risk factors of loneliness among cancer survivors. We evaluated the risk factors of loneliness in the context of COVID-19 pandemic-related prevention behaviors and lifestyle/psychosocial factors among cancer survivors. Cancer survivors (n = 1471) seen at Huntsman Cancer Institute completed a survey between August-September 2020 evaluating health behaviors, medical care, and psychosocial factors including loneliness during COVID-19 pandemic. Participants were classified into two groups: 'lonely' (sometimes, usually, or always felt lonely in past month) and 'non-lonely' (never or rarely felt lonely in past month). 33% of cancer survivors reported feeling lonely in the past month. Multivariable logistic regression showed female sex, not living with a spouse/partner, poor health status, COVID-19 pandemic-associated lifestyle factors including increased alcohol consumption and marijuana/CBD oil use, and psychosocial stressors such as disruptions in daily life, less social interaction, and higher perceived stress and financial stress were associated with feeling lonely as compared to being non-lonely (all p < 0.05). A significant proportion of participants reported loneliness, which is a serious health risk among vulnerable populations, particularly cancer survivors. Modifiable risk factors such as unhealthy lifestyle behaviors and psychosocial stress were associated with loneliness. These results highlight the need to screen for unhealthy lifestyle factors and psychosocial stressors to identify cancer survivors at increased risk of loneliness and to develop effective management strategies.

Associations of combined physical activity and body mass index groups with colorectal cancer survival outcomes.

BACKGROUND: Physical activity and BMI have been individually associated with cancer survivorship but have not yet been studied in combinations in colorectal cancer patients. Here, we investigate individual and combined associations of physical activity and BMI groups with colorectal cancer survival outcomes. METHODS: Self-reported physical activity levels (MET hrs/wk) were assessed using an adapted version of the International Physical Activity Questionnaire (IPAQ) at baseline in 931 patients with stage I-III colorectal cancer and classified into 'highly active' and'not-highly active'(≥ / < 18 MET hrs/wk). BMI (kg/m2) was categorized into 'normal weight', 'overweight', and 'obese'. Patients were further classified into combined physical activity and BMI groups. Cox-proportional hazard models with Firth correction were computed to assess associations [hazard ratio (HR), 95% profile HR likelihood confidence interval (95% CI) between individual and combined physical activity and BMI groups with overall and disease-free survival in colorectal cancer patients. RESULTS: 'Not-highly active' compared to 'highly active' and 'overweight'/ 'obese' compared to 'normal weight' patients had a 40-50% increased risk of death or recurrence (HR: 1.41 (95% CI: 0.99-2.06), p = 0.03; HR: 1.49 (95% CI: 1.02-2.21) and HR: 1.51 (95% CI: 1.02-2.26), p = 0.04, respectively). 'Not-highly active' patients had worse disease-free survival outcomes, regardless of their BMI, compared to 'highly active/normal weight' patients. 'Not-highly active/obese' patients had a 3.66 times increased risk of death or recurrence compared to 'highly active/normal weight' patients (HR: 4.66 (95% CI: 1.75-9.10), p = 0.002). Lower activity thresholds yielded smaller effect sizes. CONCLUSION: Physical activity and BMI were individually associated with disease-free survival among colorectal cancer patients. Physical activity seems to improve survival outcomes in patients regardless of their BMI.

Trajectories and risk factors of fatigue following colorectal cancer diagnosis.

AIM: This study sought to identify groups of colorectal cancer patients based upon trajectories of fatigue and examine how demographic, clinical and behavioural risk factors differentiate these groups. METHOD: Patients were from six cancer centres in the United States and Germany. Fatigue was measured using the fatigue subscale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) at five time points (baseline/enrolment and 3, 6, 12 and 24 months after diagnosis). Piecewise growth mixture models identified latent trajectories of fatigue. Logistic regression models examined differences in demographic, clinical and behavioural characteristics between fatigue trajectory groups. RESULTS: Among 1615 participants (57% men, 86% non-Hispanic White, mean age 61 ± 13 years at diagnosis), three distinct groups were identified. In the high fatigue group (36%), fatigue significantly increased in the first 6 months after diagnosis and then showed statistically and clinically significant improvement from 6 to 24 months (P values < 0.01). Throughout the study period, average fatigue met or exceeded cutoffs for clinical significance. In the moderate (34%) and low (30%) fatigue groups, fatigue levels remained below or near population norms across the study period. Patients who were diagnosed with Stage II-IV disease and/or current smokers were more likely to be in the high fatigue than in the moderate fatigue group (P values < 0.05). CONCLUSION: A large proportion of colorectal cancer patients experienced sustained fatigue after initiation of cancer treatment. Patients with high fatigue at the time of diagnosis may benefit from early supportive care.

Detectable Lipidomes and Metabolomes by Different Plasma Exosome Isolation Methods in Healthy Controls and Patients with Advanced Prostate and Lung Cancer.

Circulating exosomes in the blood are promising tools for biomarker discovery in cancer. Due to their heterogeneity, different isolation methods may enrich distinct exosome cargos generating different omic profiles. In this study, we evaluated the effects of plasma exosome isolation methods on detectable multi-omic profiles in patients with non-small cell lung cancer (NSCLC), castration-resistant prostate cancer (CRPC), and healthy controls, and developed an algorithm to quantify exosome enrichment. Plasma exosomes were isolated from CRPC (n = 10), NSCLC (n = 14), and healthy controls (n = 10) using three different methods: size exclusion chromatography (SEC), lectin binding, and T-cell immunoglobulin domain and mucin domain-containing protein 4 (TIM4) binding. Molecular profiles were determined by mass spectrometry of extracted exosome fractions. Enrichment analysis of uniquely detected molecules was performed for each method with MetaboAnalyst. The exosome enrichment index (EEI) scores methods based on top differential molecules between patient groups. The lipidomic analysis detected 949 lipids using exosomes from SEC, followed by 246 from lectin binding and 226 from TIM4 binding. The detectable metabolites showed SEC identifying 191 while lectin binding and TIM4 binding identified 100 and 107, respectively. When comparing uniquely detected molecules, different methods showed preferential enrichment of different sets of molecules with SEC enriching the greatest diversity. Compared to controls, SEC identified 28 lipids showing significant difference in NSCLC, while only 1 metabolite in NSCLC and 5 metabolites in CRPC were considered statistically significant (FDR < 0.1). Neither lectin-binding- nor TIM4-binding-derived exosome lipids or metabolites demonstrated significant differences between patient groups. We observed the highest EEI from SEC in lipids (NSCLC: 871.33) which was also noted in metabolites. These results support that the size exclusion method of exosome extraction implemented by SBI captures more heterogeneous exosome populations. In contrast, lectin-binding and TIM4-binding methods bind surface glycans or phosphatidylserine moieties of the exosomes. Overall, these findings suggest that specific isolation methods select subpopulations which may significantly impact cancer biomarker discovery.

Metabolic Dysregulation Explains the Diverse Impacts of Obesity in Males and Females with Gastrointestinal Cancers.

The prevalence of obesity, defined as the body mass index (BMI) ≥ 30 kg/m2, has reached epidemic levels. Obesity is associated with an increased risk of various cancers, including gastrointestinal ones. Recent evidence has suggested that obesity disproportionately impacts males and females with cancer, resulting in varied transcriptional and metabolic dysregulation. This study aimed to elucidate the differences in the metabolic milieu of adenocarcinomas of the gastrointestinal (GI) tract both related and unrelated to sex in obesity. To demonstrate these obesity and sex-related effects, we utilized three primary data sources: serum metabolomics from obese and non-obese patients assessed via the Biocrates MxP Quant 500 mass spectrometry-based kit, the ORIEN tumor RNA-sequencing data for all adenocarcinoma cases to assess the impacts of obesity, and publicly available TCGA transcriptional analysis to assess GI cancers and sex-related differences in GI cancers specifically. We applied and integrated our unique transcriptional metabolic pipeline in combination with our metabolomics data to reveal how obesity and sex can dictate differential metabolism in patients. Differentially expressed genes (DEG) analysis of ORIEN obese adenocarcinoma as compared to normal-weight adenocarcinoma patients resulted in large-scale transcriptional reprogramming (4029 DEGs, adj. p < 0.05 and |logFC| > 0.58). Gene Set Enrichment and metabolic pipeline analysis showed genes enriched for pathways relating to immunity (inflammation, and CD40 signaling, among others) and metabolism. Specifically, we found alterations to steroid metabolism and tryptophan/kynurenine metabolism in obese patients, both of which are highly associated with disease severity and immune cell dysfunction. These findings were further confirmed using the TCGA colorectal adenocarcinoma (CRC) and esophageal adenocarcinoma (ESCA) data, which showed similar patterns of increased tryptophan catabolism for kynurenine production in obese patients. These patients further showed disparate alterations between males and females when comparing obese to non-obese patient populations. Alterations to immune and metabolic pathways were validated in six patients (two obese and four normal weight) via CD8+/CD4+ peripheral blood mononuclear cell RNA-sequencing and paired serum metabolomics, which showed differential kynurenine and lipid metabolism, which corresponded with altered T-cell transcriptome in obese populations. Overall, obesity is associated with differential transcriptional and metabolic programs in various disease sites. Further, these alterations, such as kynurenine and tryptophan metabolism, which impact both metabolism and immune phenotype, vary with sex and obesity together. This study warrants further in-depth investigation into obesity and sex-related alterations in cancers that may better define biomarkers of response to immunotherapy.

Factors associated with changes in exercise behaviors during the COVID-19 pandemic.

PURPOSE: There is limited information on how the COVID-19 pandemic has changed health behaviors among cancer patients. We examined changes in exercise behaviors since the pandemic and identified characteristics associated with these changes among cancer patients. METHODS: Cancer patients (n = 1,210) completed a survey from August to September 2020 to assess COVID-19 pandemic-related changes in health behaviors and psychosocial factors. Patients were categorized into three groups: exercising less, exercising did not change, and exercising more. Patient characteristics were compared by exercise groups. RESULTS: One-third of the patients reported a decreased amount of regular exercise, while 10% reported exercising more during the pandemic. Patients who exercised less were more likely to be unemployed/retired and have poor health status and psychosocial stressors such as disruptions in daily life while less likely to be former smokers (all p < 0.05). In contrast, patients who exercised more were younger, had stage IV diagnosis, and also reported disruptions in daily life (all p < 0.05). Patients who were living in rural areas were also more likely not to experience changes in exercise habits (all p < 0.05), although rural-urban status was not identified as a strong predictor. CONCLUSION: A significant proportion of cancer patients experienced changes in exercise habits, especially exercising less, during the first 6 months of the COVID-19 pandemic. Age, employment status, tumor stage, health status, smoking status, and psychosocial factors were associated with changes in exercise behaviors. Our results highlight the importance of promoting physical activity guidelines for cancer survivorship during the COVID-19 pandemic and may help improve the identification of cancer patients susceptible to exercising less.

Semiautomated Measure of Abdominal Adiposity Using Computed Tomography Scan Analysis.

BACKGROUND: The obesity epidemic has prompted the need to better understand the impact of adipose tissue on human pathophysiology. However, accurate, efficient, and replicable models of quantifying adiposity have yet to be developed and clinically implemented. We propose a novel semiautomated radiologic method of measuring the visceral fat area (VFA) using computed tomography scan analysis. MATERIALS AND METHODS: We obtained a cohort of 100 patients with rectal adenocarcinoma, with a median age of 60.9 y (age range: 35-87 y) and an average body mass index of 28.8 kg/m2 ± 6.56 kg/m2. The semiautomated quantification method of adiposity was developed using a commercial imaging suite. The method was compared to two manual delineations performed using two different picture archiving communication systems. We quantified VFA, subcutaneous fat area (SFA), total fat area (TFA), and visceral-to-subcutaneous fat ratio (V/S ratio) on computed tomography axial slices that were at the L4-L5 intervertebral level. RESULTS: The semiautomated method was comparable to manual measurements for TFA, VFA, and SFA with intraclass correlation (ICC) of 0.99, 0.97, and 0.96, respectively. However, the ICC for the V/S ratio was only 0.44, which led to the identification of technical outliers that were identified using robust regression. After removal of these outliers, the ICC improved to 0.99 for TFA, VFA, and SFA and 0.97 for the V/S ratio. Measurements from the manual methodology highly correlated between the two picture archiving communication system platforms, with ICC of 0.98 for TFA, 0.98 for VFA, 0.96 for SFA, and 0.95 for the V/S ratio. CONCLUSIONS: This semiautomated method is able to generate precise and reproducible results. In the future, this method may be applied on a larger scale to facilitate risk stratification of patients using measures of abdominal adiposity.

Plasma 25-Hydroxyvitamin D3 Levels in Colorectal Cancer Patients and Associations with Physical Activity.

Physical activity (PA) and vitamin D are thought to affect colorectal cancer prognosis. The present study investigates associations between 25(OH)D3 and PA in prospectively followed colorectal cancer patients in the ColoCare study. At 6, 12, and 24 mo after surgery, patients donated a blood sample, wore an accelerometer for 10 consecutive days, and completed a PA questionnaire. Plasma 25-hydroxyvitamin D3 (25(OH)D3) levels were measured by high-performance liquid chromatography. We tested associations using partial correlations and multivariate linear regression analysis, adjusted for season, age, and body mass index. A total of 137 assessments of 25(OH)D3 levels and PA were conducted (58 at 6 mo, 51 at 12 mo, and 28 at 24 mo). More than 60% of the patients were vitamin D-deficient (25(OH)D3 ≤20 ng/ml), independent of study time point. At 6-mo follow-up, accelerometry-based vigorous and moderate-to-vigorous PAs were positively associated with 25(OH)D3 levels (P = 0.04; P = 0.006,). PA together with season was a significant predictor of elevated 25(OH)D3 levels. Our results suggest that the majority of colorectal cancer patients may suffer from vitamin D deficiency. Engaging in PA may be an effective approach to increase their 25(OH)D3 levels.

Evidence of altered brain regulatory gene expression in tobacco-exposed fetuses.

AIM: We sought to determine the association between prenatal smoking status and expression of fetal brain regulatory genes. METHODS: At delivery, we collected information from parturient women on prenatal smoking habits and analyzed salivary cotinine levels. We obtained neonatal umbilical cord blood and extracted total RNA. We then employed the quantitative polymerase chain reaction (QPCR) analyses and the comparative CT method to calculate the relative gene expression of selected fetal brain regulatory genes responsible for (1) brain growth (brain-derived neutrotrophic factor, BDNF), (2) myelination (proteolipidic protein 1, PLP1 and myelin basic protein, MBP), and (3) neuronal migration and cell-cell interactions during fetal brain development or RLN. The χ2-test, analysis of variance (ANOVA), and the Grubb test were used to evaluate the relationship between prenatal smoking status and relative gene expression levels. Further analysis using bootstrapping was performed to assess the precision of our estimates. RESULTS: Of the 39 maternal-infant dyads included in this study, 25.6% were non-smokers, 43.6% were passive smokers and 30.8% were active smokers. The results showed down-regulation of the selected fetal brain regulatory genes among active smokers. CONCLUSIONS: These findings represent preliminary evidence in humans that intrauterine tobacco exposure impacts fetal brain programming. Future studies are warranted to examine whether our findings represent potential mechanisms through which adverse childhood/adult-onset cognitive and behavioral outcomes that have been previously linked to intrauterine exposure occur.

Accelerometry and physical activity questionnaires - a systematic review.

BACKGROUND: The aim of this study is to review accelerometer wear methods and correlations between accelerometry and physical activity questionnaire data, depending on participant characteristics. METHODS: We included 57 articles about physical activity measurement by accelerometry and questionnaires. Criteria were to have at least 100 participants of at least 18 years of age with manuscripts available in English. Accelerometer wear methods were compared. Spearman and Pearson correlation coefficients between questionnaires and accelerometers and differences between genders, age categories, and body mass index (BMI) categories were assessed. RESULTS: In most investigations, requested wear time was seven days during waking hours and devices were mostly attached on hips with waist belts. A minimum of four valid days with wear time of at least ten hours per day was required in most studies. Correlations (r = Pearson, ρ = Spearman) of total questionnaire scores against accelerometer measures across individual studies ranged from r = 0.08 to ρ = 0.58 (P < 0.001) for men and from r = -0.02 to r = 0.49 (P < 0.01) for women. Correlations for total physical activity among participants with ages ≤65 ranged from r = 0.04 to ρ = 0.47 (P < 0.001) and from r = 0.16 (P = 0.02) to r = 0.53 (P < 0.01) among the elderly (≥65 years). Few studies investigated stratification by BMI, with varying cut points and inconsistent results. CONCLUSION: Accelerometers appear to provide slightly more consistent results in relation to self-reported physical activity among men. Nevertheless, due to overall limited consistency, different aspects measured by each method, and differences in the dimensions studied, it is advised that studies use both questionnaires and accelerometers to gain the most complete physical activity information.

Body Mass Index and Perioperative Complications After Esophagectomy for Cancer.

BACKGROUND: Given the increasing rate of obesity, the effects of excessive body weight on surgical outcomes constitute a relevant quality of care concern. Our aim was to determine the relationship between preoperative body mass index (BMI) on perioperative complications after esophagectomy for cancer. METHODS: From our comprehensive esophageal cancer database consisting of 510 patients, we identified 166 obese (BMI ≥30), 176 overweight (BMI 25-29), and 148 normal-weight (BMI 20-24) patients. Malnourished patients (BMI of <20) were excluded. Incidence of preoperative risk factors and perioperative complications in each group were analyzed. RESULTS: The patient group consists of 420 men and 70 women with a mean age at time of surgery were 64 years (range 28-86 years). The categories of patients (obese, overweight, and normal-weight) were similar in terms of demographics and comorbidities, with the exception of a younger age (62.5 years vs 66.2 years vs 65.3 years, P = 0.002), and a higher incidence of diabetes (23.5% vs 11.4% vs 10.1%, P = 0.001) and hiatal hernia (28.3% vs 14.8% vs 20.3%, P = 0.01) for obese patients. More patients with BMI >24 were found with adenocarcinoma, compared with the normal-weight group (90.8% vs 90.9% vs 82.5%, P = 0.03). Despite similar preoperative stage, obese patients were less likely to receive neoadjuvant treatment (47.6% vs 54.5% vs 66.2%, P = 0.004). The type of surgery performed, overall blood loss, extent of lymphadenectomy, rate of resections with negative margins, and postoperative complications were not influenced by BMI on univariate and multivariate analysis. CONCLUSIONS: In our experience, BMI did not affect number of harvested lymph-nodes, rates of negative margins, and morbidity and mortality after esophagectomy for cancer. In our experience, esophagectomy could be performed safely and efficiently in mildly obese patients.

Epigenomic characterization of locally advanced anal cancer: a radiation therapy oncology group 98-11 specimen study.

BACKGROUND: The Radiation Therapy Oncology Group 98-11 clinical trial demonstrated the superiority of standard 5-fluorouracil/mitomycin-C over 5-fluorouracil/cisplatin in combination with radiation in the treatment of anal squamous cell cancer. Tumor size (>5 cm) and lymph node metastases are associated with disease progression. There may be key molecular differences (eg, DNA methylation changes) in tumors at high risk for progression. OBJECTIVE: The objectives of this study were to determine whether there are differences in DNA methylation at individual CpG sites and within genes among locally advanced anal cancers, with large tumor size and/or nodal involvement, compared with those that are less advanced. DESIGN: This was a case-case study among 121 patients defined as high risk (tumor size >5 cm and/or nodal involvement; n = 59) or low risk (≤5 cm, node negative; n = 62) within the mitomycin-C arm of the Radiation Therapy Oncology Group 98-11 trial. DNA methylation was measured using the Illumina HumanMethylation450 Array. SETTINGS: The study was conducted in a tertiary care cancer center in collaboration with a national clinical trials cooperative group. PATIENTS: The patients consisted of 74 women and 47 men with a median age of 54 years (range, 25-79 years). MAIN OUTCOME MEASURES: DNA methylation differences at individual CpG sites and within genes between low- and high-risk patients were compared using the Mann-Whitney test (p < 0.001). RESULTS: A total of 16 CpG loci were differentially methylated (14 increased and 2 decreased) in high- versus low-risk cases. Genes harboring differentially methylated CpG sites included known tumor suppressor genes and novel targets. LIMITATIONS: This study only included patients in the mitomycin-C arm with tumor tissue; however, this sample was representative of the trial. CONCLUSIONS: This is the first study to apply genome-wide methylation analysis to anal cancer. Biologically relevant differences in methylated targets were found to discriminate locally advanced from early anal cancer. Epigenetic events likely play a significant role in the progression of anal cancer and may serve as potential biomarkers.

Spectrum of somatic mutational features of colorectal tumors in ancestrally diverse populations.

Ancestrally diverse and admixed populations, including the Hispanic/Latino/a/x/e community, are underrepresented in cancer genetic and genomic studies. Leveraging the Latino Colorectal Cancer Consortium, we analyzed whole exome sequencing data on tumor/normal pairs from 718 individuals with colorectal cancer (128 Latino, 469 non-Latino) to map somatic mutational features by ethnicity and genetic ancestry. Global proportions of African, East Asian, European, and Native American ancestries were estimated using ADMIXTURE. Associations between global genetic ancestry and somatic mutational features across genes were examined using logistic regression. TP53 , APC , and KRAS were the most recurrently mutated genes. Compared to non-Latino individuals, tumors from Latino individuals had fewer KRAS (OR=0.64, 95%CI=0.41-0.97, p=0.037) and PIK3CA mutations (OR=0.55, 95%CI=0.31-0.98, p=0.043). Genetic ancestry was associated with presence of somatic mutations in 39 genes (FDR-adjusted LRT p<0.05). Among these genes, a 10% increase in African ancestry was associated with significantly higher odds of mutation in KNCN (OR=1.34, 95%CI=1.09-1.66, p=5.74×10 -3 ) and TMEM184B (OR=1.53, 95%CI=1.10-2.12, p=0.011). Among RMGs, we found evidence of association between genetic ancestry and mutation status in CDC27 (LRT p=0.0084) and between SMAD2 mutation status and AFR ancestry (OR=1.14, 95%CI=1.00-1.30, p=0.046). Ancestry was not associated with tumor mutational burden. Individuals with above-average Native American ancestry had a lower frequency of microsatellite instable (MSI-H) vs microsatellite stable tumors (OR=0.45, 95%CI=0.21-0.99, p=0.048). Our findings provide new knowledge about the relationship between ancestral haplotypes and somatic mutational profiles that may be useful in developing precision medicine approaches and provide additional insight into genomic contributions to cancer disparities. Significance: Our data in ancestrally diverse populations adds essential information to characterize mutational features in the colorectal cancer genome. These results will help enhance equity in the development of precision medicine strategies.

Genomic Classification and Individualized Prognosis in Multiple Myeloma.

PURPOSE: Outcomes for patients with newly diagnosed multiple myeloma (NDMM) are heterogenous, with overall survival (OS) ranging from months to over 10 years. METHODS: To decipher and predict the molecular and clinical heterogeneity of NDMM, we assembled a series of 1,933 patients with available clinical, genomic, and therapeutic data. RESULTS: Leveraging a comprehensive catalog of genomic drivers, we identified 12 groups, expanding on previous gene expression-based molecular classifications. To build a model predicting individualized risk in NDMM (IRMMa), we integrated clinical, genomic, and treatment variables. To correct for time-dependent variables, including high-dose melphalan followed by autologous stem-cell transplantation (HDM-ASCT), and maintenance therapy, a multi-state model was designed. The IRMMa model accuracy was significantly higher than all comparator prognostic models, with a c-index for OS of 0.726, compared with International Staging System (ISS; 0.61), revised-ISS (0.572), and R2-ISS (0.625). Integral to model accuracy was 20 genomic features, including 1q21 gain/amp, del 1p, TP53 loss, NSD2 translocations, APOBEC mutational signatures, and copy-number signatures (reflecting the complex structural variant chromothripsis). IRMMa accuracy and superiority compared with other prognostic models were validated on 256 patients enrolled in the GMMG-HD6 (ClinicalTrials.gov identifier: NCT02495922) clinical trial. Individualized patient risks were significantly affected across the 12 genomic groups by different treatment strategies (ie, treatment variance), which was used to identify patients for whom HDM-ASCT is particularly effective versus patients for whom the impact is limited. CONCLUSION: Integrating clinical, demographic, genomic, and therapeutic data, to our knowledge, we have developed the first individualized risk-prediction model enabling personally tailored therapeutic decisions for patients with NDMM.

Prediagnostic body weight and survival in high grade glioma.

Greater adiposity has been linked to an increased risk and/or poorer survival in a variety of cancers. We examined whether prediagnostic body weight 1-5 years prior to diagnosis is associated with survival in patients with high grade glioma. The analysis was based on a series of patients with high-grade glioma (N = 853) enrolled in a US-based multicenter case-control study. Subjects reported height and weight 1-5 years prior to interview and at age 21. BMI was categorized according to WHO criteria as underweight (BMI <18.5 kg/m(2)), normal weight (BMI 18.5-24.9 kg/m(2)), overweight (BMI 25-29.9 kg/m(2)) and obese (BMI ≥30 kg/m(2)). Proportional hazards regression was used to estimate hazard ratios (HR) and 95 % confidence intervals (CIs) for glioma-related death according to body mass index (BMI, kg/m(2)). Overall survival was reduced among patients underweight (median survival: 12.0 months) or obese (median: 13.6 months) when compared to patients of normal weight (median: 17.5 months) prior to glioma diagnosis (p = 0.004). In a multivariate model controlling for other prognostic factors, an excess mortality was observed in patients reporting obese body weights 1-5 years prior to study interview when compared to patients with a normal BMI (HR = 1.32; 95 % CI 1.04-1.68). Consistent patterns of association with excess body weight were observed in men and women, and all findings were similar regardless of treatment for glioma. A lower than optimal body weight was associated with a nonsignificant excess mortality in multivariate analysis. Premorbid obesity was significantly associated with a poor patient outcome independent of treatment and established prognostic factors. Excess body weight may be an adverse prognostic factor in glioma, a relationship observed across a spectrum of cancer types. The current findings linking prediagnostic body weight with mortality in high-grade glioma warrant further research.

Risk Stratification for Early-onset Colorectal Cancer Screening: Are We Ready for Implementation?

Early-onset colorectal cancer (EOCRC) is increasing at alarming rates and identifying risk factors is a high priority. There is a need to develop risk stratification approaches for colorectal cancer screening among younger populations. Although there is a growing body of evidence identifying risk factors for EOCRC, including the report by Imperiale and colleagues in this issue, risk stratification for EOCRC screening has not been implemented into practice. This publication highlights how essential it is to bring research findings into practice and bridge the gaps between developing risk prediction modeling in epidemiology and implementation science. While encouraging, we are still a long way off from having a clinically applicable risk prediction tool. See related article by Imperiale et al., p. 513.

Whole-Exome sequencing analysis identified TMSB10/TRABD2A locus to be associated with carfilzomib-related cardiotoxicity among patients with multiple myeloma.

Background: Proteasome inhibitor Carfilzomib (CFZ) is effective in treating patients with refractory or relapsed multiple myeloma (MM) but has been associated with cardiovascular adverse events (CVAE) such as hypertension, cardiomyopathy, and heart failure. This study aimed to investigate the contribution of germline genetic variants in protein-coding genes in CFZ-CVAE among MM patients using whole-exome sequencing (WES) analysis. Methods: Exome-wide single-variant association analysis, gene-based analysis, and rare variant analyses were performed on 603,920 variants in 247 patients with MM who have been treated with CFZ and enrolled in the Oncology Research Information Exchange Network (ORIEN) at the Moffitt Cancer Center. Separate analyses were performed in European Americans and African Americans followed by a trans-ethnic meta-analysis. Results: The most significant variant in the exome-wide single variant analysis was a missense variant rs7148 in the thymosin beta-10/TraB Domain Containing 2A (TMSB10/TRABD2A) locus. The effect allele of rs7148 was associated with a higher risk of CVAE [odds ratio (OR) = 9.3 with a 95% confidence interval of 3.9-22.3, p = 5.42*10-7]. MM patients with rs7148 AG or AA genotype had a higher risk of CVAE (50%) than those with GG genotype (10%). rs7148 is an expression quantitative trait locus (eQTL) for TRABD2A and TMSB10. The gene-based analysis also showed TRABD2A as the most significant gene associated with CFZ-CVAE (p = 1.06*10-6). Conclusions: We identified a missense SNP rs7148 in the TMSB10/TRABD2A as associated with CFZ-CVAE in MM patients. More investigation is needed to understand the underlying mechanisms of these associations.

Low muscle mass is associated with a higher risk of all-cause and cardiovascular disease-specific mortality in cancer survivors.

OBJECTIVES: Individuals with prior cancer diagnosis are more likely to have low muscle mass (LMM) than their cancer-free counterparts. Understanding the effects of LMM on the prognosis of cancer survivors can be clinically important. The aim of this study was to investigate whether risks for all-cause and cardiovascular disease (CVD)-specific mortality differ by status of LMM in cancer survivors and a matched cohort without cancer history. METHODS: We used cohort data from the 1999-2006 and 2011-2014 National Health and Nutrition Examination Survey. Participants included 946 adults surviving for ≥1 since cancer diagnosis and a matched cohort (by age, sex, and race) without cancer history (N = 1857). LMM was defined by appendicular lean mass and body height (men <7.26 kg/m2, women <5.45 kg/m2). Death was ascertained via the National Death Index and cause of death was assessed via International Classification of Diseases, Tenth Revision. Multivariable Cox proportional hazards models were used to estimate adjusted hazard ratio (aHR) and 95% confidence interval (CI) of LMM. RESULTS: The mean age of cancer survivors and matched cohort was 60.6 y (SD 15) and 60.2 y (SD 14.9), respectively. The median follow-up was 10.5 y for survivors and 10.9 y for matched cohort. Overall, 22.2% of cancer survivors and 19.7% of the matched cohort had LMM, respectively. In all, 321 survivors (33.9%) and 495 participants (26.7%) in the matched cohort died during follow-up. CVD-specific deaths were identified in 58 survivors (6.1%) and 122 participants in the matched cohort (6.6%). The multivariable Cox model suggested that LMM was positively associated with all-cause (aHR, 1.73; 95% CI, 1.31-2.29) and CVD-specific (aHR, 2.13; 95% CI, 1.14-4.00) mortality in cancer survivors. The associations between LMM and risk for all-cause (aHR, 1.24; 95% CI, 0.98-1.56) and CVD-specific (aHR, 1.21; 95% CI, 0.75-1.93) mortality were not statistically significant in the matched cohort. CONCLUSION: Cancer survivors with LMM have an increased risk for all-cause and CVD-specific mortality. This increase appears to be larger than that in counterparts without cancer history.