Body Composition and Energy Expenditure in Youth With Spina Bifida: Protocol for a Multisite, Cross-Sectional Study.

BACKGROUND: Obesity prevalence in youth with spina bifida is higher than in their typically developing peers. Obesity is associated with lifelong medical, psychological, and economic burdens. Successful prevention or treatment of obesity in individuals with spina bifida is compromised by (1) the lack of valid and reliable methods to identify body fat in a clinical setting and (2) limited data on energy expenditure that are necessary to provide daily caloric recommendations. OBJECTIVE: The objectives of this study will be to develop 2 algorithms for use in youth with spina bifida in a clinical setting, one to model body fat and one to predict total daily energy expenditure. In addition, physical activity and dietary intake will be described for the sample. METHODS: This multisite, prospective, national clinical study will enroll 232 youth with myelomeningocele aged 5 to 18 years (stratified by age and mobility). Participants will be enrolled for 1 week. Data obtained include 4 measures of body composition, up to 5 height measures, a ramped activity protocol, and a nutrition and physical activity screener. Participants will wear an accelerometer for the week. On the final study day, 2 samples of urine or saliva, which complete the doubly labeled water protocol, will be obtained. The analysis will include descriptive statistics, Bland-Altman plots, concordance correlation, and regression analysis. RESULTS: The study received extramural federal funding in July 2019. Data collection was initiated in March 2020. As of April 2024, a total of 143 (female participants: n=76, 53.1%; male participants: n=67, 46.9%) out of 232 participants have been enrolled. Data collection is expected to continue throughout 2024. A no-cost extension until November 2025 will be requested for data analysis and dissemination of findings. CONCLUSIONS: This study furthers previous pilot work that confirmed the acceptability and feasibility of obtaining alternate height, body composition, and energy expenditure measures. The findings from this study will enhance screening, prevention, and treatment of abnormal weight status by facilitating the accurate identification of youths' weight status category and recommendations of daily caloric needs for this population that is at higher risk of obesity. Furthermore, the findings have the potential to impact outcomes for youth diagnosed with disabilities other than spina bifida who experience similar challenges related to alterations in body composition or fat distribution or measurement challenges secondary to mobility issues or musculoskeletal problems. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/52779.

Social determinants of health correlations and resource usefulness at a Milwaukee free clinic for uninsured individuals: A cross-sectional study.

Introduction: Addressing social determinants of health (SDOH) is fundamental to improving health outcomes. At a student-run free clinic, we developed a screening process to understand the SDOH needs and resource utilization of Milwaukee's uninsured population. Methods: In this cross-sectional study, we screened adult patients without health insurance (N = 238) for nine traditional SDOH needs as well as their access to dental and mental health care between October 2021 and October 2022. Patients were surveyed at intervals greater than or equal to 30 days. We assessed correlations between SDOH needs and trends in patient-reported resource usefulness. Results: Access to dental care (64.7%) and health insurance (51.3%) were the most frequently endorsed needs. We found significant correlations (P ≤ 0.05) between various SDOH needs. Notably, mental health access needs significantly correlated with dental (r = 0.41; 95% CI = 0.19, 0.63), medications (r = 0.51; 95% CI = 0.30, 0.72), utilities (r = 0.39; 95% CI = 0.17, 0.61), and food insecurity (r = 0.42; 95% CI = 0.19, 0.64). Food-housing (r = 0.55; 95% CI = 0.32, 0.78), housing-medications (r = 0.58; 95% CI = 0.35, 0.81), and medications-food (r = 0.53; 95% CI = 0.32, 0.74) were significantly correlated with each other. Longitudinal assessment of patient-reported usefulness informed changes in the resources offered. Conclusions: Understanding prominent SDOH needs can inform resource offerings and interventions, addressing root causes that burden under-resourced patients. In this study, patient-reported data about resource usefulness prompted the curation of new resources and volunteer roles. This proof-of-concept study shows how longitudinally tracking SDOH needs at low-resource clinics can inform psychosocial resources.

Epigenetic modifications of cfDNA in liquid biopsy for the cancer care continuum.

This review provides a comprehensive overview of the latest advancements in the clinical utility of liquid biopsy, with a particular focus on epigenetic approaches aimed at overcoming challenges in cancer diagnosis and treatment. It begins by elucidating key epigenetic terms, including methylomics, fragmentomics, and nucleosomics. The review progresses to discuss methods for analyzing circulating cell-free DNA (cfDNA) and highlights recent studies showcasing the clinical relevance of epigenetic modifications in areas such as diagnosis, drug treatment response, minimal residual disease (MRD) detection, and prognosis prediction. While acknowledging hurdles like the complexity of interpreting epigenetic data and the absence of standardization, the review charts a path forward. It advocates for the integration of multi-omic data through machine learning algorithms to refine predictive models and stresses the importance of collaboration among clinicians, researchers, and data scientists. Such cooperative efforts are essential to fully leverage the potential of epigenetic features in clinical practice.

Does Neoadjuvant Chemotherapy in Clinical T1-T2 N0 Triple-Negative Breast Cancer Increase the Extent of Axillary Surgery?

BACKGROUND: Current management strategies for early-stage triple-negative breast cancer (TNBC) include upfront surgery to determine pathologic stage to guide chemotherapy recommendations, or neoadjuvant chemotherapy (NAC) to de-escalate surgery, elucidate tumor response, and determine the role of adjuvant chemotherapy. However, patients who receive NAC with residual pathological nodal (pN) involvement require axillary lymph node dissection (ALND) as they are Z11/AMAROS ineligible. We aimed to evaluate the impact of NAC compared with upfront surgery on pN status and ALND rates in cT1-2N0 TNBC. METHODS: The National Cancer Database (NCDB) was queried for women with operable cT1-2N0 TNBC from 2014 to 2019. Demographic, clinicopathologic, and treatment data were collected. Multivariable linear regression analysis was performed to assess the odds of pN+ disease and undergoing ALND. RESULTS: Overall, 55,624 women were included: 26.9% (n = 14,942) underwent NAC and 73.1% (n = 40,682) underwent upfront surgery. The NAC cohort was younger (mean age 52.9 vs. 61.3 years; p < 0.001) with more cT2 tumors (71.6% vs. 31.0%; p < 0.001), and had lower ALND rates (4.3% vs. 5.5%; p < 0.001). The upfront surgery cohort was more likely to have one to three pathologically positive nodes (12.1% vs. 6.5%; odds ratio [OR] 2.37, 95% confidence interval (CI) 2.17-2.58; p < 0.001) but there was no difference in the likelihood of ALND (OR 1.1, 95% CI 0.99-1.24; p = 0.08). CONCLUSION: Patients who underwent upfront surgery were more likely to be pN+; however, ALND rates were similar between the two cohorts. Thus, the use of NAC does not result in a higher odds of ALND and the decision for NAC should be individualized and based on modern guidelines and systemic therapy benefits.

National trends in neoadjuvant chemotherapy utilization in patients with early-stage node-negative triple-negative breast cancer: the impact of the CREATE-X trial.

PURPOSE: Neoadjuvant chemotherapy (NAC) for triple-negative breast cancer (TNBC) allows for assessment of tumor pathological response and has survival implications. In 2017, the CREATE-X trial demonstrated survival benefit with adjuvant capecitabine in patients TNBC and residual disease after NAC. We aimed to assess national rates of NAC for cT1-2N0M0 TNBC before and after CREATE-X and examine factors associated with receiving NAC vs adjuvant chemotherapy (AC). METHODS: A retrospective cohort study of women with cT1-2N0M0 TNBC diagnosed from 2014 to 2019 in the National Cancer Database (NCDB) was performed. Variables were analyzed via ANOVA, Chi-squared, Fisher Exact tests, and a multivariate linear regression model was created. RESULTS: 55,633 women were included: 26.9% received NAC, 52.4% AC, and 20.7% received no chemotherapy (median ages 53, 59, and 71 years, p < 0.01). NAC utilization significantly increased over time: 19.5% in 2014-15 (n = 3,465 of 17,777), 27.1% in 2016-17 (n = 5,140 of 18,985), and 33.6% in 2018-19 (n = 6,337 of 18,871, p < 0.001). On multivariate analysis, increased NAC was associated with younger age (< 50), non-Hispanic white race/ethnicity, lack of comorbidities, cT2 tumors, care at an academic or integrated-network cancer program, and diagnosis post-2017 (p < 0.05 for all). Patients with government-provided insurance were less likely to receive NAC (p < 0.01). Women who traveled > 60 miles for treatment were more likely to receive NAC (p < 0.01). CONCLUSION: From 2014 to 2019, NAC utilization increased for patients with cT1-2N0M0 TNBC. Racial, socioeconomic, and access disparities were observed in who received NAC vs AC and warrants interventions to ensure equitable care.

5-hydroxymethylcytosine sequencing in plasma cell-free DNA identifies unique epigenomic features in prostate cancer patients resistant to androgen deprivation therapy.

Background: Currently there are no biomarkers to identify resistance to androgen-deprivation therapy (ADT) in men with hormone-naive prostate cancer. 5-hydroxymethylcytosines (5hmC) in the gene body are associated with gene activation and are critical for epigenomic regulation of cancer progression. Objective: To evaluate whether 5hmC signature in cell-free DNA (cfDNA) predicts early ADT resistance. Design Setting and Participants: Serial plasma samples from 55 prostate cancer patients receiving ADT were collected at three timepoints including baseline (prior to initiating ADT, N=55), 3-month (after initiating ADT, N=55), and disease progression (N=15) within 24 months or 24-month if no progression was detected (N=14). 20 of the 55 patients showed disease progression during the 24-month follow-up. The remaining 35 patients showed no progression in the same follow-up period. Outcome Measurements and Statistical Analysis: cfDNA (5-10ng) was used for selective chemical labeling (hMe-Seal) sequencing to map 5hmC abundance across the genome. Read counts in gene bodies were normalized with DESeq2. Differential methylation and gene set enrichment analyses were performed to identify the 5hmC-enriched genes and biological processes that were associated with disease progression. Kaplan-Meir analysis was utilized to determine the association of 5hmC signatures with progression-free survival. Results and Limitations: 5hmC-sequencing generated an average of 18.6 (range 6.03 to 42.43) million reads per sample with 98% (95-99%) mappable rate. Baseline sample comparisons identified significant 5hmC difference in 1,642 of 23,433 genes between 20 patients with progression and 35 patients without progression (false discovery rate, FDR<0.1). Patients with progression showed significant enrichments in multiple hallmark gene sets with androgen responses as the top enriched gene set (FDR=1.19E-13). Interestingly, this enrichment was driven by a subgroup of patients with disease progression featuring a significant 5hmC hypermethylation of the gene sets involving AR, FOXA1 and GRHL2. To quantify overall activities of these gene sets, we developed a gene set activity score algorithm using a mean value of log2 ratios of gene read counts in an entire gene set. We found that the activity scores in these gene sets were significantly higher in this subgroup of patients with progression than in the remaining patients regardless of the progression status. Furthermore, the high activity scores in these gene sets were associated with poor progression-free survival (p <0.05). Longitudinal analysis showed that activity scores in this subgroup with progression were significantly reduced after 3-month ADT but returned to high levels when the disease was progressed. Conclusions: 5hmC-sequencing in cfDNA identified a subgroup of prostate cancer patients with preexisting activation (5hmC hypermethylation) of gene sets involving AR, FOXA1 and GRHL2 before initiating ADT. Activity scores in these gene sets may serve as sensitive biomarkers to determine treatment resistance, monitor disease progression and potentially identify patients who would benefit from upfront treatment intensification. More studies are needed to validate this initial finding. Patient summary: There are no clinical tests to identify prostate cancer patients who will develop early resistance to androgen deprivation therapy within 24 months. In this study, we evaluated cell-free DNA epigenomic modification in blood and identified significant enrichment of 5-hydroxymethylation in androgen response genes in a subgroup of patients with treatment resistance. High level 5-hydroxylmethylation in these genes may serve as a discriminative biomarker to diagnose patients who are likely to experience early failure during androgen deprivation therapy.

Energy expenditure and weight-related behaviors in youth with Down syndrome: a protocol.

Background: The consequences of obesity are ominous, yet healthcare professionals are not adequately preventing or treating obesity in youth with Down syndrome (DS). Total daily energy expenditure (TDEE) is the energy expended in 24 h through physical activity and life-sustaining physiologic processes. An individual's TDEE is essential for determining the daily caloric intake needed to maintain or change body weight. Successful prevention and treatment of obesity in youth with DS is severely compromised by the lack of data on TDEE and information on weight-related behaviors for this high-risk population. This manuscript describes the protocol for the federally funded study that is in process to determine daily energy expenditure in a large cohort of children with DS. Methods: This observational cross-sectional study will include a national sample of 230 youth with DS, stratified by age (5-11 and 12-18 years of age) and sex. Doubly Labeled Water analysis will provide the criterion body fat%, fat-free mass, and TDEE. To increase accessibility and decrease the burden on participants, the entire study, including obtaining consent and data collection, is conducted virtually within the participant's home environment on weekdays and weekends. The study team supervises all data collection via a video conferencing platform, e.g., Zoom. This study will (1) examine and determine average TDEE based on age and sex, (2) develop a prediction equation based on measured TDEE to predict energy requirements with a best-fit model based on fat-free mass, sex, age, and height and/or weight, and (3) use 24-hour dietary recalls, a nutrition and physical activity screener, wearable devices, and sleep questionnaire to describe the patterns and quality of dietary intake, sleep, and physical activity status in youth with DS. Discussion: The lack of accurate information on energy expenditure and weight-related behaviors in youth with DS significantly impedes the successful prevention and treatment of obesity for this vulnerable population. The findings of this study will provide a further understanding of weight-related behaviors as obesity risk factors, currently not well understood for this population. This study will advance the science of weight management in individuals with disabilities and shift clinical practice paradigms.

National Trends in "Going Flat" After Mastectomy.

INTRODUCTION: The "Going Flat" movement became widely publicized in 2016 and provides information and support to women who choose to forego post-mastectomy breast reconstruction (PMBR). The objectives of this study were to evaluate temporal trends in PMBR to ascertain the potential impact of this movement and assess which factors are associated with going flat. METHODS: A retrospective cohort analysis was performed using the NCDB of women with non-metastatic breast cancer who underwent mastectomy between 2004 and 2019. Trends in going flat after mastectomy were examined and stratified by age (< 50, 50-69, ≥ 70). A multivariate logistic regression model was used to identify factors associated with going flat. RESULTS: 650,983 patients met the inclusion criteria: 244,201 (37.5%) underwent PMBR and 406,782 (62.5%) went flat. Among women < 70, rates of going flat steadily decreased from 2004 to 2015 and then stabilized after 2015, coinciding with the rise of the "Going Flat" movement. In multivariate analysis, non-White race, older age, increasing comorbidities, government provided insurance, treatment at a community program, radiotherapy, and adjuvant chemotherapy were associated with a higher likelihood of going flat (p < 0.001). CONCLUSION: In the first 2 years after the "Going Flat" movement, the number of women going flat after mastectomy has stabilized in women < 70 for the first time in over a decade. These trends suggest that the social and cultural impact of this movement may have contributed to the stabilization of PMBR rates.

Associations Between Hospital Volume and Overall Survival After Surgery in Older Patients with Breast Cancer.

BACKGROUND: High-volume hospitals (HVHs) are associated with improved overall survival (OS) following surgery for breast cancer compared with low-volume hospitals (LVHs). We examined this association in patients age ≥ 80 years and described patient and treatment characteristics associated with HVHs. PATIENTS AND METHODS: The National Cancer Database was queried for women age ≥ 80 years who underwent surgery for stage I-III breast cancer between 2005 and 2014. Hospital volume was defined as the average number of cases during the year of the patient's index operation and the year prior. Hospitals were categorized into HVHs and LVHs using penalized cubic spline analysis of OS. A cutoff of ≥ 270 cases/year defined HVHs. RESULTS: Among 59,043 patients, 9110 (15%) were treated at HVHs and 49,933 (85%) at LVHs. HVHs were associated with more non-Hispanic Black and Hispanic patients, earlier stage disease (stage I 54.9% vs. 52.6%, p < 0.001), higher rates of breast-conserving surgery (BCS) (68.3% vs. 61.4%, p < 0.001), and adjuvant radiation (37.5% vs. 36.1%, p = 0.004). Improved OS was associated with surgery at a HVH (HR 0.85, CI 0.81-0.88), along with receipt of adjuvant chemotherapy (HR 0.73, CI 0.69-0.77), endocrine therapy (HR 0.70, CI 0.68-0.72), and radiation (HR 0.66, CI 0.64-0.68). CONCLUSIONS: Among patients with breast cancer age ≥ 80 years, undergoing surgery at a HVH was associated with improved OS. Patients who completed surgery at HVHs had earlier stage disease and more commonly received adjuvant radiation when appropriate. Processes of care at HVHs should be identified to improve outcomes in all settings.

Annual cost-savings with the implementation of estrogen-receptor-only testing on Ductal Carcinoma in Situ specimens.

BACKGROUND: In DCIS, ER status is an important marker. The utility of concomitant PR testing remains unclear. METHODS: A single-institution retrospective cohort study was performed with a comparative analysis of the NCDB to assess annual cost-savings with omission of routine PR testing. National Medicare payment standards determined PR staining costs to be $124.92. RESULTS: 150 institutional DCIS cases with receptor data were identified. 104 (69%) were ER+/PR+, 16 (11%) were ER+/PR-, and none were ER-/PR+. Omission of routine PR testing would have resulted in $18,738 saved annually. Within the NCDB, 34,100 DCIS cases had receptor data: 29,277 (85.9%) patients were ER+, and 26,008 (76%) were both ER/PR+. 211 (0.6%) patients were ER-/PR+. Annual national cost-savings with omission of routine PR-testing would have been $4.3 million. CONCLUSION: PR testing for DCIS should be reserved only for patients with ER- DCIS undergoing breast conservation to determine the utility of adjuvant endocrine therapy.

Comparing Symmetric Dimethylarginine and Amyloid-ß42 as Predictors of Alzheimer's Disease Development.

Background: Physicians may soon be able to diagnose Alzheimer's disease (AD) in its early stages using fluid biomarkers like amyloid. However, it is acknowledged that additional biomarkers need to be characterized which would facilitate earlier monitoring of AD pathogenesis. Objective: To determine if a potential novel inflammation biomarker for AD, symmetric dimethylarginine, has utility as a baseline serum biomarker for discriminating prodromal AD from cognitively unimpaired controls in comparison to cerebrospinal fluid amyloid-ß42 (Aß42). Methods: Data including demographics, magnetic resonance imaging and fluorodeoxyglucose-positron emission tomography scans, Mini-Mental State Examination and Functional Activities Questionnaire scores, and biomarker concentrations were obtained from the Alzheimer's Disease Neuroimaging Initiative for a total of 146 prodromal AD participants and 108 cognitively unimpaired controls. Results: Aß42 (p = 0.65) and symmetric dimethylarginine (p = 0.45) were unable to predict age-matched cognitively unimpaired controls and prodromal AD participants. Aß42 was negatively associated with regional brain atrophy and hypometabolism as well as cognitive and functional decline in cognitively unimpaired control participants (p < 0.05) that generally decreased in time. There were no significant associations between Aß42 and symmetric dimethylarginine with imaging or neurocognitive biomarkers in prodromal AD patients. Conclusions: Correlations were smaller between Aß42 and neuropathological biomarkers over time and were absent in prodromal AD participants, suggesting a plateau effect dependent on age and disease stage. Evidence supporting symmetric dimethylarginine as a novel biomarker for AD as a single measurement was not found.

Plasma Copy Number Alteration-Based Prognostic and Predictive Multi-Gene Risk Score in Metastatic Castration-Resistant Prostate Cancer.

Prostate cancer (PCa) accounted for more than 34,000 deaths in US males [...].

Appendiceal Incidentalomas: Prevalence, Radiographic Characteristics, Management, and Outcomes.

BACKGROUND: Radiographically detected incidental appendiceal abnormalities, in this report termed "appendiceal incidentalomas" (AIs), are an ill-defined entity with an unknown prevalence of neoplasm. This study aimed to describe the prevalence, radiographic characteristics, and outcomes of patients with a diagnosis of AI. METHODS: The study reviewed the electronic health records for patients at a single institution undergoing abdominopelvic computed tomography and magnetic resonance imaging (MRI) from 2000 to 2020 for non-appendix-related complaints with mention of appendix abnormality in the radiology report. The suggested diagnosis at the index imaging was recorded. Outcomes were compared between the operative and non-operative patients. RESULTS: Of 5197 records, 484 were identified as reports of AIs (9 % of screened patients). Neoplasms were suggested radiographically in 16 % (n = 79) of the records, 59 % (47/79) of which were resected. Pathologically, 32 of the abnormalities were confirmed as neoplasms, yielding a diagnostic accuracy of 68 %. Compared with the non-operative patients, the operative patients had AIs with a larger mean diameter (22.7 ± 13.0 vs. 17.8 ±7.7 mm; p = 0.04), a higher colonoscopy rate (51 % vs. 22 %; p = 0.01), and diagnosis at a younger age (55.8 ± 15.6 vs. 67.2 ± 16.0 years; p = 0.003). The postoperative complications were minor (Clavien-Dindo grade 1 or 2) in 26 % and major (grades 3-5) in 4 % of the cases. During a median follow-up period of 28.3 months, 94 % of the patients were alive without disease, and 6 % died of other causes. The 32 non-operative suggested neoplastic AIs had a median follow-up period of 20.9 months. At this writing, 59 % of the operative patients are alive with a stable abnormal appendix, 13 % had no appendix abnormality at last follow-up visit, and 28 % have died of other causes. CONCLUSION: Neoplastic AIs are an uncommon finding and radiographically diagnosed with relatively high accuracy. Larger appendiceal diameter and younger age predict operative intervention. Although surgery is associated with favorable outcomes and minimal risk of postoperative complications, observation of suspected neoplastic AIs may be a safe alternative for select patients undergoing follow-up longitudinal imaging.

Primary Breast Neuroendocrine Tumors: An Analysis of the National Cancer Database.

BACKGROUND: Primary breast neuroendocrine tumors (BNETs) represent < 1% of breast cancers. Diagnosing BNETs can be challenging, and a limited amount of cohort data currently exists in literature. We aimed to describe primary BNET characteristics, treatment modalities, and survival outcomes through the National Cancer Database (NCDB). METHODS: A retrospective cohort analysis was performed using the NCDB from 2004 to 2017. BNET cases were compared with patients with invasive ductal carcinoma (IDC). A matched IDC cohort was created by matching patient age, race, and disease stage. Kaplan-Meier analysis was performed, and hazard ratios (HR) were calculated through the bootstrap sampling method. RESULTS: A total of 1389 BNET and 1,967,401 IDC cases were identified. When compared with IDC patients, BNET patients were older, had more comorbidities, and were more often male (p < 0.01). BNETs were larger, higher grade, and more frequently hormone receptor negative (p < 0.01). While BNET patients were treated with surgery and radiotherapy (p < 0.01) less often compared with IDC patients, they presented at later disease stage (p < 0.001) and received systemic treatment more frequently (53.5% vs. 40%, p < 0.01). Patients with BNET had increased mortality compared with the matched IDC cohort: stage 1 HR 1.8, stage 2 HR 2.0, stage 3 HR 1.8, and stage 4 HR 1.5 (p < 0.001 for all). CONCLUSION: Patients with BNET tend to present at higher clinical stages, are more frequently hormone receptor negative, and have inferior overall survival compared with patients with IDC. Further treatment strategies and studies are needed to elucidate optimal therapies to maximize patient outcomes.

Treatment Patterns in Women Age 80 and Over With DCIS: A Report From the National Cancer Database.

BACKGROUND: Despite an aging population, there are no established treatment guidelines for women with ductal carcinoma in situ (DCIS) age ≥80. Here we describe national treatment patterns and survival outcomes in older women with DCIS. PATIENTS AND METHODS: Women age ≥80 diagnosed with DCIS from 2005 to 2014 were identified using the National Cancer Database. χ2, Fisher's exact test, and logistic regression models were used to identify factors influencing receipt of breast surgery, and Kaplan-Meier method and Cox proportional hazard models were used to evaluate overall survival (OS). RESULTS: A total of 6,070 women with DCIS met inclusion criteria, of which the majority (98%) received surgery. Receipt of surgery was independently associated with age <90. OS was higher for those who received surgery compared to those who did not (HR 2.2 [1.72-2.83] P < .001). CONCLUSION: The vast majority of patients age ≥80 with DCIS in the National Cancer Database received primary surgical management, which was associated with a significant OS benefit. Considering comorbidities and patient fitness, surgical resection should be considered for all patients age ≥80 who are suitable operative candidates.