Sunita K. Patel

Background/Objectives: Cancer survivors frequently experience long-term neurocognitive impairments following chemotherapy and cranial irradiation, yet experimental models that enable mechanistic investigation of therapy-induced neurotoxicity at the transcriptional level remain limited. This study aimed to develop a human three-dimensional (3D) neural tissue model derived from L-MYC-immortalized neural stem cells (LMNSCs) and use transcriptomic profiling to identify molecular pathways underlying chemotherapy- and radiation-induced neural injury and extracellular vesicle (EV)-mediated recovery. Methods: LMNSCs were differentiated in a 3D, methylcellulose-based culture to generate neural tissue containing neurons, astrocytes, and oligodendrocytes in the absence of microglia. Cultures were exposed to methotrexate (MTX) or ionizing radiation to induce neural injury and subsequently treated with LMNSC-derived EVs. Neural injury and repair mechanisms were evaluated by immunocytochemistry and bulk transcriptomics. Results: MTX and irradiation induced dose-dependent injury, exhibited by loss of neuronal complexity and reduced glial populations. LMNSC-EV treatment promoted recovery of neuronal and glial populations following MTX- and irradiation-induced injury. Transcriptomic analysis of irradiated cultures revealed activation of inflammation, DNA damage, and stress-response pathways, which were attenuated after treatment with LMNSC-EVs. Conclusions: LMNSC-based 3D neural tissue provides a platform for modeling cancer therapy-induced neurotoxicity. Furthermore, LMNSC-EVs represent a promising cell-free regenerative therapeutic that modulates injury-associated inflammatory, stress, and metabolic transcriptional programs after radiation-induced neural injury.

Background/Objectives: Cancer survivors frequently experience long-term neurocognitive impairments following chemotherapy and cranial irradiation, yet experimental models that enable mechanistic investigation of therapy-induced neurotoxicity at the transcriptional level remain limited. This study aimed to develop a human three-dimensional (3D) neural tissue model derived from L-MYC-immortalized neural stem cells (LMNSCs) and use transcriptomic profiling to identify molecular pathways underlying chemotherapy- and radiation-induced neural injury and extracellular vesicle (EV)-mediated recovery. Methods: LMNSCs were differentiated in a 3D, methylcellulose-based culture to generate neural tissue containing neurons, astrocytes, and oligodendrocytes in the absence of microglia. Cultures were exposed to methotrexate (MTX) or ionizing radiation to induce neural injury and subsequently treated with LMNSC-derived EVs. Neural injury and repair mechanisms were evaluated by immunocytochemistry and bulk transcriptomics. Results: MTX and irradiation induced dose-dependent injury, exhibited by loss of neuronal complexity and reduced glial populations. LMNSC-EV treatment promoted recovery of neuronal and glial populations following MTX- and irradiation-induced injury. Transcriptomic analysis of irradiated cultures revealed activation of inflammation, DNA damage, and stress-response pathways, which were attenuated after treatment with LMNSC-EVs. Conclusions: LMNSC-based 3D neural tissue provides a platform for modeling cancer therapy-induced neurotoxicity. Furthermore, LMNSC-EVs represent a promising cell-free regenerative therapeutic that modulates injury-associated inflammatory, stress, and metabolic transcriptional programs after radiation-induced neural injury. Simple Summary: Many cancer survivors experience persistent problems with memory, attention, and learning after chemotherapy or radiotherapy, yet the biological mechanisms underlying these cognitive side effects remain poorly understood. Progress has been limited by the lack of human laboratory models that accurately reproduce treatment-induced brain injury. To address this need, we developed a three-dimensional human neural tissue model containing immature neurons, astrocytes, and oligodendrocytes derived from L-MYC-immortalized human neural stem cells, lacking microglia. This platform was used to model cancer therapy-induced neural injury and evaluate the regenerative potential of neural stem cell-derived extracellular vesicles (EVs)—small bioactive particles released by stem cells. We found that cancer therapies caused significant injury to neuronal, oligodendroglial, and astrocytic cell populations, whereas EV treatment promoted recovery of these cells and activated biological pathways associated with tissue repair. These findings establish a reproducible human neural tissue platform for studying cancer therapy-related neurotoxicity and support neural stem cell-derived EVs as a promising regenerative therapeutic strategy to prevent or reduce treatment-induced cognitive impairment.

Background: Older breast cancer survivors are susceptible to cancer‐ and treatment‐related losses in physical function that can negatively affect daily living activities, mobility, and independence. Although physical activity can improve physical function, few studies have focused on older survivors or explored interrelationships between physical activity and physical function. Longitudinal bidirectional relationships between physical activity and physical function in breast cancer survivors and noncancer controls aged 60+ years were evaluated. Methods: Survivors (aged 67 ± 7 years; n = 357) newly diagnosed with nonmetastatic breast cancer (stages 0–III) and noncancer controls (aged 67 ± 9 years; n = 254) were assessed at baseline (postsurgery and pre–systemic therapy among survivors) and annual visits for up to 36 months. Physical activity (steps per day) was assessed via actigraphy. The Timed Up and Go test (longer time indicates lower function) and 12‐item Short Form Health Survey Physical Component Score evaluated physical function. Data were analyzed via random‐intercepts cross‐lagged panel models, with controlling for covariates; p values of ˂.05 were considered statistically significant. Results: Starting from the 12‐month visit, higher daily steps predicted better subsequent Timed Up and Go time among survivors and controls, and the magnitude of effect was stronger for survivors than controls at 24 months (post hoc comparison, p = .036; survivors: β = −0.420; p = .003; controls: β = −0.211; p = .032). Timed Up and Go time did not predict later daily steps. Associations between steps and the Physical Component Score showed similar patterns. Conclusions: Higher daily steps predicted better subsequent physical function, especially in survivors. These results highlight the importance of promoting physical activity during cancer survivorship care to maintain functional independence.

Cognitive effects of breast cancer anti-estrogen endocrine therapy are a salient concern for survivors, given the growing evidence that estrogen plays a role in late-life dementia risk. The APOE4 genotype has been linked with risk for cognitive difficulties, studied mainly in younger cancer survivors. We found that women aged 60+ with non-metastatic breast cancer enrolled in the prospective Thinking and Living with Cancer study who underwent endocrine therapy had lower subjective (P=.06) and objective (P=.08) cognitive function than frequency-matched controls across time. At 5-years, however, women with breast cancer exposed to endocrine therapy and APOE4 carriers in particular exhibited lower learning and memory scores than other groups (p<.05). Our results suggest endocrine therapy may have long-term effects on cognitive function in women with breast cancer, particularly APOE4 carriers. Further characterization of genetic risk for long-term cognitive decline will be useful to inform survivorship care of older women.

Background: Neighborhood characteristics can affect aging and health. We tested the effects of neighborhood deprivation on deficit accumulation frailty scores in a prospective cohort of breast cancer survivors vs control individuals aged 60 to 98 years. Methods: Newly diagnosed, nonmetastatic breast cancer survivors (n = 477) and frequency-matched control individuals (n = 434) were enrolled between 2010 and 2023, with up to 5-year follow-up through 2024. Deficit accumulation was measured using a 48-item index (scores of 0-1); a clinically meaningful deficit increase was defined by a 0.06 score increase. Neighborhood deprivation was assessed using the Area Deprivation Index (ADI) at enrollment census block group and categorized into tertiles. Cause-specific Cox models tested the association between ADI and risk of deficit accumulation increase. Results: Participants living in more deprived areas (second and third tertiles of ADI) had a higher risk of increased deficit accumulation (adjusted hazard ratios = 1.38, 95% CI = 1.01 to 1.89, P = .04 and 1.46, 95% CI = 1.07 to 1.94, P = .01 vs first tertile, respectively). Independent of ADI, being a survivor (vs a control individual) was associated with greater risk of increased deficit accumulation (adjusted hazard ratio = 1.69, 95% CI = 1.32 to 2.17, P < .001). Patterns of cumulative incidence rates of increased deficit accumulation differed by ADI: Survivors treated with chemotherapy (with or without hormone therapy) living in more vs less deprived areas had a 20% higher incidence of increased deficit accumulation within 1 year (P = .004), while survivors receiving hormone therapy alone and noncancer control individuals had their most pronounced differences by 4 years (10%, P = .32 and 10%, P = .05, respectively). Conclusions: Neighborhood deprivation may increase deficit accumulation, with an apparent acceleration of effects among older (≥60 years of age) breast cancer survivors treated with chemotherapy.

We developed a high-intensity parenting intervention (HIP) to help parents support the academic success of childhood cancer survivors (CCSs), who often face post-treatment challenges affecting their school-related functioning. This randomized controlled trial (NCT03178617) evaluated HIP’s efficacy compared to lower-intensity, single-session, treatment-as-usual services (LIP) in Latino families. Primary outcomes were parenting efficacy and CCSs’ school functioning; secondary outcomes included parenting knowledge and measures of CCSs’ academic performance, attention, and functioning outside of school. 106 Latino survivors of childhood leukemia and lymphoblastic lymphoma (aged 6–12 years) and their parents were randomly assigned to HIP (n = 54) or LIP (n = 52). Linear mixed-effects models evaluated group differences across baseline, 6-month (T2), and 12-month (T3) assessments. Parenting efficacy and knowledge improved significantly in the HIP arm, resulting in higher scores vs LIP at T2 and T3 (P ≤ .01). No significant between-group differences were found in child school functioning; however, HIP children showed significantly better social functioning and performance on one measure of attention (CPT-3 commissions) at T3 (P < .05). While HIP adherence challenges were observed, with only 33 (61%) completing the intervention, exploratory analyses suggest that benefits were most evident among those who fully engaged. Satisfaction and perceived benefit were greater for HIP vs LIP at both time points (P < .05). Our results suggest the potential value of parent-directed behavioral interventions like HIP for CCSs and their families. Further studies are needed to address participation barriers and enhance engagement to maximize and sustain benefits.

Objective: Androgen deprivation therapy (ADT) is a common treatment for prostate cancer (PCa), with increasing numbers of men on ADT for longer. Limited evidence suggests ADT impacts cognition. This study addressed gaps in the literature by focusing on older men with PCa and assessing ADT usage longer than 1 year.Methods: This study of 133 men ≥65 years of age with PCa included two groups: (1) men on ADT for 1–3 years (ADT‐exposed), and (2) a comparison group of men with PCa not on ADT (ADT‐unexposed). Group comparisons on individual neuropsychological test scores are reported, as well as effect sizes (Cohen's d).Results: Half (n = 67) of the sample was ADT‐exposed and half (n = 66) were unexposed. The average age was 72 years, most were White, and over 50% had at least secondary education. There were no statistically significant differences between groups by age, race, or education. Unadjusted analyses showed the ADT‐exposed group, compared with the ADT‐unexposed group, performed significantly lower in domains of verbal learning (d = 0.45–0.52, p = 0.01 to d = 0.33–0.54, p = 0.06 to d = 0.33, p = 0.08 to 0.06). When controlling for age and education, similar patterns emerged. The ADT exposed‐group performed significantly lower in domains of verbal learning (d = 0.45–0.52, p = 0.06 to 0.03) and verbal recall (d = 0.33–0.54, p = 0.11 to 0.03), and possible effects in visuospatial construction d = 0.33, p = 0.18 to 0.13.Conclusions: This study suggests long‐term ADT exposure impacts verbal learning, verbal recall, and possibly visuospatial abilities in older men (≥65) with PCa. The potential cognitive effects of ADT should be discussed with older patients considering long‐term use of ADT.

Purpose: Cancer survivors commonly report cognitive declines after cancer therapy. Due to the complex etiology of cancer-related cognitive decline (CRCD), predicting who will be at risk of CRCD remains a clinical challenge. We developed a model to predict breast cancer survivors who would experience CRCD after systematic treatment. Methods: We used the Thinking and Living with Cancer study, a large ongoing multisite prospective study of older breast cancer survivors with complete assessments pre-systemic therapy, 12 months and 24 months after initiation of systemic therapy. Cognition was measured using neuropsychological testing of attention, processing speed, and executive function (APE). CRCD was defined as a 0.25 SD (of observed changes from baseline to 12 months in matched controls) decline or greater in APE score from baseline to 12 months (transient) or persistent as a decline 0.25 SD or greater sustained to 24 months. We used machine learning approaches to predict CRCD using baseline demographics, tumor characteristics and treatment, genotypes, comorbidity, and self-reported physical, psychosocial, and cognitive function. Results: Thirty-two percent of survivors had transient cognitive decline, and 41% of these women experienced persistent decline. Prediction of CRCD was good: yielding an area under the curve of 0.75 and 0.79 for transient and persistent decline, respectively. Variables most informative in predicting CRCD included apolipoprotein E4 positivity, tumor HER2 positivity, obesity, cardiovascular comorbidities, more prescription medications, and higher baseline APE score. Conclusions: Our proof-of-concept tool demonstrates our prediction models are potentially useful to predict risk of CRCD. Future research is needed to validate this approach for predicting CRCD in routine practice settings.

Purpose: To assess white matter microstructural changes in older long‐term breast cancer survivors 5–15 years post‐chemotherapy treatment.Methods: Breast cancer survivors aged 65 years or older who underwent chemotherapy (C+) and who did not undergo chemotherapy (C−) and age‐ and sex‐matched healthy controls (HC) were enrolled at time point 1 (TP1) and followed for 2 years for time point 2 (TP2). All participants underwent brain MRI with diffusion tensor images and neuropsychological (NP) testing with the NIH Toolbox Cognition Battery. Tract‐based spatial statistics (TBSS) analysis was performed on the diffusion tensor images to assess white matter microstructural changes with the fractional anisotropy (FA) parameter.Results: There were significant longitudinal alterations in FA within the C+ group over time. The C+ group showed diminished FA in the body and genu of corpus callosum, anterior corona radiate, and external capsule on both the whole brain and region of interest (ROI) based analyses after p < 0.05 family‐wise error (FWE) correction. However, there were no significant group differences between the groups at TP1. Additionally, at TP1, a positive correlation (R = 0.58, p = 0.04) was observed between the FA value of the anterior corona radiata and the crystallized composite score in the C+ group.Conclusions: Brain white matter microstructural alterations may be the underlying neural correlates of cognitive changes in older breast cancer survivors who had chemotherapy treatment years ago.

Viral pathogens are increasingly identified as the most common cause of respiratory infections. Viral respiratory panels, such as the real-time polymerase chain reaction (RT PCR), have high specificity and sensitivity for infections due to detected pathogens and are a safe tool to detect viral pathogens. The American Thoracic Society (ATS) recognizes that detecting viral pathogens or mixed viral and bacterial infections in patients with lower respiratory infections can promote appropriate antibiotic use. Optimizing the use of antibiotics is critical to effectively treat infections, protect patients from harm caused by unnecessary antibiotic use, and combat antibiotic resistance. The primary objective of this study is to determine the impact of viral respiratory panel results on the duration of antibiotic use and outcomes in patients with respiratory tract infections. A retrospective cohort study of adult patients admitted to Cleveland Clinic Mercy Hospital from November 2021 through May 2022 with a diagnosis of suspected respiratory infection and ordered an RT PCR panel was performed. Patients with a confirmed bacterial co-infection were excluded. The primary outcome of this study is the median duration of antibiotic use. Secondary outcomes include all-cause hospital mortality, hospital length of stay, all-cause hospital readmission within 30 days, and Clostridioides difficile infection within 60 days. A viral respiratory panel is a safe tool for de-escalation of inappropriate antibiotic use in patients with respiratory tract infections. All Authors: No reported disclosures