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Importance: Cancer survivors experience accelerated functional decline that threatens independence and quality of life. Previous studies have suggested that vegetable gardening may improve diet, physical activity, and physical function in this vulnerable population, which comprises more than 5% of the US population. Objective: To assess whether diet, physical activity and functioning, and other outcomes improved in older cancer survivors assigned to a vegetable gardening intervention compared with a waitlist. Design, Setting, and Participants: From May 11, 2016, to May 2, 2022, a 2-arm, assessor-blinded, crossover-designed, intent-to-treat, randomized clinical trial was conducted at cancer survivors' homes across Alabama. Medicare-eligible survivors of cancers with 5-year survival of 60% or more were registry ascertained and screened for suboptimal vegetable and fruit consumption (<5 servings per day), physical activity (<150 moderate-to-vigorous minutes per week), and physical function (36-Item Short Form Health Survey [SF-36] subscale score ≤90). Consented participants underwent baseline assessments, were randomly assigned to intervention or waitlisted arms, and were reassessed at 1-year follow-up. Intervention: One-year, home-based vegetable gardening intervention providing gardening supplies and mentorship by cooperative extension-certified master gardeners to plant and maintain spring, summer, and fall gardens. Waitlisted participants received the identical intervention after 12 months. Main Outcomes and Measures: The main outcome was a composite index of improvements in self-reported vegetable and fruit consumption, physical activity, and physical function corroborated by plasma α-carotene levels, accelerometry, and physical performance assessments, respectively. Results: Of 381 enrolled participants (mean [SD] age, 69.8 [6.4] years; range, 50-95 years; 263 [69.0%] female), 194 were assigned to the gardening intervention and 187 were waitlisted (attrition rates, 7.2% and 7.0%, respectively). Intent-to-treat analyses did not detect a significant improvement in the composite index of vegetable and fruit intake, moderate-vigorous physical activity, and physical function (intervention arm vs waitlisted arm, 4.5% vs 3.1%; P = .53) or between-arm differences in vegetable and fruit intake (mean difference, 0.3 [95% CI, -0.1 to 0.7] servings per day; P = .10). The intervention arm experienced a significant improvement in vegetable and fruit intake (mean increase, 0.3 [95% CI, 0.0-0.6] servings per day; P = .04). Significant improvements also were observed in the intervention arm vs waitlisted arm in physical performance (mean difference for 2-minute step test, 6.0 [95% CI, 0.8-11.2] steps; P = .03; for 30-second chair stand, 0.8 [95% CI, 0.1-1.5] repetitions; P = .02), perceived health (8.4 [95% CI, 3.0-13.9] points on a 100-point scale [higher scores indicate better health]; P = .003), and gut microbiome alpha diversity (84.1 [95% CI, 20.5-147.6] more observed species; P = .01). The COVID-19 pandemic significantly moderated effects (eg, odds of improvement in self-reported physical functioning were greater before vs during the pandemic: odds ratio, 2.17; 95% CI, 1.12-4.22; P = .02). Conclusions and Relevance: In this randomized clinical trial including older cancer survivors, a vegetable gardening intervention did not significantly improve a composite index of diet, physical activity, and physical function; however, survivors assigned to the intervention had significantly increased vegetable and fruit consumption and, compared with waitlisted survivors, experienced significant improvements in perceived health and physical performance. Further study in broader populations and during pandemic-free periods is needed to determine definitive benefits. Trial Registration: ClinicalTrials.gov Identifier: NCT02985411.
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Sobreviventes de Câncer , Exercício Físico , Jardinagem , Verduras , Humanos , Feminino , Masculino , Idoso , Jardinagem/métodos , Sobreviventes de Câncer/estatística & dados numéricos , Qualidade de Vida , Idoso de 80 Anos ou mais , Estudos Cross-Over , Dieta/estatística & dados numéricos , AlabamaRESUMO
INTRODUCTION: Palbociclib is a widely used treatment for advanced breast cancer in older adults. However, the existing evidence regarding its safety and tolerability in this age group is inconsistent and limited to retrospective subgroup or pooled analyses. MATERIALS AND METHODS: We conducted a prospective single-arm multicenter phase 2 study to evaluate the safety and tolerability of palbociclib in participants aged 70 years or older with advanced hormone receptor-positive breast cancer. Participants were given palbociclib in combination with their physician's choice of endocrine therapy (letrozole or fulvestrant). The primary endpoint was the incidence of grade 3+ adverse events (AEs) by six months. Secondary endpoints included AE-related dose delays, dose reductions, early discontinuations, and hospitalizations. Additionally, we compared these endpoints by age groups (70-74 and ≥ 75 years). RESULTS: Of the 90 participants (median age 74 years [70-87]) enrolled, 75.6% (95% confidence interval [CI], 65.4-84.0) had grade 3+ AEs by six months. The most frequent grade 3+ AEs were neutropenia (61%), fatigue (4%), and nausea (3%). Febrile neutropenia was uncommon (1.1%). Due to AEs, 36% had dose delays, 34% had dose reductions, 10% had early discontinuations, and 10% had hospitalizations. Compared to those aged 70-74 years, participants aged ≥75 years had higher rates of early discontinuations (5.9% vs 15.9%, a difference of 9.5% [95% CI 3.5%-22.5%]). DISCUSSION: Palbociclib has an overall favorable safety profile in adults aged ≥70 with advanced breast cancer. However, adults ≥75 years had a trend toward higher rates of AE-related early discontinuations compared to those 70-74 years. Further research is needed to evaluate tolerability and improve the delivery of palbociclib in older adults. CLINICALTRIALS: gov:NCT03633331.
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Neoplasias da Mama , Piperazinas , Piridinas , Humanos , Piridinas/efeitos adversos , Piridinas/administração & dosagem , Piridinas/uso terapêutico , Idoso , Feminino , Neoplasias da Mama/tratamento farmacológico , Piperazinas/efeitos adversos , Piperazinas/administração & dosagem , Piperazinas/uso terapêutico , Idoso de 80 Anos ou mais , Estudos Prospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Fulvestranto/administração & dosagem , Fulvestranto/uso terapêutico , Letrozol/administração & dosagem , Letrozol/uso terapêutico , Fatores EtáriosRESUMO
When evaluating the real-world treatment effect, the analysis based on randomized clinical trials (RCTs) often introduces generalizability bias due to the difference in risk factors between the trial participants and the real-world patient population. This problem of lack of generalizability associated with the RCT-only analysis can be addressed by leveraging observational studies with large sample sizes that are representative of the real-world population. A set of novel statistical methods, termed "genRCT", for improving the generalizability of the trial has been developed using calibration weighting, which enforces the covariates balance between the RCT and observational study. This paper aims to review statistical methods for generalizing the RCT findings by harnessing information from large observational studies that represent real-world patients. Specifically, we discuss the choices of data sources and variables to meet key theoretical assumptions and principles. We introduce and compare estimation methods for continuous, binary, and survival endpoints. We showcase the use of the R package genRCT through a case study that estimates the average treatment effect of adjuvant chemotherapy for the stage 1B non-small cell lung patients represented by a large cancer registry.
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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.
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Neoplasias da Mama , Sobreviventes de Câncer , Disfunção Cognitiva , Hominidae , Humanos , Feminino , Animais , Idoso , Sobreviventes de Câncer/psicologia , Neoplasias da Mama/complicações , Neoplasias da Mama/psicologia , Estudos Prospectivos , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/etiologiaRESUMO
Objective: Epilepsy patients with mesial temporal sclerosis (MTS) on imaging who are drug-resistant usually undergo epilepsy surgery without previous invasive evaluation. However, up to one-third of patients are not seizure-free after surgery. Prior studies have identified risk factors for surgical failure, but it is unclear if they are associated with bilateral or discordant seizure onset. Methods: In this retrospective case series, we identified 17 epilepsy patients who had MRI-confirmed MTS but received invasive stereo-EEG (SEEG) evaluation before definitive intervention. We analyzed their presurgical risk factors in relation to SEEG seizure onset localization and MRI/SEEG concordance. Results: SEEG ictal onset was concordant with MTS localization (i.e. seizures started only from the hippocampus with MTS) in 5 out of 13 patients with unilateral MTS (UMTS) and in 3 out of 4 patients with bilateral MTS.No statistically significant association regarding concordance of SEEG ictal onset and MTS location was found in patients with such risk factors as a history of non-mesial temporal aura, frequent focal to bilateral tonic-clonic seizures, prior viral brain infection, or family history of epilepsy. Nine out of 13 UMTS patients had resective surgery only, 5 out of 9 (56â¯%) have Engel class I outcome at most recent follow-up (median 46.5â¯months, range 22-91â¯months). In Engel class I cohort, the SEEG ictal onset was concordant with MTS location in 3 out of 5 patients, and 2 patients had ipsilateral temporal neocortical ictal onset. Conclusions: Our findings suggest that patients with MTS might have discordant SEEG ictal onset (in 61.5% patients with UMTS in presented cohort), which may explain poor surgical outcome after destructive surgery in these cases. Significance: Although no statistically significant association was found in this under-powered study, these findings could be potentially valuable for future meta-analyses.
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INTRODUCTION: This study examines the usability and comfort of a behind-the-ear seizure detection device called brain seizure detection (BrainSD) that captures ictal electroencephalogram (EEG) data using four scalp electrodes. METHODS: This is a feasibility study. Thirty-two patients admitted to a level 4 Epilepsy Monitoring Unit were enrolled. The subjects wore BrainSD and the standard 21-channel video-EEG simultaneously. Epileptologists analyzed the EEG signals collected by BrainSD and validated it using video-EEG data to confirm its accuracy. A poststudy survey was completed by each participant to evaluate the comfort and usability of the device. In addition, a focus group of UT Southwestern epileptologists was held to discuss the features they would like to see in a home EEG-based seizure detection device such as BrainSD. RESULTS: In total, BrainSD captured 11 of the 14 seizures that occurred while the device was being worn. All 11 seizures captured on BrainSD had focal onset, with three becoming bilateral tonic-clonic and one seizure being of subclinical status. The device was worn for an average of 41 hours. The poststudy survey showed that most users found the device comfortable, easy-to-use, and stated they would be interested in using BrainSD. Epileptologists in the focus group expressed a similar interest in BrainSD. CONCLUSIONS: Brain seizure detection is able to detect EEG signals using four behind-the-ear electrodes. Its comfort, ease-of-use, and ability to detect numerous types of seizures make BrainSD an acceptable at-home EEG detection device from both the patient and provider perspective.
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Background: Some human studies have identified infection with cytomegalovirus (CMV), a member of the alpha herpesvirus family, as a risk factor for Alzheimer's disease and related dementias (ADRD). To our knowledge, no studies have evaluated associations of CMV seropositivity with plasma biomarkers of ADRD risk in middle-aged adults. Objective: In participants recruited for an exercise study, we evaluated cross-sectional associations of CMV seropositivity with: Aß42/Aß40 ratio, a low ratio suggestive of central nervous system Aß accumulation; glial fibrillary acidic protein (GFAP), a measure of neuroinflammation; and neurofilament light (NfL), a measure of neurodegeneration. Methods: Anti-CMV IgG was quantified by ELISA. Plasma ADRD biomarkers were quantified using the ultrasensitive SIMOA assay. We used linear regression to evaluate associations of CMV seropositivity with the ADRD biomarkers, adjusting for age, sex, and race (nâ=â303; Ageâ=â55.7±9.2 years). For ADRD biomarkers significantly associated with CMV seropositivity, we evaluated continuous associations of anti-CMV IgG levels with the ADRD biomarkers, excluding CMV seronegative participants. Results: 53% of participants were CMV seropositive. CMV seropositivity was associated with a lesser Aß42/Aß40 ratio (ß=-3.02e-03 95% CI [-5.97e-03, -7.18e-05]; pâ=â0.045). In CMV seropositive participants, greater anti-CMV IgG levels were associated with a lesser Aß42/Aß40 ratio (ß=-4.85e-05 95% CI[-8.45e-05, -1.25e-05]; pâ=â0.009). CMV seropositivity was not associated with plasma GFAP or NfL in adjusted analyses. Conclusions: CMV seropositivity was associated with a lesser plasma Aß42/Aß40 ratio. This association may be direct and causally related to CMV neuro-cytotoxicity or may be indirect and mediated by inflammatory factors resulting from CMV infection burden and/or the immune response.
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Doença de Alzheimer , Infecções por Citomegalovirus , Humanos , Pessoa de Meia-Idade , Estudos Transversais , Peptídeos beta-Amiloides , Infecções por Citomegalovirus/complicações , Citomegalovirus , Imunoglobulina G , Biomarcadores , Anticorpos Antivirais , Proteínas tauRESUMO
ABSTRACT: With the global growing older adult population, clinicians face the common, yet complex challenge of how to evaluate and manage anemia in this population. Older age predisposes to common causes of anemia such as nutritional deficiencies, inflammatory disorders, chronic kidney disease, and hematologic malignancies. Failure to diagnose and appropriately manage anemia may result in decreased quality of life, impaired cognition, impaired mobility, and increased mortality. Anemia diagnosis in older adults presents a diagnostic conundrum because anemia may have a single cause, may be multifactorial, or may have no apparent cause even after an extensive evaluation. We believe a systematic approach to diagnosis ensures appropriate testing and avoids the pitfall of undertreatment and overtreatment. In this article we present our recommended approach through common scenarios for the management of anemia in the older adult.
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Anemia , Neoplasias Hematológicas , Humanos , Idoso , Qualidade de Vida , Anemia/diagnóstico , Anemia/etiologia , Anemia/terapia , Neoplasias Hematológicas/complicaçõesRESUMO
Interictal epileptiform discharges (IEDs) are intermittent electrophysiological events that occur in patients with epilepsy between seizures. Automated detection of IEDs helps clinician to identify cortical irritations and relations to seizure recurrence. It also reduces the necessity of visual inspection by physicians interpreting the EEG. This paper presents a novel deep learning-based approach that combines one-dimensional local binary pattern symbolization method with a regularized multi-head one-dimensional convolutional neural network to learn unique morphological patterns from different EEG sub-bands for IED detection. Experimentation using the Temple University Events corpus scalp EEG data shows promising performance, e.g. F1-score of 87.18%.
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Epilepsia , Humanos , Epilepsia/diagnóstico , Eletroencefalografia/métodos , Redes Neurais de Computação , Convulsões/diagnóstico , CabeçaRESUMO
INTRODUCTION: Although allogeneic hematopoietic stem cell transplantation (HCT) can be a curative therapy for hematologic disorders, it is associated with treatment-related complications and losses in cardiorespiratory fitness and physical function. High-intensity interval training (HIIT) may be a practical way to rapidly improve cardiorespiratory fitness and physical function in the weeks prior to HCT. The primary aim of this study was to assess the feasibility of implementing a pre-HCT home-based HIIT intervention. The secondary aim was to evaluate pre to post changes in cardiorespiratory fitness and physical function following the intervention. METHODS: This was a single-arm pilot study with patients who were scheduled to undergo allogeneic HCT within six months. Patients were instructed to complete three 30-minute home-based HIIT sessions/week between the time of study enrollment and sign-off for HCT. Sessions consisted of a 5-minute warm-up, 10 high and low intervals performed for one minute each, and a 5-minute cool-down. Prescribed target heart rates (HR) for the high- and low-intensity intervals were 80-90% and 50-60% of HR reserve, respectively. Heart rates during HIIT were captured via an Apple Watch and were remotely monitored. Feasibility was assessed via retention, session adherence, and adherence to prescribed interval number and intensities. Paired t-tests were used to compare changes in fitness (VO2peak) and physical function [Short Physical Performance Battery (SPPB), 30-second sit to stand, and six-minute walk test (6MWT)] between baseline and sign-off. Pearson correlations were used to determine the relationship between intervention length and changes in cardiorespiratory fitness or functional measures. RESULTS: Thirteen patients (58.8±11.6 years) participated in the study, and nine (69.2%) recorded their training sessions throughout the study. Median session adherence for those nine participants was 100% (IQR: 87-107). Adherence to intervals was 92% and participants met or exceeded prescribed high-intensity HR on 68.8±34.8% of intervals. VO2peak improved from baseline to sign-off (14.6±3.1 mL/kg/min to 17.9±3.3 mL/kg/min; p<0.001). 30-second sit to stand and SPPB chair stand scores significantly improved in adherent participants. Improvements in 30-second sit to stand (13.8±1.5 to 18.3±3.3 seconds) and 6MWT (514.4±43.2 to 564.6±19.3) exceeded minimal clinically important improvements established in other chronic disease populations, representing the minimum improvement considered meaningful to patients. CONCLUSIONS: Findings demonstrate that implementing a pre-HCT home-based remotely monitored HIIT program is feasible and may provide benefits to cardiorespiratory fitness and physical function.
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Aptidão Cardiorrespiratória , Transplante de Células-Tronco Hematopoéticas , Treinamento Intervalado de Alta Intensidade , Humanos , Projetos Piloto , Estudos de Viabilidade , Consumo de Oxigênio/fisiologia , Aptidão Cardiorrespiratória/fisiologiaRESUMO
Stereo-electroencephalography is a minimally invasive technique for patients with refractory epilepsy pursuing surgery to reduce or control seizures. Electrodes are implanted based on pre-surgery evaluations and can collect deep brain activities for surgery decisions. This paper presents a methodology to analyze stereo-electroencephalography and assist clinicians by recommending the optimal surgical option and target areas for focal epilepsy patients. A seizure network (graph) model is proposed to characterize the spatial distribution and temporal changes of ictal events. The network nodes and edges correspond to specific epileptogenic regions and propagation/impact pathways (weighted by directed transfer function), respectively. We then employ a K-means clustering strategy to group nodes into a few clusters, from which the target surgical areas can be identified. Ten patients with different types of focal seizures were thoroughly analyzed. Promising consistency between results of our method's recommendations, clinical decisions and surgery outcomes were observed.
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Epilepsias Parciais , Epilepsia , Humanos , Convulsões/cirurgia , Epilepsias Parciais/cirurgia , Eletroencefalografia/métodos , Eletrodos ImplantadosRESUMO
BACKGROUND: Cancer and its treatments may accelerate aging in survivors; however, research has not examined epigenetic markers of aging in longer term breast cancer survivors. This study examined whether older breast cancer survivors showed greater epigenetic aging than noncancer controls and whether epigenetic aging related to functional outcomes. METHODS: Nonmetastatic breast cancer survivors (n = 89) enrolled prior to systemic therapy and frequency-matched controls (n = 101) ages 62 to 84 years provided two blood samples to derive epigenetic aging measures (Horvath, Extrinsic Epigenetic Age [EEA], PhenoAge, GrimAge, Dunedin Pace of Aging) and completed cognitive (Functional Assessment of Cancer Therapy-Cognitive Function) and physical (Medical Outcomes Study Short Form-12) function assessments at approximately 24 to 36 and 60 months after enrollment. Mixed-effects models tested survivor-control differences in epigenetic aging, adjusting for age and comorbidities; models for functional outcomes also adjusted for racial group, site, and cognitive reserve. RESULTS: Survivors were 1.04 to 2.22 years biologically older than controls on Horvath, EEA, GrimAge, and DunedinPACE measures (p = .001-.04) at approximately 24 to 36 months after enrollment. Survivors exposed to chemotherapy were 1.97 to 2.71 years older (p = .001-.04), and among this group, an older EEA related to worse self-reported cognition (p = .047) relative to controls. An older epigenetic age related to worse physical function in all women (p < .001-.01). Survivors and controls showed similar epigenetic aging over time, but Black survivors showed accelerated aging over time relative to non-Hispanic White survivors. CONCLUSION: Older breast cancer survivors, particularly those exposed to chemotherapy, showed greater epigenetic aging than controls that may relate to worse outcomes. If replicated, measurement of biological aging could complement geriatric assessments to guide cancer care for older women.
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Neoplasias da Mama , Sobreviventes de Câncer , Feminino , Humanos , Idoso , Lactente , Sobreviventes de Câncer/psicologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/psicologia , Envelhecimento/genética , Sobreviventes , Epigênese Genética , Metilação de DNARESUMO
BACKGROUND: Daily low-dose aspirin increases major bleeding; however, few studies have investigated its effect on iron deficiency and anemia. OBJECTIVE: To investigate the effect of low-dose aspirin on incident anemia, hemoglobin, and serum ferritin concentrations. DESIGN: Post hoc analysis of the ASPREE (ASPirin in Reducing Events in the Elderly) randomized controlled trial. (ClinicalTrials.gov: NCT01038583). SETTING: Primary/community care in Australia and the United States. PARTICIPANTS: Community-dwelling persons aged 70 years or older (≥65 years for Black persons and Hispanic persons). INTERVENTION: 100 mg of aspirin daily or placebo. MEASUREMENTS: Hemoglobin concentration was measured annually in all participants. Ferritin was measured at baseline and 3 years after random assignment in a large subset. RESULTS: 19 114 persons were randomly assigned. Anemia incidence in the aspirin and placebo groups was 51.2 events and 42.9 events per 1000 person-years, respectively (hazard ratio, 1.20 [95% CI, 1.12 to 1.29]). Hemoglobin concentrations declined by 3.6 g/L per 5 years in the placebo group and the aspirin group experienced a steeper decline by 0.6 g/L per 5 years (CI, 0.3 to 1.0 g/L). In 7139 participants with ferritin measures at baseline and year 3, the aspirin group had greater prevalence than placebo of ferritin levels less than 45 µg/L at year 3 (465 [13%] vs. 350 [9.8%]) and greater overall decline in ferritin by 11.5% (CI, 9.3% to 13.7%) compared with placebo. A sensitivity analysis quantifying the effect of aspirin in the absence of major bleeding produced similar results. LIMITATIONS: Hemoglobin was measured annually. No data were available on causes of anemia. CONCLUSION: Low-dose aspirin increased incident anemia and decline in ferritin in otherwise healthy older adults, independent of major bleeding. Periodic monitoring of hemoglobin should be considered in older persons on aspirin. PRIMARY FUNDING SOURCE: National Institutes of Health and Australian National Health and Medical Research Council.
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Anemia , Aspirina , Idoso , Humanos , Estados Unidos/epidemiologia , Idoso de 80 Anos ou mais , Aspirina/efeitos adversos , Incidência , Austrália/epidemiologia , Hemorragia/epidemiologia , Anemia/epidemiologia , Anemia/prevenção & controle , Anemia/tratamento farmacológico , Ferritinas , Hemoglobinas , Método Duplo-CegoRESUMO
Importance: Long-term survivors of childhood cancer may be at elevated risk for new neurocognitive impairment and decline as they age into adulthood. Objective: To determine whether aging adult childhood cancer survivors report more new-onset neurocognitive impairments compared with their siblings and to identify risk factors associated with such impairments. Design, Setting, and Participants: Participants of this cohort study included adult survivors of childhood cancer from the Childhood Cancer Survivor Study and their siblings as a control group. The original cohort included survivors who received a diagnosis between January 1, 1970, and December 31, 1986, for whom longitudinal neurocognitive assessment was available. This study examined the prevalence of new-onset neurocognitive impairment between baseline (23.4 years after diagnosis) and follow-up (35.0 years after diagnosis). The analysis was performed from January 2021 to May 2022. Exposures: Cancer treatment exposures were abstracted from medical records. Chronic health conditions were graded using Common Terminology Criteria for Adverse Events version 4.03. Main Outcomes and Measures: The primary outcome was new-onset (present at follow-up, but not present at baseline) neurocognitive impairment (defined as a score in the worst 10% of the sibling cohort). Impairment was assessed using the Childhood Cancer Survivor Study Neurocognitive questionnaire. Relative risks (RRs) and 95% CIs were used to estimate associations of neurocognitive impairment with treatment and health behaviors and conditions using generalized linear models. Results: The cohort comprised 2375 survivors (mean [SD] age at evaluation, 31.8 [7.5] years; 1298 women [54.6%]) of childhood cancer, including acute lymphoblastic leukemia (ALL; 1316 participants), central nervous system (CNS) tumors (488 participants), and Hodgkin lymphoma (HL; 571 participants). A total of 232 siblings (mean [SD] age at evaluation, 34.2 [8.4] years; 134 women [57.8%]) were included. Compared with siblings, a higher proportion of survivors with no impairment in memory at baseline had new-onset memory impairment at follow-up: siblings proportion, 7.8% (95% CI, 4.3%-11.4%); ALL survivors treated with chemotherapy only, 14.0% (95% CI, 10.7%-17.4%); ALL survivors treated with cranial radiation (CRT), 25.8% (95% CI, 22.6%-29.0%); CNS tumor survivors, 34.7% (95% CI, 30.0%-39.5%); and HL survivors, 16.6% (95% CI, 13.4%-19.8%). New-onset memory impairment was associated with CRT in CNS tumor survivors (RR, 1.97; 95% CI, 1.33-2.90) and alkylator chemotherapy greater than or equal to 8000 mg/m2 in ALL survivors treated without CRT (RR, 2.80; 95% CI, 1.28-6.12). Neurologic conditions mediated the impact of CRT on new-onset memory impairment in CNS survivors. Smoking, low educational attainment, and low physical activity were associated with elevated risk for new-onset memory impairment. Conclusions and Relevance: These findings suggest that adult survivors of childhood cancer are at elevated risk for late-onset memory impairment related to modifiable risk factors identified early in survivorship.
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Sobreviventes de Câncer , Neoplasias do Sistema Nervoso Central , Disfunção Cognitiva , Adulto , Humanos , Criança , Feminino , Estudos de Coortes , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/etiologia , Fatores de RiscoRESUMO
The objectives of this article are to introduce a conceptual framework for physical resilience in the context of ageing and to discuss key elements and challenges in the design of studies of physical resilience after health stressors. Advancing age is associated with increasing exposure to multiple stressors and declining capacity to respond to health stressors. Resilience is defined broadly as the ability to resist or recover well from the adverse effects of a health stressor. In ageing-related study designs of physical resilience after a health stressor, this dynamic resilience response can be observed as changes in repeated measures of function or health status in various domains important to older adults. Methodologic issues in selecting the study population, defining the stressor, covariates, outcomes, and analytic strategies are highlighted in the context of an ongoing prospective cohort study of physical resilience after total knee replacement surgery. The article concludes with approaches to intervention development to optimize resilience.
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Resiliência Psicológica , Humanos , Idoso , Estudos Prospectivos , Envelhecimento/fisiologia , Estudos Longitudinais , Nível de SaúdeRESUMO
BACKGROUND: The kynurenine pathway (KP) comprises a family of tryptophan-derived metabolites that some studies have reported are associated with poorer cognitive performance and an increased risk of Alzheimer's disease and related dementias (ADRD). OBJECTIVE: The objective of this study was to determine the associations of plasma KP metabolites (kynurenine [KYN], kynurenic acid [KA], and tryptophan [TRP]) with a panel of plasma ADRD biomarkers (Aß42/ ß40 ratio, pTau-181, glial fibrillary acidic protein [GFAP], and neurofilament light [NfL]) and cognitive performance in a subset of older adults drawn from the Duke Physical Performance Across the LifeSpan (PALS) study. METHODS: The Montreal Cognitive Assessment (MoCA) was used to assess cognitive performance. We used multivariate multiple regression to evaluate associations of the KYN/TRP and KA/KYN ratios with MoCA score and plasma ADRD biomarkers at baseline and over two years (nâ=â301; Ageâ=â74.8±8.7). RESULTS: Over two years, an increasing KYN/TRP ratio was associated with increasing plasma concentrations of plasma p-Tau181 (ß=â6.151; 95% CI [0.29, 12.01]; pâ=â0.040), GFAP (ß=â11.12; 95% CI [1.73, 20.51]; pâ=â0.020), and NfL (ß=â11.13; 95% CI [2.745, 19.52]; pâ=â0.009), but not MoCA score or the Aß42/Aß40 ratio. There were no significant associations of KA/KYN with MoCA score or plasma ADRD biomarkers. CONCLUSION: Our findings provide evidence that greater concentrations of KP metabolites are associated longitudinally over two years with greater biomarker evidence of neurofibrillary tau pathology (pTau-181), neuroinflammation (GFAP), and neurodegeneration (NfL), suggesting that dysregulated KP metabolism may play a role in ADRD pathogenesis.
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Doença de Alzheimer , Cinurenina , Humanos , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico , Triptofano , Longevidade , Biomarcadores , CogniçãoRESUMO
Aging is the largest risk factor for the development of cancer. A growing body of literature indicates that aging and cancer often play a somewhat reciprocal relationship at various times. On the one hand, aging is a "driver" of cancer, and on the other, cancer is a "disease driver" of aging. Here, we synthesize our reflections on the current literature linking cancer and aging, with an eye on fundamental aging processes, such as cellular senescence. Additionally, we consider how interventions that target fundamental aging processes can potentially transform cancer care, from preventing cancer development and progression to reducing the burden of accelerated aging in cancer survivors. Finally, we conclude with a reflection highlighting our vision for future directions to advance the science of cancer and aging and its applicability to improve the care of older adults with cancer.
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Envelhecimento , Neoplasias , Humanos , Idoso , Senescência Celular , Fatores de Risco , Neoplasias/prevenção & controle , PrevisõesRESUMO
BACKGROUND: Clinical trials are needed to study topics relevant to older adults with serious illness. Investigators conducting clinical trials with this population are challenged by how to appropriately define, classify, report, and monitor serious and non-serious adverse events (SAEs/AEs), given that some traditionally reported AEs (pressure ulcers, delirium) and SAEs (death, hospitalization) are common in persons with serious illness, and may be consistent with their goals of care. OBJECTIVES: A multi-stakeholder group convened to establish greater clarity on and new approaches to address this critical issue. PARTICIPANTS: Thirty-two study investigators, members of regulatory and sponsor agencies, and patient stakeholders took part. APPROACH: The group met virtually four times and, using a collaborative approach, conducted a survey, select interviews, and reviewed regulatory guidance to collectively define the problem and identify a new approach. RESULTS: SAE/AE challenges fell into two areas: (1) definitions and classifications, including (a) implausible relationships, (b) misalignment with patient-centered care goals, and (c) well-known associations, and (2) reporting and monitoring, including (a) limited guidance, (b) inconsistent standards across regulators, and (c) Data Safety Monitoring Board (DSMB) member knowledge gaps. Problems largely reflected practice norms rather than regulatory requirements that already support context-specific and aggregate reporting. Approaches can be improved by adopting principles that better align strategies for addressing adverse events with the type of intervention being tested, favoring routine and aggregate over expedited reporting, and prioritizing how SAE/AEs relate to patient-centered care goals. Reporting plans and decisions should follow an algorithm underpinned by these principles. CONCLUSIONS: Adoption of the proposed approach-and supporting it with education and better alignment with regulatory guidance and procedures-could improve the quality and efficiency of clinical trials' safety involving older adults with serious illness and other vulnerable populations.
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Assistência Centrada no Paciente , Humanos , IdosoRESUMO
INTRODUCTION: Functional outcomes during non-small cell lung cancer (NSCLC) treatment are critically important to older adults. Yet, data on physical function and which measures best capture functional change remain limited. MATERIALS AND METHODS: This multisite, mixed methods cohort study recruited adults ≥65 years with advanced NSCLC starting systemic treatment (i.e., chemotherapy, immunotherapy, and/or targeted therapy) with non-curative intent. Participants underwent serial geriatric assessments prior to starting treatment and at one, two, four, and six months, which included the Karnofsky Performance Scale (KPS, range: 0-100%), instrumental activities of daily living (IADL, range: 0-14), European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Physical Functioning subscale (EORTC QLQ-C30 PF, range: 0-100), and Life-Space Assessment (LSA, range: 0-120). For all measures, higher scores represent better functioning. In a qualitative substudy, 20 patients completed semi-structured interviews prior to starting treatment and at two and six months to explore how treatment affected their daily functioning. We created joint displays for each interview participant that integrated their longitudinal KPS, IADL, EORTC QLQ-C30 PF, and LSA scores with patient quotes describing their function. RESULTS: Among 87 patients, median age was 73 years (range 65-96). Mean pretreatment KPS score was 79% (standard deviation [SD] 13), EORTC QLQ-C30 PF was 69 (SD 23), and LSA was 67 (SD 28); median IADL was 13 (interquartile range [IQR] 10-14). At two months after treatment initiation, 70% of patients experienced functional decline on at least one measure, with only 13% of these patients recovering at six months. At two and six months, decline in LSA was the most common (48% and 35%, respectively). Joint displays revealed heterogeneity in how well each quantitative measure of physical function captured the qualitative patient experience. DISCUSSION: Functional decline during NSCLC treatment is common among older adults. LSA is a useful measure to detect subtle functional decline that may be missed by other measures. Given heterogeneity in how well each quantitative measure captures changes in physical function, there is value to including more than one functional measure in geriatric oncology research studies.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Idoso , Idoso de 80 Anos ou mais , Qualidade de Vida , Atividades Cotidianas , Estudos de Coortes , Inquéritos e QuestionáriosRESUMO
BACKGROUND: The hard endpoint of death is one of the most significant outcomes in both clinical practice and research settings. Our goal was to discover direct causes of longevity from medically accessible data. METHODS: Using a framework that combines local causal discovery algorithms with discovery of maximally predictive and compact feature sets (the "Markov boundaries" of the response) and equivalence classes, we examined 186 variables and their relationships with survival over 27 years in 1507 participants, aged ≥71 years, of the longitudinal, community-based D-EPESE study. FINDINGS: As few as 8-15 variables predicted longevity at 2-, 5- and 10-years with predictive performance (area under receiver operator characteristic curve) of 0·76 (95% CIs 0·69, 0·83), 0·76 (0·72, 0·81) and 0·66 (0·61, 0·71), respectively. Numbers of small high-density lipoprotein particles, younger age, and fewer pack years of cigarette smoking were the strongest determinants of longevity at 2-, 5- and 10-years, respectively. Physical function was a prominent predictor of longevity at all time horizons. Age and cognitive function contributed to predictions at 5 and 10 years. Age was not among the local 2-year prediction variables (although significant in univariable analysis), thus establishing that age is not a direct cause of 2-year longevity in the context of measured factors in our data that determine longevity. INTERPRETATION: The discoveries in this study proceed from causal data science analyses of deep clinical and molecular phenotyping data in a community-based cohort of older adults with known lifespan. FUNDING: NIH/NIA R01AG054840, R01AG12765, and P30-AG028716, NIH/NIA Contract N01-AG-12102 and NCRR 1UL1TR002494-01.