A scoping review evaluating physical and cognitive functional outcomes in cancer survivors treated with chemotherapy: charting progress since the 2018 NCI think tank on cancer and aging phenotypes.

PURPOSE: The primary goal of this scoping review was to summarize the literature published after the 2018 National Cancer Institute think tank, "Measuring Aging and Identifying Aging Phenotypes in Cancer Survivors," on physical and cognitive functional outcomes among cancer survivors treated with chemotherapy. We focused on the influence of chemotherapy on aging-related outcomes (i.e., physical functional outcomes, cognitive functional outcomes, and frailty), given the known associations between chemotherapy and biologic mechanisms that affect aging-related physiologic processes. METHODS: A search was conducted across electronic databases, including PubMed, Scopus, and Web of Science, for manuscripts published between August 2018 and July 2023. Eligible studies: 1) included physical function, cognitive function, and/or frailty as outcomes; 2) included cancer survivors (as either the whole sample or a subgroup); 3) reported on physical or cognitive functional outcomes and/or frailty related to chemotherapy treatment (as either the whole sample or a subgroup); and 4) were observational in study design. RESULTS: The search yielded 989 potentially relevant articles, of which 65 met the eligibility criteria. Of the 65 studies, 49 were longitudinal, and 16 were cross-sectional; 30 studies (46%) focused on breast cancer, 20 studies (31%) focused on the age group 60 + years, and 17 (26%) focused on childhood cancer survivors. With regards to outcomes, 82% of 23 studies reporting on physical function showed reduced physical function, 74% of 39 studies reporting on cognitive functional outcomes found reduced cognitive function, and 80% of 15 studies reporting on frailty found increasing frailty among cancer survivors treated with chemotherapy over time and/or compared to individuals not treated with chemotherapy. Fourteen studies (22%) evaluated biologic mechanisms and their relationship to aging-related outcomes. Inflammation was consistently associated with worsening physical and cognitive functional outcomes and epigenetic age increases. Further, DNA damage was consistently associated with worse aging-related outcomes. CONCLUSION: Chemotherapy is associated with reduced physical function, reduced cognitive function, and an increase in frailty in cancer survivors; these associations were demonstrated in longitudinal and cross-sectional studies. Inflammation and epigenetic age acceleration are associated with worse physical and cognitive function; prospective observational studies with multiple time points are needed to confirm these findings. IMPLICATIONS FOR CANCER SURVIVORS: This scoping review highlights the need for interventions to prevent declines in physical and cognitive function in cancer survivors who have received chemotherapy.

Nephroprotective effects of coriander (Coriandrum sativum) leaves aqueous extracts in aristolochic acid-intoxicated zebrafish embryos.

Coriander is a notable medicinal plant known for its diverse properties, including anti-inflammatory, antioxidant, anticancer, analgesic, and anti-diabetic effects. Despite its recognized health benefits, research on its nephroprotective properties is limited. This study aimed to investigate the potential nephroprotective properties of an aqueous extract derived from coriander leaves using an aristolochic acid-intoxicated zebrafish model. To assess kidney abnormalities induced by aristolochic acid (AA), we utilized the transgenic line Tg(wt1b:egfp), which expresses green fluorescent protein (GFP) in the kidney. Our previous report indicated that AA exposure leads to acute renal failure in zebrafish characterized by kidney malformation and impaired renal function. However, pretreatment of coriander extract (CE) can mitigate kidney malformations induced by AA. In addition, CE pretreatment reduces the accumulation of red blood cells in the glomerular region. To verify the nephroprotective effects of CE, we analyzed renal function by measuring the glomerular filtration rate in zebrafish embryos. Results indicate that CE partially mitigates renal function impairment caused by AA exposure, suggesting its potential to attenuate AA-induced renal failure. Mechanistically, pretreatment with CE reduces the expression of proinflammatory and proapoptotic genes induced by AA. This suggests that CE likely alleviates acute renal failure by reducing inflammation and apoptosis. As a result, we regard zebrafish as a valuable model for screening natural compounds that have the potential to alleviate AA-induced nephrotoxicity.

Pilot trial testing the effects of exercise on chemotherapy-induced peripheral neurotoxicity (CIPN) and the interoceptive brain system.

Purpose: Chemotherapy-induced peripheral neurotoxicity (CIPN) is a prevalent, dose-limiting, tough-to-treat toxicity involving numbness, tingling, and pain in the extremities with enigmatic pathophysiology. This randomized controlled pilot study explored the feasibility and preliminary efficacy of exercise during chemotherapy on CIPN and the role of the interoceptive brain system, which processes bodily sensations. Methods: Nineteen patients (65±11 years old, 52% women; cancer type: breast, gastrointestinal, multiple myeloma) starting neurotoxic chemotherapy were randomized to 12 weeks of exercise (home-based, individually tailored, moderate intensity, progressive walking and resistance training) or active control (nutrition education). At pre-, mid-, and post-intervention, we assessed CIPN symptoms (primary clinical outcome: CIPN-20), CIPN signs (tactile sensitivity using monofilaments), and physical function (leg strength). At pre- and post-intervention, we used task-free ("resting") fMRI to assess functional connectivity in the interoceptive brain system, involving the salience and default mode networks. Results: The study was feasible (74-89% complete data across measures) and acceptable (95% retention). We observed moderate/large beneficial effects of exercise on CIPN symptoms (CIPN-20, 0-100 scale: -7.9±5.7, effect size [ES]=-0.9 at mid-intervention; -4.8±7.3, -ES=0.5 at post-intervention), CIPN signs (ES=-1.0 and -0.1), and physical function (ES=0.4 and 0.3). Patients with worse CIPN after neurotoxic chemotherapy had lower functional connectivity within the default mode network (R2=40-60%) and higher functional connectivity within the salience network (R2=20-40%). Exercise tended to increase hypoconnectivity and decrease hyperconnectivity seen in CIPN (R2 = 12%). Conclusion: Exercise during neurotoxic chemotherapy is feasible and may attenuate CIPN symptoms and signs, perhaps via changes in interoceptive brain circuitry. Future work should test for replication with larger samples. ClinicalTrials.gov identifier NCT03021174.

Gut butyrate-producers confer post-infarction cardiac protection.

The gut microbiome and its metabolites are increasingly implicated in several cardiovascular diseases, but their role in human myocardial infarction (MI) injury responses have yet to be established. To address this, we examined stool samples from 77 ST-elevation MI (STEMI) patients using 16 S V3-V4 next-generation sequencing, metagenomics and machine learning. Our analysis identified an enriched population of butyrate-producing bacteria. These findings were then validated using a controlled ischemia/reperfusion model using eight nonhuman primates. To elucidate mechanisms, we inoculated gnotobiotic mice with these bacteria and found that they can produce beta-hydroxybutyrate, supporting cardiac function post-MI. This was further confirmed using HMGCS2-deficient mice which lack endogenous ketogenesis and have poor outcomes after MI. Inoculation increased plasma ketone levels and provided significant improvements in cardiac function post-MI. Together, this demonstrates a previously unknown role of gut butyrate-producers in the post-MI response.

Combined Treatment of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes and Endothelial Cells Regenerate the Infarcted Heart in Mice and Non-Human Primates.

BACKGROUND: Remuscularization of the mammalian heart can be achieved after cell transplantation of human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs). However, several hurdles remain before implementation into clinical practice. Poor survival of the implanted cells is related to insufficient vascularization, and the potential for fatal arrhythmogenesis is associated with the fetal cell-like nature of immature CMs. METHODS: We generated 3 lines of hiPSC-derived endothelial cells (ECs) and hiPSC-CMs from 3 independent donors and tested hiPSC-CM sarcomeric length, gap junction protein, and calcium-handling ability in coculture with ECs. Next, we examined the therapeutic effect of the cotransplantation of hiPSC-ECs and hiPSC-CMs in nonobese diabetic-severe combined immunodeficiency (NOD-SCID) mice undergoing myocardial infarction (n≥4). Cardiac function was assessed by echocardiography, whereas arrhythmic events were recorded using 3-lead ECGs. We further used healthy non-human primates (n=4) with cell injection to study the cell engraftment, maturation, and integration of transplanted hiPSC-CMs, alone or along with hiPSC-ECs, by histological analysis. Last, we tested the cell therapy in ischemic reperfusion injury in non-human primates (n=4, 3, and 4 for EC+CM, CM, and control, respectively). Cardiac function was evaluated by echocardiography and cardiac MRI, whereas arrhythmic events were monitored by telemetric ECG recorders. Cell engraftment, angiogenesis, and host-graft integration of human grafts were also investigated. RESULTS: We demonstrated that human iPSC-ECs promote the maturity and function of hiPSC-CMs in vitro and in vivo. When cocultured with ECs, CMs showed more mature phenotypes in cellular structure and function. In the mouse model, cotransplantation augmented the EC-accompanied vascularization in the grafts, promoted the maturity of CMs at the infarct area, and improved cardiac function after myocardial infarction. Furthermore, in non-human primates, transplantation of ECs and CMs significantly enhanced graft size and vasculature and improved cardiac function after ischemic reperfusion. CONCLUSIONS: These results demonstrate the synergistic effect of combining iPSC-derived ECs and CMs for therapy in the postmyocardial infarction heart, enabling a promising strategy toward clinical translation.

Comparison the acute toxicity of two different induction chemotherapy schedules with cisplatin and fluorouracil in nasopharyngeal carcinoma patients.

PURPOSE: To compare the acute toxicity of two different induction chemotherapy (IndCT) regimen followed by the same IMRT in patients with advanced nasopharyngeal carcinoma (NPC). MATERIALS AND METHODS: From July 2015 to December 2016, 110 NPC patients with stage III-IV diseases were prospectively randomized to receive either a conventional triweekly cisplatin + 5-fluorouracil (PF) for 3 cycles or weekly P-F for 10 doses, followed by the same IMRT to both arms. The primary endpoints of this study were grade 3/4 and any grade acute toxicities during IndCT period. The secondary endpoints included tumor response and various survivals. RESULTS: Baseline patient characteristics were comparable in both groups. Patients who received weekly P-F experienced significant reduction of grade 3/4 acute toxicities, including neutropenia (12.7% vs. 40.0%, P = 0.0012), anorexia (0% vs. 14.6%, P = 0.0059), mucositis (0% vs. 14.6%, P = 0.0059), and hyponatremia (0% vs. 16.4%, P = 0.0027), compared with the triweekly PF group, resulting in fewer IndCT interruptions (1.8% vs. 16.4%, P = 0.0203), emergency room visits (0% vs. 12.7%, P = 0.0128), and additional hospitalizations (0% vs. 9.1%, P = 0.0568). The acute toxicities during IMRT period were similar. Weekly P-F arm had higher complete response rates (83.6% vs. 61.8%, P = 0.0152) and lower relapse rates (16.4% vs. 33.3%, P = 0.0402) after a median follow-up of 67 months. Kaplan-Meier survival analyses revealed a better trend of locoregional failure-free (P = 0.0892), distant metastasis failure-free (P = 0.0775), and progression-free (P = 0.0709) survivals, favoring the weekly P-F arm. CONCLUSION: IndCT of weekly schedule does reduce acute toxicities without compromised tumor response and survivals.

Effect of Yoga and Mediational Influence of Fatigue on Walking, Physical Activity, and Quality of Life Among Cancer Survivors.

BACKGROUND: Cancer-related fatigue (CRF) negatively affects survivors' walking, engagement in physical activity (PA), and quality of life (QoL). Yoga is an effective therapy for treating CRF; however, evidence from large clinical trials regarding how reducing CRF through yoga influences CRF's interference with survivors' walking, engagement in PA, and QoL is not available. We examined the effects of yoga and the mediational influence of CRF on CRF's interference with walking, PA, and QoL among cancer survivors in a multicenter phase III randomized controlled trial. PATIENTS AND METHODS: Cancer survivors (n=410) with insomnia 2 to 24 months posttreatment were randomized to a 4-week yoga intervention-Yoga for Cancer Survivors (YOCAS)-or standard care. A symptom inventory was used to assess how much CRF interfered with survivors' walking, PA, and QoL. The Multidimensional Fatigue Symptom Inventory-Short Form was used to assess CRF. Two-tailed t tests and analyses of covariance were used to examine within-group and between-group differences. Path analysis was used to evaluate mediational relationships between CRF and changes in CRF's interference with walking, PA, and QoL among survivors. RESULTS: Compared with standard care controls, YOCAS participants reported significant improvements in CRF's interference with walking, PA, and QoL at postintervention (all effect size = -0.33; all P≤.05). Improvements in CRF resulting from yoga accounted for significant proportions of the improvements in walking (44%), PA (53%), and QoL (45%; all P≤.05). CONCLUSIONS: A significant proportion (44%-53%) of the YOCAS effect on CRF's interference with walking, PA, and QoL was due to improvements in CRF among cancer survivors. Yoga should be introduced and included as a treatment option for survivors experiencing fatigue. By reducing fatigue, survivors further improve their walking, engagement in PA, and QoL.

Metabolic Changes Associated With Cardiomyocyte Dedifferentiation Enable Adult Mammalian Cardiac Regeneration.

BACKGROUND: Cardiac regeneration after injury is limited by the low proliferative capacity of adult mammalian cardiomyocytes (CMs). However, certain animals readily regenerate lost myocardium through a process involving dedifferentiation, which unlocks their proliferative capacities. METHODS: We bred mice with inducible, CM-specific expression of the Yamanaka factors, enabling adult CM reprogramming and dedifferentiation in vivo. RESULTS: Two days after induction, adult CMs presented a dedifferentiated phenotype and increased proliferation in vivo. Microarray analysis revealed that upregulation of ketogenesis was central to this process. Adeno-associated virus-driven HMGCS2 overexpression induced ketogenesis in adult CMs and recapitulated CM dedifferentiation and proliferation observed during partial reprogramming. This same phenomenon was found to occur after myocardial infarction, specifically in the border zone tissue, and HMGCS2 knockout mice showed impaired cardiac function and response to injury. Finally, we showed that exogenous HMGCS2 rescues cardiac function after ischemic injury. CONCLUSIONS: Our data demonstrate the importance of HMGCS2-induced ketogenesis as a means to regulate metabolic response to CM injury, thus allowing cell dedifferentiation and proliferation as a regenerative response.

Porous scaffold for mesenchymal cell encapsulation and exosome-based therapy of ischemic diseases.

Ischemic diseases including myocardial infarction (MI) and limb ischemia are some of the greatest causes of morbidity and mortality worldwide. Cell therapy is a potential treatment but is usually limited by poor survival and retention of donor cells injected at the target site. Since much of the therapeutic effects occur via cell-secreted paracrine factors, including extracellular vesicles (EVs), we developed a porous material for cell encapsulation which would improve donor cell retention and survival, while allowing EV secretion. Human donor cardiac mesenchymal cells were used as a model therapeutic cell and the encapsulation system could sustain three-dimensional cell growth and secretion of therapeutic factors. Secretion of EVs and protective growth factors were increased by encapsulation, and secreted EVs had hypoxia-protective, pro-angiogenic activities in in vitro assays. In a mouse model of limb ischemia the implant improved angiogenesis and blood flow, and in an MI model the system preserved ejection fraction %. In both instances, the encapsulation system greatly extended donor cell retention and survival compared to directly injected cells. This system represents a promising therapy for ischemic diseases and could be adapted for treatment of other diseases in the future.

Serum carotenoids and cancer-related fatigue: An analysis of the 2005-2006 National Health and Nutrition Examination Survey.

Cancer-related fatigue is a prevalent, debilitating condition, and preliminary evidence suggests a relationship between higher diet quality and lower fatigue. Serum-based carotenoids, Vitamin A, and Vitamin E are biomarkers of fruit and vegetable intake and therefore diet quality. To further elucidate the link between diet quality and cancer-related fatigue, associations were assessed between these serum-based nutrients and fatigue among American adults with special attention to cancer history. Data were analyzed from the United States 2005-2006 National Health and Nutrition Examination Survey (NHANES) dataset. Ten carotenoids, vitamin A, vitamin E, and γ-tocopherol were measured from fasting blood samples and fatigue was patient-reported. Associations between carotenoid concentration and fatigue were estimated using ordinal logistic regression models. Adjusted models included a diagnosis of cancer (with the exception on non-melanoma skin cancer, yes/no), age, body mass index, race/ethnicity, education, and exercise habits as covariates, and additional models included a cancer×nutrient interaction. Of 4091 participants, 272 (8.0%) reported a history of cancer. Greater fatigue was associated with lower serum trans-lycopene, retinyl palmitate, and retinyl stearate (all p<0.05) in separate models adjusting for potential confounders. For these nutrients, a one-standard deviation increase in nutrient was associated with a 6.8-9.9% lower risk of greater fatigue. Among cancer survivors only (n=272), statistically significant associations were not observed between any of the nutrients and fatigue. In conclusion, greater serum concentrations of carotenoid biomarkers were associated with less fatigue. These results support further exploration into relationships between carotenoid intake, diet quality, and persistent fatigue.

Maintenance metronomic chemotherapy for metastatic/recurrent nasopharyngeal carcinoma.

BACKGROUND: We investigated the survival impact and toxicity of maintenance metronomic chemotherapy in patients with metastatic/recurrent nasopharyngeal carcinoma (met/rec NPC). METHODS: Ninety-eight patients with met/rec NPC were first salvaged by IV cisplatin-based chemotherapy and showed nonprogression disease; then maintenance metronomic chemotherapy for at least 12 months was recommended. We analyzed the treatment outcome between patients who received (n = 51) and did not receive (n = 47) maintenance chemotherapy. RESULTS: Baseline patient characteristics showed no significant differences between both arms. Median overall survival for patients with and without maintenance chemotherapy was 36.0 and 12.3 months, respectively (p < 0.0001). Similarly, median progression-free survival was 24.7 and 7.3 months, respectively (p < 0.0001). Furthermore, toxicities during maintenance oral chemotherapy period were usually mild. Transient grade 3 leucopenia (9.8%), anemia (3.9%), thrombocytopenia (7.8%), and no grade 4 toxicity were observed. CONCLUSION: After IV salvage chemotherapy, maintenance oral metronomic chemotherapy significantly improved overall and progression-free survivals while demonstrating low toxicity in patients with met/rec NPC.

Population-based high-throughput toxicity screen of human iPSC-derived cardiomyocytes and neurons.

In this study, we establish a population-based human induced pluripotent stem cell (hiPSC) drug screening platform for toxicity assessment. After recruiting 1,000 healthy donors and screening for high-frequency human leukocyte antigen (HLA) haplotypes, we identify 13 HLA-homozygous "super donors" to represent the population. These "super donors" are also expected to represent at least 477,611,135 of the global population. By differentiating these representative hiPSCs into cardiomyocytes and neurons we show their utility in a high-throughput toxicity screen. To validate hit compounds, we demonstrate dose-dependent toxicity of the hit compounds and assess functional modulation. We also show reproducible in vivo drug toxicity results using mouse models with select hit compounds. This study shows the feasibility of using a population-based hiPSC drug screening platform to assess cytotoxicity, which can be used as an innovative tool to study inter-population differences in drug toxicity and adverse drug reactions in drug discovery applications.

A single-arm pilot study of a mobile health exercise intervention (GO-EXCAP) in older patients with myeloid neoplasms.

Many older patients with myeloid neoplasms experience treatment-related toxicities. We previously demonstrated that a home-based, progressive aerobic walking and resistance exercise program (EXCAP) improved physical and psychological outcomes in patients with cancer. However, older patients have more difficulty adhering to exercise than younger patients. Reasons may include low motivation, difficulty with transportation, and limited access to exercise professionals. To improve exercise adherence, we integrated a mobile app with EXCAP (GO-EXCAP) and assessed its feasibility and usability in a single-arm pilot study among older patients with myeloid neoplasms undergoing outpatient chemotherapy. GO-EXCAP intervention lasts for 2 cycles of treatment, and the primary feasibility metric was data reporting on the app. Usability was evaluated via the system usability scale (SUS). Patients were interviewed at mid and postintervention to elicit their feedback, and deductive thematic analysis was applied to the transcripts. Twenty-five patients (mean age, 72 years) were recruited. Recruitment and retention rates were 64% and 88%, respectively. Eighty-two percent (18/22) of patients entered some exercise data on the app at least half of the study days, excluding hospitalization (a priori, we considered 70% as feasible). Averaged daily steps were 2848 and 3184 at baseline and after intervention, respectively. Patients also performed resistance exercises 26.2 minutes per day, 2.9 days per week at low intensity (rate of perceived exertion 3.8/10). Usability was above average (SUS, 70.3). In qualitative analyses, 3 themes were identified, including positive experience with the intervention, social interactions, and flexibility. The GO-EXCAP intervention is feasible and usable for older patients with myeloid neoplasms undergoing outpatient chemotherapy. This trial was registered at www.clinicaltrials.gov as #NCT04035499.

Association of Oncologist-Patient Communication With Functional Status and Physical Performance in Older Adults: A Secondary Analysis of a Cluster Randomized Clinical Trial.

Importance: The functional status and physical performance of older adults with cancer are underassessed and undertreated despite the high prevalence of impaired functional status and physical performance in this population and their associations with chemotherapy-induced toxic effects and mortality. Objective: To examine the association between providing oncologists with a geriatric assessment (GA) summary with recommendations and having oncologist-patient conversations about functional and physical performance. Design, Setting, and Participants: Data for this secondary analysis were collected from October 29, 2014, to April 28, 2017, for a national cluster randomized clinical trial conducted by the University of Rochester Cancer Center National Cancer Institute Community Oncology Research Program evaluating the effect of a GA intervention on patient satisfaction with communication about aging-related concerns. There were 17 practice clusters in the intervention group and 14 in the usual care group. All 541 participants underwent a GA including standardized functional and physical performance measures and had 1 clinical encounter audio-recorded, transcribed, and blindly coded to categorize conversations by GA domain. Participants were aged 70 years or older, with a stage III or IV solid tumor or lymphoma with palliative treatment intent, and impairment in 1 or more GA domain. Statistical analysis was performed from August 18, 2020, to January 10, 2022. Interventions: Oncologist practices randomized to the intervention received a GA summary and validated recommendations for each patient prior to the audio-recorded clinical encounter. Main Outcomes and Measures: The primary analysis of this clinical trial assessed the effect of the intervention on patient satisfaction with oncologist communication about aging-related concerns. This secondary analysis assessed the post hoc hypothesis that the intervention would be associated with an increase in the proportion of patients having conversations with their oncologists and receiving oncologist recommendations specific to functional and physical performance concerns. Results: A total of 541 patients (276 men [51%]; mean [SD] age, 77.5 [5.2] years [range, 70-96 years]) were analyzed at baseline. Excluding 13 patients without audio recordings, 86% of patients (95% CI, 78%-91%) in the intervention group vs 59% of patients (95% CI, 47%-69%; P < .001) receiving usual care had conversations about functional or physical performance. Conversations were more frequently initiated by oncologists in the intervention group (84%; 95% CI, 77%-90%) than oncologists in the usual care group (58%; 95% CI, 45%-70%; P < .001). Oncologists in the intervention group were more likely to address patients' concerns (43%; 95% CI, 33%-53%) than oncologists in the usual care group (17%; 95% CI, 10%-26%; P < .001). Conclusions and Relevance: In this secondary analysis of a cluster randomized clinical trial, providing oncologists with a GA summary was associated with an increase in the number of oncologist-patient conversations about functional and physical performance-related concerns with recommendations to address these concerns. These findings support the use of the GA summary and recommendations as important tools in caring for older adults with advanced cancer and functional or physical impairments. Trial Registration: ClinicalTrials.gov Identifier: NCT02107443.

Association of Prognostic Understanding With Health Care Use Among Older Adults With Advanced Cancer: A Secondary Analysis of a Cluster Randomized Clinical Trial.

Importance: A poor prognostic understanding regarding curability is associated with lower odds of hospice use among patients with cancer. However, the association between poor prognostic understanding or prognostic discordance and health care use among older adults with advanced incurable cancers is not well characterized. Objective: To evaluate the association of poor prognostic understanding and patient-oncologist prognostic discordance with hospitalization and hospice use among older adults with advanced cancers. Design, Setting, and Participants: This was a post hoc secondary analysis of a cluster randomized clinical trial that recruited patients from October 29, 2014, to April 28, 2017. Data were collected from community oncology practices affiliated with the University of Rochester Cancer Center National Cancer Institute Community Oncology Research Program. The parent trial enrolled 541 patients who were aged 70 years or older and were receiving or considering any line of cancer treatment for incurable solid tumors or lymphomas; the patients' oncologists and caregivers (if available) were also enrolled. Patients were followed up for at least 1 year. Data were analyzed from January 3 to 16, 2021. Main Outcomes and Measures: At enrollment, patients and oncologists were asked about their beliefs regarding cancer curability (100%, >50%, 50%, <50%, and 0%; answers other than 0% reflected poor prognostic understanding) and life expectancy (≤6 months, 7-12 months, 1-2 years, 2-5 years, and >5 years; answers of >5 years reflected poor prognostic understanding). Any difference between oncologist and patient in response options was considered discordant. Outcomes were any hospitalization and hospice use at 6 months captured by the clinical research associates. Results: Among the 541 patients, the mean (SD) age was 76.6 (5.2) years, 264 of 540 (49%) were female, and 486 of 540 (90%) were White. Poor prognostic understanding regarding curability was reported for 59% (206 of 348) of patients, and poor prognostic understanding regarding life expectancy estimates was reported for 41% (205 of 496) of patients. Approximately 60% (202 of 336) of patient-oncologist dyads were discordant regarding curability, and 72% (356 of 492) of patient-oncologist dyads were discordant regarding life expectancy estimates. Poor prognostic understanding regarding life expectancy estimates was associated with lower odds of hospice use (adjusted odds ratio, 0.30; 95% CI, 0.16-0.59). Discordance regarding life expectancy estimates was associated with greater odds of hospitalization (adjusted odds ratio, 1.64; 95% CI, 1.01-2.66). Conclusions and Relevance: This study highlights different constructs of prognostic understanding and the need to better understand the association between prognostic understanding and health care use among older adult patients with advanced cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT02107443.

Protocol for a pilot randomized controlled trial of a mobile health exercise intervention for older patients with myeloid neoplasms (GO-EXCAP 2).

INTRODUCTION: We have shown the Exercise for Cancer Patients (EXCAP©®) exercise program improved physical function and symptoms and reduced inflammatory markers in patients with cancer. However, adherence to exercise was lower in older adults compared to their younger counterparts. We then leveraged a mobile app to deliver EXCAP©® and adapted the intervention [Geriatric-Oncology (GO)-EXCAP] for older patients with myeloid neoplasms. In this pilot randomized trial, the primary goal is to determine effect sizes. We propose to assess the preliminary efficacy of GO-EXCAP compared to a behavioral placebo control on physical function, patient-reported outcomes (fatigue, mood, and quality of life), and inflammatory markers in 100 patients aged ≥60 years with myeloid neoplasms receiving outpatient chemotherapy. METHODS: GO-EXCAP consists of the EXCAP©® exercise prescription (daily home-based progressive aerobic walking and resistance exercises with rated perceived exercise of 5-8), EXCAP©® kit (i.e., activity tracker, resistance bands, print manual, bag), a mobile app, and an in-person or virtual session with the exercise physiologist to deliver exercise prescription. The intervention will last for three cycles of chemotherapy (approximately 12 weeks). The primary outcome measure will be physical function (Short Physical Performance Battery). Secondary outcome measures include fatigue (Brief Fatigue Inventory), mood (Center for Epidemiologic Studies Depression Scale), and quality of life (Functional Assessment of Cancer Therapy-Leukemia). Exploratory outcome measures include inflammatory markers. DISCUSSION: Older adults with myeloid neoplasms receiving outpatient chemotherapy serve as an ideal model for studying an individually tailored mobile health exercise intervention in vulnerable older patients receiving cancer treatments to prevent physical function decline and improve symptoms.

Timing of Meals and Exercise Affects Hormonal Control of Glucoregulation, Insulin Resistance, Substrate Metabolism, and Gastrointestinal Hormones, but Has Little Effect on Appetite in Postmenopausal Women.

The current prevalence of obesity in the US is strongly associated with excessive food intake and insufficient physical activity. This study examined whether changing the timing of exercise before or after two daily meals could alter human appetite for food. Fifty-four healthy postmenopausal women were matched by body weight and assigned to two groups: (1) two bouts of 2-h moderate-intensity exercise ending one hour before each weight-maintenance meal (XM, n = 23), (2) two-hour moderate-intensity exercise starting 1 h after each weight-maintenance meal (MX, n = 23), and one sedentary control (SED) arm (n = 8). Measurements included appetite ratings, circulating glucose, free fatty acids (FFAs), a ketone body D-ß-hydroxybutyrate (BHB), glucoregulatory hormones insulin and glucagon, and gastrointestinal hormones associated with food digestion and absorption and implicated in appetite sensations. XM group increased concentrations of FFAs and BHB during exercise and increased insulin and homeostatic assessment of insulin resistance (HOMA-IR) during postprandial periods. MX group reduced postprandial insulin and HOMA-IR by about 50% without a major change in plasma glucose. There was brief suppression of hunger and an increase in satiation in both exercise groups near the end of the first postprandial period. The time course of hunger was unrelated to the perturbations in fuel metabolism, depletion of liver glycogen, and not correlated with concentration changes in hunger-stimulating hormone ghrelin during XM exercise before meals. Similarly, there was no correlation between the time course of fullness during exercise after meals with the postprandial secretion of gastrointestinal hormones including cholecystokinin (CCK) that has been linked to satiation. Hunger and satiation appear to depend on oral intake and gastrointestinal processing of nutrients and are not affected by metabolic and hormonal consequences of the timing of exercise with respect to meals. Moderate-intensity exercise performed shortly after meals induces a rapid and highly effective lowering of insulin resistance.

Physical Activity Patterns and Relationships With Cognitive Function in Patients With Breast Cancer Before, During, and After Chemotherapy in a Prospective, Nationwide Study.

PURPOSE: Physical activity (PA) is a promising intervention for cancer-related cognitive decline, yet research assessing its use during chemotherapy is limited. This study evaluated patterns of PA before, during, and after chemotherapy in patients with breast cancer and the association between PA and cognitive function. METHODS: In a nationwide, prospective cohort study, we assessed PA (Aerobics Center Longitudinal Study PA measure) and perceived and objectively measured cognitive functioning (Functional Assessment of Cancer Therapy-Cognitive, Delayed Match to Sample, and Rapid Visual Processing measures) at prechemotherapy (T1), postchemotherapy (T2), and 6 months postchemotherapy (T3) in patients with breast cancer and cancer-free, age-matched controls at equivalent time points. Longitudinal linear mixed-effects models (LMMs) characterized PA changes over time between patients and controls, adjusting for demographic and clinical factors. LMMs further estimated the role of prechemotherapy PA and changes in PA during chemotherapy on cognitive changes over time. RESULTS: Patients with stage I-IIIC breast cancer (n = 580; age M [standard deviation] = 53.4 [10.6] years) and controls (n = 363; age M [standard deviation] = 52.6 [10.3] years) were included. One third of patients met national PA guidelines at T1, dropping to 21% at T2 before rising to 37% at T3. LMMs revealed declines in PA from T1 to T2 in patients compared with controls (all P < .001). Patients meeting guidelines at T1 demonstrated better cognitive scores over time on the Functional Assessment of Cancer Therapy-Cognitive and Rapid Visual Processing (all P < .05), with similar patterns of objectively-measured cognitive function as controls. In patients, greater moderate-to-vigorous PA at the previous time point was significantly associated with better cognitive trajectories (all P < .05), and adherence to PA guidelines throughout chemotherapy was associated with better self-reported cognition (P < .01). CONCLUSION: This nationwide study demonstrates that PA maintenance before and during chemotherapy is associated with better cognitive function immediately and 6 months after chemotherapy completion.

Low cardiac dose and neutrophil-to-lymphocyte ratio predict overall survival in inoperable esophageal squamous cell cancer patients after chemoradiotherapy.

We aimed to determine the prognostic significance of cardiac dose and hematological immunity parameters in esophageal cancer patients after concurrent chemoradiotherapy (CCRT). During 2010-2015, we identified 101 newly diagnosed esophageal squamous cell cancer patients who had completed definitive CCRT. Patients' clinical, dosimetric, and hematological data, including absolute neutrophil count, absolute lymphocyte count, and neutrophil-to-lymphocyte ratio (NLR), at baseline, during, and post-CCRT were analyzed. Cox proportional hazards were calculated to identify potential risk factors for overall survival (OS). Median OS was 13 months (95% confidence interval [CI]: 10.38-15.63). Univariate analysis revealed that male sex, poor performance status, advanced nodal stage, higher percentage of heart receiving 10 Gy (heart V10), and higher NLR (baseline and follow-up) were significantly associated with worse OS. In multivariate analysis, performance status (ECOG 0 & 1 vs. 2; hazard ratio [HR] 3.12, 95% CI 1.30-7.48), heart V10 (> 84% vs. ≤ 84%; HR 2.24, 95% CI 1.26-3.95), baseline NLR (> 3.56 vs. ≤ 3.56; HR 2.36, 95% CI 1.39-4.00), and follow-up NLR (> 7.4 vs. ≤ 7.4; HR 1.95, 95% CI 1.12-3.41) correlated with worse OS. Volume of low cardiac dose and NLR (baseline and follow-up) were associated with worse patient survival.

Developing and adapting a mobile health exercise intervention for older patients with myeloid neoplasms: A qualitative study.

INTRODUCTION: Older patients with myeloid neoplasms (MN) receiving outpatient chemotherapy are at risk of experiencing treatment-related toxicities such as functional decline. A mobile health (mHealth) exercise intervention may ameliorate these toxicities. This qualitative study aimed to inform the design of a mHealth exercise intervention for this population. METHODS: This was a qualitative study of thirteen patients aged ≥60 years receiving hypomethylating agents for MN. EXCAP©® is a home-based walking and progressive resistance exercise program. We combined EXCAP©® with a mobile app; the combination (GO-EXCAP Mobile App) has not been previously tested. A brief verbal description about the intervention was provided to the participants but they did not perform it. Participants were interviewed and inductive thematic analysis was used to analyze the data. RESULTS: Mean age was 71.6 (SD 8.5). Three themes were identified: 1) Perceptions of the intervention feasibility, 2) Ways to leverage the app to deliver the exercise intervention, and 3) Personalized exercise goals. Walking and resistance exercises were perceived to be feasible. Patients were comfortable initiating the intervention in cycle 2 of chemotherapy, with exercise increments occurring from week 2-4 of the cycle. Ways to leverage the app to deliver EXCAP©® include 1) Video feature for exercise demonstration and interactions, and 2) Exercise data and symptom surveys to be communicated to the exercise physiologist and primary oncology team. Preservation of existing function and activity was an important goal to participants. CONCLUSIONS: Our findings provide insights about the preferences of older adults with MN for a mHealth exercise intervention.