Neurodegenerative disease pathways are perturbed in patients with cancer who self-report cognitive changes and anxiety: A pathway impact analysis.

BACKGROUND: Cancer-related cognitive impairment (CRCI) and anxiety co-occur in patients with cancer. Little is known about mechanisms for the co-occurrence of these two symptoms. The purposes of this secondary analysis were to evaluate for perturbed pathways associated with the co-occurrence of self-reported CRCI and anxiety in patients with low versus high levels of these two symptoms and to identify potential mechanisms for the co-occurrence of CRCI and anxiety using biological processes common across any perturbed neurodegenerative disease pathways. METHODS: Patients completed the Attentional Function Index and the Spielberger State-Trait Anxiety Inventory six times over two cycles of chemotherapy. Based on findings from a previous latent profile analysis, patients were grouped into none versus both high levels of these symptoms. Gene expression was quantified, and pathway impact analyses were performed. Signaling pathways for evaluation were defined with the Kyoto Encyclopedia of Genes and Genomes database. RESULTS: A total of 451 patients had data available for analysis. Approximately 85.0% of patients were in the none class and 15.0% were in the both high class. Pathway impact analyses identified five perturbed pathways related to neurodegenerative diseases (i.e., amyotrophic lateral sclerosis, Huntington disease, Parkinson disease, prion disease, and pathways of neurodegeneration-multiple diseases). Apoptosis, mitochondrial dysfunction, oxidative stress, and endoplasmic reticulum stress were common biological processes across these pathways. CONCLUSIONS: This study is the first to describe perturbations in neurodegenerative disease pathways associated with CRCI and anxiety in patients receiving chemotherapy. These findings provide new insights into potential targets for the development of mechanistically based interventions.

Effects of aerobic exercise on neurocognitive function in postmenopausal women receiving endocrine therapy for breast cancer: The Exercise Program in Cancer and Cognition randomized controlled trial.

Objective: The Exercise Program in Cancer and Cognition (EPICC) Study was a randomized controlled trial (RCT) designed to determine whether six months of moderate-intensity aerobic exercise improves neurocognitive function in women with breast cancer (BC) receiving endocrine therapy (ET). Methods: Postmenopausal women with hormone receptor+, early-stage BC, within two years post-primary therapy were randomized to the exercise intervention (six months, ≥150 minutes of moderate-intensity aerobic exercise/week) or usual care control condition. Outcomes were assessed at pre-randomization and after intervention completion. Groups were compared using linear mixed-effects modeling. Results: Participants (N=153) were X ¯ = 62.09 ± 8.27 years old, with stage I BC (64.1%) and a median of 4.7 months post-diagnosis. We found a group-by-time interaction (p=0.041) and a trend for the main effect of time (p=0.11) for processing speed with improved performance in the exercise group and no change in the controls. Similar main effects of time were observed for learning and memory (p=0.024) and working memory (p=0.01). Better intervention adherence was associated with improved processing speed (p=0.017). Conclusions: Six months of moderate-intensity aerobic exercise improves processing speed in postmenopausal women with BC receiving ET who initiate exercise within two years of completing primary therapy (surgery +/- chemotherapy). This is the first large-scale study to examine the effects of aerobic exercise on neurocognitive function in women with BC. Additional research is needed to address the long-term effects of aerobic exercise on cognitive function.

Perturbations in inflammatory pathways are associated with shortness of breath profiles in oncology patients receiving chemotherapy.

PURPOSE: One plausible mechanistic hypothesis is the potential contribution of inflammatory mechanisms to shortness of breath. This study was aimed to evaluate for associations between the occurrence of shortness of breath and perturbations in inflammatory pathways. METHODS: Patients with cancer reported the occurrence of shortness of breath six times over two cycles of chemotherapy. Latent class analysis was used to identify subgroups of patients with distinct shortness of breath occurrence profiles (i.e., none (70.5%), decreasing (8.2%), increasing (7.8%), high (13.5%)). Using an extreme phenotype approach, whole transcriptome differential gene expression and pathway impact analyses were performed to evaluate for perturbed signaling pathways associated with shortness of breath between the none and high classes. Two independent samples (RNA-sequencing (n = 293) and microarray (n = 295) methodologies) were evaluated. Fisher's combined probability method was used to combine these results to obtain a global test of the null hypothesis. In addition, an unweighted knowledge network was created using the specific pathway maps to evaluate for interconnections among these pathways. RESULTS: Twenty-nine Kyoto Encyclopedia of Genes and Genomes inflammatory signaling pathways were perturbed. The mitogen-activated protein kinase signaling pathway node had the highest closeness, betweenness, and degree scores. In addition, five common respiratory disease-related pathways, that may share mechanisms with cancer-related shortness of breath, were perturbed. CONCLUSIONS: Findings provide preliminary support for the hypothesis that inflammation contribute to the occurrence of shortness of breath in patients with cancer. In addition, the mechanisms that underlie shortness of breath in oncology patients may be similar to other respiratory diseases.

Stability and consistency of symptom clusters in younger versus older patients receiving chemotherapy.

BACKGROUND: By 2035, the number of newly diagnosed cancer cases will double and over 50% will be in older adults. Given this rapidly growing demographic, a need exists to understand how age influences oncology patients' symptom burden. The study purposes were to evaluate for differences in the occurrence, severity, and distress of 38 symptoms in younger (< 60 years) versus older (≥ 60 years) oncology patients undergoing chemotherapy and to evaluate for differences in the stability and consistency of symptom clusters across the two age groups. METHODS: A total of 1329 patients were dichotomized into the younger and older groups. Patients completed demographic and clinical questionnaires prior to the initiation of their second or third cycle of chemotherapy. A modified version of Memorial Symptom Assessment Scale was used to evaluate the occurrence, severity, and distress of 38 common symptoms associated with cancer and its treatment. Differences between the two age groups in demographic and clinical characteristics and ratings of occurrence, severity, and distress for the 38 symptoms were evaluated using parametric and nonparametric tests. Exploratory factor analyses were done within each age group to identify symptom clusters using symptom occurrence rates. RESULTS: Compared to the younger group (14.8 (± 7.0)), older adults reported a lower mean number of symptoms (12.9 (± 7.2)). Older patients experienced lower occurrence rates for almost 50% of the symptoms. Regarding symptom clusters, an eight-factor solution was selected for both age groups. Across the two age groups, the eight symptom clusters (i.e., physical and cognitive fatigue, respiratory, psychological, hormonal, chemotherapy-related toxicity, weight gain, gastrointestinal, epithelial) were stable. However, symptoms within the physical and cognitive, chemotherapy-related toxicity, and gastrointestinal clusters were not consistent across the age groups. CONCLUSIONS: To be able to provide tailored and effective symptom management interventions to older oncology patients, routine assessments of the core symptoms unique to the symptom clusters identified for this group warrants consideration. The underlying mechanism(s) for these inconsistencies in symptom burden is an important focus for future studies.

Increases in stress and adverse childhood experiences are associated with the co-occurrence of anxiety and depression in oncology patients.

PURPOSE: Identify subgroups of patients with distinct joint anxiety AND depression profiles and evaluate for differences in demographic and clinical characteristics, as well as stress, resilience, and coping. DESIGN: Longitudinal study. PARTICIPANTS: Patients (n = 1328) receiving chemotherapy. METHODS: Measures of state anxiety and depression were done six times over two cycles of chemotherapy. All of the other measures were completed prior to second or third cycle of chemotherapy. Latent profile analysis was used to identify the distinct joint anxiety and depression profiles. FINDINGS: Three classes were identified (i.e. Low Anxiety and Low Depression (57.5%); Moderate Anxiety and Moderate Depression (33.7%), High Anxiety and High Depression (8.8%)). For all of the stress measures, a dose response effect was seen among the profiles. Two worst profiles reported higher occurrence rates for a number of adverse childhood experiences. IMPLICATIONS FOR PROVIDERS: Patients need referrals for stress reduction techniques and mental health and social services.

Neonatal Diet Type and Associations With Adverse Feeding Outcomes in Neonates With Critical Congenital Heart Defects.

BACKGROUND: Neonates with critical congenital heart defects (CCHD neonates) experience high rates of feeding intolerance, necrotizing enterocolitis (NEC), and malnutrition. The benefits of human milk and direct chest/breastfeeding are well known, but research is limited in CCHD neonates. Therefore, the purpose of this study is to examine the impact of neonatal diet and feeding modality on the incidence of feeding intolerance, NEC, and malnutrition among a cohort of CCHD neonates. METHODS: A single-center retrospective study was conducted using electronic health record data of CCHD neonates admitted to a cardiac intensive care unit between April 2016 and April 2020. Regression models were fit to analyze associations between neonatal diet, feed modality, and adverse feeding outcomes. RESULTS: Seventy-four CCHD neonates were included. Increased days of direct chest/breastfeeding were associated with fewer signs of gastrointestinal distress ( P = .047) and bloody stools ( P = .021). Enteral feeding days of "all human milk" were associated with higher growth trajectory ( P < .001). CONCLUSIONS: Human milk and direct chest/breastfeeding may be protective against some adverse feeding outcomes for CCHD neonates. Larger, multicenter cohort studies are needed to continue investigating the effects of neonatal diet type and feeding modality on the development of adverse feeding outcomes in this unique population.

Identification of distinct symptom profiles in patients with gynecologic cancers using a pre-specified symptom cluster.

PURPOSE: Pain, fatigue, sleep disturbance, and depression are four of the most common symptoms in patients with gynecologic cancer. The purposes were to identify subgroups of patients with distinct co-occurring pain, fatigue, sleep disturbance, and depression profiles (i.e., pre-specified symptom cluster) in a sample of patients with gynecologic cancer receiving chemotherapy and assess for differences in demographic and clinical characteristics, as well as the severity of other common symptoms and QOL outcomes among these subgroups. METHODS: Patients completed symptom questionnaires prior to their second or third cycle of chemotherapy. Latent profile analysis was used to identify subgroups of patients using the pre-specified symptom cluster. Parametric and nonparametric tests were used to evaluate for differences between the subgroups. RESULTS: In the sample of 233 patients, two distinct latent classes were identified (i.e., low (64.8%) and high (35.2%)) indicating lower and higher levels of symptom burden. Patients in high class were younger, had child care responsibilities, were unemployed, and had a lower annual income. In addition, these women had a higher body mass index, a higher comorbidity burden, and a lower functional status. Patients in the high class reported higher levels of anxiety, as well as lower levels of energy and cognitive function and poorer quality of life scores. CONCLUSIONS: This study identified a number of modifiable and non-modifiable risk factors associated with membership in the high class. Clinicians can use this information to refer patients to dieticians and physical therapists for tailored interventions.

Anxiety in oncology outpatients is associated with perturbations in pathways identified in anxiety focused network pharmacology research.

PURPOSE: Evaluate for perturbed signaling pathways associated with subgroups of patients with low versus high levels of state anxiety. These pathways were compared to the pathways identified across eight network pharmacology studies of the anxiolytic effect(s) of a variety of compounds. METHODS: Adult outpatients had a diagnosis of breast, gastrointestinal, gynecological, or lung cancer; had received chemotherapy within the preceding four weeks; and were scheduled to receive at least two additional cycles of chemotherapy. Latent profile analysis was used to identify subgroups of patients with distinct anxiety profiles based on Spielberger State Anxiety Inventory scores that were obtained six times over two cycles of chemotherapy. Blood samples were processed using RNA sequencing (i.e., RNA-seq sample, n = 244) and microarray (i.e., microarray sample; n = 256) technologies. Pathway perturbations were assessed using pathway impact analysis. Fisher's combined probability method was used to combine test results using a false discovery rate of 0.01. RESULTS: In the RNA-seq sample, 62.3% and 37.7% of the patients were in the low- and high-anxiety classes, respectively. In the microarray sample, 61.3% and 38.7% were in the low and high-anxiety classes, respectively. Forty-one perturbed signaling pathways were identified. Eight of these pathways were common to those identified in the network pharmacology studies. CONCLUSIONS: Findings increase our knowledge of the molecular mechanisms that underlie anxiety in patients receiving chemotherapy. This study provides initial insights into how anxiety in patients with cancer may share common mechanisms with anxiety in patients with other clinical conditions.

Distinct Profiles of Morning and Evening Fatigue Co-Occurrence in Patients During Chemotherapy.

BACKGROUND: Morning and evening fatigue are distinct and distressing symptoms experienced during chemotherapy that demonstrate a large amount of interindividual variability. OBJECTIVES: The objectives of this study were to identify subgroups of patients with distinct morning and evening fatigue co-occurrence profiles and evaluate for differences among these subgroups in demographic, clinical, and symptom characteristics and quality of life. METHODS: Oncology patients ( n = 1,334) completed the Lee Fatigue Scale to self-report morning and evening fatigue, six times over two cycles of chemotherapy. Latent profile analysis was used to identify subgroups of patients with distinct morning and evening physical fatigue profiles. RESULTS: Four distinct morning and evening fatigue profiles were identified (i.e., Both Low, Low Morning + Moderate Evening, Both Moderate, and Both High). Compared to the Both Low profile, the Both High profile was significantly younger, less likely to be married or partnered, more likely to live alone, had a higher comorbidity burden, and lower functional status. The Both High profile had higher levels of anxiety, depressive symptoms, sleep disturbance, and pain and lower levels of quality of life. DISCUSSION: The variability in the morning and evening severity scores among the four profiles supports the hypothesis that morning and evening fatigue are distinct but related symptoms. Clinically meaningful levels of both morning and evening fatigue were reported by 50.4% of our sample, which suggests that the co-occurrence of these two symptoms is relatively common. Patients in Both Moderate and Both High profiles experienced an extremely high symptom burden that warrants ongoing assessments and aggressive symptom management interventions.

An Evaluation of the Multifactorial Model of Cancer-Related Cognitive Impairment.

BACKGROUND: Up to 45% of patients report cancer-related cognitive impairment (CRCI). A variety of characteristics are associated with the occurrence and/or severity of CRCI. However, an important gap in knowledge of risk factors for CRCI is the relative contribution of each factor. The multifactorial model of cancer-related cognitive impairment (MMCRCI) is a conceptual model of CRCI that can be used to evaluate the strength of relationships between various factors and CRCI. OBJECTIVES: The purpose of this study was to use structural regression methods to evaluate the MMCRCI using data from a large sample of outpatients receiving chemotherapy ( n = 1,343). Specifically, the relationships between self-reported CRCI and four MMCRCI concepts (i.e., social determinants of health, patient-specific factors, treatment factors, and co-occurring symptoms) were examined. The goals were to determine how well the four concepts predicted CRCI and determine the relative contribution of each concept to deficits in perceived cognitive function. METHODS: This study is part of a larger, longitudinal study that evaluated the symptom experience of oncology outpatients receiving chemotherapy. Adult patients were diagnosed with breast, gastrointestinal, gynecological, or lung cancer; had received chemotherapy within the preceding 4 weeks; were scheduled to receive at least two additional cycles of chemotherapy; were able to read, write, and understand English; and gave written informed consent. Self-reported CRCI was assessed using the attentional function index. Available study data were used to define the latent variables. RESULTS: On average, patients were 57 years of age, college educated, and with a mean Karnofsky Performance Status score of 80. Of the four concepts evaluated, whereas co-occurring symptoms explained the largest amount of variance in CRCI, treatment factors explained the smallest amount of variance. A simultaneous structural regression model that estimated the joint effect of the four exogenous latent variables on the CRCI latent variable was not significant. DISCUSSION: These findings suggest that testing individual components of the MMCRCI may provide useful information on the relationships among various risk factors, as well as refinements of the model. In terms of risk factors for CRCI, co-occurring symptoms may be more significant than treatment factors, patient-specific factors, and/or social determinants of health in patients receiving chemotherapy.

Epigenetic Regulation of Inflammatory Mechanisms and a Psychological Symptom Cluster in Patients Receiving Chemotherapy.

BACKGROUND: A psychological symptom cluster is the most common cluster identified in oncology patients. Although inflammatory mechanisms are hypothesized to underlie this cluster, epigenetic contributions are unknown. OBJECTIVES: This study's purpose was to evaluate associations between the occurrence of a psychological symptom cluster and levels of DNA methylation for inflammatory genes in a heterogeneous sample of patients with cancer receiving chemotherapy. METHODS: Prior to their second or third cycle of chemotherapy, 1,071 patients reported the occurrence of 38 symptoms using the Memorial Symptom Assessment Scale. A psychological cluster was identified using exploratory factor analysis. Differential methylation analyses were performed in two independent samples using Illumina Infinium 450K and EPIC microarrays. Expression-associated CpG (eCpG) loci in the promoter region of 114 inflammatory genes on the 450K and 112 genes on the EPIC microarray were evaluated for associations with the psychological cluster. Robust rank aggregation was used to identify differentially methylated genes across both samples. Significance was assessed using a false discovery rate of 0.05 under the Benjamini-Hochberg procedure. RESULTS: Cluster of differentiation 40 ( CD40 ) was differentially methylated across both samples. All six promoter eCpGs for CD40 that were identified across both samples were hypomethylated in the psychological cluster group. CONCLUSIONS: This study is the first to suggest associations between a psychological symptom cluster and differential DNA methylation of a gene involved in tissue inflammation and cell-mediated immunity. Our findings suggest that increased CD40 expression through hypomethylation of promoter eCpG loci is involved in the occurrence of a psychological symptom cluster in patients receiving chemotherapy. These findings suggest a direction for mechanistic studies.

Risk factors for worse anxiety trajectories among patients undergoing cancer chemotherapy.

PURPOSE: Patients undergoing chemotherapy for cancer often experience heightened anxiety. While receipt of chemotherapy occurs over multiple cycles, limited research has examined anxiety longitudinally. The purposes of this study, in a large sample of patients with breast, gynecological, gastrointestinal, or lung cancer, were to evaluate, over the course of two cycles of chemotherapy, for inter-individual differences in the trajectories of anxiety and identify associations between demographic, clinical, symptom, and psychological adjustment characteristics and initial levels and trajectories of anxiety. METHODS: Patients with breast, gynecologic, lung, or gastrointestinal cancer (n = 1323) were assessed with the Spielberger State Anxiety Inventory (STAI-S) six times over two cycles of chemotherapy. At enrollment, patients completed self-report instruments assessing demographic, symptom, stress, and coping characteristics. We used hierarchical linear modeling to identify risk factors associated with initial levels and trajectories of state anxiety. RESULTS: Inter-individual differences in initial levels of anxiety were associated with functional status, sleep disturbance, morning fatigue, cognitive function, global and cancer-specific stress, resilience, and several coping characteristics (i.e., sense of coherence, acceptance, using emotional support, self-distraction, denial, venting, and self-blame). Demographic and clinical characteristics associated with interindividual differences in anxiety trajectories were age, employment status, and MAX-2 score. CONCLUSION: This study provides novel data on the course and predictors of anxiety during two cycles of chemotherapy among a large sample of patients with varied cancer types. Further research focused on risk factors for heightened levels of anxiety during chemotherapy may help point toward more effective interventions for this commonly experienced symptom.

Trajectories of neuropsychological symptom burden in postmenopausal women prescribed anastrozole for early-stage breast cancer.

PURPOSE: Aromatase inhibitors (AIs) prolong survival for postmenopausal women with hormone receptor-positive breast cancer (HR + BC) but also burden patients with symptoms, a major reason for suboptimal AI adherence. This study characterizes inter-relationships among symptom measures; describes neuropsychological symptom burden trajectories; and identifies trajectory group membership predictors for postmenopausal women prescribed anastrozole for HR + BC. METHODS: This study utilized prospectively collected data from a cohort study. Relationships among various self-reported symptom measures were examined followed by a factor analysis to reduce data redundancy before trajectory analysis. Four neuropsychological scales/subscales were rescaled (range 0-100) and averaged into a neuropsychological symptom burden (NSB) score, where higher scores indicated greater symptom burden. Group-based trajectory modeling characterized NSB trajectories. Trajectory group membership predictors were identified using multinomial logistic regression. RESULTS: Women (N = 360) averaged 61 years old, were mostly White, and diagnosed with stage I HR + BC. Several measures were correlated temporally but four neuropsychological measures had strong correlations and dimensional loadings. These four measures, combined for the composite NSB, averaged (mean ± standard deviation) 17.4 ± 12.9, 18.0 ± 12.7, 19.5 ± 12.8, and 19.8 ± 13.0 at pre-anastrozole, 6, 12, and 18 months post-initiation, respectively. However, the analysis revealed five NSB trajectories-low-stable, low-increasing, moderate-stable, high-stable, and high-increasing. Younger age and baseline medication categories (pre-anastrozole), including anti-depressants, analgesics, anti-anxiety, and no calcium/vitamin D, predicted the higher NSB trajectories. CONCLUSION: This study found relationships among neuropsychological symptom measures and distinct trajectories of self-reported NSB with pre-anastrozole predictors. Identifying symptom trajectories and their predictors at pre-anastrozole may inform supportive care strategies via symptom management interventions to optimize adherence for women with HR + BC.

Symptom clusters in outpatients with cancer using different dimensions of the symptom experience.

PURPOSE: Relatively few studies have evaluated for symptom clusters across multiple dimensions. It is unknown whether the symptom dimension used to create symptom clusters influences the number and types of clusters that are identified. Study purposes were to describe ratings of occurrence, severity, and distress for 38 symptoms in a heterogeneous sample of oncology patients (n = 1329) undergoing chemotherapy; identify and compare the number and types of symptom clusters based on three dimensions (i.e., occurrence, severity, and distress); and identify common and distinct clusters. METHODS: A modified version of the Memorial Symptom Assessment Scale was used to assess the occurrence, severity, and distress ratings of 38 symptoms in the week prior to patients' next cycle of chemotherapy. Symptom clusters for each dimension were identified using exploratory factor analysis. RESULTS: Patients reported an average of 13.9 (±7.2) concurrent symptoms. Lack of energy was both the most common and severe symptom while "I don't look like myself" was the most distressing. Psychological, gastrointestinal, weight gain, respiratory, and hormonal clusters were identified across all three dimensions. Findings suggest that psychological, gastrointestinal, and weight gain clusters are common while respiratory and hormonal clusters are distinct. CONCLUSIONS: Psychological, gastrointestinal, weight gain, hormonal, and respiratory clusters are stable across occurrence, severity, and distress in oncology patients receiving chemotherapy. Given the stability of these clusters and the consistency of the symptoms across dimensions, the use of a single dimension to identify these clusters may be sufficient. However, comprehensive and disease-specific inventories need to be used to identify distinct clusters.

Impact of worst pain severity and morning fatigue profiles on oncology outpatients' symptom burden and quality of life.

PURPOSE: Pain and fatigue are common symptoms in oncology patients. In a sample of oncology outpatients receiving chemotherapy (n = 1342), the study purposes were to identify subgroups of patients with distinct worst pain and morning fatigue profiles and evaluate for differences among the subgroups in demographic and clinical characteristics, as well as the severity of common symptoms and quality of life (QOL) outcomes. METHODS: Oncology outpatients receiving chemotherapy (n = 1342) completed self-report questionnaires to assess pain and morning fatigue, a total of six times over two cycles of chemotherapy. Joint latent profile analysis was used to identify subgroups of patients with distinct pain and morning fatigue profiles. Differences among the classes were evaluated using parametric and non-parametric tests. RESULTS: Five distinct profiles were identified (no pain and low morning fatigue (27.6%), moderate pain and low morning fatigue (28.2%), moderate pain and morning fatigue (28.0%), moderate pain and increasing and decreasing morning fatigue (6.9%), severe pain and very high morning fatigue (9.3%)). Patients with the three worst profiles had clinically meaningful levels of depression and sleep disturbance and decrements in QOL. CONCLUSIONS: Over 44% of the sample had moderate to high levels of both pain and morning fatigue. Unrelieved pain may contribute to disturbed sleep which results in higher levels of morning fatigue. Clinicians need to assess for pain and fatigue, as well as sleep disturbance during chemotherapy.

Characteristics associated with inter-individual variability in financial distress in patients with breast cancer prior to and for 12 months following surgery.

PURPOSE: To evaluate for inter-individual differences in financial distress and identify demographic, clinical, and symptom characteristics associated with higher levels of financial distress. METHODS: Patients (n = 387) were enrolled prior to breast cancer surgery and followed for 12 months. Financial distress was measured using a 0 (no problem) to 10 (severe problem) numeric rating scale. Hierarchical linear modeling was used to evaluate for inter-individual differences in trajectories of financial distress and characteristics associated with financial distress at enrollment and over 12 months. RESULTS: Patients' mean age was 55.0 (± 11.7) years and the majority underwent breast conservation surgery (80.6%). Mean financial distress score prior to surgery was 3.3 (± 3.4; range 0 to 10). Unconditional model for financial distress demonstrated no significant changes over time (-0.006/month). Younger age, lower income, receipt of an axillary lymph node dissection and adjuvant chemotherapy, and lower attentional function were associated with higher preoperative levels of financial distress. CONCLUSION: Risk factors identified in this study can be used to inform clinicians regarding the need to initiate financial discussions and social work referrals for some patients. Additional clinical or system level interventions should be considered for vulnerable groups with these risk factors.

Distinct sleep disturbance and cognitive dysfunction profiles in oncology outpatients receiving chemotherapy.

PURPOSE: Sleep disturbance and cancer-related cognitive impairment (CRCI) are two of the most common symptoms reported by patients undergoing chemotherapy. Less is known about how these symptoms co-occur and their associated risk factors. Study purposes were to identify subgroups of patients with distinct sleep disturbance and CRCI profiles and evaluate for differences among the subgroups in demographic and clinical characteristics, symptom severity scores, and QOL outcomes. METHODS: A total of 1,333 oncology outpatients receiving chemotherapy completed self-report questionnaires on sleep disturbance and cognitive dysfunction six times over two cycles of chemotherapy. Latent profile analysis was used to identify distinct sleep disturbance AND cognitive dysfunction profiles. Parametric and non-parametric tests were used to evaluate for differences among the classes. RESULTS: Two distinct profiles were identified (i.e., Low = low levels of both sleep disturbance and cognitive dysfunction (53.5%); High = high levels of both sleep disturbance and cognitive dysfunction (45.5%)). Patients in the High class were younger, more likely to be female, had a lower functional status and a higher level of comorbidity. In addition, these patients had a higher symptom burden and a lower quality of life. CONCLUSION: Almost half of the patients undergoing chemotherapy experienced clinically meaningful levels of both symptoms. Of note, sleep disturbance is frequently overlooked by both clinicians and patients. Clinicians need to recommend cognitive rehabilitation and physical activity programs to decrease patients' symptom burden.

Decreased DNA Methylation of RGMA is Associated with Intracranial Hypertension After Severe Traumatic Brain Injury: An Exploratory Epigenome-Wide Association Study.

BACKGROUND: Cerebral edema and intracranial hypertension are major contributors to unfavorable prognosis in traumatic brain injury (TBI). Local epigenetic changes, particularly in DNA methylation, may influence gene expression and thus host response/secondary injury after TBI. It remains unknown whether DNA methylation in the central nervous system is associated with cerebral edema severity or intracranial hypertension post TBI. We sought to identify epigenome-wide DNA methylation patterns associated with these forms of secondary injury after TBI. METHODS: We obtained genome-wide DNA methylation profiles of DNA extracted from ventricular cerebrospinal fluid samples at three different postinjury time points from a prospective cohort of patients with severe TBI (n = 89 patients, 254 samples). Cerebral edema and intracranial pressure (ICP) measures were clustered to generate composite end points of cerebral edema and ICP severity. We performed an unbiased epigenome-wide association study (EWAS) to test associations between DNA methylation at 419,895 cytosine-phosphate-guanine (CpG) sites and cerebral edema/ICP severity categories. Given inflated p values, we conducted permutation tests for top CpG sites to filter out potential false discoveries. RESULTS: Our data-driven hierarchical clustering across six cerebral edema and ICP measures identified two groups differing significantly in ICP based on the EWAS-identified CpG site cg22111818 in RGMA (Repulsive guidance molecule A, permutation p = 4.20 × 10-8). At 3-4 days post TBI, patients with severe intracranial hypertension had significantly lower levels of methylation at cg22111818. CONCLUSIONS: We report a novel potential relationship between intracranial hypertension after TBI and an acute, nonsustained reduction in DNA methylation at cg22111818 in the RGMA gene. To our knowledge, this is the largest EWAS in severe TBI. Our findings are further strengthened by previous findings that RGMA modulates axonal repair in other central nervous system disorders, but a role in intracranial hypertension or TBI has not been previously identified. Additional work is warranted to validate and extend these findings, including assessment of its possible role in risk stratification, identification of novel druggable targets, and ultimately our ability to personalize therapy in TBI.

Distinct employment interference profiles in patients with breast cancer prior to and for 12 months following surgery.

PURPOSE: To identify subgroups of female breast cancer patients with distinct self-reported employment interference (EI) profiles and determine which demographic, clinical, and symptom characteristics, and quality of life outcomes were associated with subgroup membership. METHODS: Women with breast cancer (n = 385) were assessed for changes in EI over ten times, from prior to, through 12 months after breast cancer surgery. Latent profile analysis (LPA) was used to identify subgroups of patients with distinct EI profiles. RESULTS: Three distinct EI profiles (i.e., None - 26.2% (n = 101), Low - 42.6% (n = 164), High - 31.2% (n = 120)) were identified. Compared to the None and Low groups, patients in the High group were more likely to be younger. Higher proportions in the High group were non-White, pre-menopausal prior to surgery, had more advanced stage disease, had received an axillary lymph node dissection, had received neoadjuvant chemotherapy, had received adjuvant chemotherapy, and had a re-excision or mastectomy on the affected breast within 6 months after surgery. In addition, these patients had lower quality of life scores. Compared to the None group, the High group had higher levels of trait and state anxiety, depressive symptoms, fatigue and sleep disturbance and lower levels of cognitive function. CONCLUSIONS: This study provides new knowledge regarding EI profiles among women in the year following breast cancer surgery. The non-modifiable risk factors (e.g., younger age, being non-White, having more advanced stage disease) can inform current screening procedures. The potentially modifiable risk factors can be used to develop interventions to improve employment outcomes of breast cancer patients.

Distinct sleep disturbance profiles among patients with gynecologic cancer receiving chemotherapy.

OBJECTIVE: In a sample of patients with gynecologic cancer receiving chemotherapy, we sought to identify subgroups of patients with distinct sleep disturbance profiles and assess for differences in patient characteristics and the severity of co-occurring symptoms among these subgroups. METHODS: Adults with gynecologic cancer (n = 232) completed questionnaires six times over two chemotherapy cycles. Sleep disturbance was assessed using the General Sleep Disturbance Scale (GSDS). Clinically meaningful sleep disturbance was defined as a GSDS total score of ≥43. Subgroups of patients with distinct sleep disturbance profiles were identified using latent profile analysis. Differences in patient characteristics and co-occurring symptoms were assessed using Chi-square, Kruskal Wallis, and one-way analysis of variance. RESULTS: Four distinct sleep disturbance profiles were identified: Low (18.5%), Moderate (43.6%), High (29.3%), and Very High (8.6%). Compared to the Low class, patients in the other three classes had lower functional status scores and higher levels of depressive symptoms, trait anxiety, and morning and evening fatigue. Compared to the Low class, patients in the Very High class were younger, had a higher body mass index, and were more likely to report a diagnosis of depression or back pain. CONCLUSIONS: Over 80% of the patients with gynecologic cancer reported sleep disturbance that persisted over two cycles of chemotherapy. Patients in the Very High class experienced problems with both sleep initiation and maintenance. Clinicians should routinely assess sleep disturbance alongside depression, anxiety, and fatigue. Interventions that target the underlying mechanisms of these co-occurring symptoms are warranted.