Depressive Symptoms, Systemic Inflammation, and Survival Among Patients With Head and Neck Cancer.

Importance: Patients with head and neck cancer experience high rates of depression. Depression and systemic inflammation have been found to be associated in numerous cancer types, often independently from disease status. Depression-related inflammation may elevate the risks for poor tumor response to treatment and early mortality, and comprises a mechanism by which depression is associated with survival in head and neck cancer. Objective: To assess mediation pathways incorporating pretreatment depressive symptoms, pretreatment inflammation, and tumor response posttreatment on overall survival among patients with head and neck cancer. Design, Setting, and Participants: This was a prospective observational cohort study of patients with head and neck cancer treated in a single multidisciplinary head and neck cancer clinic from May 10, 2013, to December 30, 2019, and followed up for 2 years. Data analysis was performed from June 29, 2022, to June 23, 2023. Exposures: Patient-reported depressive symptoms using the Patient Health Questionnaire-9 item (PHQ-9) at treatment planning; pretreatment hematology workup for systemic inflammation index (SII) score; and clinical data review for tumor response (complete vs incomplete) and overall survival. Main Outcomes: Two-year overall survival. Results: The total study cohort included 394 patients (mean [SD] age, 62.5 [11.5] years; 277 [70.3%] males) with head and neck cancer. Among 285 patients (72.3%) who scored below the clinical cutoff for depression on the PHQ-9, depressive symptoms were significantly associated with inflammation (partial r, 0.168; 95% CI, 0.007-0.038). In addition, both depression and inflammation were associated with early mortality (PHQ-9: hazard ratio [HR], 1.04; 95% CI, 1.02-1.07; SII: HR, 1.36; 95% CI, 1.08-1.71). The depression-survival association was fully mediated by inflammation (HR, 1.28; 95% CI, 1.00-1.64). Depressive symptoms were also associated with poorer tumor response (odds ratio, 1.05; 95% CI, 1.01-1.08), and the depression-survival association was partially mediated by tumor response (HR, 9.44; 95% CI, 6.23-14.32). Systemic inflammation was not associated with tumor response. Conclusions: In this cohort study, systemic inflammation emerged as a novel candidate mechanism of the association of depression with mortality. Tumor response partially mediated effects of depression on mortality, replicating prior work. Thus, depression stands out as a highly feasible target for renewed clinical attention. Even mild symptoms of depression during the treatment-planning phase may be associated with higher systemic inflammation in addition to poorer tumor response to treatment and survival outcomes; therefore, depression should be clinically addressed.

Depressive symptoms and shorter survival in lung cancer: the role of leukocyte telomere length.

OBJECTIVE: To examine the association between depressive symptoms, leukocyte telomere length-a marker of cellular ageing, and survival amongst lung cancer patients. DESIGN: Patients with non-small cell lung cancer were recruited from a university-affiliated cancer center clinic. MAIN OUTCOME: Patients (N = 67) reported on depressive symptoms and provided a blood sample for leukocyte telomere length assessment at baseline and at a 3-month follow-up. Survival status was tracked over 3 years. RESULTS: Age at diagnosis and depressive symptoms, as measured by the CES-D, were associated with shorter leukocyte telomere length (p < .05), although only age at diagnosis contributed statistical significance to the model. Depressive symptoms predicted shorter survival from date of diagnosis (p < .01). Patients who reported experiencing clinically meaningful levels of depressive symptoms (CES-D scores ≥ 16) demonstrated shorter survival than those who reported sub-clinical levels of depressive symptoms (p < .05). Leukocyte telomere length did not emerge as a predictor of shorter survival. CONCLUSION: Clinically meaningful levels of depressive symptoms are associated with shorter survival amongst lung cancer patients. These findings support the on-going efforts to screen all cancer patients for low mood and to investigate mechanisms linking depressive symptoms and shorter survival in cancer contexts.

Depressive symptoms among patients with lung cancer: Elucidating the roles of shame, guilt, and self-compassion.

The link between smoking and lung cancer predisposes patients to feeling shame and guilt, which increases risk for depression. To test the hypothesis shame would have a stronger association with depressive symptoms than guilt, a hierarchical regression was conducted. Three regressions were run to examine the associations of self-compassion with shame, guilt, and depressive symptoms. The best model to explain depressive symptoms included shame, but not guilt. Greater self-compassion was associated with less shame and fewer depressive symptoms, but not guilt. Results point to interventions targeting shame via enhancing self-compassion among patients with lung cancer and histories of smoking.

Association of Stress-Health Factors among Parkinson's Disease Patient/Caregiving-Partner Dyads.

OBJECTIVE: Few studies have explored the shared effects of Parkinson's disease (PD) within patient/caregiver dyads. To fill this gap, we compared stress-health outcomes of patients with those of caregiving-partners, examined individual stress-health associations, and explored stress-health associations within dyads. METHOD: A total of 18 PD patient/caregiving-partner dyads (N = 36) reported on disease-specific distress, anxiety, quality of life (QOL), and provided saliva samples for cortisol assessment. This cross-sectional, secondary analysis of a prospective pilot study used Actor-Partner Interdependence Models to test aims. RESULTS: Patients reported greater anxiety, poorer QOL, and demonstrated flatter cortisol slopes and higher mean bedtime cortisol compared to caregiving-partners. Both patients and caregiving-partners with greater anxiety had elevated bedtime cortisol and poorer QOL. Greater disease-specific distress in an individual was associated with higher diurnal mean cortisol in their partner. CONCLUSIONS: Findings highlight the potential for psychosocial interventions at the dyadic level to reduce shared burden and promote coping among PD patient/caregiving-partner dyads.

The role of the circadian clock in cancer hallmark acquisition and immune-based cancer therapeutics.

The circadian system temporally regulates physiology to maintain homeostasis. Co-opting and disrupting circadian signals appear to be distinct attributes that are functionally important for the development of a tumor and can enable or give rise to the hallmarks that tumors use to facilitate their initiation, growth and progression. Because circadian signals are also strong regulators of immune cell proliferation, trafficking and exhaustion states, they play a role in how tumors respond to immune-based cancer therapeutics. While immuno-oncology has heralded a paradigm shift in cancer therapeutics, greater accuracy is needed to increase our capability of predicting who will respond favorably to, or who is likely to experience the troubling adverse effects of, immunotherapy. Insights into circadian signals may further refine our understanding of biological determinants of response and help answer the fundamental question of whether certain perturbations in circadian signals interfere with the activity of immune checkpoint inhibitors. Here we review the body of literature highlighting circadian disruption as a cancer promoter and synthesize the burgeoning evidence suggesting circadian signals play a role in how tumors respond to immune-based anti-cancer therapeutics. The goal is to develop a framework to advance our understanding of the relationships between circadian markers, cancer biology, and immunotherapeutics. Bolstered by this new understanding, these relationships may then be pursued in future clinical studies to improve our ability to predict which patients will respond favorably to, and avoid the adverse effects of, traditional and immune-based cancer therapeutics.

Mindfulness, self-reported health, and cortisol: A latent profile analysis.

This study utilized a latent profile analysis approach to examine the relationship between mindfulness profiles and self-reported mental and physical health, as well as salivary cortisol levels in a sample of 85 undergraduate students. Consistent with theory, the Judgmentally Observing (high monitoring, low acceptance) reported poorer mental health and exhibited flatter diurnal cortisol slopes than the Unobservant Accepting (low monitoring, high acceptance) and Average Mindfulness profiles. No differences in self-reported physical health, cortisol response to awakening, or diurnal mean cortisol were observed among the profiles. Future directions are discussed.

The association between history of traumatic events and health-related quality of life among lung cancer patients.

PURPOSE: Promoting health-related quality of life (HRQOL) is a primary goal of lung cancer treatment. Trauma history and distress can negatively impact HRQOL. DESIGN: A cross-sectional design examined the associations of trauma history, cancer-specific distress, and HRQOL. SAMPLE/METHOD: Sixty lung cancer patients completed questionnaires on trauma history including the number and severity of traumatic events experienced. Cancer-specific distress, HRQOL, and depression were also reported. FINDINGS: As hypothesized, trauma history and cancer-specific distress were negatively associated with HRQOL (all r's > -.27). Depression emerged as a confound in the association between cancer-specific distress and HRQOL. CONCLUSIONS: Retrospectively-reported trauma was linked with poorer HRQOL in lung cancer patients. IMPLICATIONS: Interventions aimed at improving lung cancer patients' HRQOL should consider the possible role of trauma history (both frequency and distress).

ELISA-based detection of Open Reading Frame protein 1 in patients at risk of developing lung cancer.

BACKGROUND: Early detection of lung cancer significantly improves survival outcomes. Thus, lung cancer screening for high-risk individuals using low-dose CT scan (LDCT) is recommended. LDCT has several limitations, and often requires invasive follow up. Previously, we have developed an ELISA for measurement of Open Reading Frame 1 protein (ORF1p) in serum. We assessed whether ORF1p can be used as a risk assessment biomarker for patients at high risk for developing lung cancer. PATIENTS: Patients with risk factors for lung cancer were enrolled in our study with consent under IRB approval. A total of 122 patients were included. The lung cancer cohort consisted of 38 patients with varying stages of cancer undergoing treatment. METHODS: ORF1p quantification was performed using our ELISA assay on serum samples. RESULTS: ORF1p was significantly increased in the serum of patients with identified lung nodules compared to those without nodules (P = 0.0007). ORF1p was also significantly increased in patients who were recommended for follow up (P = 0.0004). When comparing the at-risk cohort to patients with lung cancer, there was not a significant difference in ORF1p levels. CONCLUSION: ORF1p can be used to identify patients at high risk of developing lung cancer and may provide an effective, non-invasive risk assessment marker to complement LDCT screening.

Impact of coping strategies on perceived stress, depression, and cortisol profiles among gynecologic cancer patients.

We explored associations between problem-focused, emotional processing, and emotional expression coping strategies and markers of stress including perceived stress, depressive symptoms, and diurnal cortisol profiles among women with gynecologic cancer. Problem-focused coping was associated with less perceived stress, fewer depressive symptoms, and more rhythmic diurnal salivary cortisol profiles. Emotional processing was associated with lower perceived stress and fewer depressive symptoms. Emotional expression was associated with fewer depressive symptoms and elevated diurnal mean and evening cortisol levels. Results point to key differences in coping strategies. In this sample, only problem-focused coping was linked with adaptive differences in both psychological and physiological stress measures.

The role of dispositional mindfulness in a stress-health pathway among Parkinson's disease patients and caregiving partners.

PURPOSE: Parkinson's disease (PD) patients and their caregivers experience significant distress that impacts physical, emotional and social functioning in the patient, and in turn, has a significant impact on the caregiver. Lower levels of stress have been associated with a better prognosis in PD. The quality of dispositional mindfulness-innate present moment, non-judgmental awareness-has consistently been associated with less perceived stress, greater well-being, and better physical health in both clinical and healthy populations. To date, associations of mindfulness with distress, depression, sleep problems, and other variables that define health-related quality of life have not been examined in the context of PD patient/caregiver dyads. METHODS: We investigated the impact of dispositional mindfulness in a stress-health model among eighteen dyads consisting of PD patients and their caregivers. RESULTS: Multilevel linear modeling (actor-partner interdependence models) revealed significant associations between dispositional mindfulness and stress appraisal, interpersonal support, depressive symptoms, sleep, and health-related quality of life (HRQOL) within both dyadic partners. As expected, results demonstrated significant associations of distress with interpersonal support, depressive symptoms, sleep and HRQOL for both PD patients and caregivers. CONCLUSIONS: Dispositional mindfulness was associated with reduced distress and its downstream clinical consequences. These results support an ameliorative role for dispositional mindfulness among PD patients and caregivers, as a protective factor against psychosocial burdens imposed on couples related to disease and caregiving. Findings suggest future studies should explore mindfulness training as a therapeutic option.

Depressive symptoms predict head and neck cancer survival: Examining plausible behavioral and biological pathways.

BACKGROUND: Head and neck cancers are associated with high rates of depression, which may increase the risk for poorer immediate and long-term outcomes. Here it was hypothesized that greater depressive symptoms would predict earlier mortality, and behavioral (treatment interruption) and biological (treatment response) mediators were examined. METHODS: Patients (n = 134) reported depressive symptomatology at treatment planning. Clinical data were reviewed at the 2-year follow-up. RESULTS: Greater depressive symptoms were associated with significantly shorter survival (hazard ratio, 0.868; 95% confidence interval [CI], 0.819-0.921; P < .001), higher rates of chemoradiation interruption (odds ratio, 0.865; 95% CI, 0.774-0.966; P = .010), and poorer treatment response (odds ratio, 0.879; 95% CI, 0.803-0.963; P = .005). The poorer treatment response partially explained the depression-survival relation. Other known prognostic indicators did not challenge these results. CONCLUSIONS: Depressive symptoms at the time of treatment planning predict overall 2-year mortality. Effects are partly influenced by the treatment response. Depression screening and intervention may be beneficial. Future studies should examine parallel biological pathways linking depression to cancer survival, including endocrine disruption and inflammation. Cancer 2018;124:1053-60. © 2018 American Cancer Society.

Distress and quality of life in an ethnically diverse sample awaiting breast cancer surgery.

Poor breast cancer-related quality of life is associated with flattened cortisol rhythms and inflammation in breast cancer survivors and women with advanced disease. We explored the associations of cancer-specific distress (Impact of Events Scale), mood (Profile of Mood States), activity/sleep (wake after sleep onset, 24-hour autocorrelation coefficient) and cortisol (diurnal slope) circadian rhythms, and inflammation (interleukin-6) with quality of life (Functional Assessment of Cancer Therapy-Breast) among patients awaiting breast cancer surgery ( N = 57). Models were adjusted for differences in age and cancer stage. Distress and mood disturbance were significantly correlated with lower quality of life. Ethnic differences in the relationship between distress and mood disturbance with global quality of life and subscales of quality of life were observed. Actigraphic measures showed that in comparison with non-Hispanic patients, African Americans had significantly poorer activity/sleep (wake after sleep onset, 24-hour autocorrelation coefficient). Circadian disruption and inflammation were not associated with quality of life. Physiological dysregulation and associated comorbidities may take time to develop over the course of disease and treatment.

Intraindividual variability in cortisol: Approaches, illustrations, and recommendations.

Most of the variance in diurnal cortisol is attributable to intraindividual variability (IIV), defined as relatively short-term, reversible changes. Multiple methods for measuring IIV have been proposed, and some have already been applied to cortisol IIV. In the present review, measurement methods are described and applied to simulated cortisol data with known underlying differences in IIV and to real cortisol data from first-year law students. More slope variance and more residual or net variance were well captured by their individual standard deviations. Explorations of reliability suggested that 10 slopes and 50 residuals result in reliable and stable estimates of the individual standard deviations. A data-analytic plan for cortisol IIV is provided.

Salivary Cortisol and Regional Brain Volumes Among Veterans With and Without Posttraumatic Stress Disorder.

BACKGROUND: Human studies have often found that brain regions rich in glucocorticoid receptors exhibit smaller volume in samples with past trauma and ongoing stress; however, relatively little research has addressed the hypothesis that such smaller volumes can be traced to elevated circulating glucocorticoid hormones (GCs). This issue takes on renewed interest in light of recent proposals to treat symptoms of stress disorders such as posttraumatic stress disorder (PTSD) with exogenous synthetic GCs. We sought to examine the relation of circulating GCs to brain macrostructure among veterans with and without PTSD. METHODS: Participants (n = 90) included combat veterans with and without PTSD. Veterans completed self-report surveys, home-based cortisol samples, reactive cortisol samples over the course of two serial Trier Social Stress Tests, a low-dose dexamethasone suppression test, and structural magnetic resonance brain imaging over the course of 3 to 5 days. RESULTS: No associations were observed between any salivary cortisol index and the volumes of the hippocampus or amygdala. A negative association was observed between evening basal cortisol and both FreeSurfer global volume and BrainImage supratentorial tissue volume. This effect was moderated by PTSD. Also observed was a positive association between reactive cortisol and these same brain volumes. CONCLUSIONS: Estimates of cortical but not hippocampal or amygdala volume were moderately associated with evening basal salivary cortisol and cortisol reactivity to a social stressor. Existing models relating GC receptor density, circulating cortisol levels, and regional brain volumes received little support.

Endogenous Cortisol Exposure and Declarative Verbal Memory: A Longitudinal Study of Healthy Older Adults.

OBJECTIVE: Exposure to endogenous cortisol is associated with hippocampal degeneration and may contribute to problems with declarative memory, but effects of persistent versus phasic cortisol elevations have not been established. The present longitudinal investigation examined persistent individual differences and phasic changes in cortisol as they related to verbal memory, executive functions, and subjective cognitive function. METHODS: Older adults (n = 132, aged 60-93 years) were followed up for up to 5 years. They were assessed annually for verbal memory and every 6 months for executive functions, subjective cognitive function, and cortisol area under the curve (averaged over 3 days). RESULTS: In multilevel models, persistently but not phasically higher cortisol was associated with worse verbal memory in both learning (t(181) = 2.99, p = .003) and recall (t(280) = 3.10, p = .002). This effect withstood adjustment for stress, depression, metabolic health, and age. There was evidence for attenuated primacy in learning with higher persistent cortisol. Phasic increases in cortisol were not associated with changes in memory, and cortisol was not related to executive functions or subjective cognitive function. CONCLUSIONS: Higher secretion of cortisol may, over time, contribute to memory dysfunction in older adults.

Psychological and social resources relate to biomarkers of allostasis in newly admitted nursing home residents.

OBJECTIVES: This paper presents preliminary baseline data from a prospective study of nursing home adaptation that attempts to capture the complexity of residents' adaptive resources by examining psychological, social, and biological variables from a longitudinal conceptual framework. Our emphasis was on validating an index of allostasis. METHOD: In a sample of 26 long-term care patients, we measured 6 hormone and protein biomarkers to capture the concept of allostasis as an index of physiological resilience, related to other baseline resources, including frailty, hope and optimism, social support, and mental health history, collected via interview with the resident and collaterals. We also examined the performance of self-report measures reflecting psychosocial and well-being constructs, given the prevalence of cognitive impairment in nursing homes. RESULTS: Our results supported both the psychometric stability of our self-report measures, and the preliminary validity of our index of allostasis. Each biomarker was associated with at least one other resilience resource, suggesting that our choice of biomarkers was appropriate. As a group, the biomarkers showed good correspondence with the majority of other resource variables, and our standardized summation score was also associated with physical, social, and psychological resilience resources, including those reflecting physical and mental health vulnerability as well as positive resources of social support, optimism, and hope. CONCLUSION: Although these results are based on a small sample, the effect sizes were large enough to confer some confidence in the value of pursuing further research relating biomarkers of allostasis to psychological and physical resources and well-being.

Stress and cortisol in disaster evacuees: an exploratory study on associations with social protective factors.

Though cumulative emotional and physical effects of disasters may diminish evacuees' short and long-term mental and physical health, social factors may buffer such consequences. We approached survivors of the October 2007 San Diego, California firestorms. We gathered data during the evacuation and 3 months afterward. Questionnaires measured social support as well as PTSD, depression, and anxiety symptoms. Saliva samples were used to assess the stress hormone, cortisol. Analyses, adjusting for age, gender, and socioeconomic status, showed PTSD symptoms were associated with flattening of the diurnal cortisol rhythm during evacuation. Secondary analyses showed those reporting a family emphasis on moral and religious values had lower psychological distress. Though anxiety symptoms had significantly decreased in the overall sample at follow-up, blunted cortisol rhythms persisted among those individuals with continued high anxiety. Results highlight a possible psychological, and perhaps a physiological, benefit of social and existential factors in disaster situations. Future work should explore the role of psychosocial factors and stress physiology in the development of long-term health concerns among individuals exposed to disaster.

Mindfulness meditation alleviates fibromyalgia symptoms in women: results of a randomized clinical trial.

BACKGROUND: Several recent reviews have evaluated evidence on the efficacy of Mindfulness-Based Stress Reduction (MBSR) among fibromyalgia sufferers, and concluded that more research should test effects on both psychological and physiological functioning. PURPOSE: We conducted a randomized prospective trial of MBSR among female fibromyalgia patients. METHODS: Effects on perceived stress, pain, sleep quality, fatigue, symptom severity, and salivary cortisol were tested in treatment (n=51) versus wait-list control participants (n=40) using data at baseline, post-program, and 2-month follow-up. RESULTS: Analyses revealed that MBSR significantly reduced perceived stress, sleep disturbance, and symptom severity, with gains maintained at follow-up. Greater home practice at follow-up was associated with reduced symptom severity. MBSR did not significantly alter pain, physical functioning, or cortisol profiles. CONCLUSION: MBSR ameliorated some of the major symptoms of fibromyalgia and reduced subjective illness burden. Further exploration of MBSR effects on physiological stress responses is warranted. These results support use of MBSR as a complementary treatment for women with fibromyalgia ( ISRCTN: 34628811).

Variability and reliability of diurnal cortisol in younger and older adults: implications for design decisions.

The extant research is inconclusive regarding the best sampling methods to construct reliable measures of between-person differences in derived parameters of diurnal cortisol, and no study provides such recommendations for detecting within-person changes. These studies determined how many days of sampling are necessary to assess between-person differences and within-person changes over multiple occasions in diurnal mean, diurnal slope, and area under the curve (AUC). Generalizability and decision analyses were conducted on diurnal salivary cortisol data from two separate longitudinal studies, one with younger adults (N=124) and one with older adults (N=148). In both studies, results indicated that 3 days of data collection provided the minimal level of reliability in mean cortisol to detect between-person differences; 4-8 days were necessary to reliably assess AUC, and 10 days for cortisol slope. Similarly, in order to reliably characterize within-person changes across occasions, at least 3 days of data collection were needed for mean cortisol and AUC and 5-8 days for slope. Results also indicated that only two samples per day, taken morning and evening, could faithfully reproduce the diurnal slope calculated from 3 or 4 samples (r=.97-.99). Instead of having participants provide many samples per day over the course of a few days, we recommend collecting fewer samples per day over more days.

Learning with interactive computer graphics in the undergraduate neuroscience classroom.

Instruction of neuroanatomy depends on graphical representation and extended self-study. As a consequence, computer-based learning environments that incorporate interactive graphics should facilitate instruction in this area. The present study evaluated such a system in the undergraduate neuroscience classroom. The system used the method of adaptive exploration, in which exploration in a high fidelity graphical environment is integrated with immediate testing and feedback in repeated cycles of learning. The results of this study were that students considered the graphical learning environment to be superior to typical classroom materials used for learning neuroanatomy. Students managed the frequency and duration of study, test, and feedback in an efficient and adaptive manner. For example, the number of tests taken before reaching a minimum test performance of 90 % correct closely approximated the values seen in more regimented experimental studies. There was a wide range of student opinion regarding the choice between a simpler and a more graphically compelling program for learning sectional anatomy. Course outcomes were predicted by individual differences in the use of the software that reflected general work habits of the students, such as the amount of time committed to testing. The results of this introduction into the classroom are highly encouraging for development of computer-based instruction in biomedical disciplines.