Elizabeth Cash

Background: In patients with head and neck cancer (HNC), perceived sleep quality, actigraphy-derived sleep parameters, depressive symptoms, and diurnal cortisol may represent related behavioral and biological processes. This exploratory study tested a priori associations among these constructs. Methods: Forty patients with HNC completed the Pittsburgh Sleep Quality Index (PSQI) and Patient Health Questionnaire-9 (PHQ-9), wore wrist actigraphs, and collected salivary cortisol at waking and bedtime across a 6-day period. Separate linear regressions tested associations of PSQI scores with actigraphic sleep measures with depressive symptoms, and with cortisol slope, waking, evening and mean indices. Post hoc PSQI item analyses used Spearman correlations. Results: Global PSQI scores were not significantly correlated with actigraphic sleep parameters. Poorer perceived sleep quality was associated with higher depression scores (r = 0.64), flatter diurnal cortisol slopes (r = 0.48), and higher evening cortisol (r = 0.40). Actigraphic sleep parameters were not significantly associated with depressive symptoms or cortisol indices, and depressive symptoms were not significantly associated with cortisol indices. Post hoc item-level analyses showed that poorer overall sleep quality and greater difficulty maintaining enthusiasm were associated with greater depressive symptoms, flatter cortisol slopes, and lower waking cortisol. Conclusion: In this exploratory pilot of patients with HNC, poorer sleep quality was associated with greater depressive symptoms, flatter diurnal cortisol slopes, and higher evening cortisol, whereas actigraphic sleep parameters were not. Global PSQI scores may help identify patients warranting further assessment for depression and treatment-related symptoms.

Objective: Anorexia nervosa spectrum disorders (ANSD) are associated with high chronicity and mortality, with suicidality representing one of the most common and clinically significant comorbidities. Sleep disturbances are prevalent in individuals with ANSD and have independently been linked to both eating disorder (ED) symptom severity and suicidal ideation (SI), yet their temporal role in maintaining ANSD symptoms and SI remains poorly understood. This study examined sleep disturbances as a potential shared, transdiagnostic mechanism contributing to daily fluctuations in ANSD symptoms and SI. Method: Participants meeting diagnostic criteria for ANSD with current or past SI ( n = 128) completed daily ecological momentary assessment (EMA) surveys assessing sleep disturbances, ED symptoms, and SI. Analyses and hypotheses were pre‐registered. Results: Multilevel models tested within‐ and between‐person, temporally lagged, bidirectional associations among sleep disturbances, ANSD symptoms, and SI. Greater sleep disturbances predicted increased next‐day restriction, binge eating, compensatory behaviors, body checking, and SI. Bidirectional effects were also observed, such that elevations in restriction, binge eating, compensatory behaviors, body checking, and SI predicted greater sleep disturbances the following night. Discussion: These findings suggest that sleep disturbances are dynamically embedded in the daily maintenance of core ANSD symptoms and SI. Sleep may represent a shared, modifiable vulnerability process contributing to ANSD severity and SI, highlighting its potential as a transdiagnostic intervention target in both eating disorder treatment and suicide prevention.

Objective: Interoceptive processes have been implicated in the onset and progression of disordered eating and self‐injurious thoughts and behaviors (SITBs), but relatively little is known about how these relationships unfold in the short‐term. To clarify the influence of momentary interoception on self‐damaging behaviors, this study tested whether reactivity and volatility in interoceptive attention predicted disordered eating and SITBs in a high‐risk restrictive eating disorder sample. Method: One hundred and thirty adults with anorexia nervosa and atypical anorexia and current or lifetime suicidality completed 21 days of ecological momentary assessment evaluating disordered eating behaviors, SITBs, and interoceptive attention. We used dynamic structural equation modeling to test whether short‐term reactivity and trait‐level volatility in interoceptive attention conferred proximal risk for non‐suicidal self‐injury (NSSI), restriction, binge eating, purging, suicidal ideation, and suicidal behaviors. Results: At the within‐person level, greater reactivity in interoceptive attention was associated with increased risk for NSSI, binge eating, purging, and active suicidal ideation, whereas decreased reactivity in interoceptive attention was associated with increased risk for passive suicidal ideation. At the between‐person level, greater volatility in interoceptive attention, reflecting a larger amount of intraindividual residual variance in interoceptive processes, was also associated with increased risk for NSSI, binge eating, and purging. No significant effects were detected for restriction or suicidal behavior. Discussion: Impairments in interoception have transdiagnostic relevance for understanding eating disorders and SITB risk. Interventions that reduce the intensity of interoceptive fluctuations may help reduce certain eating disorder symptoms and SITBs in the context of anorexia nervosa and atypical anorexia.

Objective: Restrictive eating disorders are characterized by abnormalities in both HRV and interoception, yet the extent to which transient physiological changes are related to interoceptive sensibility in this population remains unclear. The present study examines the association between HRV and interoceptive sensibility among individuals with anorexia nervosa and atypical anorexia (i.e., Anorexia Nervosa Spectrum Disorders) in real‐time using a combination of biosensor and ecological momentary assessment data. Method: Seventy‐five adults with Anorexia Nervosa Spectrum Disorders and current or lifetime suicidality completed 21 days of ecological momentary assessment while wearing a sensor band that passively collected HRV data. Multilevel models examined the association between HRV and interoceptive sensibility at the within‐ and between‐person levels. Results: HRV was positively associated with interoceptive sensibility at the between‐person level, such that individuals with higher HRV demonstrated greater interoceptive sensibility. However, temporary changes in HRV (i.e., deviations from one's average) were not associated with corresponding changes in interoceptive sensibility. Discussion: Within Anorexia Nervosa Spectrum Disorders with co‐occurring suicidality, alterations in autonomic function are accompanied by differences in interoceptive sensibility at the trait, but not state, level. Both heightened HRV and irregularities in interoceptive sensibility may arise as a consequence of prolonged caloric restriction. Physiological processes distinct from HRV may be responsible for driving momentary fluctuations in interoceptive sensibility in this population. Further research is needed to continue parsing potential differences in physiological processes across specific diagnoses and illness stage.

Autonomic assessment has traditionally been used for cardiovascular evaluation, but its applications extend into the field of eating disorders and psychiatry at large. By measuring heart rate, heart rate variability, and electrodermal activity with wearable sensor technology, one can observe state and trait adaptive responses of the parasympathetic and sympathetic nervous systems. Individuals on the anorexia and atypical anorexia nervosa spectrum often present with high heart rate variability, conventionally considered cardioprotective, yet likely maladaptive in these disorders. With this phenotype, it may be advantageous to employ a unique, yet logical therapeutic strategy of enhancing sympathetic response while reducing parasympathetic response. With the integration of autonomic phenotyping (i.e., aggregating psychophysiological indices), data‐driven idiographic treatment approaches have the potential to go beyond choosing the most effective psychotherapy for an individual. Determining individual autonomic phenotypes, regardless of eating disorder diagnosis, can augment other idiographic outcomes to inform treatment options and monitor progression of the disorder.

Circadian rhythms are the daily fluctuaBons in physiological processes that govern cell cycles and Bming of behaviors (1). Cancer hallmarks are the cellular properBes that drive the perennial growth, survival and spread of cancerous cells (2). The disrupBon of circadian rhythms can contribute to the development of some cancers by affecBng the expression of cancer hallmarks (3). Circadian rhythms also temporally regulate cellular immunity, which has important implicaBons for the burgeoning field of immune-based therapeuBcs (4). Cancer paBents exhibiBng disrupted circadian rhythms tend to suffer accelerated tumor growth and metastasis, worse anB-cancer treatment outcomes, and poorer health-related quality of life and overall survival (5). The aim of this special issue is to help elucidate the impact of circadian rhythms on processes associated with cancer and its treatments, immunotherapy in parBcular. We were pleased to accept eleven original manuscripts for this research topic.Through various approaches, several groups explored the molecular underpinnings of the connecBon between the circadian clock and cancer. Pan and colleagues have extensively reviewed the role of E-box-binding transcripBon factors in cell physiology and cancer biology, as well as their potenBal as novel therapeuBc targets. The broad group of E-box-binding transcripBon factors include two core clock genes, BMAL-1 and CLOCK. With a therapeuBc outlook, this work advances our knowledge of potenBal therapeuBc targets in cancer treatment. Zheng and colleagues focus on the latest evidence implicaBng circadian rhythm disrupBon as a causal factor in endometrial cancer and further explore the potenBal for mediaBon of these effects by non-coding RNAs. New research implicaBng irregular expression of circadian-linked ncRNAs in endometrial cancer cells is described, which may have implicaBons for future targeted therapeuBc strategies. Meng and colleagues deployed a Mendelian randomizaBon analyBcal approach to large internaBonal databases to explore the impact of 5 geneBcally independent circadian features on colorectal cancer risk. Strikingly, they observed that an individual chronotype might significantly contribute to the lifeBme risk of developing colorectal cancer. Peng and colleagues offer a mulB-gene prognosBc model developed using circadian genes that demonstrated predicBve performance for gynecologic cancer prognosis. This bioinformaBcs approach -validated in human data -also provides insights into potenBal immunotherapy targets by elucidaBng immune signaling pathways associated with high-risk circadian gene profiles.Several groups criBqued or provided data implicaBng the importance of sleep and circadian influences on cancer risk and outcomes. Gouldthorpe and colleagues, reviewing studies that incorporate objecBve circadian rhythm measurement, provide a useful compendium of the diverse indices used to summarize circadian endocrine data, acBgraphy data, and sleep-wake cycles, with an urgent call for standardizaBon of measurement. The need for standardizaBon is also highlighted by Jagielo and colleagues, who find that both corBsol dysregulaBon and abnormal rest-acBvity rhythms are clearly linked with psychological comorbidiBes in advanced cancer paBents, such as pain, faBgue, nausea, vomiBng, and cachexia. Promising data on chronomodulated chemotherapy and circadian-targeBng behavioral intervenBons are discussed.Nehnin and colleagues highlight a new and promising approach to treatment that regulated the circadian funcBon of gliomas, poinBng to the importance of targeBng circadian regulaBon in the tumor microenvironment, as well as the disBnct need for research in pediatric cancers. Burch and colleagues explored the associaBon between formally diagnosed sleep disorders and cancer occurrence in a robust sample of Veterans. They idenBfy an opBmal sleep duraBon for protecBon against oncogenesis: elevated lifeBme cancer risk was noted among those who slept on average less than 6, or more than 8, hours nightly. InteresBngly, greater severity and longer duraBon of sleep disorders both displayed an impact on cancer incidence. Finally, Cash and colleagues report on pilot data that opens avenues for further exploraBon of the links between diurnal corBsol expression, head and neck cancer progression, and the potenBal role of inflammaBon. They emphasize the importance of mulB-day corBsol sampling. Together, these data suggest that by recognizing the Bming of treatment in relaBon to corBsol levels, clinicians could opBmize treatment schedules to align with paBents' circadian rhythms, potenBally enhancing therapeuBc outcomes.Through their unique mechanism of acBon, immune checkpoint inhibitors are influenced by host physiology, including circadian rhythms. Two mini reviews summarize the growing evidence of interacBons between host physiology and checkpoint inhibitors. In the first, Hughes and colleagues have criBcally revised how light exposure, physical exercise and diet, and notably their respecBve Bmings across 24 hours, can impact immunotherapy efficacy in paBents with cancer. Balachandran and colleagues review important emerging data suggesBng that sleep disturbance is inversely correlated with tumor responsiveness to immunotherapy. Nascent links to the microbiome as a mechanism for these effects are considered along with remaining unanswered quesBons, such as whether these interconnecBons can be exploited to improve paBent response to immunotherapy. These reviews lay the foundaBons for novel therapeuBc avenues with potenBal circadian-based lifestyle modificaBons that could be implemented to manipulate cancer immune responsiveness and maximize the benefit from immunotherapy (6).This issue highlights circadian effects on tumor outcomes from two perspecBves: that of the host (cancer paBent) and that of the tumor and its associated microenvironment. These two perspecBves offer unique research quesBons. To improve immunotherapy...

Introduction: Cortisol rhythm disruptions predict early mortality in renal, colorectal, lung, and metastatic breast cancer. In head and neck cancer (HNC), various cortisol indices are known to correlate with adverse psychological and biological (e.g., inflammatory) outcomes, but links to mortality have yet to be demonstrated. We hypothesize that the prognostic value of diurnal cortisol aberrations will hold in HNC. Prior work leads us to predict that flattened or elevated diurnal cortisol profiles will be associated with elevations of serum inflammatory and tumor-promoting cytokines in this population, and that these immune markers would themselves predict poor progression-free survival.Method: We prospectively recruited a pilot sample of HNC patients (N=40) at a multidisciplinary HNC clinic. Most patients presented with late-stage oral/oropharyngeal cancer, were older than 50, male, and subsequently received combined-modality (surgery and/or radiotherapy with or without chemotherapy) treatment with curative intent. Saliva was collected twice daily for six days to assess diurnal slope, mean, waking, and evening cortisol levels. Serum was assayed for an exploratory panel of inflammatory and tumor-promoting cytokines. Two years post study-entry, disease progression and survivorship status were abstracted from medical records. Bivariate correlations, linear regressions, and Cox Proportional Hazards models tested hypotheses.Results: Elevations of evening cortisol and diurnal mean levels were each associated with shorter progression-free survival (evening: Hazard Ratio [HR]=1.848, 95% Confidence Interval [CI]=1.057-3.230, p=.031; diurnal mean: HR=2.662, 95% CI=1.115-6.355, p=.027). Bivariate correlations revealed that higher levels of the serum inflammatory marker interferon (IFN)-γ were linked with elevated evening (r=.405, p=.014) and mean (r=.459, p=.004) cortisol. Higher expression of IFN-γ also predicted poorer progression-free survival (HR=4.671, 95% CI=1.409-15.484, p=.012).Discussion: Elevated evening and diurnal mean cortisol were both prognostic; suggesting cortisol secretion is both dysregulated and elevated among patients who subsequently experienced accelerated disease progression. These exploratory data from 40 HNC patients mirror relationships between cortisol and survival identified among patients with numerous other tumor types. This pilot study highlights the need for research on effects of cortisol rhythm disruption among HNC patients. Future research in larger samples should also examine the role of inflammatory and tumor-promoting factors–both systemically and within the tumor microenvironment–as potential mediators of cortisol rhythm disruption.

Background: Head and neck cancers (HNC) are associated with high rates of anxiety. Anxiety has been linked to biological pathways implicated in cancer progression, though little is known about its effects on overall survival. We hypothesized that higher pretreatment anxiety levels in patients with HNC would predict poorer 2‐year overall survival and expected this relationship to be mediated by both systemic inflammation and tumor response to treatment.Methods: Patients (N = 394) reported anxiety symptomatology via the GAD‐7 at treatment planning. Pre‐treatment hematology workup provided an index of systemic inflammation (SII; N = 292). Clinical data review yielded tumor response and overall survival. Logistic and multiple regressions and Cox proportional hazard models tested hypothesized relationships.Results: Higher pretreatment anxiety levels were significantly associated with poorer 2‐year survival (hazard ratio [HR], 1.039; 95% confidence interval [CI], 1.014–1.066, p = 0.002). The association between anxiety and SII was not significant, though anxiety was associated with poorer tumor response (odds ratio [OR], 1.033; 95% CI, 1.001–1.066, p = 0.043). Tumor response fully mediated the relationship between anxiety symptoms and 2‐year survival (HR, 9.290, 95% CI, 6.152–14.031, p < 0.001).Conclusions: Anxiety was associated with overall survival. Tumor response, but not systemic inflammation, emerged as a potential biological pathway mediating this effect. Screening for anxiety may be beneficial to help prospectively address these concerns and ameliorate potentially detrimental impact on clinically meaningful cancer outcomes.