Effects of a Cognitive Behavioral Digital Therapeutic on Anxiety and Depression Symptoms in Patients With Cancer: A Randomized Controlled Trial.

PURPOSE: Patients with cancer often experience elevated levels of distress. This double-blind, randomized controlled trial compared the impact of an app-based version of cognitive behavioral stress management (CBSM) versus a health education sham app on anxiety and depression symptoms. METHODS: Patients with nonmetastatic (stage I-III) cancer who were receiving or recently completed (≤6 months) systemic treatment were recruited nationwide. The primary outcome of change in anxiety symptoms (PROMIS-Anxiety) over 12 weeks and the top secondary outcome of change in depression symptoms (PROMIS-Depression) over 12 weeks were analyzed using mixed-effects modeling with repeated measures (weeks 0, 4, 8, 12). Patient global impressions of change in anxiety and depression were reported at weeks 4, 8, and 12. In addition, self-reported adverse events were collected throughout the study and adjudicated by the site principal investigator. RESULTS: Four hundred forty-nine patients were enrolled in the trial (age M [standard deviation] = 52.44 [11.46]; 81% female; 76% White; 53% breast cancer). Patients randomly assigned to digitized CBSM showed significantly greater reductions in anxiety (B = -0.03; P = .019) and depression (B = -0.02; P = .042) symptoms over 12 weeks. Patients who received digitized CBSM were also significantly more likely to perceive much or very much improvement (v no/minimal change or much/very much worse) in their symptoms of anxiety (χ2 = 31.76; P < .001) and depression (χ2 = 19.70; P < .001) compared with the control. CONCLUSION: The use of digitized CBSM led to significant improvements in anxiety and depression outcomes compared with the sham app.

Effectiveness and implementation of an electronic health record-integrated digital health intervention for managing depressive symptoms in ambulatory oncology: The My Well-Being Guide study rationale and protocol.

BACKGROUND: Rates of clinically elevated depressive symptoms among ambulatory oncology patients are higher than in the general population and are associated with poorer health-related quality of life. Furthermore, a reduction in depressive symptoms may be associated with improved cancer survival. Several interventions have demonstrated efficacy in reducing oncologic depressive symptoms, including cognitive-behavioral stress management (CBSM). However, more work is needed to understand how to best implement CBSM into practice, such as through stepped-care approaches and digital health interventions linked to electronic health records (EHR). This manuscript presents the protocol of the My Well-Being Guide study, a pragmatic type 1 effectiveness-implementation hybrid study. This trial will test the effectiveness of My Well-Being Guide, a seven-week structured, CBSM-based digital health intervention designed to reduce depressive symptoms. This trial will also evaluate My Well-Being Guide's implementation across two health systems. METHODS: The final sample (N = 4561) will be oncology patients at Northwestern Medicine or University of Miami Health System who are ≥18 years of age; have a cancer diagnosis; elevated depressive symptoms on the Patient-Reported Outcomes Measurement Information System Depression; and primary language is English or Spanish. Data collection will occur at baseline, and 2-, 6-, and 12-months post baseline. Outcome domains include depressive symptoms and implementation evaluation. DISCUSSION: This study may provide valuable data on the effectiveness of our depressive symptom management digital health intervention linked to the EHR and the scalability of digital health interventions in general.

Stem Cell Transplant Experiences Among Hispanic/Latinx Patients: A Qualitative Analysis.

BACKGROUND: Hispanic/Latinx (H/L) patients with cancer treated with stem cell transplant are vulnerable to adverse outcomes, including higher mortality. This study explored their unmet transplant needs, barriers, and facilitators. METHODS: Eighteen English- or Spanish-speaking H/L patients (M age = 59.2) who had a transplant in the past year were interviewed about their transplant experience and rated their interest in receiving information about transplant topics (0 = not at all to 10 = extremely). RESULTS: Content analysis revealed five main themes: (1) pre-transplant barriers and concerns; (2) complex relationships with medical teams; (3) informational mismatch; (4) impacts on daily life after transplant; and (5) methods of coping. Participants were most interested in information about ways of coping with transplant (M = 9.11, SD = 1.45) and words of hope and encouragement (M = 9.05, SD = 1.80). At just above the scale's midpoint, they were least interested in information about side effects and unintended consequences of transplant (M = 5.61, SD = 3.85). CONCLUSIONS: Cultural factors, social determinants, and structural inequalities give rise to unique needs in this growing patient population. Healthcare team members and researchers can better meet the needs of H/L transplant recipients through attention to described considerations, such as financial barriers, communication difficulties, family dynamics, and coping styles.

Relationships Between Serum Cortisol, RAGE-Associated s100A8/A9 Levels, and Self-Reported Cancer-Related Distress in Women With Nonmetastatic Breast Cancer.

OBJECTIVE: Elevated inflammation and psychological distress in patients with breast cancer (BCa) have been related to poorer health outcomes. Regulation of the hypothalamic-pituitary-adrenal axis and signaling of the receptor for advanced glycation end products (RAGE) are important in the inflammatory response and have been associated with increased stress and poorer health outcomes in patients with cancer. This study examined relationships among circulating cortisol, a measure of hypothalamic-pituitary-adrenal axis activity and physiological stress; s100A8/A9, a RAGE ligand and emerging cancer-related biological measure; and self-reported cancer-related distress. METHODS: Patients with BCa ( N = 183, stages 0-IIIb) were recruited 2 to 10 weeks after surgery but before receiving adjuvant therapies. Participants provided blood samples, from which serum cortisol and s100A8/A9 levels were determined, and completed a psychosocial questionnaire. Regression analyses, adjusting for age, cancer stage, time since surgery, race, and menopausal status, were conducted examining the relationships between cortisol, s100A8/A9, and cancer-related distress (Impact of Event Scale [IES]-Revised). RESULTS: Cortisol and s100A8/A9 levels were positively related ( ß = 0.218, t (112) = 2.332, p = .021), although the overall model was not significant. Cortisol levels were also positively associated with IES-Intrusions ( ß = 0.192, t (163) = 2.659, p = .009) and IES-Hyperarousal subscale scores ( ß = 0.171, t (163) = 2.304, p = .022). CONCLUSIONS: Patients with higher cortisol levels also reported higher s100A8/A9 levels and more cancer-related distress. The relationship between cortisol and s100A8/A9 supports a link between the stress response and proinflammatory physiological processes known to predict a greater metastatic risk in BCa. Stress processes implicated in cancer biology are complex, and replication and extension of these initial findings are important.

Does the Broaden-and-Build Theory Explain Reduction in Social Disruption After a Brief Relaxation Intervention for Women With Breast Cancer Undergoing Treatment?

Women with breast cancer experience social disruption during and after treatment. Brief cognitive-behavioral (CBT) and relaxation (RT) interventions may improve social disruption by increasing positive affect. Using the Broaden-and-Build Theory as a framework, this study examined whether short-term CBT- and RT-related increases in positive affect mediate long-term reductions in social disruption in women with breast cancer undergoing treatment (N = 183). This secondary analysis used latent change score and growth models to test 6- and 12-month intervention effects on positive affect and social disruption, respectively; a parallel-process model assessed mediation. RT demonstrated larger reductions in social disruption across 12 months compared to CBT and a health education control. Six-month latent change in positive affect was significant but not driven by condition. There was a significant direct effect linking the latent slopes of positive affect and social disruption but meditation was not observed. These preliminary findings hint at the value of promoting positive affect and inform the development of brief behavioral interventions that aim to augment social functioning among women surviving breast cancer.

Effects of brief stress management interventions on distress and leukocyte nuclear factor kappa B expression during primary treatment for breast cancer: A randomized trial.

BACKGROUND: A randomized controlled trial (RCT) of 5-week stress management interventions teaching cognitive behavioral therapy (CBT) or relaxation training (RT) techniques showed decreases in stress and serum inflammatory markers over 12 months in women undergoing treatment for breast cancer (BCa). To understand the molecular mechanisms involved, we examined the effects of these interventions on the transcription factor NF-κB DNA binding activity in leukocytes in parallel with circulating inflammatory markers, stress management skill efficacy and multiple distress indicators. METHODS: This is a secondary analysis using blood samples of 51 BCa patients (Stage 0-III) with high cancer-specific distress selected from a completed RCT (NCT02103387). Women were randomized to one of three conditions, CBT, RT or health education control (HE). Blood samples and self-reported distress measures (Affects Balance Scale-Negative Affect [ABS-NA], Impact of Events Scale-hyperarousal [IES-H] and intrusive thoughts [IES-I]) were collected at baseline (T0) and 12-month follow-up (T2). Self-reported distress measures and perceived stress management skills (PSMS) were also measured immediately post-intervention (baseline + 2 months: T1). Repeated measures analyses compared changes in distress and NF-κB expression among conditions, controlling for age, stage of cancer, days from surgery to baseline, and receipt of chemotherapy and radiation. Regression analyses related T0 to T2 change in NF-κB expression with T0 to T1 changes in self-reported PSMS and distress measures. Exploratory regression analyses also associated change in NF-κB expression with change in serum cytokines (IL-1ß, IL-6 and TNF-α); and s100A8/A9, a circulating inflammatory marker important in breast cancer progression. RESULTS: There was a significant condition (CBT/RT, HE)xtime (T0, T2) effect on NF-κB, F(1, 39)= 5.267, p = 0.036, wherein NF-κB expression significantly increased over time for HE but did not change for RT or CBT. Greater increases in PSMS from T0 to T1 were associated with less increase in NF-κB expression over 12 months (ß = -0.426, t(36) = -2.637, p = 0.048). We found that women assigned to active intervention (CBT/RT) had significant decreases in ABS-NA (F(1, 40)= 6.537, p = 0.028) and IES-I (F(1, 40)= 4.391, p = 0.043) from T0 to T1 compared to women assigned to HE, who showed no change over time (p's > 0.10). For women assigned to CBT or RT, lower NF-κB expression at T2 was related to less ABS-NA, IES-H, and IES-I, all p's < 0.05, although T0-T1 change in distress was not related to T0-T2 change in NF-κB expression for those in an active intervention. CONCLUSIONS: Brief CBT or RT stress management interventions can mitigate increases in pro-inflammatory leukocyte NF-κB binding over 12 months of primary treatment in highly distressed BCa patients. These effects are likely brought about by improved stress management skills.

Greater Post-Surgical Pain Predicts Long-Term Depressed Affect in Breast Cancer Patients: The Role of Coping.

Background: Depressed affect is observed during primary treatment for early-stage breast cancer and often persists into survivorship. Pain can influence the long-term emotions of women with breast cancer. Behavioral mechanisms explaining this relationship are less clear. Coping during primary treatment may play a role in the association between pain and depressed affect. Aims: Our observational study examined a longitudinal mediation model testing whether post-surgical pain intensity predicted depressed affect 5 years later via disengagement and/or engagement coping at the end of treatment. Method: Women (N = 240) with stage 0-III breast cancer completed measures of pain, coping, and depressed affect 4-10 weeks post-surgery, and 12 months and 5 years later. Results: Structural modeling yielded measurement models of 12-month disengagement and engagement coping. Direct effects emerged between post-surgical pain intensity and 12-month disengagement (ß = .37, p < .001) and engagement coping (ß = .16, p < .05). Post-surgical pain intensity was also related to 5-year depressed affect (ß = .25, p < .05). Disengagement and engagement coping were not associated with depressed affect at 5-year follow-up, and there was no evidence of mediation. Limitations: This is a secondary analysis of data from a trial conducted several years ago, and may not generalize due to a homogenous sample with attrition at long-term follow-up. Conclusions: Greater post-surgical pain intensity predicts more disengagement and engagement coping at the end of primary treatment, as well as depressed affect during survivorship. Managing post-surgical pain may influence the emotions of survivors of breast cancer up to 5 years later, possibly through coping or non-coping processes.

Self-reported traumatic etiology of pain and psychological function in tertiary care pain clinic patients: a collaborative health outcomes information registry (CHOIR) study.

Background and aims A sizable body of research has elucidated the significant role of psychological reactions to trauma on pain coping and outcomes. In order to best inform intervention development and clinical care for patients with both trauma and pain at the tertiary care level, greater clarity is needed regarding the magnitude of these effects and the specific pathways through which they may or may not function at the time of first presentation to such a treatment setting. To achieve this, the current study examined the cross-sectional relationships between traumatic etiology of pain, psychological distress (anger, depressive symptoms, and PTSD symptoms), and pain outcomes (pain catastrophizing, physical function, disability status). Methods Using a structural path modeling approach, analyses were conducted using a large sample of individuals with chronic pain (n = 637) seeking new medical evaluation at a tertiary pain management center, using the Collaborative Health Outcomes Information Registry (CHOIR). We hypothesized that the relationships between traumatic etiology of pain and poorer pain outcomes would be mediated by higher levels of psychological distress. Results Our analyses revealed modest relationships between self-reported traumatic etiology of pain and pain catastrophizing, physical function, and disability status. In comparison, there were stronger relationships between indices of psychological distress and pain catastrophizing, but a weaker pattern of associations between psychological distress and physical function and disability measures. Conclusions To the relatively small extent that self-reported traumatic etiology of pain correlates with pain-related outcomes, these relationships appear to be due primarily to the presence of psychiatric symptoms and manifest most notably in the context of psychological responses to pain (i.e. catastrophizing about pain). Implications Findings from this study highlight the need for early intervention for patients with traumatic onset of pain and for clinicians at tertiary pain centers to include more detailed assessments of psychological distress and trauma as a component of comprehensive chronic pain treatment.

The effects of a randomized trial of brief forms of stress management on RAGE-associated S100A8/A9 in patients with breast cancer undergoing primary treatment.

BACKGROUND: Women with breast cancer (BCa) experience heightened distress, which is related to greater inflammation and poorer outcomes. The s100 protein family facilitates the inflammatory response by regulating myeloid cell function through the binding of Toll-like receptor 4 and the receptor for advanced glycation end products (RAGE). The heterodimer s100A8/A9 RAGE ligand is associated with hastened tumor development and metastasis. Previously, a 10-week stress-management intervention using cognitive behavioral therapy (CBT) and relaxation training (RT) was associated with less leukocyte inflammatory gene expression in patients with BCa; however, its impact on s100A8/A9 was not examined. Because a 10-week intervention may be impractical during primary treatment for BCa, the authors developed briefer forms of CBT and RT and demonstrated their efficacy in reducing distress over 12 months of primary treatment. Here, the effects of these briefer interventions were tested effects on s100A8/A9 levels over the initial 12 months of BCa treatment. METHODS: Postsurgical patients with BCa (stage 0-IIIB) were randomized to a 5-week, group-based condition: CBT, RT, or health education control (HE). At baseline and at 12 months, women provided sera from which s100A8/A9 levels were determined using any enzyme-linked immunosorbent assay. RESULTS: Participants (mean age ± standard deviation, 54.81 ± 9.63 years) who were assigned to either CBT (n = 41) or RT (n = 38) had significant s100A8/A9 decreases over 12 months compared with those who were assigned to HE (n = 44; F[1,114]  = 4.500; P = .036) controlling for age, stage, time since surgery, and receipt of chemotherapy or radiation. Greater increases in stress-management skills from preintervention to postintervention predicted greater reductions in s100A8/A9 levels over 12 months (ß = -0.379; t[101]  = -4.056; P < .001). CONCLUSIONS: Brief, postsurgical, group-based stress management reduces RAGE-associated s100A8/A9 ligand levels during primary treatment for BCa.

How changes in physical activity relate to fatigue interference, mood, and quality of life during treatment for non-metastatic breast cancer.

OBJECTIVE: Physical activity (PA) following surgery for breast cancer may improve depressive symptoms and quality of life (QoL) via reduction in fatigue-related daily interference (FRDI). Less is known about how change in PA may relate to these psychosocial factors throughout the course of treatment. In a secondary analysis of a previous psychosocial intervention trial, we examined relationships between change in PA, depressive symptoms, and functional QoL, as mediated by change in FRDI, and whether naturally occurring change in PA provided benefit independent of the intervention. METHOD: Women (N=240) with non-metastatic stage 0-III breast cancer were randomized to cognitive-behavioral stress management (CBSM) or a control 2-10weeks post-surgery. PA, FRDI, clinician-rated depressive symptoms, self-reported depressed mood, and functional QoL were assessed at baseline and three months post-intervention. RESULTS: Increased PA was associated with reductions in clinician-rated depressive symptoms, depressed mood, and improved QoL, mediated by a reduction in FRDI. This was above and beyond the effect of CBSM. CONCLUSIONS: Increased PA may mitigate FRDI and improve depressive symptoms and functional QoL for women undergoing breast cancer treatment, beyond effects of a psychosocial intervention. Benefits of an integrated PA and psychosocial approach should be investigated further.

Development and Validation of a Daily Pain Catastrophizing Scale.

To date, there is no validated measure for pain catastrophizing at the daily level. The Pain Catastrophizing Scale (PCS) is widely used to measure trait pain catastrophizing. We sought to develop and validate a brief, daily version of the PCS for use in daily diary studies to facilitate research on mechanisms of catastrophizing treatment, individual differences in self-regulation, and to reveal the nuanced relationships between catastrophizing, correlates, and pain outcomes. After adapting the PCS for daily use, we evaluated the resulting 14 items using 3 rounds of cognitive interviews with 30 adults with chronic pain. We refined and tested the final daily PCS in 3 independent, prospective, cross-sectional, observational validation studies conducted in a combined total of 519 adults with chronic pain who completed online measures daily for 14 consecutive days. For study 1 (N = 131), exploratory factor analysis revealed adequate fit and-unexpectedly-unidimensionality for item responses to the daily PCS. Study 2 (N = 177) correlations indicated adequate association with related constructs (anger, anxiety, pain intensity, depression). Similarly, results for study 3 (N = 211) revealed expected correlations for daily PCS and measures of daily constructs including physical activity, sleep, energy level, and positive affect. Results from complex/multilevel confirmatory factor analysis confirmed good fit to a unidimensional model. Scores on the daily PCS were statistically comparable with and more parsimonious than the full 14-item version. Next steps include evaluation of score validity in populations with medical diagnoses, greater demographic diversity, and in patients with acute pain. PERSPECTIVE: This article describes the development and validation of a daily PCS. This daily measure may facilitate research that aims to characterize pain mechanisms, individual differences in self-regulation, adaptation, and nuanced relationships between catastrophizing, correlates, and pain outcomes.

Effects of a Pain Catastrophizing Induction on Sensory Testing in Women with Chronic Low Back Pain: A Pilot Study.

Pain catastrophizing, a pattern of negative cognitive-emotional responses to actual or anticipated pain, maintains chronic pain and undermines response to treatments. Currently, precisely how pain catastrophizing influences pain processing is not well understood. In experimental settings, pain catastrophizing has been associated with amplified pain processing. This study sought to clarify pain processing mechanisms via experimental induction of pain catastrophizing. Forty women with chronic low back pain were assigned in blocks to an experimental condition, either a psychologist-led 10-minute pain catastrophizing induction or a control (10-minute rest period). All participants underwent a baseline round of several quantitative sensory testing (QST) tasks, followed by the pain catastrophizing induction or the rest period, and then a second round of the same QST tasks. The catastrophizing induction appeared to increase state pain catastrophizing levels. Changes in QST pain were detected for two of the QST tasks administered, weighted pin pain and mechanical allodynia. Although there is a need to replicate our preliminary results with a larger sample, study findings suggest a potential relationship between induced pain catastrophizing and central sensitization of pain. Clarification of the mechanisms through which catastrophizing affects pain modulatory systems may yield useful clinical insights into the treatment of chronic pain.

Sertoli cell-specific deletion of the androgen receptor compromises testicular immune privilege in mice.

In the mammalian testis, meiotic and postmeiotic germ cell antigens are granted immune privilege. Both local immune suppression and specialized intercellular junctions between somatic Sertoli cells have been proposed to contribute to a highly restricted and effective blood-testis barrier (BTB) that helps maintain tolerance to germ cell antigens. Several studies have suggested that androgens play a role in immune suppression, although direct evidence for this is lacking. We previously reported that Sertoli cell-specific ablation of the androgen receptor (Ar) decreases expression of Cldn3, an androgen-regulated gene and component of Sertoli cell tight junctions, and increases the permeability of the BTB to biotin, a small-molecular-weight tracer. The physiological consequences of Sertoli cell-specific Ar (S-Ar) ablation on immune privilege are unknown. Here we show that in the testes of S-Ar mutant mice, the ultrastructure of Sertoli cell tight junctions is defective and testicular IgG levels are elevated. The interstitium of S-Ar mutant testes becomes populated with macrophages, neutrophils, plasma cells, and eosinophils, and serum samples of mutant mice contain antibodies against germ cell antigens. Together, these results suggest that Sertoli cell-specific deletion of the androgen receptor results in loss of testicular immune privilege. Suppressed levels of androgen signaling may be a contributing factor in idiopathic male infertility.