Jamie M. Stagl

Cognitive-Behavioral Stress Management Reverses Anxiety-Related Leukocyte Transcriptional Dynamics

BACKGROUND Chronic threat and anxiety are associated with pro-inflammatory transcriptional profiles in circulating leukocytes, but the causal direction of that relationship has not been established. This study tested whether a cognitive-behavioral stress management (CBSM) intervention targeting negative affect and cognition might counteract anxiety-related transcriptional alterations in people confronting a major medical threat. METHODS One hundred ninety-nine women undergoing primary treatment of stage 0-III breast cancer were randomized to a 10-week CBSM protocol or an active control condition. Seventy-nine provided peripheral blood leukocyte samples for genome-wide transcriptional profiling and bioinformatic analyses at baseline, 6-month, and 12-month follow-ups. RESULTS Baseline negative affect was associated with >50% differential expression of 201 leukocyte transcripts, including upregulated expression of pro-inflammatory and metastasis-related genes. CBSM altered leukocyte expression of 91 genes by >50% at follow-up (group × time interaction), including downregulation of pro-inflammatory and metastasis-related genes and upregulation of type I interferon response genes. Promoter-based bioinformatic analyses implicated decreased activity of NF-κB/Rel and GATA family transcription factors and increased activity of interferon response factors and the glucocorticoid receptor as potential mediators of CBSM-induced transcriptional alterations. CONCLUSIONS In early-stage breast cancer patients, a 10-week CBSM intervention can reverse anxiety-related upregulation of pro-inflammatory gene expression in circulating leukocytes. These findings clarify the molecular signaling pathways by which behavioral interventions can influence physical health and alter peripheral inflammatory processes that may reciprocally affect brain affective and cognitive processes.

Long-term psychological benefits of cognitive-behavioral stress management for women with breast cancer: 11-year follow-up of a randomized controlled trial.

Breast cancer survivors experience long‐term physical and psychological sequelae after their primary treatment that negatively influence their quality of life (QOL) and increase depressive symptoms. Group‐based cognitive‐behavioral stress management (CBSM) delivered after surgery for early‐stage breast cancer was previously associated with better QOL over a 12‐month follow‐up and with fewer depressive symptoms up to 5 years after study enrollment. This 8‐ to 15‐year follow‐up (median, 11 years) of a previously conducted trial (NCT01422551) evaluated whether women in this cohort receiving CBSM had fewer depressive symptoms and better QOL than controls at an 8‐ to 15‐year follow‐up.

A Systematic Review of Adherence to Oral Antineoplastic Therapies

BACKGROUND Oral antineoplastic therapies not only improve survival but also reduce the burden of care for patients. Yet patients and clinicians face new challenges in managing adherence to these oral therapies. We conducted a systematic literature review to assess rates and correlates of adherence to oral antineoplastic therapies and interventions aimed at improving adherence. METHODS Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we conducted a comprehensive literature search of the Ovid MEDLINE database from January 1, 2003 to June 30, 2015, using relevant terminology for oral antineoplastic agents. We included observational, database, and intervention studies. At least two researchers evaluated each paper to ensure accuracy of results and determine risk of bias. RESULTS We identified 927 records from the search and screened 214 abstracts. After conducting a full-text review of 167 papers, we included in the final sample 51 papers on rates/correlates of adherence to oral antineoplastic therapy and 12 papers on intervention studies to improve adherence. Rates of adherence varied widely, from 46% to 100%, depending on patient sample, medication type, follow-up period, assessment measure, and calculation of adherence. Of the intervention studies, only 1 of the randomized trials and 2 of the cohort studies showed benefit regarding adherence, with the majority suffering high risk of bias. CONCLUSIONS Although no reliable estimate of adherence to oral antineoplastic therapies can be gleaned from the literature, a substantial proportion of patients struggle to adhere to these medications as prescribed. The few intervention studies for adherence have notable methodological concerns, thereby limiting the evidence to guide practice in promoting medication adherence among patients with cancer.

The relationship between coping strategies, quality of life, and mood in patients with incurable cancer.

Patients with incurable cancer face many physical and emotional stressors, yet little is known about their coping strategies or the relationship between their coping strategies, quality of life (QOL), and mood.

NCCAM/NCI Phase 1 Study of Mistletoe Extract and Gemcitabine in Patients with Advanced Solid Tumors

Purpose. European Mistletoe (Viscum album L.) extracts (mistletoe) are commonly used for cancer treatment in Europe. This phase I study of gemcitabine (GEM) and mistletoe in advanced solid cancers (ASC) evaluated: (1) safety, toxicity, and maximum tolerated dose (MTD), (2) absolute neutrophil count (ANC) recovery, (3) formation of mistletoe lectin antibodies (ML ab), (4) cytokine plasma concentrations, (5) clinical response, and (6) pharmacokinetics of GEM. Methods. Design: increasing mistletoe and fixed GEM dose in stage I and increasing doses of GEM with a fixed dose of mistletoe in stage II. Dose limiting toxicities (DLT) were grade (G) 3 nonhematologic and G4 hematologic events; MTD was reached with 2 DLTs in one dosage level. Response in stage IV ASC was assessed with descriptive statistics. Statistical analyses examined clinical response/survival and ANC recovery. Results. DLTs were G4 neutropenia, G4 thrombocytopenia, G4 acute renal failure, and G3 cellulitis, attributed to mistletoe. GEM 1380 mg/m2 and mistletoe 250 mg combined were the MTD. Of 44 patients, 24 developed nonneutropenic fever and flu-like syndrome. GEM pharmacokinetics were unaffected by mistletoe. All patients developed ML3 IgG antibodies. ANC showed a trend to increase between baseline and cycle 2 in stage I dose escalation. 6% of patients showed partial response, 42% stable disease. Median survival was 200 days. Compliance with mistletoe injections was high. Conclusion. GEM plus mistletoe is well tolerated. No botanical/drug interactions were observed. Clinical response is similar to GEM alone.

Brief cognitive-behavioral and relaxation training interventions for breast cancer: A randomized controlled trial

OBJECTIVE Women with breast cancer (BCa) report elevated distress postsurgery. Group-based cognitive-behavioral stress management (CBSM) following surgery improves psychological adaptation, though its key mechanisms remain speculative. This randomized controlled dismantling trial compared 2 interventions featuring elements thought to drive CBSM effects: a 5-week cognitive-behavioral training (CBT) and 5-week relaxation training (RT) versus a 5-week health education (HE) control group. METHOD Women with stage 0-III BCa (N = 183) were randomized to CBT, RT, or HE condition 2-10 weeks postsurgery. Psychosocial measures were collected at baseline (T1) and postintervention (T2). Repeated-measures analyses of variance (ANOVAs) tested whether CBT and RT treatments improved primary measures of psychological adaptation and secondary measures of stress management resource perceptions from pre- to postintervention relative to HE. RESULTS Both CBT and RT groups reported reduced depressive affect. The CBT group reported improved emotional well-being/quality of life and less cancer-specific thought intrusions. The RT group reported improvements on illness-related social disruption. Regarding stress management resources, the CBT group reported increased reliability of social support networks, while the RT group reported increased confidence in relaxation skills. Psychological adaptation and stress management resource constructs were unchanged in the HE control group. CONCLUSIONS Nonmetastatic breast cancer patients participating in 2 forms of brief, 5-week group-based stress management intervention after surgery showed improvements in psychological adaptation and stress management resources compared with an attention-matched control group. Findings provide preliminary support suggesting that using brief group-based stress management interventions may promote adaptation among nonmetastatic breast cancer patients.

Randomized controlled trial of cognitive behavioral stress management in breast cancer: a brief report of effects on 5-year depressive symptoms.

OBJECTIVE Survivors of breast cancer experience stress and are at risk for depressive symptoms following primary treatment. Group-based interventions such as cognitive-behavioral stress management (CBSM) delivered postsurgery for nonmetastatic breast cancer (BCa) were previously associated with fewer depressive symptoms over a 12-month follow-up; few studies have examined the longer-term benefits of such psychosocial interventions. This 5-year follow-up study of a previously conducted trial (#NCT01422551) tested whether group-based CBSM following surgery for nonmetastatic BCa was associated with fewer depressive symptoms. METHODS Women (N = 240) with Stage 0-IIIb BCa were recruited 2-10 weeks postsurgery and randomized to a 10-week CBSM intervention group or a 1-day psycho-educational control group. Women were recontacted 5 years poststudy enrollment and reconsented to participate in the follow-up study (N = 130). Depressive symptomatology was assessed using the Center for Epidemiologic Studies-Depression scale (CES-D). ANOVA and ANCOVA analyses were employed to test for group differences on the CES-D at 5-year follow-up accounting for relevant covariates. RESULTS Participants assigned to CBSM reported significantly fewer depressive symptoms (M = 9.99, SE = 0.93) at the follow-up compared with those in the control group (M = 12.97, SE = 0.99), p = .030. With covariates, the group difference remained significant, p = .012. CONCLUSION Women who received CBSM postsurgery for BCa reported fewer depressive symptoms than those in the control group in this 5-year follow-up. Psychosocial interventions early in treatment may influence long-term psychological well-being in BCa survivors.

Postsurgical Depressive Symptoms and Proinflammatory Cytokine Elevations in Women Undergoing Primary Treatment for Breast Cancer

Objective Depression and inflammation may independently promote breast cancer (BCa) disease progression and poorer clinical outcomes. Depression has been associated with increased levels of inflammatory markers in medically healthy individuals and patients with cancer. However, inconsistencies in study time frames complicate interpretation of results within specific cancer types. This study examined relationships between depressive symptoms and inflammation in women with early-stage BCa before beginning adjuvant treatment. Methods Women with Stage 0-III BCa were recruited approximately 4 to 8 weeks after surgery. Depressive symptoms were assessed using the Hamilton Rating Scale for Depression, and blood samples were collected to quantify circulating levels of interleukin (IL)-1&bgr;, IL-6, and tumor necrosis factor &agr; (TNF-&agr;) by enzyme-linked immunosorbent assay. Analyses of covariance were used to test for group differences (elevated versus low depressive symptoms) in levels of cytokines. Multiple regression analyses were used to examine relationships between continuous severity of depressive symptoms and levels of cytokines adjusting for relevant biobehavioral covariates. Results Thirty-six (40%) of 89 patients showed elevated levels of depressive symptoms and, in adjusted models, had marginally higher levels of IL-1&bgr; (mean [M] = 14.49 [95% confidence interval {CI} = 6.11–32.65] versus M = 4.68 [95% CI = 1.96–9.86] and IL-6 [M = 88.74 {95% CI = 33.28–233.96} versus M = 61.52 {95% CI = 27.44–136.40}]) significantly higher levels of TNF-&agr; (M = 17.07 [95% CI = 8.27–34.32] versus M = 6.94 [95% CI = 3.58–12.80]) than did women with low depressive symptoms. Across the spectrum of depressive symptoms, greater magnitude of depressive symptoms was related to greater levels of IL-1&bgr; (&bgr; = 0.06, p = .006, R2 = 0.25) and TNF-&agr; (&bgr; = 0.06, p = .003, R2 = 0.27). Conclusions Postsurgery and preadjuvant treatment for early-stage BCa, depressive symptoms covary with elevated levels of multiple proinflammatory cytokines. Findings have implications for psychosocial and biological interventions concurrently focusing on depression and inflammation. Trial Registration: NCT01422551.

Postsurgical physical activity and fatigue-related daily interference in women with non-metastatic breast cancer.

Purpose: Women undergoing surgery for breast cancer experience side effects, such as fatigue, reduced quality of life (QOL) and depression. Physical activity (PA) is associated with improved psychological adjustment during treatment and survivorship, yet little is known about how PA relates to fatigue, depression and QOL in the period following surgery for breast cancer. The purpose of the study was to examine the relationships between these constructs in women who recently underwent surgery for breast cancer. Methods: At 2–10 weeks post-surgery, 240 women with non-metastatic breast cancer reported intensity and duration of moderate and vigorous PA (MVPA), fatigue (intensity and interference), depressed mood, clinician-rated depression and functional QOL. Results: In the path analysis models tested, women that reported greater weekly MVPA reported less fatigue interference, greater functional QOL, less depressed mood, and lower clinician-rated depression. Tests of indirect effects suggested that fatigue interference may be an intermediate pathway by which MVPA relates to functional QOL, clinician-rated depression and depressed mood. Conclusion: Women who are more physically active in the months after breast cancer surgery show greater psychological adaptation in the initial phases of their treatment.

Ethnic differences in types of social support from multiple sources after breast cancer surgery

ABSTRACT Objectives. Diagnosis of and treatment for breast cancer (BCa) may require psychological adaptation and often involve heightened distress. Several types of social support positively relate to psychological adaptation to BCa, and negative support is associated with poorer adaptation. Although Hispanic women report greater distress than non-Hispanic White (NHW) women after diagnosis of BCa, no studies have examined ethnic differences in types of social support received from varying sources after surgery for BCa. Design. Hispanic (N = 61) and NHW (N = 150) women diagnosed with early-stage BCa self-reported emotional, informational, instrumental, and negative support from five sources. Ethnic differences in levels of social support were compared using multiple regression analysis. Results. When controlling for age, income, days since surgery, and stage of disease in multivariable models there were no ethnic differences in levels of emotional support from any source. Hispanic women reported greater informational support from adult women family members and children and male adult family members than did NHW women. Instrumental support from adult women family members was also greater among Hispanic than NHW women. Hispanic women reported higher negative support from husbands/partners and from children and male adult family members. When the number of years in the USA was controlled, Hispanic women showed greater informational support from adult women family members, children and male adult family members, and friends. Instrumental support from adult women family members remained greater in Hispanic women, but negative support no longer differed. Conclusion. Family is a greater source of informational and instrumental support for Hispanic than NHW women. Hispanic women reported higher negative support from male sources than did NHW women. Level of support from different sources may also depend on time spent in the USA. Longitudinal studies are needed to determine whether patterns and sources of social support shift over the course of BCa treatment.