Longitudinal Changes in Sleep: Associations with Shifts in Circulating Cytokines and Emotional Distress in a Cancer Survivor Population.

BACKGROUND: Sleep disturbances are associated with numerous mood disorders. Similarly, anxiety and depression are associated with modulation of the psychoneuroimmune (PNI) axis. This study hypothesized that changes in both monitored and self-reported measures of sleep would relate to changes in circulating cytokine levels in an emotionally distressed population of cervical cancer survivors. METHODS: Biospecimens, patient-reported outcome (PRO) measures, and actigraphy were collected from cervical cancer survivors enrolled in a biobehavioral clinical trial. Longitudinal changes over a 4-month period were examined. Sleep time measured by actigraphy and PRO were analyzed for correlative changes with emotional distress and serum cytokines (n = 71). RESULTS: Longitudinal change in the actigraph measure of sleep time was inversely associated with changes in depression and anxiety (test for linear trend, p = 0.02 and p = 0.05 respectively), as well as acute-phase response/pro-inflammatory cytokines (test for linear trend, p = 0.003, interleukin (IL)-2; 0.022, IL-1ß; 0.0002, IL-6; and 0.049, tumor necrosis factor α). Conversely, changes in self-reported sleep problems were related to an increase in depression and anxiety (p = 0.001 and p = 0.01 respectively), the T helper 2 (Th2) cytokine IL-5 (p = 0.027), and the counter-regulatory cytokine IL-10 (0.016). CONCLUSION: This study showed that an increase in sleep time or decrease in sleep problems corresponded with a reduction in self-reported emotional distress and attenuation of pro-inflammatory, Th2, and counter-regulatory cytokines. Our results support sleep measurement as a meaningful biobehavioral variable in cancer survivorship. This study also indicates that sleep investigators should be aware that choice of methodology might influence concordance with different classes of immune parameters.

Relationship between social support, quality of life, and Th2 cytokines in a biobehavioral cancer survivorship trial.

OBJECTIVE: Benefits of social support (SS) during cancer survivorship are complex. This study examines change in SS over time in cervical cancer (CXCA) survivors who have completed definitive treatment and how changing SS impacts quality of life (QOL) and T-helper type 2 (Th2) cytokines. METHODS: We conducted a randomized trial in 204 CXCA survivors to test if psychosocial telephone counseling (PTC) could improve QOL compared to usual care (UC). Although PTC did not target SS, data were collected at baseline, 4 and 9 months post-enrollment using the Medical Outcomes Survey Social Support scale. Biospecimens were collected to investigate associations with patient-reported outcomes. Data were analyzed using multivariate linear models and stepwise regression. RESULTS: Participants' mean age was 43. PTC participants experienced increasing SS compared to UC at 4 months (PTC-UC = 5.1; p = 0.055) and 9 months (PTC-UC = 6.0; p = 0.046). Higher baseline SS and increasing SS were independently associated with improved QOL at 4 and 9 months after adjusting for patient characteristics (p < 0.05). Differences between study arms were not statistically significant. Improvements in QOL at 4 months were observed with increases in emotional/informational and tangible SS. Increasing SS predicted significant longitudinal decreases in IL-4 and IL-13 at 4 months that were larger in the PTC arm (interactions p = 0.041 and p = 0.057, respectively). CONCLUSION: Improved SS was significantly associated with improved QOL independent of patient characteristics and study arm. Decreasing Th2 cytokines with increasing SS and QOL are consistent with a biobehavioral paradigm in which modulation of the chronic stress response is associated with shifts in immune stance.

Validation of PROMIS emotional distress short form scales for cervical cancer.

OBJECTIVES: Cervical cancer patients are at high risk for emotional distress. In this study we evaluate the PROMIS emotional distress-Depression and -Anxiety Short Forms for assessing depression and anxiety in a cervical cancer population. METHODS: A 15-item questionnaire was used in a cervical cancer biobehavioral randomized clinical trial, testing psychosocial telephone counseling (PTC) against usual care (UC). It was administered to 204 patients prior to randomization, four months post-enrollment, and nine months post-enrollment, together with legacy measures of depression. The short forms were evaluated in patients participating in this study over three time points for internal consistency, convergent validity, and responsiveness to change over time. RESULTS: Overall, 45% and 47% of patients scored in the moderate to severe range for anxiety and depression, respectively. Internal consistency coefficients were ≥ 0.95 at baseline, 4 months, and 9 months for depression and anxiety. The average inter-item correlation was 0.65 and 0.73 at baseline assessment for depression and anxiety, respectively. The depression short form T-score was correlated with legacy distress scales ranging from 0.44-0.76, and the anxiety short form ranging from 0.45-0.78. The depression short form demonstrated sensitivity to change as patients randomized to the counseling intervention reported greater improvement over time in depression (p = 0.014), and a nonsignificant improvement in anxiety, compared to the patients receiving usual care. CONCLUSIONS: The PROMIS depression and anxiety short forms reliably and validly assess cervical cancer-specific emotional distress, capture salient features of distress in this population, and perform as well or better than legacy measures.

Consensus in controversy: The modified Delphi method applied to Gynecologic Oncology practice.

OBJECTIVES: To determine the degree of consensus regarding the probabilities of outcomes associated with IP/IV and IV chemotherapy. METHODS: A survey was administered to an expert panel using the Delphi method. Ten ovarian cancer experts were asked to estimate outcomes for patients receiving IP/IV or IV chemotherapy. The clinical estimates were: 1) probability of completing six cycles of chemotherapy, 2) probability of surviving five years, 3) median survival, and 4) probability of ER/hospital visits during treatment. Estimates for two patients, one with a low comorbidity index (patient 1) and the other with a moderate index (patient 2), were included. The survey was administered in three rounds, and panelists could revise their subsequent responses based on review of the anonymous opinions of their peers. RESULTS: The ranges were smaller for IV compared with IP/IV therapy. Ranges decreased with each round. Consensus converged around outcomes related to IP/IV chemotherapy for: 1) completion of 6 cycles of therapy (type 1 patient, 62%, type 2 patient, 43%); 2) percentage of patients surviving 5 years (type 1 patient, 66%, type 2 patient, 47%); and 3) median survival (type 1 patient, 83 months, type 2 patient, 58 months). The group required three rounds to achieve consensus on the probabilities of ER/hospital visits (type 1 patient, 24%, type 2 patient, 35%). CONCLUSIONS: Initial estimates of survival and adverse events associated with IP/IV chemotherapy differ among experts. The Delphi process works to build consensus and may be a pragmatic tool to inform patients of their expected outcomes.

Factors associated with poor quality of life among cervical cancer survivors: implications for clinical care and clinical trials.

INTRODUCTION: The purpose of this study is to identify factors that are associated with poor quality of life (QOL) among cervical cancer survivors. METHODS: Patients identified through the California Cancer Registry were recruited to participate in a randomized counseling intervention. Patient-reported outcomes (PROs) were collected at study baseline (9-30 months post-diagnosis) and subsequent to the intervention. Multivariable linear models were used to identify independent factors associated with poor baseline QOL. RESULTS: Non-Hispanic (N=121) and Hispanic (N=83) women aged 22-73 completed baseline measures. Approximately 50% of participants received radiation therapy with or without chemotherapy. Compared to the US population, cervical cancer patients reported lower QOL and significantly higher levels of depression and anxiety (26% and 28% >1 SD above the general population means, respectively). Among those in the lowest quartile for QOL, 63% had depression levels >1 SD above the mean. In addition, treatment with radiation±chemotherapy (p=0.014), and self-reported comorbidities predating the cancer diagnosis (p<0.001) were associated with lower QOL. Sociodemographic characteristics explained only a small portion of variance in QOL (r(2)=0.23). Persistent gynecologic problems, low social support, depression, somatization, less adaptive coping, comorbidities, sleep problems and low education were all independently associated with low QOL in multivariate analysis (r(2)=0.74). CONCLUSION: We have identified key psychological and physical health factors that contribute significantly to poor quality of life subsequent to definitive cancer treatment. The majority of these factors are amenable to supportive care interventions and should be evaluated at the time of primary treatment.

Biopsychological stress factors in BRCA mutation carriers.

OBJECTIVE: Cancer risk-related stressors are prominent among BRCA mutation carriers. Loss of one's mother to a BRCA-associated cancer is an additional stressor, which may be related to an enhanced inflammatory response. This study examined the effect of mother's vital status on psychological factors and stress-associated biomarkers among BRCA mutation carriers. The role of bereavement on biopsychological variables was also examined. METHODS: BRCA-carriers with known maternal transmission enrolled in the Gilda Radner Hereditary Cancer Program were invited to participate. Focus group composition was predetermined based on participants' personal cancer history and mother's vital status. Prior to the focus group, participants completed a Quality of Life (QOL) survey and collected a first morning saliva sample. Inflammatory biomarkers were analyzed from proximal archived serum. One day post focus group, a process survey, and morning saliva were collected. RESULTS: QOL was significantly lower for those whose mothers are deceased (n = 17) compared to those whose mothers are alive (n = 15) (P = 0.003) after adjusting for age, personal cancer history and prophylactic surgery. Similarly, those whose mothers are deceased reported significantly more perceived stress (P = 0.015), more intrusive thoughts related to cancer risk (P = 0.049), and more anxiety (P = 0.003). Higher bereavement scores were significantly associated with QOL and psychological measures. Biomarker correlates were consistent with and significantly correlated to the patient-reported psychological outcomes for those whose mothers were deceased. CONCLUSIONS: BRCA mutation carriers with a known maternal transmission whose mother is deceased report higher perceived stress and anxiety, lower QOL, and a stress-associated biomarker profile that is potentially globally immune suppressive.

Recruitment and retention results for a population-based cervical cancer biobehavioral clinical trial.

OBJECTIVE: Minority and low-income cancer patients are underrepresented in clinical trials, contributing to diminished access to state-of-the-art care and disparities in cancer outcomes including survivorship issues. In cervical cancer, there is a disproportionate disease burden among minority and underserved women and persistent quality of life disruption. We encountered significant challenges in both recruitment and retention in a randomized biobehavioral clinical trial for cervical cancer survivors, identified through California Cancer Registries, leading to this investigation. METHODS: To determine differential rates of accrual and retention, data from our trial are analyzed using descriptive statistics, logistic regression and multivariate analysis of variance. Ethnic differences in associations between covariables and attrition rates were tested by interaction factors. Process evaluation and focus group data were obtained to inform improvement strategies. RESULTS: Of eligible subjects with viable phone numbers, 29% enrolled and 71% actively or passively refused. Enrolled Hispanic women were more likely to have less education (p<0.001), lower income (p=0.003), and more children (p=0.028). The dropout rate was associated with less education (p=0.012), foreign-birth (p=0.061), speaking Spanish in the home (p=0.012). Reported reasons for active refusal were 'too busy' for all women, 'too emotional' for non-Hispanic women, 'too ill' and phlebotomy for Hispanic women. Subsequent focus groups identified specific strategies to improve study materials. CONCLUSION: Although population-based recruitment of minority and underserved cancer patients continues to be a challenge, specific sociodemographic and disease variables can predict accrual difficulties. The information herein, taken together with disease and culturally relevant strategies, can be useful when recruiting underserved cancer survivors.

Health Behaviors in Cervical Cancer Survivors and Associations with Quality of Life.

PURPOSE: Improvement in health behaviors following cancer diagnosis may contribute to better prognosis and well-being. This study examines the prevalence of health behaviors in cervical cancer survivors who have completed treatment, and associations between health behaviors and quality of life (QOL). METHODS: We recruited 204 women who had completed treatment for cervical cancer to participate in a randomized counseling intervention. Participants provided information on health behaviors (smoking, physical activity, and alcohol consumption); QOL (Functional Assessment of Cancer Therapy-Cervical questionnaire); and depression (Patient-Reported Outcomes Measurement Information System), anxiety (Patient-Reported Outcomes Measurement Information System), and distress (Brief Symptom Inventory) at baseline (9-30 months after diagnosis) and subsequent to the intervention. Data were analyzed using multivariate general linear models. FINDINGS: Participants ranged in age from 20 to 72 years at diagnosis (mean = 43 years), 41% were Hispanic, and 52% were non-Hispanic white. Three-fourths were stage 1 at diagnosis and 51% were treated with radiation with or without chemotherapy. At baseline, 15% of patients were current smokers, 4% reported alcohol consumption of >10 drinks per week, and 63% reported exercising <3 hours per week. Overall, 67.4% of cervical cancer survivors did not meet recommended national guidelines for at least 1 of these health behaviors. QOL scores were significantly higher for patients with greater physical activity (128 vs 118; P = 0.002) and increased with the number of recommended guidelines met (P for trend = 0.030). Associations between patient-reported outcomes and smoking and alcohol consumption did not reach statistical significance. Participants who met guidelines for all health behaviors also had less depression (P = 0.008), anxiety (P = 0.051), and distress (P = 0.142). Participants who improved their aggregate health behaviors during the 4-month follow-up experienced a greater improvement in QOL than those who did not improve their health behaviors (10.8 vs 4.5; P = 0.026). IMPLICATIONS: Results indicate that two-thirds of cervical cancer survivors are not meeting national guidelines for smoking, physical activity, and alcohol consumption following completion of definitive treatment. These adverse health behaviors were associated with impaired QOL and higher levels of depression and distress. Positive changes in health behaviors are associated with significant improvement in QOL.

Psychosocial telephone counseling for survivors of cervical cancer: results of a randomized biobehavioral trial.

PURPOSE: Survivors of cervical cancer experience quality-of-life (QOL) disruptions that persist years after treatment. This study examines the effect of a psychosocial telephone counseling (PTC) intervention on QOL domains and associations with biomarkers. PATIENTS AND METHODS: We conducted a randomized clinical trial in survivors of cervical cancer, who were ≥ 9 and less than 30 months from diagnosis (n = 204), to compare PTC to usual care (UC). PTC included five weekly sessions and a 1-month booster. Patient-reported outcomes (PROs) and biospecimens were collected at baseline and 4 and 9 months after enrollment. Changes in PROs over time and associations with longitudinal change in cytokines as categorical variables were analyzed using multivariable analysis of variance for repeated measures. RESULTS: Participant mean age was 43 years; 40% of women were Hispanic, and 51% were non-Hispanic white. Adjusting for age and baseline scores, participants receiving PTC had significantly improved depression and improved gynecologic and cancer-specific concerns at 4 months compared with UC participants (all P < .05); significant differences in gynecologic and cancer-specific concerns (P < .05) were sustained at 9 months. Longitudinal change in overall QOL and anxiety did not reach statistical significance. Participants with decreasing interleukin (IL) -4, IL-5, IL-10, and IL-13 had significantly greater improvement in QOL than those with increasing cytokine levels. CONCLUSION: This trial confirms that PTC benefits mood and QOL cancer-specific and gynecologic concerns for a multiethnic underserved population of survivors of cancer. The improvement in PROs with decreases in T-helper type 2 and counter-regulatory cytokines supports a potential biobehavioral pathway relevant to cancer survivorship.

Facilitating acquisition and transfer of a continuous motor task in healthy older adults and patients with Alzheimer's disease.

This study examined the acquisition and transfer of a fine motor skill, namely the rotary pursuit, in 99 patients with Alzheimer's disease (AD) and 100 normal controls (NCs). To identify optimal learning strategies, the authors had participants practice the rotary pursuit under constant, blocked, random, or no training conditions. Transfer was assessed using speeds that were different from those practiced during acquisition. AD patients and NCs receiving constant practice outperformed their peers in the blocked and random conditions during acquisition. Whereas all 3 types of practice facilitated transfer in the NCs, AD patients only benefited from constant practice. The inability of the AD patients to benefit from variable practice suggests that these individuals may have difficulty accessing and/or forming motor schemas.

Staurosporine promotes endothelial cell assembly and FAK phosphorylation during in vitro angiogenesis.

In the present study, we report that staurosporine, a known PKC inhibitor, enhanced in vitro angiogenesis. Endothelial cells plated in a three-dimensional matrix formed cords and enclosed structures within 4-6 hours. The cells in cord structures became elongated during the subsequent incubation. Tube formation was confirmed by confocal microscopy. Addition of VEGF enhanced the early responses of endothelial cells, leading to enhanced formation of cords. Staurosporine unexpectedly also enhanced the early endothelial responses, leading to faster alignment of cells and assembly into tube-like structures. At concentrations inhibitory to endothelial cell PKC activity, staurosporine produced 91% and 203% increases in the number of cords and the enclosed structures, respectively, as compared to the controls. Other selective inhibitors of PKC did not stimulate in vitro angiogenesis in the absence or presence of VEGF. Further investigation showed that inhibition of PI-3 kinase and Raf-1 significantly reduced the effects of staurosporine. Staurosporine-induced in vitro angiogenesis required integrins alpha2 and alphavbeta3 and was associated with significantly enhanced FAK phosphorylation. These data indicate that staurosporine enhances in vitro angiogenesis by a means unrelated to its PKC inhibition. The data suggest that enhancement of in vitro angiogenesis by staurosporine involves integrin-mediated signaling, including the stimulation of FAK phosphorylation.