Depression and anxiety in colorectal cancer patients: Ties to pain, fatigue, and inflammation.

OBJECTIVE: Colorectal cancer poses a significant threat to both psychological and physical health. This study examined relationships between anxiety and depressive symptoms with pain, fatigue, and inflammation among colorectal patients. METHODS: Colorectal cancer patients (n = 88, stages 0-IV) completed a laboratory-based study visit before undergoing adjuvant cancer treatment. Patients completed questionnaires assessing depressive, anxiety, pain, and fatigue symptoms. A blood sample was also collected to measure c-reactive protein (CRP). Analyses controlled for age, sex, cancer stage, body mass index (BMI), and menopause status. RESULTS: Multiple linear regression analyses showed colorectal patients with higher depressive and anxiety symptoms had greater pain, fatigue, and CRP (ps < 0.03). Approximately one-third of patients with clinically significant depressive (CESD >16) and anxiety symptoms (BAI >16) also had clinically-elevated levels of CRP (>3 mg/L) (ps = 0.02). CONCLUSION: These results extend findings from other cancer subgroups showing heightened symptom burden among patients with depression and anxiety. They also highlight the detrimental role that elevated anxiety and depressive symptoms may play in the physical and biological side effects associated with colorectal cancer.

The gut connection: Intestinal permeability as a pathway from breast cancer survivors' relationship satisfaction to inflammation across treatment.

BACKGROUND: Breast cancer survivors are prone to weakened gut barriers, allowing bacteria to migrate into the blood stream. Gut permeability fuels inflammation, which, among survivors, can elevate risk for comorbid disease development, cancer recurrence, and a poor quality of life; however, survivors' satisfying relationships can provide health benefits. This longitudinal study used a conceptual model addressing how intimate relationships is associated with health through changes in gut permeability and inflammation. METHOD: Breast cancer survivors (n = 139, stages 0-IIIC) completed a baseline visit before treatment and two follow-up visits 6 and 18 months after treatment ended. Women who had an abnormal breast cancer test followed by a benign diagnosis completed visits within a comparable timeframe (noncancer patient controls; n = 69). All women completed questionnaires assessing their relationship satisfaction and provided blood samples to assess two bacterial endotoxin biomarkers, lipopolysaccharide-binding protein (LBP) and soluble CD14 (sCD14), as well as C-reactive protein (CRP) and interleukin 6 (IL-6). RESULTS: Within-person multilevel mediation analyses showed that when a survivor's relationship satisfaction was higher than usual, her own LBP and LBP/sCD14 were lower, which was associated with lower than her own average CRP and IL-6 (95% CIs [-0.0104, -0.0002]). IL-6 was also higher when older survivors, but not younger survivors, experienced higher than usual intestinal permeability (p = .001). These effects of satisfying relationships held after accounting for cancer-related and behavioral factors. Post-hoc analyses showed LBP, sCD14, and LBP/sCD14 were associated with CRP for the cancer survivors, but only LBP and LBP/sCD14 were linked to CRP among the noncancer control patients. CONCLUSION: The gut environment is a new promising candidate for understanding a relationship's long-term health impact, particularly among those with elevated health risks. Survivors may reap multiple physiological benefits from satisfying relationships.

Distress Trajectories in Black and White Breast Cancer Survivors: From Diagnosis to Survivorship.

BACKGROUND: Black breast cancer survivors have greater morbidity and mortality than White survivors. However, evidence comparing Black survivors' psychological symptoms with their White counterparts has been mixed. Prior studies have not compared Black and White survivor's distress-related symptom trajectories from pre- to post-treatment - the goal of the current study. METHODS: At three annual visits from shortly after diagnosis to 6 and 18 months post-treatment, 195 women (n = 163 White; n = 32 Black) reported their cancer-related distress (intrusive thoughts and avoidance), perceived stress, anxiety and depressive symptoms, fatigue, and pain. RESULTS: Adjusting for age, educational attainment, income, treatment type, stage at diagnosis, and physical comorbidities, Black and White breast cancer survivors had different trajectories of cancer-related distress (p = .004), intrusive thoughts about cancer diagnosis and treatment (p = .002), perceived stress (p = .04), emotional fatigue (p = .01), and vigor (p = .02). Specifically, among White women, these distress-related symptoms improved from diagnosis to 6 months post-treatment (ps < 0.0001) and then remained stable between 6 and 18 months post-treatment, whereas Black women had persistently elevated distress - even 18 months after finishing treatment. Additionally, Black women reported more avoidance of cancer-related thoughts and emotions across visits (p = .047). Race was unrelated to the trajectories of anxiety and depressive symptoms, other fatigue subscales, or pain levels (ps > 0.08). CONCLUSION: Longitudinal assessment of the same breast cancer survivors from diagnosis to early survivorship revealed that Black and White survivors had divergent trajectories of psychological distress symptoms that were not reliably evident at a single timepoint. Overall, White women reported less psychological distress from pre- to post-treatment, but Black women's distress remained high from diagnosis to 18 months post-treatment. If left untreated, Black women's high distress levels may contribute to their poorer health throughout survivorship.

Breast cancer survivors' satisfying marriages predict better psychological and physical health: A longitudinal comparison of satisfied, dissatisfied, and unmarried women.

OBJECTIVE: Breast cancer survivors who experience psychological and physical symptoms after treatment have an increased risk for comorbid disease development, reduced quality of life, and premature mortality. Identifying factors that reduce or exacerbate their symptoms may enhance their long-term health and physical functioning. This study examined how survivors' marital status and marital satisfaction-key health determinants-impacted their psychological and physical health trajectories to understand when, and for whom, marriage offers health benefits. METHODS: Breast cancer survivors (n = 209, stages 0-IIIC) completed a baseline visit before treatment and two follow-up visits 6 and 18 months after treatment ended. Women completed questionnaires assessing their marital status and satisfaction when applicable, as well as their psychological (depressive symptoms, stress) and physical (fatigue, pain) health at each visit. RESULTS: Married women-both those in satisfying and dissatisfying marriages-experienced improvements in their depressive symptoms, stress, and fatigue from pretreatment to 6- and 18-month posttreatment. Unmarried (i.e., single, divorced/separated, or widowed) women's depressive symptoms, stress, fatigue, and pain did not change over time, instead remaining elevated 6 and 18 months after treatment ended. Women in satisfying marriages also had fewer psychological and physical symptoms after treatment than those who were unmarried or in dissatisfying marriages. CONCLUSIONS: Although marriage was associated with improved psychological and physical health, the gains were most notable when survivors' marriages were satisfying. Thus, the quality of survivors' marriages, rather than the marriage itself, provided the most benefits to their psychological and physical health.

Childhood abuse histories predict steeper inflammatory trajectories across time.

BACKGROUND: The Center for Disease Control (CDC) recently named childhood abuse histories as a public health risk. Clear links between abuse histories and inflammation exist. However, it remains unknown how abuse histories impact inflammatory trajectories throughout adulthood. Accordingly, this study assessed inflammatory trajectories across three visits among healthy adults with and without abuse histories. METHOD: In this secondary analysis of data from a longitudinal observational study of cancer survivors and noncancer controls, 157 noncancer controls (Mage = 55.8, range = 32-83) completed the Childhood Experiences Questionnaire (CTQ), providing data on physical, emotional, and sexual abuse prior to age 18. Cytokines interleukin-6 (IL-6), interleukin 1-beta (IL-1ß), and tumor necrosis factor-alpha (TNF-α) were collected at the baseline visit and two follow-up visits approximately one (M months = 11.52, SD = 4.10) and two years (M months = 23.79, SD = 4.40) later. To represent inflammatory changes, cytokine data at each visit were combined into a composite z-score. Covariates in all analyses included age, biological sex, race, income, body mass index, menopause status, psychological diagnosis history, and medical comorbidities. RESULTS: Compared to their nonabused peers, those who had experienced any type of abuse in childhood demonstrated steeper rises in inflammation across time. Inflammation rose more steeply for individuals with physical and emotional abuse histories compared to those without such histories. CONCLUSION: Overall, these data suggest that childhood abuse histories may quicken age-related increases in inflammation, contributing to accelerated aging, morbidity, and early mortality. These findings provide mechanistic insight into why child abuse is a public health risk.

Endotoxemia coupled with heightened inflammation predicts future depressive symptoms.

OBJECTIVE: Cross-sectional data have linked gut barrier abnormalities and endotoxemia with depression, even among those without gastrointestinal symptoms. This study examined longitudinal associations between endotoxemia markers and depressive symptoms, as well as the role of inflammation in this relationship. DESIGN: At three annual visits, 315 women (n=209 breast cancer survivors, n = 106 non-cancer patient controls, M=55 years old) completed the Center for Epidemiological Studies Depression questionnaire (CES-D) and provided blood samples to assess inflammatory markers - interleukin-6, tumor necrosis factor-alpha, and C-reactive protein - and endotoxemia markers - lipopolysaccharide-binding protein (LBP), soluble CD14 (sCD14), and their ratio. RESULTS: Adjusting for key demographic variables, health behaviors, visit 1 depressive symptoms, and cancer status and treatment, women with higher visit 1 LBP and LBP/sCD14 had more depressive symptoms at the two subsequent annual visits. Illustrating the notable impact, a woman at the 75th percentile for LBP or LBP/sCD14 at visit 1 was 18 % more likely to report clinically significant depressive symptoms (CES-D ≥16) at follow-up than a woman in the lowest quartile. Cancer status and treatment type did not modulate this relationship. In contrast, visit 1 depressive symptoms did not predict endotoxemia at follow-up. A significant interaction between LBP/sCD14 and inflammatory burden suggested that visit 1 endotoxemia fueled depressive symptoms only in the context of elevated inflammation. CONCLUSION: These results suggest that endotoxemia, combined with systemic inflammation, can drive depressive symptoms. These findings may implicate bacterial endotoxin translocation from the gut to the bloodstream in depression etiology. Interventions that reduce endotoxemia and inflammation may lessen the risk of depression.

Within-person changes in cancer-related distress predict breast cancer survivors' inflammation across treatment.

BACKGROUND: Among breast cancer survivors, elevated inflammation has been linked to greater recurrence risk. Psychological processes, such as cancer-related distress, can pose threats to a survivor's longevity and wellbeing. Although distress can heighten inflammation, little is known about how fluctuations in distress during and after treatment impact a woman's own inflammation - the primary question of this study. METHODS: Breast cancer survivors (n = 165, stages 0-III) completed a baseline visit before treatment and two follow-up visits 6 and 18 months after. At each visit, women completed the Impact of Events Scale to assess cancer-related distress, and a blood sample was collected to measure proinflammatory cytokines IL-6, TNF-α, IL-1ß, and IL-8. This longitudinal study related fluctuations in survivor's own cancer-related distress (i.e., within-person effects), as well as average effects of cancer-related distress between survivors (i.e., between-person effects) to inflammatory changes across visits. RESULTS: Women had elevated inflammation at visits where they expressed more cancer-related distress than what was typical. In contrast, the average cancer-related distress was not associated with inflammation. CONCLUSION: Larger increases in a women's cancer-related distress was linked with higher inflammation across visits. Comparing a survivor's own cancer-related distress to her average levels may prove useful in identifying links between distress and inflammation.

Relationship satisfaction predicts lower stress and inflammation in breast cancer survivors: A longitudinal study of within-person and between-person effects.

BACKGROUND: Breast cancer survivors with elevated inflammation have a greater risk for cancer recurrence, premature mortality, and comorbid disease development. The psychological stress survivors experience when confronted with a breast cancer diagnosis and cancer treatment can heighten inflammation. Identifying factors that reduce stress and inflammation could lead to improvements in survivors' long-term health. Accordingly, this study examined the health-enhancing effects of romantic relationships-a key health determinant-on breast cancer survivors' stress and inflammation. METHODS: Breast cancer survivors (n = 139, stages 0-IIIC) completed a baseline visit before treatment and two follow-up visits 6 and 18 months after treatment ended. Women completed self-report questionnaires assessing their romantic relationship satisfaction and perceived stress, and they provided a blood sample for serum markers of inflammation at each visit. The longitudinal design allowed for examination within and between survivors. We conducted multilevel mediation analyses to assess how changes in survivors' relationship satisfaction were related to changes in stress and inflammation from visit to visit (i.e., within-person effects), as well as how the average effects of relationship satisfaction were associated with average stress and inflammation levels throughout the study (i.e., between-person effects). RESULTS: At the within-person level, at visits in which survivors were more satisfied with their relationships, they also perceived less stress, which in turn was related to lower than their own average levels of serum C-reactive protein and proinflammatory cytokines (tumor necrosis factor-α, interleukin-6, and interleukin-1ß). At the between-person level, survivors who had greater relationship satisfaction throughout the study had lower perceived stress, which was linked to lower levels of inflammation. CONCLUSION: Breast cancer survivors in satisfying romantic relationships felt less stressed and in turn had lower inflammation throughout cancer treatment. This study illustrates the utility of a within-person approach to not only consider the average effects of relationship satisfaction, but also how changes in their own relationship satisfaction impact stress and inflammation over time. Our findings demonstrate important psychological and immunological pathways through which satisfying relationships may promote breast cancer survivors' long-term health.

Impact of the Addition of Digital Breast Tomosynthesis (DBT) to Standard 2D Digital Screening Mammography on the Rates of Patient Recall, Cancer Detection, and Recommendations for Short-term Follow-up.

RATIONALE AND OBJECTIVES: The addition of digital breast tomosynthesis (DBT) to digital screening mammography (DM) has been shown to decrease recall rates and improve cancer detection rates, but there is a lack of data regarding the impact of DBT on rates of short-term follow-up. We assessed possible changes in performance measures with the introduction of DBT at our facility. MATERIALS AND METHODS: In our observational study, databases were used to compare rates of recall, short-term follow-up, biopsy, and cancer detection between women undergoing DM without (n = 10,477) and women undergoing DM with (n = 2304) the addition of DBT. Regression analysis was performed to determine associations with patient age, breast density, and availability of comparison examinations. RESULTS: The addition of DBT resulted in significantly lower recall rates (16%-14%, P = .017), higher rates of biopsy (12.7%-19.1%, P < .01), and increased detection of ductal carcinoma in situ, with a difference of 2.3 cases per 1000 screens (P = .044). A 33% increase in cancer detection rates was observed with DBT, which did not reach statistical significance. Short-term follow-up of probably benign findings was 80% higher in the DBT group (odds ratio = 1.80, 95% confidence interval = 1.38-2.36, P < .001). CONCLUSIONS: To our knowledge, we are the first to study the impact of DBT on rates of short-term follow-up, and observed an 80% increase over the DM group. Further research is needed to determine the malignancy rate of Breast Imaging Reporting and Data System 3 lesions detected with DBT, and establish appropriate follow-up to maximize cancer detection while minimizing expense and patient anxiety.

Inflammatory Cytokines and Comorbidity Development in Breast Cancer Survivors Versus Noncancer Controls: Evidence for Accelerated Aging?

Purpose The sequelae of cancer treatment may increase systemic inflammation and create a phenotype at increased risk of functional decline and comorbidities, leading to premature mortality. Little is known about how this trajectory compares with natural aging among peers of the same age without cancer. This longitudinal study investigated proinflammatory cytokines and comorbidity development over time among breast cancer survivors and a noncancer control group. Methods Women (N = 315; 209 with breast cancer and 106 in the control group) were recruited at the time of their work-up for breast cancer; they completed the baseline questionnaire, interview, and blood draw (lipopolysaccharide-stimulated production of interleukin [IL] -6, tumor necrosis factor-α, and IL-1ß). Measures were repeated 6 and 18 months after primary cancer treatment (cancer survivors) or within a comparable time frame (control group). Results There were no baseline differences in comorbidities or cytokines between survivors and the control group. Over time, breast cancer survivors had significantly higher tumor necrosis factor-α and IL-6 compared with the control group. Survivors treated with surgery, radiation, and chemotherapy accumulated a significantly greater burden of comorbid conditions and suffered greater pain associated with inflammation over time after cancer treatment than did the control group. Conclusion Survivors who had multimodal treatment had higher cytokines and comorbidities, suggestive of accelerated aging. Comorbidities were related to inflammation in this sample, which could increase the likelihood of premature mortality. Given that many comorbidities take years to develop, future research with extended follow-up beyond 18 months is necessary to examine the evidence of accelerated aging in cancer survivors and to determine the responsible mechanisms.

Attachment anxiety is related to Epstein-Barr virus latency.

Attachment theory provides a framework for understanding individual differences in chronic interpersonal stress. Attachment anxiety, a type of relationship insecurity characterized by worry about rejection and abandonment, is a chronic interpersonal stressor. Stress impacts cellular immunity, including herpesvirus reactivation. We investigated whether attachment anxiety was related to the expression of a latent herpesvirus, Epstein-Barr virus (EBV), when individuals were being tested for breast or colon cancer and approximately 1 year later. Participants (N=183) completed a standard attachment questionnaire and provided blood to assess EBV viral capsid antigen (VCA) IgG antibody titers. Individuals with more attachment anxiety had higher EBV VCA IgG antibody titers than those with less attachment anxiety. The strength of the association between attachment anxiety and antibody titers was the same at both assessments. This study is the first to show an association between latent herpesvirus reactivation and attachment anxiety. Because elevated herpesvirus antibody titers reflect poorer cellular immune system control over the latent virus, these data suggest that high attachment anxiety is associated with cellular immune dysregulation.

Cognitive problems among breast cancer survivors: loneliness enhances risk.

BACKGROUND: Cancer survivors often experience cognitive difficulties after treatment completion. Although chemotherapy enhances risk for cognitive problems, it is likely only one piece of a complex puzzle that explains survivors' cognitive functioning. Loneliness may be one psychosocial risk factor. The current studies included both subjective and objective cognitive measures and tested whether lonelier breast cancer survivors would have more concentration and memory complaints and experience more concentration difficulties than their less lonely counterparts. METHODS: The relationship between loneliness and cognitive function was tested among three samples of breast cancer survivors. Study 1 was a sample of breast cancer survivors (n = 200) who reported their concentration and memory problems. Study 2a was a sample of breast cancer survivors (n = 185) and noncancer controls (n = 93) who reported their concentration and memory problems. Study 2b was a subsample of Study 2a breast cancer survivors (n = 22) and noncancer controls (n = 21) who completed a standardized neuropsychological test assessing concentration. RESULTS: Studies 1 and 2a revealed that lonelier women reported more concentration and memory problems than less lonely women. Study 2b utilized a standardized neuropsychological continuous performance test and demonstrated that lonelier women experienced more concentration problems than their less lonely counterparts. CONCLUSIONS: These studies demonstrated that loneliness is linked to concentration and memory complaints and the experience of concentration problems among breast cancer survivors. The results were also highly consistent across three samples of breast cancer survivors. These data suggest that loneliness may be a risk factor for cognitive difficulties among cancer survivors.

Social support predicts inflammation, pain, and depressive symptoms: longitudinal relationships among breast cancer survivors.

OBJECTIVE: Pain and depressive symptoms are commonly experienced by cancer survivors. Lower social support is linked to a variety of negative mental and physical health outcomes among survivors. Immune dysregulation may be one mechanism linking low social support to the development of pain and depressive symptoms over time. Accordingly, the goal of the present study was to examine the relationships among survivors' social support, pain, depressive symptoms, and inflammation. METHODS: Breast cancer survivors (N=164, stages 0-IIIA) completed two study visits, one before any cancer treatment and the other 6 months after the completion of surgery, radiation, or chemotherapy, whichever came last. Women completed self-report questionnaires assessing social support, pain, and depressive symptoms, and provided a blood sample at both visits. RESULTS: Survivors with lower social support prior to treatment experienced higher levels of pain and depressive symptoms over time than their more socially supported counterparts. Furthermore, women with lower pretreatment social support had higher levels of IL-6 over time, and these elevations in IL-6 predicted marginally larger increases in depressive symptoms. CONCLUSIONS: The results of this study suggest that social support at the time of diagnosis predicts the post-treatment development of pain, depressive symptoms, and inflammation. Consequently, early interventions targeting survivors' social networks could improve quality of life during survivorship.

Pain, depression, and fatigue: loneliness as a longitudinal risk factor.

OBJECTIVE: Pain, depression, and fatigue function as a symptom cluster and thus may share common risk factors. Interpersonal relationships clearly influence health, suggesting that loneliness may promote the development of the pain, depression, and fatigue symptom cluster. We hypothesized that loneliness would be related to concurrent symptom cluster levels and increases in symptom cluster levels over time. METHOD: We utilized two observational studies with distinct longitudinal samples. Study 1 was a sample of cancer survivors and benign controls (N = 115) assessed annually for 2 years. Study 2 was a sample of older adults caring for a spouse with dementia (caregivers) and non-caregiver controls (N = 229) assessed annually for 4 years. Participants completed annual measures assessing loneliness, pain, depression, and fatigue. RESULTS: Across both samples, lonelier participants experienced more concurrent pain, depression, and fatigue and larger increases in symptom cluster levels from one year to the next than less lonely participants. Sleep quality did not mediate the results in either study. All analyses were adjusted for relevant demographic and health variables. CONCLUSIONS: Two longitudinal studies with different populations demonstrated that loneliness was a risk factor for the development of the pain, depression, and fatigue symptom cluster over time. The current research helps identify people most at risk for pain, depression, and fatigue, and lays the groundwork for research about their diagnosis and treatment. These data also highlight the health risks of loneliness; pain, depression, and fatigue often accompany serious illness and place people at risk for poor health and mortality.

Social support and socioeconomic status interact to predict Epstein-Barr virus latency in women awaiting diagnosis or newly diagnosed with breast cancer.

OBJECTIVE: Both higher socioeconomic status (SES) and supportive personal relationships confer health benefits, including better immune function. This study assessed the joint impact of SES and social support on the expression of a latent herpesvirus, Epstein-Barr virus (EBV), in a group of highly stressed women. METHODS: Two-hundred and twenty four women either awaiting further evaluation following an abnormal mammogram or newly diagnosed with breast cancer completed questionnaires and provided blood samples to assess EBV viral capsid antigen (VCA) IgG antibody titers. RESULTS: More highly educated women with more support from friends had lower EBV VCA antibody titers, reflecting a stronger cellular immune response to the latent virus; however, among less educated women, friend support was not associated with EBV antibody titers. As revealed in an ancillary analysis, more highly educated women with more friend support had lower systolic blood pressure (SBP); however, friend support was not associated with SBP among less educated women. Neither depression nor perceived stress mediated these associations. Neither cancer status nor cancer stage among those diagnosed with cancer was significantly related to these outcomes. CONCLUSION: Lower SES women may not reap the same immunological benefits from friend support when experiencing a stressful life event as their higher SES counterparts.

Fatigue and herpesvirus latency in women newly diagnosed with breast cancer.

Fatigue is a notable clinical problem in cancer survivors, and understanding its pathophysiology is important. The current study sought to determine biomarkers of fatigue that exist before cancer treatment. Relationships between the expression of latent Epstein-Barr virus (EBV) and cytomegalovirus (CMV) and fatigue were examined in 158 women newly diagnosed with breast cancer or awaiting a positive diagnostic result. Higher CMV antibody titers, but not EBV antibody titers, were associated with a greater likelihood of being fatigued. Associations between fatigue and higher CMV antibody titers remained after controlling for alcohol use, smoking, comorbidities, depressive symptoms, age, BMI, cancer stage, and sleep problems. More sleep problems and higher levels of depressive symptoms were also associated with a greater likelihood of being fatigued. CMV antibody titers, but not EBV antibody titers, were associated with higher levels of C-reactive protein (CRP), but CRP was not associated with fatigue. When the cellular immune system is compromised, reactivation of latent herpesviruses may fuel chronic inflammatory responses. Prior work has suggested that fatigue may be related to inflammation and its associated sickness behaviors; accordingly, our findings may be tapping into this same physiological substrate.