A Qualitative Study of Knowledge of Metabolic Syndrome, Attitudes about Lifestyle Modifications, and Preferences for Lifestyle Interventions among Patients with Cancer and Metabolic Syndrome.

Background: Nearly 60% of patients with cancer have metabolic syndrome, which increases the risk of mortality, but there is no clear guidance for oncology providers about its management. Here, we report on the qualitative component of a larger mixed methods study that aimed to understand cancer patients' knowledge, attitudes, and preferences regarding metabolic syndrome. Methods: Adult cancer patients with metabolic syndrome were recruited during 2022-2023 in the MD Anderson General Internal Medicine clinic and participated in semistructured interviews focused on metabolic syndrome and lifestyle interventions. Interviews were audio-recorded and transcribed verbatim. Participants' demographic information was collected. Interviews were analyzed using hybrid thematic analysis and constant comparison involving deductive and inductive coding. Researcher triangulation and debriefing were used to ensure rigor. Results: There were 19 participants, 12 female and 12 White. Eighteen had solid tumors, including gynecologic (n = 5), genitourinary (n = 4), colorectal (n = 3), and breast (n = 2). Analysis yielded 5 major themes: 1) patients' understanding of metabolic syndrome; 2) attitudes about and approaches to managing metabolic syndrome; 3) capacity and limitations regarding managing metabolic syndrome; 4) patient-led care; and 5) tailored intervention plans. Participants had limited knowledge of metabolic syndrome and its cancer-related consequences; most desired additional education. Many participants reported that their cancer or diabetes diagnosis motivated them to prioritize lifestyle Modifications. Participants expressed strong interest in personalized care plans focused on healthy lifestyle rather than simply weight loss. As part of their tailored intervention plans, participants desired clear communication with their medical team, coordination of care among team members, and collaboration with providers about treatment decisions. Conclusion: Cancer patients with metabolic syndrome want collaborative, patient-centered care. Shared decision-making based on respect for patients' distinctive needs and preferences is an essential component of the development of such collaborative care. Tailored interventions, practical implementation strategies, and personalized care plans are needed for cancer patients with metabolic syndrome. The study findings contribute to filling the gap in knowledge regarding clear guidance for oncology providers on managing metabolic syndrome and will inform the development of future lifestyle interventions for patients diagnosed with metabolic syndrome.

A detailed description of the distress trajectory from pre- to post-treatment in breast cancer patients receiving neoadjuvant chemotherapy.

PURPOSE: To characterize the distress trajectory in patients with newly diagnosed, non-metastatic breast cancer from pre-neoadjuvant chemotherapy until 12 months after onset of treatment and to identify demographic and clinical predictors of distress in these patients. METHODS: In a retrospective, longitudinal study, chart review data were abstracted for 252 eligible patients treated at a comprehensive cancer care center. The center screens for distress at least monthly with the distress thermometer; the highest distress score per month was included in the analyses. The growth trajectory was established using mixed modeling and predictors were added to the initial growth model in subsequent models. RESULTS: Distress showed a cubic growth trajectory with highest distress prior to treatment onset followed by a steep decline in the first three months of treatment. A slight increase in distress was apparent over months 6-10. Being Hispanic was associated with a stronger increase in distress in the second half of the year (p = 0.012). NACT was associated with lower distress and surgery with higher distress (both: p < 0.001). CONCLUSION: Distress is at its peak prior to treatment onset and rapidly decreases once treatment has started. Oncologist should be aware that both completion of NACT and undergoing surgery are associated with increases in distress and Hispanic patients may be more at risk for an increase in distress at these times; this suggests that careful monitoring of distress during the treatment trajectory and in Hispanic patients in particular in order to provide timely support.

Associations between fatigue and cellular metabolism in breast cancer patients: A longitudinal study.

PURPOSE: Fatigue is frequently experienced during treatment for cancer and persists for months to years after treatment completion in a subset of patients. The underlying mechanisms remain poorly understood. We postulated that reduced cellular energy metabolism may underlie fatigue in cancer patients and survivors and tested this hypothesis in a sample of patients newly diagnosed with early-stage breast cancer (n = 49) followed for approximately 1 year from before the start of neoadjuvant chemotherapy (NACT) till after treatment completion. METHODS: Patient-reported fatigue was assessed with the Checklist Individual Strength, and blood samples were obtained before, during, and shortly after NACT. A final assessment was completed after surgery and radiation therapy, 4-6 months after NACT. At each study time point, mitochondrial oxygen consumption and glycolytic activity were measured in peripheral blood mononuclear cells (PBMC). Associations of these measures of PBMC energy metabolism with fatigue were assessed in multilevel models. RESULTS: Before NACT, higher mitochondrial oxygen consumption and glycolytic activity were associated with higher fatigue, whereas after completion of all primary treatment, these assessments were associated with lower fatigue. CONCLUSION: These findings suggest that lower cellular energy metabolism after treatment may be a novel target for interventions aimed at preventing or reducing persistent fatigue. Earlier studies investigated the use of supplements for maintaining mitochondrial health during treatment, with mixed results; when proven to be safe, such interventions may be more effective after treatment and in individuals with reduced mitochondrial oxygen consumption rates.

Clinical relevance of a Body Image Scale cut point of 10 as an indicator of psychological distress in cancer patients: results from a psychiatric oncology clinic.

PURPOSE: Adequate adjustment to bodily changes during various phases of cancer treatment is important to patients' emotional well-being. The Body Image Scale (BIS) is a widely used tool for assessment of body image concerns in different cancer types. However, a cut point score indicative of clinically relevant body image concerns has not been established. The purpose of our study was to evaluate whether the previously suggested, but not validated, BIS cut point score of ≥ 10 is an adequate indicator of psychological distress. METHODS: In a prospective cross-sectional study, 590 adult patients were recruited from a psychiatric oncology clinic (November 2017-March 2018). Patient-reported body image concerns, depression, anxiety, and emotional distress were assessed with the BIS, Patient Health Questionnaire-9, Generalized Anxiety Disorder Scale-7, and National Comprehensive Cancer Network Distress Thermometer, respectively. RESULTS: Almost half of the patients had a BIS score ≥ 10; these were more likely to be younger, female, Hispanic, and to have breast cancer than patients with a score < 10. BIS scores were positively associated with depression, anxiety, and distress scores. A BIS score ≥ 10 was a significant predictor of moderate depression and anxiety (odds ratios = 3.555 [95% CI 2.478-5.102] and 3.655 [2.493-5.358]; p < 0.001 for both). CONCLUSION: To our knowledge, this is the first study to have assessed the validity of the previously suggested clinically relevant BIS cut point score of ≥ 10 as an indicator of psychological distress. Our results suggest that a BIS score of ≥ 10 or higher should lead to follow-up on body image concerns and/or appropriate referral.

A central role for apathy in the effectiveness of interventions for cancer-related fatigue.

OBJECTIVE: Cancer-related fatigue (CRF) affects a substantial number of cancer patients and survivors. Recommendations for CRF treatments are largely based on results of randomized controlled trials. The interpretability of such results is limited to patients eligible and willing to participate in these trials. We aimed to address this limitation in a retrospective study of patients seen at a CRF clinic in a comprehensive cancer center. The objectives were to (a) determine the effectiveness of clinician-initiated interventions for CRF and identify their mediators and (b) describe the frequency and effectiveness of patient-initiated physical activity (PA) behavior for alleviating CRF and identify determinants of this PA. METHODS: Data (patient-reported somatic and mood symptoms; clinical data; clinician-documented changes in medication and behavior) from n = 213 patients collected as part of the clinic's standard of care at initial clinical consult and follow-up 4 to 11 weeks later were included. Effects of clinician-initiated interventions and patient-initiated PA on change in fatigue were analyzed using linear models. RESULTS: Of all clinician-initiated interventions, only psychostimulant start was recorded frequent enough for further investigation and was associated with reduced fatigue; this association was mediated by a reduction in apathy. PA was also associated with reduced fatigue severity. PA initiation/increase after consult was associated with lower apathy at consult. CONCLUSIONS: These results demonstrate a major role for patient apathy in the effectiveness and initiation of CRF-targeting interventions. Behavioral therapies focusing on reduction in apathy should be considered as initial treatment of CRF in those with substantial apathy.

Patient-reported fatigue prior to treatment is prognostic of survival in patients with acute myeloid leukemia.

Acute myeloid leukemia (AML) is associated with poor survival. While clinical prognostic factors of survival have been identified, the contribution of patient-reported symptoms has only received marginal attention. Fatigue is one of the most commonly reported symptoms of AML. There is some evidence that fatigue is associated with shorter survival in hematological malignancies. However, the prognostic effects of fatigue in a homogenous cohort of patients with untreated AML has not been tested. We here report results of a prospective study on the prognostic value of patient-reported fatigue prior to onset of treatment, for 2-year survival in 94 AML patients. Cox regression models controlling for demographic and clinical factors showed that those with severe fatigue (22%) had decreased survival rates (Hr = 2.255, 95% CI = 1.16-5.60, p = 0.019). Further exploration showed that fatigue was associated with increased plasma concentrations of IL-6 and TNF-α, but not with demographic or disease-related factors. In conclusion, we here show for the first time that the experience of severe fatigue prior to remission induction chemotherapy (IC) is prognostic for shorter survival in patients with AML of all ages. These findings point to the importance of interventions aimed at relieving fatigue especially before or in the early phases of treatment in order to improve survival.

An effort expenditure perspective on cancer-related fatigue.

While fatigue is the most common and debilitating side effect of cancer and cancer treatment it is still poorly understood, partly because it is usually characterized by patient-reported outcomes. As patient-reports are inherently subjective, behavioral correlates of the symptom of fatigue are needed to increase our understanding of the symptom. We focused on motivational effort expenditure as a crucial behavior in cancer-related fatigue, using a validated computerized task contrasting high effort/high reward and low effort/low reward choices under different probabilities of success. Effort expenditure-choices were analyzed in 47 cancer patients differing by their status; current evidence for disease (n = 17) or post-treatment survivors with no evidence for disease (n = 30). In addition, patient-reported fatigue, negative and positive affect, and biomarkers of inflammation were assessed. Patient-reported general and motivational fatigue, negative affect, and plasma concentrations of pro-inflammatory biomarkers were related to higher effort expenditure while positive affect was associated with lower effort expenditure. As all four measures interacted with patient status, exploratory models were computed for patients and survivors separately. These analyses indicated that the effects of fatigue and negative affect were predominantly seen in survivors. In patients still under or shortly post treatment, general fatigue, but not motivational fatigue, was associated with lower effort expenditure but only in the most favorable reward condition. Negative affect did not have an effect. Thus, the effects observed seemed primarily driven by cancer survivors in whom both fatigue and negative affect were associated with higher effort expenditure. These findings are tentatively interpreted to suggest that a tendency to invest more effort despite feelings of fatigue is a vulnerability for developing chronic fatigue. Inflammation and negative affect might contribute to fatigue in some survivors through this effort investment pathway.

The High Costs of Low-Grade Inflammation: Persistent Fatigue as a Consequence of Reduced Cellular-Energy Availability and Non-adaptive Energy Expenditure.

Chronic or persistent fatigue is a common, debilitating symptom of several diseases. Persistent fatigue has been associated with low-grade inflammation in several models of fatigue, including cancer-related fatigue and chronic fatigue syndrome. However, it is unclear how low-grade inflammation leads to the experience of fatigue. We here propose a model of an imbalance in energy availability and energy expenditure as a consequence of low-grade inflammation. In this narrative review, we discuss how chronic low-grade inflammation can lead to reduced cellular-energy availability. Low-grade inflammation induces a metabolic switch from energy-efficient oxidative phosphorylation to fast-acting, but less efficient, aerobic glycolytic energy production; increases reactive oxygen species; and reduces insulin sensitivity. These effects result in reduced glucose availability and, thereby, reduced cellular energy. In addition, emerging evidence suggests that chronic low-grade inflammation is associated with increased willingness to exert effort under specific circumstances. Circadian-rhythm changes and sleep disturbances might mediate the effects of inflammation on cellular-energy availability and non-adaptive energy expenditure. In the second part of the review, we present evidence for these metabolic pathways in models of persistent fatigue, focusing on chronic fatigue syndrome and cancer-related fatigue. Most evidence for reduced cellular-energy availability in relation to fatigue comes from studies on chronic fatigue syndrome. While the mechanistic evidence from the cancer-related fatigue literature is still limited, the sparse results point to reduced cellular-energy availability as well. There is also mounting evidence that behavioral-energy expenditure exceeds the reduced cellular-energy availability in patients with persistent fatigue. This suggests that an inability to adjust energy expenditure to available resources might be one mechanism underlying persistent fatigue.

Associations of inflammation with symptom burden in patients with acute myeloid leukemia.

The aim of the study was to assess the association inflammation with symptom burden in patients with acute myeloid leukemia (AML), assessed before and during remission induction chemotherapy (IC). Patients with AML (n = 95) were followed from baseline (before IC) to the third week of IC for severity of self-reported somatic symptoms (assessed with the MD Anderson Symptom Inventory) and plasma levels of 13 inflammation-related biomarkers (n = 64). A composite symptom burden severity score was computed as the average score of the six most severe somatic symptoms i.e., fatigue, disturbed sleep, drowsiness, dry mouth, lack of appetite, and pain. Results from cross-sectional analyses showed that inflammation was weakly associated with symptom burden before IC (multiple regression model, explained variance = 10%) but this association grew stronger during IC (week 3 explained variance = 35%). About half of the sample showed a change over time in symptom severity. These changes were not reflected in similar changes over time in inflammatory markers, suggesting that it is the absolute concentration of a given inflammatory marker at a given time point rather than its relative change over time that is of importance. In conclusion, inflammation was strongly associated with symptom burden only during IC, possibly because expression of cytokines only then becomes relevant for regulation of symptom burden. While the current study does not allow for determination of causality, the results suggest that AML patients might benefit from anti-inflammatory interventions during treatment to alleviate somatic symptom experience.

Mechanisms of Neurotoxic Symptoms as a Result of Breast Cancer and Its Treatment: Considerations on the Contribution of Stress, Inflammation, and Cellular Bioenergetics.

PURPOSE OF REVIEW: Breast cancer and its treatment are associated with a range of neurotoxic symptoms, such as fatigue, cognitive impairment, and pain. Although these symptoms generally subside after treatment completion, they become chronic in a significant subset of patients. We here summarize recent findings on neuroinflammation, stress, and mitochondrial dysfunction as mechanistic pathways leading to neurotoxic symptom experience in breast cancer patients and survivors. RECENT FINDINGS: Neuroinflammation related to stress or cancer treatment and stress resulting from diagnosis, treatment, or (cancer-related) worrying are important predictors of a neurotoxic symptom experience, both during and after treatment for breast cancer. Both inflammation and stress hormones, as well as cancer treatment, can induce mitochondrial dysfunction resulting in reduced cellular energy. SUMMARY: We propose reduced cellular energy (mitochondrial dysfunction) induced by inflammation, oxygen radical production, and stress as a result of cancer and/or cancer treatment as a final mechanism underlying neurotoxic symptoms.

Lipopolysaccharide Alters Motivated Behavior in a Monetary Reward Task: a Randomized Trial.

Inflammation-induced sickness is associated with a large set of behavioral alterations; however, its motivational aspects remain poorly explored in humans. The present study assessed the effect of lipopolysaccharide (LPS) administration at a dose of 2 ng/kg of body weight on motivation in 21 healthy human subjects in a double-blinded, placebo (saline)-controlled, cross-over design. Incentive motivation and reward sensitivity were measured using the Effort Expenditure for Rewards Task (EEfRT), in which motivation for high-effort/high-reward trials vs low-effort/low-reward trials are manipulated by variations in reward magnitude and probability to win. Because of the strong interactions between sleepiness and motivation, the role of sleepiness was also determined. As expected, the probability to win predicted the choice to engage in high-effort/high-reward trials; however, this occurred at a greater extent after LPS than after saline administration. This effect was related to the level of sleepiness. Sleepiness increased motivation to choose the high-effort/high-reward mode of response, but only when the probability to win was the highest. LPS had no effect on reward sensitivity either directly or via sleepiness. These results indicate that systemic inflammation induced by LPS administration causes motivational changes in young healthy subjects, which are associated with sleepiness. Thus, despite its association with energy-saving behaviors, sickness allows increased incentive motivation when the effort is deemed worthwhile.

Executive functioning and diabetes: The role of anxious arousal and inflammation.

Individuals who perform poorly on measures of the executive function of inhibition have higher anxious arousal in comparison to those with better performance. High anxious arousal is associated with a pro-inflammatory response. Chronically high anxious arousal and inflammation increase one's risk of developing type 2 diabetes. We sought to evaluate anxious arousal and inflammation as underlying mechanisms linking inhibition with diabetes incidence. Participants (N=835) completed measures of cognitive abilities, a self-report measure of anxious arousal, and donated blood to assess interleukin-6 (IL-6) and glycated hemoglobin (HbA1c). Individuals with low inhibition were more likely to have diabetes than those with high inhibition due to the serial pathway from high anxious arousal to IL-6. Findings remained when entering other indicators of cognitive abilities as covariates, suggesting that inhibition is a unique cognitive ability associated with diabetes incidence. On the basis of our results, we propose several avenues to explore for improved prevention and treatment efforts for type 2 diabetes.

Mechanisms of chemotherapy-induced behavioral toxicities.

While chemotherapeutic agents have yielded relative success in the treatment of cancer, patients are often plagued with unwanted and even debilitating side-effects from the treatment which can lead to dose reduction or even cessation of treatment. Common side effects (symptoms) of chemotherapy include (i) cognitive deficiencies such as problems with attention, memory and executive functioning; (ii) fatigue and motivational deficit; and (iii) neuropathy. These symptoms often develop during treatment but can remain even after cessation of chemotherapy, severely impacting long-term quality of life. Little is known about the underlying mechanisms responsible for the development of these behavioral toxicities, however, neuroinflammation is widely considered to be one of the major mechanisms responsible for chemotherapy-induced symptoms. Here, we critically assess what is known in regards to the role of neuroinflammation in chemotherapy-induced symptoms. We also argue that, based on the available evidence, neuroinflammation is unlikely the only mechanism involved in the pathogenesis of chemotherapy-induced behavioral toxicities. We evaluate two other putative candidate mechanisms. To this end we discuss the mediating role of damage-associated molecular patterns (DAMPs) activated in response to chemotherapy-induced cellular damage. We also review the literature with respect to possible alternative mechanisms such as a chemotherapy-induced change in the bioenergetic status of the tissue involving changes in mitochondrial function in relation to chemotherapy-induced behavioral toxicities. Understanding the mechanisms that underlie the emergence of fatigue, neuropathy, and cognitive difficulties is vital to better treatment and long-term survival of cancer patients.

Infection load as a predisposing factor for somatoform disorders: evidence from a Dutch General Practice Registry.

OBJECTIVE: Somatoform disorders (SDs) are characterized by chronic multiple functional somatic (FS) symptoms. It has been suggested that infections may be triggers for FS symptoms to occur, pointing to the immune system as a pathogenic factor in their development. The current study aimed to compare the prevalence of infections (i.e., infection load) in the history of patients with SDs with that of matched controls. METHODS: Samples (n = 185) were identified in the Psychiatric Case Register Middle Netherlands and the Julius General Practitioners Network. Patients with an SD diagnosis in the Psychiatric Case Register Middle Netherlands were compared with matched persons without somatoform complaints (controls) on their infection load in two periods before the date of the psychiatric diagnosis or a matched date for the controls (i.e., the total period for which data were available and a 3-year period). Infection load was defined as the total number of infections documented in the Julius General Practitioners Network. RESULTS: Patients with SD had significantly more infections than did controls in both periods (total period: mean [standard error] = 0.87 [0.10] versus 0.51 [0.06], z = -3.08, p = .002; 3-year period: 3.44 [0.47] versus 2.15 [0.50], z = -2.91, p = .004). CONCLUSIONS: Results show that patients with SD have a higher infection load preceding their diagnosis as compared with matched controls, implicating that infection load may indeed predispose for developing FS symptoms. These findings emphasize the importance of further research on immunological mechanisms in FS symptoms. Limitations of the study are discussed.

Experimental pressure-pain assessments: Test-retest reliability, convergence and dimensionality.

Introduction Experimental pain studies can provide unique insight into the dimensions of pain and into individual differences in pain responsiveness by controlling different aspects of pain-eliciting stimuli and pain measures. In experimental pain studies, pain responsiveness can be assessed as pain threshold, pain tolerance or pain ratings. The test-theoretical qualities of these different measures, however, have not yet been completely documented. In the current study, several of these qualities were investigated in a pain experiment applying different algometric techniques. The objective of the study was to investigate the reliability (test-retest) and the convergent validity (correspondence) of the different methods found in the literature of measuring pressure-pain threshold, and the interrelationship between pressure-pain threshold, pressure-pain tolerance, and pressure-pain ratings. Methods Sixty-six healthy female subjects were enrolled in the study. All pressure stimuli were applied by a trained investigator, using a digital algometer with a 1 cm2 rubber tip. Pressure-pain thresholds were assessed repeatedly on six different body points (i.e. left and right calf one third of total calf muscle length below the popliteal space), the lower back (5 cm left and right from the L3), and left and right forearm (thickest part of brachioradialis muscle). Next, pressure-pain tolerance was measured on the thumbnail of the non-dominant hand, followed by rating affective and sensory components (on visual analogue scales) of a stimulus at tolerance level. Last, affective and sensory ratings were obtained for two pressure intensities. Results With intraclass correlations above .75 for pain responses per body point, test-retest reliability was found to be good. However, values obtained from all first measurements were significantly higher as compared with the two succeeding ones. Convergent validity of pain thresholds across different body points was found to be high for all combinations assessed (Cronbach's alpha values >.80), but the highest for bilateral similar body parts (>.89). Finally, principal components analysis including measures of threshold, tolerance and pain ratings yielded a three-factor solution that explained 81.9% of the variance: Moderate-level stimulus appraisal & pain tolerance; Pain threshold; Tolerance-level stimulus appraisal. Conclusion and implications Findings of the current study were used to formulate recommendations for future algometric pain studies. Concerning pressure-pain threshold, it is recommended to exclude first measurements for every body point from further analyses, as these measurements were found to be consistently higher compared with the following measurements. Further, no more than two consecutive measurements (after the first measurement) are needed for a reliable mean threshold value per body point. When combining threshold values of several body points into one mean-aggregated threshold value, we suggest to combine bilateral similar points, as convergent validity values were highest for these combinations. The three-factor solution that was found with principal components analyses indicates that pressure-pain threshold, subjective ratings of moderate intensity stimuli, and subjective ratings of the maximum (tolerance) intensity are distinct aspects of pain responsiveness. It is therefore recommended to include a measure of each of these three dimensions of pain when assessing pressure pain responsiveness. Some limitations of our study are discussed.