DNA methylation profiles of cancer-related fatigue associated with markers of inflammation and immunometabolism.

Cancer patients are commonly affected by fatigue. Herein, we sought to examine epigenetic modifications (i.e., DNA methylation) related to fatigue in peripheral blood among patients during and after treatment for head and neck cancer (HNC). Further, we determined whether these modifications were associated with gene expression and inflammatory protein markers, which we have previously linked to fatigue in HNC. This prospective, longitudinal study enrolled eligible patients with data collected at pre-radiotherapy, end of radiotherapy, and six months and one-year post-radiotherapy. Fatigue data were reported by patients using the Multidimensional Fatigue Inventory (MFI)-20. DNA methylation (Illumina MethylationEPIC) and gene expression (Applied Biosystems Clariom S) arrays and assays for seven inflammatory markers (R&D Systems multiplex) were performed. Mixed models and enrichment analyses were applied to establish the associations. A total of 386 methylation loci were associated with fatigue among 145 patients (False Discovery Rate [FDR] < 0.05). Enrichment analyses showed the involvement of genes related to immune and inflammatory responses, insulin and lipid metabolism, neuropsychological disorders, and tumors. We further identified 16 methylation-gene expression pairs (FDR < 0.05), which were linked to immune and inflammatory responses and lipid metabolism. Ninety-one percent (351) of the 386 methylation loci were also significantly associated with inflammatory markers (e.g., interleukin 6, c-reactive protein; FDR < 0.05), which further mediated the association between methylation and fatigue (FDR < 0.05). These data suggest that epigenetic modifications associated with inflammation and immunometabolism, in conjunction with relevant gene expression and protein markers, are potential targets for treating fatigue in HNC patients. The findings also merit future prospective studies in other cancer populations as well as interventional investigations.

Multi-omics analysis of the gut microbiome and metabolites associated with the psychoneurological symptom cluster in children with cancer receiving chemotherapy.

BACKGROUND: Children with cancer receiving chemotherapy commonly report a cluster of psychoneurological symptoms (PNS), including pain, fatigue, anxiety, depression, and cognitive dysfunction. The role of the gut microbiome and its functional metabolites in PNS is rarely studied among children with cancer. This study investigated the associations between the gut microbiome-metabolome pathways and PNS in children with cancer across chemotherapy as compared to healthy children. METHODS: A case-control study was conducted. Cancer cases were recruited from Children's Healthcare of Atlanta and healthy controls were recruited via flyers. Participants reported PNS using the Pediatric Patient-Reported Outcomes Measurement Information System. Data for cases were collected pre-cycle two chemotherapy (T0) and post-chemotherapy (T1), whereas data for healthy controls were collected once. Gut microbiome and its metabolites were measured using fecal specimens. Gut microbiome profiling was performed using 16S rRNA V4 sequencing, and metabolome was performed using an untargeted liquid chromatography-mass spectrometry approach. A multi-omics network integration program analyzed microbiome-metabolome pathways of PNS. RESULTS: Cases (n = 21) and controls (n = 14) had mean ages of 13.2 and 13.1 years. For cases at T0, PNS were significantly associated with microbial genera (e.g., Ruminococcus, Megasphaera, and Prevotella), which were linked with carnitine shuttle (p = 0.0003), fatty acid metabolism (p = 0.001) and activation (p = 0.001), and tryptophan metabolism (p = 0.008). Megasphaera, clustered with aspartate and asparagine metabolism (p = 0.034), carnitine shuttle (p = 0.002), and tryptophan (p = 0.019), was associated with PNS for cases at T1. Gut bacteria with potential probiotic functions, along with fatty acid metabolism, tryptophan, and carnitine shuttle, were more clustered in cancer cases than the control network and this linkage with PNS needs further studies. CONCLUSIONS: Using multi-omics approaches, this study indicated specific microbiome-metabolome pathways linked with PNS in children with cancer across chemotherapy. Due to limitations such as antibiotic use in cancer cases, these findings need to be further confirmed in a larger cohort.

Patient-reported outcomes (PROs) in NRG Oncology RTOG 0436: a phase III trial evaluating the addition of cetuximab to paclitaxel, cisplatin, and radiation for esophageal cancer treated without surgery.

PURPOSE/OBJECTIVES: NRG/RTOG 0436 evaluated cetuximab added to chemoradiation (CRT) for non-operative esophageal cancer management. PRO objectives assessed improvement in the FACT-Esophageal cancer subscale (ECS), version 4, with cetuximab, and if improved ECS correlated with clinical complete response (cCR). MATERIALS/METHODS: Patients were randomized to cisplatin/paclitaxel/radiation ± cetuximab. Overall survival (OS) was the primary endpoint, with a 420 patient target, which also provided 82% power to detect ≥ 15 increase in the proportion of cetuximab patients with ECS improvement from baseline to 6-8 weeks post-CRT; α = 0.05, using a χ2 test. Improvement in ECS and its Swallowing and Eating Indices (SI, EI) was defined as 5, 4 and 2 point increases, respectively, from baseline to 6-8 weeks post-CRT. Univariate logistic regression assessed if cCR was associated with improved ECS. RESULTS: This study was stopped early for not meeting a pre-specified OS endpoint and did not show survival benefit. Of 420 planned patients, 344 enrolled and 281 consented to PROs. ECS was completed by 261 (93%) at baseline, 173 (66%) 6-8 weeks post-CRT, and 117 (64%) at 1 year. At 6-8 weeks, patients receiving CRT + Cetuximab didn't have improved ECS; they experienced a lower proportion of improvement compared to standard CRT (37% vs. 53%; P = 0.04). The proportion of CRT patients with improvement in SI was 9% higher than with cetuximab, but not statistically significant (39% vs. 30%, P = 0.22). There was no association between treatment and EI. When examining ECS scores at 1 year by cCR vs. residual disease, a higher proportion of cCR patients improved, but not statistically significant (48% vs. 45%, P = 0.74). CONCLUSIONS: The addition of cetuximab to CRT for the nonoperative management of esophageal cancer did not improve PROs.

The addition of androgen deprivation therapy and pelvic lymph node treatment to prostate bed salvage radiotherapy (NRG Oncology/RTOG 0534 SPPORT): an international, multicentre, randomised phase 3 trial.

BACKGROUND: In men with a detectable prostate-specific antigen (PSA) level after prostatectomy for prostate cancer, salvage prostate bed radiotherapy (PBRT) results in about 70% of patients being free of progression at 5 years. A three-group randomised trial was designed to determine whether incremental gains in patient outcomes can be achieved by adding either 4-6 months of short-term androgen deprivation therapy (ADT) to PBRT, or both short-term ADT and pelvic lymph node radiotherapy (PLNRT) to PBRT. METHODS: The international, multicentre, randomised, controlled SPPORT trial was done at 283 radiation oncology cancer treatment centres in the USA, Canada, and Israel. Eligible patients (aged ≥18 years) were those who after prostatectomy for adenocarcinoma of the prostate had a persistently detectable or an initially undetectable and rising PSA of between 0·1 and 2·0 ng/mL. Patients with and without lymphadenectomy (N0/Nx) were eligible if there was no clinical or pathological evidence of lymph node involvement. Other eligibility criteria included pT2 or pT3 disease, prostatectomy Gleason score of 9 or less, and a Zubrod performance status of 0-1. Eligible patients were randomly assigned to receive PBRT alone at a dose of 64·8-70·2 Gy at 1·8 Gy per fraction daily (group 1), PBRT plus short-term ADT (group 2), or PLNRT (45 Gy at 1·8 Gy per fraction, and then a volume reduction made to the planning target volume for the remaining 19·8-25 ·2 Gy) plus PBRT plus short-term ADT (group 3). The primary endpoint was freedom from progression, in which progression was defined as biochemical failure according to the Phoenix definition (PSA ≥2 ng/mL over the nadir PSA), clinical failure (local, regional, or distant), or death from any cause. A planned interim analysis of 1191 patents with minimum potential follow-up time of 5 years applied a Haybittle-Peto boundary of p<0·001 (one sided) for comparison of 5-year freedom from progression rates between the treatment groups. This trial is registered with ClinicalTrials.gov, NCT00567580. The primary objectives of the trial have been completed, although long-term follow-up is continuing. FINDINGS: Between March 31, 2008, and March 30, 2015, 1792 eligible patients were enrolled and randomly assigned to the three treatment groups (592 to group 1 [PBRT alone], 602 to group 2 [PBRT plus short-term ADT], and 598 to group 3 [PLNRT plus PBRT plus short-term ADT]). 76 patients subsequently found to be ineligible were excluded from the analyses; thus, the evaluable patient population comprised 1716 patients. At the interim analysis (n=1191 patients; data cutoff May 23, 2018), the Haybittle-Peto boundary for 5-year freedom from progression was exceeded when group 1 was compared with group 3 (difference 17·9%, SE 2·9%; p<0·0001). The difference between groups 2 and 3 did not exceed the boundary (p=0·0063). With additional follow-up beyond the interim analysis (the final planned analysis; data cutoff May 26, 2021), at a median follow-up among survivors of 8·2 years (IQR 6·6-9·4), the 5-year freedom from progression rates in all 1716 eligible patients were 70·9% (95% CI 67·0-74·9) in group 1, 81·3% (78·0-84·6) in group 2, and 87·4% (84·7-90·2) in group 3. Per protocol criteria, freedom from progression in group 3 was superior to groups 1 and 2. Acute (≤3 months after radiotherapy) grade 2 or worse adverse events were significantly more common in group 3 (246 [44%] of 563 patients) than in group 2 (201 [36%] of 563; p=0·0034), which, in turn, were more common than in group 1 (98 [18%] of 547; p<0·0001). Similar findings were observed for grade 3 or worse adverse events. However, late toxicity (>3 months after radiotherapy) did not differ significantly between the groups, apart from more late grade 2 or worse blood or bone marrow events in group 3 versus group 2 (one-sided p=0·0060) attributable to the addition of PLNRT in this group. INTERPRETATION: The results of this randomised trial establish the benefit of adding short-term ADT to PBRT to prevent progression in prostate cancer. To our knowledge, these are the first such findings to show that extending salvage radiotherapy to treat the pelvic lymph nodes when combined with short-term ADT results in meaningful reductions in progression after prostatectomy in patients with prostate cancer. FUNDING: National Cancer Institute.

Circulating short chain fatty acids and fatigue in patients with head and neck cancer: A longitudinal prospective study.

Fatigue among patients with head and neck cancer (HNC) has been associated with higher inflammation. Short-chain fatty acids (SCFAs) have been shown to have anti-inflammatory and immunoregulatory effects. Therefore, this study aimed to examine the association between SCFAs and fatigue among patients with HNC undergoing treatment with radiotherapy with or without concurrent chemotherapy. Plasma SCFAs and the Multidimensional Fatigue Inventory-20 were collected prior to and one month after the completion of treatment in 59 HNC patients. The genome-wide gene expression profile was obtained from blood leukocytes prior to treatment. Lower butyrate concentrations were significantly associated with higher fatigue (p = 0.013) independent of time of assessment, controlling for covariates. A similar relationship was observed for iso/valerate (p = 0.025). Comparison of gene expression in individuals with the top and bottom 33% of butyrate or iso/valerate concentrations prior to radiotherapy revealed 1,088 and 881 significantly differentially expressed genes, respectively (raw p < 0.05). The top 10 Gene Ontology terms from the enrichment analyses revealed the involvement of pathways related to cytokines and lipid and fatty acid biosynthesis. These findings suggest that SCFAs may regulate inflammatory and immunometabolic responses and, thereby, reduce inflammatory-related symptoms, such as fatigue.

Quality-adjusted survival in women with gynecologic malignancies receiving IMRT after surgery: A Ppatient Rreported Ooutcome study of NRG oncology's RTOG 1203.

INTRODUCTION: NRG/RTOG 1203 compared 3-D conformal radiotherapy (3D CRT) to intensity-modulated radiotherapy (IMRT) in patients with endometrial or cervical cancer requiring post-operative radiotherapy after hysterectomy. The purpose of this study was to report the first quality-adjusted survival analysis comparing the two treatments. METHODS: NRG/RTOG 1203 randomized patients having undergone hysterectomy to either 3DCRT or IMRT. Stratification factors included RT dose, chemotherapy, and disease site. The EQ-5D, both index and visual analog scale (VAS), were obtained at baseline, 5 weeks after the start of RT, 4-6 weeks post RT and 1 and 3-years post RT. EQ-5D index and VAS scores along with quality-adjusted survival (QAS) were compared between treatment arms using the t-test at a two-sided significance level of 0.05. RESULTS: NRG/RTOG 1203 enrolled 289 patients of which 236 consented to participate in the patient reported outcome (PRO) assessments. QAS was higher in women treated with IMRT, 1374 vs 1333 days (p = 0.5) compared to patients treated with 3DCRT, but this difference was not statistically different. Patients treated with IMRT had less of a decline in VAS score 5 weeks post RT, -5.04, compared to patients treated with 3DCRT, -7.48, although not statistically significant (p = 0.38). CONCLUSION: This is the first report of the use of the EQ-5D comparing two radiotherapy techniques in the treatment of gynecologic malignancies after surgery. While there were no significant differences in QAS and VAS scores between patients who received IMRT vs. 3DCRT, RTOG 1203 was not powered to show statistical differences in these secondary endpoints.

A network analysis of self-reported psychoneurological symptoms in patients with head and neck cancer undergoing intensity-modulated radiotherapy.

BACKGROUND: Patients with head and neck cancer experience psychoneurological symptoms (PNS) (i.e., depression, fatigue, sleep disturbance, pain, and cognitive dysfunction) during intensity-modulated radiotherapy (IMRT) that decrease their functional status, quality of life, and survival rates. The purpose of this study was to examine and visualize the relationships among PNS within networks over time and evaluate for demographic and clinical characteristics associated with symptom networks. METHODS: A total of 172 patients (mean age, 59.8 ± 9.9 years; 73.8%, male; 79.4%, White) completed symptom questionnaires four times, namely, before IMRT (T1), 1 month (T2), 3 months (T3), and 12 months (T4) post IMRT. Network analysis was used to examine the symptom-symptom relationships among PNS. Centrality indices, including strength, closeness, and betweenness, were used to describe the degrees of symptom network interconnections. Network comparison test was used to assess the differences between two symptom networks. RESULTS: Depression was associated with the other four symptoms, and fatigue was associated with the other three symptoms across the four assessments. Based on the centrality indices, depression (rstrength  = 1.3-1.4, rcloseness  = 0.06-0.08, rbetweeness  = 4-10) was the core symptom in all symptom networks, followed by fatigue. Female gender, higher levels of stress, and no alcohol use were associated with stronger symptom networks in network global strength before IMRT. CONCLUSION: Network analysis provides a novel approach to gain insights into the relationships among self-reported PNS and identify the core symptoms and associated characteristics. Clinicians may use this information to develop symptom management interventions that target core symptoms and interconnections within a network. LAY SUMMARY: This study describes the symptom-symptom relationships for five common symptoms in patients with head and neck cancer receiving radiotherapy. Depression and fatigue appeared to be two core symptoms that were connected with sleep disturbance, pain, and cognitive dysfunction within a network. Several characteristics (i.e., female, higher stress, no alcohol use) were associated with stronger symptom networks.

Obesity and patient-reported sexual health outcomes in gynecologic cancer survivors: A systematic review.

As obesity prevalence among gynecologic cancer (GC) survivors is expected to increase, the role of obesity in sexual health needs to be understood. This systematic review examined the impact of obesity on patient-reported sexual health outcomes (SHOs) in this population. PubMed, Embase, Web of Science, CINAHL, and PsycINFO were searched for original studies published between 2015 and 2020 following the Preferred Reporting Items for Systematic Review and Meta-Analyses guideline. We performed a narrative synthesis of findings via cancer type, cancer treatment, sexual health measures, and countries. Eleven observational studies were included. Most were conducted in European countries (n = 7), reported on endometrial cancer survivors (n = 7), and defined obesity as body mass index ≥30 kg/m2 (n = 10). Studies about cervical cancer survivors reported negative effects of obesity on sexual activity and body image while studies about endometrial cancer survivors reported positive effects of obesity on vaginal/sexual symptoms. Findings suggested interaction effects of radiotherapy and obesity on SHOs. Sexual functioning measured by the Female Sexual Function Index was less likely to be associated with obesity than other SHOs. A positive effect of obesity on SHOs was only found in studies conducted in European countries. Current evidence on the association between obesity and sexual health in GC survivors lacks in both quantity and quality. To better understand the effect of obesity on SHOs in the population, more studies are needed with critical evaluations of obesity and sexual health measures, careful considerations of cancer type and treatment, and a focus on the cultural context of obesity.

Pilot Feasibility Study of a Video Intervention to Educate Patients with Breast Cancer About Clinical Trials.

The purpose of this project was to develop and test the feasibility and preliminary efficacy of a video about cancer clinical trials (CCTs) developed for breast cancer patients. We developed 2 brief 7-min videos that focused on breast cancer patients describing their experiences participating in CCTs, supplemented with doctors and research staff explaining key research concepts. One video was culturally tailored to Black patients and the other to White patients. To assess feasibility study, participants and their care providers completed a survey to evaluate their satisfaction with the video. Eligibility criteria for the study included ≥ 21 years of age, English-speaking, no prior experience participating in a CCT, and being potentially eligible for breast CCT enrollment. Preliminary efficacy was evaluated with a pretest-posttest design using a single item asking about intent to enroll in a clinical trial. The mean age of the patient sample (n = 50) was 53.0 years, and 50.0% were Black. Participants reported that the video was in the right length, useful, and easy to understand. Providers' evaluation (n = 5) revealed that viewing the video helped prepare patients for further CCT discussion. Preliminary efficacy showed no statistically significant difference in participant interest in CCT enrollment pre- and post-video. Changes in patients' intent in enrollment were associated with age and education. Culturally adapted video interventions can be helpful in supporting both patients and providers throughout the CCT education process but additional work is needed to improve enrollment into clinical trials.

Epigenetic age acceleration, fatigue, and inflammation in patients undergoing radiation therapy for head and neck cancer: A longitudinal study.

BACKGROUND: The authors measured epigenetic age acceleration (EAA) during and after cancer treatment and its association with inflammation and fatigue, which is a debilitating symptom in patients with cancer. METHODS: Patients who had head and neck cancer without distant metastases were assessed before, immediately after, and at 6 months and 12 months postradiotherapy. Blood DNA methylation was assessed using a proprietary bead chip (the Illumina MethylationEPIC BeadChip). EAA was calculated using the Levine epigenetic clock (DNAmPhenoAge), adjusted for chronological age. Fatigue was assessed using the Multidimensional Fatigue Inventory-20. Inflammatory markers were measured using standard techniques. RESULTS: Most patients (N = 133) were men, White, had advanced disease, and received concurrent chemoradiation. EAA changes over time were significant, with the largest increase (4.9 years) observed immediately after radiotherapy (P < .001). Increased EAA was associated with elevated fatigue (P = .003) over time, and patients who had severe fatigue experienced 3.1 years higher EAA than those who had low fatigue (P < .001), which was more prominent (5.6 years; P = .018) for patients who had human papillomavirus-unrelated disease at 12 months posttreatment. EAA was also positively associated with inflammatory markers, including C-reactive protein (CRP) and interleukin-6 (IL-6), over time (P < .001), and patients who had high CRP and IL-6 levels exhibited increases of 4.6 and 5.9 years, respectively, in EAA compared with those who had low CRP and IL-6 levels (P < .001). CRP and IL-6 mediated the association between EAA and fatigue (CRP: 95% CI, 0.060-0.279; IL-6: 95% CI, 0.024-0.220). CONCLUSIONS: Patients with head and neck cancer experienced increased EAA, especially immediately after treatment completion. EAA was associated with greater fatigue and inflammation, including 1 year after treatment. Inflammation may be a target to reduce the impact of age acceleration on poor functional outcomes.

Do reminder emails and past due notifications improve patient completion and institutional data submission for patient-reported outcome measures?

PURPOSE: NRG Oncology, part of the National Cancer Institute's National Clinical Trials Network, took efforts to increase patient-reported outcome measures (PROMs) completion and institutional data submission rates within clinical trials. Lack of completion diminishes power to draw conclusions and can be a waste of resources. It is hypothesized that trials with automatic email reminders and past due notifications will have PROM forms submitted more timely with higher patient completion. METHODS: Automatic emails sent to the research associate were added to selected NRG Oncology trials. Comparisons between trials with and without automatic emails were analyzed using Chi-square tests with respect to patient completion and timeliness of form submission rates. Multivariable analyses were conducted using repeated measures generalized estimating equations. If PROMs were not completed, a form providing the reason why was submitted and counted towards form submission. RESULTS: For both disease sites, form submission was significantly higher within 1 month of the form's due date for the studies with automatic emails vs. those without (prostate: 79.7% vs. 75.7%, p < 0.001; breast: 59.2% vs. 31.3%, p < 0.001). No significant differences in patient completion were observed between the breast trials. The prostate trial with automatic emails had significantly higher patient completion but this result was not confirmed in the multivariable analysis. CONCLUSIONS: Although patient completion rates were higher on trials with automatic emails, there may be confounding factors requiring future study. The automatic emails appeared to have increased the timeliness of form submission, thus supporting their continued use on NRG Oncology trials.

Exploring the Vaginal Microbiome and Intravaginal Practices in Postmenopausal Women.

BACKGROUND: Evidence suggests that intravaginal practices (IVPs) women use to cleanse their vagina or enhance sexual pleasure may be associated with unhealthy changes in the vaginal microbiome (VM). However, the effects of these practices in postmenopausal women are unknown. OBJECTIVES: The objective of this pilot study was to characterize the VM communities of postmenopausal women, identify types and frequency of IVPs, and explore associations between the VM and IVPs in postmenopausal women. METHODS: We analyzed the VM data of 21 postmenopausal women in Atlanta, Georgia, from vaginal swabs collected at a routine gynecological visit. 16S rRNA gene sequencing in the V3-V4 region was used to characterize the VM. In addition, we described the IVPs of these women, identified by using our newly developed instrument: the Vaginal Cleansing Practices Questionnaire. The associations between the VM and IVPs were explored by comparing the alpha diversities, beta diversities, and the relative abundances at both the community level and individual genus level. RESULTS: The most abundant known bacterial genus found in the VM samples was Lactobacillus (35.7%), followed by Prevotella (21.4%). Eleven women (52%) reported using at least one type of IVP since menopause. The most common type of IVP was soap and water to clean inside the vagina. The use of IVPs was not associated with any alpha diversity metric, including Shannon index, inverse Simpson index, and Chao1 index; beta diversity metric, including Bray-Curtis and Jaccard distances; nor relative abundances at the community and individual genus level. Sociodemographic factors were also not associated with any alpha diversity metric. DISCUSSION: Clinicians must assess IVPs and other vaginal and sexual hygiene practices of women of all ages to educate and promote healthy behaviors. More than half of the postmenopausal women in this pilot study use IVPs. Understanding the reasoning behind participants' use of IVPs and their perceptions of the possible effects of these practices will require further research. Although the small sample did not show associations with the VM, more extensive studies are warranted.

Association Among Glucocorticoid Receptor Sensitivity, Fatigue, and Inflammation in Patients With Head and Neck Cancer.

OBJECTIVE: Fatigued cancer patients often have high peripheral inflammation; however, the biological mechanisms of this association remain unclear. We examined whether decreased sensitivity of immune cells to the anti-inflammatory effects of glucocorticoids may contribute to inflammation and fatigue in head and neck cancer (HNC) patients during treatment. METHODS: HNC patients without distant metastasis and with curative intent (n = 77) were studied 1 week before intensity-modulated radiotherapy (IMRT) and 1 month after IMRT. At each time point, fatigue was measured by the Multidimensional Fatigue Inventory-20 along with plasma inflammation markers and glucocorticoid receptor (GR) sensitivity as determined by in vitro dexamethasone suppression of lipopolysaccharide-induced interleukin 6. Linear regression models were used. RESULTS: In contrast to our hypothesis, GR sensitivity increased during treatment; however, increased fatigue was associated with a lesser increase in GR sensitivity from baseline to 1 month after IMRT (unstandardized estimate = 4.07, p = .02). This effect was more prominent in human papillomavirus-unrelated HNCs (unstandardized estimate = 8.22, p = .002). Lower increases in GR sensitivity were also associated with increased inflammation at 1 month after IMRT as represented by C-reactive protein, interleukin 6, and tumor necrosis factor α. Addition of inflammation markers to models of GR sensitivity predicting fatigue indicated that these inflammation markers were stronger predictors of fatigue than GR sensitivity. CONCLUSIONS: Lower increases in GR sensitivity during HNC treatment were significantly predictive of increased fatigue and inflammation markers. Inflammation markers in turn predicted fatigue above and beyond levels of GR sensitivity. Our findings indicate that HNC patients with cancer-related fatigue may exhibit a decreased capacity for glucocorticoids to regulate inflammatory processes, as evidenced by a lower increase in GR sensitivity. Larger studies are necessary to verify the findings.

Pilot study of combined aerobic and resistance exercise on fatigue for patients with head and neck cancer: Inflammatory and epigenetic changes.

This pilot study examined whether a combined aerobic resistance exercise program reduced fatigue and the potential inflammatory and epigenetic mechanisms in patients with head and neck cancer (HNC) receiving intensity-modulated radiotherapy. The exercise group (N = 12) received a 3-month supervised aerobic resistance exercise intervention that was initiated before a 6-week radiotherapy regimen; the control group (N = 14) received standard care. Fatigue was measured using Multidimensional Fatigue Inventory-20; physical function measures included a 6-minute walk distance (6MWD), chair stands, bicep curls, and hand grip strength. Inflammatory markers and DNA methylation data were acquired using standardized protocol. Patients were mostly white (93%) and male (81%) with a mean age of 57 years. At the end of the intervention, the exercise group had a marginal decrease in fatigue compared with the control (-5.0 vs. 4.9; P = 0.10). The exercise group had a significantly greater improvement in 6MWD (29.8 vs. -55.5 m; P = 0.04), and a marginally smaller decline in hand grip (-0.3 vs. -5.8 lbs; P = 0.05) at the end of the intervention than the control. No significant difference in inflammatory markers was observed between groups. Lower plasma interleukin (IL) 6, IL1 receptor antagonist, tumor necrosis factor α (TNFα), soluble TNF receptor II and C-reactive protein were significantly associated with increased 6MWD, chair stand, and bicep curl at the end of the intervention (p < 0.05). Among the 1152 differentially methylated sites (DMS) after intervention (p < 0.001), 163 DMS were located in gene promoter regions. Enrichment analysis suggested that the top 10 upstream regulators were associated with tumor (HNF4A, RPP38, HOXA9, SAHM1, CDK7, NDN, RPS15) and inflammation (IRF7, CRKL, ONECUT1). The top 5 diseases or functions annotations of the 62 hypermethylated DMS indicated anti-tumor and anti-inflammatory effects that might be linked to exercise. These findings suggest that exercise may improve physical performance and reduce fatigue, which could be further linked to decreased inflammation, during active radiotherapy for HNC patients. Larger studies are warranted.

How Nurse Scientists Can Stay Productive and on Track During the Pandemic.

On March 11, 2020, with the declaration of a global pandemic by the World Health Organization, an unplanned slowdown of academic research activities has taken place. Although this is not an ideal situation for nurse scientists, it presents a number of unique opportunities for researchers to shift their focus in the short term, which may actually lead to more productivity in the long term. This commentary explores ways nurse scientists can stay on track without derailing their plans for career advancement under unprecedented circumstances.

Factors Associated with Depression in African American Patients Being Treated for Cancer Pain.

BACKGROUND: Among cancer patients in the United States, African American cancer patients have the highest mortality rate and shortest survival rate. Although depression is known as a predictor of mortality in cancer and a potential barrier to health care utilization, research on depression in African American patients is limited. Cancer pain can interfere with an individual's ability to cope with depression. AIMS: To identify factors that are associated with a positive screening of depressive symptoms assessed by the PHQ-8 in African American patients treated for cancer pain. DESIGN: Secondary data analysis of a cross-sectional study of opioid adherence. SETTING: Medical oncology, palliative care, and radiation oncology clinics in Atlanta, Georgia. PARTICIPANTS/SUBJECTS: African American patients with cancer pain in the parent study. METHODS: Independent samples t-test was used to assess variable correlations with and without depressive symptoms. Adjusted logistic regression was conducted to identify factors that were associated with presence of depressive symptoms. RESULTS: Mean patient age was 55.6 years, and nearly 38% had a PHQ-8 score of >10 indicating presence of moderate to severe depressive symptoms. Participants with depressive symptoms had significantly higher means for anxiety and pain interference with mood than those without depressive symptoms. Factors that were significantly associated with depressive symptoms were anxiety, pain interfering with mood, and lack of involvement with a religious congregation. CONCLUSIONS: The findings of this study help to identify African American cancer patients at risk for depression and demonstrates the need for increased screening for depression in this underserved population.

Expanded validation of the EPIC bowel and urinary domains for use in women with gynecologic cancer undergoing postoperative radiotherapy.

OBJECTIVE: Women with endometrial or cervical cancer at risk for recurrence receive postoperative radiation therapy (RT). A patient reported outcomes (PRO) instrument to assess bowel and urinary toxicities is the Expanded Prostate Cancer Index Composite (EPIC), which has been validated in men with prostate cancer. As this instrument specifically measures bowel toxicity and the degree to which this is a problem, it was used in NRG Oncology/RTOG 1203 to compare intensity modulated RT (IMRT) to standard RT. This paper reports on the expanded validation of EPIC for use in women receiving pelvic RT. METHODS: In addition to the EPIC bowel domain, urinary toxicity (EPIC urinary domain), patient reported bowel toxicities (PRO-CTCAE) and quality of life (Functional Assessment of Cancer Therapy (FACT)) were completed before, during and after treatment. Sensitivity, reliability and concurrent validity were assessed. RESULTS: Mean bowel and urinary scores among 278 women enrolled were significantly worse during treatment and differed between groups. Acceptable to good reliability for bowel and urinary domain scores were obtained at all time points with the exception of one at baseline. Correlations between function and bother scores within the bowel and urinary domains were consistently stronger than those across domains. Correlations between bowel domain scores and PRO-CTCAE during treatment were stronger than those with the FACT. CONCLUSION: Correlations within and among the instruments indicate EPIC bowel and urinary domains are measuring conceptually discrete components of health. These EPIC domains are valid, reliable and sensitive instruments to measure PRO among women undergoing pelvic radiation.

Associations among human papillomavirus, inflammation, and fatigue in patients with head and neck cancer.

BACKGROUND: Human papillomavirus (HPV) infection has contributed to an increased incidence of squamous cell carcinoma of the head and neck (SCCHN). Fatigue is a major side effect of SCCHN and its treatment. However, to the authors' knowledge, the association between HPV and fatigue has not been examined to date, nor is it known whether HPV influences biological mechanisms of fatigue, including inflammation. METHODS: Patients with SCCHN who were without distant metastasis were assessed at baseline (pre-radiotherapy) and 1 month and 3 months postradiotherapy. Fatigue was measured using the Multidimensional Fatigue Inventory. Peripheral inflammation was assessed by plasma C-reactive protein (CRP), interleukin 1 receptor antagonist (IL-1ra), soluble tumor necrosis factor receptor 2 (sTNFR2), and IL-6. Mixed effect models were used to examine associations. RESULTS: A total of 94 patients who were newly diagnosed were enrolled; 53% had HPV-related tumors. Patients with HPV-unrelated tumors had higher fatigue and higher plasma CRP, sTNFR2, and IL-6 over time, especially at baseline and 3 months after intensity-modulated radiotherapy compared with those with HPV-related tumors (all P < .05). However, fatigue and plasma sTNFR2 increased more significantly from baseline to 1 month after radiotherapy in the HPV-related group compared with the HPV-unrelated group (both P < .01). Controlling for significant covariates, HPV status and inflammation were found to be independent predictors of fatigue over time. CONCLUSIONS: HPV status is an important marker of vulnerability to the behavioral and immune consequences of SCCHN and its treatment, providing support for different symptom management strategies. Special emphasis should be placed on addressing marked persistent fatigue in patients with HPV-unrelated tumors, whereas attention should be paid to the large increases in fatigue during treatment among patients with HPV-related tumors. Cancer 2018. © 2018 American Cancer Society.

Differential regulation of NF-kB and IRF target genes as they relate to fatigue in patients with head and neck cancer.

Previous studies have linked plasma inflammatory markers to elevated fatigue in patients with head and neck cancer (HNC). To identify the molecular mechanisms underlying this association, we conducted promoter-based bioinformatics analyses to determine the relationship between fatigue and specific gene expression profiles associated with inflammation in human papillomavirus (HPV)-related and -unrelated HNC patients undergoing treatment. Patients with newly diagnosed HNC without distant metastasis were assessed at baseline (pre-radiotherapy) and one-month post-radiotherapy. Fatigue was measured by the Multidimensional Fatigue Inventory. Genome-wide gene expression profiles were collected from peripheral blood mononuclear cells (PBMC). Promoter-based bioinformatics analyses were employed to identify transcription control pathways underlying transcriptomic correlates of fatigue in the sample as a whole and in HPV-related and HPV-unrelated HNC patients separately. In transcriptome profiling analyses of PBMC from 44 patients, TELiS bioinformatics analyses linked fatigue to increased nuclear factor-kappa B (NF-kB) transcriptional activity and decreased interferon regulatory factor family (IRF) transcription factor activity. Patients with HPV-related HNC showed lower levels of fatigue-related gene expression profile compared to HPV-unrelated HNC. Fatigue in HNC patients undergoing treatment is associated with gene expression profiles consistent with the conserved transcriptional response to adversity (CTRA) characterized by increased proinflammatory and decreased anti-antiviral transcriptional activity. Interestingly, this CTRA response was mitigated in patients with HPV-related HNC and may explain the lower level of fatigue they experience relative to HPV-unrelated HNC.

Cultural Competency Training to Increase Minority Enrollment into Radiation Therapy Clinical Trials-an NRG Oncology RTOG Study.

Despite initiatives to increase the enrollment of racial and ethnic minorities into cancer clinical trials in the National Cancer Institute National Cancer Clinical Trials Network (NCCTN), participation by Latino and African American populations remain low. The primary aims of this pilot study are (1) to develop a Cultural Competency and Recruitment Training Program (CCRTP) for physician investigators and clinical research associates (CRAs), (2) to determine if the CCRTP increases cultural competency scores among physician investigators and CRAs, and (3) to determine the impact of the CCRTP on minority patient recruitment into NRG Oncology Radiation Therapy Oncology Group (RTOG) clinical trials. Sixty-seven CRAs and physicians participated in an in-person or online 4-h CRRTP training. Five knowledge and attitude items showed significant improvements from pre- to post-training. A comparison between enrolling sites that did and did not participate in the CCRTP demonstrated a pre to 1-year post-incremental increase in minority accrual to clinical trials of 1.2 % among participating sites. While not statistically significant, this increase translated into an additional 300 minority patients accrued to NCCTN clinical trials in the year following the training from those sites who participated in the training.