Genetic, epigenetic and environmental factors in diverticular disease: systematic review.

BACKGROUND: Diverticulosis is a normal anatomical variant of the colon present in more than 70% of the westernized population over the age of 80. Approximately 3% will develop diverticulitis in their lifetime. Many patients present emergently, suffer high morbidity rates and require substantial healthcare resources. Diverticulosis is the most common finding at colonoscopy and has the potential for causing a significant morbidity rate and burden on healthcare. There is a need to better understand the aetiology and pathogenesis of diverticular disease. Research suggests a genetic susceptibility of 40-50% in the formation of diverticular disease. The aim of this review is to present the hypothesized functional effects of the identified gene loci and environmental factors. METHODS: A systematic literature review was performed using PubMed, MEDLINE and Embase. Medical subject headings terms used were: 'diverticular disease, diverticulosis, diverticulitis, genomics, genetics and epigenetics'. A review of grey literature identified environmental factors. RESULTS: Of 995 articles identified, 59 articles met the inclusion criteria. Age, obesity and smoking are strongly associated environmental risk factors. Intrinsic factors of the colonic wall are associated with the presence of diverticula. Genetic pathways of interest and environmental risk factors were identified. The COLQ, FAM155A, PHGR1, ARHGAP15, S100A10, and TNFSF15 genes are the strongest candidates for further research. CONCLUSION: There is increasing evidence to support the role of genomics in the spectrum of diverticular disease. Genomic, epigenetic and omic research with demographic context will help improve the understanding and management of this complex disease.

BUB1 regulates non-homologous end joining pathway to mediate radioresistance in triple-negative breast cancer.

Background: Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer subtype often treated with radiotherapy (RT). Due to its intrinsic heterogeneity and lack of effective targets, it is crucial to identify novel molecular targets that would increase RT efficacy. Here we demonstrate the role of BUB1 (cell cycle Ser/Thr kinase) in TNBC radioresistance and offer a novel strategy to improve TNBC treatment. Methods: Gene expression analysis was performed to look at genes upregulated in TNBC patient samples compared to other subtypes. Cell proliferation and clonogenic survivals assays determined the IC 50 of BUB1 inhibitor (BAY1816032) and radiation enhancement ratio (rER) with pharmacologic and genomic BUB1 inhibition. Mammary fat pad xenografts experiments were performed in CB17/SCID. The mechanism through which BUB1 inhibitor sensitizes TNBC cells to radiotherapy was delineated by γ-H2AX foci assays, BLRR, Immunoblotting, qPCR, CHX chase, and cell fractionation assays. Results: BUB1 is overexpressed in BC and its expression is considerably elevated in TNBC with poor survival outcomes. Pharmacological or genomic ablation of BUB1 sensitized multiple TNBC cell lines to cell killing by radiation, although breast epithelial cells showed no radiosensitization with BUB1 inhibition. Kinase function of BUB1 is mainly accountable for this radiosensitization phenotype. BUB1 ablation also led to radiosensitization in TNBC tumor xenografts with significantly increased tumor growth delay and overall survival. Mechanistically, BUB1 ablation inhibited the repair of radiation-induced DNA double strand breaks (DSBs). BUB1 ablation stabilized phospho-DNAPKcs (S2056) following RT such that half-lives could not be estimated. In contrast, RT alone caused BUB1 stabilization, but pre-treatment with BUB1 inhibitor prevented stabilization (t 1/2 , ∼8 h). Nuclear and chromatin-enriched fractionations illustrated an increase in recruitment of phospho- and total-DNAPK, and KAP1 to chromatin indicating that BUB1 is indispensable in the activation and recruitment of non-homologous end joining (NHEJ) proteins to DSBs. Additionally, BUB1 staining of TNBC tissue microarrays demonstrated significant correlation of BUB1 protein expression with tumor grade. Conclusions: BUB1 ablation sensitizes TNBC cell lines and xenografts to RT and BUB1 mediated radiosensitization may occur through NHEJ. Together, these results highlight BUB1 as a novel molecular target for radiosensitization in women with TNBC.

Pharmacological reprogramming of zebrafish lateral line supporting cells to a migratory progenitor state.

In the zebrafish lateral line, non-sensory supporting cells readily re-enter the cell cycle to generate new hair cells and supporting cells during homeostatic maintenance and following damage to hair cells. This contrasts with supporting cells from mammalian vestibular and auditory sensory epithelia which rarely re-enter the cell cycle, and hence loss of hair cells results in permanent sensory deficit. Lateral line supporting cells are derived from multipotent progenitor cells that migrate down the trunk midline as a primordium and are deposited to differentiate into a neuromast. We have found that we can revert zebrafish support cells back to a migratory progenitor state by pharmacologically altering the signaling environment to mimic that of the migratory primordium, with active Wnt signaling and repressed FGF signaling. The reverted supporting cells migrate anteriorly and posteriorly along the horizontal myoseptum and will re-epithelialize to form an increased number of neuromasts along the midline when the pharmacological agents are removed. These data demonstrate that supporting cells can be readily reprogrammed to a migratory multipotent progenitor state that can form new sensory neuromasts, which has important implications for our understanding of how the lateral line system matures and expands in fish and also suggest avenues for returning mammalian supporting cells back to a proliferative state.

Identifying Factors Associated With Disparities in Access to Integrative Oncology Program.

CONTEXT AND OBJECTIVES: Cancer centers are increasingly providing complementary medicine as part of an emerging discipline termed 'integrative oncology' (IO). The present study explored factors associated with disparities in referral and adherence to a freely-provided IO program. METHODS: The databases of three oncology centers in northern Israel were searched retrospectively for chemotherapy-treated oncology patients eligible for referral by their oncology healthcare professionals to an integrative physician (IP) consultation. Demographic and cancer-related variables associated with the referral, and attendance by patients at the consultation were identified, as was adherence to the 6-week IO treatment program (high adherence, attending ≥4 IO treatment sessions; low adherence, 0-3 sessions). RESULTS: Of 4988 eligible patients, 1694 (34%) were referred to the IP consultation, with 1331 (78.6%) attending the consultation of which 766 (57.6%) were adherent to IO treatments. Multivariate analysis revealed lower referral rates among patients speaking primarily Arabic and Russian vs. Hebrew (OR = 3.0, 95% CI = 2.0-4.6, P < 0.0001); males vs. females (OR = 1.94, CI = 1.3-2.9, P = 0.001); those not reporting emotional distress (OR = 1.5, CI = 1.02-2.16, P = 0.037); and older age (OR = 1.04, CI = 1.03-1.06, P < 0.0001). Arabic and Russian-speaking patients were less likely to adhere to IO treatments (OR = 0.52, 95% CI = 0.32-0.83, P = 0.006). CONCLUSION: Patients' ethno-national origin and immigration status (primary language, Arabic and Russian), male gender and older age were associated with lower rates of referral to and attendance of the IP consultation, with reduced adherence to weekly IO treatments. These findings require further study to identify barriers toward diversity, equity and inclusion in IO care, increasing awareness among healthcare professionals regarding the benefits of these services for improving patient wellbeing.

Are We Missing Acute Toxicities Associated With Hypofractionated Breast Irradiation? A Report From a Large Multicenter Cohort Study.

PURPOSE: The efficacy and long-term safety of hypofractionated whole breast irradiation (HF-WBI) have been established through multiple randomized trials, yet data about acute toxicities remain more limited. Since 2013, our group has prospectively collected acute toxicity data from weekly treatment evaluations and additional assessment after completion. In 2016, we intentionally shifted the posttreatment assessment follow-up visit from 1 month to 2 weeks to evaluate for missed acute toxicity occurring in that immediate posttreatment window. Here, we report whether 2-week follow-up has resulted in increased detection of acute toxicities compared with 4-week follow-up. METHODS AND MATERIALS: We prospectively compared acute toxicity for patients treated with HF-WBI between January 1, 2013, and August 31, 2015 (4 week follow-up cohort) to patients treated between January 1, 2016, and August 31, 2018 (2 week follow-up cohort). Analyses included a multivariable model that adjusted for other factors known to correlate with toxicity. We prospectively defined acute toxicity as maximum breast pain (moderate or severe rating) and/or occurrence of moist desquamation reported 7 days before the completion of radiation therapy (RT) until 42 days after completion. RESULTS: A total of 2689 patients who received postlumpectomy radiation and boost were analyzed; 1862 patients in the 2-week follow-up cohort and 827 in the 4-week follow-up cohort. All acute toxicity measures assessed were statistically similar between follow-up cohorts when compared in an unadjusted fashion. Overall acute composite toxicity was 26.4% and 27.7% for patients in the 4-week follow-up and 2-week follow-up cohorts, respectively. Overall acute composite toxicity remained similar between follow-up cohorts in a multivariable, adjusted model and was significantly related to patient's age, body mass index, smoking status, and treatment technique (intensity-modulated RT vs 3-dimensional conformal radiation therapy) but not follow-up cohort. CONCLUSIONS: An earlier posttreatment follow-up for HF-WBI patients did not reveal a significant increased incidence of acute toxicities at 2 weeks compared with 4 weeks. This study provides physicians and patients with additional data on the safety and tolerability of HF-WBI for early stage breast cancer.

American Radium Society Appropriate Use Criteria Postmastectomy Radiation Therapy: Executive Summary of Clinical Topics.

PURPOSE: To conduct an appropriate use criteria expert panel update on clinical topics relevant to current clinical practice regarding postmastectomy radiation therapy (PMRT). METHODS AND MATERIALS: An analysis of the medical literature from peer-reviewed journals was conducted from May 4, 2010 to May 4, 2022 using the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines to search the PubMed database to retrieve a comprehensive set of relevant articles. A well-established methodology (modified Delphi) was used by the expert panel to rate the appropriate use of procedures. RESULTS: Evidence for key questions in PMRT regarding benefit in special populations and technical considerations for delivery was examined and described. Risk factors for local-regional recurrence in patients with intermediate-risk disease that indicate benefit of PMRT include molecular subtype, age, clinical stage, and pathologic response to neoadjuvant chemotherapy. Use of hypofractionated radiation in PMRT has been examined in several recent randomized trials and is under investigation for patients with breast reconstruction. The use of bolus varies significantly by practice region and has limited evidence for routine use. Adverse effects occurred with both PMRT preimplant and postimplant exchange in 2-staged breast reconstruction. CONCLUSIONS: Most patients with even limited nodal involvement will likely benefit from PMRT with significant reduction in local-regional recurrence and potential survival. Patients with initial clinical stage III disease and/or any residual disease after neoadjuvant chemotherapy should be strongly considered for PMRT. Growing evidence supports the use of hypofractionated radiation for PMRT with equivalent efficacy and decreased acute side effects, but additional evidence is needed for special populations. There is limited evidence to support routine use of bolus in all patients. Timing of PMRT regarding completion of 2-staged breast reconstruction requires a discussion of increased risks with radiation postimplant exchange compared with increased risk of failure of reconstruction or surgical complications with radiation preimplant exchange.

Factors Associated With Cardiac Radiation Dose Reduction After Hypofractionated Radiation Therapy for Localized, Left-Sided Breast Cancer in a Large Statewide Quality Consortium.

PURPOSE: Limiting cardiac radiation dose is important for minimizing long-term cardiac toxicity in patients with left-sided early-stage breast cancer. METHODS AND MATERIALS: Prospectively collected dosimetric data were analyzed for patients undergoing moderately hypofractionated radiation therapy to the left breast within the Michigan Radiation Oncology Quality Consortium from 2016 to 2022. The mean heart dose (MHD) goal was progressively tightened from ≤2 Gy in 2016 to MHD ≤ 1.2 Gy in 2018. In 2021, a planning target volume (PTV) coverage goal was added, and the goal MHD was reduced to ≤1 Gy. Multivariate logistic regression models were developed to assess for covariates associated with meeting the MHD goals in 2016 to 2020 and the combined MHD/PTV coverage goal in 2021 to 2022. RESULTS: In total, 4165 patients were analyzed with a median age of 64 years. Overall average cardiac metric compliance was 91.7%. Utilization of motion management increased from 41.8% in 2016 to 2020 to 46.5% in 2021 to 2022. Similarly, use of prone positioning increased from 12.2% to 22.2% in these periods. On multivariate analysis in the 2016 to 2020 cohort, treatment with motion management (odds ratio [OR], 5.20; 95% CI, 3.59-7.54; P < .0001) or prone positioning (OR, 3.21; 95% CI, 1.85-5.57; P < .0001) was associated with meeting the MHD goal, while receipt of boost (OR, 0.25; 95% CI, 0.17-0.39; P < .0001) and omission of hormone therapy (OR, 0.65; 95% CI, 0.49-0.88; P = .0047) were associated with not meeting the MHD goal. From 2021 to 2022, treatment with motion management (OR, 1.89; 95% CI, 1.12-3.21; P = .018) or prone positioning (OR, 3.71; 95% CI, 1.73-7.95; P = .0008) was associated with meeting the combined MHD/PTV goal, while larger breast volume (≥1440 cc; OR, 0.34; 95% CI, 0.13-0.91; P = .031) was associated with not meeting the combined goal. CONCLUSIONS: In our statewide consortium, high rates of compliance with aggressive targets for limiting cardiac dose were achievable without sacrificing target coverage.

Impact of the Integrative Oncology Scholars Program on Oncology Providers' Key Knowledge of Dietary Supplements and Antioxidants for Providing Evidence-based Oncology Care.

Dietary supplements are commonly used among cancer survivors. Oncology providers rarely receive training about dietary supplements. We evaluated whether e-learning modules could improve oncology providers' dietary supplement knowledge. Oncology providers participated in the National Cancer Institute funded Integrative Oncology Scholars (IOS) program. We used posttest readiness assurance tests (RAT) to measure knowledge acquisition from modules. One cohort completed a pre and posttest RAT to assess change in knowledge. Multivariate linear regression models adjusted for gender, race, profession, and years in practice were used to determine if these characteristics were associated with posttest RAT performance and change in pre to posttest RAT scores. Scholars (N = 101) included 86% (N = 87) females; age 44 ± 10 years; 72% (N = 73) Non-Hispanic White; years in practice mean range 11-15 ± 10. There were 37 physicians, 11 physician assistants, 23 nurses, 21 social workers, 2 psychologists, 4 pharmacists, and 2 physical therapists. The posttest dietary supplement and antioxidant RAT scores for all Scholars were 67 ± 18% and 71 ± 14%. In adjusted models there were no significant associations between dietary supplement and antioxidant posttest RAT scores with Scholar characteristics. Change in RAT scores for dietary supplement and antioxidants were 25% ± 23 and 26% ± 27 (P < 0.0001). In adjusted models, there were no significant predictors of change in dietary supplement RATs. For antioxidant RATs, profession was associated with change in scores (P = 0.021). Improvement in Scholar's test scores demonstrate the IOS program can significantly increase oncology providers' knowledge of dietary supplements and antioxidants.

Cardiac Rehabilitation Improves Fitness in Patients With Subclinical Markers of Cardiotoxicity While Receiving Chemotherapy: A RANDOMIZED CONTROLLED STUDY.

PURPOSE: Heart failure (HF) due to cardiotoxicity is a leading non-cancer-related cause of morbidity and mortality in cancer survivors. Cardiac rehabilitation (CR) improves cardiorespiratory fitness (CRF) and reduces morbidity and mortality in patients with HF, but little is known about its effects on cardiotoxicity in the cancer population. The objective of this study was to determine whether participation in CR improves CRF in patients undergoing treatment with either doxorubicin or trastuzumab who exhibit markers of subclinical cardiotoxicity. METHODS: Female patients with cancer (n = 28: breast, n = 1: leiomyosarcoma) and evidence of subclinical cardiotoxicity (ie, >10% relative decrease in global longitudinal strain or a cardiac troponin of >40 ng·L -1 ) were randomized to 10 wk of CR or usual care. Exercise consisted of 3 d/wk of interval training at 60-90% of heart rate reserve. RESULTS: Cardiorespiratory fitness, as measured by peak oxygen uptake (V˙ o2peak ), improved in the CR group (16.9 + 5.0 to 18.5 + 6.0 mL∙kg -1 ∙min -1 ) while it decreased in the usual care group (17.9 + 3.9 to 16.9 + 4.0 mL∙kg -1 ∙min -1 ) ( P = .009). No changes were observed between groups with respect to high-sensitivity troponin or global longitudinal strain. CONCLUSION: This study suggests that the use of CR may be a viable option to attenuate the reduction in CRF that occurs in patients undergoing cardiotoxic chemotherapy. The long-term effects of exercise on chemotherapy-induced HF warrant further investigation.

Integrative Medicine for Pain Management in Oncology: Society for Integrative Oncology-ASCO Guideline.

PURPOSE: The aim of this joint guideline is to provide evidence-based recommendations to practicing physicians and other health care providers on integrative approaches to managing pain in patients with cancer. METHODS: The Society for Integrative Oncology and ASCO convened an expert panel of integrative oncology, medical oncology, radiation oncology, surgical oncology, palliative oncology, social sciences, mind-body medicine, nursing, and patient advocacy representatives. The literature search included systematic reviews, meta-analyses, and randomized controlled trials published from 1990 through 2021. Outcomes of interest included pain intensity, symptom relief, and adverse events. Expert panel members used this evidence and informal consensus to develop evidence-based guideline recommendations. RESULTS: The literature search identified 227 relevant studies to inform the evidence base for this guideline. RECOMMENDATIONS: Among adult patients, acupuncture should be recommended for aromatase inhibitor-related joint pain. Acupuncture or reflexology or acupressure may be recommended for general cancer pain or musculoskeletal pain. Hypnosis may be recommended to patients who experience procedural pain. Massage may be recommended to patients experiencing pain during palliative or hospice care. These recommendations are based on an intermediate level of evidence, benefit outweighing risk, and with moderate strength of recommendation. The quality of evidence for other mind-body interventions or natural products for pain is either low or inconclusive. There is insufficient or inconclusive evidence to make recommendations for pediatric patients. More research is needed to better characterize the role of integrative medicine interventions in the care of patients with cancer.Additional information is available at https://integrativeonc.org/practice-guidelines/guidelines and www.asco.org/survivorship-guidelines.

Mediators of Racial Disparities in Heart Dose Among Whole Breast Radiotherapy Patients.

BACKGROUND: Racial disparities in survival of patients with cancer motivate research to quantify treatment disparities and evaluate multilevel determinants. Previous research has not evaluated cardiac radiation dose in large cohorts of breast cancer patients by race nor examined potential causes or implications of dose disparities. METHODS: We used a statewide consortium database to consecutively sample 8750 women who received whole breast radiotherapy between 2012 and 2018. We generated laterality- and fractionation-specific models of mean heart dose. We generated patient- and facility-level models to estimate race-specific cardiac doses. We incorporated our data into models to estimate disparities in ischemic cardiac event development and death. All statistical tests were 2-sided. RESULTS: Black and Asian race independently predicted higher mean heart dose for most laterality-fractionation groups, with disparities of up to 0.42 Gy for Black women and 0.32 Gy for Asian women (left-sided disease and conventional fractionation: 2.13 Gy for Black women vs 1.71 Gy for White women, P < .001, 2-sided; left-sided disease and accelerated fractionation: 1.59 Gy for Asian women vs 1.27 Gy for White women, P = .002). Patient clustering within facilities explained 22%-30% of the variability in heart dose. The cardiac dose disparities translated to estimated excesses of up to 2.6 cardiac events and 1.3 deaths per 1000 Black women and 0.7 cardiac events and 0.3 deaths per 1000 Asian women vs White women. CONCLUSIONS: Depending on laterality and fractionation, Asian women and Black women experience higher cardiac doses than White women. This may translate into excess radiation-associated ischemic cardiac events and deaths. Solutions include addressing inequities in baseline cardiac risk factors and facility-level availability and use of radiation technologies.

MRI-guided Radiotherapy (MRgRT) for Treatment of Oligometastases: Review of Clinical Applications and Challenges.

PURPOSE: Early clinical results on the application of magnetic resonance imaging (MRI) coupled with a linear accelerator to deliver Magnetic Resonance-guided Radiation Therapy (MRgRT) have demonstrated feasibility for safe delivery of stereotactic body radiation therapy in treatment of oligometastatic disease. Here, we set out to review the clinical evidence and challenges associated with MRgRT in this setting. METHODS AND MATERIALS: We performed a systematic review of the literature pertaining to clinical experiences and trials on the use of MRgRT primarily for the treatment of oligometastatic cancers. We reviewed the opportunities and challenges associated with the use of MRgRT. RESULTS: Benefits of MRgRT pertaining to superior soft-tissue contrast, real-time imaging and gating, and online adaptive radiation therapy facilitate safe and effective dose escalation to oligometastatic tumors while simultaneously sparing surrounding healthy tissues. Challenges concerning further need for clinical evidence and technical considerations related to planning, delivery, quality assurance of hypofractionated doses, and safety in the MRI environment must be considered. CONCLUSIONS: The promising early indications of safety and effectiveness of MRgRT for stereotactic body radiation therapy-based treatment of oligometastatic disease in multiple treatment locations should lead to further clinical evidence to demonstrate the benefit of this technology.

A Scoping Review of Strategies to Increase Black Enrollment and Retention in Cancer Clinical Trials.

To address health disparities faced by Black patients with cancer, it is critical that researchers conducting cancer clinical trials (CCTs) equitably recruit and retain Black participants, develop strategies toward this aim, and document associated outcomes. This narrative scoping literature review, as part of a larger study, aimed to identify, describe, and categorize strategies and interventions intended to improve the recruitment and retention of Black participants with breast, lung, prostate, colorectal, or multiple myeloma cancer into CCTs. We conducted comprehensive searches in PubMed, Embase, Cochrane Library, PsycInfo, CINAHL, Scopus, and Web of Science with three main concepts: Black persons, neoplasms, and clinical trial recruitment. The search resulted in 1,506 articles, of which 15 met inclusion criteria. Five main categories of recruitment and retention strategies and interventions were identified based on their specific population focus and type of approach: (1) participant identification, (2) provider awareness/resources, (3) focused research staff interventions, (4) patient and community-focused awareness strategies, and (5) participant-directed resources. Thirteen studies had recruitment acceptance rates of over 30%. Eight studies with acceptance rates of ≥ 50% reported implementing ≥ 5 strategies, with an average use of seven strategies across multiple categories. Five studies with acceptance rates ≥ 50% implemented strategies in ≥ 3 categories. Four studies reported retention rates ≥ 74%. Three studies with reported retention rates ≥ 74% used strategies in ≥ 3 categories, and all included strategies aimed at meeting participant needs beyond the study. Our results show that many efforts that aim to increase the recruitment and retention of Black participants into CCTs have great potential, but the most promising strategies use a multiprong approach.

Identifying Patients Whose Symptoms Are Underrecognized During Treatment With Breast Radiotherapy.

Importance: Understanding whether physicians accurately detect symptoms in patients with breast cancer is important because recognition of symptoms facilitates supportive care, and clinical trials often rely on physician assessments using Common Toxicity Criteria for Adverse Events (CTCAE). Objective: To compare the patient-reported outcomes (PROs) of patients with breast cancer who received radiotherapy from January 1, 2012, to March 31, 2020, with physicians' CTCAE assessments to assess underrecognition of symptoms. Design, Setting, and Participants: This cohort study included a total of 29 practices enrolled in the Michigan Radiation Oncology Quality Consortium quality initiative. Of 13 725 patients with breast cancer who received treatment with radiotherapy after undergoing lumpectomy, 9941 patients (72.4%) completed at least 1 PRO questionnaire during treatment with radiotherapy and were evaluated for the study. Of these, 9868 patients (99.3%) were matched to physician CTCAE assessments that were completed within 3 days of the PRO questionnaires. Exposures: Patient and physician ratings of 4 symptoms (pain, pruritus, edema, and fatigue) were compared. Main Outcomes and Measures: We used multilevel multivariable logistic regression to evaluate factors associated with symptom underrecognition, hypothesizing that it would be more common in racial and ethnic minority groups. Results: Of 9941 patients, all were female, 1655 (16.6%) were Black, 7925 (79.7%) were White, and 361 (3.6%) had Other race and ethnicity (including American Indian/Alaska Native, Arab/Middle Eastern, and Asian), either as self-reported or as indicated in the electronic medical record. A total of 1595 (16.0%) were younger than 50 years, 2874 (28.9%) were age 50 to 59 years, 3353 (33.7%) were age 60 to 69 years, and 2119 (21.3%) were 70 years or older. Underrecognition of symptoms existed in 2094 of 6781 (30.9%) observations of patient-reported moderate/severe pain, 748 of 2039 observations (36.7%) of patient-reported frequent pruritus, 2309 of 4492 observations (51.4%) of patient-reported frequent edema, and 390 of 2079 observations (18.8%) of patient-reported substantial fatigue. Underrecognition of at least 1 symptom occurred at least once for 2933 of 5510 (53.2%) of those who reported at least 1 substantial symptom. Factors independently associated with underrecognition were younger age (younger than 50 years compared with 60-69 years: odds ratio [OR], 1.35; 95% CI, 1.14-1.59; P < .001; age 50-59 years compared with 60-69 years: OR, 1.19; 95% CI, 1.03-1.37; P = .02), race (Black individuals compared with White individuals: OR, 1.56; 95% CI 1.30-1.88; P < .001; individuals with Other race or ethnicity compared with White individuals: OR, 1.52; 95% CI, 1.12-2.07; P = .01), conventional fractionation (OR, 1.26; 95% CI, 1.10-1.45; P = .002), male physician sex (OR, 1.54; 95% CI, 1.20-1.99; P = .002), and 2-field radiotherapy (without a supraclavicular field) (OR, 0.80; 95% CI, 0.67-0.97; P = .02). Conclusions and Relevance: The results of this cohort study suggest that PRO collection may be essential for trials because relying on the CTCAE to detect adverse events may miss important symptoms. Moreover, since physicians in this study systematically missed substantial symptoms in certain patients, including younger patients and Black individuals or those of Other race and ethnicity, improving symptom detection may be a targetable mechanism to reduce disparities.

Characterizing Sensitive Cardiac Substructure Excursion Due to Respiration.

PURPOSE: Whole-heart dose metrics are not as strongly linked to late cardiac morbidities as radiation doses to individual cardiac substructures. Our aim was to characterize the excursion and dosimetric variation throughout respiration of sensitive cardiac substructures for future robust safety margin design. METHODS AND MATERIALS: Eleven patients with cancer treatments in the thorax underwent 4-phase noncontrast 4-dimensional computed tomography (4DCT) with T2-weighted magnetic resonance imaging in end-exhale. The end-exhale phase of the 4DCT was rigidly registered with the magnetic resonance imaging and refined with an assisted alignment surrounding the heart from which 13 substructures (chambers, great vessels, coronary arteries, etc) were contoured by a radiation oncologist on the 4DCT. Contours were deformed to the other respiratory phases via an intensity-based deformable registration for radiation oncologist verification. Measurements of centroid and volume were evaluated between phases. Mean and maximum dose to substructures were evaluated across respiratory phases for the breast (n = 8) and thoracic cancer (n = 3) cohorts. RESULTS: Paired t tests revealed reasonable maintenance of geometric and anatomic properties (P < .05 for 4/39 volume comparisons). Maximum displacements >5 mm were found for 24.8%, 8.5%, and 64.5% of the cases in the left-right, anterior-posterior, and superior-inferior axes, respectively. Vector displacements were largest for the inferior vena cava and the right coronary artery, with displacements up to 17.9 mm. In breast, the left anterior descending artery Dmean varied 3.03 ± 1.75 Gy (range, 0.53-5.18 Gy) throughout respiration whereas lung showed patient-specific results. Across all patients, whole heart metrics were insensitive to breathing phase (mean and maximum dose variations <0.5 Gy). CONCLUSIONS: This study characterized the intrafraction displacement of the cardiac substructures through the respiratory cycle and highlighted their increased dosimetric sensitivity to local dose changes not captured by whole heart metrics. Results suggest value of cardiac substructure margin generation to enable more robust cardiac sparing and to reduce the effect of respiration on overall treatment plan quality.

The Impact of Chemotherapy on Toxic Effects and Cosmetic Outcome in Patients Receiving Whole Breast Irradiation: An Analysis Within a Statewide Quality Consortium.

PURPOSE: We investigated whether the use of chemotherapy before whole breast irradiation (WBI) using either conventional fractionation (CWBI) or hypofractionation (HWBI) is associated with increased toxic effects or worse cosmetic outcome compared with WBI alone. METHODS AND MATERIALS: We identified 6754 patients who received WBI alone (without a third field covering the superior axillary and supraclavicular nodal regions) with data prospectively collected in a statewide consortium. We reported rates of 4 toxic effects: physician-reported acute moist desquamation, patient-reported acute moderate/severe breast pain, a composite acute toxic effect measure (including moist desquamation and either patient- or physician-reported moderate/significant breast pain), and physician-reported impaired cosmetic outcome at 1 year after WBI. Successive multivariable models were constructed to estimate the effect of chemotherapy on these outcomes. RESULTS: Rates of moist desquamation, patient-reported pain, composite acute toxic effects, and impaired cosmetic outcome were 23%, 34%, 42%, and 10% for 2859 patients receiving CWBI and 13%, 28%, 31%, and 11% for 3895 patients receiving HWBI. Receipt of chemotherapy before CWBI was not associated with higher rates of patient-reported pain, composite acute toxic effects, or impaired cosmetic outcome compared with CWBI without chemotherapy but was associated with more moist desquamation (odds ratio, 1.32 [1.07-1.63]; P = .01). Receipt of chemotherapy before HWBI was not associated with higher rates of any of the 4 toxic effects compared with HWBI alone. CONCLUSIONS: In this cohort, use of chemotherapy before WBI was generally well tolerated. CWBI with chemotherapy but not HWBI with chemotherapy was associated with higher rates of moist desquamation. Rates of acute breast pain and impaired cosmetic outcome at 1 year were comparable in patients receiving chemotherapy before either CWBI or HWBI. These data support the use of HWBI after chemotherapy.

Cardiac Magnetic Resonance Imaging and Blood Biomarkers for Evaluation of Radiation-Induced Cardiotoxicity in Patients With Breast Cancer: Results of a Phase 2 Clinical Trial.

PURPOSE: Radiation therapy (RT) can increase the risk of cardiac events in patients with breast cancer (BC), but biomarkers predicting risk for developing RT-induced cardiac disease are currently lacking. We report results from a prospective clinical trial evaluating early magnetic resonance imaging (MRI) and serum biomarker changes as predictors of cardiac injury and risk of subsequent cardiac events after RT for left-sided disease. METHODS: Women with node-negative and node-positive (N-/+) left-sided BC were enrolled on 2 institutional review board (IRB)-approved protocols at 2 institutions. MRI was conducted pretreatment (within 1 week of starting radiation), at the end of treatment (last day of treatment ±1 week), and 3 months after the last day of treatment (±2 weeks) to quantify left and right ventricular volumes and function, myocardial fibrosis, and edema. Perfusion changes during regadenoson stress perfusion were also assessed on a subset of patients (n = 28). Serum was collected at the same time points. Whole heart and cardiac substructures were contoured using CT and MRI. Models were constructed using baseline cardiac and clinical risk factors. Associations between MRI-measured changes and dose were evaluated. RESULTS: Among 51 women enrolled, mean heart dose ranged from 0.80 to 4.7 Gy and mean left ventricular (LV) dose from 1.1 to 8.2 Gy, with mean heart dose 2.0 Gy. T1 time, a marker of fibrosis, and right ventricular (RV) ejection fraction (EF) significantly changed with treatment; these were not dose dependent. T2 (marker of edema) and LV EF did not significantly change. No risk factors were associated with baseline global perfusion. Prior receipt of doxorubicin was marginally associated with decreased myocardial perfusion after RT (P = .059), and mean MHD was not associated with perfusion changes. A significant correlation between baseline IL-6 and mean heart dose (MHD) at the end of RT (ρ 0.44, P = .007) and a strong trend between troponin I and MHD at 3 months post-treatment (ρ 0.33, P = .07) were observed. No other significant correlations were identified. CONCLUSIONS: In this prospective study of women with left-sided breast cancer treated with contemporary treatment planning, cardiac radiation doses were very low relative to historical doses reported by Darby et al. Although we observed significant changes in T1 and RV EF shortly after RT, these changes were not correlated with whole heart or substructure doses. Serum biomarker analysis of cardiac injury demonstrates an interesting trend between markers and MHD that warrants further investigation.