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Purpose: Glioblastoma (GBM) is the most common primary brain cancer in adults with a very poor prognosis. Metabolic drivers of tumorigenesis are highly relevant within the central nervous system, where glucose is the critical source of energy. The impact of obesity on survival outcomes in patients with GBM is not well established. This study investigates the prognostic value of body mass index (BMI) in patients diagnosed with GBM., Methods: Adult patients with newly diagnosed GBM treated at Thomas Jefferson University Hospital between January 1, 2008, and December 31, 2022, were included in the study. BMI was calculated using the formula BMI = kg/m 2 . Patients BMI groups were underweight (BMI < 19.00), normal weight (BMI 19.00-24.99), overweight (BMI 25-29.99), and obese (BMI > 30.00). All patients received 60 Gy of radiation therapy with concurrent and adjuvant temozolomide following maximal safe resection. A difference in clinical outcomes of overall survival (OS) and progression-free survival (PFS) were evaluated between the groups using Kaplan-Meier and log-rank tests., Results: A total of 392 patients met inclusion criteria. The median age was 60.3 (range 18.9-86.7), with 144 females and 248 males. Median BMI was 27.0 (Range; 17.7-52.9). Non-overweight GBM patients (BMI < 25.00, OS 2.1 years, CI 1.7-2.4 years) had increased overall survival compared to overweight patients (BMI ≥ 25.00, OS 1.5 years, CI 1.4-1.6 years) (p < 0.001). Patients with MGMT-methylated GBM also had significantly greater OS and PFS compared to MGMT-unmethylated patients (p < 0.001). Non-overweight GBM patients (BMI < 25.00, median PFS 1.5 years, CI 1.3-2.0 years) also had increased progression-free survival compared to overweight patients (BMI ≥ 25.00, median PFS 1.1 years, CI 0.9-1.2 years) (p < 0.001)., Conclusions: Our study indicates normal BMI (19.00-24.99) at the time of GBM diagnosis is a favorable prognostic indicator for overall and progression-free survival. Additional studies are warranted for further analysis of BMI and survival outcomes in GBM patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. No grants or outside funding was acquired for the completion of this study as well., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Purpose: This study investigated imaging biomarkers derived from PSMA-PET acquired pre- and post-metastasis-directed therapy (MDT) to predict 2-year metastasis-free survival (MFS), which provides valuable early response assessment to improve patient outcomes., Materials/methods: An international cohort of 117 oligometastatic castration-sensitive prostate cancer (omCSPC) patients, comprising 34 from John Hopkins Hospital (JHH) and 83 from Baskent University (BU), were treated with stereotactic ablative radiation therapy (SABR) MDT with both pre- and post-MDT PSMA-PET/CT scans acquired. PET radiomic features were analyzed from a CT-PET fusion defined gross tumor volume ((GTV) or zone 1), and a 5 mm expansion ring area outside the GTV (zone 2). A total of 1748 PET radiomic features were extracted from these zones. The six most significant features selected using the Chi2 method, along with five clinical parameters (age, Gleason score, number of total lesions, untreated lesions, and pre-MDT prostate-specific antigen (PSA)) were extracted as inputs to the models. Various machine learning models, including Random Forest, Decision Tree, Support Vector Machine, and Naïve Bayesian, were employed for 2-year MFS prediction and tested using leave-one-out and cross-institution validation., Results: Six radiomic features, including Total Energy, Entropy, and Standard Deviation from pre-PSMA-PET zone 1, Total Energy and Contrast from post-PSMA-PET zone 1, and Entropy from pre-PSMA-PET zone 2, along with five clinical parameters were selected for predicting 2-year MFS. In a leave-one-out test with all the patients, random forest achieved an accuracy of 80 % and an AUC of 0.82 in predicting 2-year MFS. In cross-institution validation, the model correctly predicted 2-year MFS events with an accuracy of 75 % and an AUC of 0.77 for patients from JHH, and an accuracy of 78 % and an AUC of 0.80 for BU patients, respectively., Conclusion: Our study demonstrated the promise of using pre- and post-MDT PSMA-PET-based imaging biomarkers for MFS prediction for omCSPC patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Breast cancer brain metastasis (BCBM) typically results in an end-stage diagnosis and is hindered by a lack of brain-penetrant drugs. Tumors in the brain rely on the conversion of acetate to acetyl-CoA by the enzyme acetyl-CoA synthetase 2 (ACSS2), a key regulator of fatty acid synthesis and protein acetylation. Here, we used a computational pipeline to identify novel brain-penetrant ACSS2 inhibitors combining pharmacophore-based shape screen methodology with absorption, distribution, metabolism, and excretion (ADME) property predictions. We identified compounds AD-5584 and AD-8007 that were validated for specific binding affinity to ACSS2. Treatment of BCBM cells with AD-5584 and AD-8007 leads to a significant reduction in colony formation, lipid storage, acetyl-CoA levels and cell survival in vitro . In an ex vivo brain-tumor slice model, treatment with AD-8007 and AD-5584 reduced pre-formed tumors and synergized with irradiation in blocking BCBM tumor growth. Treatment with AD-8007 reduced tumor burden and extended survival in vivo . This study identifies selective brain-penetrant ACSS2 inhibitors with efficacy towards breast cancer brain metastasis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Esquea, Ciraku, Young, Merzy, Talarico, Ahmed, Karuppiah, Ramesh, Chatoff, Crispim, Rashad, Cocklin, Snyder, Beld, Simone, Reginato and Dick.)

Purpose: A novel form of lung function imaging has been developed that uses 4-dimensional computed tomography (4DCT) data to generate lung ventilation images (4DCT-ventilation). Functional avoidance uses 4DCT-ventilation to reduce doses to functional lung with the aim of reducing pulmonary side effects. A phase 2, multicenter 4DCT-ventilation functional avoidance clinical trial was completed. The purpose of this work was to quantify changes in patient-reported outcomes (PROs) for patients treated with functional avoidance and determine which metrics are predictive of PRO changes., Materials and Methods: Patients with locally advanced lung cancer receiving curative-intent radiation therapy were accrued. Each patient had a 4DCT-ventilation image generated using 4DCT data and image processing. PRO instruments included the Functional Assessment of Cancer Therapy-Lung (FACT-L) questionnaire administered pretreatment; at the end of treatment; and at 3, 6, and 12 months posttreatment. Using the FACT-Trial Outcome Index and the FACT-Lung Cancer Subscale results, the percentage of clinically meaningful declines (CMDs) were determined. A linear mixed-effects model was used to determine which patient, clinical, dose, and dose-function metrics were predictive of PRO decline., Results: Of the 59 patients who completed baseline PRO surveys. 83% had non-small cell lung cancer, with 75% having stage 3 disease. The median dose was 60 Gy in 30 fractions. CMD FACT-Trial Outcome Index decline was 46.3%, 38.5%, and 26.8%, at 3, 6, and 12 months, respectively. CMD FACT-Lung Cancer Subscale decline was 33.3%, 33.3%, and 29.3%, at 3, 6, and 12 months, respectively. Although an increase in most dose and dose-function parameters was associated with a modest decline in PROs, none of the results were significant (all P > .053)., Conclusions: The current work presents an innovative combination of use of functional avoidance and PRO assessment and is the first report of PROs for patients treated with prospective 4DCT-ventilation functional avoidance. Approximately 30% of patients had clinically significant decline in PROs at 12 months posttreatment. The study provides additional data on outcomes with 4DCT-ventilation functional avoidance., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The circadian system, a vital temporal regulator influencing physiological processes, has implications for cancer development and treatment response. Our study assessed circadian timing's impact on whole-brain radiotherapy outcomes in brain metastases for personalized cancer therapy insights. The aim of the study was to evaluate circadian influence on radiation treatment timing and its correlation with clinical outcomes and to identify patient populations benefiting from interventions synchronizing circadian rhythms, considering subgroup differences and potential disparities. An IRB-approved retrospective analysis of 237 patients undergoing whole-brain radiotherapy for brain metastases (2017-2021), receiving over 80% of treatments in the morning or afternoon, was performed. Survival analyses utilized Kaplan-Meier curves. This was a single-institution study involving patients receiving whole-brain radiotherapy. Demographic, disease, and socioeconomic parameters from electronic medical records were collected. Morning treatment ( n = 158) showed a trend toward improved overall survival vs. afternoon ( n = 79); the median survival was 158 vs. 79 days ( p = 0.20, HR = 0.84, CI 95% 0.84-0.91). Subgroup benefits for morning treatment in females ( p = 0.04) and trends in controlled primary disease ( p = 0.11) and breast cancer metastases ( p = 0.08) were observed. Black patients exhibited diminished circadian influence. The present study emphasized chronobiological factors' relevance in brain metastases radiation therapy. Morning treatment correlated with improved survival, particularly in specific subgroups. Potential circadian influence disparities were identified, laying a foundation for personalized cancer therapy and interventions synchronizing circadian rhythms for enhanced treatment efficacy.

Purpose: Traditional methods of evaluating cardiotoxicity focus on radiation doses to the heart. Functional imaging has the potential to provide improved prediction for cardiotoxicity for patients with lung cancer. Fluorine-18 ( 18 F) fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) imaging is routinely obtained in a standard cancer staging workup. This work aimed to develop a radiomics model predicting clinical cardiac assessment using 18 F-FDG PET/CT scans before thoracic radiation therapy., Methods: Pretreatment 18 F-FDG PET/CT scans from three study populations (N = 100, N = 39, N = 70) were used, comprising two single-institutional protocols and one publicly available data set. A clinician (V.J.) classified the PET/CT scans per clinical cardiac guidelines as no uptake, diffuse uptake, or focal uptake. The heart was delineated, and 210 novel functional radiomics features were selected to classify cardiac FDG uptake patterns. Training data were divided into training (80%)/validation (20%) sets. Feature reduction was performed using the Wilcoxon test, hierarchical clustering, and recursive feature elimination. Ten-fold cross-validation was carried out for training, and the accuracy of the models to predict clinical cardiac assessment was reported., Results: From 202 of 209 scans, cardiac FDG uptake was scored as no uptake (39.6%), diffuse uptake (25.3%), and focal uptake (35.1%), respectively. Sixty-two independent radiomics features were reduced to nine clinically pertinent features. The best model showed 93% predictive accuracy in the training data set and 80% and 92% predictive accuracy in two external validation data sets., Conclusion: This work used an extensive patient data set to develop a functional cardiac radiomic model from standard-of-care 18 F-FDG PET/CT scans, showing good predictive accuracy. The radiomics model has the potential to provide an automated method to predict existing cardiac conditions and provide an early functional biomarker to identify patients at risk of developing cardiac complications after radiotherapy.

The LGBTQ+ community experiences cancer disparities due to increased risk factors and lower screening rates, attributable to health literacy gaps and systemic barriers. We sought to understand the experiences, perceptions, and knowledge base of healthcare providers regarding cancer screening for LGBTQ+ patients. A 20-item IRB-approved survey was distributed to physicians through professional organizations. The survey assessed experiences and education regarding the LGBTQ+ community and perceptions of patient concerns with different cancer screenings on a 5-point Likert scale. Complete responses were collected from 355 providers. Only 100 (28%) reported past LGBTQ+-related training and were more likely to be female ( p = 0.020), have under ten years of practice ( p = 0.014), or practice family/internal medicine ( p < 0.001). Most (85%) recognized that LGBTQ+ subpopulations experience nuanced health issues, but only 46% confidently understood them, and 71% agreed their clinics would benefit from training. Family/internal medicine practitioners affirmed the clinical relevance of patients' sexual orientation (94%; 62% for medical/radiation oncology). Prior training affected belief in the importance of sexual orientation ( p < 0.001), confidence in understanding LGBTQ+ health concerns ( p < 0.001), and willingness to be listed as "LGBTQ+-friendly" ( p = 0.005). Our study suggests that despite a paucity of formal training, most providers acknowledge that LGBTQ+ patients have unique health needs. Respondents had a lack of consensus regarding cancer screenings for lesbian and transgender patients, indicating the need for clearer screening standards for LGBTQ+ subpopulations and educational programs for providers.

Community-based breast cancer prevention efforts often focus on women who live in the same neighborhoods, as they tend to have similar demographic characteristics, health behaviors, and environmental exposures; yet little research describes methods of selecting neighborhoods of focus for community-based cancer prevention interventions. Studies frequently use demographics from census data, or single breast cancer outcomes (e.g., mortality, morbidity) in order to choose neighborhoods of focus for breast cancer interventions, which may not be optimal. This study presents a novel method for measuring the burden of breast cancer among neighborhoods that could be used for selecting neighborhoods of focus. In this study, we 1) calculate a metric composed of multiple breast cancer outcomes to describe the burden of breast cancer in census tracts Philadelphia, PA, USA; 2) map the neighborhoods with the greatest breast cancer burden; and 3) compare census tracts with the highest burden of breast cancer to those with demographics sometimes used for geo-based prioritization, i.e., race and income. The results of our study showed that race or income may not be appropriate proxies for neighborhood breast cancer burden; comparing the breast cancer burden with demographics at the census tract level, we found few overlaps with the highest percentage African American or the lowest median incomes. Agencies implementing community-based breast cancer interventions should consider this method to inform the selection of neighborhoods for breast cancer prevention interventions, including education, screening, and treatment., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Purpose: This study examined the gender composition of career development award applicants and grant review panels during the pandemic compared with that beforehand. Methods: Data were collected from 14 Health Research Alliance (HRA) organizations, which fund biomedical research and training. HRA members provided the gender of grant applicants and grant reviewers during the pandemic (April 1, 2020, to February 28, 2021) and prepandemic (April 1, 2019, to February 29, 2020). The signed-rank test compared medians and the chi square test compared the overall gender distribution. Results: The total number of applicants was similar during the pandemic ( N  = 3,724) and prepandemic ( N  = 3,882) periods, as was the percentage of women applicants (45.2% pandemic vs. 44.9% prepandemic, p  = 0.78). The total number of men and women grant reviewers declined during the pandemic ( N  = 856) compared with that pre-pandemic ( N  = 1,689); this decrease was driven by a change for the largest funder. Also driven by changes for this one funder, the percentage of total grant reviewers who were women increased significantly during the pandemic (45.9%) compared with that during prepandemic (38.8%; p  = 0.001), but the median percentage of women grant reviewers across organizations remained similar during the pandemic (43.6%) and prepandemic periods (38.2%; p  = 0.53). Conclusions: In a sample of research organizations, the gender composition of grant applicants and grant review panels remained similar, except for the review panel composition for one large funder. Given evidence from other studies that have revealed gender differences in other career and life experiences of scientists during the pandemic, ongoing evaluation of women's representation in grant submission and review mechanisms is essential.

Objectives: Prevention programs that can help adults improve the quality of their diets to reduce cancer risk are needed. This Phase IIa study prospectively tested a mHealth intervention designed to improve adherence to dietary quality guidelines for cancer prevention., Methods: All participants (N = 62) received nutrition education and a self-regulation skills curriculum, with a primary target of changing grocery shopping behavior. Using a randomized, factorial design, the study varied whether each of the following 4 components were added to the 20-week intervention: (1) location-triggered app messaging, delivered when individuals arrived at grocery stores, (2) reflections on benefits of change, delivered with extra coaching time and tailored app messages, (3) coach monitoring, in which food purchases were digitally monitored by a coach, and (4) involvement of a household member in the intervention., Results: Benchmarks were successfully met for recruitment, retention, and treatment acceptability. Across conditions, there were significant reductions in highly processed food intake ( P < .001, η 2 = .48), red and processed meat intake ( P < .001, η 2 = .20), and sugar-sweetened beverage intake ( P = .008, η 2 = .13) from pre-to post-treatment. Analyses examining whether each intervention component influenced change across time found that participants who received coach monitoring increased their intake of fruits, vegetables, and fiber, whereas those with no coach monitoring had less improvement ( P = .01, η 2 = .14). The improvement in red and processed meat was stronger among participants with household support ON, at a marginally significant level, than those with household support OFF ( P = .056, η 2 = .07)., Conclusion: This study showed feasibility, acceptability, and preliminary signals of efficacy of a remotely delivered intervention to facilitate adherence to dietary guidelines for cancer prevention and that coach monitoring and household support may be especially effective strategies. A fully powered clinical trial is warranted to test an optimized version of the intervention that includes nutrition education, self-regulation skills training, coach monitoring, and household member involvement., Trial Registration: ClinicalTrials.gov NCT04947150., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Dietary intake is a powerful modifiable factor that influences cancer risk; however, most US adults do not adhere to dietary guidelines for cancer prevention. One promising pathway for improving dietary adherence is targeting grocery shopping habits. Interventions might facilitate healthy grocery choices, with a combination of mHealth and traditional methods, by promoting the salience of dietary goals while shopping, enhancing motivation to make dietary changes, and increasing household support for healthy food purchasing., Objective: This pilot study will assess feasibility and acceptability of intervention components designed to improve adherence to dietary guidelines for cancer prevention (preliminary aim). The primary aim of the study is to quantify the effect of each intervention component, individually and in combination, on dietary intake (primary aim) and grocery store food purchases (exploratory aim). Mediation analyses will be conducted to understand the mechanisms of action (goal salience, motivation, and household support-secondary aims). The overarching goal is to optimize an mHealth intervention to be tested in a future fully powered clinical trial., Methods: The study enrolled adults (N=62) with low adherence to dietary recommendations for cancer prevention. In a 20-week program, all participants attend a nutrition education workshop and receive weekly educational messages through an app. A factorial design is used to test 4 intervention components: (1) location-triggered messages: educational messages are delivered when arriving at grocery stores; (2) reflections on the benefits of change: content is added to messages to encourage reflection on anticipated benefits of healthy eating, and participants attend an additional workshop session and 3 coach calls on this topic; (3) coach monitoring: food purchases are monitored digitally by a coach who sends personalized weekly app messages and conducts 3 coaching calls that focus on feedback about purchases; and (4) household support: another adult in the household receives messages designed to elicit support for healthy food purchasing, and support is addressed in 3 coach calls and an extra workshop session attended by the index participant and household member. Assessments are completed at weeks 0, 10, and 20 using self-report measures, as well as objective capture of grocery data from the point of purchase using store loyalty accounts., Results: The National Cancer Institute funded this study (R21CA252933) on July 7, 2020. Participant recruitment began in the spring of 2021 and concluded with the successful enrollment of 62 participants. Data collection is expected to be completed in the summer of 2022, and results are expected to be disseminated in the summer of 2023., Conclusions: The results of this study will inform the development of scalable interventions to lower cancer risk via changes in dietary intake., Trial Registration: ClinicalTrials.gov NCT04947150; https://clinicaltrials.gov/ct2/show/NCT04947150., International Registered Report Identifier (irrid): DERR1-10.2196/39669., (©Olivia Z Horgan, Nicole T Crane, Evan M Forman, Brandy-Joe Milliron, Nicole L Simone, Fengqing Zhang, Meghan L Butryn. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 24.06.2022.)

Introduction: Precision breast intraoperative radiation therapy (PB-IORT) is a novel approach to adjuvant radiation therapy for early-stage breast cancer performed as part of a phase II clinical trial at two institutions. One institution performs the entire procedure in an integrated brachytherapy suite which contains a CT-on-rails imaging unit and full anesthesia capabilities. At the other, breast conserving surgery and radiation therapy take place in two separate locations. Here, we utilize time-driven activity-based costing (TDABC) to compare these two models for the delivery of PB-IORT., Methods: Process maps were created to describe each step required to deliver PB-IORT at each institution, including personnel, equipment, and supplies. Time investment was estimated for each step. The capacity cost rate was determined for each resource, and total costs of care were then calculated by multiplying the capacity cost rates by the time estimate for the process step and adding any additional product costs., Results: PB-IORT costs less to deliver at a distributed facility, as is more commonly available, than an integrated brachytherapy suite ($3,262.22 vs. $3,996.01). The largest source of costs in both settings ($2,400) was consumable supplies, including the brachytherapy balloon applicator. The difference in costs for the two facility types was driven by personnel costs ($1,263.41 vs. $764.89). In the integrated facility, increased time required by radiation oncology nursing and the anesthesia attending translated to the greatest increases in cost. Equipment costs were also slightly higher in the integrated suite setting ($332.60 vs. $97.33)., Conclusions: The overall cost of care is higher when utilizing an integrated brachytherapy suite to deliver PB-IORT. This was primarily driven by additional personnel costs from nursing and anesthesia, although the greatest cost of delivery in both settings was the disposable brachytherapy applicator. These differences in cost must be balanced against the potential impact on patient experience with these approaches., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: A disparity exists in cancer screening rates for the Sexual and Gender Minority (SGM) community. We sought to understand the perceptions and baseline knowledge of cancer screening among SGM community members., Methods: Survey administered via social media from June 2018 to October 2018. We asked 31 questions focused on cancer screening, human papillomavirus, emotional distress, and experience with the health care system. Those included were 18 years or older. Cancer screening attitudes and knowledge, as well as perceptions of the health care system were investigated., Results: There were 422 respondents analyzed: 24.6% identified as female, 25.5% as male, 40.1% transgender, and 9.6% as other. 65.4% of the SGM community is not certain what cancer screening to do for themselves. Only 27.3% and 55.7% knew that HPV was a risk factor associated with head and neck cancer and anal cancer, respectively. Half stated their emotional distress prevents them from getting cancer screening. It was identified that process changes in making appointments, comforts during the visit, and formal training for physicians and nurses could increase cancer screening compliance for this community. The transgender population had a trend in more gaps in knowledge of appropriate cancer screening and significant excess emotional distress., Conclusion: Gaps in cancer screening knowledge and emotional and financial distress may be responsible for the disparity of lower cancer screening rates for the SGM population and the transgender population may be most at risk. Appreciating the cancer screening concerns of the SGM population can help shape future clinical and institutional approaches to improve health care delivery., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Circadian disruption has been linked to cancer development, progression, and radiation response. Clinical evidence to date shows that circadian genetic variation and time of treatment affect radiation response and toxicity for women with breast cancer. At the molecular level, there is interplay between circadian clock regulators such as PER1, which mediates ATM and p53-mediated cell cycle gating and apoptosis. These molecular alterations may govern aggressive cancer phenotypes, outcomes, and radiation response. Exploiting the various circadian clock mechanisms may enhance the therapeutic index of radiation by decreasing toxicity, increasing disease control, and improving outcomes. We will review the body's natural circadian rhythms and clock gene-regulation while exploring preclinical and clinical evidence that implicates chronobiological disruptions in the etiology of breast cancer. We will discuss radiobiological principles and the circadian regulation of DNA damage responses. Lastly, we will present potential rational therapeutic approaches that target circadian pathways to improve outcomes in breast cancer. Understanding the implications of optimal timing in cancer treatment and exploring ways to entrain circadian biology with light, diet, and chronobiological agents like melatonin may provide an avenue for enhancing the therapeutic index of radiotherapy.

Understanding metabolic and immune regulation inherent to patient populations is key to improving the radiation response for our patients. To date, radiation therapy regimens are prescribed based on tumor type and stage. Patient populations who are noted to have a poor response to radiation such as those of African American descent, those who have obesity or metabolic syndrome, or senior adult oncology patients, should be considered for concurrent therapies with radiation that will improve response. Here, we explore these populations of breast cancer patients, who frequently display radiation resistance and increased mortality rates, and identify the molecular underpinnings that are, in part, responsible for the radiation response and that result in an immune-suppressive tumor microenvironment. The resulting immune phenotype is discussed to understand how antitumor immunity could be improved. Correcting nutrient deficiencies observed in these populations should be considered as a means to improve the therapeutic index of radiation therapy.

Brain metastasis is a serious consequence of breast cancer for women as these tumors are difficult to treat and are associated with poor clinical outcomes. Preclinical mouse models of breast cancer brain metastatic (BCBM) growth are useful but are expensive, and it is difficult to track live cells and tumor cell invasion within the brain parenchyma. Presented here is a protocol for ex vivo brain slice cultures from xenografted mice containing intracranially injected breast cancer brain-seeking clonal sublines. MDA-MB-231BR luciferase tagged cells were injected intracranially into the brains of Nu/Nu female mice, and following tumor formation, the brains were isolated, sliced, and cultured ex vivo. The tumor slices were imaged to identify tumor cells expressing luciferase and monitor their proliferation and invasion in the brain parenchyma for up to 10 days. Further, the protocol describes the use of time-lapse microscopy to image the growth and invasive behavior of the tumor cells following treatment with ionizing radiation or chemotherapy. The response of tumor cells to treatments can be visualized by live-imaging microscopy, measuring bioluminescence intensity, and performing histology on the brain slice containing BCBM cells. Thus, this ex vivo slice model may be a useful platform for rapid testing of novel therapeutic agents alone or in combination with radiation to identify drugs personalized to target an individual patient's breast cancer brain metastatic growth within the brain microenvironment.

Outcomes for triple negative breast cancer (TNBC) are poor and may be improved by increasing CD8 + tumor infiltrating lymphocytes (TIL) to augment antitumor immunity. Radiation (RT) can promote immunogenic cell death with increased antitumor T cell activity but also stimulates suppressive regulatory T cells (Tregs). Because metabolic alterations affect immune homeostasis and prior studies show caloric restriction (CR) combined with RT improves preclinical TNBC outcomes, we hypothesized that CR augments RT, in part, by altering intratumoral immunity. Using an in vivo model of TNBC, we treated mice with ad libitum (AL) diet, radiation, a CR diet, or CR + RT, and demonstrated an immune suppressive environment with a significant increase in CD4 + CD25 + Foxp3 + Tregs after RT but not in CR-fed mice. CD8:Treg ratio in CR + RT TIL increased 4-fold compared with AL + RT mice. In vivo CD8 depletion was performed to assess the role of effector T cells in mitigating the effects of CR, and it was found that in mice undergoing CR, depletion of CD8 T cells resulted in increased tumor progression and decreased median survival compared with isotype control-treated mice. In addition, PD-1 expression on CD3 + CD8 + T cells within the tumor microenvironment was significantly increased in CR + RT versus AL + RT treated mice as per immunofluorescence. Serum from breast cancer patients undergoing RT alone or CR and RT was collected pre- and postintervention, and a cytokine array demonstrated that patients treated with CR + RT had notable decreases in immunosuppressive cytokines such as IL-2Rγ, IL-10Rβ, and TGF-β2 and 3 compared with patients receiving RT alone. In conclusion, combining CR with RT decreases intratumoral Tregs, increases CD8:Treg, and increases PD-1 expression via a process dependent on CD8 T cells in a TNBC model. Breast cancer patients undergoing CR concurrently with RT also had significant reduction in immunosuppressive cytokine levels compared with those receiving RT alone., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: Exercise therapy (ET) is shown to improve toxicity and surrogates of survival for patients receiving chemotherapy. Current National Comprehensive Cancer Network (NCCN) guidelines lack recommendations for concurrent radiation therapy (RT) and ET. The main objective was to determine the impact of concurrent ET + RT with respect to (1) acceptability, feasibility, safety; and (2) to demonstrate how incorporating ET in cancer treatment can enhance patient-reported outcomes (PROs) and physical function-defined as strength or exercise capacity., Methods and Materials: A PICOS/PRISMA selection protocol was used to search PubMed, Cumulative Index of Nursing and Allied Health Literature (CINAHL), and Cochrane Review for prospective randomized controlled trials evaluating concurrent ET + RT, including >10 patients and with 1 or more study arms. Acceptability, feasibility, and safety rates were calculated. PROs were assessed with study-specific metrics. Physical function was defined as improvements in strength or range of motion. Statistically significant improvement was defined by P <.05., Results: Twenty-six of 693 screened studies including 1563 patients (831 receiving exercise, 732 controls) with localized breast cancer (67.1% of patients), prostate cancer (27.4%), head and neck cancers (2.8%), and spinal metastases (2.8%) were assessed. Objective 1: Among 3385 patients approached for ET, 1864 (55.1%) accepted the treatment; of those, 1563 patients (83.9%) completed the trials. Objective 2: Statistical improvements were noted in these PROs: quality of life (14 of 15 studies), fatigue (12 of 16 studies), mood/depression (9 of 13), and anxiety (6 of 7). Physical function improved statically in 16 of 16 studies., Conclusions: Combination ET + RT is safe and well-tolerated with improvements in PROs and physical function. Additional studies are needed in patients with metastatic cancers to assess survival and to compare effectiveness of different exercise regimens., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Social determinants of health directly affect cancer survival. Driven by advances in technology and recent demands due to COVID-19, telemedicine has the ability to improve patient access to care, lower health care costs, and increase workflow efficiency. The role of telemedicine in radiation oncology is not established. Materials and Methods: We conducted an IRB-approved pilot trial using a telehealth platform for the first post-radiation visit in patients with any cancer diagnosis. The primary endpoint was feasibility of using telehealth defined by completion of five telehealth visits per month in a single department. Secondary endpoints included the ability to assess patients appropriately, patient and physician satisfaction. Physicians were surveyed again during the pandemic to determine whether viewpoints changed. Results: Between May 27, 2016 and August 1, 2018, 37 patients were enrolled in the Telehealth in Post-operative Radiation Therapy (TelePORT) trial, with 24 evaluable patients who completed their scheduled telehealth visit. On average, 1.4 patients were accrued per month. All patients were satisfied with their care, had enough time with their physician and 85.7% believed the telehealth communication was excellent. All physicians were able to accurately assess the patient's symptoms via telehealth, whereas 82.3% felt they could accurately assess treatment-related toxicity. Physicians assessing skin toxicity from breast radiation were those who did not feel they were able to assess toxicity. Discussion and Conclusions: Both health care providers and patients have identified telemedicine as a suitable platform for radiation oncology visits. Although there are limitations, telemedicine has significant potential for increasing access of cancer care delivery in radiation oncology., Competing Interests: No competing financial interests exist., (© Ryan C. Miller et al., 2021; Published by Mary Ann Liebert, Inc.)

Breast cancer (BrCa) relies on specific microRNAs to drive disease progression. Oncogenic miR-21 is upregulated in many cancers, including BrCa, and is associated with poor survival and treatment resistance. We sought to determine the role of miR-21 in BrCa tumor initiation, progression and treatment response. In a triple-negative BrCa model, radiation exposure increased miR-21 in both primary tumor and metastases. In vitro, miR-21 knockdown decreased survival in all BrCa subtypes in the presence of radiation. The role of miR-21 in BrCa initiation was evaluated by implanting wild-type miR-21 BrCa cells into genetically engineered mouse models where miR-21 was intact, heterozygous or globally ablated. Tumors were unable to grow in the mammary fat pads of miR-21 -/- mice, and grew in ~50% of miR-21 +/- and 100% in miR-21 +/+ mice. The contribution of miR-21 to progression and metastases was tested by crossing miR-21 -/- mice with mice that spontaneously develop BrCa. The global ablation of miR-21 significantly decreased the tumorigenesis and metastases of BrCa, while sensitizing tumors to radio- and chemotherapeutic agents via Fas/FasL-dependent apoptosis. Therefore, targeting miR-21 alone or in combination with various radio or cytotoxic therapies may represent novel and efficacious therapeutic modalities for the future treatment of BrCa patients.

Purpose: Our objectives are to assess (1) the acceptability and feasibility of dietary interventions for patients undergoing radiation therapy (RT), and (2) the impact of dietary interventions on patient reported outcomes, toxicities, and survival., Methods: A PICOS/PRISMA/MOOSE selection protocol was used to include articles that evaluate adding dietary interventions to patients receiving RT. Acceptability was defined as (# accepting/# approached); feasibility was (# completing/# approached). Patient-reported outcomes were reported based on questionnaires used in each study and survival was measured from the date of diagnosis until death in each study. Level of evidence was assessed with Center for Evidence-Based Medicine (CEBM) criteria., Results: Sixteen articles were included; among these, 2027 patients were approached regarding the intervention, and 1661 accepted (81.9%); of these, 1543 (92.9%) completed the prescribed diet + RT course. The most common cancers included were gynecological, head and neck, and gastrointestinal. For patients with pelvic cancers, a high fiber diet may improve diarrhea (CEBM level 1b). Enteral nutrition formula, including formulas with proteins such as L-arginine, lipids such as eicosapentaenoic acids, glucids, and ribonucleotides, may help prevent of malnutrition in head and neck cancer patients undergoing RT (level 2b). Vitamin C and β-carotene may reduce of xerostomia in head and neck cancer patients; however, the studies evaluating these vitamins included vitamin E, which increases all-cause mortality (level 2b). No dietary intervention for cancer patients receiving RT has been shown to improve survival., Conclusion: There are limited data to support safe and efficacious use of dietary interventions during RT., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2020 The Authors.)

Purpose: Intraoperative radiation therapy (IORT), a form of accelerated partial breast irradiation (APBI), is an appealing alternative to postoperative whole breast irradiation for early-stage breast cancer. The purpose of this study was to examine the toxicity and cosmetic outcomes of patients treated with a novel form of breast IORT (precision breast IORT; PB-IORT), that delivers a targeted, higher dose of radiation than conventional IORT., Methods and Materials: The first 204 patients treated with PB-IORT in a Phase II clinical trial (NCT02400658) with 12 months of followup were included. Trial inclusion criteria were age ≥45 years, invasive or in situ breast cancer, tumor size ≤3 cm, and node negative. Toxicity and cosmetic scoring were performed at 6 and 12 months., Results: 98 patients (48%; 95% CI, 41-55%) experienced toxicity. Seven Grade 3 toxicities occurred (3.4%; 95% CI, 1.4-6.9%). Most patients (95%) had excellent or good cosmetic outcomes (95% CI, 91-98%) at 12 months. Most patients (94%) had little or no pigmentation change (95% CI, 90-97%), 88% little to no size change (95% CI, 82-92%), and 87% experienced minimal shape change (95% CI, 82-92%)., Conclusions: Overall, Grade 3+ toxicity was rare and cosmetic outcomes were excellent. Severe toxicity with PB-IORT is similar to that reported in the TARGIT trial (3.3% rate of major toxicity) but lower than APBI (NSABP-39, 10.1% Grade 3/4 toxicities). We propose that the toxicity of PB-IORT compared with TARGIT and NSABP-39 is related to the radiation dose and delivery schedule. PB-IORT offers low-toxicity and good cosmetic outcomes when compared with other forms of APBI., (Copyright © 2020 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

For the past 100 years, oncologists have relentlessly pursued the destruction of tumor cells by surgical, chemotherapeutic or radiation oncological means. Consistent with this focus, treatment plans are typically based on key characteristics of the tumor itself such as disease site, histology and staging based on local, regional and systemic dissemination. Precision medicine is similarly built on the premise that detailed knowledge of molecular alterations of tumor cells themselves enables better and more effective tumor cell destruction. Recently, host factors within the tumor microenvironment including the vasculature and immune systems have been recognized as modifiers of disease progression and are being targeted for therapeutic gain. In this review, we argue that-to optimize the impact of old and new treatment options-we need to take account of an epidemic that occurs independently of-but has major impact on-the development and treatment of malignant diseases. This is the rapidly increasing number of patients with excess weight and its' attendant metabolic consequences, commonly described as metabolic syndrome. It is well established that patients with altered metabolism manifesting as obesity, metabolic syndrome and chronic inflammation have an increased incidence of cancer. Here, we focus on evidence that these patients also respond differently to cancer therapy including radiation and provide a perspective how exercise, diet or pharmacological agents may be harnessed to improve therapeutic responses in this patient population.

The COVID-19 pandemic has resulted in school closures and distancing requirements that have disrupted both work and family life for many. Concerns exist that these disruptions caused by the pandemic may not have influenced men and women researchers equally. Many medical journals have published papers on the pandemic, which were generated by researchers facing the challenges of these disruptions. Here we report the results of an analysis that compared the gender distribution of authors on 1893 medical papers related to the pandemic with that on papers published in the same journals in 2019, for papers with first authors and last authors from the United States. Using mixed-effects regression models, we estimated that the proportion of COVID-19 papers with a woman first author was 19% lower than that for papers published in the same journals in 2019, while our comparisons for last authors and overall proportion of women authors per paper were inconclusive. A closer examination suggested that women's representation as first authors of COVID-19 research was particularly low for papers published in March and April 2020. Our findings are consistent with the idea that the research productivity of women, especially early-career women, has been affected more than the research productivity of men., Competing Interests: JA, MN, NS No competing interests declared, RL Founder of TIME'S UP Healthcare, a non-profit initiative that advocates for safety and equity in healthcare; advisor for FeminEM.org, a website that supports the careers of women in medicine. RJ Has stock options as compensation for her advisory board role in Equity Quotient, a company that evaluates culture in health care companies; has received personal fees from Amgen and Vizient and grants for unrelated work from the National Institutes of Health, the Doris Duke Foundation, the Greenwall Foundation, the Komen Foundation, and Blue Cross Blue Shield of Michigan for the Michigan Radiation Oncology Quality Consortium; has a contract to conduct an investigator-initiated study with Genentech; has served as an expert witness for Sherinian and Hasso and Dressman Benzinger LaVelle; uncompensated founding member of TIME'S UP Healthcare; member of the Board of Directors of ASCO., (© 2020, Andersen et al.)

Background: Metastatic cancer is incurable and understanding the molecular underpinnings is crucial to improving survival for our patients. The IGF-1/Akt signaling pathway is often impaired in cancer leading to its progression and metastases. Diet modification is known to alter the IGF-1/Akt pathway and affect the expression of microRNA involved in tumor initiation, growth and metastases. Liver metastases are one of the most common type of metastases in breast and colon cancer. In the present study, we looked at the effect of diet modification on the expression of microRNA in normal liver and liver with breast cancer metastases using in vivo model., Methodology: 6-month-old C57BL/6 J mice were put on either an ad libitum (AL) diet, or 40% calorie restricted (CR) diet or were fasted for 24 h (FA) before sacrifice. MicroRNA array analysis, western blot and qRT-PCR were performed using liver tissue to compare the treatment groups. A breast cancer model was also used to study the changes in microRNA expression in liver of a group of BALB/c mice orthotopically injected with 4 T1 cells in the mammary fat pad, put on either an AL or 30% CR diet. Liver and primary tumor tissues were used to perform qRT-PCR to compare the treatment groups., Results: MicroRNA array analysis showed significant changes in miRNA expression in both CR and FA conditions in normal liver. Expression of miR-29 and miR-30 family members was increased in both CR and FA. Western blot analysis of the normal liver tissue showed that CR and FA downregulated the IGF-1/Akt pathway and qRT-PCR showed that the expression of miR-29b, miR-29c, miR-30a and miR-30b were increased with CR and FA. Liver tissue collected from mice in the breast cancer model showed an increase in expression of miR-29b, miR-29c and miR-30b while tumor tissue showed increased expression of miR-29c, miR-30a and miR-30b., Discussion: Members of the miR-29 family are known to target and suppress IGF-1, while members of the miR-30 family are known to target and suppress both IGF-1 and IGF-1R. In the present study, we observe that calorie restriction increased the expression of miR-29 and miR-30 in both the normal liver as well as the liver with breast cancer metastases. These findings suggest that dietary alterations may play a role in the treatment of liver metastasis, which should be evaluated further., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2020.)

The collection of microbes that live in and on the human body - the human microbiome - can impact on cancer initiation, progression, and response to therapy, including cancer immunotherapy. The mechanisms by which microbiomes impact on cancers can yield new diagnostics and treatments, but much remains unknown. The interactions between microbes, diet, host factors, drugs, and cell-cell interactions within the cancer itself likely involve intricate feedbacks, and no single component can explain all the behavior of the system. Understanding the role of host-associated microbial communities in cancer systems will require a multidisciplinary approach combining microbial ecology, immunology, cancer cell biology, and computational biology - a systems biology approach., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: Radiation therapy is an essential intervention used in the treatment of more than half of cancer patients. With the increasing use of hypofractionated radiation regimens, concurrent use of radiation and chemotherapy, targeted agents and immunotherapy, the risk of radiation-induced toxicities is increased. However, much remains unknown about the molecular underpinnings responsible for radiation-induced toxicity. MicroRNA (miRNA) are small, non-coding RNA involved in post-transcriptional regulation of gene expression. miR-21 is an oncomiR that is dysregulated in a significant fraction of human malignancies, and its overexpression is linked to poor overall survival, chemoresistance, and radioresistance in several human cancers. However, the contribution of miR-21 in governing radiation sensitivity in normal, untransformed cells, and the impact of silencing this miRNA in normal tissues remains largely unexplored., Materials and Methods: miR-21 levels were evaluated in tissues by qRT-PCR without and after total body irradiation (TBI). Mice lacking miR-21 were genetically engineered, subjected to TBI, and monitored for survival. Hematopoietic stem and progenitor cell (HSPC) numbers and function were assessed using flow cytometry, histology, complete blood cell counts, and bone marrow transplantation., Results: miR-21 expression was increased in radiosensitive tissues, but not in radioinsensitive tissues following TBI in wild-type mice, suggesting it may have a critical function in the normal tissue response to irradiation. Compared to wild-type mice, mice lacking one or both alleles of miR-21 showed reduced numbers of HSPCs and increased sensitivity to an LD 50/30 dose of TBI with evidence of bone marrow failure. Transplantation of wild-type bone marrow into irradiated miR-21-deficient mice rescued the mice from death., Conclusions: Our data identify miR-21 as a critical component of HSPC viability and essential for bone marrow recovery following irradiation. Further investigation is warranted to determine whether miR-21 can be used to stratify patients at risk for hematopoietic toxicity following irradiation., (Copyright © 2019. Published by Elsevier Inc.)

Purpose: Metabolic dysregulation has been implicated as a molecular driver of breast cancer in preclinical studies, especially with respect to metastases. We hypothesized that abnormalities in patient metabolism, such as obesity and diabetes, may drive outcomes in breast cancer patients with brain metastases., Methods: We retrospectively identified 84 consecutive patients with brain metastases from breast cancer treated with intracranial radiation therapy. Radiation was delivered as whole-brain radiation to a median dose of 3000 cGy or stereotactic radiosurgery to a median dose of 2100 cGy. Kaplan Meier curves were generated for overall survival (OS) data and Mantel-Cox regression was performed to detect differences in groups., Results: At analysis, 81 survival events had occurred and the median OS for the entire cohort was 21.7 months. Despite similar modified graded prognostic assessments, resection rates, and receptor status, BMI ≥ 25 kg/m 2 (n = 45) was associated with decreased median OS (13.7 vs. 30.6 months; p < 0.001) and median intracranial progression-free survival (PFS) (7.4 vs. 10.9 months; p = 0.04) compared to patients with BMI < 25 kg/m 2 (n = 39). Similar trends were observed among all three types of breast cancer. Patients with diabetes (n = 17) had decreased median OS (11.8 vs. 26.2 months; p < 0.001) and median intracranial PFS (4.5 vs. 10.3 months; p = 0.001) compared to non-diabetics (n = 67). On multivariate analysis, both BMI ≥ 25 kg/m 2 [HR 2.35 (1.39-3.98); p = 0.002] and diabetes [HR 2.77 (1.454-5.274); p = 0.002] were associated with increased mortality., Conclusions: Elevated BMI or diabetes may negatively impact both overall survival and local control in patients with brain metastases from breast cancer, highlighting the importance of the translational development of therapeutic metabolic interventions. Given its prognostic significance, BMI should be used as a stratification in future clinical trial design in this patient population.

Triple negative breast cancer (TNBC) is a heterogeneous disease that has no available targeted therapies. Previously, we have shown that caloric restriction (CR) can augment the effects of radiation therapy in a TNBC mouse model. To build upon this, we now present data regarding the combination of chemotherapy and CR in the same 4T1 model. Chemotherapy can induce inflammation that breeds resistance to therapy. We propose CR as a mechanism to decrease chemotherapy-induced inflammation and increase efficacy of therapy. 12-week old Balb/c mice were orthotopically injected with a syngeneic triple negative breast cancer cell line (4T1) and were treated in one of six cohorts: ad lib fed (AL), 30% reduction in calorie intake (CR), cisplatin or docetaxol alone or a combination CR+cisplatin/docetaxol. Mice in the cohorts receiving chemotherapy+CR had longer overall survival (12 ± 2 days) as compared to the AL group. These mice also demonstrated less lung metastases at the final time point of in vivo imaging. In addition, downregulation of the IGF-1R and IRS signaling pathways were noted most significantly in those mice receiving combination therapy. Lastly, serum from these mice demonstrated an increase in inflammatory cytokines TNF-α and IL-1β in response to chemotherapy alone. This increase was dampened by the addition of CR. Taken together, these data suggest that while chemotherapy is effective in TNBC, it can cause inflammation, which can be a driver of resistance to therapy. This chemotherapy-induced inflammation can be reversed with the use of CR as a nontoxic adjunct to treatment.

Purpose: To determine the associated toxicity, tolerance, and safety of partial-breast reirradiation., Methods and Materials: Eligibility criteria included in-breast recurrence occurring >1 year after whole-breast irradiation, <3 cm, unifocal, and resected with negative margins. Partial-breast reirradiation was targeted to the surgical cavity plus 1.5 cm; a prescription dose of 45 Gy in 1.5 Gy twice daily for 30 treatments was used. The primary objective was to evaluate the rate of grade ≥3 treatment-related skin, fibrosis, and/or breast pain adverse events (AEs), occurring ≤1 year from re-treatment completion. A rate of ≥13% for these AEs in a cohort of 55 patients was determined to be unacceptable (86% power, 1-sided α = 0.07)., Results: Between 2010 and 2013, 65 patients were accrued, and the first 55 eligible and with 1 year follow-up were analyzed. Median age was 68 years. Twenty-two patients had ductal carcinoma in situ, and 33 had invasive disease: 19 ≤1 cm, 13 >1 to ≤2 cm, and 1 >2 cm. All patients were clinically node negative. Systemic therapy was delivered in 51%. All treatment plans underwent quality review for contouring accuracy and dosimetric compliance. All treatment plans scored acceptable for tumor volume contouring and tumor volume dose-volume analysis. Only 4 (7%) scored unacceptable for organs at risk contouring and organs at risk dose-volume analysis. Treatment-related skin, fibrosis, and/or breast pain AEs were recorded as grade 1 in 64% and grade 2 in 7%, with only 1 (<2%) grade ≥3 and identified as grade 3 fibrosis of deep connective tissue., Conclusion: Partial-breast reirradiation with 3-dimensional conformal radiation therapy after second lumpectomy for patients experiencing in-breast failures after whole-breast irradiation is safe and feasible, with acceptable treatment quality achieved. Skin, fibrosis, and breast pain toxicity was acceptable, and grade 3 toxicity was rare., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: Metastatic breast cancer is devastating and triple negative breast cancers (TNBC) have a higher propensity for metastasis. Improved local control upfront in this aggressive cancer could potentially decrease its propensity toward metastasis. We sought to determine if using caloric restriction (CR) as a systemic therapy, combined with radiation therapy (IR) to the primary tumor, may impact metastatic disease., Methods: An orthotopic mouse model using a highly metastatic, luciferase-tagged TNBC cell line (4T1), was used to generate palpable tumors. Mice were then treated with CR, IR, and a combination of the two. In vivo imaging was performed for metastatic evaluation. Molecular evaluation of the tumors was performed, generating a mechanistic hypothesis for CR, which was then tested with pertinent pathway inhibition in the model., Results: CR significantly increased the time to developing metastases, decreased the overall number and volume of lung metastases, and increased survival. CR decreased proliferation, increased apoptosis and globally downregulated the IGF-1R signaling pathway. Adding an IGF-1R/INSR inhibitor to local IR in vivo accomplished a decrease in metastases similar to CR plus IR, demonstrating the importance of the IGF-1R signaling pathway, and underscoring it as a possible mechanism for CR., Conclusions: CR decreased metastatic burden and therefore may complement cytotoxic therapies being used in the clinical setting for metastatic disease. Downregulation of the IGF-1R pathway, is in part responsible for this response and modulating IGF-1R directly resulted in similar improved progression-free survival. The novel use of CR has the potential to enhance clinical outcomes for patients with metastatic breast cancer.

Purpose of Review: This article reviews the impact the obese state has on malignancy through inflammation and immune dysregulation using recent excerpts from the medical literature., Recent Findings: The obese state creates a proinflammatory endocrinologic milieu altering cellular signaling between adipocytes, immunologic cells, and epithelial cells, leading to the over-activation of adipose tissue macrophages and the upregulation of compounds associated with carcinogenesis. Obesity correlates with a deficiency in numerous immunologic cells, including dendritic cells, natural killer cells, and T cells. In part, this can be attributed to a recent finding of leptin receptor expression on these immune cells and the upregulation of leptin signaling in the obese state. A number of clinical trials have demonstrated the feasibility of a high-fat, low-carbohydrate diet as an adjuvant treatment for cancer, and current trials are investigating the impact of this intervention on disease outcomes. In preclinical trials, a ketogenic diet has been shown to impede tumor growth in a variety of cancers through anti-angiogenic, anti-inflammatory, and proapoptotic mechanisms., Summary: Obesity is becoming more prevalent and its link to cancer is clearly established providing a rationale for the implementation of dietary interventions as an adjuvant therapeutic strategy for malignancy.

Purpose: The Next Accreditation System (NAS) requires radiation oncology residents to do a formal quality improvement project during their residency. The American Board of Radiology (ABR) Maintenance of Certification (MOC) program requires certified physicians to complete a Practice Quality Improvement (PQI) project approximately every 3 years. The purpose of our project was to develop a clinical transition of care policy via a process that resulted in quality improvement project credit for residents and PQI credit for participating faculty., Methods and Materials: Approval for project implementation was obtained from the ABR MOC committee. The PQI project consisted of an initial survey to assess resident perception on resident transition of care in our department, formal sign-out training, and 2 postintervention surveys after 1 and 11 months. The primary endpoint was the percentage of questions with ≤1 unfavorable responses. Sign-test was used to determine response difference from neutral., Results: One hundred percent of surveyed residents completed the preintervention (n = 6), postintervention 1 (n = 7), and postintervention 2 (n = 8) surveys. In the preintervention, postintervention 1, and postintervention 2 surveys, 71.4%, 57.1%, and 57.1% of questions were answered with ≤1 unfavorable response, respectively. The number of questions with ≥75% favorable response was 7 (50%), 7 (50%), and 11 (78.5%) in the preintervention, postintervention 1, and postintervention 2 surveys, respectively (P = .13). A written sign-out template and monthly protected sign-out meetings were instituted. One resident and 3 attending physicians received credit for Accreditation Council of Graduate Medical Education NAS quality improvement and ABR MOC PQI projects, respectively., Conclusions: This project shows the feasibility of a combined attending and resident physician effort to improve patient care and fulfill his or her respective ABR MOC PQI and Accreditation Council of Graduate Medical Education NAS requirements. Attending and resident physicians can tailor collaborative projects to fulfill MOC and NAS requirements unique to their subspecialty. Written sign-out templates and protected sign-out time may improve transition of care., (Copyright © 2016 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Purpose: Deep inspiration breath hold (DIBH) dramatically reduces radiation dose to the heart during radiation therapy (RT) for left-sided breast cancer, but the subsequent risk of radiation-related ischemic heart disease (IHD) is unknown. Our primary objective was to quantify the risk of IHD following RT with DIBH using modeled risk estimates (MRE)., Methods and Materials: Patients with stage 0-III left-sided breast cancer who received RT with DIBH were retrospectively studied. Computed tomography simulations were performed with DIBH and during free breathing (FB) for comparison of dosimetry. Patients were classified as high risk, at risk, or at optimal risk for IHD and baseline risk estimates for IHD were obtained from historic controls. The excess relative risk of IHD because of left breast RT was calculated using patient-specific dosimetry and an existing dose-effect model. MRE were determined from the sum of baseline risk estimates and excess risk., Results: Between 2002 and 2011, 111 patients were treated using DIBH and 104 were available for analysis. MRE for 10-year risk of IHD with DIBH and FB were 3.25% (interquartile range [IQR], 1.20-3.44) and 3.64% (IQR, 1.43-3.81) (P < .0001), respectively. MRE for lifetime risk of IHD with DIBH and FB were 9.71% (IQR, 1.98-16.62) and 10.28% (IQR, 2.05-16.97) (P < .0001), respectively. MRE were significantly reduced by use of DIBH in all risk groups. The largest absolute risk reduction resulting from the DIBH technique was observed in patients at high risk for IHD. The median relative risk reduction in MRE resulting from DIBH was 11.4% (range, 0-32.0) and 6.4% (range, 0-23.4) at 10 years and throughout the patients' lifetime, respectively. After a median follow-up of 7.0 years (range, 1.3-11.2), the estimated 10-year freedom from IHD was 99.0% (95% confidence interval 93.4-99.8)., Conclusions: RT with DIBH may provide breast cancer survivors a clinically significant reduction in the risk of IHD., (Copyright © 2015 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Purpose: Incidental radiation dose to the heart and lung during breast radiation therapy (RT) has been associated with an increased risk of cardiopulmonary morbidity. We conducted a prospective trial to determine if RT with the Active Breathing Coordinator (ABC) can reduce the mean heart dose (MHD) by ≥20% and dose to the lung., Methods and Materials: Patients with stages 0-III left breast cancer (LBC) were enrolled and underwent simulation with both free breathing (FB) and ABC for comparison of dosimetry. ABC was used during the patient's RT course if the MHD was reduced by ≥5%. The median prescription dose was 50.4 Gy plus a boost in 77 patients (90%). The primary endpoint was the magnitude of MHD reduction when comparing ABC to FB. Secondary endpoints included dose reduction to the heart and lung, procedural success rate, and adverse events., Results: A total of 112 patients with LBC were enrolled from 2002 to 2011 and 86 eligible patients underwent both FB and ABC simulation. Ultimately, 81 patients received RT using ABC, corresponding to 72% procedural success. The primary endpoint was achieved as use of ABC reduced MHD by 20% or greater in 88% of patients (P < .0001). The median values for absolute and relative reduction in MHD were 1.7 Gy and 62%, respectively. RT with ABC provided a statistically significant dose reduction to the left lung. After a median follow up of 81 months, 8-year estimates of locoregional relapse, disease-free, and overall survival were 7%, 90%, and 96%, respectively., Conclusions: ABC was well tolerated and significantly reduced MHD while preserving local control. Use of the ABC device during RT should be considered to reduce the risk of ischemic heart disease in populations at risk., (Copyright © 2015 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

As the link between metabolism and major disease processes becomes more well-defined, the identification of key molecular targets is leading to new therapeutic strategies. As a result, small non-coding RNA molecules that regulate gene expression via epigenetic alterations, microRNAs have been identified as regulators of these metabolic processes. In the last decade, dietary interventions have been used to change metabolism and to potentially alter disease progression and clinical outcomes. These interventions have been linked, at a molecular level, to microRNAs. This review will summarize the role of various dietary strategies on the expression of several microRNA families., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Purpose: Although ionizing radiation is critical in treating cancer, radiation-induced fibrosis (RIF) can have a devastating impact on patients' quality of life. The molecular changes leading to radiation-induced fibrosis must be elucidated so that novel treatments can be designed., Methods and Materials: To determine whether microRNAs (miRs) could be responsible for RIF, the fibrotic process was induced in the right hind legs of 9-week old CH3 mice by a single-fraction dose of irradiation to 35 Gy, and the left leg served as an unirradiated control. Fibrosis was quantified by measurements of leg length compared with control leg length. By 120 days after irradiation, the irradiated legs were 20% (P=.013) shorter on average than were the control legs., Results: Tissue analysis was done on muscle, skin, and subcutaneous tissue from irradiated and control legs. Fibrosis was noted on both gross and histologic examination by use of a pentachrome stain. Microarrays were performed at various times after irradiation, including 7 days, 14 days, 50 days, 90 days, and 120 days after irradiation. miR-15a, miR-21, miR-30a, and miR-34a were the miRs with the most significant alteration by array with miR-34a, proving most significant on confirmation by reverse transcriptase polymerase chain reaction, c-Met, a known effector of fibrosis and downstream molecule of miR-34a, was evaluated by use of 2 cell lines: HCT116 and 1522. The cell lines were exposed to various stressors to induce miR changes, specifically ionizing radiation. Additionally, in vitro transfections with pre-miRs and anti-miRs confirmed the relationship of miR-34a and c-Met., Conclusions: Our data demonstrate an inverse relationship with miR-34a and c-Met; the upregulation of miR-34a in RIF causes inhibition of c-Met production. miRs may play a role in RIF; in particular, miR-34a should be investigated as a potential target to prevent or treat this devastating side effect of irradiation., (Published by Elsevier Inc.)

Caloric restriction (CR) has been shown to cause tumor regression in models of triple-negative breast cancer (TNBC), and the regression is augmented when coupled with ionizing radiation (IR). In this study, we sought to determine if the molecular interaction between CR and IR could be mediated by microRNA (miR). miR arrays revealed 3 miRs in the miR-17~92 cluster as most significantly down regulated when CR is combined with IR. In vivo, CR and IR down regulated miR-17/20 in 2 TNBC models. To elucidate the mechanism by which this cluster regulates the response to CR, cDNA arrays were performed and the top 5 statistically significant gene ontology terms with high fold changes were all associated with extracellular matrix (ECM) and metastases. In silico analysis revealed 4 potential targets of the miR-17~92 cluster related to ECM: collagen 4 alpha 3, laminin alpha 3, and metallopeptidase inhibitors 2 and 3, which were confirmed by luciferase assays. The overexpression or silencing of miR-17/20a demonstrated that those miRs directly affected the ECM proteins. Furthermore, we found that CR-mediated inhibition of miR-17/20a can regulate the expression of ECM proteins. Functionally, we demonstrate that CR decreases the metastatic potential of cells which further demonstrates the importance of the ECM. In conclusion, CR can be used as a potential treatment for cancer because it may alter many molecular targets concurrently and decrease metastatic potential for TNBC.

In well-selected patients who choose to pursue breast conservation therapy (BCT) for early-stage breast cancer, partial breast irradiation (PBI) delivered externally or intraoperatively, may be a viable alternative to conventional whole breast irradiation. Two large, contemporary randomized trials have demonstrated breast intraoperative radiotherapy (IORT) to be noninferior to whole breast external beam radiotherapy (EBRT) when assessing for ipsilateral breast tumor recurrence in select patients. Additionally, IORT and other PBI techniques are likely to be more widely adopted in the future because they improve patient convenience by offering an accelerated course of treatment. Coupled with these novel techniques for breast radiotherapy (RT) are distinct toxicity profiles and unique cosmetic alterations that differ from conventional breast EBRT and have the potential to impact disease surveillance and patient satisfaction. This paper will review the level-one evidence for treatment efficacy as well as important secondary endpoints like RT toxicity, breast cosmesis, quality of life, patient satisfaction, and surveillance mammography following BCT with IORT.

As the link between obesity and metabolic syndrome and cancer becomes clearer, the need to determine the optimal way to incorporate dietary manipulation in the treatment of cancer patients becomes increasingly important. Metabolic-based therapies, such as caloric restriction, intermittent fasting and a ketogenic diet, have the ability to decrease the incidence of spontaneous tumors and slow the growth of primary tumors, and may have an effect on distant metastases in animal models. Despite the abundance of preclinical data demonstrating the benefit of dietary modification for cancer, to date there are few clinical trials targeting diet as an intervention for cancer patients. We hypothesize that this may be due, in part, to the fact that several different types of diet modification exist with no clear recommendations regarding the optimal method. This article will delineate three commonly used methods of dietary manipulation to assess the potential of each as a regimen for cancer therapy.

Dietary modification such as caloric restriction (CR) has been shown to decrease tumor initiation and progression. We sought to determine if nutrient restriction could be used as a novel therapeutic intervention to enhance cytotoxic therapies such as radiation (IR) and alter the molecular profile of triple-negative breast cancer (TNBC), which displays a poor prognosis. In two murine models of TNBC, significant tumor regression is noted with IR or diet modification, and a greater regression is observed combining diet modification with IR. Two methods of diet modification were compared, and it was found that a daily 30% reduction in total calories provided more significant tumor regression than alternate day feeding. At the molecular level, tumors treated with CR and IR showed less proliferation and more apoptosis. cDNA array analysis demonstrated the IGF-1R pathway plays a key role in achieving this physiologic response, and multiple members of the IGF-1R pathway including IGF-1R, IRS, PIK3ca and mTOR were found to be downregulated. The innovative use of CR as a novel therapeutic option has the potential to change the biology of tumors and enhance the opportunity for clinical benefit in the treatment of patients with TNBC.

Calorie restriction (CR), or a diet modification aiming to reduce the total intake of calories by 20%-40%, has been shown to increase longevity across multiple species. Recently, there has been growing interest in investigating the potential role of CR as a treatment intervention for age-related diseases, such as cancer, because an increasing body of literature has demonstrated a metabolic component to both carcinogenesis and tumor progression. In fact, many of the molecular pathways that are altered with CR are also known to be altered in cancer. Therefore, manipulation of these pathways using CR can render cancer cells, and most notably breast cancer cells, more susceptible to standard cytotoxic treatment with radiation and chemotherapy. In this review article we demonstrate the laboratory and clinical evidence that exists for CR and show compelling evidence through the molecular pathways CR induces about how it may be used as a treatment in tandem with radiation therapy to improve our rates of disease control.