BACKGROUND:The European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) is a validated tool for assessing the clinical benefit of systemic cancer therapies. However, application of the scale to radiotherapy (RT) remains limited. As part of an ongoing initiative to adapt the scale for RT, we applied Form 1a of ESMO-MCBS v2.0 to studies cited in the American Society for Radiation Oncology (ASTRO) guideline for Human Papillomavirus (HPV)-positive oropharyngeal cancer (OPC) to assess feasibility and identify shortcomings. METHODS:We screened 73 studies cited in the ASTRO OPC guideline. Eligible studies included randomized controlled trials and meta-analyses. Two radiation oncologists scored studies using ESMO-MCBS v2.0 Form 1a; consensus grading was reached through group review. Scoring outcomes and reasons for non-scoreability were analyzed to identify systematic limitations. RESULTS:Of 73 studies, 33 met eligibility with a total of 37 comparisons noted. Eleven comparisons were scorable. Six scored Grade A (notably for survival benefit from chemoradiation or altered fractionation), and five scored Grade B (toxicity or cost reduction). Twenty-six comparisons were non-scoreable. Four demonstrated benefit in locoregional survival. Six post-hoc subgroup analyses yielded clinically impactful findings. The remaining 16 comparisons showed no evidence of benefit. These results highlight key ESMO-MCBS limitations: lack of credit for improved local control, non-inferiority designs improving convenience/toxicity, and practice-changing post-hoc subgroup analyses. CONCLUSION:While ESMO-MCBS v2.0 performed reasonably in OPC RT trials, several limitations restrict its utility in radiotherapy. This study identifies actionable gaps that should be addressed in developing a validated RT-specific version.

Value frameworks (VFs) guide clinical and policy decisions in oncology by capturing therapeutic benefit, toxicity, and cost. Most VFs evaluate novel systemic therapies. Local treatment modalities have additional meaningful endpoints such as organ preservation, organ functional outcomes, hospitalization rates, and local tumor control. Therefore, VFs calibrated based on drug treatments may undervalue locoregional therapies. This topic discussion organizes contemporary VFs into quantitative, qualitative, and hybrid categories while examining their respective limitations for locoregional interventions. We also highlight the challenge of comparing value across treatment modalities and review emerging developments.

PURPOSE:The European Society of Medical Oncology (ESMO) magnitude of clinical benefit scale (MCBS) version 1.1 is an evaluation scale that was developed to evaluate the MCBS reported in clinical research studies of cancer treatments. The American Society for Radiation Oncology (ASTRO) and the European Society for Radiotherapy and Oncology (ESTRO) created joint guidelines for the use of local therapy in the management of extracranial oligometastatic non-small cell lung cancer (NSCLC). We applied the ESMO-MCBS v.1.1 to evaluate the clinical benefit reported in studies that informed the ASTRO/ESTRO guidelines. METHODS AND MATERIALS:We applied the ESMO-MCBS v1.1 to the 23 studies identified by the ASTRO/ESTRO taskforce. As well, we evaluated the recently published Consolidative Use of Radiotherapy to Block Oligoprogression study and Stereotactic Radiotherapy for Oligo-Progressive Metastatic Cancer Trial, for a total of 25 studies evaluated. All evaluated studies were graded by at least 3 of the authors. Any discrepancies were subsequently reviewed by the scoring authors. RESULTS:The addition of stereotactic body radiation therapy to all sites of oligometastatic disease in combination with standard-of-care chemotherapy was associated with substantial improvements in survival. These studies resulted in a score of 4 using form 2a (noncurative treatment with overall survival from standard therapy between 12 and 24 months). Of the 10 prospective single-arm studies, 9 received a score of 3 using form 3, due to progression-free survival exceeding 6 months. No studies received a score of 5 (highest clinical benefit). CONCLUSIONS:The use of local radiation in the treatment of extracranial oligometastatic NSCLC is associated with a substantial clinical benefit, according to the ESMO-MCBS v1.1. Radiation therapy was comparable to established and groundbreaking targeted therapies such as pembrolizumab in combination with pemetrexed for epidermal growth factor receptor and anaplastic lymphoma kinase-negative NSCLC, and osimertinib for epidermal growth factor receptor-mutated NSCLC. MCBS would be even higher if quality-of-life improvements are found in future trials.

e13596 Background: Belong.life, a global oncology social network for patients and caregivers, recently launched “Dave” the first conversational AI oncology mentor and companion. “Dave’s” objectives are to provide uninterrupted support, clarify relevant clinical issues and guide patients and caregivers with relevant and empathetic information and education in all aspects of cancer, from diagnosis to treatment protocols and side effects management. “Dave” underwent training on Belong’s unique and large datasets of patients to physicians, and patients to patients’ interactions, as well as incorporating high quality information from the latest international cancer guidelines, providing it with a robust up-to-date supportive data and a wide understanding of the patients’ cancer journey. Methods: “Dave’s” responses to inquiries from Belong members were subjected to a validation survey conducted by eight oncologists, each specializing in various solid and haematological cancers and affiliated with several medical institutions. From the social network datasets, 471 questions from patients and caregivers were randomly selected and categorized into groups, including Breast, Gastrointestinal and Pancreatic, Genito-urinary, Bone, Haematological cancers, and Radiation therapy. The oncologists assessed the AI mentor's replies for their relevance and helpfulness, aligning them with evidence-based medicine, current recommendations, and guidelines. Results: Results were categorized into positive or negative assessments. Impressively, 432 out of 471 “Dave’s” responses (91.8%) received positive validation for providing suitable and relevant recommendations. Conversely, 39/471 responses (8.2%) received a negative validation, of which only 5/471 (1%) were graded as not at all helpful or relevant. Minor variations were observed within diagnostic groups, with positive validation rates as follows: Genito-urinary 100%, Breast 98.4%, Musculoskeletal 97%, Radiation therapy 88%, Gastrointestinal and Pancreatic 86%, and Haematological cancers 84%. Conclusions: The documented results on 471 patients’ posts are very promising, indicating that “Dave” provides valuable and reliable recommendations, achieving a positive validation rate of nearly 92%, with only 1% graded as not at all helpful or relevant. The findings also offer insights into the AI mentor's performance across distinct medical domains. This validation study provides a solid foundation and adds confirmation that the addition of an AI oncology mentor and companion, like “Dave”, improves patients’ knowledge and coping mechanisms and provides helpful and relevant guidance during their cancer journey, while supporting physicians in the daily management of their cancer patients.

PURPOSE/OBJECTIVES:Rectal spacers have been shown to reduce rectal side effects in patients receiving prostate radiation. However, concerns remain regarding precise and reproducible gel injection. We evaluated efficacy and safety of a novel rectoprostatic spacer balloon that allows potential for controlled, adaptable deployment. This study tested co-primary hypotheses: (1) balloon spacer would result in ≥25% reduction of rectal V70 in >75% of subjects and (2) implantation procedure-related and rectal ≥grade 1 adverse events within 6 months (duration ≥2 days, Common Terminology Criteria for Adverse Events 4.0) would be noninferior in balloon versus control subjects. METHODS AND MATERIALS:A total of 222 subjects were enrolled at 16 centers. All patients had T1-T3 prostate cancer without magnetic resonance imaging evidence of posterior extraprostatic invasion. Randomization was 2:1 (balloon: control) and subject-blinded. Patients underwent transperineal transrectal ultrasound axial and sagittal-guided fiducial placement ± balloon, followed by Intensity-Modulated Radiation Therapy (81 Gy in 1.8 Gy fractions or biologically equivalent hypofractionated dose). For efficacy comparisons, plans were generated by a central core lab on pre- and postimplant computed tomography scans. RESULTS:The primary efficacy endpoint was met, with 97.9% of balloon subjects (139/142) having rectal V70 reduction >25% (P < .001). Mean V70 was 7.0 % pre- versus 1.1% postimplant. The primary safety endpoint was met with balloon subjects experiencing fewer ≥grade 1 events, 18% versus 23% (P < .001 for noninferiority). On predefined secondary endpoint of ≥grade 2 events, rates trended lower in balloon subjects (4.3% vs 6.5%, P = .527). Mean perirectal spacing was 19 ± 3.7 mm and maintained through radiation treatment (18 ± 3.9 mm). Balloon resorption was observed on 6-month computed tomography in 98.5% (133/135) of subjects. The Expanded Prostate Cancer Index quality of life instrument was collected throughout study, and did not differ statistically between the study arms. CONCLUSIONS:Biodegradable rectal spacer balloon was effective in significantly reducing dose to rectum, and associated with decreased cumulative rectal plus implantation-related adverse events. Balloon resorption was consistently observed by 6 months.

Purpose: The attack by Hamas on Israeli civilians (October 7, 2023) triggered the ongoing war, which could be detrimental to cancer care in general and radiation therapy (RT) in particular. To assure continuity of care within the Radiation Oncology Department of Samson Assuta Ashdod University Hospital (SAAUH), which borders on Gaza, patient-centric measures were redoubled by our institution. This study describes the impact of these measures on patients' perception and their willingness to continue RT, despite fear of war. Methods and Materials: A survey questionnaire was designed to detect changes in attitude and treatment adherence during war. It was offered to the patients undergoing RT at SAAUH. A Pearson correlation between the items relating to desire to continue the therapy was calculated. Smallest space analysis was conducted to illustrate the association between the variables. Results: Forty-seven patients enrolled in this study reported a significantly lower feeling of personal safety during wartime in comparison with the confidence in the professionalism of the staff (paired samples t test, t(43) = 4.61; P < .001). Simultaneously, patients perceived that the impact of the national situation on their health was very low (mean of 1.59 on a scale of 1-6). Both the Pearson correlation test and smallest space analysis revealed that the desire to continue treatment in general and to continue treatment at the same department were significantly related to trust in the staff's professionalism. Conclusions: Fear of war can pose a major pitfall in providing daily RT care. This obstacle may be potentially overridden by creating deep, trusting relationships between the patients and the medical staff. (c) 2024 The Authors. Published by Elsevier Inc. on behalf of American Society for Radiation Oncology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Late life depression (LLD) is an emerging challenge, and recognized as a significant barrier to long-term healthy aging. Viewed within the context of the medical/biological model, advances in brain sciences over the last several decades have led to a deeper understanding of the biology of LLD. These advances in current knowledge include the description of aging brain pathophysiology; the biology and biochemistry of neurotransmitters; the correspondence between changes in neurological structure, function, and neural network; the description of neural, hormonal and inflammatory biomarkers; and identification of typical phenotypic subtypes of LLD. Despite these advances, current treatment of LLD, which remains largely pharmacological with accompanying cognitive and behavioral interventions, has poor success rate for long-term remission among older people. A wider perspective, in keeping with several emerging aging concepts, is suggested as an alternative framework within which to view LLD. A growing body of research supports the important role in LLD of frailty, resilience, intrinsic capacity, and functional integrity. Similarly, important social determinants need to be addressed in the etiology of LLD, rooted largely in negative stereotypes of aging, with consequent repercussions of reduced participation and inclusion, growing social isolation, with loss of identity, meaning and hope. This perspective suggests the importance of a wider integrative conceptualization of depression, set against a background of emerging aging concepts.

Abstract Radiotherapy has an important role in the treatment of brain metastases (BrM) but carries risk of short and/or long-term toxicity, termed radiation-induced neurotoxicity (RIN). As the diagnosis of RIN is crucial for correct pa-tient management, there is an unmet need for reliable biomarkers for RIN. The aim of this proof-of concept study was to determine the utility of brain-derived circulating free DNA (BncfDNA), identified by specific methylation patterns for neurons, astrocytes, and oligodendrocytes, as RIN biomarkers. Twenty-four patients with BrM were monitored clinically and radiologically before, during and after brain radiotherapy, and blood for BncfDNA analysis (98 samples) was concurrently collected. Sixteen patients were treated with whole brain radiotherapy and eight patients with stereotactic radiosurgery. During follow-up nine RIN events were detected, and all correlated with significant increase in BncfDNA levels compared to baseline. Additionally, resolution of RIN correlated with de-crease in BncfDNA. Changes in BncfDNA were independent of tumor response. Elevated BncfDNA levels reflects brain cell injury incurred by radiotherapy, further research is needed to establish BncfDNA as a novel plasma-based biomarker for RIN.

BACKGROUND:Radiotherapy has an important role in the treatment of brain metastases but carries risk of short and/or long-term toxicity, termed radiation-induced brain injury (RBI). As the diagnosis of RBI is crucial for correct patient management, there is an unmet need for reliable biomarkers for RBI. The aim of this proof-of concept study is to determine the utility of brain-derived circulating free DNA (BncfDNA), identified by specific methylation patterns for neurons, astrocytes, and oligodendrocytes, as biomarkers brain injury induced by radiotherapy. METHODS:Twenty-four patients with brain metastases were monitored clinically and radiologically before, during and after brain radiotherapy, and blood for BncfDNA analysis (98 samples) was concurrently collected. Sixteen patients were treated with whole brain radiotherapy and eight patients with stereotactic radiosurgery. RESULTS:During follow-up nine RBI events were detected, and all correlated with significant increase in BncfDNA levels compared to baseline. Additionally, resolution of RBI correlated with a decrease in BncfDNA. Changes in BncfDNA were independent of tumor response. CONCLUSIONS:Elevated BncfDNA levels reflects brain cell injury incurred by radiotherapy. further research is needed to establish BncfDNA as a novel plasma-based biomarker for brain injury induced by radiotherapy.

Background: The European Society of Medical Oncology (ESMO) has suggested using the ESMO-Magnitude of Clinical Benefit Scale (MCBS) to grade the magnitude of clinical benefit of cancer therapies. This approach has not been applied to radiation therapy (RT) yet. We applied the ESMO-MCBS to experiences describing the use of RT to assess (1) the 'scoreability' of the data, (2) evaluate the reasonableness of the grades for clinical benefit and (3) identify potential shortcomings in the current version of the ESMO-MCBS in its applicability to RT.Materials and methods: We applied the ESMO-MCBS v1.1 to a selection of studies in radiotherapy that had been identified as references in the development of American Society for Radiation Oncology (ASTRO) evidence-based guidelines on whole breast radiation. Of the 112 cited references, we identified a subset of 16 studies that are amenable to grading using the ESMO-MCBS. Results: Of the 16 studies reviewed, 3/16 were scoreable with the ESMO tool. Six of 16 studies could not be scored because of shortcomings in the ESMO-MCBS v1.1: (1) in 'non-inferiority studies', there is no credit for improved patient convenience, reduced patient burden or improved cosmesis; (2) in 'superiority studies' evaluating local control as a primary endpoint, there is no credit for the clinical benefit such as reduced need for further interventions. In 7/16 studies, methodological deficiencies in the conduct and reporting were identified.Conclusions: This study represents a first step in determining the utility of the ESMO-MCBS in the evaluation of clinical benefit in radiotherapy. Important shortcomings were identified that would need to be addressed in developing a version of the ESMO-MCBS that can be robustly applied to radiotherapy treatments. Optimization of the ESMO-MCBS instrument will proceed to enable assessment of value in radiotherapy.

You have accessJournal of UrologyCME1 Apr 2023PD15-11 EFFICACY AND SAFETY OF BIODEGRADABLE RECTAL SPACER BALLOON IN PATIENTS RECEIVING PROSTATE IMRT: AN INTERNATIONAL PHASE 3 RANDOMIZED TRIAL Daniel Song, Mateusz Dabkowski, Warsaw Poland, Paulo Costa, Rizwan Nurani, Michael Kos, Ben Vanneste, David Margel, Eli Sapir, Shawn Zimberg, Oleksandr Boychak, Edward Soffen, Abdulla Alhasso, Kenneth Tokita, Dian Wang, Zvi Symon, and Richard Hudes Daniel SongDaniel Song More articles by this author , Mateusz DabkowskiMateusz Dabkowski More articles by this author , Warsaw PolandWarsaw Poland More articles by this author , Paulo CostaPaulo Costa More articles by this author , Rizwan NuraniRizwan Nurani More articles by this author , Michael KosMichael Kos More articles by this author , Ben VannesteBen Vanneste More articles by this author , David MargelDavid Margel More articles by this author , Eli SapirEli Sapir More articles by this author , Shawn ZimbergShawn Zimberg More articles by this author , Oleksandr BoychakOleksandr Boychak More articles by this author , Edward SoffenEdward Soffen More articles by this author , Abdulla AlhassoAbdulla Alhasso More articles by this author , Kenneth TokitaKenneth Tokita More articles by this author , Dian WangDian Wang More articles by this author , Zvi SymonZvi Symon More articles by this author , and Richard HudesRichard Hudes More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003262.11AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Rectal gel spacers have been shown to reduce rectal side effects in patients receiving prostate radiation. However, concerns remain regarding precise and reproducible gel injection. We report on a novel rectoprostatic spacer balloon which allows potential for controlled, adaptable deployment without time constraints associated with hydrogel injection. To determine efficacy and safety, the study had co-primary hypotheses: 1) Balloon spacer would result in ≥25% reduction of rectal V70 in >75% of subjects, and 2) Implantation procedure-related and rectal ≥ Grade 1 adverse events would be non-inferior in balloon vs control subjects (events with duration ≥2 days within 6 months, CTCAE 4.0). METHODS: 222 subjects were enrolled at 16 centers. All patients had biopsy-proven T1-T3 prostate cancer without MRI evidence of posterior extraprostatic invasion. Patients receiving brachytherapy or whole pelvic RT were excluded. Randomization was 2:1 (balloon:control) and subject-blinded. All patients underwent transperineal TRUS-guided fiducial marker placement±biodegradable balloon, followed by IMRT. For efficacy endpoint comparisons, plans were generated by central core lab on pre- and post-implant CT scans (81 Gy in 1.8 Gy fractions). Adverse events were reviewed by blinded, independent Clinical Events Committee. RESULTS: The primary efficacy endpoint was met, with 97.9% of balloon subjects (139/142) having rectal V70 reduction of >25% (pre- vs post-implant; p<0.001, 95% CI (94.0, 99.6%). Mean V70 was 7.0 % pre- vs 1.1% post-implant. Similar decreases were observed in rectal V40–V80. Mean prostate-rectal spacing achieved (19+3.7mm) was maintained through radiation treatment (18+3.9mm). Balloon placement was successful in 99% of subjects. The primary safety endpoint was met with balloon subjects experiencing fewer ≥ Grade 1 events, 18% vs 23% (p<0.001, 95% CI -15.7%, 5.5%). Event rate was higher in balloon subjects in early post-implant period, but control arm surpassed balloon group at/beyond day 44 post-implant. On pre-defined secondary endpoint of ≥Grade 2 events, rates were lower in balloon subjects (4.3% vs 6.5%). Complete balloon resorption was observed on 6-month CT in 98.5% (133/135) of subjects. CONCLUSIONS: Biodegradable rectal spacer balloon was effective in significantly reducing dose to rectum, and associated with decreased cumulative rectal plus implantation-related adverse events. Balloon resorption was consistently observed by 6 months. Source of Funding: BioProtect, Ltd © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e423 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Daniel Song More articles by this author Mateusz Dabkowski More articles by this author Warsaw Poland More articles by this author Paulo Costa More articles by this author Rizwan Nurani More articles by this author Michael Kos More articles by this author Ben Vanneste More articles by this author David Margel More articles by this author Eli Sapir More articles by this author Shawn Zimberg More articles by this author Oleksandr Boychak More articles by this author Edward Soffen More articles by this author Abdulla Alhasso More articles by this author Kenneth Tokita More articles by this author Dian Wang More articles by this author Zvi Symon More articles by this author Richard Hudes More articles by this author Expand All Advertisement PDF downloadLoading ...

Purpose: The aim of this study was to evaluate a formulation of pegylated liposomal mitomycin C lipidic prodrug (PL-MLP) in patients concomitantly undergoing external beam radiation therapy (RT). Methods and Materials: Patients with metastatic disease or inoperable primary solid tumors requiring RT for disease control or symptom relief were treated with 2 courses of PL-MLP (1.25, 1.5, or 1.8 mg/kg) at 21-day intervals, along with 10 fractions of conventional RT or 5 stereotactic body RT fractions initiated 1 to 3 days after the first PL-MLP dose and completed within 2 weeks. Treatment safety was monitored for 6 weeks, and disease status was re-evaluated at 6-week intervals thereafter. MLP levels were analyzed 1 hour and 24 hours after each PL-MLP infusion.Results: Overall, 19 patients with metastatic (18) or inoperable (1) disease received combination treatment, with 18 completing the full protocol. Most patients (16) had diagnoses of advanced gastrointestinal tract cancer. One grade 4 neutropenia event possibly related to study treatment was reported; other adverse events were mild or moderate. Of the 18 evaluable patients, 16 were free of RT target lesion progression at first re-evaluation. Median survival of the entire patient population was 63.3 weeks. Serum MLP level correlated with dose increases and similar long circulating profiles were observed before and after RT.Conclusions: PL-MLP up to 1.8 mg/kg in combination with RT treatment is safe, with a high rate of tumor control. Drug clearance is not affected by radiation. PL-MLP is potentially an attractive option for chemoradiation therapy that warrants further evaluation in randomized studies in the palliative and curative settings. & COPY; 2023 Elsevier Inc. All rights reserved.

INTRODUCTION:Ionizing radiation plays an important role in the treatment of patients with malignancy for cure and palliation. In the last decade there have been significant technological advances in radiation equipment, imaging and software. Owing to these developments, modern radiation is being shaped according to the size and form of the target organ and is accurate in locating the target location and can even take into account respiratory motion. Thanks to these developments, radiobiological concepts in radiation therapy have been tested and applied. Radiation doses have been increased to 5-20Gy/fraction and the number of treatments has been reduced to an average of five. This type of treatment is called Stereotactic Body Radiation Therapy (SBRT). The application of this treatment to various tumors may improve the effectiveness of radiation therapy, increasing local tumor control and reducing side effects. Another benefit is cutting the overall treatment time. The present article presents a review of literature on stereotactic radiation in lung tumors, prostate cancer, primary liver tumors and in oligo-metastases.

Skin exposure to high-dose irradiation, as commonly practiced in radiotherapy, affects the different skin layers, causing dry and wet desquamation, hyperkeratosis fibrosis, hard to heal wounds and alopecia and damaged hair follicles. Fetal tissue mesenchymal stromal cells (f-hPSC) were isolated from excised human fetal placental tissue, based on their direct migration from the tissue samples to the tissue dish. The current study follows earlier reports on for the mitigation of acute radiation syndrome following whole body high-dose exposure with remotely injected f-hPSC. Both the head only and a back skin flap of mice were irradiated with 16 &18 Gy, respectively, by 6MeV clinical linear accelerator electron beam. In both locations, the irradiated skin areas developed early and late radiation induced skin damages, including cutaneous fibrosis, lesions, scaring and severe hair follicle loss and reduced hair pigmentation. Injection of 2 × 106 f-hPSC, 3 and 8 weeks following 16 Gy head irradiation, and 1 and 4 weeks following the 18 Gy back skin only irradiation, resulted in significantly faster healing of radiation induced damages, with reduction of wet desquamation as measured by surface moisture level and minor recovery of the skin viscoelasticity. Detailed histological morphometry showed a clear alleviation of radiation induced hyperkeratosis in f-hPSC treated mice, with significant regain of hair follicles density. Following 16 Gy head irradiation, the hair follicles density in the scalp skin was reduced significantly by almost a half relative to the controls. A nearly full recovery of hair density was found in the f-hPSC treated mice. In the 18 Gy irradiated back skin, the hair follicles density dropped in a late stage by ~70% relative to naïve controls. In irradiated f-hPSC treated mice, it was reduced by only ~30% and was significantly higher than the non-treated group. Our results suggest that local injections of xenogeneic f-hPSC could serve as a simple, safe and highly effective non-autologous pro-regenerative treatment for high-dose radiation induced skin insults. We expect that such treatment could also be applied for other irradiated organs.

Purpose/Objective(s) There is an ongoing desire to define "value" in clinical research. ESMO-MCBS is a commonly used framework, endorsed by ESMO and used by several governments in their health technology assessments in various settings. Such value frameworks have not been validated for assessing benefit derived from radiotherapy (RT). We herein assess the applicability of the ESMO-MCBS in radiation oncology, using breast cancer as a test-case. Materials/Methods We reviewed the supportive literature used by the ASTRO Evidence-Based Guideline on Radiation Therapy for the Whole Breast for adjuvant whole breast Radiation Therapy. We delineated a pool of "core" (112 studies) and "supplemental" articles (additional 65 studies). Among these, we identified a subset of 15 randomized trials, 1 systematic review and 1 big data study. The goals of our exercise were (1) to evaluate the "scorability" of data, (2) to evaluate the reasonableness of the generated grades for clinical benefit using the current version of the ESMO-MCBS tool, and (3) to identify shortcomings in the instrument when applied to RT approaches, and suggest amendments to improve the efficacy and validity of the ESMO-MCBS tool. Results Few studies met the ESMO-MCBS criteria for crediting clinical benefit; i.e., in (1) superiority of the trials in overall survival (OS) or disease-free survival (DFS), or, (2) non-inferiority in OS or DFS with benefit in either life quality (QOL) or toxicity or reduced treatment costs as secondary end-points. OS was the primary end point in only one trial (which was a negative study). However, that study (EORTC boost trial) was practice-changing because it showed a significant improvement in local control (LC) which was a secondary outcome. Since the ESMO-MCBS does not credit local control (i.e., "local DFS"), superiority studies using this endpoint were not scoreable. Arguably, the 4 non-inferiority studies and one meta-analysis comparing hypo-fractionation with standard fractionation (that demonstrated non-inferior disease control with reduced acute and late toxicity) could be scored. Finally, reports describing cosmetic, clever technical or dosimetric advances, without verification of improved patient outcomes nor associated with clinical benefit, were not scoreable. Conclusion Currently, ESMO-MCBS does not credit LC as distinct from DFS or RFS. Since local recurrence results in a cascade of adverse events for patients, this is a clinically meaningful outcome, albeit often not always a good surrogate for OS. For consistency in research design and description of results, we propose replacing the conventional nomenclature of LC with Local-DFS (L-DFS)- a subtype of DFS most-relevant to local treatments (e.g., RT and surgery). The utility of the ESMO-MCBS in studies involving RT and surgery would be improved by incorporation of credit for statistically and clinically significant improvements in L-DFS.

The Rab subfamily of small GTPases plays an important role in the regulation of membrane traffic in eukaryotic cells. While most Rab proteins are equally expressed in polarized and nonpolarized cells, Rab17 and Rab18 show epithelial cell specificity. Here we report the genetic mapping of Rab17 and Rab18 on mouse chromosomes 1 and 18, respectively. We also discuss some implications ofRab17andRab18mapping, including their candidacy for the mouse mutationsln(leaden),Tw(twirler), andax(ataxia).

J. Takayesu: None. E. Sapir: Research Grant; LipoMedix, BioProtect. Consultant; AstraZeneca, MSD, Belong.Life. J. Xie: None. Y. Sun: None. A. Morikawa: Institutional research; Novartis, Lilly, Takeda, Eisai/H3b, Pfizer/National Comprehensive Cancer Network. L. Junck: Advisory Board; Orbus Therapeutics. D. Leung: None. Y. Umemura: None. J. Heth: None. W. Al-Holou: None. D.R. Wahl: Research Grant; Agios Inc, Innocrin Inc, American Cancer Society, NIH. Stock Options; Lycera Inc. Advisory Board Member; Agios Inc. T.S. Lawrence: None. C. Mayo: None. J.A. Hayman: Research Grant; Blue Cross Blue Shield of Michigan. M.M. Kim: Research Grant; Blue Earth Diagnostics.

Abstract BACKGROUND Brain radiotherapy is the main therapeutic modality for brain metastases (BM), but carries short and long term toxicities, termed radiation-induced neurotoxicity (RIN), and classified to acute, early-delayed and late-delayed RIN according to its time onset. Although diagnosis of RIN is crucial for patient management, there is an unmet need for sensitive biomarkers for RIN. Here we report on a novel non-invasive biomarker for detection and monitoring RIN. As radiotherapy is known to induce brain cells apoptosis as well as BBB disruption, we hypothesized that circulating cell free DNA fragments derived from dying brain cells will be elevated in the blood of patients with RIN. Using comparative methylome analysis we identified 13 genomic loci showing brain-specific DNA methylation patterns, including markers for neurons, oligodendrocytes, and astrocytes. We searched for these brain-derived cfDNA (bncfDNA) in plasma samples of patients following brain irradiation. METHODS We followed 24 patients treated by brain radiotherapy for BM by clinical and radiological examinations before, during and after treatment. In addition, we serially collected blood samples for DNA analysis, and correlated bncfDNA levels with clinical and radiological assessment. RESULTS Patient`s median age was 60 years. Most common primary tumor sites were breast (25%), lung (20.8%) and melanoma (12.5%). RIN was detected in 10 patients (62%). BncfDNA levels increased up to 292.4 fold in acute RIN, up to 138533.1 in early-delayed RIN, and up to 58.4 fold in late-delayed RIN. Resolution of RIN correlated with decrease in bncfDNA. Changes in bncfDNA levels were independent of tumor response and suggested to reflect both symptomatic and asymptomatic RIN. CONCLUSION Increase in bncfDNA levels characterizes RIN independent of tumor response. Thus, BncfDNA may serve as a novel biomarker for brain cells death incurred by radiotherapy. Further studies are required to explore the clinical utility of bncfDNA as a RIN biomarker.