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We aimed to determine the relationship between gross tumor volume (GTV) dose and tumor control in women with medically inoperable endometrial cancer, and to demonstrate the feasibility of targeting a GTV-focused volume using imaged-guided brachytherapy.An endometrial cancer database was used to identify patients. Treatment plans were reviewed to determine doses to GTV, clinical target volume (CTV), and OARs. Uterine recurrence-free survival was evaluated as a function of CTV and GTV doses. Brachytherapy was replanned with a goal of GTV D98 EQDFifty-four patients were identified. In the delivered plans, GTV D90 EQDOAR dose constraints should be prioritized over CTV coverage if GTV coverage is sufficient. Prospective evaluation of image-guided brachytherapy to a reduced, GTV-focused volume is warranted.

The study analysis plan, Figures S1-S6, Table S1

Purpose:To quantitatively predict the impact of cardiopulmonary dose on overall survival (OS) after radiotherapy for locally advanced non–small cell lung cancer.Experimental Design:We used the NRG Oncology/RTOG 0617 dataset. The model building procedure was preregistered on a public website. Patients were split between a training and a set-aside validation subset (N = 306/131). The 191 candidate variables covered disease, patient, treatment, and dose-volume characteristics from multiple cardiopulmonary substructures (atria, lung, pericardium, and ventricles), including the minimum dose to the hottest x% volume (Dx%[Gy]), mean dose of the hottest x% (MOHx%[Gy]), and minimum, mean (Mean[Gy]), and maximum dose. The model building was based on Cox regression and given 191 candidate variables; a Bonferroni-corrected P value threshold of 0.0003 was used to identify predictors. To reduce overreliance on the most highly correlated variables, stepwise multivariable analysis (MVA) was repeated on 1000 bootstrapped replicates. Multivariate sets selected in ≥10% of replicates were fit to the training subset and then averaged to generate a final model. In the validation subset, discrimination was assessed using Harrell c-index, and calibration was tested using risk group stratification.Results:Four MVA models were identified on bootstrap. The averaged model included atria D45%[Gy], lung Mean[Gy], pericardium MOH55%[Gy], and ventricles MOH5%[Gy]. This model had excellent performance predicting OS in the validation subset (c = 0.89).Conclusions:The risk of death due to cardiopulmonary irradiation was accurately modeled, as demonstrated by predictions on the validation subset, and provides guidance on the delivery of safe thoracic radiotherapy.

Radiotherapy is a critical tool for reducing locoregional recurrence, extending survival, and palliating symptoms in patients with breast cancer. With an ever-expanding armamentarium of systemic agents available, and an increasing trend toward the use of hypofractionated radiation regimens, it can be difficult to determine the safety of concurrent therapy. In particular, new targeted agents in both the adjuvant and metastatic setting have limited prospective or long-term data demonstrating safety when delivered concurrently with radiotherapy. Other systemic agents, including chemotherapy and endocrine therapy, are also important components of the overall treatment strategy for localized and metastatic breast cancer, and are often delivered concurrently with radiation in certain clinical scenarios. This review explores the safety, efficacy, and pitfalls of delivering radiation in conjunction with systemic therapies for breast cancer.

Dermatomyositis is a rare autoimmune disorder that can be idiopathic or present as a paraneoplastic syndrome. We report the case of an 83-year-old with anti-TIF-1-antibody-positive dermatomyositis, which led to the identification of a presumed left lower lobe T3 malignancy. Dramatic symptom improvement was noted after stereotactic body radiotherapy to the lesions, after no initial response to prednisone and IVIG. Recurrence of his skin findings at 6 month follow-up coincided with recurrent disease, biopsy proven for small cell lung cancer.

Accelerated partial breast irradiation and lumpectomy cavity boost radiation therapy plans generally use volumetric expansions from the lumpectomy cavity clinical target volume to the planning target volume (PTV) of 1 to 1.5 cm, substantially increasing the volume of irradiated breast tissue. The purpose of this study was to quantify intrafraction lumpectomy cavity motion during external beam radiation therapy to inform the indicated clinical target volume to PTV expansion.Forty-four patients were treated with a whole breast irradiation using traditional linear accelerator-based radiation therapy followed by lumpectomy cavity boost using magnetic resonance (MR)-guided radiation therapy on a prospective registry study. Two-dimensional cine-MR images through the center of the surgical cavity were acquired during each boost treatment to define the treatment position of the lumpectomy cavity. This was compared with the reference position to quantify intrafraction cavity motion. Free-breathing technique was used during treatment. Clinical outcomes including toxicity, cosmesis, and rates of local control were additionally analyzed.The mean maximum displacement per fraction in the anterior-posterior (AP) direction was 1.4 mm. Per frame, AP motion was5 mm in 92% of frames. The mean maximum displacement per fraction in the superior-inferior (SI) direction was 1.2 mm. Per frame, SI motion was5 mm in 94% of frames. Composite motion was5 mm in 89% of frames. Three-year local control was 97%. Eight women (18%) developed acute G2 radiation dermatitis. With a median follow-up of 32.4 months, cosmetic outcomes were excellent (22/44, 50%), good (19/44, 43%), and fair (2/44, 5%).In approximately 90% of analyzed frames, intrafraction displacement of the lumpectomy cavity was5 mm, with even less motion expected with deep inspiratory breath hold. Our results suggest reduced PTV expansions of 5 mm would be sufficient to account for lumpectomy cavity position, which may accordingly reduce late toxicity and improve cosmetic outcomes.

Purpose/Objectives To determine the utilization of and barriers to implementation of radiopharmaceutical therapy (RPT) amongst U.S. radiation oncologists. Materials/Methods An anonymous, voluntary 21-item survey directed towards attending radiation oncologists was distributed via social media platforms (Twitter, LinkedIn, Facebook, Student Doctor Network). Questions assessed practice characteristics, specific RPT prescribing patterns, RPT prescribing interest, and perceived barriers to RPT implementation. Non-parametric χ2 test was used for correlation statistics. Results Of the 142 respondents, 131 (92.3%) practiced in the U.S. and were included for this analysis. Respondents were well balanced in terms of practicing region, population size served, practice setting and years in practice. Forty-eight percent (n=63) reported prescribing at least one RPT. An additional 7% (n=8) participate in RPT administration without billing themselves. Among those that actively prescribed RPT, the mean cumulative cases per month was 4.2 (range: 1-5). The most commonly prescribed radionuclides were Radium-223 (40%; mean 2.8 cases/month), Iodine-131 (18%; mean 2.3 cases/month), Yttrium-90 (13%; mean 3.4 cases/month), “other” (8%), Samarium-153 (6%; mean 1.0 cases/month), Strontrium-89 and Phosphorous-32 (2% each; mean 1.8 and 0.4 cases/month respectively). Of those who answered “other”, Lutetium-177 dotatate was most commonly prescribed (8%). No significant (p Most radiation oncologists (56%, n=74) responded they would like to actively prescribe more RPT, while 27% (n=35) were indifferent and 17% (n=22) answered “no.” Perceived barriers to implementation were varied but broadly categorized into treatment infrastructure (44%, n=57), inter-specialty relations (41%, n=53), lack of training (23%, n=30), and financial considerations (16%, n=21). Conclusion Among surveyed U.S. radiation oncologists, a significant number reported prescribing at least one RPT. The majority expressed interest in prescribing additional RPT. Wide-ranging barriers to implementation exist, most commonly inter-specialty relations, treatment infrastructure, lack of training, and financial considerations.

PURPOSE/OBJECTIVE(S) To survey the utilization, interest in, and barriers to implementation of radiopharmaceuticals/unsealed sources amongst U.S. radiation oncologists. MATERIALS/METHODS An anonymous, voluntary survey directed towards attending radiation oncologists was distributed via social media platforms (Twitter, LinkedIn, SDN, Facebook). Questions assessed practice characteristics, radiopharmaceutical prescribing patterns (Iodine-131, Radium-223, Yttrium-90, Sumarium-153, Strontium-89, Phosphorous-32, "other"), prescribing interest level, and perceived barriers to implementation. Non-parametric χ2 test was used for correlation statistics. RESULTS Of the 120 respondents, 112 practiced in the U.S and were included for this analysis. Years of practice was broadly distributed with 30% (n = 34) of attendings in practice > 10 years, 21% (n = 23) 6-10 years, 25% (n = 28) 3-5 years, and 24% (n = 27) 0-2 years. Practice type included academic-main site amongst 39% (n = 44), academic-satellite in 18% (n = 20), and private practice/other in 43% (n = 48) of attendings. Forty-four percent (n = 49) of attendings served populations of > 500K, 22% (n = 25) 200-500K, 25% (n = 28) 100-200K, and 9% (n = 10) 0.05) association was noted between practice type, practice location, years of practice, or practice volume with utilization of any radiopharmaceuticals/unsealed sources. The majority (55%, n = 61) of attending radiation oncologists responded they would like to actively prescribe more radiopharmaceuticals/unsealed sources, while 30% (n = 31) were indifferent and 18% (n = 20) answered "no." Perceived barriers to implementation were varied but broadly categorized into treatment infrastructure (43%, n = 48), interspecialty relations (42%, n = 47), lack of training (21%, n = 24), and financial considerations (17%, n = 19). CONCLUSION Almost half of surveyed U.S. radiation oncologists reported prescribing at least one radiopharmaceuticals/unsealed source, of which Ra-223 was the most common. The majority expressed interest in prescribing additional radiopharmaceuticals/unsealed sources. Wide-ranging barriers to implementation exist, most commonly interspecialty relations, treatment infrastructure, lack of training, and financial considerations.

Background The purpose of this study was to compare the outcomes of patients with non-small cell lung cancer (NSCLC) brain metastases treated with stereotactic radiotherapy (SRT) alone versus SRT and immune checkpoint inhibitors (ICIs). Patients and Methods Patients treated for their first diagnosis of intracranial metastases with SRT or SRT plus ICI were retrospectively identified. Overall survival (OS), local control (LC), distant brain failure (DBF), neurologic death, and rates of radiation necrosis were calculated. Univariate (UVA) and multivariable (MVA) analyses with competing risk analysis were performed. Results Seventy-seven patients with 132 lesions were analyzed, including 44 patients with 68 lesions in the SRT group and 33 patients with 64 lesions in the SRT plus ICI group. There were no differences in baseline factors between groups. Use of ICI predicted for decreased DBF (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.24-0.84; P = .01), decreased rates of neurologic death (HR, 0.29; 95% CI, 0.10-0.85; P = .02), and better OS (HR, 0.46; 95% CI, 0.23-0.91; P = .03). Two-year LC was 97% for the SRT + ICI group, and 86% for the SRT-alone group (P = .046). Actuarial 2-year DBF was 39% for the SRT + ICI group and 66% for the SRT alone group (P = .016). On MVA, ICI use persisted in predicting lower incidence of neurologic death (HR, 0.25; 95% CI, 0.09-0.72; P = .01) and DBF (HR, 0.47; 95% CI, 0.25-0.85; P = .01) when adjusted for competing risk of death. Conclusion In this cohort of patients with NSCLC brain metastases, ICI use combined with SRT predicted for improved LC and OS and decreased DBF and risk of neurologic death.

This study reports dose corresponding to visible radiation induced liver damage following Stereotactic Body Radiation Therapy (SBRT) for liver metastasis, and the optimal time for follow up scans using post radiation imaging. Diagnostic magnetic resonance scans of nine patients treated with liver SBRT using a 0.35 T MRI-guided radiotherapy system were analyzed. The dice coefficients between the region of visible liver damage and the delivered dose were calculated. A median dose of 35 Gy correlated most closely with the visible radiation induced liver damage. We compared scans over two to nine months and observed maximal dice coefficients at two to five months post radiation. We have presented a new method for developing treatment planning guidelines for liver SBRT.

Purpose The role of neoadjuvant radiation for resectable pancreatic adenocarcinoma is controversial. We performed a prospective dose-escalation study of neoadjuvant stereotactic body radiation therapy (SBRT) with concurrent capecitabine and elective nodal irradiation (ENI) followed by surgical resection to explore the toxicity and feasibility of this approach. Methods and Materials Patients with biopsy proven, resectable cancers of the pancreatic head were enrolled. A 4 + 4 dose-escalation design was employed delivering 5 fractions of 5 to 7 Gy to primary tumor with concurrent capecitabine. The maximum tolerated dose level was expanded for an additional 4 patients. Patients at all dose levels were treated with ENI delivering 25 Gy in 5 fractions. Dose-limiting toxicity was defined as any grade ≥3 nonhematologic toxicity (National Cancer Institute Common Terminology Criteria for Adverse Events v4.0) attributable to chemoradiation occurring within 90 days of SBRT. Results A total of 17 patients were enrolled with 16 patients evaluable and 13 patients ultimately proceeding to surgery. The most common toxicity was nausea (56%). There were no dose-limiting toxicities, and SBRT was maximally dose escalated to 35 Gy in 5 fractions for 8 patients. All patients completing surgery had R0 resections. Seven patients (54%) had moderate treatment effect identified in pathologic specimens. Three patients (23%) developed locoregional recurrences, with 2 (15%) partially included within the treated volume. Conclusions SBRT was safely dose escalated to 35 Gy in 5 fractions along with concurrent capecitabine and ENI. This regimen will be used in a future expansion cohort.

MRI-guided radiotherapy is a novel and rapidly evolving technology that might enhance the risk-benefit ratio. Through direct visualisation of the tumour and the nearby healthy tissues, the radiation oncologist can deliver highly accurate treatment even to mobile targets. Each individual treatment can be customised to changing anatomy, potentially reducing the risk of radiation-related toxicities while simultaneously increasing the dose delivered to the tumour. MRI-guided radiotherapy offers a new tool for the radiation oncologist, and creates an opportunity to achieve durable local control of liver tumours that might not otherwise be possible. Future work will allow us to expand the population eligible for curative-intent radiotherapy, optimise and customise radiation doses to specific tumours, and hopefully create opportunities for improving outcomes through machine learning and radiomics-based approaches. This Review outlines the current and future applications for MRI-guided radiotherapy with respect to metastatic and primary liver cancers.

The aim of this study was to determine whether a higher biological effective dose (BED) would result in improved local control in patients treated with fractionated stereotactic radiotherapy (FSRT) for their resected brain metastases. Patients with newly diagnosed brain metastases without previous brain radiotherapy were retrospectively reviewed. Patients underwent surgical resection of at least one brain metastasis and were treated with adjuvant FSRT, delivering 25–36 Gy in 5–6 fractions. Outcomes were computed using Kaplan–Meier survival analysis and univariate analysis. Fifty-four patients with 63 post-operative cavities were included. Median follow-up was 16 months (3–60). Median metastasis size at diagnosis was 2.9 cm (0.6–8.1) and median planning target volume was 19.7 cm3 (6.3–68.1). Two-year local control (LC) was 83%. When stratified by dose, 2 years LC rate was 95.1% in those treated with 30–36 Gy in 5–6 fractions (BED10 of 48–57.6 Gy10) versus 59.1% lesions treated with 25 Gy in 5 fractions (BED10 of 37.5 Gy10) (p 37.5 Gy10) were associated with a significantly higher rate of LC compared to lower BED regimens. Overall, 25 Gy in 5 fractions is not an adequate dose to control microscopic disease. If selecting a 5-fraction regimen, 30 Gy in five fractions appears to provide excellent tumor bed control.

Purpose: To quantitatively predict the impact of cardiopulmonary dose on overall survival (OS) after radiotherapy for locally advanced non–small cell lung cancer. Experimental Design: We used the NRG Oncology/RTOG 0617 dataset. The model building procedure was preregistered on a public website. Patients were split between a training and a set-aside validation subset (N = 306/131). The 191 candidate variables covered disease, patient, treatment, and dose-volume characteristics from multiple cardiopulmonary substructures (atria, lung, pericardium, and ventricles), including the minimum dose to the hottest x% volume (Dx%[Gy]), mean dose of the hottest x% (MOHx%[Gy]), and minimum, mean (Mean[Gy]), and maximum dose. The model building was based on Cox regression and given 191 candidate variables; a Bonferroni-corrected P value threshold of 0.0003 was used to identify predictors. To reduce overreliance on the most highly correlated variables, stepwise multivariable analysis (MVA) was repeated on 1000 bootstrapped replicates. Multivariate sets selected in ≥10% of replicates were fit to the training subset and then averaged to generate a final model. In the validation subset, discrimination was assessed using Harrell c-index, and calibration was tested using risk group stratification. Results: Four MVA models were identified on bootstrap. The averaged model included atria D45%[Gy], lung Mean[Gy], pericardium MOH55%[Gy], and ventricles MOH5%[Gy]. This model had excellent performance predicting OS in the validation subset (c = 0.89). Conclusions: The risk of death due to cardiopulmonary irradiation was accurately modeled, as demonstrated by predictions on the validation subset, and provides guidance on the delivery of safe thoracic radiotherapy.

PURPOSE The purpose of this study was to evaluate predictors of cardiac events in esophageal cancer patients treated with neoadjuvant chemoradiotherapy (NA CRT) followed by surgery compared with surgery alone. MATERIALS AND METHODS We retrospectively identified patients treated for esophageal cancer between 2006 and 2016. A total of 123 patients were identified; 70 were treated with surgery alone, and 53 were treated with NA CRT. Cardiac events were scored based on Common Terminology Criteria for Adverse Events (version 4.03), and dosimetric data was compiled for all patients who received radiation. Univariate analysis and multivariable analysis (MVA) were performed to identify predictors of cardiac events. Competing risk of death regression was performed to a model the cumulative incidence of cardiac events. RESULTS The overall rates of grade ≥3 cardiac events were 24.5% in the NA CRT group versus 10% in the surgery group (P=0.04). On MVA, use of NA CRT (P

Background: Esophageal cancer is a highly lethal cancer with a 20% 5-year overall survival despite standard of care treatment.. Pembrolizumab (anti-PD1, Merck) is FDA-approved for PD-L1 positive esophageal cancer, which comprises roughly 40% of all patients. PD-L1 positive (+) esophageal cancers have previously been shown to demonstrate elevated CD8+ T cell infiltration (CD8+ TILs). Versican (VCAN) is an immunosuppressive extracellular matrix proteoglycan which produces an immunostimulatory fragment, versikine (Vkine), upon proteolytic cleavage by ADAMTS proteases. Previously, VCAN proteolysis has been shown to correlate with enhanced CD8+ TILs in colorectal cancer (CRC), indicating potential for use as an immune biomarker. Methods: A human esophageal cancer tissue microarray (TMA) was developed consisting of multiple samples across 106 representative esophageal cancer patients. Immunohistochemistry (IHC) was used to evaluate VCAN and Vkine expression, and a binning system was used to quantify these stains based on stromal intensity (0: 0-10%, 1: 10-25%, 2:25-50%, 3: 50-100%). IHC was also conducted for CD8, and the number of CD8+ tumor-infiltrating cells per 400x field of view was counted. PD-L1 IHC 22C3 pharmDx was performed and quantified per CPS guidelines for GEJ cancers to quantify PD-L1 status. The VCAN proteolytic predominant (VPP) phenotype was defined as both low VCAN (0 or 1) and high Vkine (2 or 3), and VCAN proteolytic weak phenotype (VPW) was defined as either high VCAN (2 or 3) or low Vkine (0 or 1). Results: Overall, 42.7% of all samples were scored as PD-L1+ (CPS≥1). PD-L1+ samples demonstrated greater CD8+ TILs than PD-L1- samples (44.5±71 vs 14±22; p Discussion: Our TMA demonstrates enhanced CD8+ TILs in PD-L1+ samples, as previously reported. Additionally, we discovered the presence of VCAN and its proteolysis are independent predictors of enhanced CD8+ TILs in esophageal cancers. These data indicate the potential importance of the tumor matrix in establishing a permissive tumor microenvironment. These data support the potential for combining VCAN testing with PD-L1 testing to further select appropriate patients for immunotherapeutic trials in esophageal cancer. Citation Format: Phillip B. Emmerich, Jacob Witt, Darya Buehler, Mitchell Depke, Nathaniel Verhagen, Linda Clipson, Kristina Matkowskyj, Nataliya Uboha, Andrew Baschnagel, Dustin Deming. PD-L1 status and versican proteolysis predict CD8+ T cell infiltration in esophageal cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3294.

Meningiomas comprise up to 30% of primary brain tumors. The majority of meningioma patients enjoy high rates of control after conventional therapies. However, patients with recurrent disease previously treated with radiotherapy have few options for salvage treatment, and systemic interventions have proven largely ineffective. The aim of this study was to determine whether pulsed reduced dose rate radiotherapy (PRDR) was well tolerated in a small cohort of patients with recurrent meningioma. We retrospectively identified eight patients with recurrent intracranial meningioma treated with PRDR from April 2013 to August of 2017 at a single institution. All patients had radiographic and/or pathologic evidence of progression prior to treatment and had previously completed conventional radiotherapy. Acute and late toxicities were graded based on CTCAE 4.0. Of eight patients, six had histologically confirmed atypical meningiomas upon recurrence. All patients were re-treated with IMRT at an apparent dose rate of 0.0667 Gy/min. Median time between radiation courses was 7.7 years. Median PRDR dose was 54 Gy in 27 fractions to a median volume of 261.6 cm3. Two patients (25%) had in field failure with a median follow up of 23.3 months. PFS at 6 months was 100%. All but one (87.5%) patient was still alive at last follow up. No patient experienced grade ≥ 2 acute or late toxicities. PRDR re-irradiation was well tolerated and appeared effective for a small cohort of patients with recurrent meningioma previously treated with radiotherapy. A phase II trial to assess this prospectively is in development.

Purpose Studies have shown that an additional mean dose of 1 Gy to the heart can increase the relative risk of cardiac events. The purpose of this study was to quantify the dose delivered to the heart and left anterior descending artery (LAD) in a series of patients with left-sided breast cancer (BC) or ductal carcinoma in situ treated with multicatheter-accelerated partial breast irradiation (MC-APBI) at a single institution. Methods and Materials Patients with left-sided BC or ductal carcinoma in situ treated consecutively from 2005 to 2011 with MC-APBI were retrospectively identified. Cardiac and LAD contours were generated for each patient. Cardiac dosimetry and distance to the planning target volume were recorded. Patient health records were reviewed and cardiac events were recorded based on Common Terminology Criteria for Adverse Events version 4.0. Results Twenty consecutive patients with left-sided BC treated with MC-APBI were retrospectively identified. Median followup was 41.4 months. Mean equivalent dose in 2 Gy fractions delivered to the heart and LAD were 1.3 (standard deviation: 0.7, range: 0.2–2.9) and 3.8 (standard deviation: 3.0, range: 0.4–11.3) Gy, respectively. There was an inverse linear relationship (R2 = 0.52) between heart-to-lumpectomy cavity distance and mean heart equivalent dose in 2 Gy fractions. One patient (5%) experienced symptomatic cardiac toxicity. Conclusions MC-APBI consistently delivers average doses to the heart and LAD that are similar to those achieved in most series with deep inspiration breath-hold and lower than free-breathing radiotherapy techniques. Distance from the heart to the lumpectomy cavity and the availability of other heart-sparing technologies should be considered to minimize the risk of cardiac toxicity.

BACKGROUND: Meningiomas comprise up to 30% of primary brain tumors. The majority of meningioma patients enjoy high rates of control after conventional therapies. However, patients with recurrent disease previously treated with radiotherapy have few options for salvage treatment, and systemic interventions have proven largely ineffective. The aim of this study was to determine whether PRDR radiotherapy was well tolerated and effective in patients with recurrent meningioma. METHODS: We retrospectively identified 8 patients with recurrent intracranial meningioma treated with PRDR from April 2013 to August of 2017 at a single institution. All patients had radiographic and/or pathologic evidence of progression prior to treatment and had previously completed conventional radiotherapy. Relevant patient, tumor, and treatment characteristics were abstracted from the electronic medical record. Acute and late toxicities were graded based on CTCAE 4.0. RESULTS: Of 8 patients, 6 had histologically confirmed atypical meningiomas upon recurrence. All patients were re-treated with IMRT at an apparent dose rate of 0.0667 Gy/min. Median time between radiation courses was 7.7 years. Median PRDR dose was 54 Gy in 27 fractions to a median volume of 261.6 cm(3). Two patients (25%) had in field failure with a median follow up of 23.3 months. PFS at 6 months was 100%. All but one (87.5%) patient was still alive at last follow up. No patient experienced grade ≥2 acute or late toxicities. CONCLUSION: PRDR re-irradiation is a viable option for patients with recurrent meningioma previously treated with radiotherapy. A phase II trial to assess this prospectively is in development.

Regulating the transition from lineage-restricted progenitors to terminally differentiated cells is a central aspect of nervous system development. Here, we investigated the role of the nucleoprotein geminin in regulating neurogenesis at a mechanistic level during both Xenopus primary neurogenesis and mammalian neuronal differentiation in vitro. The latter work utilized neural cells derived from embryonic stem and embryonal carcinoma cells in vitro and neural stem cells from mouse forebrain. In all of these contexts, geminin antagonized the ability of neural basic helix-loop-helix (bHLH) transcription factors to activate transcriptional programs promoting neurogenesis. Furthermore, geminin promoted a bivalent chromatin state, characterized by the presence of both activating and repressive histone modifications, at genes encoding transcription factors that promote neurogenesis. This epigenetic state restrains the expression of genes that regulate commitment of undifferentiated stem and neuronal precursor cells to neuronal lineages. However, maintaining geminin at high levels was not sufficient to prevent terminal neuronal differentiation. Therefore, these data support a model whereby geminin promotes the neuronal precursor cell state by modulating both the epigenetic status and expression of genes encoding neurogenesis-promoting factors. Additional developmental signals acting in these cells can then control their transition toward terminal neuronal or glial differentiation during mammalian neurogenesis.

BACKGROUND: The optimal choice of adjuvant radiation treatment of brain metastasis (BM) following metastectomy is unclear. Following metastectomy, whole brain irradiation (WBI) has been shown to increase both local (LC) and distant (DC) CNS control, however, at the expense of worsening neurocognition. SRS offers excellent local control, yet at the cost of decreased DC. The purpose of this work was to compare LC, DC, and overall survival (OS) for WBI vs SRS. METHODS: Patients with BM treated with metastectomy followed by single fraction SRS or WBRT from 2001-2013 were identified from an IRB-approved registry. Patient, tumor, and treatment related variables were collected in retrospective fashion. Clinical follow up with MR imaging was obtained every 3 months and was reviewed from time of SRS or end of WBRT to death or last follow up. LC was graded in each treated lesion and was defined as stability or decrease in the size of the treated BM at any time post-SRS. RESULTS: 104 patients were identified; 72 in the SRS group and 32 in the WBRT group. On univariate analysis, sex was the only significant factor impacting LC (p = 0.017). Univariate analysis of DC demonstrated no significant variables. OS at 12 months was 62%. SRS (p = 0.029), age (p = 0.001), and number of metastases (p = 0.027) were significant on univariate analysis for OS. Age (p = 0.001) remained significant on multivariate analysis for OS, while SRS did not. CONCLUSIONS: SRS following metastectomy is not an independent predictor of distant brain failure or a detriment to OS. Given the known detriment to neurocognition, it is safe to omit WBRT post-metastectomy in lieu of SRS for the treatment of BM.

Purpose: Accurate contour delineation is crucial for radiotherapy. Atlas based automatic segmentation tools can be used to increase the efficiency of contour accuracy evaluation. This study aims to optimize technical parameters utilized in the tool by exploring the impact of library size and atlas number on the accuracy of cardiac contour evaluation. Methods: Patient CT DICOMs from RTOG 0617 were used for this study. Five experienced physicians delineated the cardiac structures including pericardium, atria and ventricles following an atlas guideline. The consistency of cardiac structured delineation using the atlas guideline was verified by a study with four observers and seventeen patients. The CT and cardiac structure DICOM files were then used for the ABAS technique.To study the impact of library size (LS) and atlas number (AN) on automatic contour accuracy, automatic contours were generated with varied technique parameters for five randomly selected patients. Three LS (20, 60, and 100) were studied using commercially available software. The AN was four, recommended by the manufacturer. Using the manual contour as the gold standard, Dice Similarity Coefficient (DSC) was calculated between the manual and automatic contours. Five-patient averaged DSCs were calculated for comparison for each cardiac structure.In order to study the impact of AN, the LS was set 100, and AN was tested from one to five. The five-patient averaged DSCs were also calculated for each cardiac structure. Results: DSC values are highest when LS is 100 and AN is four. The DSC is 0.90±0.02 for pericardium, 0.75±0.06 for atria, and 0.86±0.02 for ventricles. Conclusion: By comparing DSC values, the combination AN=4 and LS=100 gives the best performance. This project was supported by NCI grants U24CA12014, U24CA180803, U10CA180868, U10CA180822, PA CURE grant and Bristol-Myers Squibb and Eli Lilly.

e11578 Background: While only 20% of all breast cancer is HER2+, it represents a disproportionate majority of breast cancer brain metastases, and up to half of these patients will die of CNS diseas...