BackgroundThe purpose of this study was to evaluate the delay in initiating adjuvant radiation therapy (RT) after breast-conserving surgery (BCS) in patients with early-stage breast cancer who underwent oncoplastic reduction mammoplasty (ORM) following BCS compared with a matched cohort of patients who did not undergo ORM between BCS and RT.MethodsMedical records of 112 women (56 ORMs and 56 matched non-ORMs) with carcinoma in situ or early-stage breast cancer treated with BCS were reviewed. ORM was performed in a delayed manner following BCS, allowing confirmation of negative surgical margins. Time to RT was defined as time from last oncologic surgery to start of RT.ResultsThe median follow-up time was 6.8 years for the ORM cohort and 6.7 years for the control non-ORM cohort. Patients who underwent ORM following BCS experienced a significant delay in initiating RT (>8 weeks) than matched patients not undergoing ORM (66% vs. 34%; p < 0.001). Wound complications occurred in 44.6% (n = 25) of patients in the ORM cohort, which were mostly minor, including delayed wound healing and/or infection (39%). There was no significant difference in local recurrence between patients in the non-ORM and ORM cohorts (p = 0.32).ConclusionsThis study demonstrates that ORM following BCS has the potential to delay RT >8 weeks, largely as a result of increased risk of wound complications; however, this delay did not impact local control. ORM can be safely considered for appropriately selected patients with breast cancer.

Importance:Spine metastasis can be treated with high-dose radiation therapy with advanced delivery technology for long-term tumor and pain control. Objective:To assess whether patient-reported pain relief was improved with stereotactic radiosurgery (SRS) as compared with conventional external beam radiotherapy (cEBRT) for patients with 1 to 3 sites of vertebral metastases. Design, Setting, and Participants:In this randomized clinical trial, patients with 1 to 3 vertebral metastases were randomized 2:1 to the SRS or cEBRT groups. This NRG 0631 phase 3 study was performed as multi-institutional enrollment within NRG Oncology. Eligibility criteria included the following: (1) solitary vertebral metastasis, (2) 2 contiguous vertebral levels involved, or (3) maximum of 3 separate sites. Each site may involve up to 2 contiguous vertebral bodies. A total of 353 patients enrolled in the trial, and 339 patients were analyzed. This analysis includes data extracted on March 9, 2020. Interventions:Patients randomized to the SRS group were treated with a single dose of 16 or 18 Gy (to convert to rad, multiply by 100) given to the involved vertebral level(s) only, not including any additional spine levels. Patients assigned to cEBRT were treated with 8 Gy given to the involved vertebra plus 1 additional vertebra above and below. Main Outcomes and Measures:The primary end point was patient-reported pain response defined as at least a 3-point improvement on the Numerical Rating Pain Scale (NRPS) without worsening in pain at the secondary site(s) or the use of pain medication. Secondary end points included treatment-related toxic effects, quality of life, and long-term effects on vertebral bone and spinal cord. Results:A total of 339 patients (mean [SD] age of SRS group vs cEBRT group, respectively, 61.9 [13.1] years vs 63.7 [11.9] years; 114 [54.5%] male in SRS group vs 70 [53.8%] male in cEBRT group) were analyzed. The baseline mean (SD) pain score at the index vertebra was 6.06 (2.61) in the SRS group and 5.88 (2.41) in the cEBRT group. The primary end point of pain response at 3 months favored cEBRT (41.3% for SRS vs 60.5% for cEBRT; difference, -19 percentage points; 95% CI, -32.9 to -5.5; 1-sided P = .99; 2-sided P = .01). Zubrod score (a measure of performance status ranging from 0 to 4, with 0 being fully functional and asymptomatic, and 4 being bedridden) was the significant factor influencing pain response. There were no differences in the proportion of acute or late adverse effects. Vertebral compression fracture at 24 months was 19.5% with SRS and 21.6% with cEBRT (P = .59). There were no spinal cord complications reported at 24 months. Conclusions and Relevance:In this randomized clinical trial, superiority of SRS for the primary end point of patient-reported pain response at 3 months was not found, and there were no spinal cord complications at 2 years after SRS. This finding may inform further investigation of using spine radiosurgery in the setting of oligometastases, where durability of cancer control is essential. Trial Registration:ClinicalTrials.gov Identifier: NCT00922974.

Over the past decade, concerns have arisen in radiation oncology regarding potential workforce supply and demand imbalance. The American Society for Radiation Oncology commissioned an independent analysis in 2022, looking at supply and demand in the United States radiation oncology workforce and projecting future trends for 2025 and 2030. The final report, titled Projected Supply and Demand for Radiation Oncologists in the U.S. in 2025 and 2030, is now available. The analysis included evaluating radiation oncologist (RO) supply (new graduates, exits from the specialty), potential changes in demand (growth of Medicare beneficiaries, hypofractionation, loss of indications, new indications) as well as RO productivity (growth of work relative value units [wRVUs] produced), and demand per beneficiary. The results demonstrated a relative balance between radiation oncology supply and demand for radiation services; the growth in ROs was balanced by the rapid growth of Medicare beneficiaries over the same period. The primary factors driving the model were found to be growth of Medicare beneficiaries and change in wRVU productivity, with hypofractionation and loss of indication having only a moderate effect; although the most likely scenario was a balance of workforce supply and demand, scenarios did demonstrate the possibility of over- and undersupply. Oversupply may become a concern if RO wRVU productivity reaches the highest region; beyond 2030, this is also possible if growth in RO supply does not parallel Medicare beneficiary growth, which is projected to decline and will require corresponding supply adjustment. Limitations of the analysis included uncertainty regarding the true number of ROs, the lack of inclusion of most technical reimbursement and its effect as well as failing to account for stereotactic body radiation therapy. A modeling tool is available to allow individuals to evaluate different scenarios. Moving forward, continued study will be needed to evaluate trends (particularly wRVU productivity and Medicare beneficiary growth) to allow for continued assessment of workforce supply and demand in radiation oncology.

Importance Spine metastasis can be treated with high-dose radiation therapy with advanced delivery technology for long-term tumor and pain control. Objective To assess whether patient-reported pain relief was improved with stereotactic radiosurgery (SRS) as compared with conventional external beam radiotherapy (cEBRT) for patients with 1 to 3 sites of vertebral metastases. Design, Setting, and Participants In this randomized clinical trial, patients with 1 to 3 vertebral metastases were randomized 2:1 to the SRS or cEBRT groups. This NRG 0631 phase 3 study was performed as multi-institutional enrollment within NRG Oncology. Eligibility criteria included the following: (1) solitary vertebral metastasis, (2) 2 contiguous vertebral levels involved, or (3) maximum of 3 separate sites. Each site may involve up to 2 contiguous vertebral bodies. A total of 353 patients enrolled in the trial, and 339 patients were analyzed. This analysis includes data extracted on March 9, 2020. Interventions Patients randomized to the SRS group were treated with a single dose of 16 or 18 Gy (to convert to rad, multiply by 100) given to the involved vertebral level(s) only, not including any additional spine levels. Patients assigned to cEBRT were treated with 8 Gy given to the involved vertebra plus 1 additional vertebra above and below. Main Outcomes and Measures The primary end point was patient-reported pain response defined as at least a 3-point improvement on the Numerical Rating Pain Scale (NRPS) without worsening in pain at the secondary site(s) or the use of pain medication. Secondary end points included treatment-related toxic effects, quality of life, and long-term effects on vertebral bone and spinal cord. Results A total of 339 patients (mean [SD] age of SRS group vs cEBRT group, respectively, 61.9 [13.1] years vs 63.7 [11.9] years; 114 [54.5%] male in SRS group vs 70 [53.8%] male in cEBRT group) were analyzed. The baseline mean (SD) pain score at the index vertebra was 6.06 (2.61) in the SRS group and 5.88 (2.41) in the cEBRT group. The primary end point of pain response at 3 months favored cEBRT (41.3% for SRS vs 60.5% for cEBRT; difference, −19 percentage points; 95% CI, −32.9 to −5.5; 1-sided P = .99; 2-sided P = .01). Zubrod score (a measure of performance status ranging from 0 to 4, with 0 being fully functional and asymptomatic, and 4 being bedridden) was the significant factor influencing pain response. There were no differences in the proportion of acute or late adverse effects. Vertebral compression fracture at 24 months was 19.5% with SRS and 21.6% with cEBRT ( P = .59). There were no spinal cord complications reported at 24 months. Conclusions and Relevance In this randomized clinical trial, superiority of SRS for the primary end point of patient-reported pain response at 3 months was not found, and there were no spinal cord complications at 2 years after SRS. This finding may inform further investigation of using spine radiosurgery in the setting of oligometastases, where durability of cancer control is essential. Trial Registration ClinicalTrials.gov Identifier: NCT00922974

Background: Patients with previously irradiated metastatic epidural spinal cord compression (MESCC) who are not surgical candidates are at high risk of neurologic deterioration due to disease in the setting of limited treatment options. We seek to establish the feasibility of using salvage spine stereotactic radiosurgery (SSRS) allowing for spinal cord dose constraint relaxation as the primary management of MESCC in inoperable patients monitoring for radiation related toxicity and radiographic local control (LC). Methods: Inoperable patients with previously irradiated MESCC were enrolled on this prospective Phase 1 single institution protocol. Single fraction SSRS was delivered to a prescription dose of 18 Gy. Spinal cord constraint relaxation was performed incrementally from an initial allowable Dmax cohort of 8 Gy to 14 Gy in the final planned cohort. Patients were monitored every 3 months with follow-up visits and MRI scans. Results: The trial was closed early due to slow accrual. From 2011 to 2014, 11 patients were enrolled of which 9 patients received SSRS. Five patients were in the 8 Gy cord Dmax cohort and 4 in the 10 Gy cord Dmax cohort. The median overall survival (OS) was 11.9 months (95% CI 7.1, 22 months). Of the 9 patients treated with SSRS, 1 died prior to post-SSRS evaluation. Of the remaining 8 patients, 5 experienced a local failure. Three of the five were treated with surgery while two received systemic therapy. Two of the five failures ultimately resulted in loss of neurologic function. The median LC was 9.1 months (95%CI 4.8, 20.1 months). With a median clinical follow-up of 6.8 months, there were no cases of RM. Conclusions: Despite the limited life expectancy in this high-risk cohort of patients, strategies to optimize LC are necessary to prevent neurologic deterioration. Larger prospective trials exploring optimal dose/fractionation and cord constraints are required.

Objectives Adipose tissue contains a population of multipotent adipose stem cells (ASCs) that form tumor stroma and can promote tumor progression. Given the high rate of ovarian cancer metastasis to the omental adipose, we hypothesized that omental-derived ASC may contribute to ovarian cancer growth and dissemination. Materials and Methods We isolated ASCs from the omentum of three patients with ovarian cancer, with (O-ASC4, O-ASC5) and without (O-ASC1) omental metastasis. BM-MSCs, SQ-ASCs, O-ASCs were characterized with gene expression arrays and metabolic analysis. Stromal cells effects on ovarian cancer cells proliferation, chemoresistance and radiation resistance was evaluated using co-culture assays with luciferase-labeled human ovarian cancer cell lines. Transwell migration assays were performed with conditioned media from O-ASCs and control cell lines. SKOV3 cells were intraperitionally injected with or without O-ASC1 to track in-vivo engraftment. Results O-ASCs significantly promoted in vitro proliferation, migration chemotherapy and radiation response of ovarian cancer cell lines. O-ASC4 had more marked effects on migration and chemotherapy response on OVCA 429 and OVCA 433 cells than O-ASC1. Analysis of microarray data revealed that O-ASC4 and O-ASC5 have similar gene expression profiles, in contrast to O-ASC1, which was more similar to BM-MSCs and subcutaneous ASCs in hierarchical clustering. Human O-ASCs were detected in the stroma of human ovarian cancer murine xenografts but not uninvolved ovaries. Conclusions ASCs derived from the human omentum can promote ovarian cancer proliferation, migration, chemoresistance and radiation resistance in-vitro. Furthermore, clinical O-ASCs isolates demonstrate heterogenous effects on ovarian cancer in-vitro.

Abstract Objectives: Adipose tissue contains a population of multipotent mesenchymal stromal cells (ASC) which exhibit tumor tropism, similar to bone marrow derived mesenchymal stem cells (MSC). Excess visceral adipose tissue increases the risk of ovarian cancer. The omentum is a prominent site for ovarian cancer metastasis. We hypothesize that the omentum serves as a source of ASC which promote ovarian cancer progression. Materials and Methods: ASC were isolated from the omentum (O-ASCs) of three patients with ovarian cancer. O-ASC1 was isolated from a patient with synchronous adenocarcinoma of endometrial and ovarian cancer without peritoneal metastasis; and O-ASC4 and O-ASC5 were isolated from patients with peritoneally disseminated serous ovarian cancer. Gene expression array profiling was performed with using Nimblegen arrays (Roche NimbleGen, Inc., Madison, WI). The impact of stromal cells on proliferation and chemoresistane and radio-protection of ovarian cancer cells was tested with co-culture assays using luciferase-labeled human ovarian cancer cell lines. Transwell migration assays were performed with conditioned media from O-ASC and control cell lines. To evaluate of O-ASCs tumor tropism in-vivo experiment was performed. Results: Human O-ASCs were detected engrafted within the stroma of human ovarian cancer xengrafts. O-ASC significantly promoted in-vitro proliferation and migration of ovarian cancer cell lines OVCA 429, OVCA 433, A2780. Co-culture of ovarian cancer cells with O-ASCs increased resistance to chemotherapeutic drugs and radiation. Gene expression array analysis revealed significant differences in expression profiles for group of 415 genes in sub-populations of O-ASCs. Conclusions: Adipose stem cells derived from human omentum promoted the proliferation, migration, chemoresistance and radioresistance of ovarian cancers. Clinical isolates demonstrate heterogenous effects in- vitro. Future studies will determine if tumor promoting effects of O-ASC can be predicted on the basis of clinical or disease related characteristics. Citation Format: Aleksandra Nowicka, Travis Solley, Frank C. Marini, Hadley J. Sharp, Russell R. Broaddus, Kolonin G. Mikhail, Samuel C. Mok, Wendy A. Woodward, Karen H. Lu, Ann H. Klopp. Human omental-derived adipose stem cells: Modulator of ovarian cancer proliferation, migration and chemoresistance. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr B73.

To prospectively test the hypothesis that spine stereotactic radiosurgery (SSRS) used as the primary treatment of inoperable MESCC is both feasible and safe. Two ongoing phase I/II trials enrolling patients >18 years old, with MESCC on spine MRI (ranging from involvement of epidural space not compressing the dura, to compression of the spinal cord obliterating all visible CSF at that level) and maximum of 2 contiguous vertebral levels involved with metastasis to be irradiated in a single session, motor strength ≥ 4/5, deemed to be inoperable (patient refusal, by neurosurgical evaluation, or for any reason). In the previously irradiated trial patients are limited to one prior course of spine radiation therapy <45 Gy conventional fractionation or similar biologically effective dose to the current MESCC >3 months previously. In both trials, patients have a goal GTV dose of 18 Gy in a single fraction with goal CTV dose of 16 Gy. Spinal cord constraints were initially 8 Gy to 0.01cc in the previously irradiated trial and 10 Gy to 0.01 cc in the radiation naïve trial. Spinal cord dose constraints are relaxed in 2 Gy increments per event (recurrence/progression) in each protocol while maintaining the same goal target doses in a prospective manner. Current accrual to the previously irradiated protocol is 5 patients, and radiation naïve protocol 7 patients. For these 12 patients, consult to simulation time was 0-19 days (mean 5.25 days, S.D. 5.86 days). Simulation to treatment time was never longer than 12 days (mean 7.08 days, S.D. 3.37days). Time from consult to treatment for all patients was 6-23 days (mean 12.33 days, S.D. 5.71 days). Actual planning times were documented. Utilizing class solutions, time from contour completion to first plan review averaged 8.18 hours (2.25-16 hours, S.D. 4.48 hours). Initial plan review to plan approval ranged from 0-6 hours (mean 2.42 hours, S.D. 2.31 hours). Overall, planning start to plan approval averaged 10.6 hours (2.3-18 hours, S.D. 4.83 hours). With a current mean follow up of 5.07 months (0.59-10.59), four of 12 patients have recurred/progressed, and four have died. Mean time to recurrence was 6.42 months (1.41-8.98). At present, no radiation myelopathy has been detected. The prospective trials are ongoing but this pilot data shows feasibility of SSRS in the treatment of inoperable MESCC, and that it can be performed in a timely fashion with spine class solutions. Future data to be reported on control, toxicity, patterns of failure and maximum tolerated dose defined for spinal cord.

Background Spinal stereotactic body radiation therapy (SBRT) is increasingly used to manage spinal metastases, yet the technique's effectiveness in controlling the symptom burden of spinal metastases has not been well described. We investigated the clinical benefit of SBRT for managing spinal metastases and reducing cancer-related symptoms.Methods 149 patients with mechanically stable, non-cord-compressing spinal metastases (166 lesions) were given SBRT in a phase 1-2 study. Patients received a total dose of 27-30 Gy, typically in three fractions. Symptoms were measured before SBRT and at several time points up to 6 months after treatment, by the Brief Pain Inventory (BPI) and the M D Anderson Symptom Inventory (MDASI). The primary endpoint was frequency and duration of complete pain relief. The study is completed and is registered with ClinicalTrials.gov,number NCT00508443.Findings Median follow-up was 15 . 9 months (IQR 9 . 5-30 . 3). The number of patients reporting no pain from bone metastases, as measured by the BPI, increased from 39 of 149 (26%) before SBRT to 55 of 102 (54%) 6 months after SBRT (p<0 . 0001). BPI-reported pain reduction from baseline to 4 weeks after SBRT was clinically meaningful (mean 3 . 4 [SD 2 . 9] on the BPI pain-at-its-worst item at baseline, 2 . 1 [2 . 4] at 4 weeks; effect size 0 . 47, p=0 . 00076). These improvements were accompanied by significant reduction in opioid use during the first 6 months after SBRT (43 [ 28 . 9%] of 149 patients with strong opioid use at baseline vs 20 [20 . 0%] of 100 at 6 months; p=0 . 011). Ordinal regression modelling showed that patients reported signifi cant pain reduction according to the MDASI during the fi rst 6 months after SBRT (p=0 . 00003), and signifi cant reductions in a composite score of the six MDASI symptom interference with daily life items (p=0 . 0066). Only a few instances of non-neurological grade 3 toxicities occurred: nausea (one event), vomiting (one), diarrhoea (one), fatigue (one), dysphagia (one), neck pain (one), and diaphoresis (one); pain associated with severe tongue oedema and trismus occurred twice; and non-cardiac chest pain was reported three times. No grade 4 toxicities occurred. Progressionfree survival after SBRT was 80 u 5% (95% CI 72 u 9-86 . 1) at 1 year and 72 . 4% (63 . 1-79 . 7) at 2 years.Interpretation SBRT is an effective primary or salvage treatment for mechanically stable spinal metastasis. Significant reductions in patient-reported pain and other symptoms were evident 6 months after SBRT, along with satisfactory progression-free survival and no late spinal cord toxicities.

Radiation is a primary modality in cancer treatment. Radiation can also reduce tumor growth outside the treatment field, often referred to as the abscopal effect. The mechanisms and therapeutic potential of the abscopal effect have not been fully elucidated. We evaluated the role of vaccination directed against a tumor-associated antigen (TAA) in the induction and amplification of radiation induced abscopal effects. Active-specific immunotherapy with a TAA-specific vaccine regimen was used to induce and potentiate T-cell responses against carcinoembryonic antigen (CEA) in combination with local irradiation of subcutaneous tumors. We examined the potential synergy of a poxvirus-based CEA vaccine regimen in CEA-transgenic (Tg) mice in combination with either external beam radiation or brachytherapy of local tumors. The induction of CD8+ T cells specific for multiple TAAs not encoded by the vaccine was observed after the combination therapy. In two tumor models, the antigen cascade responses induced by vaccine and local irradiation mediated the regression of antigen negative metastases at distal subcutaneous or pulmonary sites. Clinically, local control of the primary tumor is necessary and can sometimes prevent metastases; however, irradiation generally fails to control preexisting metastases. These studies suggest that by coupling tumor irradiation with immunotherapy, the abscopal effect can transcend from anecdotal observation to a defined mechanism that can be exploited for the treatment of systemic disease.

PURPOSE:To investigate the incidence of undiagnosed, asymptomatic synchronous colorectal cancer (CRC) by using screening colonoscopy before brachytherapy, and to compare the subsequent rates of CRC and rectal toxicity in this screened population with those rates in unscreened patients after brachytherapy. METHODS AND MATERIALS:Patient, disease, and treatment characteristics, including history of colonoscopy and CR malignancy, were extracted from the medical records of all men who had undergone brachytherapy as monotherapy for low- or intermediate-risk prostate cancer at a single tertiary cancer care center between January 2000 and December 2009. The frequency of biopsy or polypectomy at screening colonoscopy, incidence of CR malignancy before and after prostate cancer diagnosis, and rate of brachytherapy toxicity including rectal bleeding were compared between men who had had screening colonoscopy before brachytherapy and men who had not. RESULTS:Of the 451 men identified, 268 had undergone screening colonoscopy during the 36 months before brachytherapy and 183 had not. Of the 268 men who had had screening colonoscopy, 117 (44%) underwent biopsy or polypectomy, and 6 (3.2%) were found to have asymptomatic CRC. After brachytherapy, CRC was diagnosed in 3 (1.6%) of the 183 men who had not had screening colonoscopy before treatment versus 0 of the 268 men who had had screening colonoscopy (P = 0.035). Rectal toxicity was more common and more severe among men who had not undergone screening colonoscopy compared with those who had had screening colonoscopy before brachytherapy (14% vs 6%, P = 0.003). More unscreened patients (18% vs 5%) underwent postbrachytherapy colonoscopy (P < 0.001), with the potential of subjecting the irradiated rectum to biopsy. CONCLUSIONS:More than 3% of men with newly diagnosed prostate cancer in this study presented with undiagnosed, asymptomatic CRC, and the rate of postbrachytherapy rectal complications was higher among unscreened than among screened patients. We recommend screening colonoscopy for men who have not had CRC screening within the 3 years preceding prostate cancer diagnosis before radiation therapy to avoid unnecessary rectal biopsies and the associated risk of major complications.

Purpose: Spinal stereotactic body radiation therapy (SBRT) continues to emerge as an effective therapeutic approach to spinal metastases; however, treatment planning and delivery remain resource intensive at many centers, which may hamper efficient implementation in clinical practice. We sought to develop a generalizable class solution approach for spinal SBRT treatment planning that would allow confidence that a given plan provides optimal target coverage, reduce integral dose, and maximize planning efficiency.Methods and Materials: We examined 91 patients treated with spinal SBRT at our institution. Treatment plans were categorized by lesion location, clinical target volume (CTV) configuration, and dose fractionation scheme, and then analyzed to determine the technically achievable dose gradient. A radial cord expansion was subtracted from the CTV to yield a planning CTV (pCTV) construct for plan evaluation. We reviewed the treatment plans with respect to target coverage, dose gradient, integral dose, conformality, and maximum cord dose to select the best plans and develop a set of class solutions.Results: The class solution technique generated plans that maintained target coverage and improved conformality (1.2-fold increase in the 95% van't Riet Conformation Number describing the conformality of a reference dose to the target) while reducing normal tissue integral dose (1.3-fold decrease in the volume receiving 4 Gy (V-4Gy) and machine output (19% monitor unit (MU) reduction). In trials of planning efficiency, the class solution technique reduced treatment planning time by 30% to 60% and MUs required by similar to 20%: an effect independent of prior planning experience.Conclusions: We have developed a set of class solutions for spinal SBRT that incorporate a pCTV metric for plan evaluation while yielding dosimetrically superior treatment plans with increased planning efficiency. Our technique thus allows for efficient, reproducible, and high-quality spinal SBRT treatment planning. (C) 2012 Elsevier Inc.

Abstract Background Adipose tissue contains a population of multipotent adipose stromal cells (ASC) which migrate into tumors and form supportive tumor stroma elements. ASCs release various growth factors, cytokines and metabolites that influence on physiochemical nature of the local environment. Ovarian cancer cells have a predilection for metastasis in omentum, the primary repository for visceral adipose. The effects of omental derived adipose stem cells (O-ASC) and subcutaneous tissue derived adipose stem cells (SC-ASC) on ovarian cancer biology including ovarian cancer proliferation, gene expression and response to chemotherapy were investigated. Methods and Results Luciferase labelled ovarian carcinoma cells (OVCA 429) were co-cultured with O-ASC, SC-ASC and control fibroblast line Wi38. Significantly higher levels of luciferase activity was detected when ovarian carcinoma cells were co-cultured with O-ASC than with SC-ASC and Wi38 (3470.4 RLU vs 1253.2 RLU, p=<0.005). Moreover, co-culture of 429 cells with ASCs in presence of different concentrations of Taxol revealed that O-ASC influence tumor cell chemosensitivity. Additionally, O-ASC promoted formation of significantly more ovarian carcinoma tumorispheres which were more closer associated to each other than those created in sphere medium only. To identify differentially expressed genes in O-ASC and SC-ASC, we performed microarray experiments (NimbleGen platform) which were analyzed using Ingenuity Pathway Analysis (IPA) software. The highest expressed genes were connected with growth, proliferation and development of cells and most of the proteins coded by these genes were localized in the extracellular space, plasma membrane or exosomes (CALR, UNC5B in O-ASC or COL1A2, FN1 in SC-ASC). We also performed ELISA assays focused on release of growth factors which revealed that O-ASC and SC-ASC secrete more VEGF (1678 pg/ml) and FGF (29 pg/ml) compared to control cells Wi38 (114 pg/ml and 2.7 pg/ml respectively). Chemokine SDF-1α was also secreted in high level by O-ASC S1 (1537 pg/ml) but SC-ASC released only 187 pg/ml relative to Wi38 (706 pg/ml) which indicates that these two types of adipose stem cells can create different surrounding environment. Summary O-ASC cells have unique tumor promoting effects and create specific environmental niche by releasing growth factors, cytokines and other factors which can stimulate ovarian cancer cells to grow faster and clump together. ASC may also influence protection of ovarian cancer from toxicity of chemotherapeutics. The knowledge about microenvironmental crosstalk between normal stem cells and tumor cells can contribute in the development of new treatment to prevent metastasis of ovarian cancer and make them vulnerable to chemotherapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1492. doi:1538-7445.AM2012-1492

The findings of positron emission tomography combined with computed tomography (PET/CT) in a patient with FIGO stage IIA adenoma malignum of the uterine cervix are described in this article. PET/CT showed that the cervical tumor was intensely hypermetabolic with no evidence of disease spread. However, lymphadenectomy revealed metastatic spread to paraaortic lymph nodes. PET/CT may be useful in identifying primary site of disease in patients with adenoma malignum; however, the utility in detecting metastatic nodal disease remains to be determined.

Purpose/Objective(s)Adipose tissue retains a population of multipotent mesenchymal stromal cells (ASC) which exhibit tumor tropism, similar to bone marrow derived mesenchymal stem cells (MSC). Excess visceral adipose tissue increases the risk of ovarian cancer and the omentum is a frequent site of ovarian cancer metastasis. We hypothesize omentum is a source of ASC which form stroma in ovarian cancers and promote tumor progression and resistance to therapy.Materials/MethodsASC were isolated from the omentum (O-ASC) of 5 patients with endometrial or ovarian cancer (1-3: early stage/low grade, 4 and 5: IIIC serous ovarian). O-ASC were characterized with flow cytometry and multi-lineage differentiation assays. Luciferase expressing A2780 were co-cultured with O-ASC, irradiated at 2 Gy, 4 Gy, 6 Gy, and 8 Gy and surviving cells were quantitated with bioluminescent imaging. Luciferase expressing OVCA433 and OVCA429 were co-cultured with O-ASC and tumor cell proliferation was quantitated with bioluminescence. Transwell migration assays were performed with OVCA433 and OVCA429 with conditioned media from OSC, MSC, and subcutaneous adipose derived ASC. Nine female NOD.CB17-Prkdc SCID/j mice (age 14 weeks) received: (1) Intraperitoneal (IP) injection of SKOV3 or (2) IP injection of SKOV3 mixed directly with RFP-labeled O-ASC on day 1 and 28.ResultsO-ASC exhibited mesenchymal morphology, cell surface marker expression similar to MSC (CD45, 0.4%; CD90, 84.6%; CD44, 77.8%; CD105, 38.5%), osteogenic and adipogenic differentiation. A2780 treated with radiation had significantly increased survival when co-cultured with OSC 1 after 4, 6, and 8 Gy (luciferase activity: 647 vs. 457; p = 0.01; 660 vs. 320; p < 0.01; 551 vs. 111; p < 0.01, respectively) and OSC 4 (823 vs. 222; p < 0.01; 643 vs. 228; p < 0.01; 761 vs. 162; p < 0.01), compared to control. OVCA429 proliferation was significantly increased when co-cultured with O-ASC as compared to control (average luminescence of 1348.4 vs. 2558.6; p < 0.01). Migration of OVCA433 was significantly increased compared to tumor cells alone for all 5 OSC lines and MSC line (average absorbance reflecting number of migrated cells 0.15, 0.29, 0.32, 0.45, 0.56 for OSC1-5 and 0.50 MSC, respectively, p < 0.05 in all cases). Conditioned media from O-ASC 4 and 5, derived from patients with Stage III serous ovarian cancer, had the most potent effects on in vitro migration of OVCA429 and 433 cells. Mice bearing IP SKOV3 ovarian tumors receiving O-ASC on day 1 and 28 developed larger tumor burden compared to control (mean photons/cm2 on day 32 of 1.1 x 107 vs. 6.0 x 107, p = 0.04).ConclusionsTumor tropic mesenchymal stem cells in the omentum decrease ovarian tumor radiosensitivity and promote proliferation and migration. Purpose/Objective(s)Adipose tissue retains a population of multipotent mesenchymal stromal cells (ASC) which exhibit tumor tropism, similar to bone marrow derived mesenchymal stem cells (MSC). Excess visceral adipose tissue increases the risk of ovarian cancer and the omentum is a frequent site of ovarian cancer metastasis. We hypothesize omentum is a source of ASC which form stroma in ovarian cancers and promote tumor progression and resistance to therapy. Adipose tissue retains a population of multipotent mesenchymal stromal cells (ASC) which exhibit tumor tropism, similar to bone marrow derived mesenchymal stem cells (MSC). Excess visceral adipose tissue increases the risk of ovarian cancer and the omentum is a frequent site of ovarian cancer metastasis. We hypothesize omentum is a source of ASC which form stroma in ovarian cancers and promote tumor progression and resistance to therapy. Materials/MethodsASC were isolated from the omentum (O-ASC) of 5 patients with endometrial or ovarian cancer (1-3: early stage/low grade, 4 and 5: IIIC serous ovarian). O-ASC were characterized with flow cytometry and multi-lineage differentiation assays. Luciferase expressing A2780 were co-cultured with O-ASC, irradiated at 2 Gy, 4 Gy, 6 Gy, and 8 Gy and surviving cells were quantitated with bioluminescent imaging. Luciferase expressing OVCA433 and OVCA429 were co-cultured with O-ASC and tumor cell proliferation was quantitated with bioluminescence. Transwell migration assays were performed with OVCA433 and OVCA429 with conditioned media from OSC, MSC, and subcutaneous adipose derived ASC. Nine female NOD.CB17-Prkdc SCID/j mice (age 14 weeks) received: (1) Intraperitoneal (IP) injection of SKOV3 or (2) IP injection of SKOV3 mixed directly with RFP-labeled O-ASC on day 1 and 28. ASC were isolated from the omentum (O-ASC) of 5 patients with endometrial or ovarian cancer (1-3: early stage/low grade, 4 and 5: IIIC serous ovarian). O-ASC were characterized with flow cytometry and multi-lineage differentiation assays. Luciferase expressing A2780 were co-cultured with O-ASC, irradiated at 2 Gy, 4 Gy, 6 Gy, and 8 Gy and surviving cells were quantitated with bioluminescent imaging. Luciferase expressing OVCA433 and OVCA429 were co-cultured with O-ASC and tumor cell proliferation was quantitated with bioluminescence. Transwell migration assays were performed with OVCA433 and OVCA429 with conditioned media from OSC, MSC, and subcutaneous adipose derived ASC. Nine female NOD.CB17-Prkdc SCID/j mice (age 14 weeks) received: (1) Intraperitoneal (IP) injection of SKOV3 or (2) IP injection of SKOV3 mixed directly with RFP-labeled O-ASC on day 1 and 28. ResultsO-ASC exhibited mesenchymal morphology, cell surface marker expression similar to MSC (CD45, 0.4%; CD90, 84.6%; CD44, 77.8%; CD105, 38.5%), osteogenic and adipogenic differentiation. A2780 treated with radiation had significantly increased survival when co-cultured with OSC 1 after 4, 6, and 8 Gy (luciferase activity: 647 vs. 457; p = 0.01; 660 vs. 320; p < 0.01; 551 vs. 111; p < 0.01, respectively) and OSC 4 (823 vs. 222; p < 0.01; 643 vs. 228; p < 0.01; 761 vs. 162; p < 0.01), compared to control. OVCA429 proliferation was significantly increased when co-cultured with O-ASC as compared to control (average luminescence of 1348.4 vs. 2558.6; p < 0.01). Migration of OVCA433 was significantly increased compared to tumor cells alone for all 5 OSC lines and MSC line (average absorbance reflecting number of migrated cells 0.15, 0.29, 0.32, 0.45, 0.56 for OSC1-5 and 0.50 MSC, respectively, p < 0.05 in all cases). Conditioned media from O-ASC 4 and 5, derived from patients with Stage III serous ovarian cancer, had the most potent effects on in vitro migration of OVCA429 and 433 cells. Mice bearing IP SKOV3 ovarian tumors receiving O-ASC on day 1 and 28 developed larger tumor burden compared to control (mean photons/cm2 on day 32 of 1.1 x 107 vs. 6.0 x 107, p = 0.04). O-ASC exhibited mesenchymal morphology, cell surface marker expression similar to MSC (CD45, 0.4%; CD90, 84.6%; CD44, 77.8%; CD105, 38.5%), osteogenic and adipogenic differentiation. A2780 treated with radiation had significantly increased survival when co-cultured with OSC 1 after 4, 6, and 8 Gy (luciferase activity: 647 vs. 457; p = 0.01; 660 vs. 320; p < 0.01; 551 vs. 111; p < 0.01, respectively) and OSC 4 (823 vs. 222; p < 0.01; 643 vs. 228; p < 0.01; 761 vs. 162; p < 0.01), compared to control. OVCA429 proliferation was significantly increased when co-cultured with O-ASC as compared to control (average luminescence of 1348.4 vs. 2558.6; p < 0.01). Migration of OVCA433 was significantly increased compared to tumor cells alone for all 5 OSC lines and MSC line (average absorbance reflecting number of migrated cells 0.15, 0.29, 0.32, 0.45, 0.56 for OSC1-5 and 0.50 MSC, respectively, p < 0.05 in all cases). Conditioned media from O-ASC 4 and 5, derived from patients with Stage III serous ovarian cancer, had the most potent effects on in vitro migration of OVCA429 and 433 cells. Mice bearing IP SKOV3 ovarian tumors receiving O-ASC on day 1 and 28 developed larger tumor burden compared to control (mean photons/cm2 on day 32 of 1.1 x 107 vs. 6.0 x 107, p = 0.04). ConclusionsTumor tropic mesenchymal stem cells in the omentum decrease ovarian tumor radiosensitivity and promote proliferation and migration. Tumor tropic mesenchymal stem cells in the omentum decrease ovarian tumor radiosensitivity and promote proliferation and migration.

267 Background: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Data regarding the use of external beam radiotherapy is limited in patients from populations without endemic viral hepatitis. We examine the outcomes for patients treated with external beam radiotherapy in the modern era at a single institution. Methods: A total of 29 patients with localized HCC treated from 2000 to 2009 were reviewed. Patients with metastatic disease at the time of radiation were excluded. Median radiation dose was 50 Gy (range 30-75 Gy) with a median biologically effective dose (BED) of 80.6 (range 60-138.6). Median tumor size at the time of radiation was 5.2 cm (range 2-25 cm). Results: Median residual tumor following radiation was 80% (range 27%-278%), with a median residual α-fetoprotein of 47% (range 0.8%-8240%). Estimated one-year overall survival (OS) and in-field progression-free survival (PFS) rates for the study population were 56% and 79%, respectively. One year OS in patients treated to a BED <75 was 18% vs. 69% in patients treated to a BED ≥75 (p=0.002). One year in-field PFS rate (60% vs. 88%, p=0.023) and biochemical PFS duration (median 6.5 vs. 1.6 mos., p=0.001) were also significantly improved in patients treated to a BED ≥75. Grade 3 toxicity was seen in only 13.8% of patients. Conclusions: In a population without endemic viral hepatitis, unresectable HCC demonstrates significant response toexternal beam radiotherapy with minimal toxicity. Furthermore, our findings suggest that increased BED is associated with improved survival and local tumor control. No significant financial relationships to disclose.

PURPOSE:Consistency in defining and contouring target structures in radiation therapy (RT) is critical for highly conformal RT, for evaluating treatment plans, and for quality assurance in multi-institutional RT trials. The Radiation Therapy Oncology Group (RTOG) has published consensus guidelines for contouring targets for postmastectomy RT. To aid in contouring such structures, we evaluated the potential use of an automated contouring technique, known as deformable image registration-based breast segmentation (DEF-SEG). METHODS AND MATERIALS:The RTOG definitions were used to contour the chest wall (CW); levels I, II, and III axillary nodes (Ax1, Ax2, Ax3); supraclavicular (SCV) nodes; internal mammary (IM) nodes; and the heart. Left-sided and right-sided templates were created. The DEF-SEG was then used to generate auto-segmented contours from the appropriate template to computed tomographic scans of 20 test cases (10 left, 10 right). To assess the accuracy of this method, those contours were manually modified as necessary to match the RTOG definitions, and the extent of the overlap was compared. The dosimetric impact of the difference in contours was then evaluated by comparing dose-volume histograms for modified and unmodified contours. RESULTS:Mean volume-overlap ratios between the unmodified DEF-SEG-generated contours and modified contours were as follows: CW, 0.91; Ax1, 0.68; Ax2, 0.64; Ax3, 0.68; SCV node, 0.66; IM node, 0.32, and the heart, 0.93. Mean differences in volume receiving 45 Gy (V45) for the modified versus unmodified contours were as follows: CW, 2.1%; SCV node, 4.8%; Ax1, 5.1%; Ax2, 5.6%; Ax3, 3.0%; and IM node, 10.1%. Mean differences in V10 between the modified heart and the unmodified heart were 0.4% for right-sided treatment and 0.5% for left-sided treatment. CONCLUSIONS:The DEF-SEG can be helpful for delineating structures according to the RTOG consensus guidelines, particularly for the CW and the heart. No clinically significant dosimetric differences were found between the modified and unmodified contours. The DEF-SEG may be useful for evaluating treatment plans for postmastectomy RT in multi-institutional trials.