High-dose Radiation Treatment Research Articles

Live birth from ovarian grafted tissue after pelvic radiation for rectal cancer

ObjectiveTo study the management of a woman who returned to conceive after high dose radiation treatment (RT), with documentation of uterine dosimetry, and the efficacy of ovarian tissue grafted into an irradiated pelvis. Design, setting, interventionA 26-year-old woman underwent RT to treat rectal cancer, with half of the uterus being exposed to a radiation dose of 50 Gy and 25 Gy to the fundus. We report details of the uterine assessment, determining suitability of conception with her own uterus, pregnancy surveillance and reproductive outcome. Main outcome measures, resultsThe results of MRI and pelvic ultrasound showed a small uterus with preserved junctional zone anatomy and while the endometrium was initially thin following administration of high oestrogen administration, endometrial thickness increased with time. Twelve grafted ovarian tissue stimulation cycles led to 4 embryo transfers, the last of which resulted in a live birth. She had two cervical cerclage procedures due to cervical shortening and delivered a 3.3kg healthy girl at 38/40 via LSCS. ConclusionsSuccessful pregnancy is possible from ovarian tissue grafted into an irradiated pelvis, with high dose uterine exposure. Careful uterine assessment needs to be undertaken to determine suitability of conception attempt with a patient’s own uterus, in consultation with the medical team. Further studies are needed to correlate imaging and biopsy findings with reproductive outcomes.

Radiobiology of stereotactic radiotherapy.

This paper focuses on the radiobiological mechanisms underlying the effects of stereotactic radiotherapy (SRT ) which, despite SRT expansion, have not yet been fully elucidated. Some authors postulated that radiobiology principles, as applied to conventional fractionations (5R: reoxygenation, repair, repopulation, redistribution, radioresistence), suffice in themselves to account for the excellent clinical results of SRT; others argued that the role of the 5R was limited. Recent preclinical data showed that hypofractionated ablative treatments altered the microenvironment, thus determining cell death either directly or indirectly. Furthermore, dead tumor cells released quantities of antigens, which stimulated antitumor immunity, thus reducing the risk of relapse and metastasis. Better understanding of the radiobiological mechanisms underlying response to high-dose radiation treatment is essential for predicting its short- and long-term effects on the tumor and surrounding healthy tissues and, consequently, for improving its related therapeutic index.

Novel potent anti-STEAP1 bispecific antibody to redirect T cells for cancer immunotherapy

BackgroundThe prognosis for metastatic Ewing sarcoma family of tumors (EFT) is still poor despite high-dose chemotherapy and radiation treatment. Immunotherapies hold promise, but cancer antigen-targeting immunotherapies have largely failed to...

Successful High-Dose Radiation Treatment for Chemo-Resistant Oral Squamous Cell Carcinoma in a Kindler's Syndrome Patient.

Successful High-Dose Radiation Treatment for Chemo-Resistant Oral Squamous Cell Carcinoma in a Kindler's Syndrome Patient.

Clinical Outcomes for Larynx Cancer Patients Treated with Refinement of High-Dose Radiation Treatment Volumes

Clinical Outcomes for Larynx Cancer Patients Treated with Refinement of High-Dose Radiation Treatment Volumes

Contrast-Enhanced Ultrasound to Detect Early Microvascular Changes in Skeletal Muscle after High-Dose Radiation Treatment.

The biological response of normal tissue to high-dose radiation treatment remains poorly understood. Alterations to the microenvironment, specifically the microvasculature, have been implicated as a significant contributor to tumoral cytotoxicity. We used contrast-enhanced ultrasound (CEU) perfusion imaging, which is uniquely suited to assess functional status of the microcirculation, to measure microvascular blood flow after high-dose irradiation to normal skeletal muscle tissue in a murine model. Proximal hindlimbs of wild-type C57Bl/6 mice were irradiated with a single fraction using 6 MV photons, 1 cm bolus and a dynamic wedge. Quantitative perfusion CEU imaging of the skeletal muscle was performed at days 1 and 8 postirradiation in three different regions of interest (ROIs): 1. 15 Gy external-beam irradiated leg; 2. 12 Gy irradiated 5 mm proximal area; 3. single ROI in the nonirradiated contralateral (CL) hindlimb. Perfusion imaging was also performed in the hindlimb of nonirradiated mice. CEU time-intensity data were analyzed to measure microvascular blood flow (MBF, also referred to as perfusion), and its parametric components of microvascular flux rate and functional microvascular blood volume (MBV). Plasma measurements of two potent vasoconstrictors, endothelin-1 and angiotensin II, were also performed to assess systemic response. CEU perfusion imaging values for the 12 and 15 Gy irradiated limb regions were pooled. At day 1, MBF in the irradiated limb was significantly lower than in the CL limb (P = 0.016) but quite similar to the nonirradiated mice. At day 8, both limbs of irradiated mice exhibited a trend towards lower MBF than the limbs of nonirradiated mice (28% decrease in mean MBF, P = 0.149 for CL; 39% decrease, P = 0.065 for irradiated limb). Compared to nonirradiated animals, the reduction in perfusion in irradiated limbs at day 8 may have been more influenced by the microvascular flux rate (25% decrease in the mean, P = 0.079) than the MBV (12% decrease in the mean, P = 0.328). Examination of vasoactive compounds revealed that the average plasma concentration for endothelin-1 at day 8 postirradiation was significantly higher in 14 irradiated animals than in 4 nonirradiated animals (3.07 pg/ ml vs. 2.51 pg/ml; P = 0.011). Up to day 8 after high-dose irradiation, flow deficits in irradiated muscle appear to be a consequence of increased vascular resistance more so than loss or functional de-recruitment of microvascular units.

Validating the pivotal role of the immune system in low-dose radiation-induced tumor inhibition in Lewis lung cancer-bearing mice.

Although low‐dose radiation (LDR) possesses the two distinct functions of inducing hormesis and adaptive responses, which result in immune enhancement and tumor inhibition, its clinical applications have not yet been elucidated. The major obstacle that hinders the application of LDR in the clinical setting is that the mechanisms underlying induction of tumor inhibition are unclear, and the risks associated with LDR are still unknown. Thus, to overcome this obstacle and elucidate the mechanisms mediating the antitumor effects of LDR, in this study, we established an in vivo lung cancer model to investigate the participation of the immune system in LDR‐induced tumor inhibition and validated the pivotal role of the immune system by impairing immunity with high‐dose radiation (HDR) of 1 Gy. Additionally, the LDR‐induced adaptive response of the immune system was also observed by sequential HDR treatment in this mouse model. We found that LDR‐activated T cells and natural killer cells and increased the cytotoxicity of splenocytes and the infiltration of T cells in the tumor tissues. In contrast, when immune function was impaired by HDR pretreatment, LDR could not induce tumor inhibition. However, when LDR was administered before HDR, the immunity could be protected from impairment, and tumor growth could be inhibited to some extent, indicating the induction of the immune adaptive response by LDR. Therefore, we demonstrated that immune enhancement played a key role in LDR‐induced tumor inhibition. These findings emphasized the importance of the immune response in tumor radiotherapy and may help promote the application of LDR as a novel approach in clinical practice.

Phase 3 Study of Hypofractionated, Dose Escalation Radiation Therapy for High-Risk Adenocarcinoma of the Prostate

The low α/β ratio of prostate cancer (1.5-2) suggests high radiation-fraction sensitivity and predicts a therapeutic advantage of hypofractionated radiation treatment (RT). Most available data of moderate hypofractionated RT have focused on low, intermediate, and/or mixed risk groups. We therefore conducted the first randomized trial of moderately hypofractionated RT in high-risk prostate cancer patients, with the hypothesis that moderately hypofractionated RT is similar in safety to conventional high-dose intensity-modulated RT at 24 months. Here, we present the primary outcome of the study: safety analysis of toxicities at 6 and 24 months post-RT. We conducted a Canadian multi-centric phase III trial of conventional vs. hypofractionated intensity-modulated radiotherapy in men with high-risk prostate cancer as per the ASTRO definition. From February 2012 to March 2015, 329 patients were randomized in a 1:1 ratio to receive either conventional or hypofractionated RT. All patients received neo-adjuvant, concurrent, and adjuvant androgen suppression, with a median duration of 24 months. Conventional RT consisted of 76 Gy in 2 Gy per fraction to the prostate where 46 Gy was delivered to the pelvic lymph nodes. Hypofractionated RT consisted of concomitant dose escalation of 68 Gy in 2.72 Gy per fraction to the prostate and 45 Gy in 1.8 Gy per fraction to the pelvic lymph nodes. The primary endpoint is to compare the toxicities at 6 months and at 24 months using the CTCAE v.4. This study is registered on clinicaltrials.gov (NCT01444820). Of the 329 patients, 164 were randomized to hypofractionated RT and 165 to conventional RT. The median follow-up was 36 months (19-55 months). At 24 months, 8 patients in the conventional RT arm and 9 patients in the hypofractionated RT arm had grade 2 or worse gastrointestinal (GI) related adverse events (HR = 0.76; 95% CI = 0.26-2.19; P = ns). Similarly, 7 patients in the conventional RT arm and 5 patients in hypofractionated RT arm had grade 2 or worse genitourinary (GU) toxicities (HR = 0.57; 95% CI = 0.17-1.95; P = ns). Three patients in the hypofractionated RT arm and no patient in the conventional RT arm had grade 3 GI related toxicities, while one patient in hypofractionated RT group and 3 patients in conventional RT group had grade 3 GU related toxicities. There were no grade 4 toxicities in any of the groups. This is the first hypofractionated dose escalated radiotherapy study in high-risk prostate cancer patients treated with contemporary radiation techniques and androgen suppression. The results confirm our original hypothesis and indicate that moderate hypofractionated RT is equally well tolerated as conventionally fractionated radiotherapy at 2 years in high-risk prostate cancer patients.

Once Daily High-dose Radiation (≥60 Gy) Treatment in Limited Stage Small Cell Lung Cancer

To investigate outcomes and prognostic factors in patients treated with once daily high-dose (≥60 Gy) radiation therapy (HDRT) and concurrent platinum-based chemotherapy in limited stage small cell lung cancer (LS-SCLC). While we await current phase III trials to determine optimal radiation dose fractionation schemes in LS-SCLC, we report our experience in LS-SCLC with once daily HDRT. We hypothesized that HDRT would achieve similar efficacy and tolerability as twice daily therapy. We conducted a single institution retrospective review of all patients with LS-SCLC who underwent curative intent treatment from 2005-2013. Patients treated with HDRT (≥60 Gy) and concurrent chemotherapy (cisplatin or carboplatin and etoposide) were included in our analysis. Clinicopathologic variables assessed include gender, performance status, time to treatment, response to treatment, toxicity, volumetric tumor response at 3 months, and use of prophylactic cranial irradiation (PCI). 42 patients with LS-SCLC who initiated concurrent chemoradiation from 2005 to 2013 were included in the analysis. 38 patients (90%) completed definitive treatment to the lung; 16 (38%) also completed PCI. Median failure free survival (FFS) and overall survival (OS) were 11.9 and 23.1 months, respectively. Two-year and 5-year OS rates were 47% (CI=30-62%) and 21% (CI=7-38%), respectively. On univariate analysis, PCI was associated with improved FFS but this was not significant (p=0.18). Gender was the only co-variate significantly associated with statistical differences in FFS (p=0.03) and OS (p=0.02). Grade 3 and 4 esophagitis were 10.5% and 2.6%, respectively. Pre-HDRT tumor volume and 3-month post-treatment tumor volume were both associated with FFS (p<0.01) but not OS. In this single institution series, daily HDRT demonstrated a 2-year OS of 47% in LS-SCLC. This compares well to the historical survival of daily fractionation (47%) from INT 0096 reported by Turrisi et. al. Male gender was predictive of significantly worse FFS and OS. Once daily HDRT has similar OS to twice-daily radiation schemes; however, further studies assessing once daily HDRT for LS-SCLC are warranted.

Prostaglandin E2 Signaling through EP4 Receptor Promotes Hematopoietic Stem Cell Niche Regeneration and Enhances Hematopoietic Recovery

High-dose radiation treatment for hematological malignancies such as leukemia, lymphoma or multiple myeloma induces damage to the bone marrow microenvironment that limits hematopoietic regeneration. We previously demonstrated that single administration of dimethyl prostaglandin E2 (dmPGE2) at 24 hrs post lethal irradiation (796 cGys; LD70/30) in mice increases survival and accelerates hematopoietic recovery. Since bone marrow niches regulate hematopoiesis, we investigated whether the effects of PGE2 administration on hematopoietic recovery and survival were dependent on PGE2 signaling in bone marrow stromal cells. Total body irradiation (TBI) severely disrupts bone marrow niche components including MSC, osteoblasts and endothelial cells. Multivariate flow cytometry revealed that exposure of mice to 650 cGy TBI reduced the total number of bone marrow MSC defined as CD45- Ter119- CD31- PDGFR+ CD51+ MSC by 8 fold and reduced functional fibroblast colony formation (CFU-F) by 8.5 fold. Osteoblast (OB) and endothelial cell (EC) counts were reduced by 6.5 fold and 6 fold respectively. Treatment of mice with dmPGE2 at 24 hours post-irradiation substantially rescued MSC and EC, which were 3.5 and 2.2-fold higher compared to un-treated irradiated mice. Histological and flow cytometric analysis indicated that total OB, OB precursors and mesenchymal progenitor cells (MPC) in bone marrow were also enhanced by PGE2 administration. Interestingly, dmPGE2 failed to rescue MSC and OB from aged (24-27 mo/old) mice compared to young (4-6 mo/old) mice. Since PGE2 signals through four receptors (EP1-4), each with unique signaling pathways, we hypothesized that the hematopoietic niche regeneration was due to activation of PGE2 signaling via one or more EP receptors. Treatment of mice with the EP4 receptor agonist L-902,688 following irradiation enhanced the recovery of bone marrow MSC by 3.1 fold and EC by 2.0 fold compared to untreated irradiated control mice. EP1, EP2 and EP3 receptor agonists failed to enhance hematopoietic niche regeneration in irradiated mice. To further investigate the role of EP4 signaling in bone marrow niche reconstruction and hematopoietic recovery, we transplanted BM cells from wild-type mice into syngeneic wild-type or conditional inducible EP4-/- recipients after lethal irradiation, and analyzed stromal cells recovery and hematopoietic reconstitution. At 15 days post-transplantation, chimeric mice with EP4-/- stroma displayed attenuated niche recovery and hematopoietic reconstitution compared to mice with wild-type stroma. PGE2 or EP4 agonist administration increased the expression of the endogenous anti-apoptotic protein Survivin, and enhanced survival of MSC and EC. In conclusion, our study suggests that PGE2 signaling through the EP4 receptor increases hemotopoietic recovery after TBI by enhancing the survival and expansion of MSC and endothelial cells. Furthermore, our data suggest the modulation/regulation PGE2 signaling in hematopoietic niche components could be beneficial to enhance HSC recovery following clinical hematopoietic transplantation. Disclosures No relevant conflicts of interest to declare.

SU-E-J-85: The Effect of Different Imaging Modalities On the Delineation of the True Spinal Cord for Spinal Stereotactic Body Radiation Therapy

Purpose: SBRT allows the delivery of high dose radiation treatments to localized tumors while minimizing dose to surrounding tissues. Due to the large doses delivered, accurate contouring of organs at risk is essential. In this study, differences between the true spinal cord as seen using MRI and CT myelogram (CTM) have been assessed in patients with spinal metastases treated using SBRT. Methods: Ten patients were identified that have both a CTM and a MRI. Using rigid registration tools, the MRI was fused to the CTM. The thecal sac and true cord were contoured using each imaging modality. Images were exported and analyzed for similarity by computing the Dice similarity coefficient and the modified Hausdorff distance (greatest distance from a point in one set to the closest point in the other set). Results: The Dice coefficient was calculated for the thecal sac (0.81 ±0.06) and true cord (0.63 ±0.13). These two measures are correlated; however, some points show a low true cord overlap despite a high overlap for the thecal sac. The Hausdorff distance for structure comparisons was also calculated. For thecal sac structures, the average value, 1.6mm (±1.1), indicates good overlap. For true cord comparison, the average value, 0.3mm (±0.16),more » indicates very good overlap. The minimum Hausdorff distance between the true cord and thecal sac was on average 1.6mm (±0.9) Conclusion: The true cord position as seen in MRI and CTM is fairly constant, although care should be taken as large differences can be seen in individual patients. Avoidning the true cord in spine SBRT is critical, so the ability to visualize the true cord before performing SBRT to the vertebrae is essential. Here, CT myelogram appears an excellent, robust option, that can be obtained the day of treatment planning and is unaffected by uncertainties in image fusion.« less

PD33-10 RADIATION THERAPY IMPROVES IMMUNOGENICITY OF HUMAN RENAL CELL CARCINOMA

You have accessJournal of UrologyKidney Cancer: Basic Research III1 Apr 2015PD33-10 RADIATION THERAPY IMPROVES IMMUNOGENICITY OF HUMAN RENAL CELL CARCINOMA Jason Muhitch, Mohammad Habiby Kermany, Lilia Heit, Alexander Wald, Mary Hensen, Scott Abrams, Timothy Winslow, Anurag Singh, and Thomas Schwaab Jason MuhitchJason Muhitch More articles by this author , Mohammad Habiby KermanyMohammad Habiby Kermany More articles by this author , Lilia HeitLilia Heit More articles by this author , Alexander WaldAlexander Wald More articles by this author , Mary HensenMary Hensen More articles by this author , Scott AbramsScott Abrams More articles by this author , Timothy WinslowTimothy Winslow More articles by this author , Anurag SinghAnurag Singh More articles by this author , and Thomas SchwaabThomas Schwaab More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2015.02.2108AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Metastatic Renal Cell Carcinoma (RCC) is a lethal disease and the only curative approach is highly toxic immunotherapy via high-dose IL-2 treatment. For anti-tumor immunotherapy to be effective, CD8 T cells must detect tumor-associated antigens (TAA) presented on tumor cells to initiate contact-dependent cell lysis. Radiation has been shown to induce TAA expression in a variety of malignancies and is generally well-tolerated compared to high-dose IL-2. The recent advent of Stereotactic Body Radiation Therapy (SBRT) allows delivery of high-dose radiation to a well-defined target area with limited damage to normal tissue and is being explored in the treatment of RCC. We therefore sought to determine if TAA expression was increased following SBRT treatment of metastatic RCC tumors in a first of its kind Phase I clinical trial where patients are treated with neo-adjuvant SBRT followed by surgical resection. These studies were complemented with in vitro studies that examined TAA expression in radiated human RCC cell lines. METHODS RCC human cells lines (A498, A704, 769-P, 786-0, ACHN, and Caki-1) were treated ± radiation (16 Gy). 0 - 96 h later, TAA and costimulatory molecule expression was evaluated by flow cytometry. ELISPOT IFN-ã release assays were performed with NY-ESO-1 specific HLA-A2-restricted CD8+ T cell clones. Stage IV Renal Cell Carcinoma patients were treated ± SBRT and ∼28 days later tumors were resected (clinical trial NCT01892930). Single cell suspensions of resected tumors were evaluated for TAA and costimulatory molecules by flow cytometry. RESULTS Initial studies determined that high-dose radiation treatment improved TAA expression (NY-ESO-1, MUC-1, CA9) and costimulatory molecule expression (CD80, ICAM-1) in six commercially available RCC human cells lines. NY-ESO-1 specific CD8 T cells secreted more IFN-ã in response to radiated RCC cell lines (149.7 ± 57.1, mean ± SD per 50,000 cells) compared to control (19.7 ± 9.7, P < 0.05). Surprisingly, we also found that RCC tumors from patients treated with SBRT and later resected also showed improved expression of the TAA MUC-1, CA-9, and 5T4 (P < 0.05) and NY-ESO-1 (P < 0.07) compared to age-matched RCC patient tumors. Expression of the costimulatory molecules ICAM-1 and CD80 were also increased in SBRT-treated patient tumors compared to resected tumors from age-matched controls. CONCLUSIONS By increasing TAA and costimulatory molecule expression, SBRT treatment of RCC may unlock anti-tumor immune responses that can be further amplified with vaccination protocols and immune checkpoint blockade strategies. © 2015 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 193Issue 4SApril 2015Page: e713 Advertisement Copyright & Permissions© 2015 by American Urological Association Education and Research, Inc.MetricsAuthor Information Jason Muhitch More articles by this author Mohammad Habiby Kermany More articles by this author Lilia Heit More articles by this author Alexander Wald More articles by this author Mary Hensen More articles by this author Scott Abrams More articles by this author Timothy Winslow More articles by this author Anurag Singh More articles by this author Thomas Schwaab More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Carbon ion beam treatment in patients with primary and recurrent sacrococcygeal chordoma.

The purpose of this work was to evaluate the results of high-dose radiation treatment using carbon ion therapy, alone or combined with intensity-modulated radiation treatment (IMRT), in patients with sacral chordoma. Between 2009 and 2012, 56patients with sacral chordoma were treated in our center. The tumor was located above S3 in 33patients and in S3 or below in 23patients. In all, 41patients received radiation therapy for the primary tumor, while 15patients were treated for the recurrent tumor. Toxicity was measured using NCI CTCAE v.4.03. Local control (LC) and overall survival (OS) were evaluated with the Kaplan-Meier method. A total of 23patients were irradiated with carbon ions in combination with photon IMRT, while 33received carbon ion therapy only. Forty-three patients had a macroscopic tumor at treatment start with a median tumor size (GTV) of 244ml (range 5-1188ml). The median total dose was 66Gy (range 60-74Gy; RBE). After a median follow-up time of 25months, the 2- and 3-year local control probability was 76 % and 53 %, respectively. The overall survival rate was 100 %. Treatment for primary tumor and male patients resulted in significant better local control. No higher toxicity occurred within the follow-up time. High-dose photon/carbon ion beam radiation therapy is safe and, especially for primary sacral chordomas, highly effective. A randomized trial is required to evaluate the role of primary definitive hypofractionated particle therapy compared with surgery with or without adjuvant radiotherapy.

The use of modern imaging technologies in radiation therapy of cervical cancer

Over the past century, definitive management of unresectable cervical cancer has evolved and currently employs high-dose radiation treatment with teletherapy and intracavitary brachytherapy (ICBT) components, combined with concurrent chemotherapy. Reflecting high disease prevalence among developing nations, the International Federation of Gynecology and Obstetrics (FIGO) staging of cervical cancer relies on clinical assessment, with limited radiographic studies. However, multiple clinicopathologic analyses describe suboptimal correlation between clinical examination findings and pathologic stage. Over the past two decades, systematic evaluation of volumetric and functional imaging modalities including CT, MRI, and PET-CT has refined our ability to define disease extent and provide posttreatment surveillance. Similarly, traditional ICBT techniques relied on two-dimensional (2D) data for evaluation of target dose coverage and offered limited assessment of exposure to critical structures including the bladder, rectum, and sigmoid colon. During the last several years, investigators at leading European centers have enhanced the capabilities of existing ICBT techniques through dose optimization [high-dose rate (HDR) and pulsed dose rate (PDR)] and by incorporating volumetric imaging methods. Early results are encouraging, from both toxicity and tumor control perspectives. These techniques are currently being adopted in multiple centers. Pertinent aspects are summarized in the body of this report.

GENETIC CHANGES IN RADIATION-ASSOCIATED MENINGIOMA

BACKGROUND: Meningiomas represent the most frequently diagnosed primary brain tumor in the United States accounting for approximately one third of such tumors in adults. To date the sole consistently identified risk factor remains exposure to ionizing radiation with risks from 6-10 fold reported. Persons diagnosed with meningioma after exposure to therapeutic ionizing radiation likely represent a genetically-sensitive subpopulation of patients. Currently, radiation-associated meningiomas (RAM) are the most common form of radiation-induced neoplasm yet no sequencing data exist for this class of tumor. METHODS: Our group has identified 22 persons with confirmed high-dose therapeutic radiation treatments to the head, face or neck and subsequent pathologic confirmation of intra-cranial meningioma. To identify genetic changes and the mean number of protein altering somatic mutations associated with the development of RAM we perform whole genome sequencing on matched paraffin-embedded tumor and constitutive DNA for this group of patients. We compare these results with those obtained from the recent genetic analyses of two series of non-RAM meningiomas to determine how mutation profiles differ between RAM and non-RAM meningiomas. RESULTS: Treatment is problematic as many RAMs are in anatomic locations that are difficult to surgically access, most patients are not candidates for additional radiation therapy given their previous exposure and no beneficial chemotherapeutic agent exists. (Sequencing in process) CONCLUSIONS: RAMs represent a difficult clinical issue in neurosurgery. Our study is a focused effort to define genetic variants associated with meningioma development using cases with a unique gene*environment exposure. In addition, these data may identify mutational profiles that predict drug response for this hard to treat lesion. SECONDARY CATEGORY: Tumor Biology.

Immune effects of high dose radiation treatment: implications of ionizing radiation on the development of bystander and abscopal effects

Tumors grow progressively when they escape from immune surveillance. Cancer progression is mainly driven by the expansion of tumor cells, but tumor microenvironment and anti-tumor immunity may also play a role. Ionizing radiation therapy (RT), either alone or in combination with additional immune stimulators, can render cancer cells visible to the immune system. In addition to the direct effects of radiation, the ensuing immune response promotes the expression of inflammatory and immunostimulatory mediators, which act on neighboring, non-irradiated, cells. Bystander effects induced by radiation are characterized by biological responses, which are observed in non-irradiated cells that are in the vicinity of irradiated cells. Bystander effects are mediated via cell-to-cell gap junctions or through secreted, diffusible signaling molecules into the local milieu. After treatment with localized radiation, systemic effects in non-irradiated area (out-offield) may also occur. These effects are named abscopal effects and appear to be immune mediated, particularly by adaptive immunity. It has been suggested that a high single dose of RT may induce an immune response that leads to the priming of antigen-specific dendritic cells (DCs). The targeted intraoperative radiotherapy (TARGIT) method, using INTRABEAM ® , could reduce tumor recurrence, modifying the wound microenvironment, and eradicating residual tumor cells when applied immediately after surgery procedure.

Outcomes after Urethroplasty for Radiotherapy Induced Bulbomembranous Urethral Stricture Disease

We recently demonstrated that radiotherapy induced urethral strictures can be successfully managed with urethroplasty. We increased size and followup in our multi-institutional cohort, and evaluated excision and primary anastomosis as treatment for radiotherapy induced urethral strictures. A retrospective review was performed of 72 patients from 3 academic institutions treated for radiotherapy induced bulbomembranous strictures. Outcome parameters of successful repair included recurrence, incontinence and erectile dysfunction. Among the 72 men treated for radiotherapy induced strictures 66 (91.7%) underwent excision and primary anastomosis. Mean followup was 3.5 years (median 3.1, range 0.8 to 11.2). Prostate cancer was the most common reason for radiotherapy (in 64 of 66, 96.9%). External beam radiotherapy and brachytherapy were performed in 28 of 66 men (42.4%) each, and a combination of both was performed in 9 (13.6%). Mean time from radiation to excision and primary anastomosis was 6.4 years (range 1 to 20) and mean stricture length was 2.3 cm (range 1 to 6). Successful reconstruction was achieved in 46 men (69.7%). Mean time to recurrence was 10.2 months (range 1 to 64) with new onset of incontinence observed in 12 men (18.5%). This was associated with stricture length greater than 2 cm (p = 0.013) and treatment center (p <0.001). The rate of erectile dysfunction remained stable (preoperative 45.6%, postoperative 50.9%, p = 0.71). Radiotherapy type did not affect stricture length (p = 0.41), recurrence risk (p = 0.91), postoperative incontinence (p = 0.88) or erectile dysfunction (p = 0.53). Radiotherapy induced bulbomembranous urethral strictures can be successfully managed with excision and primary anastomosis. Substitution urethroplasty with graft or flap is needed infrequently. Patients should be counseled on the potential risks of urinary incontinence and erectile dysfunction.

Case Series: Intensity Modulated Radiotherapy to Treat Limited Stage Non-Endemic Nasal Natural Killer/T Cell Lymphoma

Initial treatment with radiation alone to doses >54 Gy with has become standard treatment for patients with limited stage extranodal natural killer/T-cell lymphoma, nasal type (NKTL-NT). We report on four consecutive non-Asian patients with NKTLNT treated with IMRT to spare critical structures while delivering high dose to the nasal and paranasal sinuses. Three patients are alive and without evidence of disease at 43.7, 19.5, and 30.4 months following radiation. One patient who died failed locally in an area of modest dose (45-50 Gy) as well as distantly. Acute toxicities were mainly mucositis (3 with Grade 2, 1 with Grade 3) managed with gabapentin and/or narcotics, Grade 2 xerostomia (1 patient), and Grade 1 dermatitis (1 patient).Two patients had late Grade 2 xerostomia and 1 patient required dacryocystorhonostomy for excessive tearing. Early stage NKTL-NT can be treated definitively with high-dose radiation treatment, and we believe that IMRT offers an advantage to improve the therapeutic index over conformal 3-dimensional RT.

Assessment of Liver Function after Irradiation by MR-derived Portal Venous Perfusion Imaging

Liver toxicity is a limiting factor for safely delivering high-dose radiation treatments for intrahepatic cancers. Radiation induced liver disease occurs weeks to months after the completion of RT. Previously, we have developed a CT-based regional venous perfusion and local dose model for prediction of liver function after irradiation. We hypothesized that liver function could be assessed individually and spatially using volumetric dynamic contrast enhanced MRI (DCE-MRI) before, during and after RT; and that the residual functioning volumes of the liver assessed by perfusion imaging would predict the overall liver function.

Single-fraction radiosurgery for the treatment of renal tumors in singular renal units.

e15168 Background: High-dose local radiation treatment (stereotactic radiosurgery, or SRS) was added for selected patients to improve local control and overall survival. We report on toxicity and local tumor control in patients with renal tumors who were treated with aggressive local irradiation using a single fraction SRS with the Cyberknife in singular renal units to avoid nephrectomy and consecutive hemodialysis. Methods: N=28 patients with renal tumors and an eastern cooperative oncology group (ECOG) status of 0 or 1 were treated with SRS. Patients with surgically removable renal lesions were not included. Prior to SRS gold markers were planted into the renal parenchyma under ultrasonographic guidance. Results: N=11 patients had transitional carcinoma of the renal pelvis and n=17 had renal cell carcinoma. No skin toxicity occurred after SRS, and SRS did not induce other side effects. Local tumor control 9 months after SRS was 98% (95% CI: 89-99%). There were no treatment related deaths, and late complications after SRS were not noted so far. Renal function remained stable with a median creatinine at baseline 1,5 mg/dl and 1,53 mg/dl after six months. None of the patients developed metastases during a median follow-up of 12 months. Dialysis and surgery were avoided in all patients. Conclusions: SRS for selected patients with renal tumors in singular renal units is safe and effective and maybe an alternative to surgery and consecutive hemodialysis. Single-fraction delivery as an outpatient procedure allows for convenient integration of SRS into various oncological treatment concepts. Further studies are needed to determine the limits of SRS in this setting.