Synchronous brain metastases as a poor prognosis factor in clear cell renal carcinoma: a strong argument for systematic brain screening.

PURPOSE: Brain metastases (BM) usually represent a poor prognostic factor in solid tumors. About 10% of patients with renal cancer (RCC) will present BM. Local therapies such as stereotactic radiotherapy (SRT), whole brain radiotherapy (WBRT), and surgery are used to achieve brain control. We compared survival between patients with synchronous BM (SynBM group) and metachronous BM (MetaBM group). METHODS: It is a retrospective study of patients with clear cell renal cell carcinoma (ccRCC) and BM treated with TKI between 2005 and 2019 at the Centre Léon Bérard in Lyon. We collected prognostic factors: The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk score, the TNM stage, the histological subtypes and the Fuhrman grade. Overall survival (OS) was defined from diagnosis of metastatic ccRCC to death. Brain progression-free survival (B-PFS) was defined from focal brain therapy to brain progression or death. RESULTS: 99 patients were analyzed, 44 in the SynBM group and 55 in the MetaBM group. OS in the MetaBM group was 49.4 months versus 19.6 months in the SynBM group, p = 0.0002. The median time from diagnosis of metastasic disease to apparition of BM in the MetaBM group was 22.9 months (4.3; 125.7). SRT was used for 101 lesions (66.4%), WBRT for 25 patients (16.4%), surgery for 21 lesions (13.8%), surgery followed by radiation for 5 lesions (3.3%). B-PFS for all patients was 7 months (IC95% [5.0-10.5]). CONCLUSIONS: Survival of patients with synchronous BM is inferior to that of patients with metachronous BM. Outcome is poor in both cases after diagnosis of BM. Brain screening should be encouraged at time of diagnosis of metastatis in ccRCC.

Risk of radiation necrosis after hypofractionated stereotactic radiotherapy (HFSRT) for brain metastases: a single center retrospective study.

INTRODUCTION: While hypofractionated stereotactic radiotherapy (HFSRT) is being increasingly used for treating brain metastases, clinical data concerning the incidence and risk factors of its main side-effect, namely radiation necrosis (RN), remain limited. In this context, we assessed risk factors of RN in a single center series of patients with brain metastases treated with three common HFSRT dose regimens: 27 Gy in 3 fractions (27 Gy/3#), 30 Gy in 5 fractions (30 Gy/5#), and 35 Gy in 5 fractions (35 Gy/5#). METHODS: In total, 360 HFSRT treatments in 294 consecutive patients were retrospectively analysed. Univariable analysis (UVA) and multivariable analysis (MVA) were performed to evaluate the relationship between clinical and dosimetric factors and RN risk. RESULTS: The 12-month RN rate was 8.8%. On MVA, risk was higher in lesions receiving 27 Gy/3# (HR 3.07 95%CI [1.13;8.36], p = 0.03) and 35 Gy/5# (HR 4.22 95%CI [1.46,12.21], p < 0.01) than in lesions receiving 30 Gy/5#. Risk was also higher in patients having received immunotherapy within 3 months of HFSRT (HR 2.69 95%CI [1.10;6.56], p = 0.03) compared with those who did not. We found no association between RN risk and other tested factors, in particular prior irradiation, lesion histology, lesion location, lesion volume, or brain dosimetric factors. CONCLUSION: In the present series, HFSRT was associated with limited RN risk. Incidence of RN was higher with dose regimens delivering a higher biologically effective dose, as well as in patients having received immunotherapy within 3 months of HFSRT.

Radiotherapy for central neurocytoma: A multicentric retrospective study in France.

PURPOSE: Neurocytomas represent 0.25 to 0.5% of primary brain tumours and are mainly found in young adults. These tumours have neuronal differentiation. The cornerstone treatment is neurosurgery. The efficacy of other therapies, including radiotherapy, is still unclear. The objective of this study was to evaluate the management of central neurocytomas and the role of radiotherapy. MATERIALS AND METHODS: All adult patients (age 18 years or older) newly diagnosed with a histologically confirmed neurocytoma between 2006 and 2015 in France were included. RESULTS: One hundred and sixteen patients were diagnosed with a central neurocytoma during the study period. All patients underwent surgical resection, and six received adjuvant radiotherapy. Eleven patients received radiotherapy due to progression. After a median follow-up of 68.7 months, local failure occurred in 29 patients. The 5-year local control rate was 73.4%. According to univariate analysis, marker of proliferation Ki67 index greater than 2% (hazard ratio [HR]: 1.48; confidence interval [CI]: 1.40-1.57; P=0.027) and subtotal resection (HR: 8.48; CI: 8.01-8.99; P<0.001) were associated with an increase in local failure. Gross total resection was associated with a higher risk of sequelae epilepsy (HR: 3.62; CI: 3.42-3.83; P<0.01) and memory disorders (HR: 1.35; CI: 1.07-1.20; P<0.01). Ten patients (8.6%) died during the follow-up. The 10-year overall survival rate was 89.0%. No prognostic factors for overall survival were found. CONCLUSION: The analysis showed that patients who underwent subtotal surgical resection, particularly when the tumour had a Ki67 index greater than 2%, had an increased risk of local recurrence. These patients could benefit from adjuvant radiotherapy.

Recommendations for Post-Operative RadioTherapy After Complete Resection of Thymoma-a French DELPHI Consensus Initiative.

INTRODUCTION: Thymomas are rare intrathoracic malignancies that can relapse after surgery. Whether or not Post-Operative RadioTherapy (PORT) should be delivered after surgery remains a major issue. RADIORYTHMIC is an ongoing, multicenter, randomized phase 3 trial addressing this question in patients with completely R0 resected Masaoka-Koga stage IIb/III thymoma. Experts in the field met to develop recommendations for PORT. METHODS: A scientific committee from the RYTHMIC network identified key issues regarding the modalities of PORT in completely resected thymoma. A DELPHI method was used to question 24 national experts, with 115 questions regarding the following: (1) imaging techniques, (2) clinical target volume (CTV) and margins, (3) dose constraints to organs at risk, (4) dose and fractionation, and (5) follow-up and records. Consensus was defined when opinions reached more than or equal to 80% agreement. RESULTS: We established the following recommendations: preoperative contrast-enhanced computed tomography (CT) scan is recommended (94% agreement); optimization of radiation delivery includes either a four-dimensional CT-based planning (82% agreement), a breath-holding inspiration breath-hold-based planning, or daily control CT imaging (81% agreement); imaging fusion based on cardiovascular structures of preoperative and planning CT scan is recommended (82% agreement); right coronary and left anterior descending coronary arteries should be delineated as cardiac substructures (88% agreement); rotational RCMI/volumetric modulated arc therapy is recommended (88% agreement); total dose is 50 Gy (81% agreement) with 1.8 to 2 Gy per fraction (94% agreement); cardiac evaluation and follow-up for patients with history of cardiovascular disease are recommended (88% agreement) with electrocardiogram and evaluation of left ventricular ejection fraction at 5 years and 10 years. CONCLUSION: This is the first consensus for PORT in thymoma. Implementation will help to harmonize practices.

Clinical outcomes and lung toxicities after lung SABR using dynamic conformal arc therapy: a single-institution cohort study.

BACKGROUND: Stereotactic ablative radiotherapy (SABR) is a validated treatment for early stage lung cancer and pulmonary metastases. It provides a high local control rate with low symptomatic toxicities. Recently, Dynamic Conformal Arc Therapy (DCAT), a delivery option that differs from conventional DCA, has been implemented in the Monaco Treatment Planning System for SABR. The aim of the study was to report clinical outcomes and toxicities for patients treated for lung SABR with this new technique. METHODS: We retrospectively identified adult patients treated for primary or secondary lung tumors with DCAT-SABR and reported their clinical, radiological, histological characteristics and dosimetric parameters. Total dose was delivered in 3 or 5 fractions for 95% of patients and prescribed on the 80% isodose line to the PTV periphery. RESULTS: 145 patients met inclusion criteria for a total of 152 lesions with a median follow up of 12 months. Local control for the irradiated site was 96.7% at 1 year. Overall survival was 93.1% at 1 year. Mean prescription dose in BED10 was 110 Gy. 92% of patients had a prescribed dose superior to 100 Gy BED10. Mean PTV coverage was 95.1%. There were 66 cases of grade 1 radiation pneumonitis (RP) (43%) and only 7 cases of symptomatic grade 2 RP (4.6%). CONCLUSION: Lung SABR for primary or metastatic lung tumors using dynamic conformal arc therapy provides efficient results of local control and low lung toxicities, similar to other SABR techniques. ADVANCES IN KNOWLEDGE: SABR using DCAT is a safe technique to treat lung lesions, allowing intra-fraction motion limitation, potentially higher OARs protection and a shortened beam delivery.

Target volume delineation for radiotherapy of meningiomas: an ANOCEF consensus guideline.

PURPOSE: Radiotherapy is, with surgery, one of the main therapeutic treatment strategies for meningiomas. No prospective study has defined a consensus for the delineation of target volumes for meningioma radiotherapy. Therefore, target volume definition is mainly based on information from retrospective studies that include heterogeneous patient populations. The aim is to describe delineation guidelines for meningioma radiotherapy as an adjuvant or definitive treatment with intensity-modulated radiation therapy and stereotactic radiation therapy techniques. This guideline is based on a consensus endorsed by a multidisciplinary group of brain tumor experts, members of the Association of French-speaking Neuro-oncologists (ANOCEF). MATERIALS AND METHODS: A 3-step procedure was used. First, the steering group carried out a comprehensive review to identify divergent issues on meningiomas target volume delineation. Second, an 84-item web-questionnaire has been developed to precisely define meningioma target volume delineation in the most common clinical situations. Third, experts members of the ANOCEF were requested to answer. The first two rounds were completed online. A third round was carried out by videoconference to allow experts to debate and discuss the remaining uncertain questions. All questions remained in a consensus. RESULTS: Limits of the target volume were defined using visible landmarks on computed tomography and magnetic resonance imaging, considering the pathways of tumor extension. The purpose was to develop clear and precise recommendations on meningiomas target volumes. CONCLUSION: New recommendations for meningiomas delineation based on simple anatomic boundaries are proposed by the ANOCEF. Improvement in uniformity in target volume definition is expected.

Harmonization of dose prescription for lung stereotactic radiotherapy.

Background and purpose: Pulmonary stereotactic treatments can be performed using dedicated linear accelerators as well as robotic-assisted units, and different strategies can be used for dose prescription. This study aimed to compare the doses received by the tumor with a gross tumor volume (GTV)-based prescription on D98%GTV using a robotic-assisted unit (method A) and planning target volume (PTV)-based prescription on D95%PTV using a dedicated linac (method B). Material & methods: Plans of 32 patients were collected for method A, and a dose of 3 × 18 Gy was prescribed using type A algorithm and recalculated using a Monte-Carlo (MC) algorithm. The plans were normalized to match D98%GTV with the mean D 98 % G T V ¯ of the cohort. The plans of 23 patients were collected for method B, and a dose of 3 × 18 Gy was prescribed to D95%PTV using a MC algorithm. A 4D-sum method was developed to estimate doses for PTV and GTV. For validation, all plans were recalculated using an independent MC double-check software. A dose harmonization on D98% GTV was determined for both methods. Results: For method A, mean doses were D2%GTV = 59.9 ± 2.1 Gy, D50%GTV = 55.6 ± 1.2 Gy, D98%GTV = 49.5 ± 0.0 Gy. For method B, the reported doses were D2%GTV = 64.6 ± 2.1 Gy, D50%GTV = 62.8 ± 1.7 Gy, and D98%GTV = 60.0 ± 1.7 Gy. The dose trade-off of D98%GTV = 55 Gy was obtained for both methods. For method A, it corresponded to a dose prescription of 3 × 20 Gy using type A algorithm, followed by rescaling to obtain D98%GTV = 55 Gy. For method B, it corresponded to a dose prescription of D95%PTV = 3 × 16.5 Gy using the MC algorithm. Conclusions: This study determined similar near-minimum doses D98% GTV of approximately 3 × 18.3 Gy (55 Gy) using a GTV-based prescription on a robotic-assisted unit (method A) and a PTV-based prescription on a dedicated linac (method B).

Toxicity and efficacy of stereotactic body radiotherapy for ultra-central lung tumours: a single institution real life experience.

OBJECTIVES: The use of stereotactic body radiotherapy (SBRT) to treat ultra-central lung tumours remains more controversial than for peripheral and central tumours. Our objective was to assess toxicities, local control (LC) rate and survival data in patients with ultra-central lung tumours treated with SBRT. METHODS: We conducted a retrospective and monocentric study about 74 patients with an ultra-central lung tumour, consecutively treated between 2012 and 2018. Ultra-central tumours were defined as tumours whose planning target volume overlapped one of the following organs at risk (OARs): the trachea, right and left main bronchi, intermediate bronchus, lobe bronchi, oesophagus, heart. RESULTS: Median follow-up was 25 months. Two patients (2.7%) showed Grade 3 toxicity. No Grade 4 or 5 toxicity was observed. 11% of patients experienced primary local relapse. LC rate was 96.7% at 1 year and 87.6% at 2 years. Median progression free survival was 12 months. Median overall survival was 31 months. CONCLUSION: SBRT for ultra-central tumours remains safe and effective as long as protecting organs at risk is treatment-planning priority. ADVANCES IN KNOWLEDGE: The present study is one of the rare to describe exclusively ultra-central tumours through real-life observational case reports. Globally, literature analysis reveals a large heterogeneity in ultra-central lung tumours definition, prescribed dose, number of fractions. In our study, patients treated with SBRT for ultra-central lung tumours experienced few Grade 3 toxicities (2.7%) and no Grade 4 or 5 toxicities, due to the highest compliance with dose constraints to OARs. LC remained efficient.

[National meetings for complex cases in pediatric radiation oncology: Back on six years experience]. / Réunions nationales de cas complexes en radiothérapie pédiatrique : retour sur six années d'expérience.

INTRODUCTION: Pediatric cancers are rare, representing almost 2,500 new cases each year in France meaning 1% of all cancers. Since 2012, a twice-monthly national web-based conference was held in France. Any patient with a pediatric type cancer requiring radiotherapy can be discussed. It aims at answering the physician with specific radiation therapy questions on rare and complex indications, at promoting the use of referential and the inclusion into clinical protocols. RESULTS: From 2012 to 2018, 1,078 cases were discussed for 940 patients in 142 meetings. Mean age was 10 years old (4 months to 45 years). The mean number of attendants was 6 (2 to 32). We review in this paper the main clinical features discussed in the web-conference and the decision of the web-conference. In 85% cases, the first treatment proposed was mostly accepted, but in 15%, other proposals were done (modifications of target volumes, doses or indications). CONCLUSIONS: Between 2012 and 2018, more than 1,000 pediatric irradiation cases were discussed in our web-based conference leading to 15% of change in radiation protocol. The rarity and the complexity of these situations need those meetings. They provide a place to improve the global knowledge and the quality of the treatments provided.

Vestibular Schwannoma: Results of Hypofractionated Stereotactic Radiation Therapy.

PURPOSE: Our purpose was to study the outcomes of hypofractionated stereotactic radiation therapy (HSRT) in terms of hearing and radiologic response for vestibular schwannomas. METHODS AND MATERIALS: This was a longitudinal retrospective study at a referral center from 2011 to 2016. All treatments were performed on a Cyberknife device with a dose of 21 Gy (3 × 7 Gy) or 25 Gy (5 × 5 Gy). We assessed tumor response, neurologic outcomes (hearing and facial nerve function), and treatment toxicity. RESULTS: A total of 82 patients were included. Fifty-three patients were treated with the 3 × 7 Gy scheme and 29 with the 5 × 5 Gy. Sixteen patients (20%) had a previous surgery. The median follow-up was 48 months (range, 12-88 months). We noted 3 recurrences leading to a control rate of 96.3%. In our cohort, predictive factors of vestibular schwannoma growth were a tumor volume >2 mm3 and a conformal index <1.1 (P < .0001). The treatment was well tolerated with only 5 grade III acute toxicities (4 vertigo and 1 headache) and no grade IV or V. As for late toxicity, we noticed 2 cases of mild peripheral facial palsy (House and Brackman grade II) in previously operated patients. There was 46.0% hearing preservation among patients with serviceable hearing after HSRT. CONCLUSIONS: Our results suggest that HSRT using 3 or 5 fractions is a well-tolerated and effective regimen. These findings are in addition to the few previous hypofractionation studies and contribute to the validity of this treatment modality.

Development of Randomized Trials in Adults with Medulloblastoma-The Example of EORTC 1634-BTG/NOA-23.

Medulloblastoma is a rare brain malignancy. Patients after puberty are rare and bear an intermediate prognosis. Standard treatment consists of maximal resection plus radio-chemotherapy. Treatment toxicity is high and produces disabling long-term side effects. The sonic hedgehog (SHH) subgroup is highly overrepresented in the post-pubertal and adult population and can be targeted by smoothened (SMO) inhibitors. No practice-changing prospective randomized data have been generated in adults. The EORTC 1634-BTG/NOA-23 trial will randomize patients between standard-dose vs. reduced-dosed craniospinal radiotherapy and SHH-subgroup patients between the SMO inhibitor sonidegib (OdomzoTM, Sun Pharmaceuticals Industries, Inc., New York, USA) in addition to standard radio-chemotherapy vs. standard radio-chemotherapy alone to improve outcomes in view of decreased radiotherapy-related toxicity and increased efficacy. We will further investigate tumor tissue, blood, and cerebrospinal fluid as well as magnetic resonance imaging and radiotherapy plans to generate information that helps to further improve treatment outcomes. Given that treatment side effects typically occur late, long-term follow-up will monitor classic side effects of therapy, but also health-related quality of life, cognition, social and professional outcome, and reproduction and fertility. In summary, we will generate unprecedented data that will be translated into treatment changes in post-pubertal patients with medulloblastoma and will help to design future clinical trials.

Brain metastases treated with hypofractionated stereotactic radiotherapy: 8 years experience after Cyberknife installation.

BACKGROUND: Hypofractionated stereotactic radiotherapy (HFSRT) is indicated for large brain metastases (BM) or proximity to critical organs (brainstem, chiasm, optic nerves, hippocampus). The primary aim of this study was to assess factors influencing BM local control after HFSRT. Then the effect of surgery plus HFSRT was compared with exclusive HFSRT on oncologic outcomes, including overall survival. MATERIALS AND METHODS: Retrospective study conducted in Léon Bérard Cancer Center, included patients over 18 years-old with BM, secondary to a tumor proven by histology and treated by HFSRT alone or after surgery. Three different dose-fractionation schedules were compared: 27 Gy (3 × 9 Gy), 30 Gy (5 × 6 Gy) and 35 Gy (5 × 7 Gy), prescribed on isodose 80%. Primary endpoint were local control (LC). Secondary endpoints were overall survival (OS) and radionecrosis (RN) rate. RESULTS: A total of 389 patients and 400 BM with regular MRI follow-up were analyzed. There was no statistical difference between the different dose-fractionations. On multivariate analysis, surgery (p = 0.049) and size (< 2.5 cm) (p = 0.01) were independent factors improving LC. The 12 months LC was 87.02% in the group Surgery plus HFSRT group vs 73.53% at 12 months in the group HFSRT. OS was 61.43% at 12 months in the group Surgery plus HFSRT group vs 50.13% at 12 months in the group HFSRT (p < 0.0085). Prior surgery (OR = 1.86; p = 0.0028) and sex (OR = 1.4; p = 0.0139) control of primary tumor (OR = 0.671, p = 0.0069) and KPS < 70 (OR = 0.769, p = 0.0094) were independently predictive of OS. The RN rate was 5% and all patients concerned were symptomatic. CONCLUSIONS: This study suggests that HFSRT is an efficient and well-tolerated treatment. The optimal dose-fractionation remains difficult to determine. Smaller size and surgery are correlated to LC. These results evidence the importance of surgery for larger BM (> 2.5 cm) with a poorer prognosis. Multidisciplinary committees and prospective studies are necessary to validate these observations.

Deformable image registration applied to lung SBRT: Usefulness and limitations.

Radiation therapy (RT) of the lung requires deformation analysis. Deformable image registration (DIR) is the fundamental method to quantify deformations for various applications: motion compensation, contour propagation, dose accumulation, etc. DIR is therefore unavoidable in lung RT. DIR algorithms have been studied for decades and are now available both within commercial and academic packages. However, they are complex and have limitations that every user must be aware of before clinical implementation. In this paper, the main applications of DIR for lung RT with their associated uncertainties and their limitations are reviewed.

Multidisciplinary Tumor Board Decision Making for Postoperative Radiotherapy in Thymic Epithelial Tumors: Insights from the RYTHMIC Prospective Cohort.

INTRODUCTION: Thymic epithelial tumors (TETs) are rare intrathoracic malignancies for which surgery represents the mainstay of the treatment. Current practice for postoperative radiotherapy (PORT) is highly variable, and there is a lack of prospective, high level evidence. Réseau Tumeurs Thymiques et Cancer (RYTHMIC) is the nationwide network for TETs in France. Established in 2012, it prospectively collects data on all TET patients, for whom management is discussed at a national multidisciplinary tumor board (MTB). We assessed whether PORT decisions at the MTB were in accordance with RYTHMIC guidelines and ultimately implemented in patients. METHODS: All consecutive patients for whom PORT was discussed at the MTB from 2012 to 2015 were identified from the RYTHMIC prospective database, and a complete review of their medical records was performed. RESULTS: A total of 274 patients, including 243 with thymoma (89%) and 31 with thymic carcinoma (11%), were analyzed. The decision of the MTB was in accordance with guidelines in 221 patients (92%) of the 241 with stage I or III TET. An MTB decision to deliver PORT was made for 117 patients (43%). PORT was ultimately initiated in 101 patients. The most frequent reason for not delivering PORT was excessive (>3 months) delay after surgery. Dose-volume constraints defined by the International Thymic Malignancy Interest Group were followed in all but four patients. CONCLUSION: Our data provide a unique insight into the decision-making process for PORT in TETs, highlighting the need for systematic discussion at an expert MTB, while stressing the value of current available guidelines.

Clinical characteristics and outcome of patients with lung cancer harboring BRAF mutations.

INTRODUCTION: BRAF (v-Raf murine sarcoma viral oncogene homolog B) mutations are identified in approximately 2% of non-small cell lung cancer (NSCLC). Because of the rarity of those mutations, associated clinical features and prognostic significance have not been thoroughly described so far. METHODS: Here we took advantage of the French National Cancer Institute Program of systematic molecular profiling of metastatic lung cancer, to collect clinical characteristics and analyze the outcome of consecutive patients with NSCLC harboring BRAF mutations at the Lyon University Hospital laboratory between February 2012 and October 2014. Especially, we compared those variables with that of patients with EGFR-, BRAF-, KRAS-, HER2-, PIK3CA- wild-type NSCLCs. RESULTS: Among 2690 patients with genotyped NSCLC during the study period, BRAF mutations were identified in 80 (3%) cases, consisting of V600E substitution in 42 (53%) cases; non-V600E mutation were observed in 38 (48%) cases. Concurrent mutations were not observed in case of BRAF V600 mutation, and were identified in 5 patients with BRAF non-V600E mutations, in all cases consisting of KRAS mutations. Non-V600E mutations were more likely to be observed in smokers, as compared V600E mutations. There was no significant difference in age, histologic type, performance status, and stage at diagnosis between cases of V600E and non-V600E mutations. Overall survival did not significantly differ in BRAF wild-type, V600E, and non-V600E patients. CONCLUSION: This one of the largest series of patients with BRAF mutant NSCLC. Our clinical data suggest that BRAF mutations define specific subsets of patients with NSCLC; while their oncogenic nature is yet to be established in lung cancer, especially for non-V600E mutations, the value of BRAF mutations to predict the efficacy of targeted agents remains unclear.

Influence of Nucleoshuttling of the ATM Protein in the Healthy Tissues Response to Radiation Therapy: Toward a Molecular Classification of Human Radiosensitivity.

PURPOSE: Whereas post-radiation therapy overreactions (OR) represent a clinical and societal issue, there is still no consensual radiobiological endpoint to predict clinical radiosensitivity. Since 2003, skin biopsy specimens have been collected from patients treated by radiation therapy against different tumor localizations and showing a wide range of OR. Here, we aimed to establish quantitative links between radiobiological factors and OR severity grades that would be relevant to radioresistant and genetic hyperradiosensitive cases. METHODS AND MATERIALS: Immunofluorescence experiments were performed on a collection of skin fibroblasts from 12 radioresistant, 5 hyperradiosensitive, and 100 OR patients irradiated at 2 Gy. The numbers of micronuclei, γH2AX, and pATM foci that reflect different steps of DNA double-strand breaks (DSB) recognition and repair were assessed from 10 minutes to 24 hours after irradiation and plotted against the severity grades established by the Common Terminology Criteria for Adverse Events and the Radiation Therapy Oncology Group. RESULTS: OR patients did not necessarily show a gross DSB repair defect but a systematic delay in the nucleoshuttling of the ATM protein required for complete DSB recognition. Among the radiobiological factors, the maximal number of pATM foci provided the best discrimination among OR patients and a significant correlation with each OR severity grade, independently of tumor localization and of the early or late nature of reactions. CONCLUSIONS: Our results are consistent with a general classification of human radiosensitivity based on 3 groups: radioresistance (group I); moderate radiosensitivity caused by delay of nucleoshuttling of ATM, which includes OR patients (group II); and hyperradiosensitivity caused by a gross DSB repair defect, which includes fatal cases (group III).

L-DNase II associated with active process during ethanol induced cell death in ARPE-19.

PURPOSE: To analyse the mechanism of ethanol-induced cell death, and particularly, the activation of the leucocyte elastase inhibitor (LEI) pathway. METHODS: Cultured ARPE-19 cells were exposed to 0-13% ethanol for 24 h. Cytotoxicity was estimated by morphologic changes within the nucleus and breakdown of DNA, assessed by agarose gel electrophoresis or flow cytometry cell sorter. Poly(ADP-ribose)polymerase cleavage (PARP) was determined by western blot analysis. Changes in transcription and translation of LEI were assessed by analysis of mRNA levels and expression of protein product (immunohistochemistry), respectively. RESULTS: We established the ability of ethanol to induce cell death in ARPE-19 cells. After a 24 h incubation with 4% ethanol, 50% of the cells died; all the cells died in the presence of 10% ethanol. After ethanol incubation, we observed nuclear condensation and DNA fragmentation; the amount of fragmentation was proportional to the ethanol level. By flow cytometry analysis and agarose gel electrophoresis, the pattern of DNA cleavage exhibited a sub-G1 peak, suggesting necrotic cell death. However, other observations, i.e. nuclei shrinkage, PARP cleavage and inhibition of cell death by cycloheximide, and activation of a caspase independent LEI/DNase II pathway were observed and are features associated with apoptotic cell death. During ethanol stress, an LEI/L-DNase II intermediate was lost, leading to complete activation L-DNase II (24 kDa). RT-PCR analysis showed an early and specific increase of the LEI mRNA. Cycloheximide inhibited LEI synthesis and protected cells against apoptosis. CONCLUSIONS: Our data indicate that ethanol stress on ARPE-19 cells can induce a pathway which is a form of programmed cell death with characteristics of both apoptosis and necrosis, possibly by triggering conversion of LEI to L-DNase II.

Dosimetric implications of an injection of hyaluronic acid for preserving the rectal wall in prostate stereotactic body radiation therapy.

PURPOSE: This study assessed the contribution of ahyaluronic acid (HA) injection between the rectum and the prostate to reducing the dose to the rectal wall in stereotactic body radiation therapy (SBRT). METHODS AND MATERIALS: As part of a phase 2 study of hypofractionated radiation therapy (62 Gy in 20 fractions), the patients received a transperineal injection of 10 cc HA between the rectum and the prostate. A dosimetric computed tomographic (CT) scan was systematically performed before (CT1) and after (CT2) the injection. Two 9-beam intensity modulated radiation therapy-SBRT plans were optimized for the first 10 patients on both CTs according to 2 dosage levels: 5 × 6.5 Gy (PlanA) and 5 × 8.5 Gy (PlanB). Rectal wall parameters were compared with a dose-volume histogram, and the prostate-rectum separation was measured at 7 levels of the prostate on the center line of the organ. RESULTS: For both plans, the average volume of the rectal wall receiving the 90% isodose line (V90%) was reduced up to 90% after injection. There was no significant difference (P=.32) between doses received by the rectal wall on CT1 and CT2 at the base of the prostate. This variation became significant from the median plane to the apex of the prostate (P=.002). No significant differences were found between PlanA without HA and PlanB with HA for each level of the prostate (P=.77, at the isocenter of the prostate). CONCLUSIONS: HA injection significantly reduced the dose to the rectal wall and allowed a dose escalation from 6.5 Gy to 8.5 Gy without increasing the dose to the rectum. A phase 2 study is under way in our department to assess the rate of acute and late rectal toxicities when SBRT (5 × 8.5 Gy) is combined with an injection of HA.

ExacTrac Snap Verification: a new tool for ensuring quality control for lung stereotactic body radiation therapy.

PURPOSE: The intrafraction verification provided by ExacTrac X-ray 6D Snap Verification (ET-SV) allows the tracking of potential isocenter displacements throughout patient position and treatment. The aims of this study were (1) to measure the intrafraction variations of the isocenter position (random errors); (2) to study the amplitude of the variation related to the fraction duration; and (3) to assess the impact of the table movement on positioning uncertainties. METHODS AND MATERIALS: ET-SV uses images acquired before or during treatment delivery or both to detect isocenter displacement. Twenty patients treated with stereotactic body radiation therapy (SBRT) for lung tumors underwent SV before or during each beam. Noncoplanar beams were sometimes necessary. The time between the setup of the patient and each SV was noted, and values of deviations were compiled for 3 SV time groups: SV performed at ≤10 min (group 1), between 11 and 20 min (group 2), and ≥21 min (group 3). Random errors in positioning during the use of noncoplanar fields were noted. RESULTS: The mean isocenter deviation±SD was 2±0.5 mm (range, 1-8 mm). The average deviations±SD increased significantly from 1.6±0.5 mm to 2.1±0.8 mm and 2.2±0.6 mm for groups 1, 2, and 3 (P=.002), respectively. Percentages of deviation≥3 mm were 7.06%, 22.83%, and 28.07% and 1.08%, 4.15%, and 8.4% for ≥5 mm (P<.0001). For 11 patients, table rotation was necessary. The mean isocenter deviation±SD increased significantly from 1.9±0.5 mm before table rotation to 2.7±0.5 mm (P=.001) for the first beam treated after rotation. CONCLUSIONS: SV detects isocenter deviations, which increase in amplitude and frequency with the fraction duration, and enables intrafraction verification for SBRT (taking into account clinical condition and technical issues). SV gives accurate targeting at any time during irradiation and may raise confidence to escalate the dose. SV appears to be an important tool for ensuring the quality control of SBRT.