Toward personalized synchrotron microbeam radiation therapy.

Synchrotron facilities produce ultra-high dose rate X-rays that can be used for selective cancer treatment when combined with micron-sized beams. Synchrotron microbeam radiation therapy (MRT) has been shown to inhibit cancer growth in small animals, whilst preserving healthy tissue function. However, the underlying mechanisms that produce successful MRT outcomes are not well understood, either in vitro or in vivo. This study provides new insights into the relationships between dosimetry, radiation transport simulations, in vitro cell response, and pre-clinical brain cancer survival using intracerebral gliosarcoma (9LGS) bearing rats. As part of this ground-breaking research, a new image-guided MRT technique was implemented for accurate tumor targeting combined with a pioneering assessment of tumor dose-coverage; an essential parameter for clinical radiotherapy. Based on the results of our study, we can now (for the first time) present clear and reproducible relationships between the in vitro cell response, tumor dose-volume coverage and survival post MRT irradiation of an aggressive and radioresistant brain cancer in a rodent model. Our innovative and interdisciplinary approach is illustrated by the results of the first long-term MRT pre-clinical trial in Australia. Implementing personalized synchrotron MRT for brain cancer treatment will advance this international research effort towards clinical trials.

Neuroinflammation After Stereotactic Radiosurgery-Induced Brain Tumor Disintegration Is Linked to Persistent Cognitive Decline in a Mouse Model of Metastatic Disease.

PURPOSE: Improved efficacy of anticancer therapy and a growing pool of survivors give rise to a question about their quality of life and return to premorbid status. Radiation is effective in brain metastasis eradication, although the optimal approach and long-term effects on brain function are largely unknown. We studied the effects of radiosurgery on brain function. METHODS AND MATERIALS: Adult C57BL/6J mice with or without brain metastases (rat 9L gliosarcoma) were treated with cone beam single-arc stereotactic radiosurgery (SRS; 40 Gy). Tumor growth was monitored using bioluminescence, whereas longitudinal magnetic resonance imaging, behavioral studies, and histologic analysis were performed to evaluate brain response to the treatment for up to 18 months. RESULTS: Stereotactic radiosurgery (SRS) resulted in 9L metastases eradication within 4 weeks with subsequent long-term survival of all treated animals, whereas all nontreated animals succumbed to the brain tumor. Behavioral impairment, as measured with a recognition memory test, was observed earlier in mice subjected to radiosurgery of tumors (6 weeks) in comparison to SRS of healthy brain tissue (10 weeks). Notably, the deficit resolved by 18 weeks only in mice not bearing a tumor, whereas tumor eradication was complicated by the persistent cognitive deficits. In addition, the results of magnetic resonance imaging were unremarkable in both groups, and histopathology revealed changes. SRS-induced tumor eradication triggered long-lasting and exacerbated neuroinflammatory response. No demyelination, neuronal loss, or hemorrhage was detected in any of the groups. CONCLUSIONS: Tumor disintegration by SRS leads to exacerbated neuroinflammation and persistent cognitive deficits; therefore, methods aiming at reducing inflammation after tumor eradication or other therapeutic methods should be sought.

A simple approximation for the evaluation of the photon iso-effective dose in Boron Neutron Capture Therapy based on dose-independent weighting factors.

The current methodology for determining the biological effect of Boron Neutron Capture Therapy (BNCT) has recently been questioned, and a more accurate framework based in the photon iso-effective dose has been proposed. In this work we derive a first order approximation to this quantity. The new approach removes the main drawbacks of the current method, being based on new weighting factors which are true constants (dose independent) but which can be evaluated from published data on the existing (dose-dependent) weighting factors. In addition to this, we apply the formalism to allow the comparison to a fractionated conventional radiotherapy treatment, for which there is a lot of knowledge from clinical practice. As an application, the photon iso-effective dose of a BNCT treatment for a brain tumor is estimated. An excel sheet used for these calculations is also provided as supplementary material and can be used also with user-provided input data for the estimation of the photon iso-effective dose for comparison with conventional radiotherapy, both to single and fractionated treatments.

Optimizing dose enhancement with Ta2O5 nanoparticles for synchrotron microbeam activated radiation therapy.

Microbeam Radiation Therapy (MRT) exploits tumour selectivity and normal tissue sparing with spatially fractionated kilovoltage X-ray microbeams through the dose volume effect. Experimental measurements with Ta2O5 nanoparticles (NPs) in 9L gliosarcoma treated with MRT at the Australian Synchrotron, increased the treatment efficiency. Ta2O5 NPs were observed to form shells around cell nuclei which may be the reason for their efficiency in MRT. In this article, our experimental observation of NP shell formation is the basis of a Geant4 radiation transport study to characterise dose enhancement by Ta2O5 NPs in MRT. Our study showed that NP shells enhance the physical dose depending microbeam energy and their location relative to a single microbeam. For monochromatic microbeam energies below ∼70keV, NP shells show highly localised dose enhancement due to the short range of associated secondary electrons. Low microbeam energies indicate better targeted treatment by allowing higher microbeam doses to be administered to tumours and better exploit the spatial fractionation related selectivity observed with MRT. For microbeam energies above ∼100keV, NP shells extend the physical dose enhancement due to longer-range secondary electrons. Again, with NPs selectively internalised, the local effectiveness of MRT is expected to increase in the tumour. Dose enhancement produced by the shell aggregate varied more significantly in the cell population, depending on its location, when compared to a homogeneous NP distribution. These combined simulation and experimental data provide first evidence for optimising MRT through the incorporation of newly observed Ta2O5 NP distributions within 9L cancer cells.

The High Radiosensitizing Efficiency of a Trace of Gadolinium-Based Nanoparticles in Tumors.

We recently developed the synthesis of ultrasmall gadolinium-based nanoparticles (GBN), (hydrodynamic diameter <5 nm) characterized by a safe behavior after intravenous injection (renal clearance, preferential accumulation in tumors). Owing to the presence of gadolinium ions, GBN can be used as contrast agents for magnetic resonance imaging (MRI) and as radiosensitizers. The attempt to determine the most opportune delay between the intravenous injection of GBN and the irradiation showed that a very low content of radiosensitizing nanoparticles in the tumor area is sufficient (0.1 µg/g of particles, i.e. 15 ppb of gadolinium) for an important increase of the therapeutic effect of irradiation. Such a promising and unexpected result is assigned to a suited distribution of GBN within the tumor, as revealed by the X-ray fluorescence (XRF) maps.

Long-term survival in gliosarcoma with radiation-induced meningeal sarcomas: Case report and molecular features.

Gliosarcoma is a rare primary malignant tumor of the central nervous system with poor prognosis. The median survival time of this disease ranges from 6 months to 14.8 months. However, a computer literature search indicated few long-term survivors. We investigated a case of a survivor of gliosarcoma with radiation-induced meningeal sarcomas, who showed no indication of recurrence for more than 9 years. A battery of molecular studies was performed to develop a molecular profile of this unique patient. We also reviewed the distinct clinical and molecular features of the tumor.

Pediatric gliosarcoma treated with adjuvant radiotherapy and temozolomide.

PURPOSE: Primary pediatric gliosarcoma (pPGS) is an extremely rare entity with only 25 cases reported in the English literature. The value of concurrent and adjuvant temozolomide is not known in this group of patient. METHODS: Five patients of pPGS treated from 2006 to 2011 were included in this retrospective analysis. All patients underwent maximal safe surgical resection. Adjuvant therapy included conformal radiation 60 Gy in 30 fractions (2 Gy daily for 5 days in a week) with concurrent temozolomide 75 mg/m(2) daily followed by six cycles of maintenance temozolomide 150-200 mg/m(2) (day 1 to day 5) every 4 weeks. We combined the survival data of 25 patients (already published) and five of our patients and analyzed them in terms of progression free survival (PFS) and overall survival (OS) using Kaplan-Meier method. RESULTS: Male to female ratio was 1:4 and median age was 12 years (range, 7-19 years). All but one patient underwent gross total resection and four patients completed adjuvant radiotherapy as well as concurrent and adjuvant temozolomide. At a median follow up of 22.6 months (range, 0 to 45.3 months), two patients were dead and two were alive without disease while one was lost to follow up. For the pooled data, estimated median PFS and OS of all 30 patients reported in literature were 12 and 43 months, respectively. Two years PFS and OS rate for all patients was 44.2 and 62.9%, respectively. CONCLUSION: Adjuvant radiotherapy and temozolomide is well tolerated and show an encouraging survival in pPGS.

Synchrotron microbeam radiation therapy induces hypoxia in intracerebral gliosarcoma but not in the normal brain.

PURPOSE: Synchrotron microbeam radiation therapy (MRT) is an innovative irradiation modality based on spatial fractionation of a high-dose X-ray beam into lattices of microbeams. The increase in lifespan of brain tumor-bearing rats is associated with vascular damage but the physiological consequences of MRT on blood vessels have not been described. In this manuscript, we evaluate the oxygenation changes induced by MRT in an intracerebral 9L gliosarcoma model. METHODS: Tissue responses to MRT (two orthogonal arrays (2 × 400Gy)) were studied using magnetic resonance-based measurements of local blood oxygen saturation (MR_SO2) and quantitative immunohistology of RECA-1, Type-IV collagen and GLUT-1, marker of hypoxia. RESULTS: In tumors, MR_SO2 decreased by a factor of 2 in tumor between day 8 and day 45 after MRT. This correlated with tumor vascular remodeling, i.e. decrease in vessel density, increases in half-vessel distances (×5) and GLUT-1 immunoreactivity. Conversely, MRT did not change normal brain MR_SO2, although vessel inter-distances increased slightly. CONCLUSION: We provide new evidence for the differential effect of MRT on tumor vasculature, an effect that leads to tumor hypoxia. As hypothesized formerly, the vasculature of the normal brain exposed to MRT remains sufficiently perfused to prevent any hypoxia.

Gliosarcoma con diferenciación epitelial. Reporte de un caso y revisión de la literatura / gliosarcoma with epithelial differentiation. Case report and literature review

El gliosarcoma es una neoplasia del sistema nervioso central de la cual se desconocen la mayoría de sus aspectos debido a su rara presentación. Presentamos el caso de un paciente de 19 años con diagnóstico de meduloblastoma que fue referido al INEN para recibir tratamiento de quimioterapia recurrente con radioterapia. La resonancia magnética realizada en dicha institución mostró una lesión sólida multilobulada heterogénea ubicada a nivel del cuarto ventrículo, con un di metro longitudinal de 4x 4,5 x 5cm, de aspecto maligno, neoformativo y con dos formaciones quísticas menores de 2 cm. A la espectroscopia por resonancia magnética (ERM), la relación de NAA/CR, fue 1,04. La revisión de l minas y análisis inmunohistoquímico dio como resultado GFAP (+), CD99 (+/-), S100 (+/-), CD56 (+/-), sinaptofisina(-), Bcl2 (-), NF(-), EMA(-), CD34(-), SMA(-), desmina(-) y Ki67: 20%. Además, se encontraron depósitos intercelulares de reticulina lo cual indicó la presencia de GSM. Recibió tratamiento con radioterapia seguido de temozolamida por 7 cursos, alcanzando una reducción del tratamiento tumoral en un 20%. A la fecha del reporte, se encuentra con enfermedad estable, en observación. AU)

The GSM is a malignancy of the CNS, most of its rare presentation. We present the case of a 19 year old women who had undergone cranial trepanation diagnosed as medulloblastoma. The patient was referred to INEN for receiving treatment with no results. The magnetic resonance images showed a solid heterogeneous multilobulated lesion localized in the 4th ventricle, multilobulated lesion localized in the 4th ventricle, with a longitudinal diameter of 4,5 x 4 x 5cm, with a malignant aspect, neoformative and with two cysts under 2 cm. To the spectroscopy (ERM), the relation NAA/CR was 1,04 revision of biopsy slides the inmunohistochemisty results were GFAP (+) , CD99 (+/-) , S100 (+ /-) , CD56 (+/-), sinaptopfisin (-), bcl2 (-), NF (-), EMA(-), CD34(-), EMA(-), CD34 (-), SMA(-), desmin(-) and Ki67: 20%. Besides, there were fou d intracellular reticulin deposits, this demonstrated the presence of GSM. The patient received treatment with radiotherapy followed by 7 courses of temozolomide, reaching a tumor size reduction of 20%. To the report’s date the patient has a stable disease condition continues with observation.

Gliossarcoma: um desafio clínico e terapêutico / Gliosarcoma: a clinical and therapeuctic challenge

O Gliossarcoma (GSa) é uma neoplasia primária rara do sistema nervoso central, caracterizada por padrão histológico bifásico que inclui os componentes glial e sarcomatoso. Os autores relatam o caso de um paciente masculino, de 49 anos de idade, que apresentou cefaleia como manifestação clínica predominante. O diagnostico foi suspeitado devido à arquitetura microscópica e confirmado pelo estudo imuno-histoquímico. Na terapêutica, foi submetido à craniotomia com microcirurgia para ressecção do tumor e tratamento radioterápico complementar. Dados epidemiológicos, histogênese e achados frequentes em exames de imagem são discutidos, assim como o tratamento e prognóstico.

The gliosarcoma (GSA) is a rare primary neoplasm of the central nervous system characterized by a biphasic histological pattern that includes the glial and sarcomatous components. Here the authors report the case of a 49-year-old male patient who presented headache as predominant clinical manifestation. The diagnosis was suspected on account of microscopic architecture and confirmed by immunohistochemical study. The patient underwent craniotomy with microsurgery for tumor resection and additional radiotherapy. Epidemiological data, histogenesis and common findings on imaging are discussed, as well as treatment and prognosis.

Increase of lifespan for glioma-bearing rats by using minibeam radiation therapy.

This feasibility work assesses the therapeutic effectiveness of minibeam radiation therapy, a new synchrotron radiotherapy technique. In this new approach the irradiation is performed on 9L gliosarcoma-bearing rats with arrays of parallel beams of width 500-700 µm. Two irradiation configurations were compared: a lateral unidirectional irradiation and two orthogonal arrays interlacing at the target. A dose escalation study was performed. A factor of three gain in the mean survival time obtained for some animals paves the way for further exploration of the different possibilities of this technique and its further optimization.

Temozolomide in the treatment of high-grade gliomas in children: a report from the Children's Oncology Group.

To determine whether temozolomide is an active agent in the treatment of children with high-grade astrocytomas and whether survival is influenced by the expression of the O6-methylguanine-methyltransferase gene (MGMT) in these patients. In the Children's Oncology Group study ACNS0126, 107 patients with a diagnosis of anaplastic astrocytoma (AA), glioblastoma multiforme (GBM), or gliosarcoma were enrolled. All patients underwent concomitant chemoradiotherapy with temozolomide, followed by adjuvant chemotherapy with temozolomide. The outcomes were compared with those of children treated in Children's Cancer Group (CCG) study CCG-945. Formalin-fixed, paraffin-embedded tumor tissue was available in 71 cases for immunohistochemical analysis of MGMT expression. Ninety patients were deemed eligible, 31 with AA, 55 with GBM, and 4 with other eligible diagnoses. The 3-year event-free survival (EFS) and overall survival (OS) rates were 11 ± 3% and 22 ± 5%, respectively. There was no evidence that temozolomide given during radiation therapy and as adjuvant therapy resulted in improved EFS compared with that found in CCG-945 (p = 0.98). The 3-year EFS rate for AA was 13 ± 6% in ACNS0126 compared with 22 ± 5.5% in CCG-945 (p = 0.95). The 3-year EFS rate for GBM was 7 ± 4% in ACNS0126 compared with 15 ± 5% in CCG-945 (p = 0.77). The 2-year EFS rate was 17 ± 5% among patients without MGMT overexpression and 5 ± 4% among those with MGMT overexpression (p = 0.045). Temozolomide failed to improve outcome in children with high-grade astrocytomas. MGMT overexpression was adversely associated with survival.

Preparation and in vitro evaluation of 131I-BmK CT as a glioma-targeted agent.

OBJECTIVE: Buthus martensi Karsch (BmK) CT, a kind of scorpion toxin peptide, was found to inhibit glioma cell proliferation in previous researches. (131)I-BmK CT may have more inhibition effect and could be used as a glioma cell-targeted therapy and imaging agent. The purpose of this study was to investigate whether (131)I-BmK CT could specifically conjugate with C6 glioma cell and induce glioma cell inhibition in vitro. METHODS: After cloning, expression, and purification, BmK CT was labeled with (131)I by indirect labeling (Bolton-Hunter method). The cell conjugation experiment was performed to investigate the connection between the reciprocal of cell conjugation rate and the reciprocal of cell count. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) method and flow cytometry were used to detect the inhibition effect of BmK CT and (131)I-BmK CT on glioma cell proliferation. RESULTS: (131)I-BmK CT was successfully prepared with the overall yield of 34.5%. The cell conjugation experiment indicated that (131)I-BmK CT could specifically conjugate with C6 cells. MTT tests indicated that both BmK CT and (131)I-BmK CT could inhibit C6 growth. The ability of (131)I-BmK CT to inhibit cell growth is superior to that of BmK CT. The inhibitory rate (IR) of glioma cells was 60.5% (p < 0.01) at the concentration of 2 microg/mL with BmK CT. And the IR was 71.2% (p < 0.01) at the radioactivity concentration of 50 microCi/mL (concentration was much lower than 2 microg/mL) with (131)I-BmK CT. BmK CT could block the C6 glioma cell cycle in the G0/G1 stage. (131)I-BmK CT blocked the cell cycle in the S stage (the proportions of C6 in the S, G0/G1, and G2/M phases were 24.5% +/- 0.4% vs. 44.0% +/- 2.3%, 63.9% +/- 0.6% vs. 51.8% +/- 1.6%, and 11.6% +/- 1.0% vs. 4.3 +/- 0.7% [p < 0.05], respectively, at an initial radioactivity concentration of 50 microCi/mL). CONCLUSIONS: On the basis of cytology experiments, it was found that (131)I-BmK CT could specifically conjugate with C6 glioma cell and inhibit cell growth. Hence, it may be used as a glioma-targeted agent.

Gliosarcoma: a rare variant of glioblastoma multiforme.

Gliosarcoma is a rare variant of Glioblastoma Multiforme (GBM). It is a very aggressive tumour and usually managed like GBM. Treatment of choice is surgery with good surgical margins followed by radiotherapy (60 Gy). Median survival is seven months. Here we present a case report of 55 years old male who was diagnosed as brain tumour in left temporoparietal region. It turned out to be gliosarcoma after surgical resection and histopathological evaluation.

The radiation response of cells from 9L gliosarcoma tumours is correlated with [F18]-EF5 uptake.

PURPOSE: Tumour hypoxia affects cancer biology and therapy-resistance in both animals and humans. The purpose of this study was to determine whether EF5 ([2-(2-nitro-1-H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)-acetamide]) binding and/or radioactive drug uptake correlated with single-dose radiation response in 9L gliosarcoma tumours. MATERIALS AND METHODS: Twenty-two 9L tumours were grown in male Fischer rats. Rats were administered low specific activity (18)F-EF5 and their tumours irradiated and assessed for cell survival and hypoxia. Hypoxia assays included EF5 binding measured by antibodies against bound-drug adducts and gamma counts of (18)F-EF5 tumour uptake compared with uptake by normal muscle and blood. These assays were compared with cellular radiation response (in vivo to in vitro assay). In six cases, uptake of tumour versus muscle was also assayed using images from a PET (positron emission tomography) camera (PENN G-PET). RESULTS: The intertumoural variation in radiation response of 9L tumour-cells was significantly correlated with uptake of (18)F-labelled EF5 (i.e., including both bound and non-bound drug) using either tumour to muscle or tumour to blood gamma count ratios. In the tumours where imaging was performed, there was a significant correlation between the image analysis and gamma count analysis. Intertumoural variation in cellular radiation response of the same 22 tumours was also correlated with mean flow cytometry signal due to EF5 binding. CONCLUSION: To our knowledge, this is the first animal model/drug combination demonstrating a correlation of radioresponse for tumour-cells from individual tumours with drug metabolism using either immunohistochemical or non-invasive techniques.

Synchrotron microbeam radiation therapy for rat brain tumor palliation-influence of the microbeam width at constant valley dose.

To analyze the effects of the microbeam width (25, 50 and 75 microm) on the survival of 9L gliosarcoma tumor-bearing rats and on toxicity in normal tissues in normal rats after microbeam radiation therapy (MRT), 9L gliosarcomas implanted in rat brains, as well as in normal rat brains, were irradiated in the MRT mode. Three configurations (MRT25, MRT50, MRT75), each using two orthogonally intersecting arrays of either 25, 50 or 75 microm wide microbeams, all spaced 211 microm on center, were tested. For each configuration, peak entrance doses of 860, 480 and 320 Gy, respectively, were calculated to produce an identical valley dose of 18 Gy per individual array at the center of the tumor. Two, 7 and 14 days after radiation treatment, 42 rats were killed to evaluate histopathologically the extent of tumor necrosis, and the presence of proliferating tumors cells and tumor vessels. The median survival times of the normal rats were 4.5, 68 and 48 days for MRT25, 50 and 75, respectively. The combination of the highest entrance doses (860 Gy per array) with 25 microm wide beams (MRT25) resulted in a cumulative valley dose of 36 Gy and was excessively toxic, as it led to early death of all normal rats and of approximately 50% of tumor-bearing rats. The short survival times, particularly of rats in the MRT25 group, restricted adequate observance of the therapeutic effect of the method on tumor-bearing rats. However, microbeams of 50 microm width led to the best median survival time after 9L gliosarcoma MRT treatment and appeared as the better compromise between tumor control and normal brain toxicity compared with 75 microm or 25 microm widths when used with a 211 microm on-center distance. Despite very high radiation doses, the tumors were not sterilized; viable proliferating tumor cells remained present at the tumor margin. This study shows that microbeam width and peak entrance doses strongly influence tumor responses and normal brain toxicity, even if valley doses are kept constant in all groups. The use of 50 microm wide microbeams combined with moderate peak doses resulted in a higher therapeutic ratio.

First trial of spatial and temporal fractionations of the delivered dose using synchrotron microbeam radiation therapy.

The technical feasibility of temporal and spatial fractionations of the radiation dose has been evaluated using synchrotron microbeam radiation therapy for brain tumors in rats. A significant increase in lifespan (216%, p < 0.0001) resulted when three fractions of microbeam irradiation were applied to the tumor through three different ports, orthogonal to each other, at 24 h intervals. However, there were no long-term survivors, and immunohistological studies revealed that 9 L tumors were not entirely ablated.

Adult gliosarcoma: epidemiology, natural history, and factors associated with outcome.

The epidemiology and natural history of adult gliosarcomas (GSMs), as well as patient and treatment factors associated with outcome, are ill defined. Patients over 20 years of age with GSM diagnosed from 1988 to 2004 were identified in the Surveillance, Epidemiology, and End Results (SEER) database. Kaplan-Meier survival analysis and Cox models were used to examine outcomes. Similar analyses were conducted for patients diagnosed with glioblastoma (GBM) over the same time period. GSM represented 2.2% of the 16,388 patients identified with either GSM or GBM. No significant differences between GSM and GBM were identified with respect to age, gender, race, tumor size, or use of adjuvant radiation therapy (RT). Patients with GSM were more likely to have temporal lobe involvement and undergo some form of tumor resection. The most important analyzed factors influencing GSM overall survival were age, extent of resection, and use of adjuvant RT. After adjusting for factors impacting overall survival, the prognosis for GSM appears slightly worse than for GBM (HR = 1.17, 95% CI, 1.05-1.31). GSM is a rare malignancy that presents very similarly to GBM with a slightly greater propensity for temporal lobe involvement. Optimal treatment remains to be defined. However, these retrospective findings suggest tumor excision, as opposed to biopsy only, and adjuvant RT may improve outcome. Despite therapy, prognosis remains dismal and outcomes may be inferior to those seen in GBM patients.

Phase II study of erlotinib plus temozolomide during and after radiation therapy in patients with newly diagnosed glioblastoma multiforme or gliosarcoma.

PURPOSE: This open-label, prospective, single-arm, phase II study combined erlotinib with radiation therapy (XRT) and temozolomide to treat glioblastoma multiforme (GBM) and gliosarcoma. The objectives were to determine efficacy of this treatment as measured by survival and to explore the relationship between molecular markers and treatment response. PATIENTS AND METHODS: Sixty-five eligible adults with newly diagnosed GBM or gliosarcoma were enrolled. We intended to treat patients not currently treated with enzyme-inducing antiepileptic drugs (EIAEDs) with 100 mg/d of erlotinib during XRT and 150 mg/d after XRT. Patients receiving EIAEDs were to receive 200 mg/d of erlotinib during XRT and 300 mg/d after XRT. After XRT, the erlotinib dose was escalated until patients developed tolerable grade 2 rash or until the maximum allowed dose was reached. All patients received temozolomide during and after XRT. Molecular markers of epidermal growth factor receptor (EGFR), EGFRvIII, phosphatase and tensin homolog (PTEN), and methylation status of the promotor region of the MGMT gene were analyzed from tumor tissue. Survival was compared with outcomes from two historical phase II trials. RESULTS: Median survival was 19.3 months in the current study and 14.1 months in the combined historical control studies, with a hazard ratio for survival (treated/control) of 0.64 (95% CI, 0.45 to 0.91). Treatment was well tolerated. There was a strong positive correlation between MGMT promotor methylation and survival, as well as an association between MGMT promotor-methylated tumors and PTEN positivity shown by immunohistochemistry with improved survival. CONCLUSION: Patients treated with the combination of erlotinib and temozolomide during and following radiotherapy had better survival than historical controls. Additional studies are warranted.

Gliosarcoma: an audit from a single institution in India of 24 post-irradiated cases over 15 years.

BACKGROUND: Gliosarcomas (GS) are biphasic brain tumors composed of glioblastoma multiforme (GBM) and sarcomatous component. Therapeutic approaches include maximum surgical decompression with postoperative radiotherapy. Outcomes in gliosarcoma are poor despite multimodality management. AIMS: To analyze the outcome in patients of GS treated in our institute over a period of 15 years and compare it with GBM treated during the same period. SETTINGS AND DESIGN: Clinical records of the post-irradiated GS patients and GBM patients seen between 1990 and 2004 were retrieved. MATERIALS AND METHODS: Demographic and treatment variables were evaluated for their influence on overall survival (OS). The survival outcomes of GBM and GS treated during the same period were also compared. STATISTICAL ANALYSIS: Univariate analysis was carried out using the Kaplan-Meier method and tested using log-rank test for significance. RESULTS: During these 15 years, 24 evaluable GS patients were treated as compared to 251 evaluable patients of GBM. There was a slight male preponderance in GS (14 males vs.10 females) with a median age of 50 years. All patients underwent surgery followed by post-operative radiotherapy (median dose of 60 Gy). None of the patient or treatment related factors were found to be significantly influencing their OS. Median OS in GS was 7.3 months compared to 7.5 months in GBM patients (P = 0.790). CONCLUSIONS: The OS appears to be similar for GS and GBM. None of the demographic variables appeared to prognosticate the survivals of GS.