Comparative epidemiology of gliosarcoma and glioblastoma and the impact of Race on overall survival: A systematic literature review.

OBJECTIVE: Gliosarcoma (GSM) is a rare subtype of glioblastoma (GBM) that accounts for approximately four percent of high-grade gliomas. There is scarce epidemiological data on patients with GSM as a distinct subgroup of GBM. METHODS: A systematic literature review was performed of peer-reviewed databases using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to evaluate the impact of race and ethnicity on survival in patients with GSM compared to patients with GBM. RESULTS: Following initial abstract screening, a total of 138 articles pertaining to GSM and 275 pertaining to GBM met criteria for full-text review, with 5 and 27 articles included in the final analysis for GSM and GBM, respectively. The majority of patients in both cohorts were non-Hispanic Whites, representing 85.6 % of total GSM patients and 87.7 % of GBM patients analyzed. Two GSM studies stratified survival by race, with one reporting the longest median survival for the Hispanic population of 10.6 months and the shortest median survival for the Asian population of 9 months. Among the GBM studies analyzed, the majority of studies reported shorter survival and higher risk of mortality among White Non-Hispanics compared to non-White patients; and of the 15 studies which reported data for the Asian population, 12 studies reported this race category to have the longest survival compared to all other races studied. Younger age, female sex, MGMT promoter methylation status, and adjuvant chemoradiation therapy were associated with improved survival in both GSM and GBM cohorts, although these were not further stratified by race. CONCLUSION: GSM portends a similarly poor prognosis to other GBM subtypes; however, few studies exist which have examined factors associated with differences in survival between these histologic variants. This review of the literature suggests there is a possible association between race and survival for patients with GBM, however data supporting this conclusion for patients with GSM is lacking. These findings suggest that GSM is a distinct disease from other GBM subtypes, with epidemiologic differences that should be further explored.

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.

NRG/RTOG 1122: A phase 2, double-blinded, placebo-controlled study of bevacizumab with and without trebananib in patients with recurrent glioblastoma or gliosarcoma.

BACKGROUND: Targeting vascular endothelial growth factor (VEGF) alone does not improve overall survival (OS) in recurrent glioblastoma (rGBM). The angiopoiein (Ang)-TIE2 system may play a role in tumor survival under VEGF inhibition. We conducted a phase 2, double-blinded, placebo-controlled trial of bevacizumab plus trebananib (a novel Fc fusion protein that sequesters Ang1/Ang2) over bevacizumab alone in rGBM. METHODS: Patients ≥18 years of age with a Karnofsky performance status ≥70 and GBM or variants in first or second relapse were randomized to bevacizumab 10 mg/kg every 2 weeks plus trebananib 15 mg/kg every week or bevacizumab plus placebo. The primary endpoint was 6-month progression-free survival (PFS). RESULTS: After an initial 6-patient lead-in cohort confirmed the safety of combining bevacizumab and trebananib, 115 eligible patients were randomized to the control (n = 58) or experimental treatment (n = 57). In the control arm, 6-month PFS was 41.1%, median survival time was 11.5 months (95% CI, 8.4-14.2 months), median PFS was 4.8 months (95% CI, 3.8-7.1 months), and radiographic response (RR) was 5.9%. In the experimental arm, 6-month PFS was 22.6%, median survival time was 7.5 months (95% CI, 6.8-10.1 months), median PFS was 4.2 months (95% CI, 3.7-5.6 months), and RR was 4.2%. The rate of severe toxicities was not significantly different between arms. CONCLUSION: The combination of bevacizumab and trebananib was well tolerated but did not significantly improve 6-month PFS rate, PFS, or OS for patients with rGBM over bevacizumab alone. The shorter PFS in the experimental arm with a hazard ratio of 1.51 (P = .04) suggests that the addition of trebananib to bevacizumab is detrimental.

Prognostic factors among single primary gliosarcoma cases: A study using Surveillance, Epidemiology, and End Results data from 1973-2013.

BACKGROUND: Prognostic factors for single primary gliosarcoma (PGS) remain unknown. OBJECTIVE: The purpose of our study was to examine patient, tumor, and treatment characteristics as potential predictors of survival using Surveillance, Epidemiology, and End Results (SEER) program data (1973-2013). METHODS: The patients of single PGS were selected based on the exclusion criteria from SEER. Kaplan-Meier survival analysis, log-rank test and Cox proportional hazards models were used to analyze all the data. RESULTS: Single PGS has an apparent popularity for the temporal lobe (35.2%, hazard ratio [HR] = 0.440, 95%CI = 0.251-0.770) and frontal lobe (20.9%, HR = 0.408, 95%CI = 0.231-0.720) which could achieve a better survival rate than cerebrum (P = .034). The mean age at diagnosis was 60.07 ± 14.161. The overall 6-month, 1-year, 2-year, and 5-year survival was 55.40%, 29.58%, 10.01%, and 2.73%. Age at diagnosis was proved to be a significant predictor of overall survival (OS) (P < .001). There is no significant difference in race, marital status, or grade. Patients' tumor size which is located in 41-60 mm (P = .047, HR = 1.468, 95%CI = 1.004-2.147) and >60 mm (P= .003, HR = 1.899, 95%CI = 1.244-2.901) showed a higher risk of death. Surgery played a critical role in OS (P < .001). Radiation after surgery was another predictor of OS of PGS (P < .001). Among all the radiation methods, combination of beam with implants or isotopes (P = .000, HR = 0.491, 95%CI = 0.412-0.585) or radiation NOS (P = .027, HR = 0.362, 95%CI = 0.148-0.889) were more beneficial to patients. CONCLUSION: This study indicated that single PGS has a poor prognosis. Prognosis of single PGS would become poorer along with patients' age and tumor size (>40 mm). Surgery intervention and radiation therapy were beneficial factors.

Clinical characteristics and disease-specific prognostic nomogram for primary gliosarcoma: a SEER population-based analysis.

Because the study population with gliosarcoma (GSM) is limited, the understanding of this disease is insufficient. In this study, the authors aimed to determine the clinical characteristics and independent prognostic factors influencing the prognosis of GSM patients and to develop a nomogram to predict the prognosis of GSM patients after craniotomy. A total of 498 patients diagnosed with primary GSM between 2004 and 2015 were extracted from the 18 Registries Research Data of the Surveillance, Epidemiology, and End Results (SEER) database. The median disease-specific survival (DSS) was 12.0 months, and the postoperative 0.5-, 1-, and 3-year DSS rates were 71.4%, 46.4% and 9.8%, respectively. We applied both the Cox proportional hazards model and the decision tree model to determine the prognostic factors of primary GSM. The Cox proportional hazards model demonstrated that age at presentation, tumour size, metastasis state and adjuvant chemotherapy (CT) were independent prognostic factors for DSS. The decision tree model suggested that age <71 years and adjuvant CT were associated with a better prognosis for GSM patients. The nomogram generated via the Cox proportional hazards model was developed by applying the rms package in R version 3.5.0. The C-index of internal validation for DSS prediction was 0.67 (95% confidence interval (CI), 0.63 to 0.70). The calibration curve at one year suggested that there was good consistency between the predicted DSS and the actual DSS probability. This study was the first to develop a disease-specific nomogram for predicting the prognosis of primary GSM patients after craniotomy, which can help clinicians immediately and accurately predict patient prognosis and conduct further treatment.

Racial/ethnic differences in survival for patients with gliosarcoma: an analysis of the National cancer database.

PURPOSE: Gliosarcoma is characterized by the World Health Organization as a Grade IV malignant neoplasm and a variant of glioblastoma. The association of race and ethnicity with survival has been established for numerous CNS malignancies, however, no epidemiological studies have reported these findings for patients with gliosarcoma. The aim of this study was to examine differences by race and ethnicity in overall survival, 30-day mortality, 90-day mortality, and 30-day readmission. METHODS: Data were obtained by query of the National Cancer Database (NCDB) for years 2004-2014. Patients with gliosarcoma were identified by International Classification of Diseases for Oncology, Third Edition (ICD-O-3)-Oncology morphologic code 9442/3 and topographical codes C71.0-C71.9. Differences in survival by race/ethnicity were examined using univariable and multivariable Cox proportional hazards models. Readmission and mortality outcomes were examined with univariable and multivariable logistic regression. RESULTS: A total of 1988 patients diagnosed with gliosarcoma were identified (White Non-Hispanic n = 1,682, Black Non-Hispanic n = 165, Asian n = 40, Hispanic n = 101). There were no differences in overall survival, 30- and 90-day mortality, or 30-day readmission between the races and ethnicities examined. Median survival was 10.4 months for White Non-Hispanics (95% CI 9.8, 11.2), 10.2 months for Black Non-Hispanics (95% CI 8.6, 13.1), 9.0 months for Asian Non-Hispanics (95% CI 5.1, 18.2), and 10.6 months for Hispanics (95% CI 8.3,16.2). 7.3% of all patients examined had an unplanned readmission within 30 days. CONCLUSION: Race/ethnicity are not associated with differences in overall survival, 30-day mortality, 90-day mortality, or 30-day readmission following surgical intervention for gliosarcoma.

Analysis of Outcomes of Multidisciplinary Management of Gliosarcoma: A Single-Center Study, 2000-2013.

BACKGROUND: Gliosarcoma is a rare tumor of the central nervous system with a reported incidence of ∼2%-8% of all gliomas. We reviewed the outcomes of patients treated at our institution over a 14-year period from 2000 to 2013 to characterize overall survival (OS) and progression-free survival as well as to elucidate the additive effect of chemoradiotherapy. METHODS: From January 1, 2000 to December 31, 2013, we retrospectively reviewed the clinical notes of all patients treated at our institution with a histopathologic diagnosis of gliosarcoma. This review yielded 21 patients whose clinicoradiologic data were analyzed with respect to age, sex, ethnicity, preoperative/postoperative Glasgow Coma Scale and Karnofsky Performance Scale, location, extent of resection, methylguanine DNA methyl transferase methylation status, and administration of adjuvant therapy. RESULTS: The median age was 58 years (range, 40-80 years) with a male preponderance (1.6:1). Tumor location was mainly temporal (n = 6) but also parietal (n = 5), frontal (n = 4), multilobar (n = 4), and cerebellar (n = 1). Surgical resection was deemed to be total in 15 patients and subtotal in 6 patients. Methylguanine DNA methyl transferase methylation status was available for only 5 patients, with a methylation rate of 60% (3/5) and no impact on survival. Nine patients received both radiotherapy and chemotherapy (OS, 7.9 months), 7 received radiotherapy only (OS, 5.7 months), and 5 patients received no adjuvant therapy (OS, 1.4 months). The overall median survival was 5.7 months (range, 1-21.5 months) and median progression-free survival was 5 months (range, 1.4-12.4 months). CONCLUSIONS: Despite an overall poor prognosis, a multimodality approach aiming for complete resection followed by radiotherapy and chemotherapy appears to be associated with better outcomes.

Primary and secondary gliosarcomas: clinical, molecular and survival characteristics.

Gliosarcoma is classified by the World Health Organization as a variant of glioblastoma. These tumors exhibit biphasic histologic and immunophenotypic features, reflecting both glial and mesenchymal differentiation. Gliosarcomas can be further classified into primary (de novo) tumors, and secondary gliosarcomas, which are diagnosed at recurrence after a diagnosis of glioblastoma. Using a retrospective review, patients seen at MD Anderson Cancer Center between 2004 and 2014 with a pathology-confirmed diagnosis of gliosarcoma were identified. 34 patients with a diagnosis of gliosarcoma seen at the time of initial diagnosis or at recurrence were identified (24 primary gliosarcomas (PGS), 10 secondary gliosarcomas (SGS)). Molecular analysis performed on fourteen patients revealed a high incidence of TP53 mutations and, rarely, EGFR and IDH mutations. Median overall survival (OS) for all patients was 17.5 months from the diagnosis of gliosarcoma, with a progression free survival (PFS) of 6.4 months. Comparing PGS with SGS, the median OS was 24.7 and 8.95 months, respectively (from the time of sarcomatous transformation in the case of SGS). The median OS in SGS patients from the initial diagnosis of GB was 25 months, with a PFS of 10.7 months. Molecular analysis revealed a higher than expected rate of TP53 mutations in GS patients and, typical of primary glioblastoma, IDH mutations were uncommon. Though our data shows improved outcomes for both PGS and SGS when compared to the literature, this is most likely a reflection of selection bias of patients treated on clinical trials at a quaternary center.

An individual patient data meta-analysis on characteristics, treatments and outcomes of glioblastoma/ gliosarcoma patients with metastases outside of the central nervous system.

PURPOSE: To determine the characteristics, treatments and outcomes of patients with glioblastoma multiforme (GBM) or gliosarcoma (GS) and metastases outside of the central nervous system (CNS). METHODS: PubMed and Web of Science searches for peer-reviewed articles pertaining to GBM/ GS patients with metastatic dissemination were conducted using the keywords gliosarcoma, glioblastoma, GBM, metastasis, metastases and metastatic. Additionally, we performed hand search following the references from the selected papers. Cases with metastases to the CNS were excluded and evaluated in a separate study. RESULTS: 109 articles published between 1928 and 2013 were eligible. They reported on 150 patients. We observed a remarkable increase in the number of cases per decade over time. Median overall survival from diagnosis of metastasis (OSM+) was 6.0 ± 0.8 months and median overall survival from initial diagnosis (OSID) 13 ± 2.4 months. On univariate analyses, gender, age, the histological subtype, the time interval between initial diagnosis and diagnosis of metastasis and pulmonary involvement did not influence OSM+. We did not observe any substantial treatment progress. A comparison of the present cohort with 84 GBM/ GS patients with exclusive CNS dissemination suggests that metastases outside the CNS are related to a slightly more favorable outcome. CONCLUSIONS: The occurrence of extra-CNS metastasis from GBM/ GS is associated with a dismal prognosis, however it seems to compare slightly favorable to CNS dissemination. Crucial treatment progress has not been achieved over recent decades. A central registry should be considered to consecutively gain more information about the ideal therapeutic approach.

Treatment and survival of patients harboring histological variants of glioblastoma.

It is unclear whether the survival difference observed between glioblastoma (GBM), giant cell glioblastoma (gcGBM), and gliosarcoma (GSM) patients is due to differences in tumor histology, patient demographics, and/or treatment regimens. The USA National Cancer Database was utilized to evaluate patients diagnosed with GBM, gcGBM, and GSM between 1998 and 2011. Kaplan-Meier survival estimates and Cox proportional hazards models were utilized to estimate overall survival. A cohort of 69,935 patients was analyzed; 67,509 (96.5%) of these patients had GBM, 592 (0.9%) gcGBM, and 1834 (2.6%) GSM. The median age for GBM and GSM patients was 61 versus 56 years for gcGBM (p<0.0001). Higher extent of resection (p<0.0001) and radiation (p=0.001) were observed in gcGBM patients compared to other histologies. Multivariate analysis showed that gcGBM patients had a 20% reduction in the hazards of mortality (hazard ratio [HR] 0.80, 95% confidence interval [CI] 0.69-0.93) compared to GBM, while GSM patients trended towards higher hazards of mortality (HR 1.04, 95% CI 0.96-1.12) than the GBM cohort. Previous studies have suggested a disparity in the survival of patients with GBM tumors and their histological variants. Using a large cohort of patients treated at hospitals nationwide, this study found a 20% reduction in the hazards of mortality in gcGBM patients compared to GBM. Similarly, gcGBM patients had a 24% reduction in the hazards of mortality compared to the GSM cohort. GSM patients had a 3% increase in the hazards of mortality compared to GBM.

Clinical management and survival outcomes of gliosarcomas in the era of multimodality therapy.

Gliosarcoma (GSM) is a rare primary malignant brain tumour accounting for less than 0.5% of all intracranial tumours. It has a biphasic histological composition, demonstrating both gliomatous and sarcomatous elements. In clinical practice GSM are generally managed similarly to glioblastoma multiforme (GBM). However, unique features including its clinical propensity for extra-cranial metastasis, distinct radiological features and possible worse prognosis than GBM suggest that GSM may be a distinct clinico-pathological entity. Hence we reviewed patterns of care and outcomes for a series of Australian patients diagnosed with GSM in the era of combined chemo-radiotherapy. Patients were identified by searching the Australian Genomics and Clinical Outcomes of Glioma (AGOG) database and the Western Australian Interhospital Neurosurgical database. Nineteen patients with GSM were identified. Of these, 15 patients were diagnosed with primary GSM and four patients developed secondary GSM after radiation therapy for primary GBM. For comparative purposes, 408 primary GBM patients were identified from the AGOG database during the same study period. The overall median survival for all primary GSM patients was 9.7 months. In comparison the overall median survival for GBM patients recruited to the AGOG database over the same period was 12.2 months. The median survival for secondary GSM patients from the time of diagnosis was 5 months. Primary and secondary GSM pose a great clinical challenge due to their rarity. Our study adds further evidence to support GSM as a unique clinical entity with a likely worse prognosis than GBM.

Primary gliosarcoma of the brain: radiologic and histopathologic features.

Gliosarcoma is a rare central nervous system (CNS) neoplasm with biphasic glial and non-glial malignant components. Here we describe the radiologic and histopathologic features observed in five cases of primary gliosarcoma. The mean age at diagnosis in the studied patients was 54.2 years; these patients were predominantly males (male:female ratio = 4:1). At diagnosis all patients had several clinical deterioration. The most common symptoms of presentation were: headache (5/5 cases), seizures (4/5 cases) and hemiparesis (1/5 cases). All the tumors were large (mean major diameter= 4.12±1.64 cm) at diagnosis as evidenced in computer tomography (CT) scans and magnetic resonance images (MRIs), with preferential involvement of the temporal lobe and frequent associated deviation of the midline structures. Other common characteristics identified on CT scans and MRIs were partial contrast medium uptake with annular pattern (5/5 cases), peripheral edema (5/5 cases), and central calcification (3/5 cases). In additional a peak of dye uptake was observed (4/5 cases) on MRI spectrometry. In the histopathology, the glial component showed malignant astrocytes, with high Ki67 (>60%) and p53 positivity; the sarcomatous components displayed pleomorphic spindle cells similarly with p53 positivity and high Ki67 (75-90%) in all cases. Dedifferentiation to pleomorphic sarcoma (two cases), fibrosarcoma (one case), leiomyosarcoma (one case) and MPNST (one case) were documented. All patients received radiotherapy/chemotherapy and had a median overall survival of ten months. The study of radiologic and histopathologic features in primary gliosarcomas of the brain is a priority to achieve early diagnosis that can be translated to better outcomes. Here we describe the radiologic and histopathologic features observed in a group of gliosarcoma patients with variable histopathologic dedifferentiation.

Intracerebral administration of heat-inactivated Staphylococcus epidermidis enhances oncolysis and prolongs survival in a 9L orthotopic gliosarcoma model.

BACKGROUND/AIMS: The association between postoperative infection and prolonged survival in high-grade glioma is still a matter of debate. Previously we demonstrated that the intracerebral (i.c.) injection of heat-inactivated staphylococcal epitopes (HISE) resulted in a well-defined infux of immunocompetent cells across the blood-brain barrier. The present study investigated the potential antitumoral effect of HISE-immunostimulation in an experimental glioma model. METHODS: Wistar rats were intracerebrally implanted with 9L gliosarcoma cells (n=6), 9L cells mixed with HISE (n=12), or phosphate buffered saline (n=4). Tumor growth was measured by serial magnetic resonance imaging (MRI). After death due to the tumor burden, the brains were histopathologically assessed for inflammation and oncolysis. A toxicity assay was performed to quantify potential impairment of HISE on tumor cell growth in vitro. RESULTS: Animals treated by HISE showed a significant increase in average survival and even complete regression of an already established mass in one case. Naïve 9L gliosarcomas failed to recruit significant numbers of systemic immune cells. In contrast, concomitant intracerebral HISE inoculation lead to a oncolysis and a distinct peri- and intratumoral infiltration of macrophages, CD8 and CD4 co-expressing T-lymphocytes in two thirds of the tumor-bearing animals. The toxicity screening showed HISE-mediated oncolysis to be ineffective ex vivo. CONCLUSION: This study describes a novel approach for combatting malignant glioma using inactivated staphylococci as potent immunomodulators. Our results provide an outline for investigating the strategic potential of bacteria as emerging future therapeutics.

Temozolomide use in adult patients with gliosarcoma: an evolving clinical practice.

The purpose of this study is to determine the factors that impact overall survival (OS) in adult patients with gliosarcoma in the modern era treated at a single institution compared with a cohort from the SEER registry. A total of 46 adult patients with pathologically confirmed gliosarcoma at MD Anderson Cancer Center from 2000 to 2010 were retrospectively analyzed. Demographic and treatment were obtained. For comparison, a total of 218 patients with gliosarcoma in the SEER database from 1991 to 2008 were analyzed. Survival analysis was conducted using the Kaplan-Meier log rank test. At MD Anderson, the overall incidence of gliosarcoma over the specified time interval was 1.5 %. Gliosarcoma was more common in males (n = 31, 67.4 %) with a median age of 56 years (range 24-92 years). Median survival in all patients was 12.5 months. A total of 17 patients (37 %) received temozolomide (TMZ) concurrently with RT and adjuvantly, with a 24 month OS of 20.0 %, compared with 10.2 % among those not treated with this regimen (p = 0.68). In contrast, the 2 year OS rate in the SEER database was 24.2 % during 2006-2008, compared to 12.1 % among those diagnosed in 2000-2003 (p = 0.03), presumably related to the widespread adoption of the chemoradiation regimen. Patients with gliosarcoma treated with TMZ at a single institution improved OS although this finding did not reach statistical significance. Patients diagnosed in the TMZ era in the SEER database display an improved OS, although the explanation for this finding requires further elucidation.

Improvement in the standard treatment for experimental glioma by fusing antibody Fc domain to endostatin.

OBJECT: Brain tumors pose many unique challenges to treatment. The authors hypothesized that Fc-endostatin may be beneficial. It is a newly synthesized recombinant human endostatin conjugated to the Fc domain of IgG with a long half-life (weeks) and unknown toxicity. The authors examined the efficacy of Fc-endostatin using various delivery methods. METHODS: Efficacy was assessed using the intracranial 9L gliosarcoma rat model treated with Fc-endostatin for use in rodents (mFc-endostatin), which was administered either systemically or locally via different delivery methods. Oral temozolomide (TMZ) was administered in combination with mFc-endostatin to determine if there was a beneficial synergistic effect. RESULTS: Intracranial delivery of mFc-endostatin via a polymer or convection-enhanced delivery 5 days after tumor implantation increased median survival, compared with the control group (p = 0.0048 and 0.003, respectively). Animals treated weekly with subcutaneous mFc-endostatin (started 5 days post-tumor implantation) also had statistically improved survival as compared with controls (p = 0.0008). However, there was no statistical difference in survival between the local and systemic delivery groups. Control animals had a median survival of 13 days. Animals treated either with subcutaneous mFc-endostatin weekly or with polymer had a median survival of 18 and 15 days, respectively, and those treated with oral TMZ for 5 days (Days 5-9) had a median survival of 21 days. Survival was further increased with a combination of oral TMZ and mFc-endostatin polymer, with a median survival of 28 days (p = 0.029, compared with TMZ alone). Subcutaneous mFc-endostatin administered every week starting 18 days before tumor implantation significantly increased median survival when compared with controls (p = 0.0007), with 12.5% of the animals ultimately becoming long-term survivors (that is, survival longer than 120 days). The addition of TMZ to either weekly or daily subcutaneous mFc-endostatin and its administration 18 days before tumor implantation significantly increased survival (p = 0.017 and 0.0001, respectively, compared with TMZ alone). Note that 12.5% of the animals treated with weekly subcutaneous mFc-endostatin and TMZ were long-term survivors. CONCLUSIONS: Systemically or directly (local) delivered mFc-endostatin prolonged the survival of rats implanted with intracranial 9L gliosarcoma. This benefit was further enhanced when mFc-endostatin was combined with the oral chemotherapeutic agent TMZ.

The natural history of extracranial metastasis from glioblastoma multiforme.

Extracranial metastasis is a unique but rare manifestation of glioblastoma multiforme. It is thought to arise from glioblastoma cells disseminated into the blood stream. We undertook a comprehensive analysis of 88 cases of extracranial glioblastoma (5 were gliosarcomas) published between 1928 and 2009. Cases included in the analysis were primary or secondary glioblastomas that subsequently invaded organs outside the brain or spinal cord. The median age was 38 years and the median overall survival time was 10.5 months (range 0.0-60.0 months). The median time from symptom onset to diagnosis of primary glioblastoma was 2.5 months, from diagnosis to detection of extracranial metastasis was 8.5 months, and from metastasis to death was 1.5 months. From 1940 to 2009, there has been progressive lengthening of the interval from detection of extracranial metastasis to death, at a rate of 0.7 months per decade (95% confidence interval 0.5-1.0 month). Use of magnetic resonance imaging correlates with an increase in overall survival but not age, gender, or site of primary glioblastoma. Patients treated with surgery + radiation + chemotherapy + cerebrospinal fluid shunting had the longest average survival interval from metastasis to death when compared to those treated with surgery alone, radiation alone, surgery + radiation, and surgery + radiation + chemotherapy. Lung metastasis is a prognostic factor of extremely poor outcomes. We conclude that patients with glioblastoma extracranial metastasis have poor prognosis, but there has been a progressive lengthening of survival in each successive decade from 1940 to 2000.

Preferential effect of synchrotron microbeam radiation therapy on intracerebral 9L gliosarcoma vascular networks.

PURPOSE: Synchrotron microbeam radiation therapy (MRT) relies on spatial fractionation of the incident photon beam into parallel micron-wide beams. Our aim was to analyze the effects of MRT on normal brain and 9L gliosarcoma tissues, particularly on blood vessels. METHODS AND MATERIALS: Responses to MRT (two arrays, one lateral, one anteroposterior (2 × 400 Gy), intersecting orthogonally in the tumor region) were studied during 6 weeks using MRI, immunohistochemistry, and vascular endothelial growth factor Western blot. RESULTS: MRT increased the median survival time of irradiated rats (×3.25), significantly increased blood vessel permeability, and inhibited tumor growth; a cytotoxic effect on 9L cells was detected 5 days after irradiation. Significant decreases in tumoral blood volume fraction and vessel diameter were measured from 8 days after irradiation, due to loss of endothelial cells in tumors as detected by immunochemistry. Edema was observed in the normal brain exposed to both crossfired arrays about 6 weeks after irradiation. This edema was associated with changes in blood vessel morphology and an overexpression of vascular endothelial growth factor. Conversely, vascular parameters and vessel morphology in brain regions exposed to one of the two arrays were not damaged, and there was no loss of vascular endothelia. CONCLUSIONS: We show for the first time that preferential damage of MRT to tumor vessels versus preservation of radioresistant normal brain vessels contributes to the efficient palliation of 9L gliosarcomas in rats. Molecular pathways of repair mechanisms in normal and tumoral vascular networks after MRT may be essential for the improvement of such differential effects on the vasculature.

[Cerebral gliosarcoma: clinico-pathologic study of 8 cases]. / Gliosarcome cérébral: etude clinico-pathologique de 8 cas.

BACKGROUND: Gliosarcomas are biphasic neoplasms composed of a glioblastoma admixed to a sarcomatous component with different lines of differentiation. Histogenesis of these tumors is still discussed. AIM: Our objective is to specify clinical and pathological characteristics of this rare neoplasm and to discuss its histogenesis. METHODS: Retrospective study of eight cases of gliosarcomas diagnosed between January 1998 and December 2004. Clinical, radiological, therapeutic and follow-up data were reviewed. Histological features and immunohistochemical results were also included in this review. RESULTS: Five patients were male, three women with a median age of 50.7 (range 31-74 years). Symptoms were dominated by intracranial hypertension and paralysis. The most common location was parietal or temporo-parietal (5 cases: 62.5%). Pathological exam including histochemical and immunohistochemical study confirmed the diagnosis of gliosarcoma in all cases. Sarcomatous component had features of fibrosarcoma in 5 cases, osteosarcoma in 2 cases and malignant fibrous histiocytoma in 1 case. All patients were treated by surgical excision (complete in five cases and partial in three cases). Adjuvant radiotherapy was received in three cases. One patient was lost on follow-up. Two patients died from postoperative. complications and the five remaining patients died with a medium follow up of 9 months (extremes: 2-24 months). CONCLUSION: Clinical, radiological and follow-up features of gliosarcomas share great similarities with glioblastomas. Histopathological, histochemical and immunohistochemical studies are helpful in accuracy diagnosis. Recent cytogenetic and molecular data support a monoclonal origin for these tumors.

Clinical characteristics and outcomes for a modern series of primary gliosarcoma patients.

BACKGROUND: Primary gliosarcoma (PGS) is a rare central nervous system tumor with limited experience reported in the literature. In the current study, the authors present a modern series of confirmed PGS cases treated in the era of magnetic resonance imaging (MRI), after the accepted glioblastoma management of resection, radiation, and temozolomide. METHODS: Using a retrospective review, patients with confirmed PGS were identified (1996-2008). Cases were determined to be PGS by central pathology review using the 2007 World Health Organization criteria. Extensive chart review was performed to gather clinical and pathologic data on these cases. RESULTS: All but 1 patient had undergone a preoperative MRI, with 1 patient receiving a computed tomography scan due to a cardiac pacemaker. A total of 10 patients received radiotherapy with concurrent and adjuvant temozolomide chemotherapy, and 8 patients received radiotherapy alone or in combination with other chemotherapeutic agents. In 2 patients, the history of adjuvant treatment could not be confirmed. The overall median survival was 13.9 months (range, 2.2-22.9 months). Patients with gliosarcomas resembling meningioma were found to have a significantly prolonged median survival compared with patients harboring gliosarcoma resembling glioblastoma multiforme (16 months vs 9.6 months; P = .011). However, no difference in survival was noted between patients who received concurrent radiotherapy and temozolomide compared with those who did not (10.4 months vs 13.9 months; P = .946). CONCLUSIONS: The results of the current study support previous hypotheses that there are 2 distinct types of PGS. The type mimicking the appearance of a meningioma appears to carry a significantly more favorable prognosis, most likely due to an increased chance at achieving macroscopic total resection.