Supratentorial Malignant Gliomas Research Articles

1244 Immunotherapy With Autological Dendritic Cells in the Structure of Complex Treatment of Gliomas

INTRODUCTION: Malignant gliomas are the most common primary brain tumor. Despite the variety of modern treatments, it is still a fatal disease with an extremely poor prognosis. The use of immunotherapy as a technique for the treatment of malignant tumors has great promise, retraining and exploiting the patient's immune response against tumors. METHODS: Long-term results of treatment of 220 patients with malignant supratentorial gliomas (anaplastic astrocytomas, glioblastomas) were analyzed. Of these patients, 110 patients, in addition to standard methods of treatment (surgery, radiation therapy and chemotherapy), underwent specific antitumor immunotherapy with autologous dendritic cells. In 110 patients, only standard methods were used in the structure of complex treatment. The relapse-free period and median life expectancy were assessed. RESULTS: Conducting specific antitumor immunotherapy in patients with malignant gliomas was safe and did not lead to an increase in the number of complications compared with the control group. It was revealed that the use of immunotherapy based on autologous dendritic cells, in addition to standard methods of treating patients, increases the average life expectancy (in patients with anaplastic astrocytomas up to 40.5 months (p = 0.001), in patients with glioblastomas up to 21.8 months (p = 0.002)) and increases the relapse-free period (in patients with anaplastic astrocytomas up to 17.4 months (p = 0.002), in patients with glioblastomas up to 14.3 months (p = 0.003)) provided that three or more courses are taken. Conducting 1 or 2 courses of immunotherapy does not significantly affect the average life expectancy and median survival of patients. CONCLUSIONS: The development and use in clinical practice of specific antitumor immunotherapy based on autologous dendritic cells seems to be a very promising direction for further research, the development of which will improve the long-term results of patient treatment.

Haemostatic technique in malignant gliomas.

Haemostasis in brain surgery is mandatory to avoid postoperative re-bleeding and a poor outcome. Postoperative intra-cavity haemorrhage is a frequent complication, especially in surgery of malignant gliomas because of the fragility of pathological vessels. In this technical note, we describe our 'compression' technique used to achieve haemostasis in adult patients who underwent surgery for supratentorial malignant gliomas (GBM) at our Institute from January 2019 to January 2022. Peri-operative work-up included clinical status, laboratory data and contrast brain CT, performed at 24 hours after surgery, or earlier for patients with neurological worsening. A total of 82 patients was included in this study, 46 males (57%) and 36 females (43%). A post-operative intra-cavity haemorrhage was documented by postoperative CT-scan in 3/82 patients (3.65%), and the mean surgical time was 3.66 hours. No late bleeding was observed 48 hours after surgery. We have documented the good results of our technique to achieve haemostasis in patients operated for malignant glioma (GBM). The technique described in this study seems to be safe and useful to avoid post-operative bleeding in the surgery of cerebral GBM.

Hypoxia and glucose metabolism assessed by FMISO and FDG PET for predicting IDH1 mutation and 1p/19q codeletion status in newly diagnosed malignant gliomas

BackgroundTumor hypoxia and glycolysis have been recognized as determinant factors characterizing tumor aggressiveness in malignant gliomas. To clarify in vivo hypoxia and glucose metabolism in relation to isocitrate dehydrogenase (IDH) mutation and chromosome 1p and 19q (1p/19q) codeletion status, we retrospectively analyzed hypoxia as assessed by positron emission tomography (PET) with [18F]-fluoromisonidazole (FMISO) and glucose metabolism as assessed by PET with [18F]-fluoro-2-deoxy-d-glucose (FDG) in newly diagnosed malignant gliomas.MethodsIn total, 87 patients with newly diagnosed supratentorial malignant (WHO grade III and IV) gliomas were enrolled in this study. They underwent PET studies with FMISO and FDG before surgery. The molecular features and histopathological diagnoses based on the 2016 WHO classification were determined using surgical specimens. Maximal tumor-to-normal ratio (TNR) was calculated for FDG PET, and maximal tumor-to-blood SUV ratio (TBR) was calculated for FMISO PET. The PET uptake values in relation to IDH mutation and 1p/19q codeletion status were statistically analyzed.ResultsIn all tumors and malignant astrocytomas, the median FMISO TBR in IDH-wildtype tumors was significantly higher than that in IDH-mutant tumors (P < 0.001 and P < 0.01, respectively). In receiver operating characteristic (ROC) analysis, the area under the curve showed that the sensitivity for the discrimination was moderate (0.7–0.8) and the specificity was low (0.65–0.68). In the same population, the median FDG TNR in IDH-wildtype tumors tended to be higher than that in IDH-mutant tumors, but the difference was not statistically significant. In WHO grade III anaplastic astrocytomas, there were no significant differences in median FMISO TBR or FDG TNR between IDH-mutant and IDH-wildtype tumors. In IDH-mutant WHO grade III anaplastic gliomas, there were no significant differences in median FMISO TBR or FDG TNR between anaplastic astrocytomas and anaplastic oligodendrogliomas.ConclusionsTumor hypoxia as assessed by FMISO PET was informative for prediction of the IDH mutation status in newly diagnosed malignant gliomas. However, the accuracy of the discrimination was not satisfactory for clinical application. On the other hand, glucose metabolism as assessed by FDG PET could not differentiate the IDH-mutant status. Moreover, PET studies using FMISO and FDG could not predict IDH mutation and 1p/19q codeletion status in WHO grade III tumors.

CT-perfusion in assessment of the malignant gliomas hemodynamics

Aim. To study the role of CT perfusion in the differential diagnosis of histological subtypes of supratentorial malignant gliomas and to determine the degree of their malignancy. Materials and methods. The study included 34 patients (20 men and 14 women, with an average age of 52 years) with newly detected supratenorial glial tumors, who subsequently underwent neurosurgical treatment in the NMIC of neurosurgery with histological verification of the diagnosis. Depending on the histological diagnosis, three groups of patients were identified: 1) anaplastic astrocytomas, 2) glioblastomas, 3) anaplastic oligodendrogliomas. The CT-perfusion protocol was performed on a 64-slice Optima 660 (GE) scanner and consisted of three separate parts: a low-dose axial CT of the brain with a slice thickness of 5 mm (90 kV), a perfusion protocol performed according to a prolonged scheme, with two consecutive continuous series of scans, and a post-contrast series of CT images in a spiral scanning mode. In addition, all patients underwent an MRI examination (using a Signa Hdxt 3.0 T (GE) MR scanner, in T2, T2-FLAIR, SWAN, DWI, and T1 modes before and after contrast enhancement).Results. The study demonstrated that anaplastic astrocytomas are characterized by significantly low absolute and normalized hemodynamics parameters (BF, BV, PS) when compared with glioblastomas, and significantly low absolute maximum values of blood flow (BF) and blood volume (BV) when compared with the group of anaplastic oligodendrogliomas. CT perfusion using the normalized permeability index (PS) can reliably differentiate glioblastomas and anaplastic oligodendrogliomas. Perfusion parameters, both absolute and normalized, did not show statistically significant differences in the differential diagnosis of various molecular and genetic subtypes of anaplastic astrocytomas.Conclusion. CT perfusion using all hemodynamic parameters demonstrated high reliability and efficacy in distinguishing between glioblastomas and anaplastic astrocytomas. Further research is required to evaluate the effectiveness of the method in distinguishing glioblastomas from anaplastic oligodendrogliomas.

STMO-04 LOCAL CONVECTION-ENHANCED DELIVERY OF CHEMOTHERAPY AS TREATMENT FOR BRAIN TUMORS

BACKGROUNDConvection-enhanced delivery (CED) of therapeutic agents is a promising local delivery technique that has been extensively studied as a treatment for CNS diseases over the last 2 decades. Applying this technique to treat brain tumors, we have been working to develop novel local chemotherapy against brain tumors. In the meanwhile, clinical trial against diffuse intrinsic brain tumor aiming at Japanese “shonin” approval is recruiting patients. In this study, potential of local CED based chemotherapy against supratentorial brain tumor is discussed.METHODSUntil today, we have evaluated the safety and efficacy of local CED of nimustine hydrochloride against supratentorial malignant glioma patients in the three prospective, single institute, nonrandomized, open-label studies. Among those, one study recruited the recurrent malignant glioma patients whose enhanced tumor can be surgically resected. After the resection of the tumor, CED of ACNU was performed targeting the surrounding brain. Temozolomide was also given for 5 days during this trial.RESULTSSeven patients; 4 male and 3 female, age 33–71 y.o. (median 54 y.o.), were treated in this study. Five patients suffered glioblastoma and two suffered anaplastic astrocytoma. After the treatment, all seven patients lived longer than a year; one survived three years, one survived four and a half years, and one with glioblastoma is still alive after 5 years.DISCUSSIONPotential efficacy of local chemotherapy delivering nimustine hydrochloride with CED against recurrent malignant glioma was suggested. Further study is required to pave the way for this strategy against supratentorial malignant gliomas.

Combining 3′-Deoxy-3′-[18F] fluorothymidine and MRI increases the sensitivity of glioma volume detection

3'-Deoxy-3'-[18F] fluorothymidine (18F-FLT) is a marker of cell proliferation and displays a high tumor-to-background ratio in brain tumor lesions. We determined whether combining 18F-FLT PET and MRI study improves the detection of tumoral tissue compared to MRI alone and whether 18F-FLT uptake has a prognostic value by studying its association with histopathological features. Thirteen patients with a supratentorial malignant glioma were recruited and scheduled for surgery. The tumor volume was defined in all patients on both 18F-FLT PET and MRI images. The images were coregistered and uploaded onto a neuronavigation system. During surgery, an average of 11 biopsies per patient were taken in regions of the brain that were positive to one or both imaging modalities, as well as from control peritumoral regions. The standardized uptake values (SUVs) of each biopsy region were correlated to histopathological data (i.e., proliferation index and number of mitoses) and the SUV values of high and low-grade samples were compared. Out of a total of 149 biopsies, 109 contained tumoral tissue at histopathological analysis. The positive predictive value was 93.1% for MRI alone and 78.3% for MRI and PET combined. In addition, 40% of the biopsy samples taken from areas of the brain that were negative at both PET and MRI had evidence of malignancy at pathology. The SUV values were not significantly correlated to either the proliferation index or the number of mitoses, and could not differentiate between high- and low-grade samples. In patients with newly diagnosed glioma, a combination of MRI and 18F-FLT-PET detects additional tumoral tissue and this may lead to a more complete surgical resection. Also, the addition of a negative PET to a negative MRI increases the negative predictive value. However, 18F-FLT still underestimated the margins of the lesion and did not correlate with histopathological features.

Intraoperative vascular fluorescence in cerebral glioblastomas and vascular histological features

Identification of fluorescent vessels located near cerebral gliomas, with a histological description of their structure, relationships with the tumor, and potential invasion of the walls by tumor cells. A prospective cohort study included 14 patients with malignant supratentorial gliomas, aged 20 to 78 years. Five patients were operated on due to continued tumor growth. Two hours before surgery, all patients received 5-ALA orally. During surgery, a microscope (Carl Zeiss OPMI Pentero, Germany) with a fluorescent module (BLUE-400) was used. In all cases, molecular-genetic and immunohistochemical examinations of the tumor material were performed. During surgery, fluorescent vessels, after evaluating their functional significance, were also resected for histological examination. Glioblastoma and anaplastic astrocytoma were verified in 10 and 4 patients, respectively. In 4 out of 10 glioblastoma cases, vessels with homogeneous or fragmentary fluorescent walls were detected in the tumor bed after resection of most of the tumor; in patients with anaplastic astrocytomas, vascular fluorescence was not observed. In the four vascular samples with intraoperatively detected wall fluorescence, tumor invasion into the vascular layers was revealed in all cases. These patients underwent an immunohistochemical examination with monoclonal antibodies to the glial GFAP marker, which clearly identified areas of ingrowth of tumor cells into the vascular wall. 5-ALA intraoperative fluorescence is a fundamentally new approach in the rapid diagnosis of tumor-infiltrated blood vessels. Invasion of tumor cells to intact vessels may be a mechanism of tumor progression and dissemination. Additional resection of fluorescent vessels may affect the radicalness of surgical treatment, but requires a mandatory assessment of their functional significance.

Malignant Gliomas as Second Neoplasms in Pediatric Cancer Survivors: Neuropathological Study.

This study presents a unique series of malignant supratentorial gliomas in children previously cured from non-CNS primary cancer. On neuroimaging these tumors were not specific, so the patients were suspected of cerebral recurrence of their primary neoplasm: leukemia in four children and sarcoma in one child. Histologically, the group contained four glioblastomas and one anaplastic astrocytoma. Three patients underwent neurosurgical resection, while the other two underwent stereotactic diagnostic biopsy only. Despite combined oncological treatment, four children died during 20 months, and only one glioblastoma patient continued to live for another twelve years. Microscopically, the neoplasms consisted of small cells with some morphologic features of astrocytic lineage, having scanty or prominent processes. Microvascular proliferation and focal or diffuse necrosis were encountered in four cases. The GFAP reactivity in neoplastic cells was low or nil, together with the expression of Olig2, vimentin, and nestin. In two cases a subpopulation of synaptophysin-positive cells was present. Molecular immunohistochemical profiling revealed the expression of phosphorylated forms of PI3Kp110 and AKT, in parallel to a strong PTEN and p53 positivity. The tumors were of IDH1R132H-wild type and immunoreactive for ATRX, HER3, and EGFR. Secondary malignant gliomas in pediatric cancer survivors pose a diagnostic challenge. The present study shows that these tumors are of IDH wild type, PI3K/AKT-activated, having no PTEN and EGFR mutations. Therefore, the biopsy of brain tumors in such patients is crucial both for accurate diagnosis and material preservation for molecular typing.

Quantitative analysis of brain edema in patients with malignant glioma treated with BCNU wafers

BCNU wafers are a form of interstitial chemotherapy that is expected to improve the survival of patients with malignant glioma. However, their adverse events, especially brain edema, sometimes cause significant clinical symptoms. In this study, we performed a volumetric analysis of brain edema after the implantation of BCNU wafers and reported on the clinical course, and exacerbation factors of brain edema. Twelve patients who underwent surgical resection of supratentorial malignant glioma and BCNU wafer implantation, were enrolled. Radiographic quantitative analysis was conducted and compared with a historical control. The volume change in brain edema was divided into three groups and correlation with clinical symptoms was then evaluated. Compared with the control group, the brain edema in the BCNU wafer implantation group was significantly prolonged after surgery. Radiographic volumetric analysis revealed an increase of more than 25% at any time after surgery in four patients (33%) and a reduction of less than 25%, 1month after surgery in three patients (25%). Grade 3 clinical deterioration related to brain edema occurred in two patients and Grade 2 in one patient. Univariate analysis revealed that the radiographic deterioration of brain edema had no correlation with age, sex, diagnosis, tumor grade, preoperative volume of brain edema and tumor, residual tumor volume, or number of BCNU wafers. Radiographic quantitative analysis of brain edema indicated that BCNU wafer implantation may induce the prolongation and enlargement of brain edema with or without neurological deterioration. Brain edema may be controlled by intensive perioperative treatment with diuretics and corticosteroids.

Peritumoral edema on magnetic resonance imaging predicts a poor clinical outcome in malignant glioma.

Peritumoral edema (PTE), one of the main characteristics of malignant glioma, is a significant contributor to the morbidity and mortality from glioma, however, a recent systematic review suggested that controversy remains with regard to its prognostic value. To further determine whether PTE was a potential prognostic factor on routine pre-operative magnetic resonance imaging (MRI) for malignant glioma, the association between survival and PTE was investigated in the present retrospective review of 109 patients with newly diagnosed supratentorial malignant glioma using MRI data from these routine scans. The Kaplan-Meier method was used to calculate overall survival (OS) in univariate analysis, and COX proportional hazards model was applied to evaluate the effect of pre-operative MRI features on OS in multivariate analysis. The PTE extent, edema shape, degree of necrosis, enhancement extent, pathological grade, patient age, Karnofsky performance status (KPS) and post-operative chemoradiotherapy were associated with OS in the patients with malignant glioma on univariate analysis. Multivariate analysis indicated that the extent of PTE and degree of necrosis shown by pre-operative MRI were independent predictors of OS, in addition to pathological grade, patient age, KPS and post-operative chemoradiotherapy. Moreover, patients with two unfavorable factors (major edema and severe necrosis) exhibited a poorer OS compared with the remainder. In summary, PTE and degree of necrosis, which are easily determined from routine MRI, can be useful for predicting a poor clinical outcome in patients with newly diagnosed malignant glioma.

AT-49 * SAFETY EVALUATION OF HIGH-DOSE BCNU-LOADED BIODEGRADABLE IMPLANTS IN CHINESE PATIENTS WITH RECURRENT MALIGNANT GLIOMAS

OBJECTIVES: Malignant gliomas are common primary brain tumors with dismal prognosis. The blood-brain barrier and unacceptable systemic toxicity limit the employment of chemotherapeutic agents. BCNU-impregnated biodegradable polymers (Gliadel®) have been demonstrated to prolong the survival of patients with malignant gliomas. Until now, no biodegradable drug delivery system has been commercially available in China. In the present study, we evaluated the safety of implants with high-dose BCNU in Chinese patients with recurrent malignant gliomas. PATIENTS AND METHODS: Adults with supratentorial recurrent malignant glioma were eligible. High-dose BCNU-loaded PLGA implants (20 mg of BCNU in each implant) were placed in the debulking cavity. The implants were investigated by a classical 3 + 3 design. Four levels of BCNU, up to 12 implants, were evaluated. Pharmacokinetic sampling was performed. The toxicity of the implants and the survival of patients were recorded. RESULTS: Fifteen recurrent patients were enrolled with 12 glioblastomas and 3 anaplastic gliomas. Among 15 patients, 3 were treated with 3 implants (60 mg of BCNU), 3 with 6 implants (120 mg), 3 with 9 implants (180 mg) and 6 with 12 implants (240 mg). No dose-limiting toxicity was observed in the cohort of patients. Subgaleal effusion was the most common adverse event, presenting in 7 patients (46.7%). The median overall survival (OS) was 322 days (95% CI, 173 - 471 days). The 6-month, 1-year and 2-year survival rates were 66.7%, 40% and 13.3%, respectively. CONCLUSIONS: The high-dose BCNU-loaded PLGA implants were safe for Chinese patients with recurrent malignant gliomas and further investigation for efficacy is warranted.

Parenchymal Anaplastic Astrocytoma Presenting With Visual Symptoms Due to Bilateral Optic Nerve Sheath Involvement

A 23 year old man presented with transient visual obscurations and was found to have optic nerve edema and a thalamic lesion that did not enhance on magnetic resonance imaging. Lumbar puncture opening pressure was normal. Subsequent magnetic resonance images demonstrated optic nerve sheath enhancement. Pathological diagnosis of the thalamic mass was anaplastic astrocytoma (WHO grade III). Visual symptoms were attributed to spread of high grade parenchymal glioma to the optic nerve sheaths causing intraorbital optic nerve compression.

Prognostic value of the interval from surgery to initiation of radiation therapy in correlation with some histo-clinical parameters in patients with malignant supratentorial gliomas

Aim of the studyTo determine the relationship between the interval from surgery to initiation of radiation therapy (ISRT) and prognostic factors, such as age, performance status, tumour location, extent of surgical resection and tumour histology in patients with malignant gliomas.Materials and methodsFrom 1995 to 2005, 308 adults patients with supratentorial malignant gliomas (198 glioblastomas, and 110 anaplastic astrocytomas) received postoperative radiotherapy with radical intent. A total tumour dose of 60 Gy in 30 fractions in 6 weeks was delivered. ISRT varied from 15 to 124 days, with median time of 37 days, and it was a cut-off value to assess the results. The end point in our study was two-year overall survival.ResultsThe two-year overall survival rate in the whole group was 17%, with 24% for patients with ISRT value ≤ 37 days, and 14% for patients with an interval longer than 37 days (p = 0.042).Univariate analysis showed that delayed initiation of radiotherapy influenced the outcome of patients with glioblastoma older than 40 years, and with other than frontal location of tumour. Two-year overall survival rates for ISRT ≤ 37 days were 15%, 18% and 22% respectively, compared to 8%, 4% and 11% for ISRT > 37 days. In a multivariate analysis (Cox's model) the only variables that were significantly associated with worse survival were older age and ISRT prolonged for more than 37 days.ConclusionThe study showed longer than 37 days waiting time from surgery to initiation of radiotherapy to be a significant predictor of overall survival for adult patients with malignant supratentorial gliomas.

452 Novel in vivo imaging of acute chemotherapy-induced vascular toxicity

To estimate the maximum-tolerated dose (MTD); study the pharmacology of escalating doses of gefitinib combined with radiation therapy in patients ⩽21 years with newly diagnosed intrinsic brainstem gliomas (BSG) and incompletely resected supratentorial malignant gliomas (STMG); and to investigate epidermal growth factor receptor (EGFR) amplification and expression in STMG.Three strata were identified: stratum 1A – BSG; stratum IB – incompletely resected STMG not receiving enzyme-inducing anticonvulsant drugs (EIACD); and stratum II – incompletely resected STMG receiving EIACD. Dose escalation using a modified 3 + 3 cohort design was performed in strata IA and II. The initial gefitinib dosage was 100 mg/m2/d commencing with radiation therapy and the dose-finding period extended until 2 weeks post-radiation. Pharmacokinetics (PK) and biology studies were performed in consenting patients.Of the 23 eligible patients, 20 were evaluable for dose-finding. MTDs for strata IA and II were not established as accrual was halted due to four patients experiencing symptomatic intratumoral haemorrhage (ITH); two during and two post dose-finding. ITH was observed in 0 of 11 patients treated at 100 mg/m2/d, 1 of 10 at 250 mg/m2/d and 3 of 12 at 375 mg/m2/d. Subsequently a second patient at 250 mg/m2/d experienced ITH. PK analysis showed that the median gefitinib systemic exposure increased with dosage (p = 0.04). EGFR was over-expressed in 5 of 11 STMG and amplified in 4 (36%) samples.This trial provides clear evidence of EGFR amplification in a significant proportion of paediatric STMG and 250 mg/m2/d was selected for the phase II trial.

A phase I and biology study of gefitinib and radiation in children with newly diagnosed brain stem gliomas or supratentorial malignant gliomas

Purpose To estimate the maximum-tolerated dose (MTD); study the pharmacology of escalating doses of gefitinib combined with radiation therapy in patients ⩽21 years with newly diagnosed intrinsic brainstem gliomas (BSG) and incompletely resected supratentorial malignant gliomas (STMG); and to investigate epidermal growth factor receptor (EGFR) amplification and expression in STMG. Patients and methods Three strata were identified: stratum 1A – BSG; stratum IB – incompletely resected STMG not receiving enzyme-inducing anticonvulsant drugs (EIACD); and stratum II – incompletely resected STMG receiving EIACD. Dose escalation using a modified 3 + 3 cohort design was performed in strata IA and II. The initial gefitinib dosage was 100 mg/m 2/d commencing with radiation therapy and the dose-finding period extended until 2 weeks post-radiation. Pharmacokinetics (PK) and biology studies were performed in consenting patients. Results Of the 23 eligible patients, 20 were evaluable for dose-finding. MTDs for strata IA and II were not established as accrual was halted due to four patients experiencing symptomatic intratumoral haemorrhage (ITH); two during and two post dose-finding. ITH was observed in 0 of 11 patients treated at 100 mg/m 2/d, 1 of 10 at 250 mg/m 2/d and 3 of 12 at 375 mg/m 2/d. Subsequently a second patient at 250 mg/m 2/d experienced ITH. PK analysis showed that the median gefitinib systemic exposure increased with dosage ( p = 0.04). EGFR was over-expressed in 5 of 11 STMG and amplified in 4 (36%) samples. Conclusion This trial provides clear evidence of EGFR amplification in a significant proportion of paediatric STMG and 250 mg/m 2/d was selected for the phase II trial.

Biopsy versus resection in the management of malignant gliomas: a systematic review and meta-analysis

The aim of this study was to answer the question whether quality of life and progression-free and overall survival are increased in adults with supratentorial malignant glioma who are treated with cytoreductive resection as compared with those who only undergo biopsy. A literature search of the electronic databases MEDLINE, EMBASE, and CENTRAL was performed to identify relevant studies published before May 2008. Hand-searching of reference lists of the identified studies and relevant review articles was also performed. A study was considered eligible, regardless of study design (prospective or retrospective), if: 1) quality of life and/or progression-free and/or overall survival was compared among adult patients undergoing biopsy or resection, and 2) patient age and Karnofsky Performance Scale scores were not significantly different among the 2 groups compared. One randomized controlled trial and 4 retrospective studies (involving a total of 1111 patients) were found eligible for this systematic review. A meta-analysis of the eligible studies demonstrated a significant increase in overall survival in the patients treated with resection instead of biopsy (hazard ratio 0.61, 95% CI 0.52-0.71, p < 0.0001, fixed-effect model). Although statistical pooling was not feasible, the available data suggest that quality of life was increased in patients treated with resection rather than biopsy, while there did not seem to be any significant difference in progression-free survival between the 2 groups. Based on the best available evidence, it appears that cytoreductive resection in adults with supratentorial malignant glioma is associated with improved overall survival as compared with biopsy. However, well-designed prospective studies are needed for more solid conclusions to be drawn.

The Prognostic Value of Erythrocyte Polyamine in the Post-Nephrectomy Stratification of Renal Cell Carcinoma Specific Mortality

The polyamines spermine and spermidine are ubiquitous polycationic structures which are essential for cell proliferation and differentiation. Circulating polyamines, spermine and spermidine, represent valuable prognostic markers in prostate cancer, acute leukemia and supratentorial malignant glioma. We tested whether spermine and spermidine could improve the prognostic ability of several established predictors of cancer specific mortality after partial or radical nephrectomy for renal cell carcinoma. Testing was performed on 399 patients with stages T(1-4), N(0-2), M(0-1) renal cell carcinoma who were treated with radical or partial nephrectomy at a single institution between 1990 and 2007. Univariable and multivariable Cox regression models tested the prognostic ability of spermine and spermidine levels in cancer specific mortality predictions. Covariates consisted of TNM stage, Fuhrman grade, tumor size and symptom classification. Harrell's concordance index (c-index) quantified accuracy and 200 bootstrap resamples were used to correct for overfit bias. The 5-year cancer specific mortality-free survival of patients with spermine levels 3 or less, 3.1 to 8, 8.1 to 13 and greater than 13 nmol/8x10(9) erythrocytes was 88.8%, 75.8%, 40.2% and 21.8%, respectively. Similarly the 5-year cancer specific mortality-free survival of patients with spermidine levels 12 or less, 12.1 to 15, 15.1 to 21 and greater than 21 nmol/8x10(9) erythrocytes was 79.0%, 56.6%, 53.2% and 27.4%, respectively. On multivariable analyses addressing cancer specific mortality after surgery spermine (p = 0.007) and spermidine (p = 0.04) achieved independent predictor status. Consideration of spermine and spermidine also improved the accuracy of established cancer specific mortality predictors by 2.2% (p <0.001). Spermine and spermidine may significantly improve the prognostic value of established cancer specific mortality predictors after partial or radical nephrectomy for all stages of renal cell carcinoma. Independent external validation of our findings is required.

Entry Points for Catheter Placement in Convection-Enhanced Delivery – A Retrospective Anatomic Analysis

Planning the trajectories for catheter positioning in convection-enhanced delivery (CED) is delicate. The bulk flow follows the path of least resistance. Additional factors such as the varying tumor location and the functional relevance of the surrounding brain areas add to complicate the trajectory planning even further. Therefore several criteria have been established, dealing with the correct general entry and target point position. The goal of our study was to analyze the trajectories for CED catheters placed in our department to find preferable entry point positions. We retrospectively looked at 51 trajectories for CED catheters planned with neuronavigation during 2003-2005 for 21 patients with supratentorial malignant gliomas. We evaluated the entry points for their anatomic position, the functional relevance of the area and their parameter to reach the important white matter tracts for CED. This was done using the anatomic literature, macroscopical studies in our laboratory on human autopsy brains and MR imaging. Most tumors were located in the fronto-temporo-parietal region. For these locations catheters were predominantly placed via the superior parietal lobule and the superior frontal gyrus. Looking at the anatomic literature and our laboratory results we characterized these areas with properties predisposing them for catheter placement as having wide superficial gyri and few deep sulci. In addition, they have far less functional relevance than the surrounding eloquent areas. Most relevant white matter tracts can be reached from these entry points. Accordingly, we have defined 2 areas that appear most suitable as entry points in CED catheter placement: the superior parietal lobule and superior frontal gyrus. Inserting CED catheter via the described entry points will presumably save time in planning and reduce side effects.

Concurrent radiotherapy: fotemustine combination for newly diagnosed malignant glioma patients, a phase II study

Fotemustine is a nitrosourea compound used for the treatment of malignant gliomas, especially in France. Recently, an EORTC-NCIC study has shown that a concomitant combination of radiotherapy plus temozolomide (an oral cytotoxic drug) improved survival in glioblastoma patients. We set out to test a concurrent combination of radiotherapy and fotemustine for newly malignant gliomas. A prospective single-center phase II study opened for accrual in September 2004. Patients over 18 years of age able to give informed consent and with histologically proven, newly diagnosed supratentorial malignant gliomas were eligible. All patients were treated by a standard cranial irradiation (conformal irradiation, tumor bulk plus a margin of 2.5 cm) and concomitant daily administration of 10 mg/m(2) of fotemustine (5 days per week, 6 weeks, 1 h 30 min before radiation therapy). Adjuvant chemotherapy, fotemustine, was administered at tumor progression as standard and classic regimen. Twenty-two patients were enrolled, 16 men and 6 women, median age 56 years (range 32-74), median Karnofsky performance status 70 (range 60-90). Histology included 16 glioblastomas, 3 anaplastic astrocytomas, 2 anaplastic oligodendrogliomas and 1 mixed glioma. Eight patients underwent surgery (three total resections). Fourteen patients had a stereotactic biopsy. The concurrent radiotherapy-fotemustine combination was well tolerated: toxicity was mild and three hematologic toxicities grade 3-4 were observed. Median survival from the initial diagnosis was 9.9 months, two patients are currently alive. Median survival was 11 months for surgery and 9 months for stereotactic biopsy. Concomitant radiotherapy-fotemustine combination is safe and well tolerated. Overall survival of over 10 months for the whole population compares favorably with other reports.

Bevacizumab and irinotecan treatment for progressive diffuse brainstem glioma: case report

Diffuse brainstem glioma carries a dismal prognosis. The current cornerstone of treatment is radiation therapy. Chemotherapy appears to be ineffective and the role of this treatment in the recurrent or progressive setting is not known. Bevacizumab and irinotecan have been reported to have shown radiographic response and improvement in progression-free survival among patients with malignant supratentorial gliomas. In this paper, we report our experience in an adult patient with progressive diffuse brainstem glioma treated with bevacizumab and irinotecan.