Topotecan in combination with radiotherapy in unresectable glioblastoma: a phase 2 study.

Improving glioblastoma multiforme (GBM) treatment with radio-chemotherapy remains a challenge. Topotecan is an attractive option as it exhibits growth inhibition of human glioma as well as brain penetration. The present study assessed the combination of radiotherapy (60 Gy/30 fractions/40 days) and topotecan (0.9 mg/m(2)/day on days 1-5 on weeks 1, 3 and 5) in 50 adults with histologically proven and untreated GBM. The incidence of non-hematological toxicities was low and grade 3-4 hematological toxicities were reported in 20 patients (mainly lymphopenia and neutropenia). Partial response and stabilization rates were 2% and 32%, respectively, with an overall time to progression of 12 weeks. One-year overall survival (OS) rate was 42%, with a median OS of 40 weeks. Topotecan in combination with radiotherapy was well tolerated. However, while response and stabilization concerned one-third of the patients, the study did not show increased benefits in terms of survival in patients with unresectable GBM.

Cerebellar pleomorphic xanthoastrocytoma: case report and literature review.

BACKGROUND: PXA generally has histologic features characteristic of benign biological behavior, although malignant forms have been reported. This neoplasm has also been observed in atypical locations. METHODS: The authors report a case of cerebellar PXA with rapid malignant transformation in a 58-year-old woman and review the rare presentations and atypical features of this tumor. RESULTS: Among the "unusual" locations, the most frequent is the cerebellum with 15 cases having been described, 9 in adults, with an average age of 33 years. In contrast, supratentorial forms had a younger age profile (26 years). The time from onset of symptoms to diagnosis was approximately 5.3 months. PXA in the posterior fossa had a higher rate of solid enhancing tumor (9/14). Regarding histologic appearance, two thirds were composite lesions. CONCLUSIONS: The clinicopathologic features of cerebellar PXA show some differences from PXA located in the cerebral hemispheres. Recognizing the potential for PXA to present with unusual manifestations, regardless of location, has an obvious impact on the accuracy of diagnosis.

Pathophysiology of glioma cyst formation.

Fluid filled cystic cavities are accompaniments of some cerebral gliomas. These tumoural cysts together with peritumoural vasogenic brain oedema add to the morbid effects of the gliomas in terms of mass effect and increased intracranial pressure. Although different mechanisms have been suggested as to the pathogenesis of glioma-associated cysts, it is still unclear why these cysts appear in only a limited number of cerebral gliomas while brain oedema, a probable precursor of glioma cysts, is a usual accompaniment of most gliomas. Here, the authors present a two-hit hypothesis of brain glioma cyst formation. We suggest that after the formation of vasogenic tumoural brain oedema, microvascular phenomena may lead to the formation of microcysts, which might later become confluent and grow to form macroscopic cysts. Progress in the understanding of pathogenesis of cerebral glioma cysts might set targets for treatment of brain edema and glioma cysts.

Oligodendroglioma: clinical study and survival analysis correlated with chromosomal anomalies.

OBJECT: Demonstration of the loss of chromosomes 1p and 19q in the presence of a brain neoplasm marks the emergence of genotype as a prognostic indicator. The authors report gene expression data for oligodendroglioma and correlate genotype with response to therapy. Gene expression subgroups may represent distinct types of disease. METHODS: Eighty-seven cases of supratentorial oligodendroglioma were selected from 145 cases treated in a single center between January 1990 and December 2001. Fluorescence in situ hybridization was used to determine the status of chromosomes 1p and 19q. Parameters evaluated included clinical data and radiological and histological features. Univariate and multivariate analyses were performed and a probability value less than 0.05 was considered significant. The patients included 48 women and 39 men. The overall mean age at presentation was 45 years for women and 36 years for men (p = 0.006). The univariate analysis identified the following as favorable prognostic factors: younger patient age (p = 10(-5)), female sex (p = 0.0025), seizure as a presenting symptom (p = 10(-5)), normal clinical examination (p = 10(-5)), absence of lesion enhancement on neuroimaging studies (p = 0.0231), lack of histological necrosis (p = 0.0003), absence of mitoses (p = 0.0014), 1p and 19q deletions (p = 0.0001), absence of recurrence (p = 0.0021), and adjuvant radiotherapy and/or chemotherapy (p = 10(-5)). The multivariate analysis identified patient age (p = 10(-5)) and chromosomal anomalies (p = 0.002) as independently linked to survival. Three molecular subtypes emerged: oligodendroglioma with 1p and 19q deletions, oligodendroglioma demonstrating polysomia and a lack of meaningful response to radiotherapy or chemotherapy, and oligodendroglioma with no 1p-9q deletion in which partial response was seen. CONCLUSIONS: According to our data, oligodendrogliomas could be divided into three molecular subtypes. Although chemotherapy seems efficient for managing this tumor, additional studies should be conducted to compare the efficacy of radiotherapy and chemotherapy.

Gowers intrasyringal hemorrhage. Case report and review of the literature.

The concept of hemorrhage in a preexisting syringomyelic cavity was first described by Gowers in 1904. Since its first description only 13 cases have been reported. The aims of this report are to describe a new case, bring this entity to wider attention, and summarize the existing literature on the subject. This 36-year-old woman presented with progressive gait disturbance and unsteadiness. Physical examination revealed incomplete quadriparesis, predominantly on the left side, and hypesthesia below C-7. Magnetic resonance imaging revealed hematomyelia characterized by a heterogeneous hyperintense signal within the central cervical cord. A liquefied well-limited hematoma was evacuated. The postoperative course was uneventful; a near-complete recovery was observed at the 7-year follow-up examination. Most cases of intrasyringal hemorrhage (ISH) have occurred in syringomyelic cavities associated with scoliosis or Chiari malformation Type I. Although there is no specific clinical picture associated with this entity, it can be characterized by three neurological forms: 1) sudden onset or rapid development of signs and symptoms, 2) acute worsening of symptoms that may improve but leaving greater neurological dysfunction than before the previous episode, and 3) ISH may initiate progressive deterioration in a patient with known syringomyelia. Intrasyringal bleeding is most probably caused by a sudden dilation of the syringomyelic cavity, which may provoke rupture of the intrasyringal vessels by an acute distension of the accompanying strands. Magnetic resonance imaging is the most accurate diagnostic modality, and recognition of ISH can lead to early, safe, and efficient surgical treatment.

Cerebellar malignant fibrous histiocytoma: case report and literature review.

OBJECTIVE AND IMPORTANCE: Malignant fibrous histiocytoma in the central nervous system is uncommon. Fewer than 70 cases have been documented and, to the best of our knowledge, this is the first case arising from the cerebellum. CLINICAL PRESENTATION: A 44-year-old woman presented with headaches, vomiting, and dizziness. A neurological examination revealed right cerebellar syndrome. Brain computed tomographic scans revealed an isodense tumor in the right cerebellar hemisphere. The breast ultrasonographic, bone scintigraphic, and thoracoabdominal computed tomographic findings were normal. INTERVENTION: The patient was surgically treated. The tumor recurred 1.5 months later, demonstrating hemorrhagic characteristics on brain computed tomographic scans. The patient underwent a second operation, followed by radiotherapy. CONCLUSION: Malignant fibrous histiocytoma is still a controversial entity, and the lack of specific criteria means that it must be diagnosed via the process of elimination. With currently available therapy, our review can provide only a very poor prognosis. The median survival time was 27 months. In attempts to develop better therapeutic strategies, total excision and radiotherapy seem to represent the best treatment approach.

Malignant transformation of intracranial epidermoid cyst with leptomeningeal carcinomatosis: case report.

INTRODUCTION: Although rare, the malignant degeneration of epidermoid cysts is well documented. Its occurrence with leptomeningeal dissemination and malignant cells in CSF is scarce. To the best of our knowledge only four cases have been reported. CASE REPORT: The authors report the case of malignant transformation of an epidermoid cyst with leptomeningeal carcinomatosis (which simulates aseptic meningitis) in a 54 year-old woman. Changes in CSF and radiological features are not correlated with the clinical course. Despite improvement of both the lesions on the scan images and the malignant cells in the CSF under chemotherapy the patient died. CONCLUSION: The differential diagnosis of malignant degeneration of epidermoid cyst, and leptomeningeal carcinomatosis are discussed. The diagnosis of malignant transformation should be retained when MRI (or CT scan) shows contrast enhancement at the epidermoid site, and malignant cells are detected in CSF The prognosis is generally poor.

Expression of nine tumour antigens in a series of human glioblastoma multiforme: interest of EGFRvIII, IL-13Ralpha2, gp100 and TRP-2 for immunotherapy.

In this study, we investigated the mRNA and protein expression of nine tumour antigens in human glioblastoma multiforme with a view to their possible use in dendritic cell-based immunotherapy. Expression of ALK, EGFRvIII, GALT3, gp100, IL-13Ralpha2, MAGE-A3, NA17-A, TRP-2 and tyrosinase were studied by real-time RT-PCR on frozen tissues using a series of 47 tumour samples from patients with glioblastoma. Results were compared with non-neoplastic brain expression or glioblastoma samples with very low levels of expression near the limits of detection for EGFRvIII and MAGE-A3, as these latter two antigens were not detected in non-neoplastic brain. Tumour antigens showing a 5-fold increase in mRNA expression were considered as positive, and only antigens displaying an mRNA over-expression in a significant number of cases were analysed by immunohistochemistry on paraffin-embedded sections. Using real time RT-PCR, we found EGFRvIII, gp100, IL-13Ralpha2 and TRP-2 to be positive in 64, 38, 32 and 21% of cases, respectively. While we observed no over-expression for ALK, GALT3 and tyrosinase, 3 samples out of 47 were positive for MAGE-3 and 1 sample for NA17-A. More than 25% of tumour cells showed strong protein expression in 13, 34, 85 and 96% of GBM samples for gp100, TRP-2, EGFRvIII and IL-13Ralpha2, respectively. Interestingly, protein expression of at least 3 antigens was observed in 38% of cases. These results point out the importance of EGFRvIII, IL-13Ralpha2 and, to a less extent gp100 and TRP-2, for developing an immunotherapy strategy against glioblastoma.

Proposal of a scoring scale as a survival predictor in intracranial oligodendrogliomas.

INTRODUCTION: Histological, clinical and radiological features, and molecular genetic analysis are among the factors that have been considered in defining the prognosis of oligodendrogliomas (OD), but they have yielded conflicting results. The purpose of this study was to test out a scoring scale based on clinical, radiological, pathological and molecular features. MATERIAL AND METHOD: To identify factors with prognostic significance, we analyzed 87 treated patients with a histological diagnosis of OD. Of the parameters analyzed, age, onset, clinical status, radiological enhancement, histological necrosis, mitosis and chromosomal anomalies emerged as significant prognosis factors using univariate analysis. Multivariate analysis revealed age and chromosomal anomalies as independent factors of survival. RESULTS: The factors with a significant prognostic value were combined to determine which grouping factors best predict outcome. The proposed score is a pure number resulting from a combination of: 2 major factors: age and chromosomal anomalies (scored 3-0); 5 minor factors: onset, clinical examination, necrosis, mitoses (scored 1-0), and radiological enhancement (scored 2-0). According to our scale, 10 survival curves were produced for overall survival. Recursive partitioning of patients with the nearest score and outcome produced four groups with a significant difference in survival (p=10(-5)). The power of both the scale and the partitioned groups for predicting outcome was more accurate than the WHO and St Anne grading systems, and the molecular sub-classification. CONCLUSIONS: Our scale is a plausible way of classifying patients harboring intracranial OD according to expected survival.

Malignant transformation of intra-cranial epithelial cysts: systematic article review.

INTRODUCTION: Epidermoid and dermoid cysts are among the most benign intra cranial tumors. Their malignant transformation into squamous cell carcinoma is rare. The authors reviewed the literature. MATERIALS AND METHODS: MEDLINE and SCIENCE DIRECT searches, and examination of the references in the selected articles yielded 74 patients, 52 of whom fulfilled Garcia's criteria and were selected for the study. Survival analyses were performed to determine whether survival differences were of statistical significance, and P < 0.05 was considered as significant. RESULTS: Malignant transformation is characterized by a rapid onset of symptoms, recurrence, leptomeningeal carcinomatosis (LC), and tumor enhancement at Computed Tomography Scan or Magnetic Resonance Imaging (87.8 showed this radiological feature). In this review, the SCCs were classified in five groups: (1) Initial malignant transformation of a benign cyst; (2) malignant transformation from a remnant cyst; (3) malignant transformation of a dermoid and epithelial cyst; (4) malignant transformation with leptomeningeal carcinomatosis; (5) other malignancies arising from benign cysts. The median survival was 9 months. Statistics show that LC was of poor prognosis and radiotherapy, although not statistically significant, seems effective against such lesions, with a median survival of 26 months as opposed to 3 months (P=0.077). CONCLUSION: Although rare, malignant transformation of intracranial epithelial cysts has a poor prognosis and surgery followed by radiotherapy seems to be the best therapeutic modality.

Phase I study of topotecan in combination with concurrent radiotherapy in adults with glioblastoma.

A phase I study was performed to determine the maximum tolerated dose and the recommended dose of continuous intravenous infusion of topotecan in combination with radiotherapy (RT) in patients with previously untreated glioblastoma multiforme (GBM). Twenty patients with histologically proven GBM and 1 with rhabdoid tumor were enrolled. After surgery or stereotactic biopsy, patients received cranial RT (60 Gy/30 fractions/40 days) and 3 cycles of topotecan as continuous infusion (CIV) from day 1 to 5 on weeks 1, 3, and 5 during RT. The dose of topotecan was escalated from 0.6 to 1.0 mg/m2/day. Four dose levels were tested. One grade 4 thrombocytopenia was seen at level 1 (topotecan dose 0.6 mg/m2/day; 6 patients). No dose-limiting toxicity was seen at level 2 (0.8 mg/m2/day; 3 patients) or an intermediate level of 2 bis (0.9 mg/m2/day; 6 patients). Six patients were included at level 3 (1.0 mg/m2/day), 4 of whom experienced dose-limiting toxicities, including 3 episodes of grade 4 thrombocytopenia, 1 platelet transfusion, 1 febrile neutropenia, and 1 grade 4 neutropenia of more than 7 days. Eighty percent of patients with GBM were alive at 12 months. The dose-limiting toxicity of topotecan administered as CIV for 5 days every 2 weeks is hematological. The maximum tolerated dose is 1.0 mg/m2/day and the recommended dose is 0.9 mg/m2/day. A phase II trial using the recommended dose of topotecan is ongoing.