Natural history and management of brainstem gliomas in adults. A retrospective Italian study.

Brainstem gliomas in adults are rare tumors, with heterogeneous clinical course; only a few studies in the MRI era describe the features in consistent groups of patients. In this retrospective study, we report clinical features at onset, imaging characteristics and subsequent course in a group of 34 adult patients with either histologically proven or clinico-radiologically diagnosed brainstem gliomas followed at two centers in Northern Italy. Of the patients 18 were male, 14 female, with a median age of 31. In 21 of the patients histology was obtained and in 20 it was informative (2 pilocytic astrocytoma, 9 low-grade astrocytoma, 8 anaplastic astrocytoma and 1 glioblastoma). Contrast enhancement at MRI was present in 14 patients. In all of the 9 patients who were investigated with MR spectroscopy, the Cho/NAA ratio was elevated at diagnosis. In 8 of the patients, an initial watch and wait policy was adopted, while 24 were treated shortly after diagnosis with either radiotherapy alone [4] or radiotherapy and chemotherapy [20] (mostly temozolomide). Only minor radiological responses were observed after treatments; in a significant proportion of patients (9 out of 15) clinical improvement during therapy occurred in the context of radiologically (MRI) stable disease. Grade III or IV myelotoxicity was observed in 6 patients. After a follow-up ranging from 9 to 180 months, all but 2 patients have progressed and 14 have died (12 for disease progression, 2 for pulmonary embolism). Median overall survival time was of 59 months. Investigation of putative prognostically relevant parameters showed that a short time between disease onset and diagnosis was related to a shorter survival. Compared with literature data, our study confirms the clinical and radiological heterogeneity of adult brainstem gliomas and underscores the need for multicenter trials in order to assess the efficacy of treatments in these tumors.

Methotrexate based chemotherapy and deferred radiotherapy for primary central nervous system lymphoma (PCNSL): single institution experience.

In the following study, we present our experience in the treatment of PCNSL patients using a multi-step schedule combining chemotherapy and deferred radiotherapy. Patients were treated with two modified M-BACOD cycles and then differently according to radiological response For PR, SD and PD patients, chemotherapy was interrupted and radiotherapy initiated immediately (45 Gy Whole-brain RT). With CR patients, chemotherapy was continued with a combination of HMTX, VCZ, PCB and HD Ara-C up to a total of nine cycles. In 36 patients suitable for evaluation (2 patients had undergone tumour resection): 69.4% (25 of 36) had a complete response (CR), 19.4% (7 of 36) had a partial response(PR), 8.3% (3 of 36) had stable disease(SD), and 2.7% (one of 36) had progressive disease (PD). The PR, SD and PD patients were immediately treated by radiotherapy. In this cohort of patients, we observed 6 CR, 4 PR and 2 PD, respectively, following radiotherapy. At first relapse, a total of 16 CR patients were treated by radiotherapy for a total dose of 45 Gy. The OS was 42.1 months for the entire group of patients. In CR patients treated at the moment of recurrence by salvage radiotherapy, the TTP (time lasting from histological diagnosis until recurrence of disease before RT) was 28.3 months, with a 43.4% of disease free patients observed at 2 years. The median disease-free time observed after complete response to radiotherapy was 10.5 months. In 16 patients (34%), further progression of disease was observed following radiotherapy. Two patients developed extra-CNS disease in the breast and testis. When taking into account the patients with radiotherapy delayed at recurrence, the OS was 48 months and the survival rates were 70% and 60% at 2 years and 5 years, respectively.

Expression of cannabinoid receptors and neurotrophins in human gliomas.

Recent studies have shown an anti-tumour activity of cannabinoid receptors CB1 and CB2 in gliomas. This effect was mediated by neurotrophins in breast and prostate carcinoma, while in gliomas this relationship has not yet been considered. The aim of this study was to investigate the expression of cannabinoid receptors CB1 and CB2, neurotrophin NGF and NT-3 and their receptors TrkA and TrkC in glioma and endothelial cells. The analysis was performed in 14 gliomas and 2 non-tumour brain specimens by immunohistochemistry and real-time quantitative-polymerase chain reaction (RTQ-PCR). Gliomas showed a weak immunoreactivity for CB1 and CB2 in tumour and in endothelial cells, and for NGF/TrkA mainly in tumour cells, while a moderate/diffuse immunoreactivity was found for NT-3/TrkC. CB2 was expressed on 3 out of 6 low-grade gliomas and in all high-grade gliomas. Non-tumour brain tissues were weakly positive in astrocytes and endothelium for CB1, CB2, NT-3 and TrkC and negative for NGF and TrkA. By RTQ-PCR, gliomas showed low mRNA levels of NGF/TrkA and moderate levels of CB1, NT-3 and TrkC. CB2 mRNA expression was low or absent. A potential role of cannabinoids, particularly of CB2 agonists devoid of psychotropic side effects, in glioma therapy could have a basis in glioblastomas, because they were all positive, though weakly, to CB2. The presence of neurotrophins and their receptors, mainly NT-3 and TrkC, suggests a possible role of these pathways in glioma growth/invasion, but further investigations are required to verify this hypothesis and a potential relationship between cannabinoids and neurotrophins.

Meningitis following relapsing painful ophthalmoplegia in aspergillus sphenoidal sinusitis: a case report.

We report the case of a 58-year-old woman in whom relapsing painful ophthalmoplegia related to a mycetoma of the sphenoid sinus gave origin to meningitis with markedly depressed glucose levels in the cerebrospinal fluid. Surgical exeresis of the mycetoma allowed aetiological diagnosis (aspergillosis) and--together with antimycotic therapy--led to durable clinical response.

Molecular markers of gliomas: a clinical approach.

Over the last decade, the knowledge on the molecular genetic background of gliomas has dramatically increased. This information provides the basis for the molecular target therapies and molecular tests serve to complement the subjective nature of histopathologic criteria and add useful data regarding response to treatments and prognosis. In particular, the use of loss of heterozygosity (LOH) and methylation specific polymerase chain reaction (PCR) (MSP) based testing of gliomas is already in place and used clinically in several centers. This paper provides a brief overview of these molecular genetic aberrations and discusses the clinical utility, as well as the advantages and disadvantages of such approach. Newly developed molecular techniques, such as LOH testing, fluorescence in situ hybridization (FISH), DNA sequencing and MSP, are currently being employed in assessment of gliomas in some laboratories. However, the clinical use of some markers and the context in which the information obtained should be used are still not entirely understood. Therefore, this paper will focus on validation and implementation of molecular testing in gliomas, with emphasis on LOH on chromosomes 1p, 19q, 17p and 10q and O(6)-methylguanine-DNA methyltransferase (MGMT) methylation status.

Systemic temozolomide combined with loco-regional mitoxantrone in treating recurrent glioblastoma.

Twenty-two recurrent GBM patients were enrolled for second tumor debulking with local positioning of a Rickam reservoir, in order to locally deliver chemotherapy with the aim of controlling local tumor recurrence. We designed a protocol using systemic temozolomide (150 mg/sqm days 1-5 every 28) in association with mitoxantrone, delivered through the reservoir (4 mg/day 1-5 every 28) positioned into the area of tumor exeresis. After re-operation a residual tumor mass no larger than 2 cm was identified in 18/22 patients. The patients were treated with monthly cycles of chemotherapy until evolution of the tumor, but in no case for more than 10 cycles. Responses were evaluated by MRI scans performed every 2 months and images assessed according to MacDonald's criteria. Response rate: no complete responses (CR), 5 partial responses (PR), 13 stable disease (SD) and 4 progressive disease (PD) occurred. The median progression-free survival (PFS) and survival time (ST) of the whole group of treated patients was 7 and 11 months, respectively and more than a quarter of the patients survived over 18 months. During the study, the patients' compliance was complete and no dropouts occurred. Hematological toxicity was mild and after repeated local injections only minor neurological side-effects occurred. Despite some bias in patients' selection not excluded in this pilot study, results are interesting: the PFS was as long as the survival of recurrent GBM reported in the literature.

CXCL12 expression is predictive of a shorter time to tumor progression in low-grade glioma: a single-institution study in 50 patients.

The clinical course of 50 patients with low-grade glioma (31 male, 19 female) undergoing surgery at a single Institution from 1992 to 1996 was analyzed in relationship with known prognostic factors as far as time to tumor progression (TTP) and survival time (ST) are concerned. Moreover, microvessel density (MVD) and expression of the angiogenesis-related chemokine CXCL12 were investigated in surgical specimens. Age at diagnosis ranged from 1 to 68 years (median 30). Histology revealed 11 fibrillary, 6 protoplasmatic, 5 gemistocytic astrocytoma, 18 oligoastrocytoma and 10 oligodendroglioma. Mean follow-up was 86 months. Four patients were lost to follow-up. Of the remaining 46, twenty-four have shown disease progression and 14 have died. Median overall survival was not achieved; an estimated 75% percentage of survivors was found at 78 months. Complete gross tumor removal was associated to a longer TTP (P = 0.04 logrank). Of the investigated immunohistochemical parameters, while MVD was not predictive of subsequent TTP, expression of CXCL12 was associated with a significantly shorter TTP (P = 0.01 logrank): this predictive value remained significant (P = 0.02) at multivariate analysis. The data suggest the possible prognostic value for CXCL-12 (an angiogenesis- and tumor-growth-related chemokine) on TTP in low-grade gliomas.

Expression of drug resistance proteins Pgp, MRP1, MRP3, MRP5 and GST-pi in human glioma.

Chemotherapy in glioma is poorly effective: the blood-brain barrier and intrinsic and/or acquired drug resistance of tumor cells could partly explain this lack of major effect. We investigated expression of P-glycoprotein (Pgp), multidrug resistance protein (MRP) 1, MRP3, MRP5 and glutathione-S-transferase pi (GST-pi) in malignant glioma patients. Cytofluorimetric analysis of 48 glioma specimens and 21 primary cultures showed high levels of MRP1, moderate levels of MRP5 and low levels of Pgp, GST-pi and MRP3. Immunohistochemistry (25 glioma specimens) showed expression of GST-pi (66.7% of cases), MRP1 (51.3%), MRP5 (45.8%), Pgp (34.8%) and MRP3 (29.9%) in tumor cells. Moreover, analysis of tumor samples by real time quantitative PCR showed mRNA expression of all investigated genes. Tumor vasculature, analyzed in glioma specimens and in tumor derived endothelial cells, showed expression of all investigated proteins. Non-tumor brain samples (from a patient with arteriovenous malformation and from one with epilepsy), normal human astrocytes and cultured endothelial cells were also analyzed: astrocytes and endothelial cells expressed the highest levels of the investigated proteins, mainly MRP1 and MRP5. No significant differences in proteins expression were detected between primary or recurrent gliomas, suggesting that glioma chemoresistance is mostly intrinsic. Therefore, we detected, for the first time, the presence of MRP3 and MRP5 on glioma specimens--both in tumor and endothelial cells--and we delineated an expression profile of chemoresistance proteins in glioma. The possible association of inhibitors of drug efflux pumps with chemotherapy could be investigated to improve drugs delivery into the tumor and their cytotoxic effects.

Local drug delivery in recurrent malignant gliomas.

In recurrent malignant gliomas, we scheduled a protocol by adding to systemic temozolomide a local treatment delivered through a reservoire positioned in the surgically created cavity, consisting of either mitoxantrone, liposome-loaded doxorubicine or nimustine (ACNU). The progression-free survival (PFS) and survival time (ST) of the whole group of 112 patients were 8.3 and 11 months, respectively, in GBM patients, and 14 and 18 months in AA patients. To limit the selection bias in recruitment we matched locally treated patients with the whole group of patients treated for 3 years and having undergone the same protocol with the exception of local drug delivery. Variables such as age, histology and local chemotherapy delivery were proved to be statistically significant independent factors on adjunctive PFS and ST. Another group of 12 recurrent malignant gliomas with further progression was locally managed according to convection-enhanced delivery (CED) of mitoxantrone; the preliminary results show good tolerability of the schedule.

The role of the neurologist.

The contribution of the neurologist should focus on timely diagnosis with accurate differential diagnosis, indications for surgery and post-surgical treatment (in the setting of a multidisciplinary team), and follow-up of disease course/treatment-related complications.

Facets and determinants of quality of life in patients with recurrent high grade glioma.

OBJECTIVES: To assess patients with recurrent high grade brain glioma with the aim of evaluating facets of quality of life (QOL) and their association with mood, cognition, and physical performance. METHODS: Ninety four glioma patients (four groups with different duration of glioma recurrence) were compared with 24 patients with other chronic neurological diseases and 48 healthy subjects. The Functional Living Index-Cancer (FLIC) provided QOL self evaluations, and standardised scales and neuropsychological tests assessed physical performance, mood, and cognition. RESULTS: In glioma patients, factor analysis of the FLIC items documented five domains: Psychological well being, Role/sociability, Inner experience of disease, Isolation/sharing, and Nausea. Higher FLIC total scores were related to better cognition, physical performances, and mood, and lower grading; poorer Psychological well being and worse Inner experience of disease to depressed mood; minor Role/sociability to worse cognitive and physical performances and higher grading; worse Nausea to longer disease duration. Compared with healthy subjects, all glioma groups were cognitively impaired and more anxious, and two groups with short duration of recurrence were also more depressed. Patients with chronic neurological diseases showed worse mood and cognitive abilities compared with healthy subjects, but performed attention tests better than glioma patients. Glioma and chronic disease patients showed similar FLIC scores and autonomy. CONCLUSIONS: These results show that QOL of recurrent high grade glioma patients is multifaceted and determined by multiple factors. Disease severity does not necessarily eliminate the possibility of expressing personal feelings and opinions which could provide criteria for clinical decision making and psychological support.

Headache in brain tumours: a symptom to reappraise critically.

Headache can be either a late or early symptom of a brain tumour, depending on the location of the tumour. A constant, progressively increasing pain, or a change in the character of headache pain, may alert the physician to this occurrence. Fortunately most people with headache, even persistent or severe headaches, do not have a tumour. In this work we review the literature about prevalence of headache as an isolated/early symptom of brain tumour and report our experience.

Immunotherapy with bovine aortic endothelial cells in subcutaneous and intracerebral glioma models in rats: effects on survival time, tumor growth, and tumor neovascularization.

High-grade gliomas are aggressive tumors of the central nervous system characterized by endothelial cell proliferation and a high degree of vascularity. Conventional antitumoral treatments (i.e., surgery, radiotherapy, and chemotherapy) do not achieve satisfactory results (median survival in glioblastoma 12-18 months). It has been suggested that immunotherapy with xenogenic endothelial cells could slow tumor growth rate in a number of tumors in a murine model, but the study did not include gliomas. In experiments performed in our laboratory, vaccination with proliferating bovine aortic endothelium increased survival time in Fischer rats inoculated intracerebrally with 9L. Immunotherapy was also able to reduce the growth of subcutaneously injected 9L gliosarcoma cells in Fischer rats and to decrease microvessel density within the tumors, in the absence of major organ toxicity. Immunoglobulins (Ig) in the sera from vaccinated rats stained bovine aortic endothelium as well as human umbilical vein endothelium in active proliferation. Moreover, immune sera from immunized rats stained microvessels of human malignant glioma specimens and vessels of intracerebrally implanted tumors. Two proteins of MW of 11 and 19 kDa were identified by Western blot as targets of Ig elicited by vaccination. A possible future development is to select peptides/proteins suitable for vaccination in humans, avoiding the biohazards connected with xenogenic whole-cell vaccination.

Effects of thalidomide on parameters involved in angiogenesis: an in vitro study.

In an attempt to elucidate the mechanism(s) of action of thalidomide, a reportedly antiangiogenic molecule recently tested in the treatment of relapsing malignant gliomas, we performed an in vitro study on the following parameters: (a) effect of thalidomide on proliferation of endothelial cells; (b) effect of thalidomide on expression of alpha(v)beta3 integrin on the surface of endothelial cells; (c) effect of thalidomide on the release by endothelial cells of MMP-2, IL-8 and TNF-alpha. The results show that thalidomide inhibits endotelial cell proliferation induced by bFGF and VEGF, more so if the cells are grown on vitronectin; moreover, treatment with thalidomide reduces the release of MMP-2 and IL-8 by endothelial cells, suggesting a further pathway for the antiangiogenic activity of drug. On the other hand, thalidomide does not modify expression of alpha(v)beta3 on endothelial cells.

New approach in delivering chemotherapy: locoregional treatment for recurrent glioblastoma (rGBM).

The treatment of GBM tumor recurrence is generally a hopeless challenge, since recurred tumor is resistant to the most common therapeutic efforts. Some partial results can be achieved by targeting local disease control, in view of the fact that 95% of recurrences occur locally. We present results concerning three pilot studies, all performed in recurrent GBM patients who underwent second surgery and have been treated systemically with temozolomide and locally through an Ommaya reservoire according to the following schedules: a) in 20 rGBM, 4 mg novantrone was delivered day 1,5 every 30 days; in 26 rGBM, 4 mg novantrone was delivered every 20 days in association with locoregional radioimmunotherapy (RIT); in 12 rGBM pegylated liposomal doxorubicin 4 mg was delivered day 1,5,10,15,20 with 20 days interval. Results seem very promising since there is an extension of disease free and survival, both of more than 50 % if results are evaluated in relation with the most frequent data of the literature.

Intra-arterial ACNU and carboplatin versus intravenous chemotherapy with cisplatin and BCNU in newly diagnosed patients with glioblastoma.

Thirty glioblastoma patients treated at our institute between April 1998 and September 1999 were randomized in a two-arm study to receive carboplatin plus ACNU intraarterial (IA) chemotherapy (arm A) or cisplatin plus BCNU intravenous (IV) treatment (arm B). After the second course of chemotherapy and before the third cycle they also received concomitant radiotherapy, consisting of a median dose of 56.5 Gy. There were 3 (21.4%) partial responses and 11 (78.6%) disease stabilizations in group A. There were 5 (33%) partial responses and 10 disease stabilizations in group B. Time to tumor progression was 5.2 and 5.8 months for IA and IV treatment respectively. Median survival time was 18.3 months for arm A patients and 18.6 for arm B patients. Our IA chemotherapy schedule has produced no conclusive evidence of benefit compared with intravenous treatment. Moreover, its cost-benefit ratio is not good enough to justify its continued pursuit.