Activity and safety of bevacizumab plus fotemustine for recurrent malignant gliomas.

BACKGROUND: No established chemotherapeutic regimen exists for the treatment of recurrent malignant gliomas (rMGs). Herein, we report the activity and safety results of the bevacizumab (B) plus fotemustine (FTM) combination for the treatment of rMGs. PATIENTS AND METHODS: An induction phase consisted of B 10 mg/kg days 1, 15 plus FTM 65 mg/m(2) days 1, 8, and 15. Nonprogressive patients entered the maintenance phase with B 10 mg/kg plus FTM 75 mg/m(2) every 3 weeks. The primary endpoint was response rate; secondary endpoints included safety, progression free survival (PFS), and overall survival (OS). RESULTS: Twenty-six patients affected by recurrent MGs (50% glioblastoma) were enrolled. Eight partial responses (31%) were observed. Median PFS and OS were 4 (95% C.I.: 2.8-5.1) and 6 months (95% C.I.: 4.2-7.8), respectively. Responses were significantly associated with both improved PFS and OS (P = 0.002 and P = 0.001, resp.). Treatment adverse events were mostly mild to moderate in intensity. Bevacizumab-related adverse events included grade 3 venous thromboembolic event (8%), grade 2 epistaxis (4%), hypertension (8%), and gastrointestinal perforation (4%). CONCLUSIONS: Bevacizumab plus FTM showed activity and good tolerability in pretreated MGs. Further investigations are needed in order to verify the benefits deriving from the addition of B to a cytotoxic in this clinical setting of patients.

Lacosamide as add-on in brain tumor-related epilepsy: preliminary report on efficacy and tolerability.

Lacosamide (LCM) is an antiepileptic drug (AED) that has demonstrated a good efficacy in controlling seizures as an add-on in adult epilepsy. To date, there have been no studies on LCM in patients with brain tumor-related epilepsy (BTRE). To evaluate efficacy and tolerability of LCM as an add-on in BTRE, we followed 14 patients suffering from BTRE who had already been treated with other AEDs and who had not experienced adequate seizure control. Eleven patients underwent chemotherapy while being treated with LCM. Mean duration of follow up was 5.4 months (min < 1 max 10 months). Mean seizure number in the last month prior to the introduction of LCM had been 15.4. At last follow-up, the mean seizure number was reduced to 1.9/month. Lacosamide mean dosage was of 332.1 mg/day (min 100 max 400 mg/day). Responder rate was 78.6%. One patient discontinued LCM because of side-effects. There were no other reported side-effects. Preliminary data on the use of LCM in add-on in patients with BTRE indicate that this drug may represent a valid alternative as an add-on in this particular patient population. However, larger samples are necessary in order to draw definitive conclusions.

Efficacy and tolerability of zonisamide as add-on in brain tumor-related epilepsy: preliminary report.

BACKGROUND: Zonisamide (ZNS) is an antiepileptic drug (AED) with broad spectrum action that demonstrated a good efficacy in controlling seizures as add-on in adult and pediatric epilepsy. To date there have been no studies on ZNS in patients with brain tumor-related epilepsy (BTRE). AIM OF THE STUDY: To evaluate efficacy and tolerability of ZNS as add-on in BTRE. METHODS: We followed six patients suffering from BTRE who had already been treated with other AEDs and who had had not experienced adequate seizure control. Three patients underwent chemotherapy while being treated with ZNS. Mean duration of follow-up was 8 months. RESULTS: Mean seizure number in the last month prior to the introduction of ZNS had been 27.7/month. ZNS mean dosage was of 283.3 mg/day. At last follow-up, the mean seizure number was reduced to 8.8/month. Responder rate was 83.3%.Two patients discontinued the drug because of side effects. There were no other reported side effects. CONCLUSIONS: Preliminary data on the use of ZNS in add-on in patients with BTRE indicate that this drug may represent a valid alternative as add-on in this particular patient population. However, larger samples are necessary to draw definitive conclusions.

Outcome and tolerability of topiramate in brain tumor associated epilepsy.

Epilepsy in brain tumor patients is often refractory to pharmacological treatments and can complicate the therapeutic management of these patients. We conducted a prospective, observational study. The aim of this study was to investigate the efficacy and tolerability of topiramate (TPM) in brain tumor associated epilepsy. We studied 47 patients with brain tumors and epilepsy. The entire group was administered AEDs. TPM was the first therapeutic choice in 14 patients, while in the remaining 33 patients previous AEDs were modified and TPM was introduced due to side effects or inefficacy of the first drug. Follow-up ranged from 3 to 48 months (mean 16.5 months). Considering the final follow-up of each patient who assumed TPM for at least 3 months, we observed 45 patients: 25 were seizure free (55.6%), 9 had a reduction of seizure frequency (SF) higher than 50% (20%) and 11 were stable (24.4%). TPM responder rate was 75.6%. Three patients (6.4%) discontinued TPM for severe side effects (1 after 4 months and 2 after 1 month) and 4 (8.5%) had mild and reversible side effects. In the group of patients who had been in therapy with other AEDs prior to entering the study (n = 33), 19 patients had side effects (57.6%). During follow-up, the haematological parameters were in the normative ranges. Tumor-related seizures are difficult to control with AEDs; the precise reasons for this difficulty are not yet clear. Using TPM, we obtained good seizure control with a low incidence of side effects.

Early post-operative MRI: correlation with progression-free survival and overall survival time in malignant gliomas.

Forty-seven patients with Glioblastoma (42) and Anaplastic Astrocytoma (5) were studied with MR 24 hrs after surgery. In order to evaluate the role of early MR in defining the extent of surgical resection and its relation with the prognosis of malignant glioma patients, three categories of surgical resection were considered: gross total, sub-total and partial resection. The results were correlated with progression-free survival (PFS) and overall survival (ST). As demonstrated by early-MR, gross total resection was performed in 17 patients, sub-total and partial resection in 19 and 11 patients, respectively. The PFS was 6 months in gross total resection, 6 and 3 months in sub-total and in partial resection, respectively. The median survival time was 16 months in total resection patients, 13 months and 7 months in sub-total resection and partial resection patients, respectively. The study confirms that early-MR has to be considered an accurate technique for monitoring the extension of malignant glioma surgical resection and shows a good correlation between early-MR findings, PFS and ST.

Temozolomide chemotherapy for progressive low-grade glioma: clinical benefits and radiological response.

BACKGROUND: The optimal treatment for low-grade glioma (LGG) is still controversial. Recent data indicate a potential influence of chemotherapy on the natural evolution of these tumors, allowing for the deferral of more aggressive therapies. PATIENTS AND METHODS: Forty-three patients affected with LGG (29 astrocytoma, four oligodendroglioma and 10 mixed oligo-astrocytoma) were treated with temozolomide (TMZ) at the time of documented clinical and radiological progression. McDonald's response criteria were utilized to evaluate TMZ activity. Thirty patients (69.7%) had previously received radiotherapy; 16 (37.2%) had received prior chemotherapy. Clinical benefit was evaluated measuring seizure control, reduction in steroid dose and modification of Karnofsky performance status and Barthel index. Quality of life was assessed with the QLQ-C30 questionnaire. RESULTS: We observed a complete response in four patients, 16 partial responses, 17 stable disease (with four minor response) and six progressive disease. Median duration of response was 10 months [95% confidence interval (CI) 8-12], with a 76% rate of progression free survival (PFS) at 6 months, and a 39% rate of PFS at 12 months. A relevant clinical benefit was observed particularly in patients presenting epilepsy. CONCLUSIONS: The high response rate of 47% (95% CI 31% to 61%) confirms that TMZ chemotherapy is a valid option in the treatment of progressive LGG. The present preliminary results seem interesting and warrant further evaluation of TMZ clinical activity in a larger series of progressive LGG.

Investigation of genetic alterations associated with development and adverse outcome in patients with astrocytic tumor.

Models describing progression in the genetic derangement of glial tumors have shown chromosomal loss and gain occurring most frequently in high-grade lesions, suggesting that identification of these aberrations may be prognostically significant. In this study, Fluorescence in situ hybridization (FISH) has been used to determine, and to confirm, loss and gain of chromosomes 1, 8, 10, 12 and 17, in formalin-fixed, paraffin-embedded brain biopsy tissue taken from 60 brain gliomas submitted to surgical resection or stereotactic biopsy. FISH analysis may be a valuable adjunct to histological grading. The results showed that this molecular cytogenetic technique is an important clinical and experimental tool that provides new insight on genetic alterations, confirming gain and loss of genetic material that occurs at the initiation and progression of human glioma. Our data suggests that potentially useful prognostic information may be obtained through this approach. Monosomy 10 was the most statistically significant negative predictor of patient survival, showing a significant correlation with the histological grading.

Comparative analysis of proliferating cell nuclear antigen and epidermal growth factor receptor expression in glial tumours: correlation with histological grading.

The present study analyzed the combined immunostaining for proliferating cell nuclear antigen (PCNA) and epidermal growth factor receptor (EGFR) with the aim of obtaining an objective method for the evaluation of the growth fraction in human glial tumors. A retrospective study was undertaken on 157 gliomas employing MoAb PC10 and MoAb 108, recognizing a 36 Kd nuclear protein associated with the cell cycle and the extracellular domain of the EGFR, respectively. The results of this immunohistochemical analysis showed that the rate of PCNA positive cell is directly associated to EGFR expression and significantly (P < 0.0001) correlates with tumor morphological grading, this was also the case in patients submitted to multiple surgical treatments for recurrent tumors. PCNA and/or EGFR are expressed by a minority of low grade astrocytoma, while anaplastic astrocytoma and glioblastoma displayed an intense immunoreactivity for the two antigens in more than 85% of tested cases. These findings indicate that the combined evaluation of PCNA and EGFR could allow a more definite biopathological grading of neuroepithelial brain tumours.

Epilepsy and gliomas: incidence and treatment in 119 patients.

One hundred and nineteen consecutive patients affected by supratentorial gliomas were studied in order to determine the incidence of seizure at diagnosis, the occurrence of subsequent seizures and the efficacy of anticonvulsant treatment. The overall incidence of seizures as presentation symptom was 52% (62 patients). Preoperative seizures were present in 83% of patients affected by low-grade astrocytoma, in 46% of patients affected by anaplastic astrocytoma and in 36% of patients affected by glioblastoma. Postoperative epilepsy refractory to anticonvulsant treatment significantly related to low-grade histology and presence of preoperative seizures occurred in 48% of patients. Adverse effects associated with anticonvulsants were observed in 33.8% of patients treated with phenobarbital, 14.3% in the group treated with carbamazepine and 12% of patients treated with vigabatrin. We conclude that anticonvulsant treatment in patients affected by gliomas is often ineffective and prophylactic treatment should be discontinued after 6 months in patients preoperative seizures free. In patients with high risk of seizures antiepileptic drugs with good efficacy and lower incidence of adverse effects than phenobarbital are indicated.

[Magnetic resonance features in cerebral primary lymphomas in non-immunocompromised subjects]. / Aspetti della Risonanza Magnetica nei linfomi primitivi cerebrali nei soggetti non immunocompromessi.

In the past few years, non-Hodgkin's lymphomas have been paid increasing attention to because of their recently increasing frequency. We reviewed the MR images of 17 patients with histologically proved primary CNS lymphoma, all of them immunocompetent at diagnosis. We studied the site, number and shape of the lesions, the presence and grade of edema and possible periventricular spread. The exams were performed with 0.5 T and 1.5 T MR units, using SE sequences on the sagittal, axial and coronal planes, before and after Gd-DTPA administration. The most typical neuroradiologic signs which may suggest the diagnosis of CNS lymphoma are deep or periventricular lesion site, diffuse and marked contrast enhancement, poorly defined borders, moderate edema surrounding the mass and a tendency to periventricular spread. MRI demonstrated 35 lesions in 17 patients. The lymphoma was unifocal in 9 cases (53%) and 7 lesions were localized in subtentorial site. Lesion size did not exceed 2 cm in 49% of cases, ranged 2-4 cm in 40% and exceeded 4 cm in 11% of cases only. These lesions and hypo- to isointense on T1-weighted images (97%) and their signal intensity varies on T2-weighted images, with mainly iso-/hypointense patterns (79%). All lesions enhanced after Gd-DTPA administration, 74% of them markedly and 26% moderately; enhancement was mostly homogeneous (80% of cases). Perilesional edema was observed in 74% of cases. In conclusion, MRI yields some useful information for the diagnosis of primary CNS lymphoma, but the clinical and radiologic signs of this lesion may exhibit aspecific signal features, meaning that no correct diagnosis can be made even in immuno-competent patients.

Potential role of in vitro 1H magnetic resonance spectroscopy in the definition of malignancy grading of human neuroepithelial brain tumours.

The increasing sensitivity of neuro-imaging in the diagnosis of brain expanding lesions is not directly related to biopathological specificity and new technological approaches are under study. In particular Magnetic Resonance Spectroscopy (MRS) allows evaluation of some biochemical pathways whose metabolic alterations may be correlated with the nature and malignancy grading of primary brain tumours. In the present study the author performed an in vitro high field 1H MRS (9.4 and 14.1 T) analysis of specimens obtained from stereotactic biopsy or microsurgical removal of primary brain tumours. Different samples derived from heterogeneous areas and/or infiltrated perilesional regions were examined. This study was principally focused on malignancy grading of gliomas and its correlation with the ratio (R) between the resonance band arising from choline containing compounds (between 3.14 and 3.35 ppm) and the total creatine signal (3.0 ppm). Analyses allowed significant discrimination between astrocytomas (R = 2.4 +/- 0.6) and glioblastoma (GBM) (R = 4.4 +/- 1.3) [p < 0.002]; however the results did not allow discrimination between differentiated and anaplastic astrocytomas. The GBM showed the largest spread of values corresponding to their higher level of tissue heterogeneity and de-differentiation. Studies on non astrocytic brain tumours indicated that even higher R values were exhibited by oligodendrogliomas, even in well differentiated forms (p < 0.02 with respect to GBM). Moreover, preliminary observations indicated that signals arising from other metabolites may also contribute to a differential diagnosis of different oncotypes. Among these glycine appears particularly relevant, since higher levels were measured for this amino acid in GBM with respect to both astrocytomas and oligodendrogliomas.

Differentiation of glioblastoma multiforme from astrocytomas by in vitro 1H MRS analysis of human brain tumors.

In vitro high resolution 1H NMR spectroscopy allows non-invasive metabolic evaluation of specimens derived from surgically biopsied or resected brain tumors, with the aim of identifying potential markers of different malignancy grading, and improving diagnostic and therapeutic strategies. In the present study we evaluated 36 patients affected by different brain gliomas (7 well differentiated astrocytomas, 7 anaplastic astrocytomas, 16 glioblastomas, 6 oligodendrogliomas). These analyses allowed discrimination between well differentiated and anaplastic astrocytomas (AII + AA) and glioblastoma multiforme (GM) samples on the basis of the ratio between the integrated choline-containing resonance (b"Cho") and the creatine peaks (creatine (Cr) + Phosphocreatine (PCr)). While no definite difference was found between AII and AA, significantly higher values were observed for this ratio in GM. Other signals, derived from different metabolites, such as Glycine (Gly) and N-acetyl-aspartate (NAA), may also assume relevance in differential tumor diagnosis. In this study an increased [Gly]/[Cr + PCr] ratio was observed in GM with respect to AII and AA. The NAA levels observed in our tumor specimens may be explained on the basis of tumor cell infiltration into brain adjacent tissue. Interesting, but inconclusive, are the data concerning oligodendrogliomas, which, also in well differentiated forms, exhibit increased levels of b"Cho"/(Cr + PCr) ratio. The present study confirms the role of MRS in the biochemical characterization of neoplastic brain tissue and its potential contribution to a better selection of multidisciplinary treatment strategies.

Somatostatin receptor imaging in CNS tumours using 111In-octreotide.

This study evaluates the in vivo visualization of somatostatin (SS) receptors in central nervous system (CNS) tumours using 111In-octreotide imaging and discusses the clinical implications. Ninety-five patients with histologically confirmed diagnosis of CNS tumours were imaged 2-4 and 24 h after the intravenous injection of 111-185 MBq of 111In-octreotide. An uptake index was computed using tumour/non-tumour ratios evaluated using a standard region-of-interest method. Semi-quantitative immunohistochemical studies of SS binding sites were performed on frozen tumour sections. All meningiomas, most pituitary adenomas and many glial tumours showed a positive scan, whereas all neurinomas, craniopharingiomas and ependymomas had negative receptor scans. Radio-octreotide uptake varied among the SS receptor positive CNS tumours: very intense in meningioma, intermediate in pituitary adenoma and of a low grade in glioma. The results of immunohistochemical studies confirmed the scintigraphic findings in all cases. We believe 111In-octreotide is a suitable radiopharmaceutical for characterizing CNS tumours in vivo as SS receptor positive or negative. This new neuronuclear imaging technique may be useful for differential diagnosis in selected cases, for post-surgical follow-up and in the assessment of differentiation in glial tumours.

Indium-111 octreotide scintigraphy in neurofibromatosis.

Scintigraphy with the radiolabelled somatostatin analogue indium-111-DTPA-D-Phe-1-octreotide has recently been proposed for the imaging of CNS neoplasms expressing somatostatin receptors. While meningiomas are imaged with high sensitivity, neurinomas do not take up octreotide owing to the lack of somatostatin receptors. Neurofibromatosis is a relatively uncommon disorder in which meningiomas and neurinomas often occur in the same patient. Differential diagnosis between these two tumours by computed tomography and magnetic resonance imaging can be difficult. This study reports on 111In-octreotide scintigraphy in four patients with neurofibromatosis. 111In-octreotide scintigraphy was shown to be very helpful in the in vivo differential diagnosis: all four meningiomas showed intense tracer uptake, while all 15 neurinomas were negative (P < 0.001 by Fisher's exact test). It may be concluded that scintigraphy with 111In-octreotide is a useful diagnostic procedure in neurofibromatosis, complementing standard neuroradiological imaging procedures.

Defective human retinoblastoma protein identified by lack of interaction with the E1A oncoprotein.

Inactivating mutations of the retinoblastoma susceptibility gene (Rb) are involved in the pathogenesis of hereditary and sporadic retinoblastoma. Alterations in the Rb gene have also been found in several other human tumors occurring with epidemiological incidence higher than that of retinoblastoma. Four human malignant glioma cell lines were examined for abnormalities in the retinoblastoma gene product (pRb), using a procedure based on the interaction of pRb with an in vitro-translated adenovirus E1A oncoprotein. In the CRS-A2 cell line, derived from a glioblastoma multiforme, pRb did not bind with the in vitro-translated E1A protein. Restriction analysis of the CRS-A2 Rb gene and Rb mRNA expression provided patterns that could not be distinguished from the other glioma cell lines. Further investigation revealed the presence of a truncated pRb in the CRS-A2 cell line, due to a nucleotide insertion in the coding sequence at position 2550. In addition, this truncated Rb protein was undetectable in phosphorylated form. The binding assay with the in vitro-translated E1A was also used to study other cell lines with known mutations in the Rb gene. This method, which evaluates the interaction between in vitro-translated E1A and the pRb, is proposed as a rapid screening for detecting functional alterations in the retinoblastoma protein.

Effects of 17 beta-estradiol, progesterone and tamoxifen on in vitro proliferation of human pituitary adenomas: correlation with specific cellular receptors.

Six human pituitary adenoma cultures, characterized for estrogen and progesterone (Pg) receptors, were treated with 17 beta-estradiol (17 beta-E2), Pg and tamoxifen (TAM) at different concentrations, alone and in combination, for 2, 4 and 8 days. Cell proliferation data showed in most cases a stimulating effect of 17 beta-E2 and an inhibitory effect of Pg on cell growth, which appeared to be correlated with specific receptor expression, but independent of pituitary cell hormone content. A marked inhibitory effect of TAM on cell proliferation was present in all cases, but, on the contrary, was independent of estrogen receptor expression.

Brain-stem auditory evoked potentials in supratentorial brain tumors.

A group of 42 adult patients with supratentorial brain tumors were studied with computed tomography (CT or/and NMR) and brain-stem evoked potentials (BAEPs). 12 patients had meningiomas and 30 had malignant tumors (gliomas and metastases). The latencies of wave V and of the interpeak latency I-III, III-V and I-V were evaluated both on the lesion side and the opposite side. In meningiomas mean latencies did not show significant differences from normal, while mean latencies in malignant tumors were significantly prolonged, except for the I-III interpeak latency. The results of this study demonstrate that BAEPs may be altered by supratentorial brain tumors. This examination appears to be useful in the monitoring of these lesions after treatment.

The VEP in evaluation of pituitary tumors.

12 patients with pituitary tumors were studied with VEP, to demonstrate involvement of the optic chiasma. In 3 patients VEP was recorded pre- and post-surgery to evaluate a modification in the shape and latencies of the potentials. 2 patients were studied only pre-surgery, the other 7 post-surgery. The utility of this test is discussed.

The membrane-bound hexokinase as a potential marker for malignancy in human gliomas.

Hexokinase is a key enzyme in carbohydrate metabolism. Its activity has been shown elevated in cells with high mitotic index. In particular, experimental cancer cells, due to their peculiar energy metabolism, display a hexokinase activity proportional to the degree of malignancy. This is the case also for human gliomas in which glucose metabolism, evaluated via positron emission tomography, has been shown to be predictive for patient prognosis. In order to better correlate these findings, specific reagents for tumor hexokinase (a polyclonal antibody and a full-length cDNA probe both specific for murine tumor hexokinase) have been successfully employed to quantitate the protein and its messenger in cultured cell lines; the antibody was also tested in four specimens obtained from human astrocytomas.

The progression in astrocytic tumors.

Progression represents the qualitative tumor evolution during the time. Recently it received great consideration, mainly since the introduction of the neuroradiological imaging (CT and MRI). A series of 224 supratentorial astrocytic tumors of the juvenile and adult age have been analyzed: we found the morphological features of progression in 26% of them. These data introduce, perhaps, the most important information about progression: the "crisis" of the concept that low-grade tumors are stable lesions during the time.