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.

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.

Divry-Van Bogaert syndrome. Clinical and ultrastructural findings.

A case of a progressive disease with epilepsy, marble skin, and roentgenographic evidence of tapering of the distal carotid branches with corticomeningeal angiomatosis was studied. The clinical course, angiographic findings, and skin biopsy results justified the diagnosis of noncalcifying venous capillary angiomatosis, or Divry-Van Bogaert syndrome.

Peripheral arterial vascular function at altitude: sea-level natives versus Himalayan high-altitude natives.

OBJECTIVES: Regulation of the vascular system may limit physical performance and contribute to adaptation to high altitude. We evaluated vascular function in 10 Himalayan high-altitude natives and 10 recently acclimatized sea-level natives at an altitude of 5,050 m. METHODS: We registered electrocardiogram, blood flow velocity in the common femoral artery, and blood pressure in the radial artery using non-invasive methods under baseline conditions, and during maximal vasodilation after 2 min leg occlusion. Vascular mechanics were characterized by estimating pulse wave velocity and input impedance. RESULTS: Pulse wave velocity and parameters of input impedance did not differ between groups under baseline conditions. In the post-ischemic period, the ratio between maximal hyperemic and baseline blood flow velocity was significantly higher in the high-altitude than in the sea-level natives (5.7 +/- 2.5 versus 3.8 +/- 1.2, P < 0.05). The leg vascular resistance decreased in the post-occlusive period without differences between groups. Characteristic impedance decreased in the post-ischemic period by about one third of the baseline level without differences between groups. The post-ischemic decrease of input impedance modulus was more marked in the high-altitude than in the sea-level natives at low frequencies (28 +/- 12 versus 6.4 +/- 20% at 2 Hz, P < 0.01). CONCLUSIONS: Our results demonstrate a superior ability to increase blood flow velocity as a response to muscular ischemia in high-altitude natives compared to sea-level natives. This phenomenon may be associated with a more effective coupling between blood pressure and blood flow which is probably caused by differences in conduit vessel function.

Circulating intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and plasma thrombomodulin levels in glioblastoma patients.

Cellular adhesion molecules have been implicated in tumor progression and metastasis. Serum samples from 22 patients with glioblastoma (GBM), before surgery, and 19 sex and age matched healthy controls were analyzed for circulating levels of ICAM-1 and VCAM-1. At the same time also soluble plasma thrombomodulin, a marker of endothelial cell damage and activation, was detected. Soluble ICAM-1 and VCAM-1 levels were comparable in glioblastoma patients and healthy controls, while plasma thrombomodulin (TM) was significantly increased in cancer patients. There was no correlation between thrombomodulin levels and the presence of an intratumoral hemorrhage detected by CT scan, while entity of post-contrast enhacemement at CT correlated with higher TM levels. Further study with serial sampling of GBM patients and correlation with enhancement at CT will allow to ascertain the value of serum TM as a marker of disease recurrence or angiogenesis in those tumors.

Characterization of an established human, malignant, glioblastoma cell line (GBM) and its response to conventional drugs.

A cell line, GBM, was established from a human malignant glioblastoma and was characterized with particular reference to its response to conventional drugs. The GBM cell line exhibited a 73 +/- 7 h doubling time in monolayer cultures. Expression of glial fibrillary acidic and S-100 proteins was observed. Karyotype analysis of GBM cells at early passages revealed the presence of two near-triploid clones (A and B) with multiple chromosome rearrangements; a 100% frequency for clone B was observed in the established cell line. GBM cells had tumorigenic properties, since the s.c. injection of cultured cells into nude mice gave rise to slowly growing tumors. The morphology of GBM cells was retained during in vitro and in vivo passages, as judged by light microscopy. GBM cells were relatively resistant to most conventional drugs; among the tested drugs, only taxol exhibited a marked cytotoxic effect comparable to that found in cells of a different tumor type. GBM cells were found positive for the epidermal growth factor receptor, HER2-neu and P-glycoprotein by flow cytometry of cells labelled with monoclonal antibodies. In spite of the expression of relatively high gamma-glutamyltransferase activity, the intracellular glutathione level was comparable to that of other chemosensitive tumor cells. This glioblastoma cell line is a suitable model for the identification and preclinical studies of new agents and provides an additional system to explore the molecular basis of the intrinsic drug resistance of glioblastoma.

Tumor necrosis factor microsatellite polymorphisms in Italian glioblastoma patients.

Tumor necrosis factor (TNF) genes map on the short arm of chromosome 6 and have been described to contain several polymorphic regions, the most informative of which are TNFa (13 alleles) and TNFb (8 alleles) microsatellites. We analyze TNFa and TNFb microsatellite polymorphisms in 58 Italian patients with glioblastoma (GBL) and 95 unrelated healthy controls. At the TNFb locus, we detected a statistically significant decrease in the TNFb4 allele in GBL patients compared with the controls (P = 0.002; Pcorr = 0.015). Among the patients, 8 were homozygous TNFb4 (+/+), 23 were TNFb4 heterozygous (+/-), and 27 were negative for TNFb4 (-/-). In a comparison with the controls, we detected a statistically significant difference (P = 0.017). In fact, although no difference was detected in +/-, statistically significant differences were detected both for an increase in -/- and for a decrease in +/+ in the patient groups (P = 0.006 and P = 0.047, respectively). These data suggest that TNFb4-negative individuals might preferentially develop a Th2-type immune response that could lead to a reduction in antitumor activity.

Distribution of daunorubicin and daunorubicinol in human glioma tumors after administration of liposomal daunorubicin.

DaunoXome is a liposome formulation containing daunorubicin (DM). Encapsulation of the drug in liposomes presents the advantage of low-level systemic exposure and better drug penetration into the tumor. We studied the distribution of DM and its 13-dihydro metabolite, daunorubicinol (DMol), in surgical biopsies from different parts of glioblastomas. The study was performed in eight patients with recurrent glioblastoma, all of whom had previously undergone surgery and been treated with radiotherapy and chemotherapy, who received 50 mg of DaunoXome as a 1-h infusion. Surgery was performed at 24 and 48 h after the infusion in seven cases and one case, respectively. Biopsies were divided into three parts: the central area of the tumor, peripheral tumor tissue, and brain-adjacent tumor (BAT) tissue. A complete plasma pharmacokinetics study was conducted in seven cases, with samples being taken for up to 48 h after the end of the infusion. DM and DMol were determined in plasma and tissue by high-performance liquid chromatography with fluorescence detection after solvent extraction. At 24 h, concentrations of DM and DMol in the central part of the tumor ranged between < 0.005 and 0.80 microg/g and between 0.005 and 1.58 microg/g, respectively. Concentrations were similar in the peripheral tumor and in BAT tissue. From the data obtained on the patient who underwent surgery at 48 h it appears that DM and DMol remain in tumor tissue for a long time, the concentrations being 0.4 and 2.8 microg/g, respectively. DaunoXome was rapidly cleared from the body, with the plasma levels of DM and DMol determined at 48 h lying in the range of < 5-50 and < 5-20 ng/ml, respectively. The mean (+/-SD) half-life and plasmatic clearance of DM were 4.8+/-1.0 h and 0.2+/-0.06 l h(-1) m(-2). In conclusion, DaunoXome achieved and maintained potentially cytotoxic levels of both DM and DMol in glioblastoma for a long time in association with low-level systemic exposure. Further studies are therefore warranted. Although only preliminary and obtained in previously treated patients, these data suggest that DaunoXome merits investigation in CNS tumors.

Alternating myasthenia and myastheniform syndrome in the same subject.

A man of 23 years was affected by myasthenia with amyotrophic patterns. From the neurophysiological viewpoint, there were typical electrophysiological aspects of myasthenia gravis and the Eaton-Lambert syndrome simultaneously. In some instances the various electrophysiological tests were preceeded by the administration of Tensilon, calcium gluconate and sodium benzoate caffeine. It is hypothesized that there are two types of endplates present, or there is a functional variability by which at different moments a block results from a defect in the formation or liberation of acetylcholine.

Effects of threshold, low frequency, long lasting stimulation on single motor unit electrical responses from the extensor digitorum brevis muscle in normal and myasthenic subjects.

The authors studied the recruitment of motor units of EDB muscle by long lasting threshold intensity stimulation at 1 c/sec of external popliteal nerve at the ankle in healthy subjects and in myasthenic patients. In the healthy volunteers, at steady intensity of threshold stimuli, maximum number of motor units never exceeded 5--6 electrical increments with a final incremental response of constant amplitude during 60 min of stimulation. In myasthenic patients, both an early exhaustion of threshold motor units and a marked facilitation phenomenon occurred with massive recruitment of incremental responses, while in a small number of cases no changes were observed. These data are discussed in the light of various morphofunctional hypotheses regarding the localization of the myasthenic impairment.

Chronic cluster headache: response to lithium treatment.

A clinical trial of lithium carbonate was undertaken in a group of 20 patients suffering from chronic cluster headache. Blood levels of lithium were determined at regular intervals to monitor the therapeutic dosage. Lithium was found to be an effective prophylactic agent for chronic cluster headache patients. The effectiveness of lithium was evident in less than a week after the beginning of treatment. It is not clear in what way lithium may act on cluster headache.

Neurological and pharmacological evaluation of a case of stiff-man syndrome.

A typical case of stiff-man syndrome was studied neurophysiologically and pharmacologically focusing the attention on a central disorder, either spinal or suprasegmental. The results support the hypothesis that a gamma type of hypertonia is one of the causes of the stiff-man syndrome, ruling out the participation of the Renshaw circuits. The syndrome should be considered a central disorder of the descending pathways that control and modify gamma activity and the startle reaction mechanisms, especially affecting the circuits that use Gabaergic mediators.

A peculiar case of malignant cerebral reticulosis: clinico-pathological study.

A man aged 56 years, previously healthy, developed asthenia, hypersonnia, apathy, later polydipsia and bulimia, headache and episodes of unconsciousness. There was temporary improvement with steriod therapy, but ever-deepening stupor appeared till death due to bronchopneumonia. All blood chemistry examinations were normal. The CSF IgG was elevated but no neoplastic cells were seen. At autopsy areas of grayish color in the basal gagnlia and granulomatous tissue in the floor of the third ventricle and in the mamillary bodies were seen, and the gonads were attrophied. Microscopically, in the floor of third ventricle, mamillary bodies and adjacent leptomeninges there was granulomatous tissue made up of more-or-less typical cells of the reticulum, polymorphonuclear cells, plasma cells and some phagocytes along with proliferation of small blood vessels and reticulin fibers. In addition, the white matter of the frontal lobes, pons, middle cerebellar peduncle and cerebellar white matter contained diffuse proliferation of pleomorphic histiocytic elements with questionable atypical mitoses. Notwithstanding, the morphology of our case suggests that it is a peculiar form of malignant reticulosis (or malignant histocytosis) related to histiocytosis X. The duplicity of the features of our case suggests it to be neoplastic, where the proliferative phase is followed by a granulomatous and sclerotic one.

Peripheral nerve involvement in Churg-Strauss syndrome.

Peripheral neuropathy associated with bronchial asthma, multisystem organ dysfunction and idiopathic hypereosinophilia may be found in Churg-Strauss syndrome, hypereosinophilic syndrome and polyarteritis nodosa. Some authors have diagnosed their patients according to the presence in tissue biopsies of the three histological criteria of Churg and Strauss (necrotizing vasculitis, tissue eosinophilic infiltration, extravascular granulomas). We have observed three patients with a common history of a prodromal phase of allergic diseases (bronchial asthma and rhinitis) followed by a vasculitic phase with mononeuritis multiplex, purpura and arthritis, associated with hypereosinophilia of more than 1500 cells/mm3. All responded well to steroid treatment. Sural nerve biopsy revealed true vasculitis in two of these cases and a mild perivascular inflammatory infiltration in the other. On the basis of their characteristic clinical pattern, we think that our cases best fit the diagnosis of Churg-Strauss syndrome even though the typical histological features were not found in the sural nerves examined.

Chemotherapy as first treatment for primary malignant non-Hodgkin's lymphoma of the central nervous system preliminary data.

Non-Hodgkin's lymphoma of the central nervous system (NHL-CNS) is thought to account for about 1% of primary brain tumours. Radiation therapy has mainly been applied to treat cerebral lymphoma, but the low cure rate and the lack of enduring response have stimulated the search for alternatives. With the aim of postponing radiotherapy as long as possible, we tested the efficacy of a M-BACOD schedule administered immediately after histological diagnosis in 14 patients. After two M-BACOD courses 10 (71%) patients displayed an objective response (i.e. were apparently tumour-free when examined by CT). In 6 (60%) M-BACOD-responsive patients, radiotherapy was delayed for 5 months (without recurrences after a follow-up ranging from 9 to 18 months). Moreover, in 3 M-BACOD-responsive patients, no recurrence took place (even without radiotherapy) after a follow-up of 6-12 months. We conclude that radiation can be postponed after chemotherapy or delayed until tumor recurrence.

Diffuse arachnoiditis following epidural analgesia.

Four cases of spinal arachnoiditis are reported, which occurred as a delayed complication of epidural anaesthesia. Different causes are considered: the most convincing hypothesis is that there was a subarachnoid hyperergic reaction to the drugs injected during epidural anaesthesia.

A case of glioblastoma with multiple centers above and below the tentorium.

A case of multicentric glioblastoma with the clinical and histopathological findings is presented in which three lesions are located above and below the tnetorium. Multicentric glioblastomas are those which have no macroscopic or microscopic connection.

5-OH-Tryptophane in migraine: clinical and neurophysiological considerations.

The clinical effects of the protracted treatment with 5-OH Tryptophane (5-HTP) of some patients with chronic migraine are compared with other patients with acetylsalicylic acid. The pain threshold was neurophysiologically determined in migraneous on patients whose response to 5-HTP therapy was specially good. The results with 5-HTP can be accounted for by an action of the substance on the serotonin turnover with activation of the serotoninergic antinociceptive system.

Chemotherapy is effective as early treatment for primary central nervous system lymphoma.

Primary central nervous system lymphoma (PCNSL) is a lymphoma arising within the brain or spinal cord in the absence of evident localisation outside the central nervous system (CNS). Poor results in the management of relapsed PCNSL justify the need for vigorous initial therapeutic regimens, and chemotherapy should not be reserved for recurrent disease. Chemotherapy (MBACOD scheme) was delivered prior to irradiation in a group of 20 PCNSL patients, another 8 PCNSL patients underwent radiotherapy only, and the overall survival was evaluated. Computed tomography (CT) images in the group of patients treated with chemotherapy, showed there to be 70% complete responders (CR), 15% non-responders (NR) and 15% partial responders (PR). Half of the CR were scheduled for radiotherapy only at tumour recurrence. The median disease-free period and survival time of the whole group treated with early chemotherapy followed by radiotherapy were 24 and 32 months, respectively, but in the subgroup of CR (70%), taking into account also the patients not yet receiving radiotherapy, these were 38 and 48 months, respectively. The disease-free and survival times in the group of CR (75%) of patients treated with radiotherapy only were 13 and 18 months, respectively. At tumour recurrence, CR to chemotherapy had a second disease-free period longer than 2 years after radiotherapy. Our data support the belief that in scheduling the treatment of PCNSL after histological diagnosis, the first step is to devise high-dose chemotherapy with drugs able to cross an intact blood-brain barrier. The results of our primary approach with early chemotherapy in PCNSL support a consensus to continue chemotherapy until tumour recurrence, and only at that event to initiate radiotherapy. It is a challenge and an option worthy of continuing investigation.

Neurogenic muscle hypertrophy. Report of two cases.

Muscle hypertrophy is rare in denervating diseases. A patient with calf enlargement associated with L5-S1 radiculopathy and another with thenar, hypothenar, forearm and calf muscle hypertrophy in the course of chronic relapsing inflammatory demyelinating polyneuropathy are described. Gastrocnemius muscle biopsy revealed both type I and type II fibre hypertrophy in the former case and predominant type I fibre hypertrophy in the latter. Passive stretching and abnormal spontaneous muscular activity might have played a role in the origin of hypertrophy in both patients, but a satisfactory explanation for denervation hypertrophy has yet to be provided.