1-39-08 Paraneoplastic cerebellar degeneration

New-o-Oncology

S58 l-39-03

lnterleukin-6 glioblastoma

plays an essential autocrine development

role in

S. Chevalier, M. Fourcin, C. Guillet, J. Froger, L. Denechaud, G. Al Hayek, H. Gascan, A. Barthelaix-Pouplard. Laborafoire de Biologic Cellulaire, C/-/U Angers, France Human glioblastoma are highly malignant intracranial tumors. In the present study we have analyzed the implication of Interfeukin-6 (11-6) and related cy tokines in the glioblastoma progression. IL-6 belongs to a cytokine family that all share gp130 signaling protein as co-receptor. ELISA analysis of spontaneous production of IL-6 family of cytokines by 13 established glioblastoma cell lines showed a massive IL-6 synthesis, that could exceed one &ml for some of them. Similarly, examination of the soluble form of IL-6 receptor binding component revealed a production level IO-fold higher to that observed for other studied tumor cell types. Implication of IL-6 in the autocrine growth of glioblastoma derived cell lines was established by showing a dramatic inhibitory effect of antisense oligonucleotides targeted against IL-6 or IL-6 receptor. A similar result was also obtained by neutralizing the STAT3 transcription factor, which is required for gp130 signaling. Cell cycle analysis showed that antisense treated glioblastoma cells were blocked in Go/G1 phase. The U118MG glioblastoma cells were engrafted to nude mice and IL-6 sense- or antisense oligonucleotides, or PBS, were continuously delivered for 28 days by using mini-osmotic pumps. Tumor development was similar in treated and control groups for the first 10 days, but at the end of the treatment the tumor mass remained measurable in only 50% of the treated animals. Implication of IL-6 and its receptor was also analyzed in patients, and the presence of IL-6 and IL-6 receptor were observed in tumors from patients displaying grade IV glioblastomas. Activation of the lL-6/11-6 receptor pathway in patients was evidenced by analyzing the tyrosine phosphorylation of gp130 signaling receptor and of STAT1 and STAT3 transcription factors in tumors. These signaling components were respectively phosphotylated in fJO%, 50% and 100% of the tested samples. Collectively, these results strongly suggest that IL-6/lL-6 receptor pathway could play an essential autocrine role in glioblastoma development.

l-39-04 P.E. Marchiorf, Brazil

Paraneoplastic cerebellar degeneration associated with anti-purkinje cell antibody (anti-yo syndrome) Ft. Hirsch, J.E. Kalil. SZo Paul0 University

School

of Medicine,

Objective: To describe the response of surgical resection of ovary and intravenous pulsotherapy with cyclophosphamide in a patient with paraneoplastic cerebellar degeneration (PCD) associated with anti-Purkinje cell antibody (PCA) without an evidence of ovary cancer. Background: PCD is a rare condition in which PCA is generated through effect of a cancer which leads to cerebellar degeneration and progressive cerebellar symptoms in patients. Although non-specific immunotherapy has been tried, they are rarely of benefit in the treatment of this condition. Design/Methods: a 73 years old, white woman developed severe cerebellar ataxia, dysartria, tremor and nystagmus, diagnosis of PCD associated to PCA as done. All search of neoplasia was negative. In spite of clinical and radiological absence of neoplasia she was submitted to surgical resection of both ovary and treated with monthly intravenous pulsotherapy with cyclosphosphamide. Results: The histopathological evaluation of both ovaries not showed any evidence of the ovaries cancer. A moderate improvement of the neurological symptoms occurred. Conclusion: In some situations when the anti-Purkinje cell antibody is positive the surgical resection of ovaries and the non-specific immunotherapy may be justified in a patient without clinical, laboratorial and radiological evidence of a ovary neoplasia.

l-39-05

lntraoperative delimitation of brain tumor resection margins by means of tissue autofluorescence

G. Bottiroli, A.C. Croce, D. Locatelli, Ft. Nano, E. Giombelli I, A. Messina’, M. Ceroni z, E. Benericetti ’ Centro di Studio per I’lstochimica, CNR, Dip Biologia Animale, Pavia, Ita/,! ’ 1st. Neurobgico “Mondino”, UniversitC, Pavia, /tab ’ Div Neurochirurgia, AZ. Ospedaliera “E. More//~ Sondalo, (So), /ta/y Biological tissues, under excitation at suitable wavelengths, give rise to a fluorescence emission in the UV-Visible range, attributable to endogenous fluorophores involved both in functional and metabolic processes, and in histological tissue organization. Since the emission is related to the nature and amount of the fluorophores. and to their tissue distrfbution, its properties are currently studied for in situ cancer diagnosis, the histological and histochemical characteristics of the tissue being strongly affected by the pathological conditions. In this work autofluorescence properties of human brain tissue were studied as a possible parameter for discriminating tumor from normal tissue, in real

time during surgical operation. In neurosurgery, the time and quality of survival of the patients depend on the accuracy in the removal of the tumor mass. A clear discrimination from the normal tissue during operation, required to avoid both the excessive resection of the healthy tissue, and the incomplete removal of the tumor mass causing tumor recurrences, is hindered by the difficulty to clearly distinguish the boundary of gliomas. Spectrofluodmetrfc analysis was done both on sections of resected samples, and on patients during surgical operation via fibreoptic probe. Ex vivo analysis evidenced differences in the autofluorescence pattern, between normal tissue and glioblastoma, in tears of signal amplitude and spectral shape. Fluorescence intensity values significantly lower in glioblastoma than in normal surrounding tissue (3-5, and 1.2-2.5 times less than white matter and cortex, respectively) were found on the patients, confirming the potentials of autofluorescence based technique as an aid to improve the efficacy of neurosurgical operations.

l-39-06

Organic psychosis encephalopathy

secondary

M. Rosich, A. Labad, Ma. Garcia. Hospital Pete Mata. Reus. Catalonia, Spain

to postradiation

Psiqui&ric

Universitari.

lnstitut

Introductton: Radiation treatment has two different pathological effects: direct effects on macromolecules (DNA) and indirect effects which lead to free radicals. Glial and endothelial cells are the most sensitive in the central nervous system. The main lesions are white matter necrosis, vascular endothelial proliferation and vascular fibrinoid necrosis. The clinical signs are encephalopathic and can appear some weeks, months or years after. Aims: To present a case of organic psychosis which is secondary to brain radiation, and to review the bibliography. Material 81 Methods: A 40-year-old patient was admitted to Hospital with a progressive clinical picture of tempospatial disorientation, psychomotor agitation, visual and auditory hallucination and difficulties to retain him at home. He had been operated on 6 years previously for a cerebellar anaplastic astrocytoma and treated with intraarterial cisplatin and holocranial cobaltotherapy. Examination: irregular collaboration alternating agitation with stupor, considerable impairment of short-term memory, attention wandering, and moderate dysdiadochokinesia. Results: Normal blood analysis. CAT-scan: periventricular demyelation, postsurgical changes in posterior fossa. MRI: white matter hyperdensity on T2, compatible with postradiation necrosis. CSF: no cells, 200 mgr protein. Fusion-SPECT non-specific temporal hypoperfusion. Conclusion: Organic psychoses are difficult to diagnose. The present case is considerated to be secondary to a postradiation encephalopathy because of the patients history, the atypical psychotic findings, the results of complementary studies and the slow temporal evolution.

l-39-07

A new schedule of treatment for primary central nervous system lymphoma (PCNSL)

A. Silvani, A. Pozzi, A. Salmaggi, A. Solari, A. Boiardi. Neurologico “C. Besta”, Milan, /ta/y

lstituto

Nazionale

Discouraging results in the management of PCNSLjustify the need for vigorous initial therapeutic regimens and chemotherapy should not be resewed for recurrent disease. High dose methotrexate (3500 mg/sqm) delivered prior radiotherapy was efficacious in a group of 20 PCNSL patients. CT images displayed 70% of the complete responses (CR), 15% of no responses (NR), and 15% of partiale responses (PR). Half of the CR patients were scheduled for radiotherapy only at tumor recurrence. The median TTP and ST of the whole group of 20 PCNSL treated with early chemotherapy followed by radiotherapy, were 24 and 32 months, but in the subgroup of CR (70%) taking into account also the patients not yet receiving radiotherapy it was 38 and 46 months respectively. Patients CR to chemotherapy at tumor recurrence had a second disease-free period longer than two years after radiotherapy. Our data support the knowledge that in scheduling the treatment of PCNSL after histological diagnosis, the first step is devising high-dose chemotherapy with drugs able to cross an intact BBB. Our primary approach with eany chemotherapy in PCNSL, corroborate a consensus to continue chemotherapy until tumor recurrence, and only at that time initiate radiotherapy. It is a challenge and an option worthy of continuing investigation.

1 39 08

Paraneoplastlc

cerebellar

degeneration

I__I D. Simonetti, M. Mundo, N. Micillo, G. Piran Arce, N. Mendyk, P. Santoro, A. Gardella ‘, A. Tarulla, P. Elorza, R. Rotta Escalante. Department of Neurology, Banking Hospital, Buenos Aires, Argentina, ’ Department of internal Medicine, Banking Hospital, Buenos Aires, Argentina Neurologic paraneoplastic lar degeneration (PCD),

syndromes are uncommon. Paraneoplastic cerebelalso infrequent, is the most common paraneoplastic

Neumphanmcology syndrome that affects the brain. The diagnostic is made on the basis of clinical, laboratory (Purkinje Cell Cytoplasmatic Antibodies - Anti-Yo) and radiological features. We report the case of a woman, aged 39, who suffered from vertigo and gait disturbance and over eight months progressed to a cerebellar syndrome with gait ataxia, dysarthria, upper extremities tremor and dysmetria accompanied with bilateral pyramidal and extrapyramidal signs and oculomotor abnormalities. Brain MRI showed and increased signal in Ts weighted images of the cerebral white matter and moderate atrophy of the cerebellum. Having excluded another etiologies and with positive serologic Yo autoantibody test, PCD was diagnosed. At the beginning of symptoms the gynecologic exam was nonal; on the basis of the diagnosis of PCD another examination was performed. A breast carcinoma was found and a mastectomy was performed. We emphasize the value of the diagnosis of this disease in patients with occult cancer because it’s helpful in the early detection and treatment of the associated carcinoma.

42

Neuropharmacology

l-42-01

Use of psychotropic population

medication

in a geriatric

R.L. Arizaga, Ft. Jorge, F. Taragano, E. Comesafia, C.A. Mangone, Ft. F. Allegri. Comisidn National de Gerontoneuropsiquiatrfa, Asociacidn

Argentina

de Psiquiatras,

To study the use of psychotropic medication in an urban geriatric population from Buenos Aires. Wthods: Study Population: A randomized sample of individuals applying for admission to a Social Service during July and August, 1996. Instrument: Ad hoc questionnaire to record the use of any type of medication during the month prior to the survey, the length of its use, the source of the prescription and the subjective appraisal of treatment’s objective. Results: The survey included 1674 individuals (1052 females) with a mean age of 69.5 years and a SD of 6.9 years. Psychotropic medications were used by 28% of the individuals. Anxiolytics comprised 85% of the psychotropic prescriptions, hypnotics 7%, antidepressants 5% and neuroleptics 3%. The most frequently prescribed were bromazepan (40.47%) lorazepan (30.3%) and alprazolam (20.47%). Cf the individuals consuming psychotropic medications, 38% considered them as tranquilizers, 37% as medication to induce and I or maintain sleep and 6% as medication to improved mood. The remaining individuals associated the use of psychotropic medications to the treatment of other medical conditions (cardiovascular disease, hypertension, etc). With regard to antidepressants, 61.7% of the prescriptions were trtcyclics and 30.3% corresponded to selective serotonin reuptake inhibitors. The majority of antidepressants prescriptions (72%) were give by a neurologist or a psychiatrist. At least 60% of the prescribed antidepressants have a low safety profile for its use in the geriatric population. Conclusion: Psychotropic medications were frequently used by elderly subjects during prolonged periods of time. Benzodiacepines accounted for the majority of prescriptions and were prescribed predominantly by general practitioners. Antidepressants were taken by a minority of patients. Long half life BDZs and low safety profile antidepressants were frequently used. These prescription patterns are not in line with international recommendations regarding the use of psychotropic medication in geriatric practice.

N. Artsimovich,

1 l-42-03

1 Osteomaiacia: diff icuity

S. Baig. Department

Karachi,

Presenting

of Medicine,

as progressive

The Aga Khan Universiry,

walking

PO. Box 3500,

Pakistan

The clinical manifestations and laboratory data of 30 (28 females) patients are described who presented at the consulting clinic with complaints of progressive walking difficulty. Their age ranged between 12-55 years (mean 28 years). The major clinical manifestations which developed insidiously were, backache, thigh pains, pain in heels, dlluse body aches and pains, respectively. Half of the patients were unable to walk without support, and they were almost bed-ridden, while others were able to walk with minimal support. Almost half of the female patients developed their clinical manifestations during pregnancy. The laboratory investigations showed mildly below normal serum calcium in 7 of the patients, the serum phosphorus was reduced in all patients examined. The isolated Alkaline Phosphatase was raised in all of the patients, while Parathomrone was raised in 90% of the patients. The two male patients were suffering from chronic renal failure. The majorii of the patients had developed osteomalacia due to nutritional deficiency. All of the patients improved with appropriate nutritional supplements along with addition of calcium and vit D.

T. Galushina,

Moscow,

A. Kornev,

T. Fadeeva.

Institute

1 l-42-04

of Immunology,

Russia

Aggravation of ecological situation including disasters followed by radioactive contamination, enlargement of professional hammesses, stress etc. are reasons for immunodeficiency and Central Nervous System (CNS) disorders. This disorders may develop into chronic persistent diseases tolerant to traditional complex of therapy. In this connection a new drugs for treatment of disorders for both CNS and immune systems were set up. As a specific therapy new neuroimmunomodulator - Kemantan and Bromamtan -are successfully used. Adamantane-based compounds possess a wide range of pharmacological properties. As immune correctives these drugs are active regulators of humoral and cellular processes of immunogenesis, possess stress protection

1 Therapeutic effect and tolerance in Parkinson’s Disease of iisuride added to low doses to L-DOPA + Benserarid combination

‘, G. Kaya*, A. Tuncel*, R. D&i 3. ’ Dept. of Neurolog)! Adnan Menderes University Medical School, Aydm, Turkeys *Dept. of Neurology, Haseki Hospital, istanbuf, Turkey, 3Dept. of Public Health Istanbul University Medical School, Istanbul, Turkey

K. Baytilkem

Thirteen idiopathic parkinsonian patients ranging between 45-78 years of age (mean age 62 f 0.8) were included in this study to investigate, the effect of lisurfde and tolerance to it in Parkinson’s disease. The duration of simple clinical study which had no control group was 12 weeks. The duration of disease varied between 1 to 14 years, with an average of 6.5 f 3.5 years. In the evaluation of the results, Webster’s Evaluation Scale (WES), Hoehn’s and Yahr classification and Unified Parkinson& Disease Rating Scale (UPDRS) were employed. A 50% relief in total disability and daily life activities (DLA) were observed in 13 patients with the combined therapy of low doses of lisurtde added to L-DOPA + Benserazid for 12 weeks (p 4 0.01). Optimal lisuride doses added to L-DOPA + Benserazid were between 0.1-0.8 mg (mean: 0.5 f 0.2 mg). With the addition of lisurfde to treatment, L-Dope + Benserazid dose was reduced in 6 of 13 at a rate of 38%. It was our impression that except for some mild side effects, lisurtde was well-tolerated. Not only will such a combined therapy contribute to the end-of-dose and peak dose dyskinesias and similar other motor fluctuations, but also it may play a prophylactic role in their prevention or delay.

I1 42

05

F. Bieber’, M. Gleeson

Pecuiarities of therapy by new chemical neuroimmunomoduiators

Clinics for Neuroses,

activity, partly prevent the development of supressor’s action by T-lymphocytes. The mechanism of neurotropic activity of Kemantan and Bromantan is explained by their stimulating action on dopamine systems. They enhance spontaneous motional activity and physical ability for work, prevent the development dopamine uptake by synaptosomes. Both drugs enhance energetic patients capacity posses an expressed antiviral (HHV-1, HHV-2, CMV, EBV) as well as neuroimmunocorrective activity. Kemantan and Bromantan are low toxic and well tolerated by patients. A significant number of patients (include Chronic Fatique Syndrome) show complete improvement after complex treatment.

Buenos Aires, Argentina

Objective:

l-42-02

s59

Clinical studies of metrifonate as a treatment for Airheimer’s disease: An overview D. Meuliens,

I. Ouvry*,

3. ’ Bayer AG, German)r

0. Collins3,

J. Curram3,

2 Bayer Pharma,

F. Gibbons3,

France, 3 Bayer P/c, UK

Metrifonate is a prodrug that is converted non-enzymatically to the active substance DDVP (2,2-dimethyl dichlorovinyl phosphate). DDVP elevates acetylcholine levels by competitively inhibiting the acetylcholinesterase (AChE) enzyme. Preclinical and pharmacokinetic studies have shown that metrifonate has a high level of bioavailability. Metrifonate is metabolized mainly by glucuronidation, and undergoes little protein binding, which promotes an absence of drug-drug interactions. The effects of metrifonate on the cognitive, functional and behavioral symptoms of Alzheimer’s disease (AD) have been investigated in several clinical studies. Results from a three month, double-blind, placebo-controlled, dose-finding study will be presented. These results show that metrffonate improved AD symptoms in a dose-related manner consistent with the degree of red blood cell (RBC) AChE inhibition. Data will be discussed in the context of additional results from a six month, double-blind, placebo-controlled study ex-