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Biomedical subjects

M A Gerosa

Publications and source records attributed to M A Gerosa.

At least 19 recordsLinked to original sources
PubMed1990

Characterization of BK virus variants rescued from human tumours and tumour cell lines.

Episomal BK virus (BKV) DNA was detected in primary human brain tumours, in Kaposi's sarcoma and in cell lines from brain tumours. Ewing sarcoma and osteogenic sarcoma. Infectious BKV was rescued from several tumours and tumour cell lines by transfection of total cellular DNA into human embryonic fibroblasts. Restriction endonuclease and nucleotide sequence analysis showed that all the rescued viruses are similar to BKV-IR, a BK variant previously isolated from a human tumour of pancreatic islets, indicating that a specific BKV strain may be associated with certain types of human tumours. All the variants contain a putative transposable elements in the regulatory region of the viral genome. This region has mutagenic properties and enhancing activity in transformation, suggesting a possible role of these variants in tumour induction or progression.

Animals↗
PubMed1989

Overexpression of N-ras oncogene and epidermal growth factor receptor gene in human glioblastomas.

Five human glioblastoma cell lines were analyzed for oncogene activation with a panel of probes. Abnormal expression of the epidermal growth factor receptor (EGFr) gene was detected in four of five lines; N-ras oncogene overexpression was found in all five cell lines. These results were subsequently confirmed with fresh brain tumor and nonneoplastic brain tissue biopsy samples; increased expression of the N-ras proto-oncogene was observed in five of five glioblastomas, all of which also showed EGFr gene overexpression, but not in well-differentiated gliomas or in nonneoplastic brain tissue specimens. No significant differences in Ha-ras and Ki-ras expression were observed. Preliminary histochemical observations showed that intracellular levels of transforming growth factor alpha, a putative biochemical link between these two oncogenes, were significantly higher in glioblastoma cells than in controls.

Blotting, Northern↗
PubMed1988

Sensitivity of human glioma cells to cytotoxic heteroconjugates.

Several anti-human glioma cytotoxic conjugates were studied in vitro. Monoclonal antibodies (MAbs) to the GE2 glioma-associated antigen (anti-GE 2) and MAbs to HLA-DR antigens (D1/12) or human diferric transferrin (Tfn) were linked to the potent cytotoxin ricin (anti-GE 2-ricin) or to its A subunit (anti-GE 2-RTA, D1/12-RTA, Tfn-RTA). Anti-GE 2-RTA had low cytotoxic activity in both the absence and the presence of lysosomotropic substances inhibiting intracellular degradation. Anti-GE 2-ricin was about 1,000 times more toxic than RTA alone, but showed only 14-fold target specificity. D1/12-RTA was about 20 times more toxic than RTA and its cytotoxic effect increased about 6- to 7-fold when cell-surface HLA-DR antigen expression was enhanced by IFN-gamma treatment. Human diferric Tfn linked to RTA demonstrated the highest cytotoxic activity, being about 5,000 times more toxic than RTA alone for glioma cells and about 6,000 times more toxic for Jurkat cells in the presence of the carboxylic ionofore monensin. Ricin toxin was only about 5 times more toxic for Jurkat and glioma cells than Tfn-RTA-monensin. Tfn-RTA was over 100,000 times more potent than the chemotherapeutic agent BCNU in reducing glioma cell survival in vitro. Addition of 80% human pooled cerebrospinal fluid (CSF) reduced Tfn-RTA toxicity about 10-fold. Kinetics of Tfn-RTA cytotoxicity at non-saturating concentrations indicated that over 80% of target cells could be killed within 8-10 hr in the absence and within 10-12 hr in the presence of human pooled CSF.

Animals↗
PubMed1986

In vitro analysis of BCNU-sensitivity in human malignant gliomas. II. Cross-resistance studies with cisplatinum and nitrosoureas.

With the use of the Human Brain Tumor Stem Cell Assay (HBTSCA) in a cross-resistance study, four early (3-4) culture passages of human malignant gliomas (glioblastoma multiforme) were tested for in vitro chemosensitivity with three of the most effective single agents for brain tumor chemotherapy: BCNU, CCNU and cisplatinum (DDP). The shapes of the dose-response curves indicated complete cross-resistance between BCNU and CCNU, i.e. two chloroethyl-nitrosoureas sharing a common alkylating-carbamoylating activity, with no evident cross-resistance between the two nitrosoureas and the DDP, a DNA binder with a putatively different antitumor action. Probably because of differences in drug delivery kinetics or in the cytotoxic mechanism, DDP might play a role in the treatment of nitrosourea-resistant gliomas.

Brain Neoplasms↗
PubMed1985

In vitro analysis of BCNU-sensitivity in human malignant gliomas. I. A model study with alkylating, cross-linking and carbamoylating agents in anaplastic astrocytomas of pediatric age.

Like all chloroethyl-nitrosoureas of major clinical use, 1,3 bis-(2-chloroethyl)-1-nitrosourea (BCNU) - which is one of the most effective chemotherapeutic agents for CNS malignancies - biologically degrades into active alkylating and carbamoylating moieties. Using a human brain tumor stem cell assay, we analyzed a series of anaplastic astrocytomas of pediatric age, characterized by different degrees of BCNU-resistance. Early (2-4) passage cultures from these tumors were treated in vitro with model drugs for alkylation (BCNU, CHLZ (2-[3-(2-chloroethyl)-3-nitrosoureido]-2-deoxy-D-glucopyranose), ENU (N-ethyl-N-nitrosourea), cross-linking (BCNU, CHLZ) and carbamoylation BHCNU (1,3 bis (trans-4-hydrocyclohexyl)-1-nitrosourea): dose-schedules were compatible with clinically achievable levels. Results of chemosensitivity tests confirmed that - as previously reported in malignant gliomas of the adult - cellular resistance to BCNU was closely related to the cross-linking activity of alkylating species. However, in pediatric gliomas the levels of cell kill after treatment with the purely carbamoylating agent BHCNU, even at the highest doses tested, were lower than expected.

Age Factors↗
PubMed1984

Prediction of the relative in vitro sensitivity of 9L rat brain tumor cells to nitrosoureas by the sister chromatid exchange assay.

In an earlier study we showed that there is a good correlation between sister chromatid exchange induction and cell kill in 9L cells treated with certain nitrosoureas. In the study reported here, we treated four 9L cell lines that have different sensitivities to chloroethylnitrosoureas with 1,3-bis (2-chloroethyl)-1-nitrosourea, chlorozotocin, and ethylnitrosourea and determined the number of sister chromatid exchanges induced. Cell lines that were most sensitive to the drugs with respect to cell kill were also most sensitive to induction of sister chromatid exchanges for a given drug, and the assay based on sister chromatid exchange is therefore predictive of the relative sensitivity of these cells to the drugs used.

Animals↗
PubMed1983

Opto-chiasmatic arachnoiditis in the young.

14 young patients, operated upon for opto-chiasmatic arachnoiditis by craniotomy are presented. 2 main etiopathogenetic forms (and their respective clinical equivalents) of the disease could be recognized. Only 1 postoperative death occurred, in a patient with a dominant clinical picture of intracranial hypertension. Results of surgery (craniotomy and lysis of adhesions) could be distinguished as positive (functional improvement) in 5 cases, indifferent or negative in the others, with a follow-up duration of up to 23 years. The role of the diagnostic value of the pneumoencephalogram as a basis for surgical indication is discussed: it is felt that this examination, when reported as negative, is not of sufficient value to rule out the diagnosis, which must essentially rely upon clinical data.

Adolescent↗
PubMed1983

Stem cell studies of human malignant brain tumors. Part 1: Development of the stem cell assay and its potential.

A stem cell assay for human malignant gliomas has been developed. Cells obtained from tumor biopsies grew into colonies composed of malignant glial cells, as documented by histochemical, immunohistochemical, and immunobiological techniques. Studies suggest that the disaggregated cells are representative of the cells within the solid tumor. Clonogenic cells were obtained from 48 tumors and analyzed for their in vitro sensitivity to graded doses of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). The in vitro anti-tumor activity of BCNU at clinically achievable doses was compared to clinical response to the agent based on changes in computerized tomographic scan, radionuclide brain scan, and neurological examinations. Twenty-two patients received nitrosoureas before or after tumor specimen analysis, and were eligible for in vitro-in situ correlations. Clinical tumor sensitivity to nitrosoureas was predicted by culture results in 42% of all evaluable patients, and clinical resistance was predicted in 100%. The capability of the assay can be appreciated best for the 13 patients not treated with BCNU prior to culture; the in vitro prediction of clinical sensitivity and resistance was 71% and 100%, respectively. Preliminary findings show that clinical tumor resistance to BCNU may result from "intrinsic" cell resistance in some patients and from inadequate delivery of drug to tumor cells in other cases. The potential utility of this method to study the reason(s) for tumor cell resistance to drugs, to screen new chemotherapeutic agents, to individualize patient treatment, and to investigate tumor biology is discussed.

Biological Assay↗
PubMed1983

Improved treatment of a brain-tumor model. Part 1: Advantages of single- over multiple-dose BCNU schedules.

Clonogenic cell and animal survival studies were used to determine the most effective BCNU therapy schedule in the 9L rat brain-tumor model. Survival of tumor cells following a single LD10 dose of BCNU (13.3 mg/kg intraperitoneally) was compared to cell survival after one to four daily 0.5 X LD10 doses. The posttreatment kinetics of surviving clonogenic cells were investigated at various times after BCNU was given in single doses of 0.25 to 1 X LD10 and in two daily doses of 0.5 X LD10. The cell kill was greater, time to reinitiation of cell growth was later, posttreatment rate of clonogenic cell proliferation was slower, and the interval to total repopulation of the clonogenic cell pool was longer with a single LD10 dose as compared to the multiple-dose schedules. Animal survival studies confirmed that a single LD10 dose of BCNU was at least as effective as a cumulative level of up to 1 1/2 times that amount when treatment was administered in smaller doses, regardless of the fractionation schedule. Clinical experience with patients harboring malignant brain tumors has shown that a single BCNU dose of 185 to 200 mg/sq m is tolerated well. Results of these animal experiments suggest that this therapy should have anti-tumor activity at least equivalent to the more commonly employed schedule of 80 mg/sq m/day given for 3 days. Although direct comparison of treatment efficacy using the two schedules is not possible, no adverse clinical effects have been observed with the recently adopted single-dose schedule. Furthermore, the duration of patient hospitalization for chemotherapy has decreased.

Animals↗
PubMed1983

Improved treatment of a brain-tumor model. Part 2: Sequential therapy with BCNU and 5-fluorouracil.

A combination chemotherapy regimen for brain tumors was developed, based on investigations of the survival of animals harboring the intracerebral 9L rat brain-tumor model and on analyses of their clonogenic tumor cells. Fischer 344 rats harboring 9L brain tumors were treated with 2-day courses of 5-fluorouracil (5-FU), in order to expose all cycling tumor cells to the drug during DNA synthesis and achieve maximum anti-tumor activity for this cell-cycle-specific anti-metabolite. Although a 74% cell kill was obtained for a total dose of 45 mg/kg or greater, animal life span was not increased over that of untreated tumor-bearing controls. However, when 5-FU (48 to 96 mg/kg total dose over 2 days) was administered after a single LD10 dose of BCNU (13.3 mg/kg), additive cell kill was suggested. In three large series, long-term animal survivors and occasional tumor cures were observed with this drug combination, a result never observed following BCNU alone. Schedule dependency was not apparent. A previously published protocol for treating recurrent malignant gliomas with sequential courses of BCNU and 5-FU was partially planned based upon these initial observations. Anti-tumor activity with the combination of drugs was superior to therapy with BCNU alone. Both animal and human studies confirm that, contrary to presently accepted oncological tenets, a chemotherapeutic agent that kills significant numbers of tumor cells but is clinically ineffective when given alone might, nevertheless, be useful in combination therapy regimens.

Animals↗
PubMed1982

Impaired immunocompetence in patients with malignant gliomas: the possible role of Tg-lymphocyte subpopulations.

T-lymphocyte subpopulations (Tg or "suppressor cells" and Tm or "helper cells") in the peripheral blood of 16 patients with malignant intracranial gliomas were analyzed. The number of Tm-lymphocytes was very close to normal in both pre- and postoperative samples, whereas Tg-lymphocytes were significantly increased preoperatively (18.55 +/- 1.11 vs. 12.72 +/- 1.19 p less than 0.001) and were still slightly higher than normal after operation and radiation treatment. These preliminary findings suggest a possible role of T-suppressor lymphocytes in the impairment of cell-mediated immunocompetence that has been observed repeatedly in patients with malignant gliomas.

Adolescent↗
PubMed1981

VM-26 monochemotherapy trial in the treatment of recurrent supratentorial gliomas: preliminary report.

Twenty-five adults with recurrent supratentorial malignant gliomas were treated with VM-26 in a monochemotherapy schedule, the antiblastic region covering a period of 24 weeks. Five cases were excluded from the final evaluation, 4 because of protocol violations and 1 due to intolerance to the drug. In the group of 20 patients who met the criteria for evaluation, 7 (35%) showed a partial or complete response, with clinical or radiological tumor aggression, and the conditions of 7 (35%) were unchanged at the end of the chemotherapy courses. The progression-free intervals turned out to be 10.4 months and 8.5 months, respectively. Six patients (30%) complained of tumor progression despite the treatment. Most of the patients are still alive, and the actuarial survival rate is encouraging. Toxicity was mainly hematologic, but usually moderate and easily reversible.

Anemia↗
PubMed1981

Cerebrospinal fluid levels of cyclic nucleotides and monoaminergic metabolites in subarachnoid haemorrhage: preliminary report.

c-AMP, c-GMP, HVA and 5 HIAA cerebrospinal fluid levels were investigated in 18 patients with subarachnoid haemorrhage (SAH). The main findings in the acute stage after SAH were represented by a marked increase of c-AMP and 5 HIAA values, whereas HVA levels were only slightly higher. In the chronic phase c-GMP levels turned out to be significantly increased, and were clearly related to intracranial hypertension. 5 HIAA and particularly HVA levels were decreased, probably due to the functional and anatomical lesion of the periventricular adrenergic structures, following the raised intracranial pressure.

Acute Disease↗
PubMed1981

Multidisciplinary treatment of medulloblastoma: a 5-year experience with the SIOP trial.

A 5-year experience of the multidisciplinary treatment of pediatric medulloblastoma with the SIOP (International Society of Pediatric Oncology) trial is presented. 33 eligible patients finally reduced to a total of 30 evaluative cases were treated with major surgical resection, extensive irradiation, and combined chemotherapy (vincristine + CCNU). The overall survival rate without recurrence was encouraging, and the actuarial survival rate is satisfactory. At follow-up controls, most of the patients showed a good performance status and a promising neurological stage. However, the problem concerning quality of life remains unsolved: morbidity and sequelae following high-dose radiotherapy and concomitant antiblastic treatment were noticeable.

Adolescent↗
PubMed1981

Cerebral arteriovenous malformations in children (56 cases).

A survey of 56 patients aged less than or equal to 16 years, admitted (1954-1979) for cerebral arteriovenous malformations, is presented. The clinical manifestation was mostly related to hemorrhage, less frequently to epilepsy or to a cerebral 'steal' syndrome. The most frequent site was the parietal lobe, with supply from the middle cerebral artery. Deep malformations were not uncommon and most lesions were of medium or large size. 38 patients were operated upon, and 18 were given treatment other than surgical (including radiotherapy). 23 malformations were completely excised, in 4 patients only a partial excision could be carried out, and in 10 patients surgery consisted of occlusion (clipping or coagulation) of feeding vessels. In 1 patient, surgery had to be limited to removal of an intracerebral hematoma. The immediate and long-term results of treatment are much better in the surgical than in the nonsurgical group.

Adolescent↗