S. Pezzotta

Glial fibrillary acidic protein and vimentin in the experimental glial reaction of the rat brain

Glial reaction has been studied in the rat by the immunohistochemical demonstration of glial fibrillary acidic protein (GFAP) and vimentin (VIM) in two experimental conditions. The first was represented by a necrotic cerebral lesion obtained by laser irradiation and the second by the development of experimental tumors induced by transplacental ethylnitrosourea. Reactive astrocytes develop not only in the proximity of the lesion but also distant from it. The intensity of the glial response seems to depend upon the normal distribution of astrocytes and the perilesional edema. GFAP decorates all the reactive astrocytes, whereas VIM is positive only in those at the edges of the lesion. The significance of the different responses in the two models and between the two intermediate filaments is discussed.

Cerebral tumors induced by transplacental ENU: Study of the different tumoral stages, particularly of early proliferations

SummaryExperimental cerebral tumors have been induced by transplacental ENU. A systematic diachronic study of the brains has been performed starting from the 15th day of extrauterine life. The tumoral lesions firstly appear as “early stage proliferations” or oligodendroglial foci and develop as glial micro-and macrotumors or as isomorphic and polymorphic oligodendrogliomas respectively.Neurinomas appear later than glial tumors.The duration of the different lesions is sketched out. The usefulness of the model for chemotherapy studies is discussed.

Arachnoid cysts: diagnosis and treatment

Twenty supratentorial and 10 infratentorial arachnoid cysts are reported. The patients were from 0 to 15 years of age. The commonest presenting symptoms in children were cranial enlargement, epileptic seizures, and psychomotor retardation. Neuroradiological evaluation included CT, metrizamide CT, cisternography, and angiography. Echography was performed in 5 newborns. Therapeutic criteria according to the clinical and neuroradiological findings are reviewed. Cystoperitoneal shunting in combination with ventriculoperitoneal shunting for associated hydrocephalus is considered the treatment of choice.

Experimental brain tumors by transplacental ENU - Multifactorial study of the latency period

SummaryExperimental cerebral tumors have been induced by transplacental ENU. The morphologic study of the brains of treated rats revealed that cellular hyperplasias appear at the 30th day of extrauterine life in the paraventricular white matter, i.e., before the already known “early neoplastic proliferations”. Cytofluorimetric investigations failed to demonstrate differences between treated and control rats during the 1st month. On the contrary, adenylate cyclase activity is very high in that period. The duration of the latency period is discussed.

Freshly dissociated fetal neural stem/progenitor cells do not turn into blood.

Earlier studies suggested that stem cells from one somatic tissue may generate differentiated elements of another, embryologically unrelated, tissue after an exchange in their positions through transplantation. Two reports indicated that murine and human neural stem cells of clonogenic origin after in vitro expansion in growth factor-supplemented media, may sustain hematopoiesis when injected into sublethally irradiated mice. Here we investigated if freshly dissociated fetal neural cells (fNC) share the reported hemopoietic potential of in vitro expanded neural cells. In order to minimize the risk of hemopoietic contamination, donor cells were taken from mouse E10.5 developing brains, before completion of blood vessel ingrowth into the brain; 10(6) fNC derived directly from fetal brains of transgenic mouse expressing an enhanced version of the green fluorescent protein were injected into the tail vein or directly into the bone marrow of sublethally irradiated (6 Gy) C57B16 mice. After transplantation, the presence of donor-derived cells was assessed at different survival times by FACS analysis, PCR, and clonogenic stem cell assays on peripheral blood and bone marrow. While bone marrow-derived cells were detected from 2 weeks onward after grafting, none of the mice grafted with neural embryonic cells demonstrated any sign of transdifferentiation into hemopoietic cells up to 16 months after transplantation. Our data indicate that ability to transdifferentiate from neural into the hematopoietic phenotype, if present, is acquired only after in vitro expansion of neural stem/progenitor cells and it is not present in vivo.

Effects of vitamin D and retinoic acid on human glioblastoma cell lines

SummaryThe biological significance of vitamin D receptors expressed by glioblastoma and other glial tumours is still unclear. In an effort to clarify this issue we studied the effects of increasing concentrations of 25-dihydroxyvitamin D3 and its metabolite 1 α, 25-dihydroxyvitamin D3 on two human glioblastoma cell lines. Both substances were capable of inducing a significant (> 50%) reduction in growth of the two glioblastoma cell lines at dosages over 5 μM. When the HU 70 cell line was treated by increasing dilutions of 25-dihydroxyvitamin D3 combined with 1 μM all trans-retinoic acid, significant inhibition was apparent even after addition of 25-dihydroxyvitamin D3 in the nanomolar range. Reduction of growth index was mainly due to induced cell death.Our results providein vitro evidence that vitamin D metabolites alone or in combination with retinoids may be potentially useful agents in the differentiation therapy of human malignant gliomas.

CNS-85 trial: a cooperative pediatric CNS tumor study--results of treatment of medulloblastoma patients.

Between 1985 and 1989, 38 children with newly diagnosed medulloblastoma entered our therapeutic protocol. After surgery and postoperative staging assessments, patients were assigned to risk groups. Eleven with “standard-risk” (SR) tumors were treated with radiation therapy alone, while 27 with “high-risk” (HR) tumors received radiation therapy plus adjuvant chemotherapy with vincristine, methotrexate, VM-26, and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU). After a minimum follow-up of 5 years (range 5–9 years) 21/38 children had developed a recurrence or progression of their disease and 19/38 patients had died. Five-year event-free survival rates and 5-year total survival rates for all 38 patients were 47.4% and 50% respectively. The event-free survival rates at 5 years for SR and HR patients separately were 27.3% and 55.6%, respectively. The corresponding 5-year total survival rates were 27.3% and 59.3%. The differences were not statistically significant. Univariate analysis showed age at diagnosis to be the most important prognostic factor. Infants aged 5 years or less had a significantly shorter event-free survival time than older patients (P=0.00897). Similar effects were found when total survival time was considered. There were significant differences in outcome in patients receiving different doses of radiation, suggesting a dose-response relationship. A Cox stepwise multivariate analysis showed age at diagnosis as the only independent prognostic factor. Variables relating to treatment entered the model, suggesting that chemotherapy could play an important role in determining outcome.

Cyclic nucleotides in experimental and human brain tumors

It is well known that the system of cyclic nucleotides plays an important role in cell differentiation and proliferation. Cyclic AMP is capable of stimulating cell growth, and cyclic GMP is thought to control cell division and growth. The authors measured adenylcyclase activity (AC) and cGMP content in the tumor latency period and in early neoplastic proliferations in rats with brain tumors induced by transplacental ethylnitrosourea (ENU). AC activity, which is high during the first days of life, decreases until it reaches, at the 60th day, levels lower than those in control animals. Cyclic GMP, on the contrary, increases during the first month in treated animals and remains consistently higher than controls up to the 45th day.In fully developed experimental brain tumors (mixed gliomas, isomorphic and polymorphic oligodendrogliornas) the percentage of reduction in AC activity is significantly higher.AC activity was measured also in human tumoral tissue. In malignant tumors it is markedly lower than in benign tumors. In the same patients cAMP in the cerebrospinal fluid was measured with results similar to those obtained in tissues.These findings confirm that the system of cyclic nucleotides is implicated in all the developmental phases of brain tumors and therefore may reveal how research can clarify the first transformations of tumoral cells.

Glycosaminoglycans in human cerebral tumors: Part II. Histochemical findings and correlations

SummaryThe occurrence and the distribution of GAGs have been studied histochemically in 224 human cerebral tumors by means of Alcian blue techniques. In the normal peritumoral gray matter the alcianophilia is stronger than in the white matter and demonstrated the presence of HA and CS. In the glioma group the alcianophilia, due to HA and CS, is mainly related to the presence of infiltrated cortex. In the other tumors, GAGs are histochemically disclosed in relation to collagen, reticulin, mesodermic areas, etc. The vessels of every tumor show a positive staining for HA, CS, and HS. The histochemical findings are consistent with the biochemical ones as reported in Part I, even though the significance of GAGs in cerebral tumors remains unknown.

Shunt in high-risk newborns

Twenty-four high-risk newborns with a low birth weight developed progressive hydrocephalus and underwent ventriculoperitoneal shunting (at the time of shunting they weighed 1,100–1,990 g, mean 1,541.5 g). The changes in hydrocephalus after shunting were determined by ultrasound examinations; preoperative examination was by CT. Of the factors evaluated for their relationship to shunt complication, we considered in particular babies with a CSF protein level of over 1.5 g/l (7 cases). These cases were treated with external drainage and later with ventriculoperitoneal shunting. Shunt infections occurred in 20.9%, in contrast with a low incidence of shunt blockage (8.3%), probably owing to previous external shunting in children with high CSF protein. There were 2 deaths (8.3%). All children underwent careful follow-up during the 1st year and serial checkups subsequently for 5 years.