Biomedical subjects

P Cavalla

Publications and source records attributed to P Cavalla.

At least 19 recordsLinked to original sources

PubMed2006

Fertility in patients with multiple sclerosis: current knowledge and future perspectives.

The issue of fertility in patients with multiple sclerosis (MS) has not been exhaustively studied. Epidemiological data have suggested that spontaneous fecundity might be reduced; several endocrine and sexual disturbances potentially interfering with reproduction have been evidenced in MS patients of both sexes. Moreover, some medical treatments used in MS (e. g., mitoxantrone, cyclophosphamide) may exert detrimental effects on spermatozoa as well as on oocytes, leading to early impairment of fertility. This review illustrates the factors potentially interfering with fertility in MS and discusses the therapeutic tools that may be used to promote fertility in these patients. The safety of hormonal therapies in MS is also examined. The current applications of assisted reproductive technology (ART) are discussed, including in vitro fertilisation (IVF) techniques. Currently available methods to preserve fertility in patients that undergo cytotoxic treatments by means of sperm/oocyte cryostorage or by ovarian fragment cryopreservation and autografting are considered.

Antineoplastic Agents↗

PubMed2001

Distribution of activated caspase-3 in relation with apoptosis in human malignant gliomas.

Activated caspase-3has been immunohistochemically studied in 30glioblastomas. Its distribution has been compared with that of apoptotic nuclei demonstrated by terminal dUTP nick-end labeling (TUNEL) and morphology. The best procedure for the demonstration of caspase-3 requires formalin fixation, followed by Carnoy fixation, with microwave irradiation. The number of positive cells is lower than that of apoptotic nuclei shown by TUNEL technique, especially in perinecrotic pseudo-palisadings, and there are also qualitative variations. Positive staining occurs in nuclei, cytoplasms or in both cell compartments. The interpretation of Caspase-3 positive staining is based on its crucial position in the final pathway to apoptosis and on the mechanisms by which it cleaves cytoplasmic and nuclear proteins among which inhibitory/caspase-activated DNase system is included.

Apoptosis↗

PubMed2001

CDKN2A/p16 in ependymomas.

Sixteen cases of ependymoma were studied for CDKN2A/p16 inactivation by immunohistochemistry using a p16 monoclonal antibody, by homozygous deletion (HD) assay and 5'CpG promoter methylation assay (methylation-specific PCR). Three out of 16 cases were p16 immuno-negative: two corresponded to grade II ependymomas and one to grade III. The latter ependymoma, characterized by a high Ki-67/MIB-1 LI, was the only one of the whole series to show CDKN2A HD. No promoter methylation was found in the two immuno-negative cases without CDKN2A HD. Alternative mechanisms, such as point mutations or alterations in p16 post-translational regulation, may be responsible for p16 inactivation. Since in our series just one out of eight anaplastic cases showed negative immunostaining and CDKN2A HD, p16/CDKN2A inactivation may not play an important role in the malignant transformation of ependymomas. Amplification of CCNDI and CDK4, p27/Kipl degradation and TP53 mutations were previously studied by other authors and were demonstrated not to correlate with anaplasia. Up to date, molecular genetic studies have not been useful in recognizing the anaplastic variant in ependymomas.

Adolescent↗

PubMed2001

Cyclin D1 expression in normal oligodendroglia and microglia cells: its use in the differential diagnosis of oligodendrogliomas.

Cyclin D1 regulates G1-S progression. In many carcinomas it is overexpressed and it might even correlate with prognosis. However, the amplification of CCND1 contributes to the loss of cell cycle control only in a small fraction of malignant gliomas. Cyclin D1 can be immunohistochemically demonstrated by DCS-6 mAb. In astrocytic gliomas the fraction of tumor cells with positive nuclei is almost null in well differentiated tumors and increases with the increase of proliferation rate that occurs in anaplasia. The correct evaluation of this fraction is hindered by the positive staining of normal oligodendrocytes and microglia cells. The cyclin D1-positive staining of normal oligodendrocytes and microglia cells has been studied in a series of 20 oligodendrogliomas, five diffuse astrocytomas and five oligoastrocytomas and in 10 samples of normal cortex and white matter, using cyclin D1 DCS-6 mAb, Feulgen reaction and CR3.43 mAb for microglia cells. As well as microglial nuclei, the nuclei of normal oligodendrocytes of the cortex and white matter, including peri-neuronal satellites and pericapillary cells, were immunostained by DCS-6 mAb. In infiltrative areas of oligodendrogliomas, normal, cyclin D1-positive oligodendrocytes and cyclin D1-negative tumor cells coexisted. In anaplastic oligodendrogliomas, cycling tumor oligodendrocytes may regain the capacity to express cyclin D1, which is thus positive in some tumor cells. The occurrence of positive oligodendrocytes in the peripheral parts of tumors can be useful in distinguishing astrocytomas from oligoastrocytomas.

Antibodies, Monoclonal↗

PubMed2001

Neuroendocrine tumors in the brain.

Somatostatin and other neuropeptides are expressed in tumors originating from neuronal precursors and paraganglia, namely medulloblastoma, central Primitive Neuro-Ectodermal Tumors (cPNETs), neurocytoma, gangliocytoma. olfactory neuroblastoma, paraganglioma. In medulloblastoma, the most common malignant tumor in childhood, there is an extensive expression of somatostatin in addition to somatostatin receptors (SSTR) type 2. Although density of SSTR-2 and intensity of expression of somatostatin genes have no prognostic significance in medulloblastoma. their presence may bring along important information on oncogenesis and relate medulloblastoma to cPNETs. Radio-labeled octreotide scintigraphy may be useful in the follow-up of these patients. allowing differentiation between scar and tumoral tissue. Moreover, on the basis of octreotide-induced inhibition of cell proliferation in medulloblastoma, a trial with octreotide in patients with recurrent or high-risk tumor is warranted. Meningiomas and low-grade astrocytic gliomas, even if not displaying a clear neuroendocrine phenotype, have high levels of SSTR-2. In meningiomas, SSTRs-scintigraphy is not part of the routine pre-operative assessment; moreover, a therapeutic trial with somatostatin-analogues in patients with recurrent or inoperable meningiomas should be carried-out with great caution, because somatostatin and octreotide slightly increase cell proliferation in cultured meningiomatous cells. Low-grade gliomas (WHO grade 2), and a smaller fraction of anaplastic astrocytomas, express SSTR-2, while glioblastomas usually do not. Unfortunately, radiolabeled-octreotide scintigraphy is not useful in the differential diagnosis of gliomas, because the results are altered by the disruption of the blood brain barrier (BBB); in addition, radionuclide-labeled somatostatin analogues are not useful in the therapy of low-grade gliomas, because the intact BBB prevents them from reaching the target SSTR-2. Recently, a pilot study in gliomas, has proposed the use of a radio-labeled somatostostatin analogue with a loco-regional approach in order to overcome the intact BBB.

Antineoplastic Agents↗

PubMed2000

CDKN2A/p16 inactivation in the prognosis of oligodendrogliomas.

The cell-cycle regulator p16 inhibits the complex cdk4-cyclin D1 and controls G1-S transition. In human tumors, p16 inactivation is often accomplished by homozygous deletion (HD) of its encoding gene, CDKN2A. Methylation of the 5' CpG island promoter has been proposed as an alternative mechanism of inactivation. Expression of p16, CDKN2A HD and 5' CDKN2A CpG island methylation was studied in 25 oligodendrogliomas by immunohistochemistry and PCR amplification. Ten oligodendrogliomas were p16-immunonegative, and CDKN2A HD was determined in 8 of these cases. In the 2 immunonegative cases without HD, no CpG island methylation was found. The absence of CpG island methylation in the p16-immunonegative cases without HD suggests either non-genetic regulation of p16 or different genetic changes. CDKN2A HD did not correlate with histological grading (p = n.s.); however, it showed a correlation with survival (p = 0.03), supporting an important role of CDKN2A in the prognosis of oligodendrogliomas.

Brain Neoplasms↗

PubMed1999

Cell-cycle inhibitor p27/Kip-1 expression in non-astrocytic and non-oligodendrocytic human nervous system tumors.

p27/kip-1 is a 'universal inhibitor' which inhibits cyclin complexes with cyclin-dependent kinases (CDKs), preventing cell cycle from the G1-S progression. It is expressed in normal oligodendrocytes and in differentiated glial tumors, decreasing with anaplasia and malignancy. In non-astrocytic and non-oligodendrocytic tumors of the nervous system, such as meningiomas, schwannomas, medulloblastomas, neuroblastomas and malignant lymphomas, p27/kip-1 is inconstantly and sometimes poorly expressed. This can be due to the lacking of p27 expression in the normal counterpart of tumor cells. In some tumors, p27/kip-1 expression can be attributed to a differentiation process, as in the pale islands of desmoplastic medulloblastoma and in neuroblastomas. A correlation of p27/kip-1 expression with histology was not found, with the exception of apoptosis in medulloblastomas. p27/kip-1 is in feed-back with cyclins and CDKs for the control of cell proliferation and its expression may occur where requested by the interplay with cyclins and other inhibitors.

Apoptosis↗

PubMed1999

p27/kip1 expression in oligodendrogliomas and its possible prognostic role.

p27/kip1 regulates the G1-S transition of the cell cycle by inhibiting cyclinD-CDK4, cyclinE-CDK2 and cyclinA-CDK2 complexes. Regulation of p27 levels occurs mainly post-translationally by ubiquitin-mediated proteasomal proteolysis. Although genetic changes of p27/kip1 are extremely rare, in many human carcinomas p27 levels are reduced, correlate with histological malignancy, and are associated with poor prognosis. In astrocytic gliomas, p27 decreases with anaplasia and is almost absent in glioblastomas. p27/kip1 was immunohistochemically studied in 37 oligodendrogliomas, categorized according to WHO classification. In this series, the immunohistochemical reaction for p27 was confined to nuclei. p27 score showed a tendency to decrease with malignancy. When the p27 score was considered as high versus low expression (cut-off of p27 labeling index, LI, at 25%), it represented an independent prognostic factor in univariate (P = 0.02) and in multivariate analysis (P = 0.04). The risk ratio suggested that the p27 low expression group had a threefold increased possibility to show a reduced survival. Moreover, p27 levels did not correlate with MIB-1 LI, suggesting that p27 is not merely associated with the control of proliferation.

Brain Neoplasms↗

PubMed1999

Proteasome-dependent degradation of p27/kip1 in gliomas.

p27/kip1 regulates the G1-S transition of the cell cycle by inhibiting cyclin D-CDK4, cyclin E-CDK2, and cyclin A-CDK2. Modulation of p27 cellular abundance occurs mainly at post-translational level by the ubiquitin-proteasome proteolysis. Although rearrangements and mutations of p27/kip1 are extremely rare events, p27 levels are reduced and associated with a poor prognosis in many human carcinomas. In astrocytic tumors, p27 decreases with advancing anaplasia and is almost absent in glioblastomas. To verify whether the degradation of p27 protein was responsible for its reduced levels in malignant gliomas, p27 degradation activity was tested in 22 tissue extracts that represented high, low, and absent p27 protein levels. p27 protein expression was detected by immunohistochemistry and immunoblot analysis and comparable results between the 2 methods were obtained. Low or undetectable p27 degradation activity was found in samples that displayed high levels of p27, i.e. all 4 normal brain biopsies, and 4 out of 6 grade II astrocytomas. Enhanced degradation activity resulted in malignant gliomas with low or absent p27 protein levels. The proteasome inhibitor LLnL abolished p27 degradation, demonstrating that it occurs in a proteasome-dependent manner. These data suggest that proteasome degradation of p27 may be instrumental in the deregulation of the cell cycle and to the malignant transformation of gliomas.

Astrocytoma↗

PubMed1999

Biohumoral parameters and bone mineral content in the identification of high risk subjects for postmenopausal osteoporosis.

BACKGROUND: The aim of this study was to evaluate the possibility of identifying women with a high risk of postmenopausal osteoporosis by using computerised bone mineral analysis (CBMA) associated with markers of bone turnover in order to provide a valid and reliable screening test. METHODS: A total of 925 patients were evaluated, 252 of whom had already undergone a preliminary densitometric test six months earlier and were diagnosed as fast bone losers. 225 of them (89%) also showed altered bone turnover markers. CBMA was negative in the remaining 673 patients but 13 patients showed altered bone turnover markers and three of the latter then showed a positive CBMA 18 months later. The 673 patients who, after six months of study, were not fast bone losers were monitored over time. RESULTS: It emerges from these results that fast bone losers are characterised by higher levels of hydroxyprolinuria and calcium, lower levels of oestrone and estradiol, and reduced body weight compared to healthy subjects. CONCLUSIONS: This simplified method enabled 79% of the fast bone losers to be identified, whereas densitometry identified 87.5% of the high-risk subjects. The main advantage of our simplified method compared to the measurement of bone mineral content is that it identifies the majority of fast bone losers in the initial postmenopausal period, before a substantial reduction in BMC has taken place.

Bone and Bones↗

PubMed1998

Cyclin D1 expression in gliomas.

Cyclin D1 (cycD1) expression was defined immunohistochemically using monoclonal antibody DCS-6 and polyclonal antiserum H-295 in 50 glioma biopsies. The number of positive nuclei was higher for H-295 than for DCS-6, with a ratio of 3:1. The labelling index (LI) was compared to the grade of histological malignancy and to Ki-67 MIB-1 LI. The LI for cycD1 increased with histological malignancy, in parallel with the increase in MIB-1 LI. In most tumours, the maximum LI for cycD1 and MIB-1 were found in the same areas. The mean MIB-1 LI: mean cycD1 LI ratio does not vary in the three grades of astrocytic tumours. However, in this study the correlation between the two LIs was not statistically significant. Staining for cycD1 antigen does not necessarily imply that the gene is overexpressed since other molecular mechanisms can also be responsible for cell cycle deregulation. In invasive areas, the cycD1 LI is frequently higher than in solid tumour, either because more tumour cells are positive or because reactive astrocytes and activated microglia express cycD1. The relative contribution of neoplastic and reactive cells remains to be defined.

Astrocytes↗

PubMed1998

CDKN2/p16 inactivation and p16 immunohistochemistry in astrocytic gliomas.

CDKN2/p16 inactivation is the most frequent alteration in the molecular regulation of G1-S transition. CDKN2/p16 homozygous deletions was studied in paraffin-embedded sections of 45 astrocytic tumours by multiplex PCR. Immunohistochemistry for p16 and proliferation marker Ki-67 MIB-1 was performed in adjacent sections; their labelling index (LI) have been calculated. CDKN2/p16 gene was not deleted in astrocytomas, while homozygous deletion was found in 26.7% anaplastic astrocytomas, and in 55.0% of glioblastomas. Analysis of CDKN2/p16 homozygous deletion in discrete areas of the same tumour, showed that the deletion occurred independently of the phenotypic aspect of the areas. Nevertheless a genotypic and phenotypic heterogeneity is present in few cases. p16 immunohistochemistry mostly corresponds to the genotypic pattern. No correlation was found between CDKN2/p16 homozygous deletion and MIB-1 LI.

Astrocytoma↗

PubMed1997

p27/kip1 expression in human astrocytic gliomas.

In the cell cycle, p27/kip1 acts as an inhibitory protein of cyclin-cdk complexes. p27/kip1 immunohistochemistry was performed in 50 gliomas (15 astrocytomas, 15 anaplastic astrocytomas and 20 glioblastomas) by a polyclonal antiserum. In the same tumours, proliferation marker Ki-67 was studied by MIB-1 antibody. For both, a labelling index (LI) was calculated after counting at least 1000 cells at x1000 magnification. p27 is diffusely and strongly expressed in astrocytomas (LI mean = 44.4%), whereas positive nuclei decrease in number and in staining intensity in anaplastic astrocytomas (LI mean = 5.86%) and glioblastomas (LI mean = 2.1%). An inverse correlation has been found between MIB-1 LI and p27 LI calculated in the same areas. Interestingly, in malignant gliomas the absence of p27 was independent from any histological feature of differentiation or anaplasia. p27 expression is thus reduced in malignant gliomas as in other malignancies. Since mutations of p27/kip1 are extremely rare, posttranslational changes are hypothesised also in astrocytic gliomas.

Astrocytoma↗

PubMed1997

Role of apoptosis in the prognosis of oligodendrogliomas.

Prognostic factors in oligodendrogliomas are not well defined, even considering the labeling index of proliferation markers. As in other neuroepithelial tumors, the difficulty in calculating cell loss may contribute to this uncertainty. Proliferation markers Ki-67/MIB.1 and PCNA, mitoses, apoptotic nuclei, p53 and bcl-2 expression were investigated in 98 oligodendrogliomas. Apoptosis was assessed by the aspect of nuclei, by in situ end-labeling (ISEL) technique and by c-Jun immunohistochemical demonstration. The Bcl-2 also was immunohistochemically studied for its anti-apoptotic role. Mitotic index (MI), labeling index (LI) for MIB.1 and PCNA and apoptotic index (AI) were calculated and compared among themselves and with histology and survival. It was found that AI correlated with MI (p = 0.001) and was significantly higher in anaplastic than in classic oligodendrogliomas (p = 0.001). Apoptosis occurred only slightly more frequently in cases with high LIs for proliferation markers (MIB.1 and PCNA) (p = non-significant) and it was definitely higher in p53-positive cases (p = 0.008). It did not correlate with bcl-2 which was poorly expressed in oligodendrogliomas, with the exception of cells with astrocytic features. Apoptotic index correlated very weakly with survival (p = 0.05); therefore, it cannot be considered a highly reliable prognostic factor in oligodendrogliomas.

Adult↗

PubMed1997

Prognostic factors in oligodendroglioma.

BACKGROUND: A reliable marker for tumor oligodendroglial cells is not yet available, so that the histological recognition of the tumor still encounters uncertainties. There is no general agreement also on prognostic factors in oligodendroglioma. The inconsistency concerns mainly the histopathological factors. The aim of the study was recognition of prognostic factors in oligodendroglioma. METHODS: In a series of ninety-eight oligodendrogliomas, including twenty mixed oligoastrocytomas, clinical [sex, age at surgery, tumor location, symptoms at presentation], therapeutic [extent of resection, year of surgery, post-operative Karnofsky score, post-operative radiotherapy, post-operative chemotherapy], histological [cell density, nuclear pleomorphism, vascular endothelial proliferation, necrosis, microcysts, mitoses, mitotic index (MI), apoptosis, apoptotic index (AI)] and immunohistochemical parameters [MIB-1 and PCNA Labeling Indexes (LIs), staining for GFAP, positivity for p53] were correlated with survival in uni- and multivariate analysis in order to identify their prognostic significance. RESULTS: Age at surgery, extent of surgical resection, year of surgery, post-operative Karnofsky score and MIB-1 LI were associated with survival in both uni- and multivariate analysis. Location, symptoms at presentation, mitoses, MI, AI, and PCNA LI showed a significant correlation with survival in uni- but not in multivariate analysis. The twenty cases of oligoastrocytomas did not show any difference in survival from pure oligodendrogliomas. CONCLUSIONS: Some clinical and therapeutic factors together with MIB-1 LI play a prognostic role. MIB-1 LI is prognostic with a cutoff of 8%. Histology gives a limited contribution to the prognosis. Oligoastrocytomas had the same outcome and prognostic factors as pure oligodendrogliomas.

Adolescent↗

PubMed1997

Proliferative activity and prognosis of low-grade astrocytomas.

Well-differentiated astrocytomas may transform into malignant astrocytomas in time. In surgical specimens, when the histological picture strictly corresponds to that of grade II glioma, the transformation is unpredictable. Clinically, the bad outcome of a quota of astrocytomas is a well known phenomenon. The use of proliferation markers, and recently of MIB-1 LI, for detecting the proliferation potential comes out to be a useful tool for prognosis. A survival analysis of fifty astrocytomas grade II according to the WHO classification was performed with univariate and multivariate analysis of a series of clinical and histological parameters. MIB-1 LI was calculated and compared with all the other parameters. A cut-off of 8% of MIB-1 LI divided the astrocytomas in two groups with significantly different survival (p = 0.0066): median survival time of 1062 versus 1686 days. According to multivariate analysis MIB-1 LI resulted to be an independent factor (p = 0.002) along with extension of surgical removal (partial versus total), postoperative Karnofsky status (> or = 70 versus < 70) and age (< or = 30 versus > 30). The interpretation of well-differentiated astrocytomas with high MIB-1 LI is that the increasing number of cycling cells precedes phenotypic transformation. MIB-1 LI can be used as a prognostic factor.

Adult↗

PubMed1997

Is medulloblastoma the same tumor in children and adults?

The appearance of medulloblastoma in adult age and the uncertain overlapping of prognostic factors in pediatric and adult populations stimulate the question of whether medulloblastoma is different in adults and in children. The pathologic features, proliferation potential and glial/neuronal differentiation have been investigated in 42 adult medulloblastomas and 42 medulloblastomas of children; the quantitative data have been compared between the two groups of age. Homer-Wright rosettes, nuclear polymorphism and histologic signs of neuronal differentiation were more frequent in children cases; GFAP-positive tumor cells and desmoplastic type were more frequent in adult cases. The mean, median and rage of Lis, with PCNA and MIB-1 were significantly (p < 0.05) higher in adults than in children. All cases, independently from age of the patients were immunoreactive with markers of neuronal commitment (class III beta tubulin isotype, MAP-2, neurofilaments). The immunoreactivity pattern suggested a more mature neuronal character in desmoplastic cases of adults than of children and in classic cases of children than of adults. In conclusion, some phenotypic differences between childhood and adult medulloblastoma exist, but do not support a substantially different course of the disease. The higher proliferation potential in adult than in childhood cases is unexpected in a tumor of embryonal origin, and reduces the applicability of Collin's law to medulloblastoma.

Adolescent↗

PubMed1997

Ultrasound diagnostic criteria in breast disease.

The Kasumi-Kamio parameters (margins, peripheral echoes, internal echoes, posterior echoes, lateral shadow cones) and the ratio between the longitudinal and transverse diameter of the breast lump form the basis for a list of standardised diagnostic criteria on which to base an analysis of breast disease that assesses the specificity and sensitivity of ultrasonography as a valid, reliable initial step in the diagnosis of breast tumours. The study was based on a series of 129 tumour cases and produced correct diagnosis in 89.28% of benign, 83.33% of malignant cases.

Breast Neoplasms↗