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Background: There are a few and conflicting results from randomised controlled trials (RCTs) pertaining to the influence of gender in response to currently used disease modifying drugs in Multiple Sclerosis (MS). Observational studies may be especially valuable for answering effectiveness questions in subgroups not studied in RCTs., Objective: To conduct a post-marketing analysis aimed to evaluate the gender effect on Interferon beta (IFNbeta) treatment response in a cohort of relapsing (RR) MS patients., Methods: A cohort of 2570 IFNbeta-treated RRMS was prospectively followed for up to 7 years in 15 Italian MS Centers. Cox proportional hazards regression models were used to assess gender differences for risk of reaching 1st relapse and risk of progression by 1 point on Expanded Disability Status Scale (EDSS) score. Gender effects were also explored by a propensity score (PS) matching algorithm, and a tree-growing technique., Results: The multivariate Cox Regression analyses showed that male patients had a significant (p=0.0097) lower risk for 1st relapse and a trend (p=0.0897) for a higher risk to reach 1 point EDSS progression than females. The PS matched multivariate Cox Regression confirmed these results. The RECPAM analysis showed that male sex conferred a significant reduction in the risk for 1st relapse (HR=0.86; 95% CI=0.76-0.98; p=0.0226) in the subgroup with a low pre-treatment number of bouts, and a significant increase in the risk for 1 point EDSS progression (HR=1.33; 95% CI: 1.00-1.76; p<0.05) in the subgroup with a delayed treatment, but a still young age at the start of treatment., Conclusion: The results of this exploratory analysis seem to suggest that male patients do not respond to IFNbeta treatment in the same way of females.

Objective: Recent findings support greater efficacy of early vs. delayed interferon beta (IFNbeta) treatment in patients with a first clinical event suggestive of multiple sclerosis (MS). We aimed to evaluate the effectiveness of early IFNbeta treatment in definite relapsing-remitting MS (RRMS) and to assess the optimal time to initiate IFNbeta treatment with regard to the greatest benefits on disability progression., Methods: A cohort of 2,570 IFNbeta-treated RRMS patients was prospectively followed for up to 7 years in 15 Italian MS Centers. A Cox proportional hazards regression model adjusted for propensity score (PS) quintiles was used to assess differences between groups of patients with early vs. delayed IFNbeta treatment on risk of reaching a 1-point progression in the Expanded Disability Status Scale (EDSS) score, and the EDSS 4.0 and 6.0 milestones. A set of PS-adjusted Cox hazards regression models were calculated according to different times of treatment initiation (within 1 year up to within 5 years from disease onset). A sensitivity analysis was performed to assess the robustness of findings., Results: The lowest hazard ratios (HRs) for the three PS quintiles-adjusted models were obtained by a cutoff of treatment initiation within 1 year from disease onset. Early treatment significantly reduced the risk of reaching a 1-point progression in EDSS score (HR = 0.63; 95% CI = 0.48-0.85; p < 0.002), and the EDSS 4.0 milestone (HR = 0.56; 95% CI = 0.36-0.90; p = 0.015). Sensitivity analysis showed the bound of significance for unmeasured confounders., Interpretation: Greater benefits on disability progression may be obtained by an early IFNbeta treatment in RRMS.

Background: Recovery from multiple sclerosis (MS) relapses is variable. The factors influencing persistence of residual disability (RD) after a relapse are still to be thoroughly elucidated., Aims of Study: To assess RD after MS relapses and to define the factors associated with persistence of RD., Methods: Data were retrospectively collected for all relapses in a population of relapsing-remitting MS patients during 3 years. Relapse severity and RD after 1 year were calculated on Expanded Disability Status Scale basis. A multivariable analysis for factors influencing RD and relapse severity was performed (variables: age, gender, disease duration, oligoclonal bands, relapse severity, monosymptomatic/polysymptomatic relapse, immunomodulating treatment, incomplete recovery at 1 month)., Results: A total of 174 relapses were assessed. RD after 1 year was observed in 54.5% of the relapses. Higher risk of RD was associated with occurrence of a severe relapse (P = 0.024). Incomplete recovery at 1 month was highly predictive of RD at 1 year (P < 0.0001). Risk of a severe relapse was associated with age

An immunological function has been proposed for the choroid plexus (CP). In multiple sclerosis (MS) brains, CPs show (immunohistochemistry to HLA-DR, CD3, CD20, CD68, VCAM-1, CD138) T lymphocytes in vessels and stroma, VCAM-1 expression on endothelia, intense HLA-DR immunostaining on cells in CP stroma, among CP epithelium and on epiplexus cells. CPs in control or amyotrophic lateral sclerosis brains do not show such inflammatory changes. Intense CP inflammation is observed in viral encephalitis. Changes in MS CPs suggest persisting immune activation, with intensity similar to acute encephalitis, even in MS phases in which neurodegeneration prevails. In MS, CPs could represent a site for lymphocyte entry in the CSF and for CSF antigens presentation.

The F-box protein Skp2 regulates G1-S transition by controlling p27/Kip.1. The deregulated expression of p27/Kip.1 plays a critical role in the pathogenesis of many human tumors. Its cellular levels depend on ubiquitin-mediated degradation. Recently, Skp2 has been demonstrated to mediate p27/Kip.1 degradation and to have oncogenic properties. In a series of astrocytic gliomas, immunohistochemistry and Western blot of p27/Kip.1 and Skp2 have been compared. p27/Kip.1 decreased with anaplasia and almost disappeared in glioblastomas (GBM), whereas Skp2 was absent or poorly expressed in well differentiated astrocytomas and it was diffusely or focally expressed in most GBM. Since the expression of Skp2 increases during G1-S transition, the correlation of Skp2 levels with malignancy might simply reflect the highest percentage of proliferating cells in anaplastic gliomas or alternatively be instrumental to p27/Kip.1 degradation.

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.

In brain tumors, the prognostic value of apoptosis is still debated, even though recent observations are rather negative. In 50 astrocytic gliomas, apoptotic nuclei were recognized by TUNEL technique and morphology and apoptotic index (AI), mitotic index (MI) and the MI/AI ratio were calculated in proliferative areas and in areas containing perinecrotic palisadings and hypercellular centres. In proliferative areas, a positive linear correlation between MI and AI and a MI/AI ratio > I were found. The latter was < I in perinecrotic palisadings and hypercellular centres. This suggests the possibility that apoptosis is triggered respectively by cell proliferation and hypoxia. A small number of apoptotic nuclei was positive for c-Jun and JNKI, suggesting the involvement of this pathway in apoptosis as well as that of sphingomyelinase/ceramide. No relationship was found between AI and labeling indices of Bcl-2, Bcl-x, Bax, p53, APO.I/Fas. The rationale for a prognostic value of apoptosis in gliomas is thus poor.

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., (Copyright 2000 Wiley-Liss, Inc.)

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.

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.

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.

Cell proliferation is characteristic, though non specific, of tumors. The cell cycle is regarded as a clock with ordered activation of protein complexes triggering initiation and advancement through checkpoints. The cell cycle and its control mechanisms are briefly described herein focusing on neuroepithelial tumors. The assessment of cell proliferation in brain tumors is a very important tool in diagnosis and especially in prognosis. It can be performed by different methods: counting mitoses, calculating the labeling index (Ll) of [3H] Thymidine, BrdU, Ki-67, MIB.1, PCNA, cytometry and AgNORs. Each method has its advantages and disadvantages. The main obstacles to the usefulness of different Lls in establishing prognosis in individual cases are sampling error, heterogeneity of the proliferation potential of brains tumors and the wide overlapping of Ll ranges between classic and anaplatic variants. The principal findings are critically described and commented upon.

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.

Cell proliferation and invasion were studied in sixty biopsies of malignant gliomas selected to reproduce the spreading modalities identified in ninety autopsy cases of glioblastoma. Cell proliferation was studied by the immunohistochemical demonstration of PCNA and MIB-1 and by the calculation of their labeling indexes (LI). The main finding was that cell proliferation and cell invasion are not necessarily associated. The interface between the solid tumor and the adjacent brain was represented either by a gradient of tumor cell density or by a clearcut demarcation of the tumor. In the first case the LI either did not change in the infiltration area in comparison with solid tumor or it was much lower, whereas in the second case there was a ring with a high density of labeled nuclei at the tumor periphery. Perineuronal satellites were usually positive for proliferation markers. Cells accumulated in the outer cortical layers, from a deeply located tumor, were almost negative, whereas those originating from subarachnoidal or subpial invasion showed a high LI. High LIs were also found in subarachnoidal and subpial growths, and in a cell population descending into the brain parenchyma around meningeal penetrating vessels. The relationship between cell proliferation and invasion from in vivo studies is not a direct and a simple one.

The proto-oncogene bcl-2 is involved in the regulation of cell death and is able to block apoptosis in neurones through reduced generation of reactive oxygen species (ROS). We have studied the immunohistochemical expression of bcl-2 protein in the aged brain and in various human neurodegenerative diseases. In all cases, bcl-2 was strongly enriched within lipofuscin and autophagic vacuoles of neurones, glial and vascular cells. Our data show that accumulation of bcl-2 is not disease-specific and represents a general cellular response which accompanies the increased formation of lipofuscin. Since oxidative stress is directly involved in lipofuscinogenesis, accumulation of bcl-2 may reflect a mechanism for counterbalancing ROS-mediated damage, or it might represent the impairment of bcl-2-dependent protection from ROS.

The non-astrocytic cells which proliferate in the rat brain after the induction of an area of necrosis have been characterized and counted by means of combined in vivo bromodeoxyuridine (BrdU) administration and immunohistochemical demonstration of glial fibrillary acid protein (GFAP), vimentin, Ricinus communis agglutinin 120 (RCA-1), Griffonia simplicifolia B4 isolectin (GSI-B4), keratan sulphate (KS), carbonic anhydrase C (CA.C), transferrin (TF) and ferritin. Two days after the injury, 7.5% of the proliferating cells were GFAP-positive reactive astrocytes, 5.7% were RCA-1-positive cells and 17.4% were GSI-B4-positive cells. Lectin-binding cells had the microscopic and ultrastructural aspects of microglia; they proliferated around the needle track and in the corpus callosum. Microglia represented a large fraction of the proliferating cells. Evidence is presented for the origin of at least a proportion of perilesional astrocytes and microglia from the periventricular matrix, and of microglia from blood precursors. Other non-proliferating microglia cells transiently appeared in the normal brain around the wound, in agreement with the existence of two different microglia cell populations reacting with different modalities to an area of necrosis.