Definition of the smallest pathological CAG expansion in SCA7.
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Adult↗
Biomedical subjects
D Schiffer
Publications and source records attributed to D Schiffer.
Lack of apoptosis in mice with ALS.
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Aging↗
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↗
Prognostic significance of telomerase in brain tumors
Telomeres help to maintain chromosomal stability and integrity. They are progressively lost, conditioning aging and mortality. Telomerase enzyme activation stabilizes the telomere length, permitting the proliferation of cancer cells. Four papers are reviewed dealing with increased expression of telomerase associated with increased labelling index of MIB-1 (Ki-67) and malignancy in astrocytomas, ependymomas, and oligodendrogliomas. Telomerase expression can be utilized for differentiating malignant from benign tumors with histological resemblance. The significance of telomerase in tumor progression is discussed within the field of brain neoplasias.
Journal Article↗
Prevalence of Parkinson's disease in Northwestern Italy: comparison of tracer methodology and clinical ascertainment of cases.
The prevalence of idiopathic Parkinson's disease (PD) in an area of Northwestern Italy (Socio-Sanitary District of Cossato, 61,830 inhabitants) was analyzed and the reliability of "drug tracer methodology" evaluated. The patients were identified by both conventional epidemiological methodology (general practitioners, consultant neurologist, computerized archives) and drug tracer methodology (registered levodopa prescriptions). The diagnosis of PD was clinically verified by examining all patients. Of 146 patients examined, 104 were affected by PD; the remaining by other types of parkinsonism. The crude point prevalence rate (October 20, 1991) was 168 per 100,000 population (95% confidence interval [95% CI] 138-204), with a progressive increase up to the 80-89 age group. Using "tracer" methodology, the estimated crude point prevalence rate was 196 (95% CI 163-235), with an overestimation of the prevalence in older patients and women and an underestimation in younger and less seriously affected cases. The uneven distribution of PD in Italy appears to be the result of, at least in part, methodological factors. "Tracer" methodology may cause biases in the evaluation of the epidemiological characteristics of PD, especially if the clinical diagnosis of cases identified by this method is not carefully verified. Nevertheless, it appears useful as an additional source of cases for descriptive surveys.
Aged↗
Reduced glutathione in amyotrophic lateral sclerosis: an open, crossover, randomized trial.
The present study set out to define the possible effect of reduced glutathione (GSH), the substrate of glutathione peroxidase (GSH-Px), a free radical inactivating enzyme, in amyotrophic lateral sclerosis (ALS). Thirty-two patients affected by definite ALS seen in our institution between August 1993 and July 1994 were admitted to the study. The effect of GSH was studied in an open, crossover, randomized study. GSH was given at the dose of 600 mg each day intramuscularly for 12 weeks. The patients, taken sequentially, were randomly assigned to two groups. The first group received the drug while the second received only symptomatic therapies for 12 weeks. After a week of washout, the second group received GSH and the first only symptomatic therapies for 12 weeks. The rate of progression of the diseases was compared in the two groups. Clinical evaluation included manual test for muscle strength, Norris scale, bulbar scale, and forced vital capacity (FVC) percent. No significant difference was found in the progression of ALS in the two periods, although a slight slowing of the disease progression rate was found during the period of treatment, probably related to the open design of the study. Our data do not show any significant effect of reduced glutathione in modifying the progression of ALS.
Amyotrophic Lateral Sclerosis↗
Prognostic factors in medulloblastoma.
Medulloblastoma is a highly malignant cerebellar tumor of children and, less frequently, of adults, with a tendency to early recurrence and dissemination through the cerebrospinal fluid. The prognosis has improved significantly in recent decades, in parallel with the improvement in neurosurgical techniques and the use of postoperative radiotherapy. An overview is given of the prognostic role of clinical and pathological features of individual cases as reported in the literature. Apart from the presence or absence of metastases at diagnosis and the radiotherapy modality, none of the factors studied was generally thought to have a definite significant prognostic role. The extent of surgical excision seems to influence survival more in pediatric cases than in adults. Ongoing cytogenetic studies and molecular biology investigations are aimed at better categorization of medulloblastomas and individualized postoperative treatment.
Adult↗
Prognosis of ependymoma.
Ependymoma is a rare tumor entity. It affects children and adults and has four preferential locations: supra- and infra-tentorial, spinal, and conus-cauda-filum. For statistical reasons, therefore, it is difficult to identify prognostic factors in series from single institutions because of the limited number of cases. The problem is complicated by the existence of some variants and by the difficulty in recognizing the anaplastic variant, because the common criteria used for recognizing malignancy in gliomas are not completely reliable in ependymomas. Apart from age and location, many parameters have been considered for prognostic purposes, including extension of surgical removal and radiotherapy. Among histological factors, the number of mitoses, labelling indices of proliferation markers, and cell density turned out to be good parameters for prognostic purposes. An overview is given of the contributions in the literature, including our own, on this problem.
Adult↗
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↗
PCV chemotherapy for recurrent oligodendrogliomas and oligoastrocytomas.
OBJECTIVE: The role of chemotherapy in the treatment of low-grade oligodendrogliomas and oligoastrocytomas is still unclear. A Phase II study was conducted to determine the benefits and toxicity of the procarbazine, lomustine, and vincristine (PCV) regimen in patients with low-grade oligodendrogliomas and oligoastrocytomas recurrent after surgery alone or surgery with radiotherapy. METHODS: Patients with both enhancing and nonenhancing tumors were treated with up to six cycles of standard PCV, and response was evaluated by conventional criteria based on computed tomography or magnetic resonance imaging. RESULTS: Sixteen of 26 patients (62%) responded to PCV: 3 (12%) experienced complete response, 13 (50%) experienced partial response, 8 (31%) had stable disease, and 2 (8%) had progressive disease. All symptomatic patients who responded and three with stable disease improved in seizure frequency, lateralizing signs, and symptoms of intracranial hypertension. The response rate for patients with enhancing lesions revealed by computed tomography or magnetic resonance imaging (74%) was significantly higher than that of patients with nonenhancing lesions (29%) (P < 0.05). Both oligodendrogliomas and oligoastrocytomas responded to PCV, with complete responses occurring in association with pure tumors only. The median time to tumor progression of all 26 patients was 24 months and was significantly longer for those with oligodendrogliomas compared with those with oligoastrocytomas (32 versus 12 mo) (P < 0.001). Chemotherapy was well tolerated, with mild hematological toxicity and rare skin rashes being the most frequent sequelae. CONCLUSION: These results suggest that chemotherapy with PCV is effective in the treatment of recurrent low-grade oligodendrogliomas and oligoastrocytomas.
Adult↗
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↗
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↗
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↗
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↗
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↗
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↗
c-Jun, JNK/SAPK kinases and transcription factor NF-kappa B are selectively activated in astrocytes, but not motor neurons, in amyotrophic lateral sclerosis.
There is increasing evidence that oxidative damage plays a major role in amyotrophic lateral sclerosis (ALS), but how it contributes to motor neuron degeneration and astrocytic gliosis, two pathologic hallmarks of the disease, is unknown. A few studies have suggested that ALS motor neurons die via apoptosis and show upregulation of c-jun, an immediate early gene that is necessary for neuronal apoptosis. In order to elucidate the mechanisms of cell damage induced by oxidant stress, we have studied in ALS and control spinal cord the immunohistochemical expression of c-Jun, of JNK/SAPK, a kinase that activates c-Jun following various types of stress, and of NF-kappa B, a transcription factor that is induced by oxidant stress and has prominent neuroprotective functions. An in situ end-labeling assay was performed for detecting apoptotic cells. We show that (a) the JNK/SAPK-c-Jun pathway is dramatically overexpressed in ALS spinal cord; (b) the strongest activation occurs in astrocytes, while motor neurons show unusually low expression of the pathway; (c) increased JNK/SAPK expression in glial cells is accompanied by NF-kappa B activation, indicating the presence of a protective response to oxidant sress, which is deficient in motor neurons; (d) activation of JNK/SAPK, c-Jun and NF-kappa B is unrelated to apoptotic cell death. These results support the view that astrocytes are directly involved in the pathologic process of ALS, and might explain the selective vulnerability of motor neurons by their relative lack of antioxidant defenses.
Amyotrophic Lateral Sclerosis↗
Corpus callosum: neuropathology.
The anatomical and histological structure of Corpus callosum is analysed, mainly in relation with cell composition and fibre distribution. The vascularization of Corpus callosum is analyzed in relation with the distribution of the supplying arteries and the fine organization of small vessels. The first part of the presentation deals with damages of corpus callosum as a consequence of hemorrhagic and ischemic vasculopathies. The lesions may be direct or indirect; the latter follow the distruction of hemispheric areas interconnecting through the corpus callosum or occur as the product of reduced flow in the territories of carotid and vertebral arteries. A special mention is dedicated to the anatomoclinical syndromes developing after damages to the anterior or posterior section of Corpus callosum. The second part deals with specific diseases such as Marchiafava-Bignami's disease, which is treated as an example of glial cell pathology and chronic edema. The third part deals with tumors. Besides lymphomas which need a separate consideration for their modality of growth, neuroepithelial tumors are discussed. The most important problem is that of invasion through the Corpus callosum. The cell traffic in this structure with all the connected questions about cell migration, adhesiveness and motility are presented. Pathology of Corpus callosum is extended also to anatomically related median structures such as fornix and septum pellucidum. The latter is one of the principal pathways of diffusion in gliomas.
Corpus Callosum↗