Many observations have been carried out on astrogliosis in the cerebral cortex in amyotrophic lateral sclerosis (ALS), whereas little attention has been paid to astrogliosis in the spinal cord. ...Twenty autopsy cases of sporadic, common form of ALS have been studied. Spinal cords have been examined at the cervical, thoracic and lumbar levels by histological methods and immunohistochemistry for GFAP, Vimentin, Tau-protein, Neurofilaments, PCNA. A gliosis was found in the ventral horns, in dorsal horns and at the transition between gray matter and anterior and lateral funiculi, especially close to laminae VII, VI and V as being due to secondary gliosis. The findings cannot be interpreted on the only basis of the substitutive role of reacting glia. The proposed pathogenetic mechanisms of ALS are evaluated as possible responsible stimuli; the coincidence of the distribution of reactive astrocytes with the entering points of the corticospinal tracts into the gray matter is considered of primary importance. Of special interest are reactive astrocytes at the transition between laminae VII, VI and V and the lateral funiculus, where dystrophic neurites are known to concentrate.
Abstract
Background
Supratotal resection is advocated in lower-grade gliomas (LGGs) based on theoretical advantages but with limited verification of functional risk and data on oncological outcomes. ...We assessed the association of supratotal resection in molecularly defined LGGs with oncological outcomes.
Methods
Included were 460 presumptive LGGs; 404 resected; 347 were LGGs, 319 isocitrate dehydrogenase (IDH)–mutated, 28 wildtype. All patients had clinical, imaging, and molecular data. Resection aimed at supratotal resection without any patient or tumor a priori selection. The association of extent of resection (EOR), categorized on volumetric fluid attenuated inversion recovery images as residual tumor volume, along with postsurgical management with progression-free survival (PFS), malignant (M)PFS, and overall survival (OS) assessed by univariate, multivariate, and propensity score analysis. The study mainly focused on IDH-mutated LGGs, the “typical LGGs.”
Results
Median follow-up was 6.8 years (interquartile range, 5–8). Out of 319 IDH-mutated LGGs, 190 (59.6%) progressed, median PFS: 4.7 years (95% CI: 4–5.3). Total and supratotal resection obtained in 39% and 35% of patients with IDH1-mutated tumors. In IDH-mutated tumors, most patients in the partial/subtotal group progressed, 82.4% in total, only 6 (5.4%) in supratotal. Median PFS was 29 months (95% CI: 25–36) in subtotal, 46 months (95% CI: 38–48) in total, while at 92 months, PFS in supratotal was 94.0%. There was no association with molecular subtypes and grade. At random forest analysis, PFS strongly associated with EOR, radiotherapy, and previous treatment. In the propensity score analysis, EOR associated with PFS (hazard ratio, 0.03; 95% CI: 0.01–0.13). MPFS occurred in 32.1% of subtotal total groups; 1 event in supratotal. EOR, grade III, previous treatment correlated to MPFS. At random forest analysis, OS associated with EOR as well.
Conclusions
Supratotal resection strongly associated with PFS, MPFS, and OS in LGGs, regardless of molecular subtypes and grade, right from the beginning of clinical presentation.
MGMT
(
O
6
-methylguanine-DNA methyltransferase) promoter hypermethylation is a helpful prognostic marker for chemotherapy of gliomas, although with some controversy for low-grade tumors. The ...objective of this study was to retrospectively investigate
MGMT
promoter hypermethylation status for a series of 350 human brain tumors, including 275 gliomas of different malignancy grade, 21 glioblastoma multiforme (GBM) cell lines, and 75 non-glial tumors. The analysis was performed by methylation-specific PCR and capillary electrophoresis. MGMT expression at the protein level was also evaluated by both immunohistochemistry (IHC) and western blotting analysis. Associations of
MGMT
hypermethylation with
IDH1/IDH2
mutations,
EGFR
amplification,
TP53
mutations, and 1p/19q co-deletion, and the prognostic significance of these, were investigated for the gliomas.
MGMT
promoter hypermethylation was identified in 37.8% of gliomas, but was not present in non-glial tumors, with the exception of one primitive neuroectodermal tumor (PNET). The frequency was similar for all the astrocytic gliomas, with no correlation with histological grade. Significantly higher values were obtained for oligodendrogliomas.
MGMT
promoter hypermethylation was significantly associated with
IDH1/IDH2
mutations (
P
= 0.0207) in grade II–III tumors, whereas it had a borderline association with 1p deletion (
P
= 0.0538) in oligodendrogliomas. No other association was found. Significant correlation of
MGMT
hypermethylation with MGMT protein expression was identified by IHC in GBMs and oligodendrogliomas (
P
= 0.0001), but not by western blotting. A positive correlation between MGMT protein expression, as detected by either IHC or western blotting, was also observed. The latter was consistent with
MGMT
promoter hypermethylation status in GBM cell lines. In low-grade gliomas,
MGMT
hypermethylation, but not MGMT protein expression, was associated with a trend, only, toward better survival, in contrast with GBMs, for which it had favorable prognostic significance.
The association of HLA A*02 with multiple sclerosis (MS) was recently confirmed by the authors, and it was observed that the combined presence of HLA Cw*05 significantly enhanced (threefold) the ...protective effect of HLA A*02.
Since A*02-Cw*05 is carried by two HLA extended haplotypes characterised by the B*4402 and B*1801 alleles, respectively, the association analysis was extended to HLA B*44 and B*18 in an Italian sample (1445 MS cases and 973 controls) and these associations were verified in a UK cohort (721 MS cases, 408 controls and 480 family trios).
A strong protective effect, independent of DR15, of the A*02-Cw*05 combination carrying B*44 (OR 0.27, p=3.3×10(-5)) was seen in the Italian samples and confirmed in UK family trios (OR 0.33, p=5.5×10(-4)) and in a combined cohort of UK families and case-controls (OR 0.53, p=0.044). This protective effect was significantly stronger than that mediated by A*02 alone. Logistic regression showed that A*02-Cw*05 maintained a significant protection when adjusted for B alleles (Italy: OR 0.38, p=6.5×10(-7); UK: OR 0.60, p=0.0029), indicating that it was not secondary to linkage disequilibrium with B*44. Different from A*02, the other HLA class I tested markers individually showed no significant (Cw*05, B*18) or a modest (B*44) protection when adjusted for the remaining markers.
This study identified at least two independent protective effects which are tagged by A*02-Cw*05 and A*02, respectively. Further studies are needed to elucidate whether this protective effect is due to the presence of an unanalysed factor characterising the HLA extended haplotype(s) carrying A*02 and Cw*05 or to a direct interaction between these alleles.
Increased C-reactive protein (CRP) is a known predictor of vascular events in asymptomatic individuals and stroke patients. Only a few studies included transient ischaemic attack (TIA) patients. We ...assessed CRP levels in addition to traditional risk factors in a cohort of patients with TIA to examine the relationship of these parameters to the occurrence of ischaemic stroke.
This is a prospective, longitudinal clinical evaluation of the efficacy of CRP as a prognostic indicator. CRP levels were measured in 194 TIA patients and in 1,024 asymptomatic individuals (recruited from a project on stroke prevention, the PrATO, which was ongoing at the same time in the Aosta Valley). A clinical risk score was determined using the ABCD² score in TIA patients. The area under the receiver operating characteristic curve (AUC) was used to evaluate the significance of the markers as predictors. Two models were evaluated: model 1 used the ABCD² score and model 2 used serum CRP levels in addition to the ABCD²) score. The primary outcome was an ischaemic stroke.
Within 2 years ischaemic strokes occurred in 33/194 patients. The Cox proportional hazards models, after adjustments for conventional risk factors, identified CRP levels ≥3 mg/l and ABCD² scores ≥4 as independent predictors of stroke. The corresponding AUCs were 0.565 and 0.636, based on model 1 and model 2, respectively; this represented a statistically significant difference (p = 0.043). The absolute integrated discrimination improvement was 0.0249 (p = 0.007) and the relative integrated discrimination improvement was 2.3710. The net benefit became significant from a predicted probability ≥10% and was 0.077 when based on model 1 and 0.087 when based on model 2.
Routine CRP measurements in the acute phase might be a useful tool for identifying TIA patients who are at a higher risk of ischaemic stroke. The additional use of CRP levels for the risk assessment in TIA patients improves risk definition in terms of the ABCD² score alone.
Symptomatic brain metastases of carcinomas in patients without a previously diagnosed malignancy are frequent in neurosurgical series. Such tumors often lack distinctive morphological characteristics ...so that the routine histological examination can be unsuccessful in identifying the site of origin. Objectives of the present study were to evaluate the frequency of brain metastases as the only manifestation of an unknown primary cancer by the retrospective analysis of a series of consecutively operated single cerebral metastases; to verify the efficacy of clinical investigations in detecting the site of origin; to investigate whether the primary site can be identified by the immunohistochemical study of the neurosurgical specimens. Antibodies to the following antigens were used: carcinoembryonic antigen (CEA), carbohydrate antigen (CA) 19.9, CA 125, BCA-225, cytokeratin 20, PSA, HMB-45. Out of 181 patients operated for single cerebral metastasis of carcinoma, 99 (54.7%) were in patients without any previously diagnosed systemic neoplasm. In 26.7% the primary remained undiagnosed after clinical investigations, in 9 cases even at autopsy. PSA and HMB45 antibodies specifically identified metastases from prostate carcinomas and skin melanomas, respectively. No other specific immunophenotype was identified; the immunoreactivity of the single cases was more or less suggestive for a primary site. Precocious metastases of lung carcinomas expressed CEA more frequently than late metastases. It has been hypothesized that CEA plays some role as a contact mediating device. CEA expression can have some link with the tendency to metastasize precociously to the brain. No major difference of p53 and k-ras expression has been found in precocious versus late brain metastases.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuron loss and astrogliosis. We studied the immunohistochemical expression of S-100
β, a ...calcium-binding protein with both neurotrophic and neurotoxic activities, in the spinal cord of patients with ALS. Adjacent sections were processed with an in situ end-labeling technique for the demonstration of apoptosis-related DNA fragmentation. In controls, low expression of S-100
β was found in astrocytes but not motor neurons. Compared to controls, S-100
β was overexpressed in ALS. Most stained cells were reactive astrocytes, but a minority of motor neurons was also labeled. Neuronal labeling was unrelated to the presence of signs of atrophy/degeneration. S-100
β expression was also unrelated to neuronal or glial apoptosis. S-100
β upregulation in ALS spinal cord suggests that the protein might be involved in cellular defense mechanisms against oxidative stress.
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.
In amyotrophic lateral sclerosis (ALS) it is not known which motoneuron is affected first. The study of synaptic proteins may contribute to the clarification of the problem. Fifteen cases of ALS and ...five control cases were studied with the immunohistochemical demonstration of synaptophysin (Sy) and chromogranin A (CgA). Sy is a typical membrane protein of small synaptic vesicles (SSV), whereas CgA is found in large dense core vesicles (LDCV) and in neurosecretory granules. In controls, Sy is distributed as dots on the neuronal surface, on proximal dendrites and in neuropil, whereas CgA is found in perikarya and dendrites and as puncta in the neuropil. In ALS there is a marked decrease of Sy-positive dots. In chromatolytic neurons and spheroids a diffuse reaction may occur. CgA-positive dots disappear in ALS, sometimes replaced by a dust-like positivity. CgA is produced by Golgi apparatus and its reduction in ALS corresponds to the fragmentation of the Golgi complex, described in the literature. The findings are interpreted as secondary to the lower motoneuron degeneration and discussed in relation to our knowledge on vesicle production and migration in the neuron and on synapses in the anterior horns of spinal cord.
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