Kappa free light chains index in the differential diagnosis of Multiple Sclerosis from Neuromyelitis optica spectrum disorders and other immune-mediated central nervous system disorders.

The K free light chains index (K-FLC index) has been proposed as an alternative test for intrathecal immunoglobulin synthesis in MS diagnosis. Aim of the study was to assess the accuracy of the K-FLC index in differentiating MS from other immune-mediated CNS disorders and NMOSD. Data were available from a cohort of 371 patients. K-FLC index was significantly higher in MS: MS mean K-FLC index 90.897 ± 134.198; NMOSD 17.992 ± 15.103; other immune-mediated CNS disorders 12.568 ± 24.440. The overall diagnostic accuracy of the K-FLC index was similar to intrathecal oligoclonal bands detection. However, as a quantitative variable, K-FLC index allowed easier discrimination of MS from other immune-mediated CNS disorders: highest K-FLC index values (> 100) were observed almost only in MS and are therefore strongly predictive of MS, in patients with the appropriate clinical presentation.

Inflammatory responses in Multiple Sclerosis normal-appearing white matter and in non-immune mediated neurological conditions with wallerian axonal degeneration: A comparative study.

Inflammatory-like changes in the white matter (WM) are commonly observed in conditions of axonal degeneration by different etiologies. This study is a systematic comparison of the principal features of the inflammatory-like changes in the WM in different pathological conditions characterized by axonal damage/degeneration, focusing in particular on Multiple Sclerosis (MS) normal-appearing white matter (NAWM) compared to non immune-mediated disorders. The study was performed on sections of NAWM from 15 MS cases, 11 cases of non immune-mediated disorders with wallerian axonal degeneration (stroke, trauma, amyotrophic lateral sclerosis), 3 cases of viral encephalitis, 6 control cases. Common features of the inflammatory-like changes observed in all of the conditions of WM pathology were diffuse endothelial expression of VCAM-1, microglial activation with expression of M2 markers, increased expression of sphingosine receptors. Inflammation in MS NAWM was characterized, compared to non immune-mediated conditions, by higher VCAM-1 expression, higher density of perivascular lymphocytes, focal perivascular inflammation with microglial expression of M1 markers, ongoing acute axonal damage correlating with VCAM-1 expression but not with microglia activation. Inflammatory changes in MS NAWM share all the main features observed in the WM in non immune-mediated conditions with wallerian axonal degeneration (with differences to a large extent more quantitative than qualitative), but with superimposition of disease-specific perivascular inflammation and ongoing acute axonal damage.

Monocytes of patients with amyotrophic lateral sclerosis linked to gene mutations display altered TDP-43 subcellular distribution.

AIMS: Cytoplasmic accumulation of the nuclear protein transactive response DNA-binding protein 43 (TDP-43) is an early determinant of motor neuron degeneration in most amyotrophic lateral sclerosis (ALS) cases. We previously disclosed this accumulation in circulating lymphomonocytes (CLM) of ALS patients with mutant TARDBP, the TDP-43-coding gene, as well as of a healthy individual carrying the parental TARDBP mutation. Here, we investigate TDP-43 subcellular localization in CLM and in the constituent cells, lymphocytes and monocytes, of patients with various ALS-linked mutant genes. METHODS: TDP-43 subcellular localization was analysed with western immunoblotting and immunocytofluorescence in CLM of healthy controls (n = 10), patients with mutant TARDBP (n = 4, 1 homozygous), valosin-containing protein (VCP; n = 2), fused in sarcoma/translocated in liposarcoma (FUS; n = 2), Cu/Zn superoxide dismutase 1 (SOD1; n = 6), chromosome 9 open reading frame 72 (C9ORF72; n = 4), without mutations (n = 5) and neurologically unaffected subjects with mutant TARDBP (n = 2). RESULTS: TDP-43 cytoplasmic accumulation was found (P < 0.05 vs. controls) in CLM of patients with mutant TARDBP or VCP, but not FUS, in line with TDP-43 subcellular localization described for motor neurons of corresponding groups. Accumulation also characterized CLM of the healthy individuals with mutant TARDBP and of some patients with mutant SOD1 or C9ORF72. In 5 patients, belonging to categories described to carry TDP-43 mislocalization in motor neurons (3 C9ORF72, 1 TARDBP and 1 without mutations), TDP-43 cytoplasmic accumulation was not detected in CLM or in lymphocytes but was in monocytes. CONCLUSIONS: In ALS forms characterized by TDP-43 mislocalization in motor neurons, monocytes display this alteration, even when not manifest in CLM. Monocytes may be used to support diagnosis, as well as to identify subjects at risk, of ALS and to develop/monitor targeted treatments.

Progranulin gene variability increases the risk for primary progressive multiple sclerosis in males.

Progranulin (GRN) gene variability has been analyzed in a sample of 354 patients with multiple sclerosis (MS) compared with 343 controls. No significant differences were observed, but by stratifying according to MS subtypes, a significant increased frequency of the rs2879096 TT genotype was found in primary progressive MS (PPMS) patients versus controls (16.0 vs 3.5%, P=0.023, odds ratio (OR) 5.2, 95% confidence interval (CI) 1.2-21.4). In addition, in PPMS, an association with the C allele of rs4792938 was observed (55.3 vs 33.5%, P=0.011, OR 2.4, 95% CI 1.2-4.7). An independent population was studied as replication, failing to confirm results previously obtained. Stratifying according to gender, an association with rs4792938 C allele was found in male PPMS patients compared with controls (40.7 vs 26.9%, P=0.002, OR 1.87, 95% CI 1.2-2.8). An association with the rs2879096T allele was observed (29.2 in patients compared with 18.9% in controls, P=0.012, OR 1.77, 95% CI 1.1-2.8). Haplotype analysis showed that TC haplotype frequency is increased in PPMS male patients compared with male controls (25.7 vs 16.6%; P=0.02, OR 1.69, 95% CI 1.1-2.7), whereas the respective GC haplotype seems to exert a protective effect, as its frequency is decreased in patients compared with controls (55.8% vs 70.9%; P=0.001, OR 0.52, 95% CI 0.4-0.8). Therefore, GRN haplotypes likely influence the risk of developing PPMS in males.

DCUN1D1 is a risk factor for frontotemporal lobar degeneration.

BACKGROUND AND PURPOSE: Frontotemporal lobar degeneration (FTLD) is considered as a proteinopathy; therefore, it is conceivable that genes encoding for factors involved in protein misfolding and/or degradation could play a role in its pathogenesis. METHODS: An association study of defective in cullin neddylation 1 (DCN-1)-domain containing 1 (DCUN1D1), which is involved in protein degradation, was carried out in a population of 220 patients with FTLD as compared with 229 age-matched controls. RESULTS: A statistically significant increased frequency of the GG genotype of the DCUN1D1 rs4859146 single nucleotide polymorphism (SNP) was observed in patients compared with controls (6.9 vs. 1.7%, P = 0.011, adjusted OR: 4.39, 95% CI: 1.40-13.78). Stratifying according to the clinical syndrome, significant differences were observed between the behavioral variant of frontotemporal dementia and controls (GG frequency: 6.3 vs. 1.7%, P = 0.02, OR:4.0, 95%, CI = 1.24-12.92), as well as between patients with progressive aphasia compared with controls (15.4 vs. 1.7%, P = 0.014, OR = 11.30, 95%, CI = 1.63-78.45), but not in patients with SD versus controls (8.3 vs. 1.7%, P = 0.18, OR = 5.24, 95% C.I. = 0.45-60.63). No significant differences in allelic and genotypic frequencies of the DCUN1D1 rs4859147 SNP were found. CONCLUSIONS: The GG genotype of the DCUN1D1 rs4859147 SNP represents a risk factor for the development of FTLD, increasing the risk of about fourfold.

The NOS3 G894T (Glu298Asp) polymorphism is a risk factor for frontotemporal lobar degeneration.

BACKGROUND AND AIMS: Neuronal nitric oxide synthase (NOS)1 C276T polymorphism was shown to increase the risk for frontotemporal lobar degeneration (FTLD). In the brain, both NOS1 and NOS3 (endothelial isoform) have been detected. The distribution of NOS3 G894T (Glu298Asp) and T-786C single nucleotide polymorphisms (SNPs) was analyzed in a population of 222 patients with FTLD compared with 218 age-matched controls to determine whether they could influence the susceptibility to develop the disease. RESULTS: A statistically significant increased frequency of the NOS3 G894T SNP was observed in patients as compared with controls (40.0 vs. 31.4%, P = 0.011, OR: 1.65, CI: 1.13-2.42). Conversely, the distribution of the T-786C SNP was similar in patients and controls. No differences were observed stratifying according to gender. DISCUSSION: The NOS3 G894T polymorphism likely acts as risk factor for sporadic FTLD, but studies in larger populations are needed to confirm these preliminary findings.

Functional rehabilitation and brain tumour patients. A review of outcome.

The increasing prevalence of brain tumours and longer duration of survival achieved by recent advances in treatment prompt a critical analysis of the impact of functional rehabilitation on patients with brain tumours. In this review brain tumours and outcome of brain tumour patients are discussed from a rehabilitation perspective, taking into account not only life expectancy but also the direct and indirect causes of functional impairment. Results of functional rehabilitation and factors involved in its effectiveness are presented and analysed to serve as a basis to neurologists involved in the management of patients with brain tumours.

Morphophenotype of medulloblastoma in children and adults. The size of nuclei.

OBJECTIVE: Uniform cells with round, regular nuclei characterize the typical histologic aspect of medulloblastoma. Enlargement of nuclei distinguishes the large-cell medulloblastoma variant and is associated with a poor prognosis in pediatric medulloblastomas. The aim of the present study was to compare the size of nuclei between pediatric and adult medulloblastomas by a morphometric analysis. MATERIAL AND METHODS: In 79 neurosurgical specimens of cerebellar medulloblastomas, the maximum nuclear diameter of the largest nuclei was measured. Measurements were performed with a digital-image analysis system. The measure of the maximum diameter was chosen in order to reduce the split cell error. RESULTS: The difference between the mean values in children and adults was statistically significant (p = 0,001). The distribution of maximum values measured in each case had two distinct peaks in the two age groups, in 3.5% of adult cases and in more than 30% of pediatric cases the maximum nuclear size was superior to 12 microm. CONCLUSIONS: The present results show that nuclei of tumor cells in pediatric medulloblastomas are larger than those in adult medulloblastomas and confirm that the phenotype of medulloblastoma is different in the two age groups. Distinct genetic events can, thus, underlie medulloblastoma in childhood and adult age, the prognostic role of genetic variables can differ by age.

Olanzapine therapy in hallucinatory visions related to Bonnet syndrome.

Charles Bonnet syndrome (CBS) is characterised by the triad of complex visual hallucinations, ocular pathology causing visual deterioration and preserved cognitive status. We report a case of a 62-year-old man with a brief history of visual hallucinations. The patient complained of amaurosis with optic nerve atrophy in his left eye and a severe impairment of visual acuity in the right and suddenly experienced complex, vivid, elaborate and coloured visual hallucinations persisting long after eye closure and stopping during sleep. The patient maintained his insight, criticising these visions as unreal and felt distressed by them. Hallucination onset was 3 days before hospital admission. No cognitive impairment and no diseases apart from prostatic adenoma treated with alpha-lythic therapy were reported. Neurological examination and neuroimaging data were normal. Therapy with olanzapine (OLZ) 5 mg/day led to a progressive clearance of visual hallucinations in seven days and was gradually reduced and withdrawn. Three months later the visions reappeared and OLZ 5 mg/day yielded a persisting remission so that at the follow-up examination after 1 year on therapy the patient is still asymptomatic. To date, no established treatment for CBS is stated and in some patients the hallucinations fade spontaneously; in our case an antipsychotic therapy with OLZ was effective while generally anticonvulsant drugs with different mechanism of action such as carbamazepine, valproate and gabapentin are proposed.

Molecular genetic study of a metastatic oligodendroglioma.

Extracranial spread of neuroectodermal tumors is an unusual event, most frequently expected from glioblastomas and medulloblastomas. Single cases of metastatic oligodendrogliomas have been described, but no genetic data are reported. Oligodendrogliomas are characterized by distinct genetic alterations, i.e. loss of heterozygosity (LOH) of 1p and 19q; therefore, molecular genetic analysis of metastatic cases is of considerable interest. It may be instrumental in defining the distant tumor as metastatic oligodendroglioma and give clues to the genetic events associated with the highly malignant transformation. We present the case of a patient with multiple bone metastases from a cerebral oligodendroglioma. Oligodendroglioma grade II was the diagnosis both at original and second operation, performed 7 and 1 years before the extracranial dissemination. The extraneural spread presented before the local intracranial recurrence. The patient received procarbazine, lomustine, vincristine chemotherapy and radiotherapy after the second surgery. The computed tomography-guided biopsy of the bone lesions revealed tumor cells positive for GFAP, S-100 and Leu-7 and negative for cytokeratin, LCA and EMA. The genetic analysis of DNA from the original tumor, the bone metastasis and the autoptic brain tumor showed LOH of 1p; heterozygous deletion of CDKN2A/p 16 was detected as additional alteration in the metastasis and in the intracranial tumor at autopsy. TP53, MDM2 and CDKN2A/p14ARF genes were unchanged. Repeated brain surgery and extended survival may have acted as promoter of extraneural dissemination. Loss of CDKN2A most probably played an important role in the malignant progression: its involvement in metastatic potential remains to be clarified. Our data confirm that malignant transformation of oliogodendrogliomas may be undetected by histology and underscore the importance of genetic analysis. Coincidentally with intensive anticancer therapy, chemotherapy included, employed in patients with oligodendroglioma and the ensuing long survival, the frequency of metastatic oliogodendrogliomas may increase.

MIB-1 immunoreactivity in craniopharyngiomas: a clinico-pathological analysis.

BACKGROUND: Craniopharyngiomas are epithelial tumors of the suprasellar region, unanimously defined as benign. Despite the benign histological aspect and apparent gross total resection achieved in a proportion of cases, recurrence rate remains about 30% at 10 years. The role of 7 pathological factors as predictors of recurrence and clinical outcome in craniopharyngioma patients is controversial, as well as the prognostic role of the evaluation of proliferation potential. MATERIAL AND METHODS: In the present study, the proliferation potential of 37 craniopharyngiomas was investigated by analyzing the pattern of Ki-67-MIBI immunoreactivity; the data have been analyzed in relation to age of the patient, histologic type (adamantinomatous/squamous papillary), microscopic and cytochemical features. RESULTS: Craniopharyngiomas operated in adults have a higher MIB-1-LI than those of children; the epithelial cells abutting the stromal cysts are engaged in the cell cycle, while this is not the case for the cells abutting the nervous tissue; MIB-1-LIs of adamantinomatous craniopharyngiomas are not different from those of squamous papillary craniopharyngiomas, the localization of MIB-1-positive nuclei is different in the 2 craniopharyngioma types, non-epithelial cells proliferate in the stromal component of craniopharyngiomas. CONCLUSIONS: By analyzing these data while considering all available information on the efficacy of surgery and radiotherapy, the proliferation potential of craniopharyngiomas, when evaluated by MIB-1, has no role in the outcome. The very low MIB-1-LI of the intracerebral tumor growth indicates that uncompletely resected tumor remnants do not represent an active starting point of recurrence.

Guillain-Barré syndrome: a prospective, population-based incidence and outcome survey.

OBJECTIVE: The authors evaluated the incidence and long-term prognostic factors of Guillain-Barré syndrome (GBS) in a prospective, population-based study. METHODS: Patients with GBS diagnosed according to National Institute of Neurological and Communicative Disorders and Stroke criteria in the 2-year period 1995 to 1996 in two Italian regions were prospectively followed up for 2 years after onset of GBS. RESULTS: A total of 120 patients were found, corresponding to a crude annual incidence rate of 1.36/100,000 population (95% CI, 1.13 to 1.63). A total of 7 (5.8%) patients, all but one with axonal or mixed EMG pattern, died acutely within 30 days from the onset of the disease. Acute mortality was due to respiratory involvement and intensive care unit complications. In multivariate analysis, a worse 2-year outcome (Hughes score >or=2) was related to a higher Hughes grade at nadir, axonal or mixed EMG, age >or=50 years, and absence of respiratory infections preceding GBS. The persistence of disability 2 years after the acute phase was related to axonal involvement and a worse status at nadir. CONCLUSIONS: After adjustment to US population, the incidence rates for GBS from different countries showed no significant differences. Both acute mortality and long-term disability in GBS seem to be related to an axonal involvement and a Hughes grade >or=2 at nadir.

Persistent neutralizing antibodies abolish the interferon beta bioavailability in MS patients.

BACKGROUND: MxA is an antiviral protein exclusively induced by type I interferons (IFN) and some viruses, and MxA gene expression is one of the most appropriate markers for measuring the biologic activity of exogenous IFNbeta. METHODS: A new quantitative-competitive PCR method was used to quantify MxA mRNA in peripheral blood mononuclear cells of 99 treatment-naïve and 92 IFNbeta-treated patients with MS (22 Avonex, 17 Betaferon, and 53 Rebif-22). Every 3 months, IFNbeta-induced neutralizing antibodies (NAb) were evaluated in sera using a cytopathic effect assay. Three categories of patients were identified: NAb negative (NAb-), persistent NAb positive (NAb+, >or=2 consecutive positive samples), and isolated NAb+ (one positive sample). RESULTS: Treatment-naïve patients expressed detectable MxA mRNA levels (mean = 36 +/- 32 fg MxA/pg glyceraldehyde-3-phosphate dehydrogenase (GAPDH); range 1 to 160) and an upper normal threshold was established (mean + 3 SD = 132 fg MxA/pg GAPDH). IFNbeta-treated patients exhibited more than 11-fold higher levels (mean = 412 +/- 282 fg MxA/pg GAPDH; range 16 to 1,172). However, 17 patients did not exhibit an increase in MxA mRNA level; 15 of these 17 patients showed a concurrent Nab+ titer. Moreover, 13 were persistent NAb+. Isolated NAb+ patients did not show a decrease in bioavailability of IFNbeta (n = 9; mean = 567 +/- 366 fg MxA/pg GAPDH; range 83 to 1,120). In NAb- patients, bioavailability was comparable among the three different IFNbeta preparations 12 hours after injection. CONCLUSION: During IFNbeta therapy, the presence of NAb reduced or abolished bioavailability in a relevant percentage of patients. These data could be important for the early detection of patients with MS who are not responsive to IFNbeta therapy.

Early symptom progression rate is related to ALS outcome: a prospective population-based study.

OBJECTIVE: To define the factors related to ALS outcome in a population-based, prospective survey. METHODS: The 221 patients (120 men and 101 women) listed in the Piemonte and Valle d'Aosta ALS Register between 1995 and 1996 were enrolled in the study. The patients were prospectively monitored with a standard evaluation form after diagnosis. RESULTS: Mean age at onset was 62.8 (SD = 11.2) years. According to El Escorial diagnostic criteria (EEDC), 112 patients had definite ALS, 85 probable ALS, 18 possible ALS, and six suspected ALS. The median survival time from symptom onset was 915 days (95% CI = 790 to 1065). The median survival time from diagnosis was 580 days (95% CI = 490 to 670). In univariate analysis, outcome was significantly related to age, onset site, EEDC classification, and symptom progression rate (i.e., the rate of decline of muscle strength and bulbar and respiratory function in the 6 months after diagnosis). In the Cox multivariate model, age, progression rate of respiratory, bulbar, and lower limb symptoms, EEDC classification, percutaneous endoscopic gastrostomy, and treatment with riluzole were significantly related to outcome. CONCLUSIONS: The rate of progression of symptoms in early ALS is predictive of disease outcome.

Differential effects of three interferon betas on neutralising antibodies in patients with multiple sclerosis: a follow up study in an independent laboratory.

OBJECTIVE: To evaluate the incidence and the prevalence of neutralising antibodies (NABs) to three interferon beta (IFNbeta) products in patients with multiple sclerosis (MS). METHODS: Sera were tested from 125 patients with relapsing-remitting MS. Patients were treated with IFNbeta-1b (Betaferon, n = 29) 8 MIU subcutaneously every other day, IFNbeta-1a (Avonex, n = 44) 30 microg intramuscularly once weekly, or IFNbeta-1a (Rebif, n = 36) 22 microg subcutaneously three times weekly for 6 to 18 months. An additional 16 patients were treated with Rebif 22 microg intramuscularly once or twice weekly. NABs were assessed using the cytopathic effect assay before treatment and every three months during treatment. Patients with two or more consecutive positive samples were considered to be persistent NAB positive (NAB+). RESULTS: At baseline, no patients were NAB+. NABs developed during the first three months of treatment and continued to develop until month 18. Over 18 months of treatment, the risk of being persistent NAB+ was 31% for Betaferon, 15% for Rebif, and 2% for Avonex (Betaferon versus Avonex, p = 0.001; Betaferon versus Rebif, p = 0.19; Rebif versus Avonex, p = 0.04). In all patients with one or more NAB+ samples, the risk of becoming NAB+ was 38% for Betaferon, 18% for Rebif, and 7% for Avonex (Betaferon versus Avonex, p = 0.0007; Betaferon versus Rebif, p = 0.10; Rebif versus Avonex, p = 0.07). At month 18, the prevalence of persistent NAB+ patients was 31.6% for Betaferon, 18.7% for Rebif, and 4% for Avonex. Numbers of NAB+ patients observed were similar with intramuscular Rebif and with subcutaneous Rebif. CONCLUSION: The three IFNbeta preparations have different degrees of immunogenicity, with Betaferon producing the highest incidence of NABs and Avonex the lowest. These differences should be considered by neurologists when selecting treatment for their patients with MS because NABs can reduce both bioavailability and clinical efficacy of IFNbeta.

Abnormal ubiquitination of axons in normally myelinated white matter in multiple sclerosis brain.

The hallmark of the lesions in multiple sclerosis (MS) is inflammatory demyelination with sparing of axons. Recent neuropathological and neuroradiological investigations show that structural changes of the axons occur, both in plaques and in the normal appearing white matter. A better understanding of the axonal damage in MS is important, since this may be responsible for permanent disability. We have investigated the immunoreactivity for ubiquitin, a sensitive method to detect axonal dystrophy and accumulation of abnormal proteins in pathological conditions of the nervous system, in the brains of six cases of MS (age range 39-66 years). Tissue blocks were fixed in formalin and embedded in paraffin. A panel of antibodies was used: anti-ubiquitin, anti-neurofilament (SMI-31 + SMI-32), anti-amyloid precursor protein and anti-PGP9.5. We focused our attention on chronic plaques, recognized by the absence of Luxol Fast Blue B-positive inclusions in macrophages. SMI-31 + SMI-32 showed the presence of a variable amount of axons within the plaques; the axonal network within the plaques was looser than outside. No ubiquitin reactivity was present in chronic plaques. In the normally myelinated white matter surrounding the plaques, a dense granular ubiquitin immunoreactivity was found both near and far from the plaque edge. No similar staining was found in control brains. Ubiquitination is the first step of a non-lysosomal degradation pathway of proteins. The present findings suggest a derangement of this proteolytic pathway in the axons outside the plaques, possibly as a consequence of chronic absence of myelin in the axonal segment inside the plaque. The spectrum of axonal changes in MS appears to be wider than expected and involves the apparently normal white matter.

Evaluation of bioavailability of three types of IFNbeta in multiple sclerosis patients by a new quantitative-competitive-PCR method for MxA quantification.

Intracellular expression of human myxovirus protein A (MxA) is exclusively induced by type I IFNs (IFNalpha,beta,omega) or by some viruses and it is strongly increased under IFN treatment. We set up an internally controlled quantitative-competitive polymerase chain reaction (qc-PCR) that quantifies MxA mRNA expressed in human peripheral blood mononuclear cells (PBMC). Our qc-PCR is accurate because the mean ratio of copy number estimated by qc-PCR to that quantified spectrophotometrically is 1.08+/-0.03, moreover it is repeatable with high sensitivity (1 fg MxA/pg GAPDH). MxA mRNA was tested in 47 Relapsing-Remitting Multiple Sclerosis (RR-MS) untreated patients and in 48 patients treated with one of the 3 IFNbeta licensed for MS (24 with Rebif, 14 with Avonex and 10 with Betaferon). All the 48 treated patients were negative to IFNbeta neutralising antibodies (NABs) as tested in our laboratory using a cytopathic assay (CPE). MxA mRNA levels were detectable in all untreated patients (mean 24+/-18 fg MxA/pg GAPDH) and significantly higher levels were found in all the treated patients 12 h after IFNbeta administration (mean 499+/-325 fg MxA/pg GAPDH); furthermore, the three types of IFNbeta showed comparable bioavailability. Our data indicate that the bioavailability of the three available types of IFNbeta can be evaluated by MxA qc-PCR.

Medulloblastoma with lipidized cells versus lipomatous medulloblastoma.

BACKGROUND: Lipomatous medulloblastoma is a recently identified clinicopathological entity, characterized by areas of lipomatous differentiation, manifestation in adults, and apparently by a favorable prognosis. MATERIAL AND METHODS: In our series of medulloblastomas of adults and children we have found lipidized cells within the tumor in 6 out of 78 cases of adults and in 8 out of 44 cases of children. In 3 adult cases and 3 children cases, lipidized cells were particularly numerous and clustered. RESULTS: Neuronal differentiation was found in 4/6 cases; no case showed GFAP-positive tumor cells. Lipidized cells were constantly immunopositive for vimentin and some of them also for KP-1 and CR3/43. The proliferation potential was evaluated by the immunohistochemical demonstration of MIB-1; MIB-1-labeling index (LI) ranged from 20.8% to 40.5%. No case survived longer than 7 years after diagnosis and postoperative radiotherapy. CONCLUSION: The present 6 cases of heavily lipidized medulloblastoma are not uniform as for age of occurrence, proliferation potential and survival. They do not share the clinical and pathologic features of "lipomatous medulloblastoma". Therefore, the finding of large numbers of lipidized cells in a medulloblastoma does not authorize to diagnose the tumor as "lipomatous medulloblastoma", for which a favorable clinical prognosis is foreseen.

Cerebral metastases as first symptom of cancer: a clinico-pathologic study.

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.

Epidemiology of adult medulloblastoma.

Medulloblastoma is one of the most common primary tumors of the central nervous system seen in children; in contrast, it is somewhat uncommon in adult age. Due to the infrequent occurrence, data on incidence rates are sparse. The present study was aimed at ascertaining the epidemiological characteristics of medulloblastoma in adult age in Piedmont during the period 1976-1995. Piedmont is a region in northwest Italy, which had a total population of 4.30 millions/year for the period mentioned. From the files of clinical records of patients hospitalized in neurologic and neurosurgical departments, 45 cases (32 males, 13 females) of histologically verified medulloblastoma were recorded. The incidence rate (annual per million) in the whole period studied was 0.5 (95% confidence interval, 0.36-0.67). The incidence rate was high in the age group 15 to 19 years (2.33/million/year) and decreased up to age 40, consistent with the embryonal origin of the tumor. No time-trend of incidence rate was found. Male excess was evident in all age groups and in each time period. Median survival time was 17.6 years; the 5-year survival rate was 69.9%. Survival rate in the present group of adult medulloblastoma is slightly better than that reported in clinical series. A comparison was made with incidence data concerning pediatric medulloblastoma reported in the Registry of Childhood Cancer of Piedmont: from 1980 to 1989, adult medulloblastomas represented 34% of medulloblastomas. The figure is higher than that generally assumed, and indicates that the occurrence of this embryonal tumor in adult age is relevant. Our epidemiological data are consistent with an embryonal origin of medulloblastoma.