Adriano Chiò

Università degli Studi di Torino, Neuroscience, Faculty Member

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Papers by Adriano Chiò

The role of TREM2 R47H as a risk factor for Alzheimer's disease, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and Parkinson's disease

by Vincenzo Silani, Gabriella Restagno, Adriano Chiò, and Harald Hampel

Alzheimer's & dementia : the journal of the Alzheimer's Association, Jan 29, 2015

A rare variant in TREM2 (p.R47H, rs75932628) was recently reported to increase the risk of Alzhei... more A rare variant in TREM2 (p.R47H, rs75932628) was recently reported to increase the risk of Alzheimer's disease (AD) and, subsequently, other neurodegenerative diseases, i.e. frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Here we comprehensively assessed TREM2 rs75932628 for association with these diseases in a total of 19,940 previously untyped subjects of European descent. These data were combined with those from 28 published data sets by meta-analysis. Furthermore, we tested whether rs75932628 shows association with amyloid beta (Aβ42) and total-tau protein levels in the cerebrospinal fluid (CSF) of 828 individuals with AD or mild cognitive impairment. Our data show that rs75932628 is highly significantly associated with the risk of AD across 24,086 AD cases and 148,993 controls of European descent (odds ratio or OR = 2.71, P = 4.67 × 10(-25)). No consistent evidence for association was found between this marker...

The MITOS system predicts long-term survival in amyotrophic lateral sclerosis

by Fabio Giannini, Giuseppe Borghero, Giuseppe Lauria, and Adriano Chiò

Journal of Neurology, Neurosurgery & Psychiatry, 2015

The choice of adequate proxy for long-term survival, the ultimate outcome in randomised clinical ... more The choice of adequate proxy for long-term survival, the ultimate outcome in randomised clinical trials (RCT) assessing disease-modifying treatments for amyotrophic lateral sclerosis (ALS), is a key issue. The intrinsic limitations of the ALS Functional Rating Scale-Revised (ALSFRS-R), including non-linearity, multidimensionality and floor-effect, have emerged and its usefulness argued. The ALS Milano-Torino staging (ALS-MITOS) system was proposed as a novel tool to measure the progression of ALS and overcome these limitations. This study was performed to validate the ALS-MITOS as a 6-month proxy of survival in 200 ALS patients followed up to 18 months. Analyses were performed on data from the recombinant human erythropoietin RCT that failed to demonstrate differences between groups for both primary and secondary outcomes. The ALS-MITOS system is composed of four key domains included in the ALSFRS-R scale (walking/self-care, swallowing, communicating and breathing), each with a threshold reflecting the loss of function in the specific ALSFRS-R subscores. Sensitivity, specificity and the area under the curve of the receiver operating characteristic curves of the ALS-MITOS system stages and ALSFRS-R decline at 6 months were calculated and compared with the primary outcome (survival, tracheotomy or &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;23-hour non-invasive ventilation) at 12 and 18 months Predicted probabilities of the ALS-MITO system at 6 months for any event at 12 and 18 months were computed through logistic regression models. Disease progression from baseline to 6 months as defined by the ALS-MITOS system predicted death, tracheotomy or &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;23-hour non-invasive ventilation at 12 months with 82% sensitivity (95% CI 71% to 93%, n=37/45) and 63% specificity (95% CI 55% to 71%, n=92/146), and at 18 months with 71% sensitivity (95% CI 61% to 82%, n=50/70) and 68% specificity (95% CI 60% to 77%, n=76/111). The analysis of ALS-MITOS and ALSFRS-R progression at 6-month follow-up showed that the best cut-off to predict survival at 12 and 18 months was 1 for the ALS-MITOS (ie, loss of at least one function) and a decline ranging from 6 to 9 points for the ALSFRS-R. The ALS-MITOS system can reliably predict the course of ALS up to 18 months and can be considered a novel and valid outcome measure in RCTs.

Percutaneous radiological gastrostomy: a safe and effective method of nutritional tube placement in advanced ALS

Journal of Neurology Neurosurgery & Psychiatry

Enteral nutrition may be required in amyotrophic lateral sclerosis (ALS), and is usually achieved... more Enteral nutrition may be required in amyotrophic lateral sclerosis (ALS), and is usually achieved by percutaneous endoscopic gastrostomy (PEG). As PEG is not indicated in patients with severe respiratory impairment, an alternative is percutaneous radiological gastrostomy (PRG), involving air insufflation into the stomach under fluoroscopic guidance for tube insertion. To evaluate the safety of PRG and its effect on survival and respiratory function in ALS patients with respiratory failure. 25 consecutive ALS patients with severe dysphagia and forced vital capacity (FVC) <50% underwent PRG after October 2000. They were compared with 25 consecutive ALS patients with FVC <50% who underwent PEG before October 2000. Respiratory function was evaluated before and after the procedure. The two groups were similar for all relevant characteristics. PRG was successful in all cases, PEG in 23/25. One patient in each group died after the procedure. The mean survival time after the procedure...

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MGMT promoter hypermethylation in a series of 104 glioblastomas

by Adriano Chiò and Laura Annovazzi

Cancer genomics & proteomics

To evaluate MGMT promoter hypermethylation as prognostic factor in a retrospective study of 104 c... more To evaluate MGMT promoter hypermethylation as prognostic factor in a retrospective study of 104 cases of glioblastoma multiforme (GBM). The O(6)-methylguanine-DNA methyltransferase (MGMT) status was evaluated by methylation-specific PCR (MSP), immunohistochemistry and Western blotting analysis in formalin-fixed paraffin-embedded surgical samples. The MGMT gene was found to be methylated in 29 of 101 tumors (28.7%) by MSP, according to the evaluation methods employed. By immunohistochemistry, different categories were identified on the basis of reaction intensity, percentage of positive cells and homogeneous or heterogeneous distribution. MSP did not correlate with immunohistochemistry, with the exception of the category with the highest percentage of positive cells and homogeneity of immunostaining. Western blotting analysis correlated with immunohistochemical findings (Pearson's correlation coefficient r=0.268, p=0.0211), but not with MSP. By Kaplan-Meier survival analysis, rad...

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A de novo missense mutation of the FUS gene in a “true” sporadic ALS case

by Gabriella Restagno and Adriano Chiò

Mutations in the Cu/Zn superoxide dismutase (SOD1), transactive response (TAR)-DNA binding protei... more Mutations in the Cu/Zn superoxide dismutase (SOD1), transactive response (TAR)-DNA binding protein (TARDBP) and fused in sarcoma (FUS) genes account for approximately one third of familial amyotrophic lateral sclerosis (ALS) cases. Mutations in these genes have been found in 1 to 2% of apparently sporadic cases. We present the first case of an ALS patient carrying a de novo missense mutation of the FUS gene (c.1561C>T, p.R521C). This report highlights the importance of screening ALS patients, both familial and sporadic, for FUS mutations and also suggests that de novo mutations is a relevant mechanism underlying sporadic neurodegenerative disease.

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Proliferative activity and prognosis of low-grade astrocytomas

Well-differentiated astrocytomas may transform into malignant astrocytomas in time. In surgical s... more 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 (≥ 70 versus < 70) and age (≤ 30 versus > 30). The interpretation of well-differentiated astrocytomas with high MIB-1LI is that the increasing number of cycling cells precedes phenotypic transformation. MIB-1 LI can be used as a prognostic factor.

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Resting state functional connectivity alterations in primary lateral sclerosis

by Adriano Chiò and Vincenzo Silani

Neurobiology of aging, 2014

Resting state functional connectivity of the sensorimotor and extramotor brain networks was studi... more Resting state functional connectivity of the sensorimotor and extramotor brain networks was studied in 24 patients with primary lateral sclerosis (PLS) relative to 26 healthy controls. The relationships of RS functional connectivity with patient clinical and cognitive status and white matter tract damage (i.e., corticospinal tracts, corpus callosum, and superior longitudinal fasciculus) were investigated. Compared with controls, PLS patients showed an increased functional connectivity within the sensorimotor, frontal, and left frontoparietal networks spanning the pre- and postcentral, medial and dorsal frontal, insular, and superior temporal regions. Patients with more severe physical disability and a more rapid rate of disease progression had increased sensorimotor connectivity values. The increased functional connectivity within the frontal network was associated with executive dysfunction. In addition, higher functional connectivity correlated with greater structural damage to ne...

A familial ALS case carrying a novel p.G147C SOD1 heterozygous missense mutation with non-executive cognitive impairment

by B. Iazzolino, Angelina Cistaro, M. Brunetti, Piercarlo Fania, Adriano Chiò, and Gabriella Restagno

Journal of neurology, neurosurgery, and psychiatry, 2014

ABSTRACT Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease causing progressive ... more ABSTRACT Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease causing progressive muscle weakness and wasting. Death usually occurs within 3-5 years from respiratory failure. Approximately 10% of cases are familial (fALS).The frequency of SOD1 gene mutations in patients with fALS varies among populations, from 0% in Ireland to 13.6% in Italy and 23.5% in Scandinavia.1 SOD1 encodes for the Cu/Zn Superoxide Dismutase 1. Mutations are usually autosomal dominant, but the p.D90A and the p.D96N may be autosomal recessive.2 Performing the genetic screening of an Italian fALS series, we found a novel c.442g&gt;t heterozygous missense mutation of SOD1 gene leading to a substitution of cysteine for glycine (p.G147C). Such mutation was absent in healthy controls (n=130). The patient provided written informed consent. The index case displayed progressive weakness and wasting of both hands when he was 52 years old. One year after the onset he also exhibited tongue hypotrophy with fasciculations, spastic paraparesis, impairment of feet extension and brisk jaw jerk and lower limbs reflexes. Plantar response was absent bilaterally. He referred diffuse cramps and fasciculations. Dysphagia, dysarthria, dysphonia and dyspnoea were absent. The amyotrophic lateral sclerosis funcional rating scale revised (ALSFRS-R) was 44/48. Needle electromyography (EMG) showed chronic and active denervation in bulbar and spinal regions. Forced vital capacity was 106%. The neuropsychological evaluation showed an impaired performance in the Rey-Osterrieth Complex Figure (ROCF) Test, in copy and recall task, while other tests had normal scores. Brain MRI showed selective atrophy of the right supramarginal gyrus (figure 1 …

State of play in amyotrophic lateral sclerosis genetics

Nature neuroscience, 2014

Considerable progress has been made in unraveling the genetic etiology of amyotrophic lateral scl... more Considerable progress has been made in unraveling the genetic etiology of amyotrophic lateral sclerosis (ALS), the most common form of adult-onset motor neuron disease and the third most common neurodegenerative disease overall. Here we review genes implicated in the pathogenesis of motor neuron degeneration and how this new information is changing the way we think about this fatal disorder. Specifically, we summarize current literature of the major genes underlying ALS, SOD1, TARDBP, FUS, OPTN, VCP, UBQLN2, C9ORF72 and PFN1, and evaluate the information being gleaned from genome-wide association studies. We also outline emerging themes in ALS research, such as next-generation sequencing approaches to identify de novo mutations, the genetic convergence of familial and sporadic ALS, the proposed oligogenic basis for the disease, and how each new genetic discovery is broadening the phenotype associated with the clinical entity we know as ALS.

Genetic counselling in ALS: facts, uncertainties and clinical suggestions

by Debora Pain, Gabriella Restagno, S. Penco, Adriano Chiò, and Fabio Giannini

Journal of neurology, neurosurgery, and psychiatry, 2014

The clinical approach to patients with amyotrophic lateral sclerosis (ALS) has been largely modif... more The clinical approach to patients with amyotrophic lateral sclerosis (ALS) has been largely modified by the identification of novel genes, the detection of gene mutations in apparently sporadic patients, and the discovery of the strict genetic and clinical relation between ALS and frontotemporal dementia (FTD). As a consequence, clinicians are increasingly facing the dilemma on how to handle genetic counselling and testing both for ALS patients and their relatives. On the basis of existing literature on genetics of ALS and of other late-onset life-threatening disorders, we propose clinical suggestions to enable neurologists to provide optimal clinical and genetic counselling to patients and families. Genetic testing should be offered to ALS patients who have a first-degree or second-degree relative with ALS, FTD or both, and should be discussed with, but not offered to, all other ALS patients, with special emphasis on its major uncertainties. Presently, genetic testing should not be...

Coffee and risk of amyotrophic lateral sclerosis

by Carlo Ferrarese, Adriano Chiò, Cristina Cereda, Alessandro Padovani, Lucio Tremolizzo, Cristina Moglia, and Mauro Ceroni

American Journal of Epidemiology

The relation between coffee intake and risk of amyotrophic lateral sclerosis (ALS) was investigat... more The relation between coffee intake and risk of amyotrophic lateral sclerosis (ALS) was investigated in 377 newly diagnosed ALS patients from 4 Italian population-based registries in the European ALS Consortium (EURALS Group) (2007)(2008)(2009)(2010). For each patient, 2 age-and sex-matched hospital controls were selected, one from a neurology department and one from a nonneurologic department. Two additional healthy control groups were identified from local general practitioners' (GPs') lists (n ¼ 99) and residents of the same area as a cancer cohort (n ¼ 7,057). Coffee intake was defined in terms of status (ever consuming coffee daily for 6 months vs. never), duration, and history (never, former, or current). Ever coffee drinkers comprised 74.7% of ALS patients, 80.4% of neurologic controls, 85.6% of nonneurologic controls (P ¼ 0.0004), 88.9% of GP controls (P ¼ 0.0038), and 86.0% of cancer cohort controls (P < 0.0001). Current coffee drinkers comprised 60.2% of ALS patients, 70.2% of neurologic controls (P ¼ 0.0294), 76.4% of nonneurologic controls (P < 0.0001), and 82.3% of GP controls (P ¼ 0.0002); duration of intake was 30 years for 62.3%, 67.7%, 74.7%, and 72.6%. ALS patients had lower lifetime coffee exposure: Odds ratios were 0.7 (95% confidence interval (CI): 0.5, 1.1), 0.6 (95% CI: 0.4, 0.8), and 0.4 (95% CI: 0.2, 0.9) in comparison with neurologic, nonneurologic, and GP controls, respectively. In current (vs. never) coffee drinkers, odds ratios were 0.7 (95% CI: 0.5, 1.0), 0.5 (95% CI: 0.3, 0.7), and 0.4 (95% CI: 0.2, 0.8), respectively. These findings provide epidemiologic evidence of an inverse correlation between coffee intake and ALS risk. amyotrophic lateral sclerosis; coffee; motor neuron disease Abbreviations: ALS, amyotrophic lateral sclerosis; EURALS Group, European ALS Consortium; GP, general practitioner.

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Genome-Wide Analysis of the Heritability of Amyotrophic Lateral Sclerosis

by Pentti Tienari, Gabriella Restagno, and Adriano Chiò

JAMA Neurology, 2014

IMPORTANCE Considerable advances have been made in our understanding of the genetics underlying a... more IMPORTANCE Considerable advances have been made in our understanding of the genetics underlying amyotrophic lateral sclerosis (ALS). Nevertheless, for the majority of patients who receive a diagnosis of ALS, the role played by genetics is unclear. Further elucidation of the genetic architecture of this disease will help clarify the role of genetic variation in ALS populations.

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Primary lymphomas of the brain: a clinico-pathologic review of 37 cases

by Adriano Chiò and Maria Giordana

Tumori

The clinico-pathologic data of 37 primary lymphomas of the brain were retrospectively reviewed. T... more The clinico-pathologic data of 37 primary lymphomas of the brain were retrospectively reviewed. The tumors were classified according to the Kiel classification and the Working Formulation System. They represented 1.02% of all primary intracranial tumors of our series. The radiologic prediction appeared to be difficult: the suspicion was maximal when the absence of pathologic vessels at angiography occurred in a meningioma-like lesion at CT. Median survival was 4.53 months in the 16 cases who underwent surgery only versus 25.7 months in the 8 cases operated and irradiated with 40-60 Gy (p less than 0.01). The prognosis of lymphomas of the CNS, even if radioresponsive tumors, remains poor. Most patients relapse after treatment, most often locally in the brain, with a variable frequency of spinal or systemic localization.

Analysis of the KIFAP3 gene in amyotrophic lateral sclerosis: a multicenter survival study

by Gabriella Restagno, Philip Van Damme, Gabriele Mora, Vincenzo Silani, A. Al-chalabi, Adriano Chiò, and P. Andersen

Neurobiology of aging, 2014

Sporadic amyotrophic lateral sclerosis is a multifactorial disease of environmental and genetic o... more Sporadic amyotrophic lateral sclerosis is a multifactorial disease of environmental and genetic origin. In a previous large multicenter genome wide study, common genetic variation in the Kinesin-Associated Protein 3 (KIFAP3) gene (rs1541160) was reported to have a significant effect on survival in amyotrophic lateral sclerosis patients. However, this could not be replicated in 3 smaller independent cohorts. We conducted a large multicenter multivariate survival analysis (n = 2362) on the effect of genetic variation in rs1541160. The previously reported beneficial genotype did not show a significant improvement in survival in this patient group.

Mutations in the CHCHD10 gene are a common cause of familial amyotrophic lateral sclerosis

by Gabriella Restagno and Adriano Chiò

Brain, 2014

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Sclerosi laterale amiotrofica e atrofie muscolari spinali

by Adriano Chiò and Gabriele Mora

Con il termine “malattie dei motoneuroni” si indica una serie di patologie caratterizzate dalla d... more Con il termine “malattie dei motoneuroni” si indica una serie di patologie caratterizzate dalla degenerazione dei neuroni motori. La classificazione della World Federation of Neurology riconosce in questa dizione numerose entità nosologiche differenti [1]. Le principali forme cliniche includono: la sclerosi laterale amiotrofica, l’atrofia muscolare spinale e la neuronopatia bulbospinale (o malattia di Kennedy).

Extramotor Damage Is Associated with Cognition in Primary Lateral Sclerosis Patients

by Vincenzo Silani and Adriano Chiò

PLoS ONE, 2013

Objectives: This is a cross-sectional study aimed at investigating cognitive performances in pati... more Objectives: This is a cross-sectional study aimed at investigating cognitive performances in patients with primary lateral sclerosis (PLS) and using diffusion tensor (DT) magnetic resonance imaging (MRI) to determine the topographical distribution of microstructural white matter (WM) damage in patients with or without cognitive deficits.

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Amyotrophic Lateral Sclerosis Outcome Measures and the Role of Albumin and Creatinine

by Adriano Chiò, Umberto Manera, Enrica Bersano, Fabrizio Pisano, and S. Cammarosano

JAMA Neurology, 2014

There is an urgent need to identify reliable biomarkers of amyotrophic lateral sclerosis (ALS) pr... more There is an urgent need to identify reliable biomarkers of amyotrophic lateral sclerosis (ALS) progression for clinical practice and pharmacological trials. To correlate several hematological markers evaluated at diagnosis with ALS outcome in a population-based series of patients (discovery cohort) and replicate the findings in an independent validation cohort from an ALS tertiary center. The discovery cohort included 712 patients with ALS from the Piemonte and Valle d&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;Aosta Register for Amyotrophic Lateral Sclerosis from January 1, 2007, to December 31, 2011. The validation cohort comprised 122 patients with ALS at different stages of disease consecutively seen at an ALS tertiary center between January 1, 2007, and January 1, 2009. The following hematological factors were investigated and correlated with survival: total leukocytes, neutrophils, lymphocytes, monocytes, glucose, creatinine, uric acid, albumin, bilirubin, total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, creatine kinase, thyroid-stimulating hormones, and erythrocyte sedimentation rate; all analyses were performed separately by sex. The patient of the validation cohort also underwent bioelectrical impedance analysis for the calculation of fat-free mass. Of the 712 patients in the examined period in Piemonte and Valle d&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;Aosta, 638 (89.6%) were included in the study. Only serum albumin (men: ≤ 4.3 vs &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;4.3 mg/dL, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; .001; women: ≤ 4.3 vs &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;4.3 mg/dL, P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; .001) and creatinine levels (men: ≤ 0.82 vs &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;0.82 mg/dL, P = .004; women: ≤ 0.65 vs &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;0.05 mg/dL, P = .004) and lymphocyte count (men: ≤ 1700 vs &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;1700/μL, P = .04; women: ≤ 1700 vs &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;1700/μL, P = .02) were significantly associated with ALS outcome in both sexes with a dose-response effect (better survival with increasing levels). These findings were confirmed in the validation cohort. Multivariable analysis showed that serum albumin (men: hazard ratio [HR], 1.39; 95% CI, 1.05-1.90; P = .02; women: HR, 1.73; 95 % CI, 1.35-2.39; P = .001) and creatinine (men: HR, 1.47; 95% CI, 1.11-1.95; P = .007; women: HR, 1.49; 95% CI, 1.07-2.05; P = .02) were independent…

Motor neuron disease in 2014: Biomarkers for ALS—in search of the Promised Land

Nature Reviews Neurology, 2014

The past year has seen some extraordinary activity in clinical amyotrophic lateral sclerosis (ALS... more The past year has seen some extraordinary activity in clinical amyotrophic lateral sclerosis (ALS) research. Two trials were completed, with negative results, but the discovery of novel ALS-associated genes, and body fluid and imaging biomarkers warrants cautious optimism. Here, we provide a snapshot of some of the main findings in 2014.

The prognostic role of vessel productive changes and vessel density in oligodendroglioma

Journal of Neuro-Oncology, 1999

The recognition of the anaplastic variant of oligodendroglioma is difficult, since it is not easy... more The recognition of the anaplastic variant of oligodendroglioma is difficult, since it is not easy to identify histological prognostic factors. Among the latter, vascular productive changes have been inconsistently put in relation with survival. In 95 cases of operated oligodendrogliomas, endothelial cell hyperplasia, microvascular proliferations and capillary density were studied by histological and immunohistochemical methods. Capillary density was evaluated on CD31-stained sections by a grid of 100 squares placed in the ocular of the microscope. Statistical analysis was performed in order to compare these parameters with survival. A nodular growth pattern was observed more frequently among tumor grades 3-4 than among tumor grades 1-2. Endothelial cell hyperplasia was more frequent in nodular growth pattern, but it did not correlate with survival. The highest capillary density was found in nodular growth pattern, but it did not correlate with survival as well. Microvascular proliferations correlated with survival only in univariate, but not in multivariate analysis. Age, extent of surgical removal, year of surgery, post-operative Karnofsky score and MIB-1 LI remained associated with survival, as observed in a previous study.

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