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Objective: To report the safety and efficacy results of patients enrolled in the Italian Nivolumab Renal Cell Cancer Expanded Access Programme. Patients and Methods: Patients with metastatic renal cell cancer (mRCC) previously treated with agents targeting the vascular endothelial growth factor pathway were eligible to receive nivolumab 3 mg/kg once every 2 weeks. Patients included in the analysis had received ≥1 dose of nivolumab and were monitored for adverse events (AEs) using Common Terminology Criteria for Adverse Events (CTCAE) v.4.0. Results: A total of 389 patients were enrolled between July 2015 and April 2016, of whom 18% were aged ≥75 years, 6.7% had non-clear cell RCC, 49.6% had bone and 8.2% brain metastases, and 79% had received ≥2 previous lines of therapy. The most common any-grade treatment-related AEs were fatigue (13%) and rash (9%). Twenty-two patients (5.7%) discontinued treatment because of AEs. There were no treatment-related deaths. The objective response rate was 23.1%. At a median follow-up of 12 months, the median progression-free survival was 4.5 months (95% confidence interval 3.7–6.2) and the 12-month overall survival rate was 63%. Similar survival rates were reported among patients with non-clear-cell histology, elderly patients, those with bone and/or brain metastases, and those who had received prior first-line sunitinib or pazopanib, or prior everolimus. Conclusion: The safety and efficacy observed were consistent with those reported in the pivotal Checkmate 025 trial. Results in patients with non-clear-cell mRCC who were elderly, pretreated with everolimus, and had bone and/or brain metastases encourage the use of nivolumab in these categories of patients. © 2018 The Authors BJU International

Background and purpose Heterozygous mutations in the STUB1 gene have recently been associated with an autosomal dominant form of spinocerebellar ataxia (SCA) associated with cerebellar cognitive-affective syndrome (CCAS), named SCA48. Methods Molecular screening was performed in a cohort of 235 unrelated patients with adult-onset, autosomal dominant (17) or sporadic (218) cerebellar ataxia, negative for pathological trinucleotide expansions in the common SCAs, FRDA and FXTAS loci, by using targeted multigene panels or whole-exome sequencing. Bioinformatics analyses, detailed neurological phenotyping and family segregation studies corroborated the pathogenicity of the novel STUB1 mutations. Clinico-diagnostic findings were reviewed to define the phenotypic spectrum. Results Eight heterozygous STUB1 mutations were identified, six of which were novel in 11 patients from eight index families, giving an estimated overall frequency of 3.4% (8/235) for SCA48 in our study cohort, rising to 23.5% (4/17) when considering only familial cases. All our SCA48 patients had cerebellar ataxia and dysarthria associated with cerebellar atrophy on brain magnetic resonance imaging; of note, many cases were also associated with parkinsonism, chorea and dystonia. CCAS also occurred frequently, whereas definite signs of pyramidal tract dysfunction and peripheral nervous system involvement were absent. One SCA48 patient presented with hypogonadism, associated with other autoimmune endocrine dysfunctions. Conclusions Our results support SCA48 as a significant cause of adult-onset SCA. Besides CCAS, our SCA48 patients often showed movement disorders and other clinical manifestations previously described in SCAR16, linked to biallelic variants in the same gene, thus suggesting a continuous clinical spectrum and significant overlap amongst recessive and dominantly inherited mutations in STUB1.

Background: Cerebellar hemorrhage (CBH) represents the main form of direct cerebellar injury in preterm infants. Most CBHs occur bilaterally, while isolated unilateral hemorrhages are less frequent and often associated with focal atrophy. Limited and heterogeneous data exist on preterm birth, unilateral CBH and consequent long-term neurodevelopmental and non-motor outcomes. Case report: This is the case of a six-year-old child, born preterm, diagnosed with a complete atrophy of the right cerebellar hemisphere through brain MRI and presenting mild social atypies, visuo-perceptive and pragmatic language impairment, but only minor neurological signs. Discussion: Despite the large extension of the patient's CBH neurological sequelae were mild, likely due to cerebellar plasticity, and only specific deficits in non-motor, behavioral and social skills were shown. Evidence exists on cerebellar contribution to dynamic visual information processing and to perceptual signals detection and prediction, that might explain the presence of non-motor signs.

Background: Recent studies have suggested the presence of a significant atrophy affecting the cerebellar cortex in Friedreich ataxia (FRDA) patients, an area of the brain long considered to be relatively spared by neurodegenerative phenomena. Cognitive deficits, which occur in FRDA patients, have been associated with cerebellar volume loss in other conditions. The aim of this study was to investigate the correlation between cerebellar volume and cognition in FRDA. Methods: Nineteen FRDA patients and 20 healthy controls (HC) were included in this study and evaluated via a neuropsychological examination. Cerebellar global and lobular volumes were computed using the Spatially Unbiased Infratentorial Toolbox (SUIT). Furthermore, a cerebellar voxel-based morphometry (VBM) analysis was also carried out. Correlations between MRI metrics and clinical data were tested via partial correlation analysis. Results: FRDA patients showed a significant reduction of the total cerebellar volume (p = 0.004), significantly affecting the Lobule IX (p = 0.001). At the VBM analysis, we found a cluster of significant reduced GM density encompassing the entire lobule IX (p = 0.003). When correlations were probed, we found a direct correlation between Lobule IX volume and impaired visuo-spatial functions (r = 0.58, p = 0.02), with a similar correlation that was found between the same altered function and results obtained at the VBM (r = 0.52; p = 0.03). Conclusions: With two different image analysis techniques, we confirmed the presence of cerebellar volume loss in FRDA, mainly affecting the posterior lobe. In particular, Lobule IX atrophy correlated with worse visuo-spatial abilities, further expanding our knowledge about the physiopathology of cognitive impairment in FRDA.

Sixty-six patients with possible or probable MSA (multiple system atrophy) cerebellar type, personally observed between 2006 and 2018 were retrospectively reviewed. The time point of data collection was January 1, 2019. Forty-nine patients lost independent walking after a median time of 5 years (95% C. I. 4–6). Thirty-two patients were confined to wheelchair after a median time of 7 years (95% C. I. 7–8). Twenty-seven patients were deceased after a median time of 9 years (95% C. I. 8–10). A later onset predicted an earlier loss of independent walking (HR 1.07; 95% C.I. 1.03–1.11; p = 0.001). Higher UMSARS score predicted shorter time to loss of independent walking (HR 1.04; 95% C.I. 1.02–1.06; p = 0.001) and to wheelchair (HR 1.03; 95% C.I. 1.01–1.06; p = 0.021). No predictor of time to death was found.

The diagnosis of sporadic adult onset ataxia is a challenging task since a large collection of hereditary and non-hereditary disorders should be taken into consideration. Sporadic adult onset ataxias include degenerative non-hereditary, hereditary, and acquired ataxias. Multiple system atrophy and idiopathic late cerebellar ataxia are degenerative non-hereditary ataxias. Late-onset Friedreich's ataxia, spinocerebellar ataxia type 6 and 2, and fragile X-associated tremor/ataxia syndrome account for most sporadic hereditary ataxias. Alcoholic cerebellar degeneration, paraneoplastic and other autoimmune cerebellar degeneration, vitamin deficiencies, and toxic-induced and infectious cerebellar syndrome are the main causes of acquired cerebellar degeneration. The diagnostic approach should include a history taking, disease progression, general and neurological examination, brain MRI, and laboratory and genetic tests. Novel opportunities in massive gene sequencing will increase the likelihood to define true etiologies.

Introduction Spinocerebellar ataxia 48 has recently been described as an adult onset ataxia associated with a cerebellar cognitive affective syndrome, caused by a heterozygous mutation in the STUB1 gene. Methods We characterized the clinical and neuroimaging phenotype of eight patients from two autosomal dominant ataxia multigenerational Italian families, in whom we conducted whole exome sequencing, targeted multigene sequencing, and Sanger sequencing studies. Results We describe a complex syndrome characterized by ataxia and cognitive-psychiatric disorder in all cases, variably associated with chorea, parkinsonism, dystonia, urinary symptoms, and epilepsy. MRI showed a significant cerebellar atrophy, coupled to a T2-weighted hyperintensity affecting the dentate nuclei and extending to the middle cerebellar peduncles, whereas FDG-PET studies revealed glucose hypometabolism in cerebellum, striatum, and cerebral cortex. We identified two different novel STUB1 mutations segregating in the two families. One of the two mutations, p.(Gly33Ser), occurs in the TRP domain, whereas p.(Pro228Ser) is located in the ubiquitin ligase region. Discussion We emphasize the similarity of the described clinical picture with that of SCAR16, an autosomal recessive ataxia caused by biallelic mutations in the same gene, and of spinocerebellar ataxia type 17, which is considered the main Huntington's disease-like syndrome. The pathogenesis of the disease and the relationship between SCA48 and SCAR16 remain to be clarified.

One hundred-eighteen spinocerebellar ataxia type 2 patients from 35 distinct families personally observed between 1973 and 2016 were retrospectively reviewed. The time point of data collection was 1 January 2017. Thirty-one patients were confined to wheelchair. The median time to wheelchair was 21 years (95% CI, 17.5-24.6). Thirty-seven patients were deceased. The median time to death was 25 years (95% CI, 22.9-27.1). CAG repeat number and ataxia score at first visit influenced the time to wheelchair and death.