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Analisi delle principali questioni di politica legislativa in vista dell'apertura della nuova consiliatura (2018).

Purpose: Despite multimodal therapy, prognosis of pediatric intracranial ependymomas remains poor with a 5-year survival rate below 70% and frequent late deaths. Experimental design: This multicentric European study evaluated putative prognostic biomarkers. Tenascin-C (TNC) immunohistochemical expression and copy number status of 1q25 were retained for a pooled analysis of 5 independent cohorts. The prognostic value of TNC and 1q25 on the overall survival (OS) was assessed using a Cox model adjusted to age at diagnosis, tumor location, WHO grade, extent of resection, radiotherapy and stratified by cohort. Stratification on a predictor that did not satisfy the proportional hazards assumption was considered. Model performance was evaluated and an internal-external cross validation was performed. Results: Among complete cases with 5-year median follow-up (n = 470; 131 deaths), TNC and 1q25 gain were significantly associated with age at diagnosis and posterior fossa tumor location. 1q25 status added independent prognostic value for death beyond the classical variables with a hazard ratio (HR) = 2.19 95%CI = [1.29; 3.76] (p = 0.004), while TNC prognostic relation was tumor location-dependent with HR = 2.19 95%CI = [1.29; 3.76] (p = 0.004) in posterior fossa and HR = 0.64 [0.28; 1.48] (p = 0.295) in supratentorial (interaction p value = 0.015). The derived prognostic score identified 3 different robust risk groups. The omission of upfront RT was not associated with OS for good and intermediate prognostic groups while the absence of upfront RT was negatively associated with OS in the poor risk group. Conclusion: Integrated TNC expression and 1q25 status are useful to better stratify patients and to eventually adapt treatment regimens in pediatric intracranial ependymoma.

Essential oils (EOs) and entomopathogenic fungi such as Beauveria bassiana (Bb) strains have the potential to be used as alternative insecticides and acaricides for controlling ectoparasites as Dermanyssus gallinae. These compounds have some limitations in their use: the acaricidal effect of EOs is rapid, but short-lived, whilst that of Bb is delayed, but long-lived. To evaluate the effect of both compounds combined against D. gallinae, the non-toxic dose of Eucalyptus globulus, Eucalyptus citriodora, Thymus vulgaris and Eugenia caryophyllata essential oils were firstly calculated for "native" strains of Bb. Subsequently, the effects of the combination of selected EOs with Bb against nymph and adult poultry red mites (PRMs) was assessed. EO concentrations ranging from 0.0015 to 8% v/v (i.e., nine double dilutions) were used to evaluate their effect on germination, sporulation and vegetative growth rates of native strains of Bb. A total of 1440 mites (720 nymphs and 720 adults) were divided into three-treated group (TGs) and one control group (CG). In TGs, mites were exposed to Bb in combination with the selected EO (TG1), EO alone (TG2) or Bb (TG3) alone. In the CG, mites were exposed to 0.1% tween 80 plus EO solvent (CG). E. globulus and E. citriodora were toxic for Bb in concentrations higher than 0.2% and 0.003% respectively, whilst E. caryophyllata and T. vulgaris were toxic at all concentrations tested against Bb. Based on the results of the toxicity assays against Bb, E. globulus was chosen to be tested as acaricide resulting non-toxic for Bb at concentration lower than 0.4%. Increased mortality of D. gallinae adults was recorded in TG1 than those in other TGs from 4days post-infection (T+4DPI). A 100% mortality of D. gallinae was recorded in adults at T+9DPI and at T+10DPI in nymphs in TG1 and later than T+11DPI in the other TGs. Used in combination with E. globulus, Bb displayed an earlier acaricidal effect towards both haematophagous D. gallinae stages. The combination of B. bassiana and E. globulus at 0.2% might be used for controlling arthropods of medical and veterinary importance as D. gallinae.

Background Recent transcriptomic approaches have demonstrated that there are at least 4 distinct subgroups in medulloblastoma (MB); however, survival studies of molecular subgroups in adult MB have been inconclusive because of small sample sizes. The aim of this study is to investigate the molecular subgroups in adult MB and identify their clinical and prognostic implications in a large, single-institution cohort. Methods We determined gene expression profiles for 13 primary adult MBs. Bioinformatics tools were used to establish distinct molecular subgroups based on the most informative genes in the dataset. Immunohistochemistry with subgroup-specific antibodies was then used for validation within an independent cohort of 201 formalin-fixed MB tumors, in conjunction with a systematic analysis of clinical and histological characteristics. Results Three distinct molecular variants of adult MB were identified: the SHH, WNT, and group 4 subgroups. Validation of these subgroups in the 201-tumor cohort by immunohistochemistry identified significant differences in subgroup-specific demographics, histology, and metastatic status. The SHH subgroup accounted for the majority of the tumors (62%), followed by the group 4 subgroup (28%) and the WNT subgroup (10%). Group 4 tumors had significantly worse progression-free and overall survival compared with tumors of the other molecular subtypes. Conclusions We have identified 3 subgroups of adult MB, characterized by distinct expression profiles, clinical features, pathological features, and prognosis. Clinical variables incorporated with molecular subgroup are more significantly informative for predicting adult patient outcome.

INTRODUCTION Pediatric brain tumors (PBT) represent the second most common pediatric cancer, with the highest mortality rate among childhood malignancies. Improvement of PBT diagnostic accuracy is fundamental to optimize treatment strategy. OBJECTIVES: We aimed to explore the impact of DNA methylation arrays implementation in PBT clinical practice. METHODS 214 PBT were analyzed by Illumina 850KEPICmethylation array. Low score and discordant cases were collegially reviewed. RESULTS Calibrated score was 0.8 or higher in 159 cases (74.3%), with pathological diagnosis confirmation in 132 cases and molecular subgroup definition in 47 of them, including cases of medulloblastoma, CNS neuroblastoma FOXR2, HGNET MN1; methylation profiling amended diagnosis in 10 cases, e.g. HGNET BCOR and anaplastic PXA, was non-contributory in 4 and misleading in 12 cases, including glioneural tumors and tumors arising in syndromic contexts. Calibrated score ranged between 0.8 and 0.3 in 37 cases (17.3%) and was below 0,3 (no match) in 18 cases (8.4%). Calibrated score below 0,8 was more frequently assigned to low grade gliomas and low grade glioneural tumors (p CONCLUSION Methylation profiling refine on diagnostic accuracy in PBT classification. Improvements are needed in classifying low grade glioma/glioneuronal tumors and challenging/very rare PBT. In syndromic cases, there is a high rate of misleading profiles and/or low scores.

Non-celiac gluten sensitivity (NCGS) is an emerging gluten-related condition. We investigated whether the presence of autoimmune stigmata in a group of patients with clinical suspicion of NCGS and a histological picture of microscopic enteritis (ME) could be a predictive factor of NCGS. Patients with ME were followed up by periodical examinations. At baseline, we collected data about previous clinical history, including autoimmune diseases. NCGS was diagnosed according to Salerno criteria, other causes of ME were diagnosed according to well-established protocols. Patients with celiac disease were excluded. Student&rsquo, s and chi-square tests were used in univariate analysis. Kaplan-Meier curves and Cox regression were used to estimate hazard ratios (HR). Sixty-three patients were included. Twenty-two had a final diagnosis of NCGS, the remaining 41 had non-gluten-related causes of ME. Prevalence of autoimmune thyroiditis was higher among NCGS patients (40.1%) than in other ME (14.6%, p = 0.03). NCGS showed higher positivity rate for anti-gliadin (27.3% versus 2.5%, p = 0.006) and anti-nucleus (45.4% versus 12.2%, p = 0.005). Autoimmune thyroiditis had a non-significant trend (p = 0.06) for NCGS diagnosis, (HR = 2.4). Both anti-gliadin (HR = 2.4, p = 0.04) and anti-nucleus (HR = 2.7, p = 0.04) were directly associated with NCGS diagnosis. In conclusion, NCGS may have a cohort of autoimmune stigmata that can precede its diagnosis.

Elongation of telomeres is necessary for tumor cell immortalization and senescence escape; neoplastic cells use to alternative pathways to elongate telomeres: telomerase reactivation or a telomerase-independent mechanism termed alternative lengthening of telomeres (ALT). Telomerase and ALT pathway has been explored in adult and pediatric gliomas and medulloblastomas (MDBs); however, these mechanisms were not previously investigated in MDBs metastatic at the onset. Therefore, we analyzed the activation of telomerase and ALT pathway in a homogenous cohort of 43 pediatric metastatic medulloblastomas, to investigate whether telomere elongation could play a role in the biology of metastatic MDB. We evaluated telomeres length via telomere-specific fluorescence in situ hybridization (Telo-FISH); we assessed nuclear expression of ATRX by immunohistochemistry (IHC). H3F3A and TERT promoter mutations were analyzed by pyrosequencing, while UTSS methylation status was analyzed via methylation-specific-PCR (MS-PCR). H3F3A mutations were absent in all MDBs, 30% of samples showed ATRX nuclear loss, 18.2% of cases were characterized by TERT promoter mutations, while 60.9% harboured TERT promoter hyper-methylation in the UTSS region. Elongation of telomeres was found in 42.8% of cases. Metastatic MDBs control telomere elongation via telomerase activation (10.7%), induced by TERT promoter mutations in association with UTSS hyper-methylation, and ALT mechanism (32.1%), triggered by ATRX inactivation. Among non-metastatic MDBs, only 5.9% (1/17) showed ATRX nuclear loss with activation of ALT. Our metastatic cases frequently activate ALT pathway, suggesting that it is a common process for senescence escape in primary metastatic medulloblastomas. Furthermore, the activation of mechanisms for telomere elongation is not restricted to certain molecular subgroups in this high-risk group of MDBs.

High-throughput analysis has improved the knowledge of medulloblastoma (MB), the leading cause of cancer related death in children, allowing a better comprehension of the key molecular pathways in MB pathogenesis. However, despite these advances, 30% of patients still die from the disease and survivors face severe long-term side effects. Cancer stem cells (CSCs) represent a subset of cells that not only drive tumorigenesis, but are also one of the main determinants of chemoresistance. Epithelial mesenchymal transition (EMT) is a hallmark of cancer and up to now few data is available in MB. To give insight into the role of the EMT process in maintaining the mesenchymal phenotype of CSCs, we analyzed the expression of EMT related transcripts and microRNAs in these cells. We firstly isolated CSCs from Sonic Hedgehog (SHH) MB derived from Ptch1 heterozygous mice and compared their expression level of EMT-related transcripts and microRNAs with cerebellar NSCs. We identified two molecules linked to SHH and EMT, Vegfa and its receptor Nrp2, over-expressed in SHH MB CSCs. Inhibition of Vegfa showed impairment of cell proliferation and self-renewal ability of CSCs concurrent with an increase of the expression of the EMT gene, E-cadherin, and a decrease of the EMT marker, Vimentin. Moreover, among deregulated microRNAs, we identified miR-466f-3p, a validated inhibitor of both Vegfa and Nrp2. These results allowed us to describe a new EMT molecular network, involving the down-regulation of miR-466f-3p together with the concordant up-regulation of Vegfa and Nrp2, that sustains the mesenchymal phenotype of SHH MB CSCs.

Numb is an intracellular protein with multiple functions. The two prevalent isoforms, Numb p66 and Numb p72, are regulators of differentiation and proliferation in neuronal development. Additionally, Numb functions as cell fate determinant of stem cells and cancer stem cells and its abnormal expression has been described in several types of cancer. Involvement of deregulated Numb expression has been described in the malignant childhood brain tumor medulloblastoma, while Numb isoforms in these tumors and in cancer stem-like cells derived from them, have not been studied to date. Here we show that medulloblastoma stem-like cells and cerebellar neuronal stem cells (NSCs) express Numb p66 where its expression tampers stemness features. Furthermore, medulloblastoma samples evaluated in this study express decreased levels of Numb p66 while overexpressed Numb p72 compared with normal tissues. Our results uncover different roles for the two major Numb isoforms examined in medulloblastoma and a critical role for Numb p66 in regulating stem-like cells and NSCs maintenance.

Presentation at the Conference on “Circolazione ed impatto dei patogeni enterici in Italia” organized by the Istituto Superiore di Sanità, European Food Safety Autority (EFSA) focal point in Italy, and Directorate General of Collegiate Bodies for Health Protection, Office 3, Ministry of Health, held in Rome, Italy, on the 18th of October 2018, Awarded as second best poster presentation at the Conference

Verso la fine del 2012 la Regione Friuli Venezia Giulia ha conferito l’incarico all’Università degli Studi di Trieste di effettuare uno studio su un’ipotesi di “Città metropolitana di Trieste”. Il primo passo è stata la ricognizione degli ambiti disciplinari e delle competenze utili per analizzare il tema. Sono stati individuati quattro ambiti che indicheremo come: • Ambito urbanistico-territoriale • Ambito economico-trasportistico • Ambito socio-politico • Ambito giuridico-legislativo Pur non essendo esaustivo, ciascuno di questi ambiti ha un sicuro rilievo nel definire e valutare l’impatto che la costituzione della città metropolitana potrebbe avere rispetto all’assetto territoriale, economico, sociale e amministrativo esistente. Si è quindi formato un ampio gruppo di ricerca proveniente da studiosi appartenenti a quattro diversi Dipartimenti: il Dipartimento di Ingegneria e Architettura, il Dipartimento di Scienze Economiche, Aziendali, Matematiche e Statistiche, il Dipartimento di Scienze Politiche e Sociali e il Dipartimento di Scienze Giuridiche, del Linguaggio, dell`Interpretazione e della Traduzione. Per il Dipartimento di Ingegneria e Architettura hanno partecipato Paola Di Biagi, Alessandra Marin, Claudia Marcon e Igor Ciuffarin; per il Dipartimento di Scienze Economiche, Aziendali, Matematiche e Statistiche Romeo Danielis, Lucia Rotaris; per il Dipartimento di Scienze Politiche e Sociali Giorgio Osti, Giovanni Carrosio e Marco Cesa; e per il Dipartimento di Scienze Giuridiche, del Linguaggio, dell`Interpretazione e della Traduzione Paolo Giangaspero, Alessia Ottavia Cozzi, Pietro Faraguna e Federico Gambini. La provenienza multidisciplinare del gruppo di ricerca ha permesso di evidenziare le specificità di ciascuna disciplina nell’affrontare il tema oggetto di studio e di metterle a confronto, facendole interagire, nel caso specifico dell’ipotesi della Città Metropolitana di Trieste.

Molecular classification has improved the knowledge of medulloblastoma (MB), the most common malignant brain tumour in children, however current treatments cause severe side effects in patients. Cancer stem cells (CSCs) have been described in MB and represent a sub population characterised by self-renewal and the ability to generate tumour cells, thus representing the reservoir of the tumour. To investigate molecular pathways that characterise this sub population, we isolated CSCs from Sonic Hedgehog Medulloblastoma (SHH MB) arisen in Patched 1 (Ptch1) heterozygous mice, and performed miRNA- and mRNA-sequencing. Comparison of the miRNA-sequencing of SHH MB CSCs with that obtained from cerebellar Neural Stem Cells (NSCs), allowed us to obtain a SHH MB CSC miRNA differential signature. Pathway enrichment analysis in SHH MB CSCs mirnome and transcriptome was performed and revealed a series of enriched pathways. We focused on the putative targets of the SHH MB CSC miRNAs that were involved in the enriched pathways of interest, namely pathways in cancer, PI3k-Akt pathway and protein processing in endoplasmic reticulum pathway. In silico analysis was performed in SHH MB patients and identified several genes, whose expression was associated with worse overall survival of SHH MB patients. This study provides novel candidates whose functional role should be further investigated in SHH MB.

The bovine viral diarrhea virus type 1 species is responsible for cosmopolitan diseases affecting cattle and other ruminants, with relevant impact on animal production. The species presents high genomic heterogeneity, with implications on control and prophylactic programs. Genomic traits of different genetic groups are often related to geographic origin. Atypical sequences have been reported from Pestivirus isolates originated from cattle in Turkey. Based on phylogenetic analysis of 5' untranslated region and Npro and secondary structure analysis of the 5'-UTR RNA, Turkish isolates have been segregated in two distinct genotypes. Out of the twenty-three identified BVDV-1 genotypes, the Turkish clusters, named L and R or 1.16 and 1.14, according to palindromic nucleotide substitution genotyping method, represent genomic clusters so far, not described elsewhere, suggesting geographic segregation. In order to avoid confusion in the current taxonomy of the species, nomenclature of described homonymous genotypes, referred to different genomic clusters, should be corrected.

Peroxisome proliferator-activated receptor alpha (PPARα) has been involved in the regulation of somatotroph tumour cells and may be targeted by different drugs, some of them are in current clinical use. The aim of this study was to investigate the expression of PPARα in additional phenotypes of pituitary adenomas (PA), the relationship between PPARα and its potential molecular partner aryl hydrocarbon receptor interacting protein (AIP) in these tumours, and the effects of PPARα agonists on lactotroph cells. Seventy-five human PA – 57 non-functioning (NFPA) and 18 prolactinomas (PRL-PA) – were characterised for PPARα and AIP expression by real time RT-PCR and/or immunohistochemistry (IHC), and the effects of fenofibrate and WY 14 643 on MMQ cells were studied in vitro. PPARα was expressed in a majority of PA. PPARα immunostaining was observed in 93.7% PRL-PA vs. 60.6% NFPA (p=0.016), the opposite being found for AIP (83.3% in NFPA vs. 43.7% in PRL-PA, p=0.003). PPARα expression was unrelated to gonadotroph differentiation in NFPA, but positively correlated with tumour volume in PRL-PA. Both drugs significantly reduced MMQ cell growth at high concentrations (100–200 μM). At the same time, despite modest stimulating effects on PRL secretion were observed, these were overcome by the reduction in cell number. In conclusion, PPARα is commonly expressed by PRL-PA and NFPA, regardless of AIP, and may represent a new target of PPARα agonists.

The HERBY trial was a phase-II open-label, randomised, multicentre trial evaluating bevacizumab in addition to temozolomide/radiotherapy in patients with newly-diagnosed non-brainstem high-grade glioma between the ages of 3-18 years. We collected specimens from 89/113 patients consenting to translational research, and carried out comprehensive molecular analysis integrated with pathology, radiology and immune profiling. 7/89 patients harboured H3F3A_G34R/V mutations (diffusely infiltrative with predominant deep left temporoparietal involvement), whilst 24/89 harboured H3F3A_K27M, both conferring a worse outcome. Of the latter, two patients had distinct, separate lesions in the thalamus and hypothalamus, whilst the remaining had symmetrical central thalamic and midbrain localization. Four older patients had tumours harbouring IDH1 mutations, whilst three younger patients had tumours which by methylation profiling resembled low grade lesions; both of these hemispheric subgroups had a significantly longer survival. Hypermutator tumours (driven by mismatch repair deficiency and somatic POLE / POLD1 mutations) and those biologically resembling pleomorphic xanthoastrocytoma (PXA-like, driven by BRAF_V600E or NF1 mutation) had an elevated immune response in the form of CD8-positive tumour infiltrating lymphocytes (p=0.0018), and had longer overall survival in the bevacizumab arm (p=0.0489). Histone H3 subgroups (hemispheric G34R/V and midline K27M) had a worse outcome and were immune cold. Although the experimental arm did not improve survival across the whole cohort, we identify disease subgroups with MAPK activation to harbour an enhanced immune response and derive benefit from the addition of bevacizumab to standard temozolomide/radiotherapy.

CNS-PNET is no longer regarded a single disease but encompassed many distinct molecular entities. After removal of the term from the 2016 WHO classification of CNS tumours, diagnostic and therapeutic uncertainty remains. Through a world-wide collaboration, tumour samples from patients with the “historic” diagnosis of CNS-PNET were re-evaluated by DNA methylation profiling (n=405) and blinded neuropathological panel review (n=256). Clinical data on treatment and outcome were pooled with data on previously published patients. The given numbers represent preliminary data of the ongoing project. The re-evaluation by DNA methylation identified many distinct entities as expected, including high grade glioma (HGG, n=70), embryonal tumors with multilayered rosettes (ETMR, n=57) and CNS-neuroblastoma with FOXR2 alteration (CNS-NB-FOXR2, n=42) as the most frequent molecular diagnostic categories. Poor clinical outcome was confirmed for patients with HGG (5y-PFS 12%/5y-OS 12%, n=24), and ETMR (5y-PFS 12%/5y-OS 18%, n=62), while most patients with CNS-NB-FOXR2 survived (5y-PFS 52%/5y-OS 96%, n=31). Seven of 12 relapses/progressions of CNS-NB-FOXR2 occurred in radiotherapy-naïve patients. Classification into other newly described and less common entities included HGNET-MN1 (n=19), HGNET-BCOR (n=11), and EFT-CIC (n=13). Independent neuropathological review demonstrated that samples of these entities presented as non-embryonal tumours. Furthermore, marked clinical differences exist (HGNET-MN1: 5y-PFS 25%/5y-OS 95%, n=22; HGNET-BCOR: 5y-PFS 0%/5y-OS 44%, n=16; CNS-EFT-CIC: 5y-PFS 40%/5y-OS 60%, n=10). Our results show that implementation of DNA methylation profiling together with histopathological analysis will improve prospective diagnostic accuracy and facilitates the retrospective outcome analysis of treatment protocols used for this variety of biologically distinct entities.

Cyclospora species are socioeconomically important protistan pathogens. Cyclospora cayetanensis is usually transmitted via food or water to a human host via the faecal-oral route and can cause the gastrointestinal disease cyclosporiasis, which can be complicated by extra-intestinal disorders, particularly in immune-compromised people. Although more than 2 million children die each year from diarrhoeal diseases worldwide, it is not known to what extent cyclosporiasis is involved. Few epidemiological data are available on Cyclospora as a water-borne and food-borne pathogen in both underprivileged communities and developed countries. To gain an improved understanding of human cyclosporiasis, this Review describes the background of Cyclospora, summarises salient aspects of the pathogenesis, epidemiology, diagnosis, treatment, and control of cyclosporiasis, and explores what is known about its prevalence and geographical distribution. The findings show that the effect on human health of cyclosporiasis is likely underestimated, and recommendations are made about areas of future research and the prevention and control of this disease within an international collaborative context.

The HERBY trial was a phase II open-label, randomized, multicenter trial evaluating bevacizumab (BEV) in addition to temozolomide/radiotherapy in patients with newly diagnosed non-brainstem high-grade glioma (HGG) between the ages of 3 and 18 years. We carried out comprehensive molecular analysis integrated with pathology, radiology, and immune profiling. In post-hoc subgroup analysis, hypermutator tumors (mismatch repair deficiency and somatic POLE/POLD1 mutations) and those biologically resembling pleomorphic xanthoastrocytoma ([PXA]-like, driven by BRAF_V600E or NF1 mutation) had significantly more CD8+ tumor-infiltrating lymphocytes, and longer survival with the addition of BEV. Histone H3 subgroups (hemispheric G34R/V and midline K27M) had a worse outcome and were immune cold. Future clinical trials will need to take into account the diversity represented by the term ‘‘HGG’’ in the pediatric population.

PurposeBevacizumab (BEV) is approved in more than 60 countries for use in adults with recurrent glioblastoma. We evaluated the addition of BEV to radiotherapy plus temozolomide (RT+TMZ) in pediatric patients with newly diagnosed high-grade glioma (HGG).MethodsThe randomized, parallel group, multicenter, open-label HERBY trial (ClinicalTrials.gov identifier: NCT01390948) enrolled patients age ≥ 3 years to ≤ 18 years with localized, centrally neuropathology-confirmed, nonbrainstem HGG. Eligible patients were randomly assigned to receive RT + TMZ (RT: 1.8 Gy, 5 days per week, and TMZ: 75 mg/m² per day for 6 weeks; 4-week treatment break; then up to 12 3 28-day cycles of TMZ [cycle 1: 150 mg/m² per day, days 1 to 5; cycles 2 to 12: 200 mg/m² per day, days 1 to 5]) with or without BEV (10 mg/kg every 2 weeks). The primary end point was event-free survival (EFS) as assessed by a central radiology review committee that was blinded to treatment. We report findings of EFS at 12 months after the enrollment of the last patient.ResultsOne hundred twenty-one patients were enrolled (RT+TMZ [n = 59]; BEV plus RT+TMZ [n = 62]). Central radiology review committee–assessed median EFS did not differ significantly between treatment groups (RT+TMZ, 11.8 months; 95% CI, 7.9 to 16.4 months; BEV plus RT+TMZ, 8.2 months; 95% CI, 7.8 to 12.7 months; hazard ratio, 1.44; P = .13 [stratified log-rank test]). In the overall survival analysis, the addition of BEV did not reduce the risk of death (hazard ratio, 1.23; 95% CI, 0.72 to 2.09). More patients in the BEV plus RT+TMZ group versus the RT+TMZ group experienced one or more serious adverse events (n = 35 [58%] v n = 27 [48%]), and more patients who received BEV discontinued study treatment as a result of adverse events (n = 13 [22%] v n = 3 [5%]).ConclusionAdding BEV to RT+TMZ did not improve EFS in pediatric patients with newly diagnosed HGG. Our findings were not comparable to those of previous adult trials, which highlights the importance of performing pediatric-specific studies.

Diffuse leptomeningeal glioneuronal tumors (DLGNT) represent rare CNS neoplasms which have been included in the 2016 update of the WHO classification. The wide spectrum of histopathological and radiological features can make this enigmatic tumor entity difficult to diagnose. In recent years, large-scale genomic and epigenomic analyses have afforded insight into key genetic alterations occurring in multiple types of brain tumors and provide unbiased, complementary tools to improve diagnostic accuracy. Through genome-wide DNA methylation screening of > 25,000 tumors, we discovered a molecularly distinct class comprising 30 tumors, mostly diagnosed histologically as DLGNTs. Copy-number profiles derived from the methylation arrays revealed unifying characteristics, including loss of chromosomal arm 1p in all cases. Furthermore, this molecular DLGNT class can be subdivided into two subgroups [DLGNT methylation class (MC)-1 and DLGNT methylation class (MC)-2], with all DLGNT-MC-2 additionally displaying a gain of chromosomal arm 1q. Co-deletion of 1p/19q, commonly seen in IDH-mutant oligodendroglioma, was frequently observed in DLGNT, especially in DLGNT-MC-1 cases. Both subgroups also had recurrent genetic alterations leading to an aberrant MAPK/ERK pathway, with KIAA1549:BRAF fusion being the most frequent event. Other alterations included fusions of NTRK1/2/3 and TRIM33:RAF1, adding up to an MAPK/ERK pathway activation identified in 80% of cases. In the DLGNT-MC-1 group, age at diagnosis was significantly lower (median 5 vs 14 years, p < 0.01) and clinical course less aggressive (5-year OS 100, vs 43% in DLGNT-MC-2). Our study proposes an additional molecular layer to the current histopathological classification of DLGNT, of particular use for cases without typical morphological or radiological characteristics, such as diffuse growth and radiologic leptomeningeal dissemination. Recurrent 1p deletion and MAPK/ERK pathway activation represent diagnostic biomarkers and therapeutic targets, respectively-laying the foundation for future clinical trials with, e.g., MEK inhibitors that may improve the clinical outcome of patients with DLGNT.

Accurate pathological diagnosis is crucial for optimal management of patients with cancer. For the approximately 100 known tumour types of the central nervous system, standardization of the diagnostic process has been shown to be particularly challenging-with substantial inter-observer variability in the histopathological diagnosis of many tumour types. Here we present a comprehensive approach for the DNA methylation-based classification of central nervous system tumours across all entities and age groups, and demonstrate its application in a routine diagnostic setting. We show that the availability of this method may have a substantial impact on diagnostic precision compared to standard methods, resulting in a change of diagnosis in up to 12% of prospective cases. For broader accessibility, we have designed a free online classifier tool, the use of which does not require any additional onsite data processing. Our results provide a blueprint for the generation of machine-learning-based tumour classifiers across other cancer entities, with the potential to fundamentally transform tumour pathology.

Glioblastoma, the most aggressive and malignant form of glioma, appears to be resistant to various chemotherapeutic agents. Hence other approaches have been investigated to target more pathways involved in glioblastoma development and progression. Here we investigate the anticancer effect of Aloe-Emodin (AE), an anthraquinone compound presents in the leaves of Aloe arborescens, on human glioblastoma cell line U87MG. U87MG were treated with various concentrations of AE (20 and 40 μM) for different times (24, 48, and 72 hr). Cell growth was monitored by daily cell count after treatments. Growth analysis showed that AE significantly decrease proliferation of U87MG in a time and dose dependent manner. FACS analysis demonstrates a block of cell cycle in S and G2/M phase. AE probably induced also apoptosis by releasing of apoptosis-inducing factor: PARP and Lamin activation leading to nuclear shrinkage. In addition, exposure of U87MG to AE reduced pAKT phosphorylation. AE inhibition of U87MG growth is a result of more mechanism together. Here we report that AE has a specific growth inhibition on U87MG also in in vivo. The growth of U87MG, subcutaneously injected in nude mice with severe combined immunodeficiency, is inhibited without any appreciable toxic effects on the animals after AE treatment. AE might represent a conceptually new lead antitumor adjuvant drug.

Background: Post-therapy differentiation in medulloblastoma (MB) is a rare event that has been described only in pediatric age. Methods: We describe the long term follow up of a case of medulloblastoma maturation after chemotherapy and radiotherapy in an adult MB patient. Results and Discussion: A 20-year-old patient was partially resected of a MB with ki-67 of 60%. DNA methylation-derived subgroup showed a molecular SHH profile. The patient received cranio-spinal tomotherapy (32.4 Gy in 18 fractions) with a boost on posterior fossa (23.4 Gy in 17 fractions, total dose: 55.8 Gy in 32 fractions). The MRI performed 2 months after revealed a minimal volumetric increase. The patient underwent 2 cycles of Cisplatin - Etoposide chemotherapy. The MRI showed stable disease. The patient underwent second surgery. The specimen showed neuronal cells showing various degrees of maturation from neurocytic to ganglion cells. No embryonal cells were present. Mitoses were absent. The residual lesion showed the post-therapy neuronal maturation of a medulloblastoma. DNA methylation-derived subgrouping confirmed the SHH profile. No other treatments were delivered after the second resection. To date the patient is still alive and free from progression 54 months after primary surgery. Conclusion: After a long term follow up, we showed that tumor maturation in an adult patient with medulloblastoma is characterized by a favorable outcome. Physicians should take into account that tumor maturation may occur and that its recognition is essential to define the prognosis and to manage adult patients.

International audience; Pilocytic astrocytomas represent the most common glioma subtype in young patients and account for 5.4% of all gliomas. They are characterized by alterations in the RAS-MAP kinase pathway, the most frequent being a tandem duplication on chromosome 7q34 involving the BRAF gene, resulting in oncogenic BRAF fusion proteins. BRAF fusion involving the KIAA1549 gene is a hallmark of pilocytic astrocytoma, but it has also been recorded in rare cases of gangliogliomas, 1p/19q co-deleted oligodendroglial tumors, and it is also a common feature of disseminated oligodendroglial-like leptomeningeal neoplasm. In some difficult cases, evidence for KIAA1549-BRAF fusion is of utmost importance for the diagnosis. Moreover, because the KIAA1549-BRAF fusion constitutively activates the MAP kinase pathway, it represents a target for drugs such as MEK inhibitors, and therefore, the detection of this genetic abnormality is highly relevant in the context of clinical trials applying such new approaches. In the present study, we aimed to use the high sensitivity of Droplet Digital PCR (DDPCR™) to predict KIAA1549-BRAF fusion on very small amounts of formalin-fixed paraffin-embedded tissue in routine practice. Therefore, we analyzed a training cohort of 55 pilocytic astrocytomas in which the KIAA1549-BRAF fusion status was known by RNA sequencing used as our gold standard technique. Then, we analyzed a prospective cohort of 40 pilocytic astrocytomas, 27 neuroepithelial tumors remaining difficult to classify (pilocytic astrocytoma versus ganglioglioma or diffuse glioma), 15 dysembryoplastic neuroepithelial tumors, and 18 gangliogliomas. We could demonstrate the usefulness and high accuracy (100% sensitivity and specificity when compared to RNA sequencing) of DDPCR™ to assess the KIAA1549-BRAF fusion from very low amounts of DNA isolated from formalin-fixed paraffin-embedded specimens. BRAF duplication is both necessary and sufficient to predict this fusion in most cases and we propose that this single analysis could be used in routine practice to save time, money, and precious tissue.

Aims Paediatric low-grade gliomas (pLGGs) are a heterogeneous group of brain tumours associated with a high overall survival: however, they are prone to recur and supratentorial lesions are difficult to resect, being associated with high percentage of disease recurrence. Our aim was to shed light on the biology of pLGGs. Methods We performed microRNA profiling on 45 fresh-frozen grade I tumour samples of various histological classes, resected from patients aged ≤16 years. We identified 93 microRNAs specifically dysregulated in tumours as compared to non-neoplastic brain tissue. Pathway analysis of the microRNAs signature revealed PI3K/AKT signalling as one of the centrally enriched oncogenic signalling. To date, activation of the PI3K/AKT pathway in pLGGs has been reported, although activation mechanisms have not been fully investigated yet. Results One of the most markedly down-regulated microRNAs in our supratentorial pLGGs cohort was miR-139-5p, whose targets include the gene encoding the PI3K's (phosphatidylinositol 3-kinase) catalytic unit, PIK3CA. We investigated the role of miR-139-5p in regulating PI3K/AKT signalling by the use of human cell cultures derived from supratentorial pLGGs. MiR-139-5p overexpression inhibited pLGG cell proliferation and decreased the phosphorylation of PI3K target AKT and phosphorylated-p70 S6 kinase (p-p70 S6K), a hallmark of PI3K/AKT/mTORC1 signalling activation. The effect of miR-139-5p was mediated by PI3K inhibition, as suggested by the decrease in proliferation and phosphorylation of AKT and p70 S6K after treatment with the direct PI3K inhibitor LY294002. Conclusions These findings provide the first evidence that down-regulation of miR-139-5p in supratentorial pLGG drives cell proliferation by derepressing PI3K/AKT signalling.

In Europe, since 2005, campylobacteriosis is considered among the most frequent cause of bacterial gastrointestinal infectious disease. The diffusion is cosmopolitan, accounting for an increasing global burden on public health, affecting primarily children under 4 years of age, causing gastroenteric symptoms, but also different extra intestinal pathologies. The infection appears associated also with malnutrition and growth impairment in disadvantaged communities. The consumption of contaminated poultry meat is considered to be the most frequent way of transmission. The progressive diffusion and increase of antibiotic-resistant Campylobacter strains is an issue, particularly in South America and Southeast Asia. Effective regulatory approaches are necessary at national and international level by both sanitary and veterinary authorities to counter such serious zoonosis, in the spirit of One Health.

The use of chemotherapy to manage newly diagnosed low grade glioma (LGG) was first introduced in the 1980s. One randomised trial has studied two- versus four-drug regimens with a duration of 12 months of treatment after resection.Within the European comprehensive treatment strategy for childhood LGG, the International Society of Paediatric Oncology-Low Grade Glioma (SIOP LGG) Committee launched a randomised trial involving 118 institutions and 11 countries to investigate the addition of etoposide (100 mg/mNo differences between the two arms were found in term of survival and radiological response. Response and non-progression rates at 24 weeks for VC and VCE, were 46% versus 41%, and 93% versus 91% respectively; 5-year Progression-Free Survival (PFS) and Overall Survival (OS) were 46% (StDev 3.5) versus 45% (StDev 3.5) and 89% (StDev 2.1) versus 89% (StDev 2.1) respectively. Age and diencephalic syndrome are adverse clinical risk factors for PFS and OS. 5-year OS for patients in early progression at week 24 were 46% (StDev 13.8) and 49% (StDev 16.5) in the two arms, respectively.The addition of etoposide to VC did not improve PFS or OS. High non-progression rates at 24 weeks justify retaining VC as standard first-line therapy. Infants with diencephalic syndrome and early progression need new treatments to be tested. Future trials should use neurological/visual and toxicity outcomes and be designed to discriminate between the impact on disease outcomes of 'duration of therapy' and 'age at stopping therapy'.

Dermanyssus gallinae, also known as the Poultry Red Mite (PRM) is the most debilitating blood-feeding arthropod attacking birds and mammals. It costs circa 230 million euros per year to the European poultry industry and has a prevalence around 80% in many European countries. Since the first paper published 90 years ago on Dermanyssus we have seen over 85 countries publishing on such pest with many papers targeting control methods. As in other pest arthropods, resistance against some pesticides (esp. some of the authorized acaricides) were recorded in some PRM populations. Besides, due to the specific biology of this mite (which spends almost its whole life in the environment at a distance from the host), the efficiency of most sprayed substances is insufficient due to the product not reaching the largest part of the PRM population. Many countries have worked on approaches linked to their national legislation and what products were available and legalised or depending of the research priorities their national funding bodies were interested to support. Such national approach created fragmented data and a lack of potential replication and comparability between countries. Fortunately, since 2014 a new EU initiative from the COST scheme under the COREMI FA1404 Cost Action (www.coremi.eu) has developed a strong network (28 countries and over 300 members) to work together. In recent years the research focus has been towards new control methods including organic/biological approaches, antigen candidates for potential vaccines or understanding the vector capacity, reproduction or detoxification of Dermanyssus gallinae and many more. Such collaborative work has created new knowledge on such pest, increasing co-authorship of scientific publications between the COREMI members. The authors would like to thank the European Cooperation in Science and Technology (COST Action (FA1404 – COREMI)“Improving current understanding and research for sustainable control of the poultry red mite Dermanyssus gallinae” ).

The majority of glioblastomas develop rapidly with a short clinical history (primary glioblastoma IDH wild-type), whereas secondary glioblastomas progress from diffuse astrocytoma or anaplastic astrocytoma. IDH mutations are the genetic hallmark of secondary glioblastomas. Gliosarcomas and giant cell glioblastomas are rare histological glioblastoma variants, which usually develop rapidly. We determined the genetic patterns of 36 gliosarcomas and 19 giant cell glioblastomas. IDH1 and IDH2 mutations were absent in all 36 gliosarcomas and in 18 of 19 giant cell glioblastomas analyzed, indicating that they are histological variants of primary glioblastoma. Furthermore, LOH 10q (88%) and TERT promoter mutations (83%) were frequent in gliosarcomas. Copy number profiling using the 450k methylome array in 5 gliosarcomas revealed CDKN2A homozygous deletion (3 cases), trisomy chromosome 7 (2 cases), and monosomy chromosome 10 (2 cases). Giant cell glioblastomas had LOH 10q in 50% and LOH 19q in 42% of cases. ATRX loss was detected immunohistochemically in 19% of giant cell glioblastomas, but absent in 17 gliosarcomas. These and previous results suggest that gliosarcomas are a variant of, and genetically similar to, primary glioblastomas, except for a lack of EGFR amplification, while giant cell glioblastoma occupies a hybrid position between primary and secondary glioblastomas.

To identify the geographical origins of larvae of Wohlfahrtia magnifica (Diptera: Sarcophagidae) causing myiasis of sheep in Italy, comparative DNA sequence analysis of the mitochondrial cytochrome b gene was performed, based on gene fragments amplified by PCR from genomic DNA isolated from individual specimens. DNA extractions of 19 larvae from Lazio, Molise, Puglia, and Sicilia generated 17 readable sequences homologous to 2 haplotypes, either CB_magn01 or CB_magn02; DNA extracts from 4 adult flies from Calabria (reared from larvae) produced 4 readable sequences belonging to the haplotype CB_magn01. The two haplotypes found represent both the East and West phylogenetic lineages of W. magnifica, which is consistent with the species' arrival from central/southeast Europe (East lineage) and/or from southwest Europe/northwest Africa (West lineage). This is the first report of the sympatric occurrence of the two lineages, which could have resulted from natural or human-assisted dispersal. Polymorphic nuclear loci will have to be characterized in order to explain the origins and lack of mitochondrial haplotype diversity of this pest in Italy, where it poses increasing veterinary problems.

OBJECT Human lactoferrin (HLF) is a natural protein with antitumor activity. The aim of this study was to investigate the effects of HLF alone and in combination with temozolomide (TMZ), a conventional chemotherapeutic, on human glioblastoma (GBM) cells. METHODS The authors cultured fresh human primary cell lines NMD and FN and the continuous cell line U87MG to evaluate proliferation in the presence of HLF alone at different doses (1, 10, and 100 mg/ml, and 1 mg/ml) and in combination with TMZ. In in vivo experiments they assessed tumor size reduction in CD1 nude mice carrying an orthotopic GBM xenograft and orally treated with HLF. RESULTS Lactoferrin causes growth inhibition in the NMD and FN primary cell lines and in the U87MG continuous cell line. This inhibition seemed to be modulated by the downregulation of cyclin D1 and D4. Western blot and fluorescence-activated cell sorting analysis showed inhibition of the cell cycle in G0/G1 and G2 phases. When administered in nude mice, HLF (60 mg/kg/day) decreased tumor size about 30%, as shown in both histological analyses and high-field brain MRI. Administration of HLF with TMZ enhanced the effect of chemotherapy both in vitro and in vivo. CONCLUSIONS This study demonstrated that HLF can inhibit GBM cell growth, suggesting that this nontoxic substance may have a role in potentiating the effect of current TMZ treatment of GBM.

SummaryDevelopmental Hedgehog signaling controls proliferation of cerebellar granule cell precursors (GCPs), and its aberrant activation is a leading cause of medulloblastoma. We show here that Hedgehog promotes polyamine biosynthesis in GCPs by engaging a non-canonical axis leading to the translation of ornithine decarboxylase (ODC). This process is governed by AMPK, which phosphorylates threonine 173 of the zinc finger protein CNBP in response to Hedgehog activation. Phosphorylated CNBP increases its association with Sufu, followed by CNBP stabilization, ODC translation, and polyamine biosynthesis. Notably, CNBP, ODC, and polyamines are elevated in Hedgehog-dependent medulloblastoma, and genetic or pharmacological inhibition of this axis efficiently blocks Hedgehog-dependent proliferation of medulloblastoma cells in vitro and in vivo. Together, these data illustrate an auxiliary mechanism of metabolic control by a morphogenic pathway with relevant implications in development and cancer.

Geographic spread of parasites and pathogens poses a constant risk to animal health and welfare, particularly given that climate change is expected to potentially expand appropriate ranges for many key species. The spread of deleterious organisms via trade routes and human travelling is relatively closely controlled, though represents only one possible means of parasite/pathogen distribution. The transmission via natural parasite/pathogen movement between geographic locales, is far harder to manage. Though the extent of such movement may be limited by the relative inability of many parasites and pathogens to actively migrate, passive movement over long distances may still occur via migratory hosts. This paper reviews the potential role of migrating birds in the transfer of ectoparasites and pathogens between geographic locales, focusing primarily on ticks. Bird-tick-pathogen relationships are considered, and evidence provided of long-range parasite/pathogen transfer from one location to another during bird migration events. As shown in this paper not only many different arthropod species are carried by migrating birds but consequently these pests carry many different pathogens species which can be transmitted to the migrating birds or to other animal species when those arthropods are dropping during these migrations. Data available from the literature are provided highlighting the need to understand better dissemination paths and disease epidemiology.

Giardia duodenalis, Cryptosporidium parvum and Toxoplasma gondii are important parasitic protists linked to water- and food-borne diseases. The accurate detection of these pathogens is central to the diagnosis, tracking, monitoring and surveillance of these protists in humans, animals and the environment. In this study, we established a multiplex real-time PCR (qPCR), coupled to high resolution melting (HRM) analysis, for the specific detection and quantification of each G. duodenalis (assemblage A), C. parvum and T. gondii (Type I). Once optimised, this assay was applied to the testing of samples (n = 232) of treated wastewater and mussels (Mytilus galloprovincialis). Of 119 water samples, 28.6% were test-positive for G. duodenalis, C. parvum and/or both pathogens; of 113 mussel samples, 66.6% were test-positive for G. duodenalis, C. parvum and/or both pathogens, and 13.2% were test-positive for only T. gondii. The specificity of all amplicons produced was verified by direct sequencing. The oo/cysts numbers (per 5 μl of DNA sample) ranged from 10 to 64. The present multiplex assay achieved an efficiency of 100% and a R(2) value of >0.99. Current evidence indicates that this assay provides a promising tool for the simultaneous detection and quantitation of three key protist taxa.

In this paper, results are presented for a number of benchmark cases, proposed at the 2nd International Workshop on High-Order CFD Methods in Cologne, Germany, in 2013. A robust high-order-accurate finite difference method was used that was developed during the last 10–15 years. The robustness stems from the fact that the entire numerical procedure, including various kinds of boundary conditions, can be proven stable. This paper outlines the methodology, and it summarizes results presented at the workshop along with some more data and tests

Eponyms are used almost daily in the clinical practice of dermatology. And yet, information about the person behind the eponyms is difficult to find. Indeed, who is? What is this person’s nationality? Is this person alive or dead? How can one find the paper in which this person first described the disease? Eponyms are used to describe not only disease, but also clinical signs, surgical procedures, staining techniques, pharmacological formulations, and even pieces of equipment. In this article we present the symptoms starting with (O) and other. The symptoms and their synonyms, and those who have described this symptom or phenomenon.

Background/Aim: In celiac disease (CD), there is increased mRNA coding for tissue transglutaminase (tTG) and interferon gamma (IFNα). In seronegative celiac patients, the mucosal immune complexes anti-tTG IgA/tTG are found. We assayed tTG- and IFNα-mRNA in the mucosa of patients with a clinical suspicion of seronegative CD and correlated the values with intraepithelial CD3 lymphocytes (IELs). Materials and Methods: Distal duodenum specimens from 67 patients were retrieved and re-evaluated for immunohistochemically proven CD3 IELs. Five 10 μm sections were used for the extraction and assay of tTG and IFNα coding mRNA levels using reverse transcriptase real-time polymerase chain reaction (RT-PCR). Samples from 15 seropositive CD patients and 15 healthy subjects were used as positive and negative controls. Results were expressed as fold-change. Results: Our series was divided into three groups based on IEL count: >25 (14 patients: group A), 15–25 (26 patients: group B), and 0–15 (27 patients: Group C). tTG-mRNA levels were (mean ± SD): CD = 9.8 ± 2.6; group A = 10.04 ± 4.7; group B = 4.99 ± 2.3; group C = 2.26 ± 0.8, controls = 1.04 ± 0.2 (CD = group A > group B > group C = controls). IFNα-mRNA levels were: CD = 13.4 ± 3.6; group A = 7.28 ± 3.6; group B = 4.45 ± 2.9; group C = 2.06 ± 1.21, controls = 1.04 ± 0.4. Conclusions: Our results suggest that tTG- and IFNγmRNA levels are increased in both seropositive and potential seronegative patients with CD, showing a strong correlation with the CD3 IEL count at stage Marsh 1. An increase in both molecules is found even when IELs are in the range 15–25 (Marsh 0), suggesting the possibility of a "gray zone" inhabited by patients which should be closely followed up in gluten-related disorders.

Item does not contain fulltext Background.: Pineoblastoma is a rare pineal region brain tumor. Treatment strategies have reflected those for other malignant embryonal brain tumors. Patients and Methods.: Original prospective treatment and outcome data from international trial groups were pooled. Cox regression models were developed considering treatment elements as time-dependent covariates. Results.: Data on 135 patients with pineoblastoma aged 0.01-20.7 (median 4.9) years were analyzed. Median observation time was 7.3 years. Favorable prognostic factors were age >/=4 years (hazard ratio [HR] for progression-free survival [PFS] 0.270, P < .001) and administration of radiotherapy (HR for PFS 0.282, P < .001). Metastatic disease (HR for PFS 2.015, P = .006), but not postoperative residual tumor, was associated with unfavorable prognosis. In 57 patients /=4 years, PFS/OS were 72 +/- 7%/73 +/- 7% for patients without metastases, and 50 +/- 10%/55 +/- 10% with metastases. Seventy-three patients received radiotherapy (48 conventionally fractionated CSI, median dose 35.0 [18.0-45.0] Gy, 19 hyperfractionated CSI, 6 local radiotherapy), with (n = 68) or without (n = 6) chemotherapy. The treatment sequence had no impact; application of HDCT had weak impact on survival in older patients. Conclusion.: Survival is poor in young children treated without radiotherapy. In these patients, combination of HDCT and local radiotherapy may warrant further evaluation in the absence of more specific or targeted treatments. CSI combined with chemotherapy is effective for older non-metastatic patients.

Background This prospective study stratified patients by surgical resection (complete = NED vs incomplete = ED) and centrally reviewed histology (World Health Organization [WHO] grade II vs III). Methods WHO grade II/NED patients received focal radiotherapy (RT) up to 59.4 Gy with 1.8 Gy/day. Grade III/NED received 4 courses of VEC (vincristine, etoposide, cyclophosphamide) after RT. ED patients received 1-4 VEC courses, second-look surgery, and 59.4 Gy followed by an 8-Gy boost in 2 fractions on still measurable residue. NED children aged 1-3 years with grade II tumors could receive 6 VEC courses alone. Results From January 2002 to December 2014, one hundred sixty consecutive children entered the protocol (median age, 4.9 y; males, 100). Follow-up was a median of 67 months. An infratentorial origin was identified in 110 cases. After surgery, 110 patients were NED, and 84 had grade III disease. Multiple resections were performed in 46/160 children (28.8%). A boost was given to 24/40 ED patients achieving progression-free survival (PFS) and overall survival (OS) rates of 58.1% and 68.7%, respectively, in this poor prognosis subgroup. For the whole series, 5-year PFS and OS rates were 65.4% and 81.1%, with no toxic deaths. On multivariable analysis, NED status and grade II were favorable for OS, and for PFS grade II remained favorable. Conclusions In a multicenter collaboration, this trial accrued the highest number of patients published so far, and results are comparable to the best single-institution series. The RT boost, when feasible, seemed effective in improving prognosis. Even after multiple procedures, complete resection confirmed its prognostic strength, along with tumor grade. Biological parameters emerging in this series will be the object of future correlatives and reports.

Esame della vicenda che ha condotto a due sentenze della Corte costituzionale di accoglimento di questioni sollevate in sede di giudizio in via incidentale sulla legge di bilancio del Piemonte in ragione del non adeguato finanziamento delle funzioni provinciali

Esame di alcuni profili problematici della legge di revisionen costituzionale sottoposta a referendum ex art. 138 Cost.