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Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease, including one-third of cases overexpressing MYC and BCL2 proteins (double expressor lymphoma, DEL) and 5-10% of patients with chromosomal rearrangements of MYC, BCL2 and/or BCL-6 (double/triple-hit lymphomas, DH/TH). TP53 mutations are detected in 20- 25% of DEL. We report the efficacy of dose-adjusted EPOCH and rituximab (DA-EPOCH-R) in a series of 122 consecutive patients, including DEL (n=81, 66%), DEL-MYC (n=9, 7%), DEL-BCL2 (n=13, 11%), or high-grade lymphomas (DH/TH) (n=19, 16%). Central nervous system (CNS) prophylaxis included intravenous methotrexate (n=66), intrathecal chemotherapy (IT) (n=40) or no prophylaxis (n=16). Sixty-seven patients (55%) had highintermediate or high International Prognostic Index (IPI) and 30 (25%) had high CNS-IPI. The 2-year progression-free survival (PFS) and overall survival (OS) for the entire study population were 74% and 84%, respectively. There was a trend for inferior OS for DH/TH (2-year OS: 66%, P=0.058) as compared to all the others. The outcome was significantly better for the IPI 0-2 versus IPI 3-5 (OS: 98% vs. 72%, P=0.002). DA-EPOCH-R did not overcome the negative prognostic value of TP53 mutations: 2-year OS of 62% versus 88% (P=0.036) were observed for mutated as compared to wild-type cases, respectively. Systemic CNS prophylaxis conferred a better 2-year OS (94%) as compared to IT or no prophylaxis (76% and 65%, respectively; P=0.008). DA-EPOCH-R treatment resulted in a favorable outcome in patients with DEL and DEL with single rearrangement, whereas those with multiple genetic alterations such as DEL-DH/TH and TP53 mutated cases still have an inferior outcome.

Introduction: Myeloid malignancies are associated with a number of recurrent and sporadic rearrangements that may be oncogenic by ensuring growth advantage and/or increased survival. t(3;3)(q21;q26) has been recognized as a recurrent abnormality in myelodysplastic syndromes (MDS) with poor prognostic significance. Inversion of chr(11) engendering NUP98-DDX10 chimeric product is sporadic and usually associated with diseases with poor prognosis (therapy-related myeloid neoplasm). To date, these cytogenetic abnormalities have been described as isolated events. Case description: We report the first case of an 80-year-old man with high-risk MDS harboring a translocation t(3,3)(q21q26) jointly with an inv(11)(p15q22) detected by fluorescent in situ hybridization analysis and conventional cytogenetic techniques. Conclusion: A similar pattern of acquisition was never described before in MDS. The coexistence of two independent, high-risk oncogenic, rare events in the same clone suggests that there may be a functional constraint for synergy between the two events, leading to a proliferative advantage and suggests the utility of extended genotyping in myeloid malignancies.

Summary Oral squamous cell carcinoma (OSCC) is the most common oral cancer, and major efforts is being made to identify molecular markers capable to differentiate oral potentially malignant lesions (OPMLs) with indolent course from lesions with aggressive behavior. We undertook a study to evaluate if gain of the human telomerase RNA component (hTERC) gene in OPMLs could indicate lesions at high risk of developing OSCC. The study was performed on 30 OPMLs with long-term follow-up using a dual-color interphase fluorescence in situ hybridization (FISH) for hTERC status. Progression to malignancy was observed in 9 of 10 cases harboring hTERC gain and in 1 of 20 cases retaining a normal copy number of hTERC (P

The Mitochondrial Human Proteome Project aims at understanding the function of the mitochondrial proteome and its crosstalk with the proteome of other organelles. Being able to choose a suitable and validated enrichment protocol of functional mitochondria, based on the specific needs of the downstream proteomics analysis, would greatly help the researchers in the field. Mitochondrial fractions from ten model cell lines were prepared using three enrichment protocols and analyzed on seven different LC-MS/MS platforms. All data were processed using neXtProt as reference database. The data are available for the Human Proteome Project purposes through the ProteomeXchange Consortium with the identifier PXD007053. The processed data sets were analyzed using a suite of R routines to perform a statistical analysis and to retrieve subcellular and submitochondrial localizations. Although the overall number of identified total and mitochondrial proteins was not significantly dependent on the enrichment protocol, specific line to line differences were observed. Moreover, the protein lists were mapped to a network representing the functional mitochondrial proteome, encompassing mitochondrial proteins and their first interactors. More than 80% of the identified proteins resulted in nodes of this network but with a different ability in coisolating mitochondria-associated structures for each enrichment protocol/cell line pair.

The spectrum of corticotroph cell adenomas is very wide. Though rarely, silent corticotroph cell adenomas (SCA) may transform into corticotroph cell adenomas associated with Cushing's disease (CD). The aim of the study was to investigate the role of prohormone convertase 1/3 (PC1/3) in the transformation of SCA into CD. We reviewed the records of 1259 consecutive endoscopic endonasal procedures for pituitary adenomas from 1998 to 2013. Of these, 132 were CD and 44 were SCA. During the follow-up, three patients with SCA showed a clear transformation from SCA into CD and underwent surgery once again to remove the recurrent tumour. The PC1/3 expression was analysed by both immunohistochemistry and quantitative real time-polymerase chain reaction (qRT-PCR) in primary and recurrent tumours. The immunohistochemical PC1/3 expression was negative or weak in the three patients in the initial phase of SCA, while a strong expression was observed in the majority of neoplastic cells in tissue specimens obtained from the same three patients at the time of recurrence as CD. The immunohistochemical PC1/3 expression showed a strict correlation with the PC1/3 levels obtained by qRT-PCR. In 14 cases of SCA with no change of phenotype during the follow-up, the immunohistochemical PC1/3 expression was low and strictly associated with the level of PC1/3 obtained by qRT-PCR both in primary (14/14 cases) and in recurrent tumours (4/4 cases). Our study provides insight into the crucial role of the PC1/3 protein in the transformation of phenotype from SCA to CD.

Background Mutations in HPCA , a gene implicated in calcium signaling in the striatum, have been recently described in recessive dystonia cases previously grouped under the term "DYT2 dystonia". Positive patients reported so far show focal onset during childhood with subsequent generalization and a slowly progressive course to adulthood. Methods 73 patients with isolated dystonia of various distribution, manifesting within 21 years of age, were enrolled in this Italian study and underwent a mutational screening of HPCA gene by means of Sanger sequencing. Results/conclusions Mean age at onset was 10.2 (±5.1) years and mean age at the time of genetic testing was 33 (±14.2) years. Mean disease duration at the time of enrollment was 22.7 (±12.8) years. None of the patients enrolled was found to carry HPCA mutations, rising suspicion that these probably represent a very rare cause of dystonia in childhood-adolescence. Larger studies will help determining the real mutational frequency of this gene also in different ethnic groups.

Introduction ADCY5 mutations have been recently identified as an important cause of early-onset hyperkinetic movement disorders. The phenotypic spectrum associated with mutations in this gene is expanding. However, the ADCY5 mutational frequency in cohorts of paediatric patients with hyperkinetic movement disorders has not been evaluated. Methods We performed a screening of the entire ADCY5 coding sequence in 44 unrelated subjects with genetically undiagnosed childhood-onset hyperkinetic movement disorders, featuring chorea alone or in combination with myoclonus and dystonia. All patients had normal CSF analysis and brain imaging and were regularly followed-up in tertiary centers for paediatric movement disorders. Results We identified five unrelated subjects with ADCY5 mutations (11% of the cohort). Three carried the p. R418W mutation, one the p. R418Q and one the p. R418G mutation. Mutations arose de novo in four cases, while one patient inherited the mutation from his similarly affected father. All patients had delayed motor and/or language milestones with or without axial hypotonia and showed generalized chorea and dystonia, with prominent myoclonic jerks in one case. Episodic exacerbations of the baseline movement disorder were observed in most cases, being the first disease manifestation in two patients. The disease course was variable, from stability to spontaneous improvement during adolescence. Conclusion Mutations in ADCY5 are responsible for a hyperkinetic movement disorder that can be preceded by episodic attacks before the movement disorder becomes persistent and is frequently misdiagnosed as dyskinetic cerebral palsy. A residual degree of neck hypotonia and a myopathy-like facial appearance are frequently observed in patients with ADCY5 mutations., Highlights • ADCY5 mutational frequency in paediatric patients is unknown. • 5/44 (11%) subjects in our cohort carried pathogenic ADCY5 mutations. • Chorea-dystonia, exacerbations and developmental delay are often observed together. • Disease course and clinical features are variable among patients with ADCY5 mutations. • Residual cervical hypotonia and a myopathy-like face are additional diagnostic clues.

Background: Recent scientific reports have shown that older persons treated with antipsychotics for dementia-related behavioural symptoms have increased mortality. However, the impact of these drugs prescribed during hospitalization has rarely been assessed. We aimed to investigate whether antipsychotics are associated with an increased risk of mortality during hospitalization and at 3-month follow-up in elderly inpatients. Methods: We analyzed data gathered during two waves (2010 and 2012) by the REPOSI (Registro Politerapie Società Italiana Medicina Interna). All new prescriptions of antipsychotic drugs during hospitalization, whether maintained or discontinued at discharge, were collected, and logistic regression models were used to analyze their association with in-hospital and 3-month mortality. Covariates were age, sex, the Short Blessed Test (SBT) score, and the Cumulative Illness Rating Scale. Results: Among 2703 patients included in the study, 135 (5%) received new prescriptions for antipsychotic drugs. The most frequently prescribed antipsychotic during hospitalization and eventually maintained at discharge was haloperidol (38% and 36% of cases, respectively). Patients newly prescribed with antipsychotics were older and had a higher Cumulative Illness Rating Scale comorbidity index both at admission and at discharge compared to those who did not receive a prescription. Of those prescribed antipsychotics, 71% had an SBT score ≥10 (indicative of dementia), 12% had an SBT score of 5-9 (indicative of questionable dementia); and 17% had an SBT score

Perineural invasion (PNI) hinders the ability to establish local control of oral squamous cell carcinoma (OSCC). To date, PNI can be evaluated only in surgical specimens and not in preoperative biopsy material, rendering timely therapeutic planning impossible. Insulin-like growth factor-II mRNA binding protein-3 (IMP3) expression appears to be of diagnostic and prognostic utility for many solid tumours, and laminin-5 expression in surgical specimens has been identified as a valid predictor of neural spread of head-and-neck neoplasms. The ability to use preoperative biopsy material to identify patients exhibiting PNI is fundamental for good management of OSCC. We examined a series of 64 consecutive patients treated (primarily via surgery) for OSCC between 2009 and 2014 at the Maxillofacial Surgery Unit, University of Bologna. We evaluated IMP3 and laminin-5 expression in preoperative biopsy material using immunohistochemistry and quantitative reverse transcription polymerase chain reaction. We sought to correlate expression of IMP3 and laminin-5 with PNI evident in surgical specimens. Expression of IMP3 and laminin-5 in preoperative biopsy material appeared to be predictive of PNI in patients with OSCC (P

Purpose Oral squamous cell carcinoma (OSCC) is commonly preceded by oral potentially malignant lesions (OPML). The aim of the present study was to assess, by bisulfite next-generation sequencing (NGS), the methylation status of a list of candidate genes obtained from oral brushings to early detect OPML and OSCC. Material and methods Oral brushing specimens from 11 OSCC, 11 high-grade squamous intraepithelial lesions (HG-SIL), 9 low-grade SIL (LG-SIL), 9 oral lichen planus (OLP), and 8 healthy donors were included in this study. We investigated, by means of bisulfite NGS, the promoter of GP1BB, ZAP70, KIF1A, p16[CDKN2A], CDH1, miR137, and miR375. Statistical significance between lesions and a pool of healthy donors were evaluated with the Mann–Whitney U test. Results ZAP70 was found to be hypermethylated in 100% of OSCC and HG-SIL and in 28.6% of LG-SIL. GP1BB hypomethylation was detected in 90.9% OSCC and HG-SIL and in 37.5% of LG-SIL. MiR137 was hypermethylated in 100% of OLP, 44.4% of OSCC, 40% HG-SIL, and 25% LG-SIL. KIF1A hypermethylation was found to be associated with TP53 mutations ( p Conclusion In the present preliminary cohort of patients, DNA methylation analysis of GP1BB and ZAP70 seems to be a promising noninvasive tool for early detection of OSCC and HG SIL from oral brushing specimens.

Male breast cancer (MBC) is an uncommon disease whose molecular profile is not well known. X chromosome gain has been described as a marker of aggressive behavior in female breast cancer. The aim of this study is to investigate the role of the X chromosome in male breast cancer. Twenty cases of male breast invasive ductal carcinoma were retrieved and compared with 10 cases of gynecomastia. Cases were tested by fluorescence in situ hybridization to assess a cytogenetic profile for the X chromosome. The X chromosome status was compared with histopathologic features and stage at presentation. All MBC cases harbored an X chromosome gain (100%) in a variable percentage of neoplastic cells, ranging from 31% to 85% (mean, 59%). On the contrary, all cases of gynecomastia showed wild X chromosome asset. The patients' age at surgery and tumor grading showed a statistically significant correlation (P = .0188-.04), with the percentages of neoplastic cells showing an X chromosome gain. These data suggest that this X chromosome gain plays a role in the neoplastic transformation of male breast epithelial cells.

Introduction Mutations in GNAL have been associated with adult-onset cranio-cervical dystonia, but a limited number of cases have been reported so far and the clinical spectrum associated with this gene still needs to be fully characterized. Methods We identified an Italian family with adult-onset, dominantly-inherited dystonia whose members presented with different combinations of dystonia affecting the cervical, oro-mandibular and laryngeal regions associated with prominent tremor in some cases. Pure asymmetric upper limb dystonic tremor was present in one of the members and jerky cervical dystonia was also observed. A dedicate dystonia gene panel (Illumina) was used to screen for dystonia-associated genes and Sanger sequencing was performed to confirm results obtained and to perform segregation analysis. Results A novel single-base mutation in GNAL exon 9 (c.628G>A; p.Asp210Asn) leading to an aminoacidic substitution was identified and confirmed by Sanger sequencing. In silico prediction programmes as well as segregation analysis confirmed its pathogenicity. Clinically, no generalization of dystonia was observed after onset and DBS lead to an excellent motor outcome in two cases. Conclusion We report a novel GNAL mutation and expand the clinical spectrum associated with mutations in this gene to comprise pure asymmetric dystonic tremor and a jerky cervical phenotype partially mimicking DYT11 positive cases.

The structure of the telomeres of four aphid species (Acyrthosiphon pisum, Megoura viciae, Myzus persicae and Rhopalosiphum padi) was evaluated by Southern blotting and fluorescent in situ hybridization, revealing that each chromosomal end consists of a (TTAGG) n repeat. The presence of a telomerase coding gene has been verified successively in the A. pisum genome, revealing that aphid telomerase shares sequence identity ranging from 12% to 18% with invertebrate and vertebrate homologues, and possesses the two main domains involved in telomerase activity. Interestingly, telomerase expression has been verified in different somatic tissues suggesting that, in aphids, telomerase activity is not as restricted as in human cells. The study of telomeres in a M. persicae strain with a variable chromosome number showed that aphid telomerase can initiate the de novo synthesis of telomere sequences at internal breakpoints, resulting in the stabilization of chromosomal fragments.