Search

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.

Gastroblastoma (GB) is a rare gastric epithelial-mesenchymal neoplasm, first described by Miettinen et al. So far, all reported cases described the tumor in children or young adults, and similarities with other childhood blastomas have been postulated. We report a case of GB in a 43-year-old patient with long follow up and no recurrence up to 100 months after surgery. So far, this is the second case of GB occurring in the adult age >40-year-old. Hence, GB should be considered in the differential diagnosis of microscopically comparable conditions in adults carrying a worse prognosis and different clinical approach.

Epithelioid sarcoma (ES) is a rare mesenchymal malignancy marked by SMARCB1/INI1 deficiency. Retrospective clinical data report on the activity of anthracycline- and gemcitabine-based regimens. EZH2 inhibitors are currently being tested in clinical trials. Since comparisons of these agents are unlikely to be prospectively evaluated in the clinics, we took advantage of an INI1-deficient proximal-type ES patient-derived xenograft (PDX ES-1) to comparatively assess its preclinical antitumor activity. Mice were treated with doxorubicin and ifosfamide, singly or in combination, gemcitabine, and the EZH2 inhibitor EPZ-011989. Comparable antitumor activity (max tumor volume inhibition: ~90%) was caused by gemcitabine, EPZ-011989, and the doxorubicin&ndash, ifosfamide combination. The integration of RNAseq data, generated on tumors obtained from untreated and EPZ-011989-treated mice, and results from functional studies, carried out on the PDX-derived ES-1 cell line, revealed autophagy induction as a possible survival mechanism in residual tumor cells following EPZ-011989 treatment and identified HMGA2 as a main player in this process. Our data support the clinical use of gemcitabine and the doxorubicin&ndash, ifosfamide combination, confirm EZH2 as a therapeutic target in proximal-type ES, and suggest autophagy as a cytoprotective mechanism against EZH2 inhibition.

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: Diffuse Large B-Cell Lymphoma (DLBCL) is an heterogeneous disease: 30-40% of cases have high expression of MYC and BCL2 proteins (Dual Expressor, DE) and 5-10% have chromosomal rearrangements involving MYC, BCL2 and/or BCL6 (Double-/ Triple-Hit, DH/TH). Although the optimal treatment for those high-risk lymphomas remains undefined, DA-EPOCH-R produces durable remission with acceptable toxicity (Dunleauvy K, Lancet 2018). TP53 mutation is an independent marker of poor prognosis in patients (pts) with DLBCL treated with R-CHOP therapy. However, its prognostic value in poor prognosis lymphomas, receiving intensive therapy, has not been investigated yet. Methods: A series of consecutive pts (n=87) with biopsy proven diagnosis of DE DLBCL (MYC expression ≥40% and BCL2 expression ≥ 50% of tumor cells) or DE-Single Hit (DE-SH, i.e., DE-DLBCL with a single rearrangement of either MYC, BCL2 or BCL6 oncogenes) or DE-DH/TH (MYC, BCL2 and/or BCL6 rearrangements obtained by FISH) were treated with 6 cycles of DA-EPOCH-R and central nervous system (CNS) prophylaxis consisting of two courses of high-dose intravenous Methotrexate. Additional eligibility criteria included age ≥18 years and adequate organ functions. Cell of origin (COO) was defined according to Hans algorithm [germinal center B cell like (GCB) and non GCB)]. TP3 mutations were evaluated by next generation sequencing (NGS) based on AmpliseqTM technology or Sanger sequencing and considered positive when a variant allelic frequency ≥10% was detected. Results: Eighty-seven pts were included [n=36 DE only, n=32 DE-SH (n=8 MYC, n=10 BCL2, n=14 BCL6), n=19 DE-DH/TH] with 40 patients (46%) showing a non GCB COO. Pts had a median age of 59 years (range, 24-79 years). Seventy-three pts (84%) had advanced disease and 44 (50%) an high-intermediate/high-risk score as defined by International Prognostic Index (IPI). Only 8 of 87 pts (9%) were consolidated in first clinical remission with autologous stem cell transplantation following DA-EPOCH-R. After a median follow-up of 24 months, 73 are alive (84%) and 14 died [n=12 disease (n=2 CNS disease); n=1 pneumonia; n=1 suicide]. The 2-year PFS and OS were 71% (95%CI, 60-80%) and 76% (95%CI, 61%-85%) for the entire population. For those with IPI 3-5 the PFS and OS were not significant different for DE and DE-SH pts versus DE-DH/TH pts [64% vs 57% p=0.77); 78% vs 57% p=0.12)]. The COO did not influence the outcome for DE only and DE-SH [PFS: 78% vs 71% (p=0.71); 92% vs 86% (p=0.16) for GCB vs non -GCB, respectively]. Fourty-six pts (53%;n=18 DE only, n=18 DE-SH, n=10 DE-DH/TH ) were evaluated for TP53 mutations with 11 pts (24%) carrying a clonal mutation (n=6 in DE, n=3 in DE-SH, n=2 in DE-DH/TH). The 2-year PFS and OS did not significantly change for pts DE and DE-SH TP53 wild type as compared to DE and DE-SH mutated [PFS: 84 % vs 77%, (p=0.45); OS: 87% vs 88%, (p=0.92)]. The two pts DE-DH/TH with TP53 mutation are alive and in complete remission.Conclusions: High risk DLBCL pts treated with DA-EPOCH-R have a favourable outcome independently from high IPI score, DE-SH and DE-DH/TH. Also the presence of TP53 mutations does not negatively affect the outcome of pts treated with this intensive regimen. The efficacy of DA-EPOCH-R in overcoming poor prognostic genetic features in DLBCL should be confirmed in a larger prospective clinical trial. Disclosures Rossi: Daiichi-Sankyo: Consultancy; Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Mundipharma: Honoraria; BMS: Honoraria; Sandoz: Honoraria. Carlo-Stella:Takeda: Other: Travel, accommodations; F. Hoffmann-La Roche Ltd: Honoraria, Other: Travel, accommodations, Research Funding; Rhizen Pharmaceuticals: Research Funding; Celgene: Research Funding; Amgen: Honoraria; AstraZeneca: Honoraria; Janssen Oncology: Honoraria; MSD: Honoraria; BMS: Honoraria; Genenta Science srl: Consultancy; Janssen: Other: Travel, accommodations; Servier: Consultancy, Honoraria, Other: Travel, accommodations; Sanofi: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Other: Travel, accommodations, Research Funding; Novartis: Consultancy, Research Funding; Boehringer Ingelheim: Consultancy. Corradini:AbbVie: Consultancy, Honoraria, Other: Travel Costs; KiowaKirin: Honoraria; Gilead: Honoraria, Other: Travel Costs; Amgen: Honoraria; Celgene: Honoraria, Other: Travel Costs; Daiichi Sankyo: Honoraria; Janssen: Honoraria, Other: Travel Costs; Jazz Pharmaceutics: Honoraria; Kite: Honoraria; Novartis: Honoraria, Other: Travel Costs; Roche: Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Other: Travel Costs; Servier: Honoraria; BMS: Other: Travel Costs.

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

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.