Cryptic Chromosome Rearrangements in Five Patients, with Normal and/or Abnormal Karyotypes, Associated with Mental Retardation, Autism and/or Epilepsy, Detected by BAC Genome Array-CGH

This report describes the usefulness of the BAC genome array-CGH platform in the detection of cryptic rearrangements. We examined ten patients with normal and/or abnormal karyotypes and dysmorphic features, associated with mental retardation, autism and/or epilepsy. This approach led us to discover further cryptic chromosomal rearrangements, not previously detected by conventional cytogenetic procedures, and allowed us to better delineate genotype/phenotype correlation. Our experience shows the validity of the BAC platform as a reliable method for genome-wide screening of chromosomal aberrations in patient with idiopathic mental retardation and/or in association with autism and epilepsy

Antifungal metabolites produced by <i>Trichoderma viride</i> against <i>Sclerotium rolfsii</i>

In this comunication we report our progress regarding the isolation and characterization of new antifungal metabolites from this strain of T. viride

Distinct Mechanisms Are Responsible for Nrf2-Keap1 Pathway Activation at Different Stages of Rat Hepatocarcinogenesis

Activation of the Nrf2-Keap1 pathway, the main intracellular defense against environmental stress, has been observed in several human cancers, including hepatocellular carcinoma (HCC). Here, we assessed whether distinct mechanisms of activation may be involved at different stages of hepatocarcinogenesis. We adopted an experimental model consisting of treatment with diethylnitrosamine (DENA) followed by a choline-devoid methionine-deficient (CMD) diet for 4 months. The CMD diet was then replaced with a basal diet, and the animals were killed at 6, 10 or 13 months after DENA injection. Nrf2 activation occurred at early steps of hepatocarcinogenesis and persisted throughout the tumorigenic process. WhileNrf2mutations were extremely frequent at early steps (90%), their incidence diminished with the progression to malignancy (25%). Conversely, while p62 was almost undetectable in early nodules, its accumulation occurred in HCCs, suggesting that Nrf2 pathway activation at late stages is mainly due to Keap1 sequestration by p62. We demonstrate that, in a model of hepatocarcinogenesis resembling human non-alcoholic fatty liver disease,Nrf2mutations are the earliest molecular changes responsible for the activation of the Nrf2-Keap1 pathway. The progressive loss of mutations associated with a concomitant p62 accumulation implies that distinct mechanisms are responsible for Nrf2-Keap1 pathway activation at different stages of hepatocarcinogenesis

<i>Angiostrongylus chabaudi</i> Biocca, 1957: a new parasite for domestic cats?

Background Natural infection with a species of Angiostrongylus has been reported only once in wildcats from central Italy by Biocca in 1957. The causative species of this infection was identified as Angiostrongylus chabaudi. Following this report, this parasite had never been found in either wild or domestic cats. Findings The lungs and the pulmonary arteries of an adult female cat (Felis silvestris catus), roadkilled in Sardinia, Italy, were macroscopically examined and dissected under a light microscope for the presence of parasites. A slender nematode was detected and its morphometrical features were consistent with those of A. chabaudi. Morphological data were supplemented by sequencing of the partial cytochrome oxidase c subunit 1 (cox1) gene, as well as the internal transcribed spacer 2 (ITS2) of the rDNA. Nucleotide sequences displayed 99% homology with the ITS2 sequence [GenBank KM216825.1] of a specimen of Angiostrongylus sp. recovered recently from the pulmonary artery of a wildcat in Germany and 91% with cox1 sequence [GenBank GU138118.1] of Angiostrongylus vasorum. Conclusion The results of the present study indicate, for the first time, that A. chabaudi may also infect domestic cats, and thus should be considered in the diagnosis of metastrongyloid species infecting their cardio-pulmonary system.</br

Thyroid hormone inhibits hepatocellular carcinoma progression via induction of differentiation and metabolic reprogramming

The limited therapeutic options available for hepatocellular carcinoma (HCC) make mandatory to find alternative effective treatments for this tumor. Based on the recent finding that systemic or local hypothyroidism is associated with HCC development in humans and rodents, we investigated whether the thyroid hormone triiodothyronine (T3) could inhibit the progression of hepatocellular carcinomas (HCCs)

Long-term home ventilation of children in Italy: A national survey.

BACKGROUND: Improved technology, as well as professional and parental awareness, enable many ventilator-dependent children to live at home. However, the profile of this growing population, the quality and adequacy of home care, and patients' needs still require thorough assessment. OBJECTIVES: To define the characteristics of Italian children receiving long-term home mechanical ventilation (HMV) in Italy. METHODS: A detailed questionnaire was sent to 302 National Health Service hospitals potentially involved in the care of HVM in children (aged <17 years). Information was collected on patient characteristics, type of ventilation, and home respiratory care. RESULTS: A total of 362 HMV children was identified. The prevalence was 4.2 per 100,000 (95% CI: 3.8-4.6), median age was 8 years (interquartile range 4-14), median age at starting mechanical ventilation was 4 years (1-11), and 56% were male. The most frequent diagnostic categories were neuromuscular disorders (49%), lung and upper respiratory tract diseases (18%), hypoxic (ischemic) encephalopathy (13%), and abnormal ventilation control (12%). Medical professionals with nurses (for 62% of children) and physiotherapists (20%) participated in the patients' discharge from hospital, though parents were the primary care giver, and in 47% of cases, the sole care giver. Invasive ventilation was used in 41% and was significantly related to young age, southern regional residence, longer time spent under mechanical ventilation, neuromuscular disorders, or hypoxic (ischemic) encephalopathy. CONCLUSIONS: Care and technical assistance of long-term HMV children need assessment, planning, and resources. A wide variability in pattern of HMV was found throughout Italy. An Italian national ventilation program, as well as a national registry, could be useful in improving the care of these often critically ill children

A Clinical Prognostic Model Based on Machine Learning from the Fondazione Italiana Linfomi (FIL) MCL0208 Phase III Trial

BACKGROUND Multicenter clinical trials are producing growing amounts of clinical data. Machine Learning (ML) might facilitate the discovery of novel tools for prognostication and disease-stratification. Taking advantage of a systematic collection of multiple variables, we developed a model derived from data collected on 300 patients with mantle cell lymphoma (MCL) from the Fondazione Italiana Linfomi-MCL0208 phase III trial (NCT02354313). METHODS We developed a score with a clustering algorithm applied to clinical variables. The candidate score was correlated to overall survival (OS) and validated in two independent data series from the European MCL Network (NCT00209222, NCT00209209); Results: Three groups of patients were significantly discriminated: Low, Intermediate (Int), and High risk (High). Seven discriminants were identified by a feature reduction approach: albumin, Ki-67, lactate dehydrogenase, lymphocytes, platelets, bone marrow infiltration, and B-symptoms. Accordingly, patients in the Int and High groups had shorter OS rates than those in the Low and Int groups, respectively (Int→Low, HR: 3.1, 95% CI: 1.0-9.6; High→Int, HR: 2.3, 95% CI: 1.5-4.7). Based on the 7 markers, we defined the engineered MCL international prognostic index (eMIPI), which was validated and confirmed in two independent cohorts; Conclusions: We developed and validated a ML-based prognostic model for MCL. Even when currently limited to baseline predictors, our approach has high scalability potential

A Clinical Prognostic Model Based on Machine Learning from the Fondazione Italiana Linfomi (FIL) MCL0208 Phase III Trial

SIMPLE SUMMARY: The interest in using Machine-Learning (ML) techniques in clinical research is growing. We applied ML to build up a novel prognostic model from patients affected with Mantle Cell Lymphoma (MCL) enrolled in a phase III open-labeled, randomized clinical trial from the Fondazione Italiana Linfomi (FIL)—MCL0208. This is the first application of ML in a prospective clinical trial on MCL lymphoma. We applied a novel ML pipeline to a large cohort of patients for which several clinical variables have been collected at baseline, and assessed their prognostic value based on overall survival. We validated it on two independent data series provided by European MCL Network. Due to its flexibility, we believe that ML would be of tremendous help in the development of a novel MCL prognostic score aimed at re-defining risk stratification. ABSTRACT: Background: Multicenter clinical trials are producing growing amounts of clinical data. Machine Learning (ML) might facilitate the discovery of novel tools for prognostication and disease-stratification. Taking advantage of a systematic collection of multiple variables, we developed a model derived from data collected on 300 patients with mantle cell lymphoma (MCL) from the Fondazione Italiana Linfomi-MCL0208 phase III trial (NCT02354313). Methods: We developed a score with a clustering algorithm applied to clinical variables. The candidate score was correlated to overall survival (OS) and validated in two independent data series from the European MCL Network (NCT00209222, NCT00209209); Results: Three groups of patients were significantly discriminated: Low, Intermediate (Int), and High risk (High). Seven discriminants were identified by a feature reduction approach: albumin, Ki-67, lactate dehydrogenase, lymphocytes, platelets, bone marrow infiltration, and B-symptoms. Accordingly, patients in the Int and High groups had shorter OS rates than those in the Low and Int groups, respectively (Int→Low, HR: 3.1, 95% CI: 1.0–9.6; High→Int, HR: 2.3, 95% CI: 1.5–4.7). Based on the 7 markers, we defined the engineered MCL international prognostic index (eMIPI), which was validated and confirmed in two independent cohorts; Conclusions: We developed and validated a ML-based prognostic model for MCL. Even when currently limited to baseline predictors, our approach has high scalability potential

MATRix-RICE therapy and autologous haematopoietic stem-cell transplantation in diffuse large B-cell lymphoma with secondary CNS involvement (MARIETTA): an international, single-arm, phase 2 trial.

BACKGROUND Secondary CNS lymphoma is a rare but potentially lethal event in patients with diffuse large B-cell lymphoma. We aimed to assess the activity and safety of an intensive, CNS-directed chemoimmunotherapy consolidated by autologous haematopoietic stem-cell transplantation (HSCT) in patients with secondary CNS lymphoma. METHODS This international, single-arm, phase 2 trial was done in 24 hospitals in Italy, the UK, the Netherlands, and Switzerland. Adults (aged 18-70 years) with histologically diagnosed diffuse large B-cell lymphoma and CNS involvement at the time of primary diagnosis or at relapse and Eastern Cooperative Oncology Group Performance Status of 3 or less were enrolled and received three courses of MATRix (rituximab 375 mg/m2, intravenous infusion, day 0; methotrexate 3·5 g/m2, the first 0·5 g/m2 in 15 min followed by 3 g/m2 in a 3 h intravenous infusion, day 1; cytarabine 2 g/m2 every 12 h, in 1 h intravenous infusions, days 2 and 3; thiotepa 30 mg/m2, 30 min intravenous infusion, day 4) followed by three courses of RICE (rituximab 375 mg/m2, day 1; etoposide 100 mg/m2 per day in 500-1000 mL over a 60 min intravenous infusion, days 1, 2, and 3; ifosfamide 5 g/m2 in 1000 mL in a 24 h intravenous infusion with mesna support, day 2; carboplatin area under the curve of 5 in 500 mL in a 1 h intravenous infusion, day 2) and carmustine-thiotepa and autologous HSCT (carmustine 400 mg/m2 in 500 mL glucose 5% solution in a 1-2 h infusion, day -6; thiotepa 5 mg/kg in saline solution in a 2 h infusion every 12 h, days -5 and -4). The primary endpoint was progression-free survival at 1 year. Overall and complete response rates before autologous HSCT, duration of response, overall survival, and safety were the secondary endpoints. Analyses were in the modified intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02329080. The trial ended after accrual completion; the database lock was Dec 31, 2019. FINDINGS Between March 30, 2015, and Aug 3, 2018, 79 patients were enrolled. 75 patients were assessable. 319 (71%) of the 450 planned courses were delivered. At 1 year from enrolment the primary endpoint was met, 42 patients were progression free (progression-free survival 58%; 95% CI 55-61). 49 patients (65%; 95% CI 54-76) had an objective response after MATRix-RICE, 29 (39%) of whom had a complete response. 37 patients who responded had autologous HSCT. At the end of the programme, 46 patients (61%; 95% CI 51-71) had an objective response, with a median duration of objective response of 26 months (IQR 16-37). At a median follow-up of 29 months (IQR 20-40), 35 patients were progression-free and 33 were alive, with a 2-year overall survival of 46% (95% CI 39-53). Grade 3-4 toxicity was most commonly haematological: neutropenia in 46 (61%) of 75 patients, thrombocytopenia in 45 (60%), and anaemia in 26 (35%). 79 serious adverse events were recorded in 42 (56%) patients; four (5%) of those 79 were lethal due to sepsis caused by Gram-negative bacteria (treatment-related mortality 5%; 95% CI 0·07-9·93). INTERPRETATION MATRix-RICE plus autologous HSCT was active in this population of patients with very poor prognosis, and had an acceptable toxicity profile. FUNDING Stand Up To Cancer Campaign for Cancer Research UK, the Swiss Cancer Research foundation, and the Swiss Cancer League