Publications by authors named "Andrea Fontana"

199 Publications

Comparison of the ability of the King's and MiToS staging systems to predict disease progression and survival in amyotrophic lateral sclerosis.

Amyotroph Lateral Scler Frontotemporal Degener 2021 Apr 8:1-9. Epub 2021 Apr 8.

INSERM, University of Limoges, CHU Limoges, IRD, U1094 Tropical Neuroepidemiology, Institute of Epidemiology and Tropical Neurology, GEIST,Limoges, France.

Assessing clinical progression in amyotrophic lateral sclerosis (ALS) remains a challenge. We evaluated the validity and predictive capabilities of the King's and Milano-Torino Staging (MiToS) systems in a cohort of patients with ALS to demonstrate their benefit in clinical practice. A cohort study was performed by including ALS incident cases in a referral center from 2007 to 2016. The staging systems were determined at time of diagnosis and follow-up. The standardized median times to reach each stage were computed. A multi-state model in the framework of the Cox model evaluated the predictive value of measurements. The survival C-statistic was reported as a measure of prediction ability. Overall, 298 incident cases were included. The King's and MiToS systems described a progressive increase in the risk of dying with each elapsed stage. However, a lower resolution for late disease description for the King's system was observed, and late stages overlapped for the MiToS system. Slight variations in the staging systems appeared to improve performance based on validity and prediction abilities: (i) in the King's (-statistic = 0.783), by adding a new stage involving the need for both gastrostomy and NIV: (ii) in the MiToS (-statistic = 0.792), by merging stage 3 and stage 4 into a single stage 3. Both King's and MiToS are valid systems but have certain limitations. Variations in the staging systems may provide a more suitable framework for describing progression and survival. Further research is needed to evaluate the variations in the staging systems.
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http://dx.doi.org/10.1080/21678421.2021.1903506DOI Listing
April 2021

Adaptation and Psychometric Analysis of the Test of Mobile Phone Dependence-Brief Version in Italian Adolescents.

Int J Environ Res Public Health 2021 Mar 5;18(5). Epub 2021 Mar 5.

Department of Dynamic and Clinical Psychology, Faculty of Medicine and Psychology, Sapienza University of Rome, 00185 Rome, Italy.

Since the diffusion of recent models of mobile phones, anyone with an internet connection can communicate continuously and search for information. This raises some questions about the possible consequences of problematic mobile phone use (PMPU) in a complex life phase such as adolescence. Therefore, we performed a psychometric analysis of the brief version of the Test of Mobile Phone Dependence (TMD) in Italy. The sample comprised 575 Italian adolescents aged 11 to 18 years. Data were collected using the TMD-brief, the Personality Inventory for the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) and the Patient-Reported Outcomes Measurement Information System (PROMIS) Sleep Disturbance Short Form. Regarding test dimensionality, the best-fit measurement model included four factors: "Abstinence"; "Abuse and interference with other activities"; "Tolerance"; and "Lack of control" (Satorra-Bentler χ (48) = 185.96, < 0.01; robust root mean square error of approximation (RMSEA) = 0.079 (90% confidence interval (CI): 0.067; 0.091); robust TLI = 0.904; robust comparative fit index (CFI) = 0.930). The Italian version of the TMD-brief was found to have good reliability and psychometric properties, and a four-factorial structure. PMPU predicted significant sleep disturbances and this relationship was moderated by clinical personality traits. Findings from this study support the use of the Italian version of the TMD-brief as a screening tool to investigate PMPU in Italian adolescents.
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http://dx.doi.org/10.3390/ijerph18052612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7967521PMC
March 2021

Comparison of Direct Oral Anticoagulant Use for the Treatment of Non-Valvular Atrial Fibrillation in Pivotal Clinical Trials vs. the Real-World Setting: A Population-Based Study from Southern Italy.

Pharmaceuticals (Basel) 2021 Mar 25;14(4). Epub 2021 Mar 25.

Department of Diagnostic Public Health, University of Verona, 37129 Verona, Italy.

Patients enrolled into pivotal randomized controlled trials (RCTs) may differ substantially from those treated in a real-world (RW) setting, which may result in a different benefit-risk profile. The aim of the study was to assess the external validity of pivotal RCT findings concerning direct oral anticoagulants (DOACs) for the treatment of nonvalvular atrial fibrillation (NVAF) by comparing patients recruited in RCTs to those treated with DOACs registered in a southern Italian local health unit (LHU) in the years 2013-2017. The Palermo LHU claims database was used to describe the baseline characteristics of incident DOAC users (washout > 1 year) with NVAF compared with those of enrolled patients in DOAC pivotal RCTs. In the RW, DOAC treatment discontinuation was calculated during the follow-up and compared with DOAC treatment discontinuation of enrolled patients in DOAC pivotal RCTs. Rates of effectiveness and safety outcomes during the follow-up were calculated in an unmatched and in a simulated RCT population, by matching individual incidental RW and RCT DOAC users (excluding edoxaban users) on age, sex, and CHADS score. Overall, 42,336 and 7092 incident DOAC users with NVAF were identified from pivotal RCTs and from the RW setting, respectively. In RCTs, DOAC use was more common among males (62.6%) compared with an almost equal sex distribution in the RW. RCT patients were younger (mean age ± standard deviation: 70.7 ± 9.2 years) than RW patients (76.0 ± 8.6 years). Compared with RCTs, a higher proportion of RW dabigatran users (30.4% vs. 19.6%) and a lower proportion of RW apixaban (15.9% vs. 25.3%) and rivaroxaban (20.4% vs. 23.7%) users discontinued the treatment during the follow-up (-value < 0.001). The rate of ischemic stroke was lower in RW high-dose dabigatran users (unmatched/-matched population: 0.40-0.11% per year) than in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) population (0.93% per year). Major bleeding rates were lower in RW users than in RCT users. In conclusion, except for dabigatran, a lower proportion of DOAC discontinuers was observed in the real-world than in pivotal RCT settings. This study provides reassurance to practicing physicians that DOAC use appears to be effective in stroke prevention and is likely safer in RW patients than in RCT enrolled patients. These results may be related to a lower burden of comorbidities despite more advanced age in the RW population compared to the pivotal RCT population.
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http://dx.doi.org/10.3390/ph14040290DOI Listing
March 2021

Contextual behavioural plasticity in Italian agile frog () tadpoles exposed to native and alien predator cues.

J Exp Biol 2021 Apr 1. Epub 2021 Apr 1.

Dipartimento di Scienze della Terra e dell'Ambiente, Università di Pavia, I-27100 Pavia, Italy

Predation is a strong driver for the evolution of prey behaviour. To properly assess the actual risk of predation, anuran tadpoles mostly rely on water-borne chemical cues, and their ability to evaluate environmental information is even more crucial when potential predators consist of unknown alien species. Behavioural plasticity, that is the capacity to express changes in behaviour in response to different environmental stimuli, is crucial to cope with predation risk. We explored the defensive behaviour of Italian agile frog () tadpoles when exposed to the chemical cues of two predators' species, one native (dragonfly larvae) and one alien (red swamp crayfish). Firstly, we observed if a sensible life history trait (i.e. hatching time) might be affected by native predatory cues. Secondly, we recorded a suite of behavioural responses (activity level, lateralization and sinuosity) to each cue. For assessing lateralization and sinuosity, we developed a C++ code for the automatic analysis of digitally recorded tadpole tracks. Hatching time seemed not to be affected by the potential risk of predation, while both predator species and diet affected tadpoles' defensive behaviour. Tadpoles responded to predator threat by two main defensive strategies: freezing and "zig-zagging". While the first behaviour had been previously reported, the analysis of individual trajectories pointed out that tadpoles can also increase path complexity, probably to prevent predators from anticipating their location. We also recorded a decrease in lateralization intensity, which suggested that under predation risk tadpoles tend to scrutinize the surrounding environment equally on both sides.
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http://dx.doi.org/10.1242/jeb.240465DOI Listing
April 2021

Investigation of Nasal/Oropharyngeal Microbial Community of COVID-19 Patients by 16S rDNA Sequencing.

Int J Environ Res Public Health 2021 02 23;18(4). Epub 2021 Feb 23.

Gastroenterology Unit Fondazione-IRCCS "Casa Sollievo della Sofferenza" Hospital, 71013 San Giovanni Rotondo, Italy.

Since December 2019, SARS-CoV-2 infection has been still rapidly spreading, resulting in a pandemic, followed by an increasing number of cases in countries throughout the world. The severity of the disease depends on the patient's overall medical condition but no appropriate markers are available to establish the prognosis of the patients. We performed a 16S rRNA gene sequencing, revealing an altered composition of the nasal/oropharyngeal (NOP) microbiota in 21 patients affected by COVID-19, paucisymptomatic or in an Intensive Care Unit (ICU), as compared to 10 controls negative for COVID-19 or eight affected by a different Human Coronavirus (HKU, NL63 and OC43). A significant decrease in Chao1 index was observed when patients affected by COVID-19 (in ICU) were compared to paucisymptomatic. Furthermore, patients who were in ICU, paucisymptomatic or affected by other Coronaviruses all displayed a decrease in the Chao1 index when compared to controls, while Shannon index significantly decreased only in patients under ICU as compared to controls and paucisymptomatic patients. At the phylum level, Deinococcus-Thermus was present only in controls as compared to SARS-CoV-2 patients admitted to ICU, paucisymptomatic or affected by other coronaviruses. Candidatus Saccharibacteria (formerly known as TM7) was strongly increased in negative controls and SARS-CoV-2 paucisymptomatic patients as compared to SARS-CoV-2 ICU patients. Other modifications were observed at a lower taxonomy level. Complete depletion of Bifidobacterium and Clostridium was exclusively observed in ICU SARS-CoV-2 patients, which was the only group characterized by the presence of Salmonella, Scardovia, Serratia and Pectobacteriaceae. In conclusion, our preliminary results showed that nasal/oropharyngeal microbiota profiles of patients affected with SARS-CoV-2 may provide valuable information in order to facilitate the stratification of patients and may open the way to new interventional strategies in order to ameliorate the outcome of the patients.
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http://dx.doi.org/10.3390/ijerph18042174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7926517PMC
February 2021

Pulmonary rehabilitation after COVID-19.

J Bras Pneumol 2021 Feb 24;47(1):e20210034. Epub 2021 Feb 24.

. Laboratório de Pesquisa em Fisioterapia Pulmonar - LFIP - Centro de Ciências da Saúde, Universidade Estadual de Londrina - UEL - Londrina (PR) Brasil.

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http://dx.doi.org/10.36416/1806-3756/e20210034DOI Listing
February 2021

Interobserver agreement of the Paris and simplified classifications of superficial colonic lesions: a Western study.

Endosc Int Open 2021 Mar 19;9(3):E388-E394. Epub 2021 Feb 19.

Fondazione "Casa Sollievo della Sofferenza", IRCCS, Gastroenterology and Endoscopy Units, San Giovanni Rotondo, Foggia, Italy.

The Paris classification of superficial colonic lesions has been widely adopted, but a simplified description that subgroups the shape into pedunculated, sessile/flat and depressed lesions has been proposed recently. The aim of this study was to evaluate the accuracy and inter-rater agreement among 13 Western endoscopists for the two classification systems. Seventy video clips of superficial colonic lesions were classified according to the two classifications, and their size estimated. The interobserver agreement for each classification was assessed using both Cohen k and AC1 statistics. Accuracy was taken as the concordance between the standard morphology definition and that made by participants. Sensitivity analyses investigated agreement between trainees (T) and staff members (SM), simple or mixed lesions, distinct lesion phenotypes, and for laterally spreading tumors (LSTs). Overall, the interobserver agreement for the Paris classification was substantial (κ = 0.61; AC1 = 0.66), with 79.3 % accuracy. Between SM and T, the values were superimposable. For size estimation, the agreement was 0.48 by the κ-value, and 0.50 by AC1. For single or mixed lesions, κ-values were 0.60 and 0.43, respectively; corresponding AC1 values were 0.68 and 0.57. Evaluating the several different polyp subtypes separately, agreement differed significantly when analyzed by the k-statistics (0.08-0.12) or the AC1 statistics (0.59-0.71). Analyses of LSTs provided a κ-value of 0.50 and an AC1 score of 0.62, with 77.6 % accuracy. The simplified classification outperformed the Paris classification: κ = 0.68, AC1 = 0.82, accuracy = 91.6 %. Agreement is often measured with Cohen's κ, but we documented higher levels of agreement when analyzed with the AC1 statistic. The level of agreement was substantial for the Paris classification, and almost perfect for the simplified system.
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http://dx.doi.org/10.1055/a-1352-3437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895665PMC
March 2021

Time-trend evolution and determinants of sex ratio in Amyotrophic Lateral Sclerosis: a dose-response meta-analysis.

J Neurol 2021 Feb 25. Epub 2021 Feb 25.

Unit of Biostatistics, Fondazione IRCCS Casa Sollievo Della Sofferenza, San Giovanni Rotondo, Italy.

Background: A noticeable change of the male-to-female sex ratio (SR) has been observed in Amyotrophic Lateral Sclerosis (ALS) leading to an apparent regression of SR with time (SR close to 1:1).

Objective: To provide a global SR estimate and investigate its relation with respect to population age.

Methods: A systematic review and meta-analysis was conducted including only population-based studies with a high-quality methodology in European ancestral origin population. Male-to-female SR was estimated by three different measures: SR number, SR crude incidence and SR standardized incidence. Standard and dose-response meta-analyses were performed to assess the pooled SR measures (irrespective of population age) and the evolution of the SR measures with respect to population age, respectively. Potential sources of heterogeneity were investigated via meta-regression.

Results: Overall, 3254 articles were retrieved in the literature search. Thirty-nine studies stratified by time periods were included. The overall pooled male-to-female ratio was 1.28 (95% CI 1.23-1.32) for SR number, 1.33 (95% CI 1.29-1.38) for SR crude incidence and 1.35 (95% CI 1.31-1.40) for SR standardized incidence. The SR number with respect to population age reveals a progressive reduction of SR at increasing age, while the SR crude incidence in relation to age displays a U-shaped curve.

Conclusions: The number and the incidence of ALS cases were consistently higher in males than females. Dose-response meta-analysis showed that SR measures change with respect to population age. Further original research is needed to clarify if our findings are reproducible in other populations.
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http://dx.doi.org/10.1007/s00415-021-10464-2DOI Listing
February 2021

Prospective, randomised, multicentre, open-label trial, designed to evaluate the best timing of closure of the temporary ileostomy (early versus late) in patients who underwent rectal cancer resection and with indication for adjuvant chemotherapy: the STOMAD (STOMa closure before or after ADjuvant therapy) randomised controlled trial.

BMJ Open 2021 Feb 19;11(2):e044692. Epub 2021 Feb 19.

Department of Surgery, Humanitas Gradenigo, Torino, Italy.

Introduction: Temporary ileostomy is a valuable aid in reducing the severity of complications related to rectal cancer surgery. However, it is still unclear what is the best timing of its closure in relation to the feasibility of an adjuvant treatment, especially considering patient-reported outcomes and health system costs. The aim of the study is to compare the results of an early versus late closure strategy in patients with indication to adjuvant chemotherapy after resection for rectal cancer.

Methods And Analysis: This is a prospective multicentre randomised trial, sponsored by Rete Oncologica Piemonte e Valle d'Aosta (Oncology Network of Piedmont and Aosta Valley-Italy). Patients undergone to rectal cancer surgery with temporary ileostomy, aged >18 years, without evidence of anastomotic leak and with indication to adjuvant chemotherapy will be enrolled in 28 Network centres. An early closure strategy (between 30 and 40 days from rectal surgery) will be compared with a late one (after the end of adjuvant therapy). Primary endpoint will be the compliance to adjuvant chemotherapy with and without ileostomy. Complications associated with stoma closure as well as quality of life, costs and oncological outcomes will be assessed as secondary endpoints.

Ethics And Dissemination: The trial will engage the Network professional teams in a common effort to improve the treatment of rectal cancer by ensuring the best results in relation to the most correct use of resources. It will take into consideration both the patients' point of view (patient-reported outcome) and the health system perspective (costs analysis). The study has been approved by the Ethical Review Board of Città della Salute e della Scienza Hospital in Turin (Italy). The results of the study will be disseminated by the Network website, medical conferences and peer-reviewed scientific journals.

Trial Registration Number: NCT04372992.
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http://dx.doi.org/10.1136/bmjopen-2020-044692DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7896613PMC
February 2021

Combined analysis of miR-200 family and its significance for breast cancer.

Sci Rep 2021 Feb 3;11(1):2980. Epub 2021 Feb 3.

Laboratorio Di Oncologia, Fondazione IRCCS Casa Sollievo della Sofferenza, Viale Padre Pio, 71013, San Giovanni Rotondo, FG, Italy.

While the molecular functions of miR-200 family have been deeply investigated, a role for these miRNAs as breast cancer biomarkers remains largely unexplored. In the attempt to clarify this, we profiled the miR-200 family members expression in a large cohort of breast cancer cases with a long follow-up (H-CSS cohort) and in TCGA-BRCA cohort. Overall, miR-200 family was found upregulated in breast tumors with respect to normal breast tissues while downregulated in more aggressive breast cancer molecular subtypes (i.e. Luminal B, HER2 and triple negative), consistently with their function as repressors of the epithelial-to-mesenchymal transition (EMT). In particular miR-141-3p was found differentially expressed in breast cancer molecular subtypes in both H-CSS and TCGA-BRCA cohorts, and the combined analysis of all miR-200 family members demonstrated a slight predictive accuracy on H-CSS cancer specific survival at 12 years (survival c-statistic: 0.646; 95%CI 0.538-0.754).
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http://dx.doi.org/10.1038/s41598-021-82286-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859396PMC
February 2021

Progression of cognitive and behavioral disturbances in motor neuron diseases assessed using standard and computer-based batteries.

Amyotroph Lateral Scler Frontotemporal Degener 2021 Jan 19:1-14. Epub 2021 Jan 19.

Neuroimaging Research Unit, Division of Neuroscience, Milan, Italy.

Detecting and monitoring cognitive and behavioral deficits in motor neuron diseases (MND) is critical due to their considerable clinical impact. In this scenario, computer-based batteries may play an important role. In this study, we investigated the progression of cognitive and behavioral deficits in MND patients using both standard and computer-based neuropsychological batteries. : This is a retrospective study on 74 MND patients (52 amyotrophic lateral sclerosis [ALS], 12 primary lateral sclerosis [PLS], and 10 progressive muscular atrophy [PMA]) who were followed up for 12 months and underwent up to three cognitive/behavioral assessments, 6 months apart, including standard and/or computerized based (the Test of Attentional Performance [TAP]) batteries. Behavioral/cognitive changes were investigated over time using generalized linear model for longitudinal data accounting for time and revised-ALS Functional Rating Scale. : Over 12 months, ALS patients showed a global cognitive decline (Mini Mental State Examination) at the standard battery and reduced performance in the alertness, sustained and divided attention, go/nogo, cross-modal and incompatibility TAP tasks. Most of these findings remained significant when ALSFRS-R changes over time were included as covariate in the analyses. ALS patients did not show significant behavioral abnormalities over time. No cognitive and behavioral changes were found in PLS and PMA cases. : Computer-based neuropsychological evaluations are able to identify subtle cognitive changes in ALS, unique to this condition. This study highlights the need of specific, accurate and well-tolerated tools for the monitoring of cognitive deficits in MND.
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http://dx.doi.org/10.1080/21678421.2020.1867179DOI Listing
January 2021

Assessment of Personality Functioning in Adolescence: Development of the Adolescent Personality Structure Questionnaire.

Assessment 2021 Jan 16:1073191120988157. Epub 2021 Jan 16.

Università degli Studi di Milano Bicocca, Milan, Italy.

Adolescence is a crucial period for the development of personality and its dysfunctions. In this regard, it is essential to evaluate the nature and degree of maladaptive personality functioning. However, measures currently available present some limitations, mainly being adaptations from adult's tailored instruments and length. Moreover, no instrument considers the crucial dimensions related to body development and sexuality. This contribution presents data on the Adolescent Personality Structure Questionnaire (APS-Q) development, a self-report measure to capture core aspects of personality functioning in adolescence while being agile and reliable. On two large samples of adolescents (total = 1,664), we investigated the psychometric properties of the APS-Q. We explored its factor structure and construct and incremental validity in the first sample, testing specific associations with existing measures of severity of personality pathology, maladaptive personality traits, and psychological distress. In the second sample, we confirmed its factor structure, assessing gender and age invariance. Overall, our findings support the APS-Q's validity as a reliable and useful measure to assess personality functioning. Moreover, the APS-Q highlighted developmentally vital dimensions such as self-functioning (encompassing mental and bodily changes and considering the dimension of sexuality), interpersonal functioning (discriminating the dimensions of family and peers), and emotion regulation.
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http://dx.doi.org/10.1177/1073191120988157DOI Listing
January 2021

Is positivity for hepatitis C virus antibody predictive of lower risk of death in COVID-19 patients with cirrhosis?

World J Clin Cases 2020 Nov;8(22):5831-5834

Department of Biostatistics, Fondazione IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo 71013, Italy.

Liver injury has been reported in coronavirus disease 2019 (COVID-19) cases but the impact of pre-existing liver damage and related etiology have not been completely elucidated. Our research interests include the potential reciprocal influence of COVID-19 and pre-existing liver damage related to hepatitis C virus (HCV) infection, in particular. To this end, we have evaluated three cohorts of patients admitted at three Italian hospitals during the coronavirus pandemic; these included 332 patients with COVID-19 and 1527 patients with HCV who were from established real-world antiviral treatment study cohorts (sofosbuvir/velpatasvir), with either liver disease (various severities; = 1319) or cirrhosis ( = 208). Among the COVID-19 patients, 10 had cirrhosis (3%), including 7 of metabolic origin and 3 of viral origin. Mortality among the COVID-19 patients was 27.1%, with 70% of those with cirrhosis of metabolic etiology having died. Cirrhosis, older age, low white blood cell count and lymphocyte count being identified as risk predictors of death [odds ratio (OR) = 13.7, 95% confidence interval (CI): 2.59-83.01, = 0.006; OR = 1.05, 95%CI: 1.03-1.08, = 0.0001; OR = 1.09, 95%CI: 1.36-1.16, = 0.001; OR = 0.61, 95%CI: 0.39-0.93, = 0.023, respectively]. In the two cohorts of HCV patients, COVID-19 diagnosis was made in 0.07% of those with liver disease and 1% of those with cirrhosis. Thus, the prevalence of HCV antibodies among COVID-19-infected patients was comparable to that currently reported for the general population in Italy. Amongst the COVID-19 patients, pre-existing metabolic cirrhosis appears to be associated with higher mortality, while HCV antibodies may be suggestive of "protection" against COVID-19.
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http://dx.doi.org/10.12998/wjcc.v8.i22.5831DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716316PMC
November 2020

Early-Onset Diabetes as Risk Factor for Pancreatic Cancer: miRNA Expression Profiling in Plasma Uncovers a Role for miR-20b-5p, miR-29a, and miR-18a-5p in Diabetes of Recent Diagnosis.

Front Oncol 2020 11;10:1567. Epub 2020 Sep 11.

Division of Gastroenterology and Research Laboratory, Fondazione IRCCS Casa Sollievo della Sofferenza, Foggia, Italy.

The high prevalence of early-diabetes in patients with pancreatic cancer (PanC) implies that its recognition could help identify people at high risk of developing PanC. Candidate microRNAs (miRNAs) associated with recent diabetes were screened from our previous miRNA expression profiling on 10 pools of plasma from PanC patients and non-PanC controls, both including also subjects with early- and late-diabetes. The droplet digital PCR (ddPCR) was used to re-test candidate miRNAs in a new independent cohort of 69 subjects (40 PanC, 29 non-PanC) with early- (17 PanC, 13 non-PanC) or late-diabetes (23 PanC, 16 non-PanC), and in 100 non-diabetic healthy subjects (HS). miRNA levels were evaluated for differences between subjects enrolled into the study and for their diagnostic performance, also compared to the CA 19-9 determinations. MiR-20b-5p, miR-29a, and miR-18a-5p were selected from the previous miRNA expression profiling. The ddPCR confirmed the increase of miR-20b-5p and miR-29a levels in PanC with early- compared to those with late-diabetes. Conversely, miR-20b-5p, miR-29a, and miR-18a-5p were over-expressed in both PanC and non-PanC with recent diabetes compared to HS, and each miRNA achieved a similar diagnostic performance in distinguishing either PanC or non-PanC with early-diabetes from HS (miR-20b-5p: AUC = 0.877 vs. AUC = 0.873; miR-29a: AUC = 0.838 vs. AUC = 0.810; miR-18a-5p: AUC = 0.824 vs. AUC = 0.875). Despite miR-20b-5p and miR-29a expressions were also higher both in PanC and non-PanC with late-diabetes with respect to HS, the diagnostic accuracy in PanC with late-diabetes vs. HS reached by each miRNA (miR-20b-5p: AUC = 0.760; miR-29a: AUC = 0.630) was lower than the ones achieved in PanC with early-diabetes vs. HS. Furthermore, miR-20b-5p achieved a higher diagnostic accuracy to discriminate non-PanC with early-diabetes from HS (AUC = 0.868; SP = 81%; PPV = 32.1%) compared to the CA 19-9 (AUC = 0.700; SP = 40.0%; PPV = 15.5%), and the joint (miR-20b-5p and CA 19-9) discrimination ability was higher than the one achieved by the CA 19-9 tested alone (AUC = 0.900, = 0.003). Our data highlighted the association between miR-18a-5p and early-diabetes, and suggested for miR-20b-5p and miR-29 a role in identifying early diabetes in PanC, albeit not as an early manifestation of cancer. MiR-20b-5p as more informative marker than CA 19-9 in distinguishing non-PanC with recent diabetes from HS was also uncovered.
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http://dx.doi.org/10.3389/fonc.2020.01567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7533599PMC
September 2020

PI3K mutations detected in liquid biopsy are associated to reduced sensitivity to CDK4/6 inhibitors in metastatic breast cancer patients.

Pharmacol Res 2021 Jan 10;163:105241. Epub 2020 Oct 10.

Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Italy.

Background: PI3K pathway hyperactivation due to PIK3CA mutations contributes to endocrine resistance, and PIK3CA is one of the most frequently mutated genes in breast cancer (BC), occurring approximately 40 % of HR+, HER2- advanced BC (ABC). Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) have changed the treatment landscape of HR+, HER2- ABC. Putative mechanisms of resistance to CDK4/6i have been identified, but limited data are available on PI3K deregulation. The present study evaluates the impact of PIK3CA mutations on CDK4/6i plus hormone therapy and evaluates potential characteristics that may suggest for a PI3K screening in patients with ABC.

Methods: ABC patients were enrolled, and 12 mL of blood were collected in EDTA tubes at baseline prior to CDK4/6i plus hormone therapy. Plasma was separated and circulating free DNA (cfDNA) was extracted. PIK3CA mutation analysis was performed on a ddPCR. Selected and analyzed mutations included: p.C420R, p.E542 K, p.E545A, p.E545D, p.E545G, p.E545K, p.Q546E, p.Q546R, p.H1047L, p.H1047R, p.H1047Y. Statistical analysis were performed to investigate the predictive power of such mutations and any association with clinical factors.

Results: Thirty patients were enrolled. PIK3CA mutation status at baseline was independently associated with shorter median PFS (7.44 vs 12.9 months, p = 0.01) in subject receiving CDK4/6i plus hormone therapy. PIK3CA mutations were found to be associated to Ki67 expression in primary lesions (p = 0.006). Moreover, the probability to find a PI3K mutation improved considering also the therapeutic management in previous lines of treatment (McFadden's R = 0.415, p = 0.004; AUC of the ROC curve = 0.914).

Conclusion: The findings of this pilot study suggest that the presence of a PI3K mutation in liquid biopsy correlates with a worse PFS in patients with ABC receiving CDK4/6i, and that liquid biopsy is a useful tool to suggests a better tailored pharmacological intervention.
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http://dx.doi.org/10.1016/j.phrs.2020.105241DOI Listing
January 2021

Brain Structural Changes in Focal Dystonia-What About Task Specificity? A Multimodal MRI Study.

Mov Disord 2021 01 26;36(1):196-205. Epub 2020 Sep 26.

Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Background: The neural basis of task specificity in dystonia is still poorly understood. This study investigated gray and white matter (WM) brain alterations in patients with task-specific dystonia (TSD) and non-task-specific dystonia (NTSD).

Methods: Thirty-six patients with TSD (spasmodic dysphonia, writer's cramp), 61 patients with NTSD (blepharospasm, cervical dystonia), and 83 healthy controls underwent 3D T1-weighted and diffusion tensor magnetic resonance imaging (MRI). Whole brain cortical thickness and voxel-based morphometry; volumes of basal ganglia, thalamus, nucleus accumbens, amygdala, and hippocampus; and WM damage were assessed. Analysis of variance models were used to compare MRI measures between groups, adjusting for age and botulinum toxin (BoNT) treatment.

Results: The comparison between focal dystonia patients showed cortical thickness and gray matter (GM) volume differences (ie, decreased in NTSD, increased in TSD) in frontal, parietal, temporal, and occipital cortical regions; basal ganglia; thalamus; hippocampus; and amygdala. Cerebellar atrophy was found in NTSD patients relative to controls. WM damage was more severe and widespread in task-specific relative to NTSD patients. TSD patients receiving BoNT, relative to nontreated patients, had cortical thickening and increased GM volume in frontoparietal, temporal, and occipital regions. NTSD patients experiencing pain showed cortical thickening of areas involved in pain-inhibitory mechanisms.

Conclusions: TSD and NTSD are characterized by opposite alterations of the main cortical and subcortical sensorimotor and cognitive-controlling brain structures, suggesting the possible presence of different pathophysiological and/or compensatory mechanisms underlying the complexity of the two clinical phenotypes of focal dystonia. © 2020 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28304DOI Listing
January 2021

Hsa-miR-155-5p Up-Regulation in Breast Cancer and Its Relevance for Treatment With Poly[ADP-Ribose] Polymerase 1 (PARP-1) Inhibitors.

Front Oncol 2020 12;10:1415. Epub 2020 Aug 12.

Fondazione IRCCS Casa Sollievo Della Sofferenza, Laboratorio di Oncologia, San Giovanni Rotondo, Italy.

miR-155-5p is a well-known oncogenic microRNA, showing frequent overexpression in human malignancies, including breast cancer. Here, we show that high miR-155-5p levels are associated with unfavorable prognostic factors in two independent breast cancer cohorts (CSS cohort, = 283; and TCGA-BRCA dataset, = 1,095). Consistently, miR-155-5p results as differentially expressed in the breast cancer subgroups identified by the surrogate molecular classification in the CSS cohort and the PAM50 classifier in TCGA-BRCA dataset, with the TNBC and -amplified tumors carrying the highest levels. Since the analysis of TCGA-BC dataset also demonstrated a significant association between miR-155-5p levels and the presence of mutations in homologous recombination (HR) genes, we hypothesized that miR-155-5p might affect cell response to the PARP-1 inhibitor Olaparib. As expected, miR-155-5p ectopic overexpression followed by Olaparib administration resulted in a greater reduction of cell viability as compared to Olaparib administration alone, suggesting that miR-155-5p might induce a synthetic lethal effect in cancer cells when coupled with PARP-1-inhibition. Overall, our data point to a role of miR-155-5p in homologous recombination deficiency and suggest miR-155-5p might be useful in predicting response to PARP1 inhibitors in the clinical setting.
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http://dx.doi.org/10.3389/fonc.2020.01415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7435065PMC
August 2020

Traceability of Pediatric Antibiotic Purchasing Pathways in Italy: A Nationwide Real-World Drug Utilization Analysis.

Front Pharmacol 2020 12;11:1232. Epub 2020 Aug 12.

Department of Clinical and Experimental Medicine, University of Campania "L. Vanvitelli", Naples, Italy.

Purpose: The aim of the present study was to describe the purchasing patterns of a set of antibiotics used exclusively in an out-patient pediatric setting in Italy using the Farma360 wholesale drug database (IQVIA Solutions Italy), identifying the proportion of medications which are not captured by Italian National Health Service (NHS) pharmacy claims databases and examining the implications of such findings from a public health and pharmaceutical policy perspective.

Methods: Using a systematic approach, sixty-six antibiotic pediatric formulations were selected for the 5 most commonly used antibiotics in Italy in children and adolescents: amoxicillin in combination with clavulanic acid, amoxicillin, azithromycin, clarithromycin and cefixime. The Farma360 wholesale drug purchasing database was used to identify the yearly proportion of antibiotics not purchased based on NHS reimbursement in primary care from 2015-2017 at the national level. The relationship between product cost and purchase outside the NHS was assessed by a scatterplot. All analyses were stratified by geographic area: Northwest, Northeast, Central and Southern Italy.

Results: The proportion of antibiotics not reimbursed by the NHS increased nationally from 24% in 2015 to 29% in 2017. The antibiotic with the highest proportion of purchases outside the NHS was amoxicillin, with almost two-thirds of all amoxicillin purchases in Southern Italy being made in this way in 2017. The relationship between antibiotic price and antibiotic purchase outside the NHS was almost linear for many geographic areas.

Conclusions: This study showed that a large proportion of antibiotics with a pediatric formulation is purchased outside the NHS drug purchasing pathway, especially in Southern Italy, indicating that it is not possible to fully monitor drug utilization, including appropriateness, for these antibiotics. A better strategy is needed to improve drug utilization monitoring, such as better data collection or data linkage.
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http://dx.doi.org/10.3389/fphar.2020.01232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7435014PMC
August 2020

Exploring the Role of Gut Microbiota in Major Depressive Disorder and in Treatment Resistance to Antidepressants.

Biomedicines 2020 Aug 27;8(9). Epub 2020 Aug 27.

Fondazione IRCCS Casa Sollievo della Sofferenza Hospital, Division of Gastroenterology, 71013 San Giovanni Rotondo, Italy.

Major depressive disorder (MDD) is a common severe psychiatric illness, exhibiting sub-optimal response to existing pharmacological treatments. Although its etiopathogenesis is still not completely understood, recent findings suggest that an altered composition of the gut microbiota might play a role. Here we aimed to explore potential differences in the composition of the gut microbiota between patients with MDD and healthy controls (HC) and to identify possible signatures of treatment response by analyzing two groups of MDD patients characterized as treatment-resistant (TR) or responders (R) to antidepressants. Stool samples were collected from 34 MDD patients (8 TR, 19 R and 7 untreated) and 20 HC. Microbiota was characterized using the 16S metagenomic approach. A penalized logistic regression analysis algorithm was applied to identify bacterial populations that best discriminate the diagnostic groups. Statistically significant differences were identified for the families of and , for the genus , and the species , , and among others. The phyla and the family were more abundant in TR, whereas the phylum was enriched in R patients. Moreover, a number of bacteria only characterized the microbiota of TR patients, and many others were only detected in R. Our results confirm that dysbiosis is a hallmark of MDD and suggest that microbiota of TR patients significantly differs from responders to antidepressants. This finding further supports the relevance of an altered composition of the gut microbiota in the etiopathogenesis of MDD, suggesting a role in response to antidepressants.
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http://dx.doi.org/10.3390/biomedicines8090311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554953PMC
August 2020

Diagnostic accuracy of faecal calprotectin in a symptom-based algorithm for early diagnosis of inflammatory bowel disease adjusting for differential verification bias using a Bayesian approach.

Scand J Gastroenterol 2020 Oct 24;55(10):1176-1184. Epub 2020 Aug 24.

Department of Clinical and Experimental Medicine, Clinical Unit for Chronic Bowel Disorders, University of Messina, Messina, Italy.

Background: Diagnostic delay in IBD is a major problem and diagnosis is frequently arrived when irreversible damage has already occurred. This study evaluated accuracy of faecal calprotectin (fCAL) integrated with diagnostic criteria for early diagnosis of IBD in a primary care setting.

Methods: General practitioners (GPs) were trained to recognize alarm symptoms for IBD classified as major and minor criteria. Fulfilment of one major or at least two minor criteria was followed by free fCAL testing and a visit by an IBD specialist and follow-up over 12 months. All patients with positive fCAL testing, i.e., ≥70 μg/g underwent colonoscopy. The diagnostic accuracy of fCAL was estimated after adjusting for differential-verification bias following a Bayesian approach.

Results: Thirty-four GPs participated in the study and 133 patients were tested for fCAL between July 2016 and August 2017. Positivity of fCAL was seen in 45/133 patients (34%) and a final IBD diagnosis was made in 10/45 (22%). According to the threshold of 70 μg/g, fCAL achieved a sensitivity of 74.8% (95%CI: 39.10-96.01%), a specificity of 70.4% (95%CI: 61.76-78.16%) and an overall diagnostic accuracy of 70.6% (95%CI: 61.04-78.37%). As for prognostic accuracy, despite positive predictive value being low, 21.9% (95%CI: 11.74-35.18%), the negative predictive value was definitely higher: 96.2% (95%CI: 84.96-99.51%).

Conclusions: fCAL with a threshold set at 70 μg/g seems to represent a potentially reliable negative test to be used in primary care settings for patients with symptoms suggestive of IBD.
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http://dx.doi.org/10.1080/00365521.2020.1807599DOI Listing
October 2020

Gender differences in COPD management in a Sicilian general practice setting: a cohort study evaluating the impact of educational interventions.

ERJ Open Res 2020 Jul 17;6(3). Epub 2020 Aug 17.

Dept of Biomedical Sciences, Dentistry and Functional and Morphologic Imaging, University of Messina, Messina, Italy.

Aim: The aim of this study was to measure gender differences among COPD patients' quality of care (QOC) before and after two educational interventions in Southern Italy.

Methods: In this prospective cohort study, COPD patients were identified from primary care electronic medical records (EMRs). Twelve process indicators concerning diagnosis, preventative measures and therapeutic processes were developed as a measure of QOC. Educational interventions consisted of clinical seminars and audits on COPD QOC at baseline, and at 12 and 24 months. QOC indicators were stratified by gender: odds ratios (ORs) (males as reference group) of having a good QOC indicator were calculated at baseline, 12 and 24 months, with 95% confidence intervals (CIs) using hierarchical generalised linear models.

Results: Of 46 326 people registered in the EMRs, 1463 COPD patients (3.1%) were identified, of which 37% were women. QOC indicators reflecting best practice 24 months after the educational programme were generally not different to baseline, often favouring men. On the other hand, the composite global QOC indicator suggested that while a good overall QOC at baseline was significantly higher in men than women (OR: 0.74; 95% CI: 0.57-0.96), it became nonsignificant at 24 months (OR: 0.96; 95% CI: 0.72-1.29).

Conclusions: Specific QOC indicators among COPD patients often favoured men. However, several gender disparities seen at baseline disappeared at 24 months, suggesting that even general educational interventions which do not target gender can improve the gender disparity in QOC.
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http://dx.doi.org/10.1183/23120541.00279-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430144PMC
July 2020

Clinical outcomes of patients with breast cancer relapsing after (neo)adjuvant trastuzumab and receiving trastuzumab rechallenge or lapatinib-based therapy: a multicentre retrospective cohort study.

ESMO Open 2020 08;5(4)

U.O.S.D. Breast Unit, IRCCS Ospedale Policlinico San Martino, Genova, Italy

Background: In the prepertuzumab era, we evaluated the clinical outcomes of patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer who underwent first-line trastuzumab-based or lapatinib-based therapy according to prior exposure to (neo)adjuvant trastuzumab.

Materials And Methods: In this multicentre retrospective cohort study conducted in 14 Italian centres of the Gruppo Italiano Mammella, consecutive patients undergoing first-line trastuzumab or lapatinib-based therapy were included. Analyses were performed according to the type of first-line therapy for metastatic disease (trastuzumab or lapatinib). Dichotomous clinical outcomes were analysed using logistic regression and time-to-event outcomes using Cox proportional hazard models controlling for relevant demographic, clinicopathological and therapy characteristics.

Results: Out of 450 patients included in the study, 416 (92%) received trastuzumab and 34 (7.5%) lapatinib. As compared with the trastuzumab cohort, more patients in the lapatinib cohort had a trastuzumab-free interval <1 month (37% vs 13.9%; p=0.017) and brain metastasis as first site of relapse (38.2% vs 9.4%; p<0.001). Among the 128 patients who relapsed after prior (neo)adjuvant trastuzumab, 101 (78.9%) received first-line trastuzumab and 27 (21.1%) first-line lapatinib. The following outcomes were observed with first-line lapatinib or trastuzumab, respectively: overall response rate 45.5% vs 61.3% (p=0.184), clinical benefit rate 68.2% vs 72.5% (p=0.691), median progression-free survival (PFS) 11.4 vs 12.0 months (p=0.814) and median overall survival (OS) 34.7 vs 48.2 months (p=0.722). In patients with brain metastasis as first site of relapse, median PFS was 12.2 vs 9.9 months (p=0.093) and median OS 33.7 vs 28.5 months (p=0.280), respectively.

Conclusions: In patients with HER2-positive breast cancer relapsing after prior (neo)adjuvant trastuzumab, first-line treatment with trastuzumab or lapatinib was not associated with a significant difference in the clinical outcomes. A non-significant trend favouring the use of lapatinib was observed in patients with brain metastasis as the first site of relapse.
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http://dx.doi.org/10.1136/esmoopen-2020-000719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7437709PMC
August 2020

Progressive brain atrophy and clinical evolution in Parkinson's disease.

Neuroimage Clin 2020 7;28:102374. Epub 2020 Aug 7.

Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy.

Clinical manifestations and evolution are very heterogeneous among individuals with Parkinson's disease (PD). The aims of this study were to investigate the pattern of progressive brain atrophy in PD according to disease stage and to elucidate to what extent cortical thinning and subcortical atrophy are related to clinical motor and non-motor evolution. 154 patients at different PD stages were assessed over time using motor, non-motor and structural MRI evaluations for a maximum of 4 years. Cluster analysis defined clinical subtypes. Cortical thinning and subcortical atrophy were assessed at baseline in patients relative to 60 healthy controls. Longitudinal trends of brain atrophy progression were compared between PD clusters. The contribution of brain atrophy in predicting motor, non-motor, cognitive and mood deterioration was explored. Two main PD clusters were defined: mild (N = 87) and moderate-to-severe (N = 67). Two mild subtypes were further identified: mild motor-predominant (N = 43) and mild-diffuse (N = 44), with the latter group being older and having more severe non-motor and cognitive symptoms. The initial pattern of brain atrophy was more severe in patients with moderate-to-severe PD. Over time, mild-diffuse PD patients had the greatest brain atrophy accumulation in the cortex and the left hippocampus, while less distributed atrophy progression was observed in moderate-to-severe and mild motor-predominant patients. Baseline and 1-year cortical thinning was associated with long-term progression of motor, cognitive, non-motor and mood symptoms. Cortical and subcortical atrophy is accelerated early after the onset of PD and becomes prominent in later stages of disease according to the development of cognitive, non-motor and mood dysfunctions. Structural MRI may be useful for monitoring and predicting disease progression in PD.
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http://dx.doi.org/10.1016/j.nicl.2020.102374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7453060PMC
August 2020

Renal Resistive Index of the Main Renal Arteries and Transmitral Flow in Hypertensive Patients.

Ultrasound Med Biol 2020 Oct 20;46(10):2700-2710. Epub 2020 Jul 20.

Department of Medical Sciences, Division of Nephrology and Dialysis, Casa Sollievo Della Sofferenza, San Giovanni Rotondo, Italy.

In hypertensive patients, diastolic dysfunction is related to increased resistive index (RI) of parenchymal renal arteries. To determine the existence of a link between RI of the main renal arteries (RRI) and diastolic dysfunction, a group of 127 hypertensive patients, with glomerular filtration rates >50 mL/min (mean estimated glomerular filtration rate: 88.6 ± 15.2 mL/min) and no comorbidities, was studied. RRI and transmitral flow were evaluated using the deceleration time (DT) and E/A ratio. A statistically significant correlation between RRI and DT (>240 ms) was noted (p < 0.001). The RRI cutoff that best discriminated patients with DT >240 ms was 0.675. For each unitary increment of 10 mm in DT, the log-transformed RRI significantly increased by a mean of 0.006 point (p < 0.001). This study revealed the importance of the link between RRI and transmitral DT in addition to the renowned significance of the increase in RI as a cardiovascular risk factor in hypertensive patients without comorbidities.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2020.06.017DOI Listing
October 2020

Potential Prognostic Role of Methylation in Non-Small-Cell Lung Cancer.

Cells 2020 06 22;9(6). Epub 2020 Jun 22.

Laboratory of Oncology, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, 71013 Foggia, Italy.

The silencing of (secreted protein acid and rich in cysteine) gene through methylation of its promoter region represents a common event in many solid tumors and it is frequently associated with tumor progression and an aggressive clinical outcome. Anyhow, the data concerning the epigenetic mechanism of deregulation and its prognostic value in lung cancer are still incomplete. We explored the aberrant methylation of and its effects in 4 non-small cell lung cancer (NSCLC) cell lines and 59 NSCLC tissues and correlated the methylation levels with clinical-pathological features and disease outcome of patients. In 3 out of 4 tumor cell lines high methylation levels were observed. An inverse correlation between the epigenetic silencing and SPARC expression was confirmed by 5-Aza-2'-deoxycytidine ((5-Aza-CdR) treatment that also significantly induced a reduction in cell viability, proliferation and tumor cell migration. In tissues, the DNA methylation levels of the gene were significantly lower in paired non-neoplastic lungs (NLs) and normal lungs distant from tumor (NLDTs) than in NSCLCs ( = 0.002 and = 0.0034 respectively). A promoter hypermethylation was detected in 68% of squamous cell carcinoma (SqCCs, 17/25) and 56% of adenocarcinoma (ADCs, 19/34), with SqCC showing the highest levels of methylation. Higher methylation levels were significantly associated with higher mortality risk both in all NSCLCs early stage patients (Hazard Ratio, HR = 1.97; 95% Confidence Interval, CI: 1.32-2.93; = 0.001) and in those with SqCC (HR = 2.96; 95% CI: 1.43-6.12; = 0.003). Promoter methylation of gene should represent an interesting prognostic biomarker in NSCLC, with potential application in the squamous early-stage context. Further research in this setting on larger independent cohorts of lung patients with different histologies and stages of disease are warranted.
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http://dx.doi.org/10.3390/cells9061523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349117PMC
June 2020

Biomethane production from anaerobic co-digestion and steel-making slag: A new waste-to-resource pathway.

Sci Total Environ 2020 Oct 28;738:139764. Epub 2020 May 28.

Centre for Technology in Water and Wastewater, School of Civil and Environmental Engineering, University of Technology Sydney, NSW 2220, Australia; NTT Institute of Hi-Technology, Nguyen Tat Thanh University, Ho Chi Minh City, Viet Nam. Electronic address:

A proof of concept of using steel-making slag to upgrade biogas to biomethane is demonstrated in this study. Biogas is generated from the anaerobic co-digestion of sewage sludge and beverage waste. The CO capture capacity of an alkaline liquor derived from the release of calcium from the steel-making slag is comparable to that of the commercial adsorbent monoethanolamine. Although only 5% of Ca in the steel-making slag was released to the alkaline liquor, 1 ton of steel-making slag could be capable of upgrading 10 m of biogas to over 90% methane content. The results also show that pH can be used as a surrogate parameter to monitor and control biogas upgrading. Further research to improve the release of calcium is essential for the acceleration of the weathering process of steel-making slag for subsequent construction applications.
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http://dx.doi.org/10.1016/j.scitotenv.2020.139764DOI Listing
October 2020

Global epidemiology of Duchenne muscular dystrophy: an updated systematic review and meta-analysis.

Orphanet J Rare Dis 2020 06 5;15(1):141. Epub 2020 Jun 5.

Department of Biomedical and Dental Sciences and Morphofunctional Imaging, G. Martino Hospital/University of Messina, Building G, 1, Via Consolare Valeria, 98125, Messina, Italy.

Background: Duchenne Muscular Dystrophy (DMD) is a rare disorder caused by mutations in the dystrophin gene. A recent systematic review and meta-analysis of global DMD epidemiology is not available. This study aimed to estimate the global overall and birth prevalence of DMD through an updated systematic review of the literature.

Methods: MEDLINE and EMBASE databases were searched for original research articles on the epidemiology of DMD from inception until 1st October 2019. Studies were included if they were original observational research articles written in English, reporting DMD prevalence and/or incidence along with the number of individuals of the underlying population. The quality of the studies was assessed using a STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) checklist adapted for observational studies on rare diseases. To derive the pooled epidemiological prevalence estimates, a meta-analysis was performed using random-effects logistic models for overall and birth prevalence and within two different underlying populations (i.e. all individuals and in males only), separately. Heterogeneity was assessed using Cochran's Q-test along with its derived measure of inconsistency I.

Results: A total of 44 studies reporting the global epidemiology of DMD were included in the systematic review and only 40 were included in the meta-analysis. The pooled global DMD prevalence was 7.1 cases (95% CI: 5.0-10.1) per 100,000 males and 2.8 cases (95% CI: 1.6-4.6) per 100,000 in the general population, while the pooled global DMD birth prevalence was 19.8 (95% CI:16.6-23.6) per 100,000 live male births. A very high between-study heterogeneity was found for each epidemiological outcome and for all underlying populations (I > 90%). The test for funnel plot asymmetry suggested the absence of publication bias. Of the 44 studies included in this systematic review, 36 (81.8%) were assessed as being of medium and 8 (18.2%) of low quality, while no study was assessed as being of high quality.

Conclusions: Generating epidemiological evidence on DMD is fundamental to support public health decision-making. The high heterogeneity and the lack of high quality studies highlights the need to conduct better quality studies on rare diseases.
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http://dx.doi.org/10.1186/s13023-020-01430-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275323PMC
June 2020

Safety profile of immune checkpoint inhibitors: An analysis of the Italian spontaneous reporting system database.

Br J Clin Pharmacol 2021 Feb 9;87(2):527-541. Epub 2020 Jul 9.

Dept. of Biomedical and Dental Sciences and Morpho-functional Imaging, University of Messina, Messina, Italy.

Aims: To provide an overview of immune checkpoint inhibitors (ICIs) safety profile using the Italian spontaneous adverse drug reaction (ADR) reporting system.

Methods: We selected all ADR reports attributed to ipilimumab (CTLA-4 inhibitor), nivolumab, pembrolizumab, atezolizumab (PD-1/PD-L1 inhibitors) from the Italian spontaneous reporting system (2011-2018). Descriptive analyses of reports for ICIs have been conducted. Time to onset of adverse effects was stratified by system organ class. Reporting odds ratio was used as measure of ADR reporting disproportionality. ICI-related ADR reports were compared with 2 reference groups, i.e. all other suspected drugs or all other antineoplastic agents.

Results: Overall, 2217 (0.7%) reports were related to ICIs (nivolumab: 72.2% of those reports; ipilimumab: 14.3%; pembrolizumab: 10.3%; and atezolizumab: 3.5%). ICI-related ADR reports mostly involved males (65%) and median age was 67 (interquartile range 59-73) years. Serious reports accounted for 48.8%. Frequencies of endocrine, general, hepatobiliary, metabolism, musculoskeletal, respiratory disorders, infections and neoplasms were significantly higher for ICIs than for all other drugs (P < .001). Except for infections, similar results emerged through comparison with other anticancer drugs. Colitis, hypophysitis and skin disorders were more frequently reported for anti-CTLA-4 drugs than PD-1/PD-L1 ICIs, and the opposite for musculoskeletal effects, pneumonia, and thyroid dysfunctions. ICIs were disproportionally associated also with less known risks, e.g. ischaemic heart disease, cardiac failure and optic nerve disorders.

Conclusion: The most frequently reported safety issues were probably immune-related adverse events including general, gastrointestinal and respiratory disorders. Potentially emerging safety signals, such as ischaemic heart disease and cardiac failure, requiring further investigation were detected.
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http://dx.doi.org/10.1111/bcp.14413DOI Listing
February 2021

Longitudinal brain connectivity changes and clinical evolution in Parkinson's disease.

Mol Psychiatry 2020 May 14. Epub 2020 May 14.

Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Longitudinal connectivity studies might guide our understanding of the underlying neurodegenerative processes. We report the results of a longitudinal study in patients at different stages of Parkinson's disease (PD), who performed motor and non-motor evaluations and serial resting state (RS) functional MRI (fMRI). Cluster analysis was applied to demographic and clinical data of 146 PD patients to define disease subtypes. Brain network functional alterations were assessed at baseline in PD relative to 60 healthy controls and every year for a maximum of 4 years in PD groups. Progression of brain network changes were compared between patient clusters using RS fMRI. The contribution of network changes in predicting clinical deterioration was explored. Two main PD clusters were identified: mild PD (86 patients) and moderate-to-severe PD (60 patients), with the latter group being older and having earlier onset, longer PD duration, more severe motor, non-motor and cognitive deficits. Within the mild patient cluster, two clinical subtypes were further identified: mild motor-predominant (43) and mild-diffuse (43), with the latter being older and having more frequent non-motor symptoms. Longitudinal functional connectivity changes vary across patients in different disease stages with the coexistence of hypo- and hyper-connectivity in all subtypes. RS fMRI changes were associated with motor, cognitive and non-motor evolution in PD patients. Baseline RS fMRI presaged clinical and cognitive evolution. Our network perspective was able to define trajectories of functional architecture changes according to PD stages and prognosis. RS fMRI may be an early biomarker of PD motor and non-motor progression.
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http://dx.doi.org/10.1038/s41380-020-0770-0DOI Listing
May 2020

Outcomes of vascular resection associated with curative intent hepatectomy for intrahepatic cholangiocarcinoma.

Eur J Surg Oncol 2020 09 19;46(9):1727-1733. Epub 2020 Apr 19.

Department of Surgery, Division of General and Hepatobiliary Surgery, G.B. Rossi University Hospital, University of Verona, Verona, Italy.

Background And Aims: We aimed to investigate the impact of vascular resection (VR) on postoperative outcomes and survival of patients undergoing hepatectomy for intrahepatic cholangiocarcinoma (ICC).

Methods: A retrospective analysis of a multi-institutional series of 270 patients with resected ICC was carried out. Patients were divided into three groups: portal vein VR (PVR), inferior vena cava VR (CVR) and no VR (NVR). Univariate and multivariate analysis were applied to define the impact of VR on postoperative outcomes and survival.

Results: Thirty-one patients (11.5%) underwent VR: 15 (5.6%) to PVR and 16 (5.9%) to CVR. R0 resection rates were 73.6% in NVR, 73.3% of PVR and 68.8% in CVR. The postoperative mortality rate was increased in VR groups: 2.5% in NVR, 6.7% in PVR and 12.5% in CVR. The 5-years overall survival (OS) rates progressively decreased from 38.4% in NVR, to 30.1% in CVR and to 22.2% in PVR, p = 0.030. However, multivariable analysis did not confirm an association between VR and prognosis. The following prognostic factors were identified: size ≥50 mm, patterns of distribution of hepatic nodules (single, satellites or multifocal), lymph-node metastases (N1) and R1 resections. In the VR group the 5-years OS rate in patients without lymph-node metastases undergoing R0 resection (VRR0N0) was 44.4%, while in N1 patients undergoing R1 resection was 20% (p < 0.001).

Conclusion: Vascular resection (PVR and CVR) is associated with higher operative risk, but seems to be justified by the good survival results, especially in patients without other negative prognostic factors (R0N0 resections).
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http://dx.doi.org/10.1016/j.ejso.2020.04.007DOI Listing
September 2020