Publications by authors named "Dario Consonni"

333 Publications

Professor Pietro (Pier) Alberto Bertazzi (1945-2021).

Occup Environ Med 2021 Oct 29. Epub 2021 Oct 29.

Epidemiology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

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http://dx.doi.org/10.1136/oemed-2021-108032DOI Listing
October 2021

Burden of Mortality from Asbestos-Related Diseases in Italy.

Int J Environ Res Public Health 2021 09 23;18(19). Epub 2021 Sep 23.

Department of Occupational and Environmental Medicine, Epidemiology and Hygiene, Istituto Nazionale per l'Assicurazione Contro gli Infortuni sul Lavoro, 00100 Roma, Italy.

Asbestos is one of the major worldwide occupational carcinogens. The global burden of asbestos-related diseases (ARDs) was estimated around 231,000 cases/year. Italy was one of the main European asbestos producers until the 1992 ban. The WHO recommended national programs, including epidemiological surveillance, to eliminate ARDs. The present paper shows the estimate of the burden of mortality from ARDs in Italy, established for the first time. National standardized rates of mortality from mesothelioma and asbestosis and their temporal trends, based on the National Institute of Statistics database, were computed. Deaths from lung cancer attributable to asbestos exposure were estimated using population-based case-control studies. Asbestos-related lung and ovarian cancer deaths attributable to occupational exposure were estimated, considering the Italian occupational cohort studies. In the 2010-2016 period, 4400 deaths/year attributable to asbestos were estimated: 1515 from mesothelioma, 58 from asbestosis, 2830 from lung and 16 from ovarian cancers. The estimates based on occupational cohorts showed that each year 271 deaths from mesothelioma, 302 from lung cancer and 16 from ovarian cancer were attributable to occupational asbestos exposure in industrial sectors with high asbestos levels. The important health impact of asbestos in Italy, 10-25 years after the ban, was highlighted. These results suggest the need for appropriate interventions in terms of prevention, health care and social security at the local level and could contribute to the global estimate of ARDs.
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http://dx.doi.org/10.3390/ijerph181910012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8508095PMC
September 2021

Evans syndrome in adults: an observational multicentre study.

Blood Adv 2021 Sep 30. Epub 2021 Sep 30.

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Evans syndrome (ES) is a rare condition, defined as the presence of two autoimmune cytopenias, more frequently autoimmune hemolytic anemia and immune thrombocytopenia, and rarely autoimmune neutropenia. ES can be classified as primary or secondary to various conditions, including lymphoproliferative disorders, other systemic autoimmune diseases, and primary immunodeficiencies, particularly in children. In adult ES, little is known about clinical features, disease associations and outcome. In this retrospective international study, we analyzed 116 adult patients followed at 13 European tertiary centers, focusing on treatment requirement, occurrence of complications and death. ES was secondary to or associated with an underlying condition in 24 cases (21%), mainly other autoimmune diseases and hematologic neoplasms. Bleeding occurred in 42% of subjects, mainly low grade and at ITP onset. Almost all patients received first line treatment (steroids+/-IVIG), and 23% needed early additional therapy for primary refractoriness. Further therapy lines included rituximab, splenectomy, immunosuppressants, thrombopoietin receptor agonists, and others, with response rates greater than 80%. However, a remarkable number of relapses occurred, requiring ≥3 therapy lines in 54% of cases. Infections and thrombotic complications occurred in 33% and 21% of subjects, respectively, mainly grade ≥3, and correlated with the number of therapy lines. Besides age, other factors negatively impacting on survival were severe anemia at onset and occurrence of relapse, infections and thrombosis. These data show that adult ES is often severe and marked by a relapsing clinical course and potentially fatal complications, pinpointing the need for high clinical awareness, prompt therapy, and anti-infectious/anti-thrombotic prophylaxis.
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http://dx.doi.org/10.1182/bloodadvances.2021005610DOI Listing
September 2021

Right ventricular outflow tract abnormalities in monochorionic twin pregnancies without twin-to-twin transfusion syndrome: Prenatal course and postnatal long-term outcomes.

Prenat Diagn 2021 Nov 5;41(12):1510-1517. Epub 2021 Oct 5.

Department of Women, Mother and Newborn, Vittore Buzzi Children's Hospital, University of Milan, Milan, Italy.

Objectives: Right ventricular outflow tract abnormalities (RVOTA) have been mostly reported in recipient twins (RT) of monochorionic/diamniotic (MC/DA) twin pregnancies with twin-to-twin transfusion syndrome (TTTS). Aim of the study was to describe RVOTA detected in MC/DA pregnancies without TTTS.

Methods: Cases of RVOTA were retrieved from our database among all MC/DA pregnancies without TTTS from 2009 to 2018.

Results: Out of 891 MC/DA twin pregnancies without TTTS, 14 (1.6%) were associated with RVOTA: 10 pulmonary stenosis (PS), one steno-insufficiency, one insufficiency and two atresia (PA). In 93% of cases (13/14), pregnancy was complicated either by amniotic fluid discrepancy (AFD) or by TAPS or mostly by selective fetal growth restriction (sFGR) (11/13: 85%), involving predominantly (10/11: 91%) the large twin, with high incidence (9/11: 82%) of sFGR and AFD coexistence. Eight out of 14 (57%) survived after the perinatal period (7 PS, 1 PA). Five (62%) underwent pulmonary balloon valvuloplasty, whereas 3 children still showed persistent mild PS at cardiac follow up after 1 year of life.

Conclusions: RVOTA can occur in MC/DA pregnancies without TTTS, particularly when other complications coexist. In complicated cases specialized fetal echocardiographic evaluation is recommended during pregnancy; RVOTA cases should be delivered in a tertiary level center, where cardiologists are available.
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http://dx.doi.org/10.1002/pd.6052DOI Listing
November 2021

Increased Risk of Urticaria/Angioedema after BNT162b2 mRNA COVID-19 Vaccine in Health Care Workers Taking ACE Inhibitors.

Vaccines (Basel) 2021 Sep 11;9(9). Epub 2021 Sep 11.

Infectious Diseases Unit, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy.

Urticarial eruptions and angioedema are the most common cutaneous reactions in patients undergoing mRNA COVID-19 vaccinations. The vasoactive peptide bradykinin has long been known to be involved in angioedema and recently also in urticaria. Bradykinin is mainly catabolized by angiotensin-converting enzyme (ACE), which is inhibited by ACE inhibitors, a commonly employed class of antihypertensive drugs. We evaluated the risk of developing urticaria/angioedema after inoculation with the BNT162b2 mRNA COVID-19 vaccine in a population of 3586 health care workers. The influences of ACE inhibitors and selected potential confounding variables (sex, age, previous SARS-CoV-2 infection, and allergy history) were evaluated by fitting univariate and multivariable Poisson regression models. The overall cumulative incidence of urticaria/angioedema was 1.8% (65 out of 3586; 95% CI: 1.4-2.3%). Symptoms were mild, and no subject consulted a physician. Subjects taking ACE inhibitors had an adjusted three-fold increased risk of urticaria/angioedema (RR 2.98, 95% CI: 1.12-7.96). When we restricted the analysis to those aged 50 years or more, the adjusted RR was 3.98 (95% CI: 1.44-11.0). In conclusion, our data indicate that subjects taking ACE inhibitors have an increased risk of urticaria/angioedema after vaccination with the BNT162b2 mRNA COVID-19 vaccine. Symptoms are mild and self-limited; however, they should be considered to adequately advise subjects undergoing vaccination.
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http://dx.doi.org/10.3390/vaccines9091011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8473401PMC
September 2021

Development and Preliminary Validation of an Electromyography-Scoring Protocol for the Assessment and Grading of Muscle Involvement in Patients With Juvenile Idiopathic Inflammatory Myopathies.

Pediatr Neurol 2021 Nov 6;124:6-10. Epub 2021 Aug 6.

Pediatric Rheumatology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Introduction: We performed a pilot study in order to investigate the feasibility of an electromyography (EMG)-scoring protocol for the assessment of disease activity in juvenile idiopathic inflammatory myopathies (JIIM).

Methods: Children with JIIM followed up in a tertiary-level care center underwent standardized clinical, laboratory, and EMG assessment. An EMG-scoring protocol was devised by a consensus panel including a pediatric neurophysiologist and two pediatric rheumatologists, based on a combined score obtained as the sum of (1) the presence of denervation signs (fibrillation potentials) and (2) motor unit remodeling (mixed pattern of short- and long-duration motor unit action potentials). The EMG-scoring protocol was then validated following the Outcome Measures in Rheumatoid Arthritis Clinical Trials filter for outcome measures in rheumatology and the consensus-based standards for the selection of health measurement instruments methodology.

Results: Thirteen children (77% females) were included in the study, with a median age of 10 years (interquartile range: 7-17 years) and median disease duration of 11.8 months (interquartile range: 2.1-44.5). A total of 39 EMG examinations were evaluated. A strong positive association between a standardized tool for muscle strength assessment and the combined score was observed. No significant associations were found with both creatine kinase and erythrocyte sedimentation rate levels.

Discussion: Our EMG-scoring protocol is the first standardized and reproducible tool for the neurophysiologic evaluation and grading of muscle involvement in patients with JIIM and could provide relevant additional information in the assessment and follow-up of these rare conditions.
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http://dx.doi.org/10.1016/j.pediatrneurol.2021.07.017DOI Listing
November 2021

Genomic and evolutionary classification of lung cancer in never smokers.

Nat Genet 2021 09 6;53(9):1348-1359. Epub 2021 Sep 6.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.

Lung cancer in never smokers (LCINS) is a common cause of cancer mortality but its genomic landscape is poorly characterized. Here high-coverage whole-genome sequencing of 232 LCINS showed 3 subtypes defined by copy number aberrations. The dominant subtype (piano), which is rare in lung cancer in smokers, features somatic UBA1 mutations, germline AR variants and stem cell-like properties, including low mutational burden, high intratumor heterogeneity, long telomeres, frequent KRAS mutations and slow growth, as suggested by the occurrence of cancer drivers' progenitor cells many years before tumor diagnosis. The other subtypes are characterized by specific amplifications and EGFR mutations (mezzo-forte) and whole-genome doubling (forte). No strong tobacco smoking signatures were detected, even in cases with exposure to secondhand tobacco smoke. Genes within the receptor tyrosine kinase-Ras pathway had distinct impacts on survival; five genomic alterations independently doubled mortality. These findings create avenues for personalized treatment in LCINS.
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http://dx.doi.org/10.1038/s41588-021-00920-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8432745PMC
September 2021

Nasopharyngeal Testing among Healthcare Workers (HCWs) of a Large University Hospital in Milan, Italy during Two Epidemic Waves of COVID-19.

Int J Environ Res Public Health 2021 08 19;18(16). Epub 2021 Aug 19.

Infectious Diseases Unit, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy.

Background: since October 2020, a second SARS-CoV-2 epidemic wave has hit Italy. We investigate the frequency of positive nasopharyngeal swabs among HCWs during the two waves and the association with occupation and demographic characteristics.

Methods: this is a retrospective, observational study conducted in a large university hospital in Milan, Northern Italy. We defined two epidemic waves: 1st (February 2020-July 2020) and 2nd (August 2020-January 2021). Occupational and demographic characteristics of HCWs who underwent nasopharyngeal swabs for SARS-CoV-2 were collected.

Results: in the 1st wave, 242 positive subjects (7.2%) were found among 3378 HCWs, whereas in the 2nd wave, the positive subjects were 545 out of 4465 (12.2%). In both epidemic waves positive NPSs were more frequent among HCWs with health-related tasks and lower among students ( < 0.001). However, in the 2nd wave, workers engaged in non-health-related tasks had a peak of 20.7% positivity. Among 160 positive HCWs in the 1st wave who were tested again in the 2nd wave, the rate of reinfection based on SARS-CoV2 RNA cycle quantification value was 0.6%.

Conclusions: during the 2nd epidemic wave, we confirmed a significant impact of COVID-19 among HCWs. The rise of infection rate among HCWs seems to reflect the increasing spread of SARS-CoV-2 among the overall population.
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http://dx.doi.org/10.3390/ijerph18168748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8392643PMC
August 2021

Long- and Short-Term Exposures to PM Can Shorten Telomere Length in Individuals Affected by Overweight and Obesity.

Life (Basel) 2021 Aug 10;11(8). Epub 2021 Aug 10.

Department of Clinical Sciences and Community Health, University of Milan, 20138 Milan, Italy.

Reduced telomere length (TL) has been associated with increased risk of age-related diseases, most likely through oxidative stress and inflammation, which have also been claimed as mechanisms underlying health effects of air pollution exposure. We aimed to verify whether exposure to particulate matter with diameter ≤10 µm (PM) affects TL. We recruited 1792 participants with overweight/obesity in Milan (Italy) in 2010-2015 who completed a structured questionnaire on sociodemographic data, gave a blood sample for TL measurement by real-time PCR, and were assigned air pollution and meteorological data of their residential address. In multivariate mixed-effects linear models (with a random intercept on PCR plate), we observed a -0.51% change in TL (95% confidence interval (CI): -0.98; -0.05)) per 10 µg/m increase in PM at the day of recruitment. A similar decreasing trend in TL was observed up to two weeks before withdrawal, with percentage changes as low as -1.53% (average exposure of the 12 days before recruitment). Mean annual exposure to PM was associated with -2.57% TL reduction (95%CI: -5.06; -0.08). By showing consistent associations between short- and long-term PM exposures and reduced TL, our findings shed light on the potential mechanisms responsible for the excess of age-related diseases associated with air pollution exposure.
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http://dx.doi.org/10.3390/life11080808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8400348PMC
August 2021

Clinical Implications of Inter- and Intra-Tumor Heterogeneity of Immune Cell Markers in Lung Cancer.

J Natl Cancer Inst 2021 Aug 17. Epub 2021 Aug 17.

Integrative Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, MD, USA.

Background: Immune cell transcriptome signatures have been widely used to study the lung tumor microenvironment (TME). However, it is unclear to what extent the immune cell composition in the lung TME varies across histological and molecular subtypes (inter-tumor heterogeneity or Inter-TH) and within tumors (intratumor heterogeneity or ITH), and whether ITH has any prognostic relevance.

Methods: Using RNA sequencing in 269 tumor samples from 160 lung cancer patients we quantified the Inter-TH of immune gene expression and immune cell abundance and evaluated the association of median immune cell abundance with clinical/pathological features and overall survival. In 39 tumors with 132 multi-region samples, we also analyzed the ITH of immune cell abundance in relation to overall survival using a variance-weighted multivariate Cox model not biased by the number of samples per tumor.

Results: Substantial Inter-TH of 14 immune cell types was observed even within the same histological and molecular subtypes, but early-stage tumors had higher lymphocyte infiltration across all tumor types. In multi-region samples, an unbiased estimate of low ITH of overall immune cell composition (hazard ratio [HR] = 0.40, 95% confidence interval [CI] = 0.21 to 0.78; P = .007), dendritic cells (HR = 0.24, 95% CI = 0.096 to 0.58; P = .002) and macrophages (HR = 0.50, 95% CI = 0.30 to 0.84; P = .009) was strongly associated with poor survival. The ITH of three markers, including CD163 and CD68 (macrophages) and CCL13 (dendritic cells), was enough to characterize the ITH of the corresponding immune cell abundances and its association with overall survival.

Conclusion: This study suggests that lack of immune cell diversity may facilitate tumor evasion and progression. ITH inferred from CCL13, CD163 and CD68 could be used as a prognostic tool in clinical practice.
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http://dx.doi.org/10.1093/jnci/djab157DOI Listing
August 2021

Reply.

J Pediatr 2021 11 3;238:345. Epub 2021 Aug 3.

Center for HUS Prevention Control and Management at the Laboratory of Microbiology, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milano, Italy.

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http://dx.doi.org/10.1016/j.jpeds.2021.07.061DOI Listing
November 2021

Pleural mesothelioma in a circus worker.

J Occup Health 2021 Jan;63(1):e12250

Occupational Health Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Objectives: To describe an unusual occupational asbestos exposure in a patient with mesothelioma.

Methods: Since 2000, the Lombardy Mesothelioma Registry (LMR) collects cases of malignant mesothelioma (MM) occurring among people residing in the Lombardy Region, North-West Italy, with a population of 10 million inhabitants. For each case, clinical records and asbestos exposure are collected. Each case is then classified in agreement with the guidelines of the National Mesothelioma Registry.

Results: We identified a male (86 years old), former smoker, who had been working for 53 years as a circus truck driver and tamer of lions and tigers. The first circumstance of exposure was the use of an asbestos tape that wrapped around the hoop in the feline jumping show with a flaming hoop. The second one was the presence of insulating panels protecting the engine placed inside the trucks.

Conclusion: A new MM case with an occupational etiology has been found in the public entertainment, an occupational sector not usually considered at risk for the presence of asbestos.
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http://dx.doi.org/10.1002/1348-9585.12250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8344853PMC
January 2021

SARS-CoV-2 anti-spike antibody titres after vaccination with BNT162b2 in naïve and previously infected individuals.

J Infect Public Health 2021 08 17;14(8):1120-1122. Epub 2021 Jul 17.

Infectious Diseases Unit, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy; Centre for Multidisciplinary Research in Health Science (MACH), University of Milan, Milan, Italy.

Great expectations are placed in vaccines against COVID-19 to control the pandemic. We reviewed the antibody titres in a cohort of healthcare workers (HCWs) vaccinated with BNT162b2 to assess the influence of a previous infection on them. We stratified the results according to the individual history of nasopharyngeal swab (NPS) and symptoms. Among 3475 HCWs the highest titres were recorded among those infected more than 6 months before vaccination, independently of symptoms, followed by those infected less than 6 months before vaccination, especially in those with symptoms, and by uninfected HCWs. Vaccination with BNT162b2 can boost immunity acquired through infection, particularly in those infected more than 6 months before vaccination.
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http://dx.doi.org/10.1016/j.jiph.2021.07.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8285930PMC
August 2021

Effect of Asbestos Consumption on Malignant Pleural Mesothelioma in Italy: Forecasts of Mortality up to 2040.

Cancers (Basel) 2021 Jul 3;13(13). Epub 2021 Jul 3.

Department of Translational Medicine, University of Eastern Piedmont, 28100 Novara, Italy.

Statistical models used to forecast malignant pleural mesothelioma (MPM) trends often do not take into account historical asbestos consumption, possibly resulting in less accurate predictions of the future MPM death toll. We used the distributed lag non-linear model (DLNM) approach to predict future MPM cases in Italy until 2040, based on past asbestos consumption figures. Analyses were conducted using data on male MPM deaths (1970-2014) and annual asbestos consumption using data on domestic production, importation, and exportation. According to our model, the peak of MPM deaths is expected to occur in 2021 (1122 expected cases), with a subsequent decrease in mortality (344 MPM deaths in 2039). The exposure-response curve shows that relative risk (RR) of MPM increased almost linearly for lower levels of exposure but flattened at higher levels. The lag-specific RR grew until 30 years since exposure and decreased thereafter, suggesting that the most relevant contributions to the risk come from exposures which occurred 20-40 years before death. Our results show that the Italian MPM epidemic is approaching its peak and underline that the association between temporal trends of MPM and time since exposure to asbestos is not monotonic, suggesting a lesser role of remote exposures in the development of MPM than previously assumed.
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http://dx.doi.org/10.3390/cancers13133338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267929PMC
July 2021

A morphological classification of the fat particles found in the urinary sediment of patients with Fabry disease.

Clin Chem Lab Med 2021 Oct 6;59(11):1832-1843. Epub 2021 Jul 6.

U.O.C. di Nefrologia, Dialisi e Trapianto di Rene, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Objectives: The search in the urinary sediment (U-sed) of fat particles with peculiar morphology is a simple and inexpensive tool for the diagnosis of Fabry disease (FD) nephropathy. In this study we investigated the morphology of a high number of such fat particles with the aim to obtain a morphological classification to be used for their identification.

Methods: Study of the morphology of fat particles in the U-sed of a cohort of FD patients using: bright field plus phase contrast microscopy (BF + PC), polarized light microscopy (POL), and transmission electron microscopy (TEM). Comparison of these results with those obtained for the fat particles seen in the U-sed of a control group (CG) of patients with non-FD glomerulopathies.

Results: FD: 18 U-sed from six patients (three samples/patient) were prospectively investigated and 506 fat particles identified. With BF + PC, these were classified in eight morphological categories (seven of which were confirmed by TEM), and with POL in 10 others. CG: eight U-sed from eight patients were investigated and 281 fat particles identified. These fell into four BF + PC morphological categories and into eight POL categories. While some categories were significantly more frequent in FD others were more frequent in the CG.

Conclusions: Our study demonstrates that 1. The morphology of fat particles found in the U-sed of FD patients is much wider and complex than that described so far 2. Several significant differences exist in the morphology of such fat particles between FD and CG patients.
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http://dx.doi.org/10.1515/cclm-2021-0079DOI Listing
October 2021

Novel MAPK/AKT-impairing germline NRAS variant identified in a melanoma-prone family.

Fam Cancer 2021 Jul 3. Epub 2021 Jul 3.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 9609 Medical Center Drive, EPS 7106, Bethesda, MD, 20892, USA.

While several high-penetrance melanoma risk genes are known, variation in these genes fail to explain melanoma susceptibility in a large proportion of high-risk families. As part of a melanoma family sequencing study, including 435 families from Mediterranean populations we identified a novel NRAS variant (c.170A > C, p.D57A) in an Italian melanoma-prone family. This variant is absent in exomes in gnomAD, ESP, UKBiobank, and the 1000 Genomes Project, as well as in 11,273 Mediterranean individuals and 109 melanoma-prone families from the US and Australia. This variant occurs in the GTP-binding pocket of NRAS. Differently from other RAS activating alterations, NRAS D57A expression is unable to activate MAPK-pathway both constitutively and after stimulation but enhances EGF-induced PI3K-pathway signaling in serum starved conditions in vitro. Consistent with in vitro data demonstrating that NRAS D57A does not enrich GTP binding, molecular modeling suggests that the D57A substitution would be expected to impair Mg2 + binding and decrease nucleotide-binding and GTPase activity of NRAS. While we cannot firmly establish NRAS c.170A > C (p.D57A) as a melanoma susceptibility variant, further investigation of NRAS as a familial melanoma gene is warranted.
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http://dx.doi.org/10.1007/s10689-021-00267-9DOI Listing
July 2021

Bloody Diarrhea and Shiga Toxin-Producing Escherichia coli Hemolytic Uremic Syndrome in Children: Data from the ItalKid-HUS Network.

J Pediatr 2021 Oct 29;237:34-40.e1. Epub 2021 Jun 29.

Azienda socio sanitaria territoriale (ASST) Melegnano e della Martesana - Vizzolo Predabissi, Milano, Italy.

Objective: To analyze the results of an enhanced laboratory-surveillance protocol for bloody diarrhea aimed at identifying children with Shiga toxin-producing Escherichia coli (STEC) infection early in the course of the disease toward the early identification and management of patients with hemolytic uremic syndrome (HUS).

Study Design: The study (2010-2019) involved a referral population of 2.3 million children. Stool samples of patients with bloody diarrhea were screened for Shiga toxin (Stx) genes. Positive patients were rehydrated and monitored for hemoglobinuria until diarrhea resolved or STEC-HUS was diagnosed.

Results: A total of 4767 children were screened; 214 (4.5%) were positive for either Stx1 (29.0%) or Stx2 (45.3%) or both Stx1+2 (25.7%); 34 patients (15.9%) developed STEC-HUS (0.71% of bloody diarrheas). Hemoglobinuria was present in all patients with HUS. Patients with Stx2 alone showed a greater risk of STEC-HUS (23.7% vs 12.7%) and none of the patients with Stx1 alone developed HUS. During the same period of time, 95 other patients were diagnosed STEC-HUS but were not captured by the screening program (26 had nonbloody diarrhea, 11 came from areas not covered by the screening program, and 58 had not been referred to the screening program, although they did meet the inclusion criteria). At HUS presentation, serum creatinine of patients identified by screening was significantly lower compared with that of the remaining patients (median 0.9 vs 1.51 mg/dL).

Conclusions: Nearly 1% of children with bloody diarrhea developed STEC-HUS, and its diagnosis was anticipated by the screening program for Stx. The screening of bloody diarrhea for Stx is recommended, and monitoring patients carrying Stx2 with urine dipstick for hemoglobinuria is suggested to identify the renal complication as early as possible.
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http://dx.doi.org/10.1016/j.jpeds.2021.06.048DOI Listing
October 2021

Cerebral Oxygenation by Near-Infrared Spectroscopy in Infants Undergoing Thoracoscopic Lung Resection.

J Laparoendosc Adv Surg Tech A 2021 Sep 25;31(9):1084-1091. Epub 2021 Jun 25.

Department of Pediatric Surgery, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan Italy.

Thoracoscopic resection is the standard of care for congenital lung malformations (CLMs) in infants. However, there is rising concern that capnothorax may affect cerebral perfusion and oxygenation, carrying potential long-term effects on neurodevelopmental behavior. The aim of our study was to investigate, using near-infrared spectroscopy (NIRS), the regional cerebral oxygenation (CrSO) in infants undergoing thoracoscopic lung resection; the secondary aim was to assess the relationship between rSO and standard monitoring. In this retrospective study, we reviewed all infants (<1 year old, ASA II) who underwent thoracoscopic CLM resection in double-lung ventilation under fixed capnothorax parameters (5 mmHg of pressure, 1 L/minute flow), standardized anesthetic protocol, standard monitoring, and multisite NIRS in our center. We focused our attention on 8 anesthetic and surgical maneuvers, potentially affecting tissue oxygen saturation. Ten infants met the inclusion criteria. At surgery, median age was 5.5 (4-7) months, median weight 7.2 (6.6-8) kg, median operative time 110 (55-180) minutes, and median capnothorax duration 79 (34-168) minutes. No conversion to open surgery occurred. CrSO values remained within clinically accepted values during thoracoscopy, beside a CrSO drop >20% of basal value in 1 patient, during capnothorax induction. Renal NIRS added very little to standard monitoring, which appeared generally inadequate to consistently appraise end-organ perfusion. ETCO best correlated with CrSO variations, suggesting to be able to realistically predict them. The thoracoscopic treatment of CLMs under the given conditions appears well tolerated in infants, pending the continuous adjustment of ventilator settings by an experienced anesthetist, confident with NIRS technology.
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http://dx.doi.org/10.1089/lap.2021.0177DOI Listing
September 2021

Risk of Atypical HUS Among Family Members of Patients Carrying Complement Regulatory Gene Abnormality.

Kidney Int Rep 2021 Jun 25;6(6):1614-1621. Epub 2021 Mar 25.

Medical Genetics Laboratory, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano, Italy.

Introduction: Atypical hemolytic uremic syndrome (aHUS) is mainly due to complement regulatory gene abnormalities with a dominant pattern but incomplete penetrance. Thus, healthy carriers can be identified in any family of aHUS patients, but it is unpredictable if they will eventually develop aHUS.

Methods: Patients are screened for 10 complement regulatory gene abnormalities and once a genetic alteration is identified, the search is extended to at-risk family members. The present cohort study includes 257 subjects from 71 families: 99 aHUS patients (71 index cases + 28 affected family members) and 158 healthy relatives with a documented complement gene abnormality.

Results: Fourteen families (19.7%) experienced multiple cases. Over a cumulative observation period of 7595 person-years, only 28 family members carrying gene mutations experienced aHUS (overall penetrance of 20%), leading to a disease rate of 3.69 events for 1000 person-years. The disease rate was 7.47 per 1000 person-years among siblings, 6.29 among offspring, 2.01 among parents, 1.84 among carriers of variants of uncertain significance, and 4.43 among carriers of causative variants.

Conclusions: The penetrance of aHUS seems a lot lower than previously reported. Moreover, the disease risk is higher in carriers of causative variants and is not equally distributed among generations: siblings and the offspring of patients have a much greater disease risk than parents. However, risk calculation may depend on variant classification that could change over time.
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http://dx.doi.org/10.1016/j.ekir.2021.03.885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8207326PMC
June 2021

Muscular de-conditioning and reduced cardiac inotropism due to iron deposition reduce exercise tolerance in beta thalassemia major.

Am J Hematol 2021 10 5;96(10):E370-E373. Epub 2021 Jul 5.

Department of Clinical Sciences and Community Health, University of Milan and Center for Rare Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

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http://dx.doi.org/10.1002/ajh.26278DOI Listing
October 2021

Functional gastrointestinal and somatoform symptoms five months after SARS-CoV-2 infection: A controlled cohort study.

Neurogastroenterol Motil 2021 Jun 1:e14187. Epub 2021 Jun 1.

Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Background: Gastrointestinal infections represent a risk factor for functional gastrointestinal and somatoform extraintestinal disorders. We investigated the prevalence and relative risk (RR) of gastrointestinal and somatoform symptoms 5 months after SARS-CoV-2 infection compared with a control cohort.

Methods: One hundred and sixty-four SARS-CoV-2 infected patients and 183 controls responded to an online questionnaire about symptoms and signs during the acute phase of the infection and after 4.8 ± 0.3 months. Presence and severity of gastrointestinal symptoms, somatization, anxiety, and depression were recorded with standardized questionnaires. Stool form and presence of irritable bowel syndrome (IBS) were also recorded. Any association between exposure to infection and symptoms was evaluated by calculating crude and adjusted RR values and score differences with 95% confidence intervals (CI).

Key Results: Fever, dyspnea, loss of smell/taste/weight, diarrhea, myalgia, arthralgia, and asthenia were reported by more than 40% of patients during the acute phase. Compared with controls, adjusted RRs for loose stools, chronic fatigue, and somatization were increased after infection: 1.88 (95% CI 0.99-3.54), 2.24 (95% CI 1.48-3.37), and 3.62 (95% CI 1.01-6.23), respectively. Gastrointestinal sequelae were greater in patients with diarrhea during the acute phase.

Conclusions & Inferences: Mild gastroenterological symptoms persist 5 months after SARS-CoV-2 infection, in particular in patients reporting diarrhea in the acute phase. Infected patients are at increased risk of chronic fatigue and somatoform disorders, thus supporting the hypothesis that both functional gastrointestinal and somatoform disorders may have a common biological origin.
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http://dx.doi.org/10.1111/nmo.14187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209890PMC
June 2021

Kidney transplant in patients with atypical hemolytic uremic syndrome in the anti-C5 era: single-center experience with tailored Eculizumab.

J Nephrol 2021 Dec 6;34(6):2027-2036. Epub 2021 May 6.

Kidney Transplant Unit, Center for HUS Prevention, Control and Management, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Rationale And Objective: Patients with atypical hemolytic uremic syndrome (aHUS) have long been considered ineligible for kidney transplantation (KTx) in several centers due to the high risk of disease recurrence, graft loss and life-threatening complications. The availability of Eculizumab (ECU) has now overcome this problem. However, the best approach towards timing, maintenance schedule, the possibility of discontinuation and patient monitoring has not yet been clearly established.

Study Design: This is a single center case series presenting our experience with KTx in aHUS.

Setting And Participants: This study included 26 patients (16 females) with a diagnosis of aHUS, who spent a median of 5.5 years on kidney replacement therapy before undergoing KTx. We compared the aHUS relapse rate in three groups of patients who underwent KTx: patients who received no prophylaxis, patients who underwent plasma exchange, those who received Eculizumab prophylaxis. Complement factor H-related disease was by far the most frequent etiology (n = 19 patients).

Results: Untreated patients and patients undergoing pre-KTx plasma exchange prophylaxis had a relapse rate of 0.81 (CI 0.30-1.76) and 3.1 (CI 0.64-9.16) events per 10 years cumulative observation, respectively, as opposed to 0 events among patients receiving Eculizumab prophylaxis. The time between Eculizumab doses was tailored based on classic complement pathway activity (target to < 30%). Using this strategy, 12 patients are currently receiving  Eculizumab every 28 days, 5 every 24-25 days, and 3 every 21 days.

Conclusion: Our experience supports the prophylactic use of Eculizumab in patients with a previous history of aHUS undergoing KTx, especially when complement dysregulation is well documented by molecular biology.
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http://dx.doi.org/10.1007/s40620-021-01045-7DOI Listing
December 2021

Application of two job indices for general occupational demands in a pooled analysis of case-control studies on lung cancer.

Scand J Work Environ Health 2021 Sep 3;47(6):475-481. Epub 2021 May 3.

Jan Hovanec, IPA, Bürkle-de-la-Camp-Platz 1, 44789 Bochum, Germany.

Objectives: We investigated general job demands as a risk factor for lung cancer as well as their role in the association between occupational prestige and lung cancer.

Methods: In 13 case-control studies on lung cancer, as part of the international SYNERGY project, we applied indices for physical (PHI) and psychosocial (PSI) job demands - each with four categories (high to low). We estimated odds ratios (OR) and 95% confidence intervals (CI) for lung cancer by unconditional logistic regression, separately for men and women and adjusted for study centre, age, smoking behavior, and former employment in occupations with potential exposure to carcinogens. Further, we investigated, whether higher risks among men with low occupational prestige (Treiman's Standard International Occupational Prestige Scale) were affected by adjustment for the job indices.

Results: In 30 355 men and 7371 women, we found increased risks (OR) for lung cancer with high relative to low job demands in both men [PHI 1.74 (95% CI 1.56-1.93), PSI 1.33 (95% CI 1.17-1.51)] and women [PHI 1.62 (95% CI 1.24-2.11), PSI 1.31 (95% CI 1.09-1.56)]. OR for lung cancer among men with low occupational prestige were slightly reduced when adjusting for PHI [low versus high prestige OR from 1.44 (95% CI 1.32-1.58) to 1.30 (95% CI 1.17-1.45)], but not PSI.

Conclusions: Higher physical job demands were associated with increased risks of lung cancer, while associations for higher psychosocial demands were less strong. In contrast to physical demands, psychosocial demands did not contribute to clarify the association of occupational prestige and lung cancer.
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http://dx.doi.org/10.5271/sjweh.3967DOI Listing
September 2021

Arterial hypertension and cystatin C during neonatal physiologic dehydration.

J Hum Hypertens 2021 May 2. Epub 2021 May 2.

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Pediatric Nephrology, Dialysis and Transplantation Unit, Milan, Italy.

A reduced nephron number may play a role in the pathogenesis of arterial hypertension (AH), and it is well recognized that individual nephron endowment is widely variable. However, nephrons count is technically impossible in vivo. Based on the observation that subjects with a reduced nephron mass exhibit an increase in renal functional biomarkers during acute dehydration, we hypothesized that cystatin C concentration during neonatal physiological dehydration could identify subjects with reduced nephron endowment. This is a prospective, observational, cohort study enrolling healthy, caucasian, term neonates born after an uneventful pregnancy. Two groups of newborns were compared: neonates born to fathers on antihypertensive treatment (HF) versus those born to proven normotensive fathers older than 40 years of age (NF). Enrolled newborns underwent cystatin C determination at the time of newborn screening. Forty newborns with HF and 80 with NF were enrolled. No differences in baseline characteristics were observed between the two groups except for the number of hypertensive grandparents higher among newborns to HF (47.8% vs. 21.1%; p: 0.001). Cystatin C was significantly higher in newborns with HF (1.62 ± 0.30 mg/L vs 1.41 ± 0.27 mg/L; p < 0.001). Linear regression analysis corrected for confounders confirmed that paternal hypertension was the only variable significantly associated with high cystatin C level during post-natal dehydration. Besides offering new insights on the pathogenesis of familial hypertension, our results support the specific role of nephron endowment and suggest the possibility of identifying subjects at risk for reduced nephron endowment as early as at birth.
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http://dx.doi.org/10.1038/s41371-021-00541-4DOI Listing
May 2021

Cumulative Pesticides Exposure of Children and Their Parents Living near Vineyards by Hair Analysis.

Int J Environ Res Public Health 2021 04 2;18(7). Epub 2021 Apr 2.

Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Via S. Barnaba, 8, 20122 Milan, Italy.

The aim of the present work was the application of hair biomonitoring to investigate exposure to pesticides in children and their parents residing in a vineyard area. Thirty-three children and 16 parents were involved in the study. Hair samples were self-collected before and after the application season (PRE- and POST-EXP samples). Information on study subjects and the use of pesticides in the area were obtained. Thirty-nine pesticides were analyzed by liquid chromatography tandem mass spectrometry, and thirty-one pesticides were quantifiable in at least one hair sample. Most frequently detected pesticides were chlorpyrifos, cycloxidim, dimethomorph, metalaxyl, spiroxamine, and tetraconazole. From PRE-EXP to POST-EXP the percentage of quantification and/or the concentration of pesticides increased; the concentration was typically in the low pg/mg hair range with comparable levels in children and parents. An inverse correlation was found between the total exposure to pesticides in POST-EXP hair samples and the distance between home and the treated fields (Spearman ρ = -0.380, = 0.01). The results of this study show that the majority of the study pesticides were measured in the hair of subjects living in the close proximity of treated vineyards, supporting the determination of pesticides in hair for the purpose of biomonitoring cumulative exposure in the general population.
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http://dx.doi.org/10.3390/ijerph18073723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038297PMC
April 2021

Granulomatous Lymphocytic Interstitial Lung Disease (GLILD) in Common Variable Immunodeficiency (CVID): A Multicenter Retrospective Study of Patients From Italian PID Referral Centers.

Front Immunol 2021 10;12:627423. Epub 2021 Mar 10.

Department of Molecular Medicine, "Sapienza" University of Rome, Rome, Italy.

Granulomatous and Lymphocytic Interstitial Lung Diseases (GLILD) is a severe non-infectious complication of Common Variable Immunodeficiency (CVID), often associated with extrapulmonary involvement. Due to a poorly understood pathogenesis, GLILD diagnosis and management criteria still lack consensus. Accordingly, it is a relevant cause of long-term loss of respiratory function and is closely associated with a markedly reduced survival. The aim of this study was to describe clinical, immunological, laboratory and functional features of GLILD, whose combination in a predictive model might allow a timely diagnosis. In a multicenter retrospective cross-sectional study we enrolled 73 CVID patients with radiologic features of interstitial lung disease (ILD) associated to CVID (CVID-ILD) and 125 CVID patients without ILD (controls). Of the 73 CVID-ILD patients, 47 received a definite GLILD diagnosis while 26 received a clinical-radiologic diagnosis of CVID related ILD defined as uILD. In GLILD group we found a higher prevalence of splenomegaly (84.8 vs. 39.2%), autoimmune cytopenia (59.6 vs. 6.4%) and bronchiectasis (72.3 vs. 28%), and lower IgA and IgG serum levels at CVID diagnosis. GLILD patients presented lower percentage of switched-memory B cells and marginal zone B cells, and a marked increase in the percentage of circulating CD21lo B cells (14.2 vs. 2.9%). GLILD patients also showed lower total lung capacity (TLC 87.5 vs. 5.0%) and gas transfer (DLCO 61.5 vs. 5.0%) percent of predicted. By univariate logistic regression analysis, we found IgG and IgA levels at CVID diagnosis, presence of splenomegaly and autoimmune cytopenia, CD21lo B cells percentage, TLC and DCLO percent of predicted to be associated to GLILD. The joint analysis of four variables (CD21lo B cells percentage, autoimmune cytopenia, splenomegaly and DLCO percent of predicted), together in a multiple logistic regression model, yielded an area under the ROC curve (AUC) of 0.98 (95% CI: 0.95-1.0). The AUC was only slightly modified when pooling together GLILD and uILD patients (0.92, 95% CI: 0.87-0.97). we propose the combination of two clinical parameters (splenomegaly and autoimmune cytopenia), one lung function index (DLCO%) and one immunologic variable (CD21lo%) as a promising tool for early identification of CVID patients with interstitial lung disease, limiting the use of aggressive diagnostic procedures.
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http://dx.doi.org/10.3389/fimmu.2021.627423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987811PMC
September 2021

Prevalence of Dysphonia in Non hospitalized Patients with COVID-19 in Lombardy, the Italian Epicenter of the Pandemic.

J Voice 2021 Mar 14. Epub 2021 Mar 14.

Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy; Otolaryngology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Introduction: Dysphonia has been described in patients affected by coronavirus disease 2019 (COVID-19). The aim of this study was to evaluate the prevalence of dysphonia, and its severity and extent, of voice fatigue and of dysphagia in non hospitalized patients affected by COVID-19 in Lombardy, the Italian region most hit by the first explosive outbreak of COVID-19 in Europe.

Methods: Demographic and clinical data of 160 consecutive patients, with COVID-19 diagnosis confirmed by nasal swabs processed by reverse transcription polymerase chain reaction, were gathered by means of telephone interviews performed by physicians in charge of daily follow-up. General and specific symptoms concerning voice and swallowing impairment were investigated. Dysphonia grade and duration were graded on 4-point scales, while voice fatigue was graded on a 5-point scale.

Results: Dysphonia was reported by 70 (43.7%) patients and was positively associated with voice fatigue (P < 0.001), cough (P = 0.005), rhinitis (P = 0.01), and dyspnea (P = 0.06); it was mild and/or moderate in 69 patients, but its duration was > 2 weeks in 33/70 (47.1%) patients and >1 month in 11/70 (15.7%). Grade and duration of dysphonia were positively associated with cough and rhinitis (all P values < 0.01). Voice fatigue was reported by 43/160 patients (26.8%) and its severity was correlated with dysphonia (P < 0.0001), cough (P = 0.02), rhinitis (P = 0.02), dyspnea (P < 0.001), and loss of appetite (P = 0.01). Dysphagia was encountered in 27/160 patients (16.9%) and was associated with dysgeusia, cough, arthralgia, myalgia and loss of appetite but not with dysphonia.

Conclusions: Dysphonia was a highly prevalent and long-lasting symptom in this series; it has been underestimated to date. Further studies might shed light on the pathophysiology of voice disorders in COVID-19 patients.
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http://dx.doi.org/10.1016/j.jvoice.2021.03.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955941PMC
March 2021

Accuracy of pleural biopsy for the diagnosis of histologic subtype of malignant pleural mesothelioma: Necropsy-based study of 134 cases.

Tumori 2021 Mar 15:300891620988354. Epub 2021 Mar 15.

Pathology Unit, Ospedale di Monfalcone, Azienda Sanitaria Universitaria Giuliano Isontina, Gorizia, Italy.

Background: Definition of histologic subtype of malignant pleural mesothelioma (MPM) is important for management of patients, because surgical treatment improves prognosis for patients with epithelioid but not biphasic or sarcomatoid MPM. In a series of necropsies performed in a hospital specialized for MPM diagnosis, we retrospectively investigated the accuracy of histologic diagnosis performed on pathologic specimens collected through pleural biopsies obtained at video-assisted thoracoscopic surgery (VATS) or surgery.

Methods: We reviewed histologic records of an unselected series of autopsies performed in patients with MPM employed in the Monfalcone shipyards (Northeast Italy) or living with shipyard workers from 1999 through 2017. Using necropsy results as a gold standard, we calculated sensitivity, specificity, and positive and negative predictive values of histology from VATS or surgery after combining nonepithelioid subtypes.

Results: We retrieved necropsy records for 134 patients: 62 (46.3%) with epithelioid, 51 (38.1%) with biphasic, and 21 (15.7%) with sarcomatoid MPM. We observed good sensitivity of VATS (0.94) and surgery (0.89) in diagnosing epithelioid MPM. Conversely, specificity was low (VATS: 0.46; surgery: 0.32). Therefore, positive predictive values were also low (VATS: 0.58; surgery: 0.60). Misclassification was particularly high for biphasic MPM (three-fourths of biphasic MPM at necropsy had been classified as epithelioid at VATS or surgery).

Conclusions: We observed a substantial degree of misclassification between epithelioid and biphasic MPM for pleural biopsies performed during VATS. Our results suggest caution should be taken in using histologic subtype obtained from VATS in selecting patients with MPM for surgical treatment. We also observed substantial misclassification of biospecimens collected during MPM surgery.
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http://dx.doi.org/10.1177/0300891620988354DOI Listing
March 2021

Clinical and prognostic significance of small paroxysmal nocturnal hemoglobinuria clones in myelodysplastic syndrome and aplastic anemia.

Leukemia 2021 Nov 4;35(11):3223-3231. Epub 2021 Mar 4.

Department of Hematological medicine, King's College Hospital, London, UK.

In this large single-centre study, we report high prevalence (25%) of, small (<10%) and very small (<1%), paroxysmal nocturnal hemoglobinuria (PNH) clones by high-sensitive cytometry among 3085 patients tested. Given PNH association with bone marrow failures, we analyzed 869 myelodysplastic syndromes (MDS) and 531 aplastic anemia (AA) within the cohort. PNH clones were more frequent and larger in AA vs. MDS (p = 0.04). PNH clone, irrespective of size, was a good predictor of response to immunosuppressive therapy (IST) and to stem cell transplant (HSCT) (in MDS: 84% if PNH+ vs. 44.7% if PNH-, p = 0.01 for IST, and 71% if PNH+ vs. 56.6% if PNH- for HSCT; in AA: 78 vs. 50% for IST, p < 0.0001, and 97 vs. 77%, p = 0.01 for HSCT). PNH positivity had a favorable impact on disease progression (0.6% vs. 4.9% IPSS-progression in MDS, p < 0.005; and 2.1 vs. 6.9% progression to MDS in AA, p = 0.01), leukemic evolution (6.8 vs. 12.7%, p = 0.01 in MDS), and overall survival [73% (95% CI 68-77) vs. 51% (48-54), p < 0.0001], with a relative HR for mortality of 2.37 (95% CI 1.8-3.1; p < 0.0001) in PNH negative cases, both in univariate and multivariable analysis. Our data suggest systematic PNH testing in AA/MDS, as it might allow better prediction/prognostication and consequent clinical/laboratory follow-up timing.
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http://dx.doi.org/10.1038/s41375-021-01190-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8550969PMC
November 2021
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