Publications by authors named "Marek Niedoszytko"

64 Publications

Clinical Impact of Skin Lesions in Mastocytosis: A Multicenter Study of the European Competence Network on Mastocytosis (ECNM).

J Invest Dermatol 2021 Feb 10. Epub 2021 Feb 10.

Department of Internal Medicine I, Division of Hematology and Hemostaseology Medical University of Vienna, Austria;; Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Austria;. Electronic address:

Mastocytosis is a rare neoplasm characterized by expansion and accumulation of mast cells in various organ systems. Systemic mastocytosis (SM) may or may not presents with cutaneous lesions. To examine the frequency and clinical impact of cutaneous involvement, 1510 mastocytosis patients collected in the registry of the European Competence Network on Mastocytosis were analyzed. Cutaneous involvement was found in 1195/1510 (79.1%) patients. Of these, 286 had cutaneous mastocytosis (CM) and 721 had SM with skin involvement (SM+). Adult patients with skin involvement who did not have a bone marrow examination (n=188) were defined as mastocytosis in the skin (MIS). In 315 patients with SM, no skin involvement was found (SM-). The percentage of cases with cutaneous involvement was higher in indolent SM (100%) and smoldering SM (87.9%) compared to aggressive SM (46.8%) or mast cell leukemia (38.5%). After a median follow-up of 5.6 years no patient with CM had died, but 2.6% of the patients with MIS, 5.7% with SM+ and 28.95% with SM- had died. Overall survival was longer in patients with skin involvement (CM/MIS/SM+) compared to SM- patients (p<0.0001). These data argue for a thorough examination of both the skin and bone marrow in adult patients with mastocytosis.
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http://dx.doi.org/10.1016/j.jid.2020.12.030DOI Listing
February 2021

A Challenge for Allergologist: Application of Allergy Diagnostic Methods in Mast Cell Disorders.

Int J Mol Sci 2021 Feb 1;22(3). Epub 2021 Feb 1.

Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, 1090 Vienna, Austria.

Primary and secondary mast cell activation syndromes (MCAS) can occur in patients with mastocytosis. During the past few years our knowledge about the pathogenesis and disease-triggering mechanisms in MCAS and mastocytosis have increased substantially. Whereas mastocytosis is characterized by an accumulation of neoplastic (clonal) mast cells (MC) in various organ systems, MCAS is defined by a massive and systemic activation of these cells. Mast cells are crucial effector cells in allergic diseases, thus their elevated number and activation can cause severe anaphylactic reactions and MCAS in patients with mastocytosis. However, these cells may also degranulate spontaneously or degranulate in response to non-allergic triggers leading to clinical symptoms. In mastocytosis patients, such symptoms may lead to the diagnosis of a primary MCAS. The diagnosis of a concomitant allergy in mastocytosis patients is challenging. In these patients, a mixed form (primary and secondary) of MCAS may be diagnosed. These patients may also suffer from life-threatening anaphylactic reactions when exposed to allergens. In these cases, the possibility of severe side effects of in vivo provocations can sometimes also limit diagnostic evaluations. In the current article, we discuss the diagnosis and management of patients suffering from mastocytosis and concomitant MCAS, with special emphasis on novel diagnostic tests and management, including allergen microarrays, recombinant allergen analysis, basophil activation tests, optimal prophylaxis, and specific therapies.
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http://dx.doi.org/10.3390/ijms22031454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867197PMC
February 2021

Clinical Impact of Inherited and Acquired Genetic Variants in Mastocytosis.

Int J Mol Sci 2021 Jan 2;22(1). Epub 2021 Jan 2.

Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, 1090 Vienna, Austria.

Mastocytosis is a rare and complex disease characterized by expansion of clonal mast cells (MC) in skin and/or various internal organ systems. Involvement of internal organs leads to the diagnosis of systemic mastocytosis (SM). The WHO classification divides SM into indolent SM, smoldering SM and advanced SM variants, including SM with an associated hematologic neoplasm, aggressive SM, and MC leukemia. Historically, genetic analysis of individuals with pure cutaneous mastocytosis (CM) and SM have focused primarily on cohort studies of inherited single nucleotide variants and acquired pathogenic variants. The most prevalent pathogenic variant (mutation) in patients with SM is p.D816V, which is detectable in most adult patients. Other somatic mutations have also been identified-especially in advanced SM-in , , , , and , and shown to impact clinical and cellular phenotypes. Although only small patient cohorts have been analyzed, disease associations have also been identified in several germline variants within genes encoding certain cytokines or their receptors (, , , , ) and toll-like receptors. More recently, an increased prevalence of hereditary alpha-tryptasemia (HαT) caused by increased copy number encoding alpha-tryptase has been described in patients with SM. Whereas HαT is found in 3-6% of general Western populations, it is identified in up to 17% of patients with SM. In the current manuscript we review the prevalence, functional role and clinical impact of various germline and somatic genetic variants in patients with mastocytosis.
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http://dx.doi.org/10.3390/ijms22010411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7795405PMC
January 2021

Cytogenetic and molecular aberrations and worse outcome for male patients in systemic mastocytosis.

Theranostics 2021 1;11(1):292-303. Epub 2021 Jan 1.

Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria.

In systemic mastocytosis (SM), the clinical features and survival vary greatly. Patient-related factors determining the outcome in SM are largely unknown. We examined the impact of sex on the clinical features, progression-free survival (PFS), and overall survival (OS) in 3403 patients with mastocytosis collected in the registry of the European Competence Network on Mastocytosis (ECNM). The impact of cytogenetic and molecular genetic aberrations on sex differences was analyzed in a subset of patients. Of all patients enrolled, 55.3% were females. However, a male predominance was found in a subset of advanced SM (AdvSM) patients, namely SM with an associated hematologic neoplasm (SM-AHN, 70%; 0.001). Correspondingly, organomegaly (male: 23% female: 13%, 0.007) was more, whereas skin involvement (male: 71% female: 86%, 0.001) was less frequent in males. In all patients together, OS ( 0.0001) was significantly inferior in males, and also within the WHO sub-categories indolent SM, aggressive SM (ASM) and SM-AHN. PFS was significantly ( 0.0002) worse in males when all patients were grouped together; due to low numbers of events, this significance persisted only in the subcategory smoldering SM. Finally, prognostically relevant cytogenetic abnormalities (10% 5%, 0.006) or molecular aberrations (// profile; 63% 40%, 0.003) were more frequently present in males. Male sex has a major impact on clinical features, disease progression, and survival in mastocytosis. Male patients have an inferior survival, which seems related to the fact that they more frequently develop a multi-mutated AdvSM associated with a high-risk molecular background.
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http://dx.doi.org/10.7150/thno.51872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7681091PMC
January 2021

Scoring the Risk of Having Systemic Mastocytosis in Adult Patients with Mastocytosis in the Skin.

J Allergy Clin Immunol Pract 2020 Dec 23. Epub 2020 Dec 23.

Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria; Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria.

Background: Mastocytosis in adults often presents with skin lesions. A bone marrow biopsy is necessary to confirm or exclude the presence of systemic mastocytosis (SM) in these cases. When a bone marrow biopsy is not performed, the provisional diagnosis is mastocytosis in the skin (MIS). No generally accepted scoring system has been established to estimate the risk of SM in these patients.

Objective: To develop a risk score to predict SM in adults with MIS.

Methods: We examined 1145 patients with MIS from the European Competence Network on Mastocytosis Registry who underwent a bone marrow biopsy. A total of 944 patients had SM and 201 patients had cutaneous mastocytosis; 63.7% were female, and 36.3% were male. Median age was 44 ± 13.3 years. The median serum tryptase level amounted to 29.3 ± 81.9 ng/mL. We established a multivariate regression model using the whole population of patients as a training and validation set (bootstrapping). A risk score was developed and validated with receiver-operating curves.

Results: In the multivariate model, the tryptase level (P < .001), constitutional/cardiovascular symptoms (P = .014), and bone symptoms/osteoporosis (P < .001) were independent predictors of SM (P < .001; sensitivity, 90.7%; specificity, 69.1%). A 6-point risk score was established (risk, 10.7%-98.0%) and validated.

Conclusions: Using a large data set of the European Competence Network on Mastocytosis Registry, we created a risk score to predict the presence of SM in patients with MIS. Although the score will need further validation in independent cohorts, our score seems to discriminate safely between patients with SM and with pure cutaneous mastocytosis.
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http://dx.doi.org/10.1016/j.jaip.2020.12.022DOI Listing
December 2020

Diagnosis, Classification and Management of Mast Cell Activation Syndromes (MCAS) in the Era of Personalized Medicine.

Int J Mol Sci 2020 Nov 27;21(23). Epub 2020 Nov 27.

Laboratory of Allergic Diseases, NIAID, NIH, Bethesda, MD 20852, USA.

Mast cell activation (MCA) is seen in a variety of clinical contexts and pathologies, including IgE-dependent allergic inflammation, other immunologic and inflammatory reactions, primary mast cell (MC) disorders, and hereditary alpha tryptasemia (HAT). MCA-related symptoms range from mild to severe to life-threatening. The severity of MCA-related symptoms depends on a number of factors, including genetic predisposition, the number and releasability of MCs, organs affected, and the type and consequences of comorbid conditions. In severe systemic reactions, MCA is demonstrable by a substantial increase of basal serum tryptase levels above the individual's baseline. When, in addition, the symptoms are recurrent, involve more than one organ system, and are responsive to therapy with MC-stabilizing or mediator-targeting drugs, the consensus criteria for the diagnosis of MCA syndrome (MCAS) are met. Based on the etiology of MCA, patients can further be classified as having i) primary MCAS where -mutated, clonal, MCs are detected; ii) secondary MCAS where an underlying IgE-dependent allergy or other reactive MCA-triggering pathology is found; or iii) idiopathic MCAS, where neither a triggering reactive state nor -mutated MCs are identified. Most severe MCA events occur in combined forms of MCAS, where -mutated MCs, IgE-dependent allergies and sometimes HAT are detected. These patients may suffer from life-threatening anaphylaxis and are candidates for combined treatment with various types of drugs, including IgE-blocking antibodies, anti-mediator-type drugs and MC-targeting therapy. In conclusion, detailed knowledge about the etiology, underlying pathologies and co-morbidities is important to establish the diagnosis and develop an optimal management plan for MCAS, following the principles of personalized medicine.
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http://dx.doi.org/10.3390/ijms21239030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731385PMC
November 2020

Genetic and Epigenetic Aspects of Atopic Dermatitis.

Int J Mol Sci 2020 Sep 4;21(18). Epub 2020 Sep 4.

Department of Medical Laboratory Diagnostics-Biobank, Medical University of Gdańsk, 80-210 Gdańsk, Poland.

Atopic dermatitis is a heterogeneous disease, in which the pathogenesis is associated with mutations in genes encoding epidermal structural proteins, barrier enzymes, and their inhibitors; the role of genes regulating innate and adaptive immune responses and environmental factors inducing the disease is also noted. Recent studies point to the key role of epigenetic changes in the development of the disease. Epigenetic modifications are mainly mediated by DNA methylation, histone acetylation, and the action of specific non-coding RNAs. It has been documented that the profile of epigenetic changes in patients with atopic dermatitis (AD) differs from that observed in healthy people. This applies to the genes affecting the regulation of immune response and inflammatory processes, e.g., both affecting Th1 bias and promoting Th2 responses and the genes of innate immunity, as well as those encoding the structural proteins of the epidermis. Understanding of the epigenetic alterations is therefore pivotal to both create new molecular classifications of atopic dermatitis and to enable the development of personalized treatment strategies.
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http://dx.doi.org/10.3390/ijms21186484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554821PMC
September 2020

Hereditary α tryptasemia is a valid genetic biomarker for severe mediator-related symptoms in mastocytosis.

Blood 2021 Jan;137(2):238-247

Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.

Mastocytosis is a hematopoietic neoplasm characterized by expansion of KIT D816V-mutated clonal mast cells in various organs and severe or even life-threatening anaphylactic reactions. Recently, hereditary α-tryptasemia (HαT) has been described as a common genetic trait with increased copy numbers of the α-tryptase encoding gene, TPSAB1, and associated with an increased basal serum tryptase level and a risk of mast cell activation. The purpose of our study was to elucidate the clinical relevance of HαT in patients with mastocytosis. TPSAB1 germline copy number variants were assessed by digital polymerase chain reaction in 180 mastocytosis patients, 180 sex-matched control subjects, 720 patients with other myeloid neoplasms, and 61 additional mastocytosis patients of an independent validation cohort. α-Tryptase encoding TPSAB1 copy number gains, compatible with HαT, were identified in 17.2% of mastocytosis patients and 4.4% of the control population (P < .001). Patients with HαT exhibited higher tryptase levels than patients without HαT (median tryptase in HαT+ cases: 49.6 ng/mL vs HαT- cases: 34.5 ng/mL, P = .004) independent of the mast cell burden. Hymenoptera venom hypersensitivity reactions and severe cardiovascular mediator-related symptoms/anaphylaxis were by far more frequently observed in mastocytosis patients with HαT than in those without HαT. Results were confirmed in an independent validation cohort. The high prevalence of HαT in mastocytosis hints at a potential pathogenic role of germline α-tryptase encoding TPSAB1 copy number gains in disease evolution. Together, our data suggest that HαT is a novel emerging robust biomarker in mastocytosis that is useful for determining the individual patient´s risk of developing severe anaphylaxis.
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http://dx.doi.org/10.1182/blood.2020006157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116780PMC
January 2021

Results from a Genome-Wide Association Study (GWAS) in Mastocytosis Reveal New Gene Polymorphisms Associated with WHO Subgroups.

Int J Mol Sci 2020 Jul 31;21(15). Epub 2020 Jul 31.

Department of Allergology, Medical University of Gdansk, 80-211 Gdansk, Poland.

Mastocytosis is rare disease in which genetic predisposition is not fully understood. The aim of this study was to analyze associations between mastocytosis and single nucleotide polymorphisms (SNPs) by a genome-wide association study (GWAS) approach. A total of 234 patients were enrolled in our study, including 141 with cutaneous mastocytosis (CM; 78 children and 63 adults) and 93 with systemic mastocytosis (SM, all adults). The control group consisted of 5606 healthy individuals. DNA samples from saliva or blood were genotyped for 551 945 variants using DNA microarrays. The prevalence of certain SNPs was found to vary substantially when comparing patients and healthy controls: rs10838094 of was less frequently detected in CM and SM patients (OR = 0.2071, = 2.21 × 10), rs80138802 in (OR = 5.739, = 1.98 × 10) and rs11845537 in (rs11845537, OR = 6.587, = 6.16 × 10) were more frequently detected in CM in children and adults. Additionally, we found that rs2279343 in and rs7601511 in are less prevalent in CM compared to controls. We identified a number of hitherto unknown associations between certain SNPs and CM and/or SM. Whether these associations are clinically relevant concerning diagnosis, prognosis, or prevention remains to be determined in future studies.
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http://dx.doi.org/10.3390/ijms21155506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432708PMC
July 2020

Risk and management of patients with mastocytosis and MCAS in the SARS-CoV-2 (COVID-19) pandemic: Expert opinions.

J Allergy Clin Immunol 2020 08 17;146(2):300-306. Epub 2020 Jun 17.

Division of Allergy, Department of Dermatology, and Department of Biomedicine, University of Basel, Basel, Switzerland.

The coronavirus disease 2019 (COVID-19) (caused by severe acute respiratory syndrome coronavirus 2) pandemic has massively distorted our health care systems and caused catastrophic consequences in our affected communities. The number of victims continues to increase, and patients at risk can only be protected to a degree, because the virulent state may be asymptomatic. Risk factors concerning COVID-19-induced morbidity and mortality include advanced age, an impaired immune system, cardiovascular or pulmonary diseases, obesity, diabetes mellitus, and cancer treated with chemotherapy. Here, we discuss the risk and impact of COVID-19 in patients with mastocytosis and mast cell activation syndromes. Because no published data are yet available, expert opinions are, by necessity, based on case experience and reports from patients. Although the overall risk to acquire the severe acute respiratory syndrome coronavirus 2 may not be elevated in mast cell disease, certain conditions may increase the risk of infected patients to develop severe COVID-19. These factors include certain comorbidities, mast cell activation-related events affecting the cardiovascular or bronchopulmonary system, and chemotherapy or immunosuppressive drugs. Therefore, such treatments should be carefully evaluated on a case-by-case basis during a COVID-19 infection. In contrast, other therapies, such as anti-mediator-type drugs, venom immunotherapy, or vitamin D, should be continued. Overall, patients with mast cell disorders should follow the general and local guidelines in the COVID-19 pandemic and advice from their medical provider.
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http://dx.doi.org/10.1016/j.jaci.2020.06.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297685PMC
August 2020

COMMD8 changes expression during initial phase of wasp venom immunotherapy.

J Gene Med 2020 11 10;22(11):e3243. Epub 2020 Jul 10.

Department of Allergology, Medical University of Gdańsk, Gdańsk, Poland.

Background: Hymenoptera venom allergy (HVA) is of great concern because of the possibility of anaphylaxis, which may be fatal. Venom immunotherapy (VIT) is the only disease-modifying treatment in HVA and, although efficient, its mechanism remains partially unknown. Gene expression analysis may be helpful for establishing a proper model of tolerance induction during the build-up phase of VIT. The present study aimed to analyze how the start of VIT changes the expression of 15 selected genes.

Methods: Forty-five patients starting VIT with a wasp venom allergy were enrolled. The diagnosis was established based on anaphylaxis history (third or fourth grade on the Mueller scale) and positive soluble immunoglobulin E and/or skin tests. Two blood collections were performed in the patient group: before and after 3 months of VIT. One sample was taken in the control group. Gene expression analysis was performed using a reverse transcriptase-polymerase chain reaction with microfluidic cards and normalized to the 18S housekeeping gene.

Results: Commd8 was the only gene that changed expression significantly after the start of VIT (p = 0.012). Its expression decreased towards the levels observed in the healthy controls. Twelve out of 15 genes (commd8, cldn1, cngb3, fads1, hes6, hla-drb5, htr3b, prlr, slc16a4, snx33, socs3 and twist2) revealed a significantly different expression compared to the healthy controls.

Conclusions: The present study shows that commd8 changes significantly its expression during initial phase of VIT. This gene might be a candidate for VIT biomarker in future studies.
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http://dx.doi.org/10.1002/jgm.3243DOI Listing
November 2020

ARIA digital anamorphosis: Digital transformation of health and care in airway diseases from research to practice.

Authors:
Jean Bousquet Josep M Anto Claus Bachert Tari Haahtela Torsten Zuberbier Wienczyslawa Czarlewski Anna Bedbrook Sinthia Bosnic-Anticevich G Walter Canonica Victoria Cardona Elisio Costa Alvaro A Cruz Marina Erhola Wytske J Fokkens Joao A Fonseca Maddalena Illario Juan-Carlos Ivancevich Marek Jutel Ludger Klimek Piotr Kuna Violeta Kvedariene Ltt Le Désirée E Larenas-Linnemann Daniel Laune Olga M Lourenço Erik Melén Joaquim Mullol Marek Niedoszytko Mikaëla Odemyr Yoshitaka Okamoto Nikos G Papadopoulos Vincenzo Patella Oliver Pfaar Nhân Pham-Thi Christine Rolland Boleslaw Samolinski Aziz Sheikh Mikhail Sofiev Charlotte Suppli Ulrik Ana Todo-Bom Peter-Valentin Tomazic Sanna Toppila-Salmi Ioanna Tsiligianni Arunas Valiulis Erkka Valovirta Maria-Teresa Ventura Samantha Walker Sian Williams Arzu Yorgancioglu Ioana Agache Cezmi A Akdis Rute Almeida Ignacio J Ansotegui Isabella Annesi-Maesano Sylvie Arnavielhe Xavier Basagaña Eric D Bateman Annabelle Bédard Martin Bedolla-Barajas Sven Becker Kazi S Bennoor Samuel Benveniste Karl C Bergmann Michael Bewick Slawomir Bialek Nils E Billo Carsten Bindslev-Jensen Leif Bjermer Hubert Blain Matteo Bonini Philippe Bonniaud Isabelle Bosse Jacques Bouchard Louis-Philippe Boulet Rodolphe Bourret Koen Boussery Fluvio Braido Vitalis Briedis Andrew Briggs Christopher E Brightling Jan Brozek Guy Brusselle Luisa Brussino Roland Buhl Roland Buonaiuto Moises A Calderon Paulo Camargos Thierry Camuzat Luis Caraballo Ana-Maria Carriazo Warner Carr Christine Cartier Thomas Casale Lorenzo Cecchi Alfonso M Cepeda Sarabia Niels H Chavannes Ekaterine Chkhartishvili Derek K Chu Cemal Cingi Jaime Correia de Sousa David J Costa Anne-Lise Courbis Adnan Custovic Biljana Cvetkosvki Gennaro D'Amato Jane da Silva Carina Dantas Dejan Dokic Yves Dauvilliers Giulia De Feo Govert De Vries Philippe Devillier Stefania Di Capua Gerard Dray Ruta Dubakiene Stephen R Durham Mark Dykewicz Motohiro Ebisawa Mina Gaga Yehia El-Gamal Enrico Heffler Regina Emuzyte John Farrell Jean-Luc Fauquert Alessandro Fiocchi Antje Fink-Wagner Jean-François Fontaine José M Fuentes Perez Bilun Gemicioğlu Amiran Gamkrelidze Judith Garcia-Aymerich Philippe Gevaert René Maximiliano Gomez Sandra González Diaz Maia Gotua Nick A Guldemond Maria-Antonieta Guzmán Jawad Hajjam Yunuen R Huerta Villalobos Marc Humbert Guido Iaccarino Despo Ierodiakonou Tomohisa Iinuma Ewa Jassem Guy Joos Ki-Suck Jung Igor Kaidashev Omer Kalayci Przemyslaw Kardas Thomas Keil Musa Khaitov Nikolai Khaltaev Jorg Kleine-Tebbe Rostislav Kouznetsov Marek L Kowalski Vicky Kritikos Inger Kull Stefania La Grutta Lisa Leonardini Henrik Ljungberg Philip Lieberman Brian Lipworth Karin C Lodrup Carlsen Catarina Lopes-Pereira Claudia C Loureiro Renaud Louis Alpana Mair Bassam Mahboub Michaël Makris Joao Malva Patrick Manning Gailen D Marshall Mohamed R Masjedi Jorge F Maspero Pedro Carreiro-Martins Mika Makela Eve Mathieu-Dupas Marcus Maurer Esteban De Manuel Keenoy Elisabete Melo-Gomes Eli O Meltzer Enrica Menditto Jacques Mercier Yann Micheli Neven Miculinic Florin Mihaltan Branislava Milenkovic Dimitirios I Mitsias Giuliana Moda Maria-Dolores Mogica-Martinez Yousser Mohammad Steve Montefort Ricardo Monti Mario Morais-Almeida Ralph Mösges Lars Münter Antonella Muraro Ruth Murray Robert Naclerio Luigi Napoli Leyla Namazova-Baranova Hugo Neffen Kristoff Nekam Angelo Neou Björn Nordlund Ettore Novellino Dieudonné Nyembue Robyn O'Hehir Ken Ohta Kimi Okubo Gabrielle L Onorato Valentina Orlando Solange Ouedraogo Julia Palamarchuk Isabella Pali-Schöll Peter Panzner Hae-Sim Park Gianni Passalacqua Jean-Louis Pépin Ema Paulino Ruby Pawankar Jim Phillips Robert Picard Hilary Pinnock Davor Plavec Todor A Popov Fabienne Portejoie David Price Emmanuel P Prokopakis Fotis Psarros Benoit Pugin Francesca Puggioni Pablo Quinones-Delgado Filip Raciborski Rojin Rajabian-Söderlund Frederico S Regateiro Sietze Reitsma Daniela Rivero-Yeverino Graham Roberts Nicolas Roche Erendira Rodriguez-Zagal Christine Rolland Regina E Roller-Wirnsberger Nelson Rosario Antonino Romano Menachem Rottem Dermot Ryan Johanna Salimäki Mario M Sanchez-Borges Joaquin Sastre Glenis K Scadding Sophie Scheire Peter Schmid-Grendelmeier Holger J Schünemann Faradiba Sarquis Serpa Mohamed Shamji Juan-Carlos Sisul Mikhail Sofiev Dirceu Solé David Somekh Talant Sooronbaev Milan Sova François Spertini Otto Spranger Cristiana Stellato Rafael Stelmach Michel Thibaudon Teresa To Mondher Toumi Omar Usmani Antonio A Valero Rudolph Valenta Marylin Valentin-Rostan Marilyn Urrutia Pereira Rianne van der Kleij Michiel Van Eerd Olivier Vandenplas Tuula Vasankari Antonio Vaz Carneiro Giorgio Vezzani Frédéric Viart Giovanni Viegi Dana Wallace Martin Wagenmann De Yun Wang Susan Waserman Magnus Wickman Dennis M Williams Gary Wong Piotr Wroczynski Panayiotis K Yiallouros Osman M Yusuf Heather J Zar Stéphane Zeng Mario E Zernotti Luo Zhang Nan Shan Zhong Mihaela Zidarn

Allergy 2021 01 23;76(1):168-190. Epub 2020 Oct 23.

University Clinic of Respiratory and Allergic Diseases, Golnik, Slovenia.

Digital anamorphosis is used to define a distorted image of health and care that may be viewed correctly using digital tools and strategies. MASK digital anamorphosis represents the process used by MASK to develop the digital transformation of health and care in rhinitis. It strengthens the ARIA change management strategy in the prevention and management of airway disease. The MASK strategy is based on validated digital tools. Using the MASK digital tool and the CARAT online enhanced clinical framework, solutions for practical steps of digital enhancement of care are proposed.
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http://dx.doi.org/10.1111/all.14422DOI Listing
January 2021

New Approach to Paediatric Mastocytosis: Implications of KIT D816V Mutation Detection in Peripheral Blood.

Acta Derm Venereol 2020 May 28;100(10):adv00149. Epub 2020 May 28.

Department of Dermatology, Venereology and Allergology, Medical University of Gdańsk, Gdańsk, Poland.

is missing (Short communication).
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http://dx.doi.org/10.2340/00015555-3504DOI Listing
May 2020

Clinical features and survival of patients with indolent systemic mastocytosis defined by the updated WHO classification.

Allergy 2020 08 16;75(8):1927-1938. Epub 2020 Mar 16.

Department of Internal Medicine I, Division of Hematology and Hemostaseology, Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria.

Background: In indolent systemic mastocytosis (ISM), several risk factors of disease progression have been identified. Previous studies, performed with limited patient numbers, have also shown that the clinical course in ISM is stable and comparable to that of cutaneous mastocytosis (CM). The aim of this project was to compare the prognosis of patients with ISM with that of patients with CM.

Methods: We employed a dataset of 1993 patients from the registry of the European Competence Network on Mastocytosis (ECNM) to compare outcomes of ISM and CM.

Results: We found that overall survival (OS) is worse in ISM compared to CM. Moreover, in patients with typical ISM, bone marrow mastocytosis (BMM), and smoldering SM (SSM), 4.1% of disease progressions have been observed (4.9% of progressions in typical ISM group, 1.7% in BMM, and 9.4% in SSM). Progressions to advanced SM were observed in 2.9% of these patients. In contrast, six patients with CM (1.7%) converted to ISM and no definitive progression to advanced SM was found. No significant differences in OS and event-free survival (EFS) were found when comparing ISM, BMM, and SSM. Higher risk of both progression and death was significantly associated with male gender, worse performance status, and organomegaly.

Conclusion: Our data confirm the clinical impact of the WHO classification that separates ISM from CM and from other SM variants.
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http://dx.doi.org/10.1111/all.14248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7115854PMC
August 2020

MicroRNAs: future biomarkers and targets of therapy in asthma?

Curr Opin Pulm Med 2020 05;26(3):285-292

Department of Allergology, Medical University of Gdańsk, Gdańsk, Poland.

Purpose Of Review: MicroRNAs (miRNAs) are small noncoding RNA molecules that are considered one of the fundamental regulatory mechanisms of gene expression. They are involved in many biologic processes, such as signal transduction, cell proliferation and differentiation, apoptosis and stress responses. The purpose of this review is to present recent knowledge about the role of miRNAs in asthma and outline possible applications of miRNAs.

Recent Findings: A core set of miRNAs involved in asthma includes downregulated let-7 family, miR-193b, miR-375 as well as upregulated miR-21, miR-223, miR-146a, miR-142-5p, miR-142-3p, miR-146b and miR-155. Recently it has been shown that most of the involved miRNAs increase secretion of Th2 cytokines, decrease secretion of Th1 cytokines, promote differentiation of T cells towards Th2 or play a role in hyperplasia and hypertrophy of bronchial smooth muscle cells. The profiles of miRNAs correlate with clinical characteristics, including lung function, phenotype and severity of asthma.

Summary: Recent publications confirmed crucial regulatory role of miRNAs in the pathomechanism of asthma. Some single miRNAs or their sets hold the promise for their use as asthma biomarkers facilitating diagnosis or prediction of treatment outcomes. They are also possible target of future therapies. The studies in this field are lacking though.
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http://dx.doi.org/10.1097/MCP.0000000000000673DOI Listing
May 2020

How to diagnose mast cell activation syndrome: practical considerations.

Pol Arch Intern Med 2020 04 25;130(4):317-323. Epub 2020 Feb 25.

Department of Allergology, Medical University of Gdańsk, Gdańsk, Poland

Mast cells (MCs) are an important component of the immune system. Their physiological function is involved in multiple areas of human physiology, thus symptoms of their increased activation vary greatly from severe allergic reactions, such as anaphylaxis, to chronic symptoms, such as depression or osteoporosis. Studies on mastocytosis revealed a subgroup of patients presenting symptoms of increased MC degranulation, defined as mast cell activation syndrome (MCAS). This population includes patients with primary MCAS with clonal abnormal MCs, who do not fulfill the criteria for mastocytosis. These symptoms often overlap with comorbidities, which makes the diagnosis and treatment of MCAS difficult. The syndrome is diagnosed on the basis of 3 criteria: 1) the presence of typical symptoms; 2) elevation of serum tryptase levels; and 3) response to anti-mediator treatment. The diagnosis of MCAS is important especially in patients with anaphylaxis or osteoporosis who require the use of an epinephrine emergency kit and insect venom immunotherapy. In this review, genetic mechanisms and typical symptoms of MCAS as well as its diagnostic criteria and implications were discussed, with a special emphasis on practical guidance with the aim to improve patient care.
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http://dx.doi.org/10.20452/pamw.15212DOI Listing
April 2020

Smoking history is negatively associated with allergen specific immunotherapy efficacy: a retrospective analysis.

Postepy Dermatol Alergol 2019 Dec 30;36(6):673-676. Epub 2019 Dec 30.

Department of Allergology, Medical University of Gdansk, Gdansk, Poland.

Introduction: Allergen specific immunotherapy (AIT) is the only treatment modifying the course of the disease in patients allergic to airborne allergens. It has been proven to be effective in allergic populations, however individual patients vary in terms of response to the therapy.

Aim: To assess the factors that might affect the efficacy of AIT.

Material And Methods: Patients treated with AIT for grass pollen or house dust mites were included. The efficacy of AIT was assessed with the use of Allergy Control Score (ACS), performed before and at least 1 year after AIT. The following variables were assessed as potential risk factors for a worse response to AIT: age, gender, type of allergy, type of allergen, type of vaccine, type of AIT and smoking history.

Results: The study group consisted of 145 subjects.AIT was effective in the entire group; the mean ACS results decreased from 21.14 to 14.41 points (< 0.0001). No differences in efficacy in terms of assessed risk factors were found, except for smoking history (ACS change in the smoking group was smaller: from 21.8 to 18.1 points; = 0.09, OR = 0.323; 95% CI: 0.11-0.88; = 0.02).

Conclusions: Smoking history may affect AIT outcomes.
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http://dx.doi.org/10.5114/ada.2018.80654DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6986293PMC
December 2019

Prognostic impact of eosinophils in mastocytosis: analysis of 2350 patients collected in the ECNM Registry.

Leukemia 2020 04 18;34(4):1090-1101. Epub 2019 Nov 18.

Department of Internal Medicine I, Division of Hematology and Hemostaseology, Vienna, Austria.

Systemic mastocytosis (SM) is frequently associated with eosinophilia. To examine its prevalence and clinical impact in all WHO classification-based subcategories, we analyzed eosinophil counts in 2350 mastocytosis patients using the dataset of the European Competence Network on Mastocytosis. Ninety percent of patients had normal eosinophil counts, 6.8% mild eosinophilia (0.5-1.5 × 10/l), and 3.1% hypereosinophilia (HE; >1.5 × 10/l). Eosinophilia/HE were mainly present in patients with advanced SM (17%/19%), and only rarely recorded in patients with indolent and smoldering SM (5%/1%), and some patients with cutaneous mastocytosis. The eosinophil count correlated with organomegaly, dysmyelopoiesis, and the WHO classification, but not with mediator-related symptoms or allergy. Eosinophilia at diagnosis had a strong prognostic impact (p < 0.0001) on overall survival (OS) and progression-free survival (PFS), with a 10-year OS of 19% for patients with HE, 70% for those with mild eosinophilia, and 88% for patients with normal eosinophil counts. In 89% of patients with follow-up data (n = 1430, censored at start of cytoreductive therapy), eosinophils remained stable. In those with changing eosinophil counts (increase/decrease or mixed pattern), OS and PFS were inferior compared with patients with stable eosinophil counts. In conclusion, eosinophilia and HE are more prevalent in advanced SM and are predictors of a worse outcome.
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http://dx.doi.org/10.1038/s41375-019-0632-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7115841PMC
April 2020

International prognostic scoring system for mastocytosis (IPSM): a retrospective cohort study.

Lancet Haematol 2019 Dec 31;6(12):e638-e649. Epub 2019 Oct 31.

Department of Internal Medicine I, Division of Hematology and Hemostaseology, and Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, Vienna, Austria.

Background: The WHO classification separates mastocytosis into distinct variants, but prognostication remains a clinical challenge. The aim of this study was to improve prognostication for patients with mastocytosis.

Methods: We analysed data of the registry of the European Competence Network on Mastocytosis including 1639 patients (age 17-90 years) diagnosed with mastocytosis according to WHO criteria between Jan 12, 1978, and March 16, 2017. Univariate and multivariate analyses with Cox regression were applied to identify prognostic variables predicting survival outcomes and to establish a prognostic score. We validated this International Prognostic Scoring System in Mastocytosis (IPSM) with data of 462 patients (age 17-79 years) from the Spanish network Red Española de Mastocitosis diagnosed between Jan 22, 1998, and Nov 2, 2017.

Findings: The prognostic value of the WHO classification was confirmed in our study (p<0·0001). For patients with non-advanced mastocytosis (n=1380), we identified age 60 years or older (HR 10·75, 95% CI 5·68-20·32) and a concentration of alkaline phosphatase 100 U/L or higher (2·91, 1·60-5·30) as additional independent prognostic variables for overall survival. The resulting scoring system divided patients with non-advanced mastocytosis into three groups: low (no risk factors), intermediate 1 (one risk factor), and intermediate 2 (two risk factors). Overall survival and progression-free survival differed significantly among these groups (p<0·0001). In patients with advanced mastocytosis (n=259), age 60 years or older (HR 2·14, 95% CI 1·42-3·22), a concentration of tryptase 125 ng/mL or higher (1·81, 1·20-2·75), a leukocyte count of 16 × 10 per L or higher (1·88, 1·27-2·79), haemoglobin of 11 g/dL or lower (1·71, 1·13-2·57), a platelet count of 100 × 10 per L or lower (1·63, 1·13-2·34), and skin involvement (0·46, 0·30-0·69) were prognostic variables. Based on these variables, a separate score for advanced mastocytosis with four risk categories was established, with significantly different outcomes for overall survival and progression-free survival (p<0·0001). The prognostic value of both scores was confirmed in 413 patients with non-advanced disease and 49 with advanced mastocytosis from the validation cohort.

Interpretation: The IPSM scores for patients with non-advanced and advanced mastocytosis can be used to predict survival outcomes and guide treatment decisions. However, the predictive value of the IPSM needs to be confirmed in forthcoming trials.

Funding: Austrian Science Fund, Deutsche Forschungsgemeinschaft, Koeln Fortune Program, Charles and Ann Johnson Foundation, Instituto de Salud Carlos III, Fondos FEDER, Research-Foundation Flanders/Fonds Wetenschappelijk Onderzoek, Clinical Research-Fund of the University Hospitals Leuven, and Research-Foundation Flanders/Fonds Wetenschappelijk Onderzoek.
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http://dx.doi.org/10.1016/S2352-3026(19)30166-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7115823PMC
December 2019

Impairment of lung diffusion capacity-a new consequence in the long-term childhood leukaemia survivors.

Ann Hematol 2019 Sep 2;98(9):2103-2110. Epub 2019 Jul 2.

Department of Allergology and Pneumonology, Medical University of Gdańsk, 7 Debinki Street, 80-211, Gdansk, Poland.

Childhood leukaemia survivors (CLS) are known to have developed long-term impairment of lung function. The reasons for that complication are only partially known. The aims of this study were to assess pulmonary function in CLS and identify (1) risk factors and (2) clinical manifestations for the impairment of airflow and lung diffusion. The study group included 74 CLS: 46 treated with chemotherapy alone (HSCT-), 28 with chemotherapy and haematopoietic stem cell transplantation (HSCT+), and 84 healthy subjects (control group (CG)). Spirometry and diffusion limit of carbon monoxide (DLCO) tests were performed in all subjects. Ten (14%) survivors had restrictive, five (7%) had obstructive pattern, and 47 (66%) had reduced DLCO. The age at diagnosis, type of transplant, and type of conditioning regimen did not significantly affect the pulmonary function tests. The DLCO%pv were lower in CLS than in CG (p < 0.03) and in the HSCT+ than in the HSCT- survivors (p < 0.05). The pulmonary infection increased the risk of diffusion impairment (OR 5.1, CI 1.16-22.9, p = 0.019). DLCO was reduced in survivors who experienced CMV lung infection (p < 0.001). The main symptom of impaired lung diffusion was poor tolerance of exercise (p < 0.005). The lower lung diffusion capacity is the most frequent abnormality in CLS. HSCT and pulmonary infection, in particular with CMV infection, are strong risk factors for impairment of lung diffusion capacity in CLS. Clinical manifestation of DLCO impairment is poor exercise tolerance. A screening for respiratory abnormalities in CLS seems to be of significant importance.
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http://dx.doi.org/10.1007/s00277-019-03745-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6700051PMC
September 2019

Proposed Diagnostic Algorithm for Patients with Suspected Mast Cell Activation Syndrome.

J Allergy Clin Immunol Pract 2019 04 5;7(4):1125-1133.e1. Epub 2019 Feb 5.

Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.

Mast cell activation (MCA) accompanies diverse physiologic and pathologic processes and is one of the more frequently encountered conditions in medicine. MCA-related symptoms are usually mild and often transient. In such cases, histamine receptor blockers and other mediator-targeting drugs can usually control MCA. In severe cases, an MCA syndrome (MCAS) may be diagnosed. However, overt MCAS is an unusual condition, and many patients referred because of suspected MCAS are diagnosed with other diseases (autoimmune, neoplastic, or infectious) unrelated to MCA or suffer from MCA-related (eg, allergic) disorders and/or comorbidities without fulfilling criteria of an overt MCAS. These considerations are important as more and more patients are informed that they may have MCA or even MCAS without completing a thorough medical evaluation. In fact, in several instances, symptoms are misinterpreted as MCA/MCAS, and other clinically relevant conditions are not thoroughly pursued. The number of such referrals is increasing. To avoid such unnecessary referrals and to prevent misdiagnoses, we here propose a diagnostic algorithm through which a clinically relevant (systemic) MCA can be suspected and MCAS can subsequently be documented or excluded. In addition, the algorithm proposed should help guide the investigating care providers to consider the 2 principal diagnoses that may underlie MCAS, namely, severe allergy and systemic mastocytosis accompanied by severe MCA. Although validation is required, we anticipate that this algorithm will facilitate the management of patients with suspected MCAS.
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http://dx.doi.org/10.1016/j.jaip.2019.01.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6643056PMC
April 2019

Mast cells in mastocytosis and allergy - Important player in metabolic and immunological homeostasis.

Adv Med Sci 2019 Mar 11;64(1):124-130. Epub 2019 Jan 11.

Department of General and Medical Biochemistry, University of Gdańsk, Gdańsk, Poland.

The role of mast cell (MC) activity in pathophysiology is complex and challenging and its clinical effects are difficult to predict. Apart from the known role of MCs in basic immunological processes and allergy, underlined is their importance in bone mineralization and in regulation of autoimmune reactions. Mast cell mediators, especially those released from mast cells in degranulation, but also those released constitutively, are important both in metabolic and immunological processes. Mastocytosis is a heterogeneous group of disorders characterized by accumulation of MC in one or more organs. There are scientific data indicating that mastocytosis patients are at increased risk of osteoporosis in the systemic form of the disease and children with cutaneous mastocytosis have a higher rate of hypogammaglobulinemia. Moreover, the origin of osteoporosis in patients with allergy is no longer considered as linked to steroid therapy only, but to the mast cell mediators' activity as well. There are indications that osteoporosis symptoms in this group of patients may develop independently of the cumulative steroids' dose. Thus, the influence of mast cells on metabolic and immunologic processes in allergic patients should be investigated. The assessment of mast cell activity and burden in mastocytosis may be used to guide clinical management of patients with allergy.
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http://dx.doi.org/10.1016/j.advms.2018.08.013DOI Listing
March 2019

The Data Registry of the European Competence Network on Mastocytosis (ECNM): Set Up, Projects, and Perspectives.

J Allergy Clin Immunol Pract 2019 01 8;7(1):81-87. Epub 2018 Nov 8.

Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, Austria; Ludwig Boltzmann Institute for Hematology & Oncology, Medical University of Vienna, Vienna, Austria.

Mastocytosis is a unique hematologic neoplasm with complex biology and pathology and a variable clinical course. The disease can essentially be divided into cutaneous mastocytosis (CM) and systemic mastocytosis (SM). In adults, SM is diagnosed in most cases and manifests as either indolent or advanced disease. Patients with advanced SM have an unfavorable prognosis with reduced survival. However, so far, little is known about the prevalence of various categories of SM and about prognostic factors. In an attempt to learn more about the behavior and evolution of various forms of CM and SM, the European Competence Network on Mastocytosis (ECNM) initiated a mastocytosis registry in 2012. In this article, the set up and start phase of this registry are described. Until 2018, more than 3000 patients from 12 countries and 25 centers have been enrolled. In a majority of all patients, robust follow-up data and relevant clinical end points are available. Using this data set, a series of registry projects have been launched, with the aim to validate previously identified diagnostic and prognostic variables and to identify new disease-related and patient-related parameters in various forms of mastocytosis. Moreover, the core data set of the registry will be useful to establish multiparametric scoring systems through which prognostication and individualized management of patients with mastocytosis should improve in the foreseeable future.
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http://dx.doi.org/10.1016/j.jaip.2018.09.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7115815PMC
January 2019

The Possible Role of Gene Variant Coding Nonfunctional Toll-Like Receptor 2 in the Pathogenesis of Mastocytosis.

Int Arch Allergy Immunol 2018 15;177(1):80-86. Epub 2018 Jun 15.

Department of Dermatology, Venereology and Allergology, Medical University of Gdansk, Gdansk, Poland.

Background: Data on the genetic predisposition to mastocytosis are scarce. The aim of this work was to study the association of single nucleotide polymorphisms of Toll-like receptor (TLR)-2, TLR-4, and TLR-9 genes in Polish patients with mastocytosis.

Objectives: The study comprised 137 patients with mastocytosis (102 cutaneous [60 children and 42 adults] and 35 systemic cases); 171 disease-free individuals were used as controls.

Method: The frequency of polymorphisms R753Q (rs5743708) of TLR-2, 896 A>G (rs496790) of TLR-4, and -1237C>T (rs5743836) of TLR-9 genes were determined with the use of the amplification refractory mutation system polymerase chain reaction method.

Results: It was found that the R753Q TLR-2 gene polymorphism was significantly more frequent in patients with mastocytosis in comparison to healthy controls (p = 0.037) and in the group of SM versus controls (p = 0.0076). The presence in the genotype 753Q variant of TLR-2 gene increased the risk of mastocytosis more than 2-fold (OR 2.51; p = 0.04), and the risk of SM more than 4-fold (OR 4.22; p = 0.01). TLR-4 and TLR-9 polymorphisms were not associated with mastocytosis.

Conclusions: Our results suggest that the R753Q polymorphism of the TLR-2 gene may be involved in the pathogenesis of mastocytosis.
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http://dx.doi.org/10.1159/000489343DOI Listing
September 2018

Transient improvement of skin symptoms in an adult patient with pediatric-onset cutaneous mastocytosis treated with interferon-α.

Int J Dermatol 2018 10 6;57(10):1237-1241. Epub 2018 Apr 6.

Department of Dermatology, Venerology and Allergology, Medical University of Gdańsk, Gdansk, Poland.

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http://dx.doi.org/10.1111/ijd.13965DOI Listing
October 2018

Differences in gene expression related to the outcomes of obesity treatment, peak oxygen uptake, and fatty acid metabolism measured in a cardiopulmonary exercise test.

Pol Arch Intern Med 2018 05 26;128(5):280-286. Epub 2018 Mar 26.

INTRODUCTION The obesity pandemic requires development of methods that could be used on a large scale, such as the cardiopulmonary exercise test (CPET). Gene expression may explain CPET results on the molecular level. OBJECTIVES The aim of this study was to compare gene expression in obesity, depending on CPET results. PATIENTS AND METHODS The study group consisted of 9 obese patients and 7 controls. The treatment encompassed diet, rehabilitation, and behavioral therapy. Diet was based on the body composition analyzed by bioelectrical impedance, resting metabolic rate, and subjective patient preferences. The rehabilitation depended on the CPET results: maximal oxygen uptake and fatty acid metabolism. Behavioral intervention focused on the diagnosis of health problems leading to obesity, lifestyle modification, training in self‑assessment, and development of healthy habits. The intensive treatment lasted for 12 weeks and consisted of consultations with a physician, dietitian, and medical rehabilitation specialist. RNA was isolated from the whole blood. A total of 47 323 transcripts were analyzed, of which 32 379 entities were confirmed to have high quality of RNA. RESULTS We observed differences in gene expression related to the CPET results indicating abnormalities in fat oxidation and maximal oxygen uptake. The genes with major differences in expression were: CLEC12A, HLA‑DRB1, HLA‑DRB4, HLA‑A29.1, IFIT1, and LOC100133662. CONCLUSIONS The differences in gene expression may account for the outcomes of treatment related to inflammation caused by obesity, which affects the muscles, fat tissue, and fatty acid metabolism.
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http://dx.doi.org/10.20452/pamw.4228DOI Listing
May 2018

The role of regulatory T cells and genes involved in their differentiation in pathogenesis of selected inflammatory and neoplastic skin diseases. Part II: The Treg role in skin diseases pathogenesis.

Postepy Dermatol Alergol 2017 Oct 31;34(5):405-417. Epub 2017 Oct 31.

Department of Dermatology, Venereology and Allergology, Medical University of Gdansk, Gdansk, Poland.

Regulatory FOXP3+ T cells (Tregs) constitute 5% to 10% of T cells in the normal human skin. They play an important role in the induction and maintenance of immunological tolerance. The suppressive effects of these cells are exerted by various mechanisms including the direct cytotoxic effect, anti-inflammatory cytokines, metabolic disruption, and modulation of the dendritic cells function. The deficiency of Treg cells number or function are one of the basic elements of the pathogenesis of many skin diseases, such as psoriasis, atopic dermatitis, bacterial and viral infections. They also play a role in the pathogenesis of T cell lymphomas of the skin (cutaneous T cell lymphomas - CTCL), skin tumors and mastocytosis. Here, in the second part of the cycle, we describe dysfunctions of Tregs in selected skin diseases.
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http://dx.doi.org/10.5114/ada.2017.71105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5835974PMC
October 2017

The role of regulatory T cells and genes involved in their differentiation in pathogenesis of selected inflammatory and neoplastic skin diseases. Part III: Polymorphisms of genes involved in Tregs' activation and function.

Postepy Dermatol Alergol 2017 Dec 31;34(6):517-525. Epub 2017 Dec 31.

Department of Dermatology, Venereology and Allergology, Medical University of Gdansk, Gdansk, Poland.

Regulatory T cells (Tregs) represent a cell type that promotes immune tolerance to autologous components and maintains immune system homeostasis. The abnormal function of Tregs is relevant to the pathogenesis of several skin diseases like psoriasis, atopic dermatitis, systemic lupus erythematosus, cutaneous T-cell lymphomas, and skin cancer and is also important in rheumatoid arthritis, diabetes and other autoimmune diseases. In this review, we will summarize the role of mutations and/or polymorphisms of genes involved in Tregs development, and functions in the pathogenesis of selected skin diseases.
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http://dx.doi.org/10.5114/pdia.2017.67053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5799752PMC
December 2017

The role of regulatory T cells and genes involved in their differentiation in pathogenesis of selected inflammatory and neoplastic skin diseases. Part I: Treg properties and functions.

Postepy Dermatol Alergol 2017 Aug 31;34(4):285-294. Epub 2017 Jul 31.

Department of Dermatology, Venereology and Allergology, Medical University of Gdansk, Gdansk, Poland.

Regulatory T cells (Treg) can be divided into two types: the natural cells (tTreg), which arise in the thymus, and the induced cells (iTreg), which are produced in peripheral tissues during immune response. The most recently published studies indicate that the supervisory functions of these cells are weakened in the pathogenesis of autoimmune and neoplastic diseases of the skin. This may be a result of the domination of other immune cells in the skin, such as Th1/Th17/Th22 and Tc1 type in psoriasis and Th2 in atopic dermatitis. The excessive activity of Treg cells can lead to immunosuppression and decrease in the number of Th1 cells, which promote the development and progression of skin cancers. In the case of cutaneous T-cell lymphomas, there are suggestions that tumor progression is associated with the acquisition of the suppressor phenotype of malignant cells. There is genetic background of Treg dysfunction in skin disorders. This article describes the types and functions of Treg cells.
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http://dx.doi.org/10.5114/ada.2017.69305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5560174PMC
August 2017

Masitinib for treatment of severely symptomatic indolent systemic mastocytosis: a randomised, placebo-controlled, phase 3 study.

Lancet 2017 02 7;389(10069):612-620. Epub 2017 Jan 7.

Department of Hematology, Université Paris Descartes, Hôpital Necker Enfants Malades, Assistance Publique Hôpitaux de Paris, Paris, France; Institut Imagine INSERM U1163 and CNRS ERL8654, Université Paris Descartes, Hôpital Necker Enfants Malades, Assistance Publique Hôpitaux de Paris, Paris, France; AB Science, Paris, France. Electronic address:

Background: Indolent systemic mastocytosis, including the subvariant of smouldering systemic mastocytosis, is a lifelong condition associated with reduced quality of life. Masitinib inhibits KIT and LYN kinases that are involved in indolent systemic mastocytosis pathogenesis. We aimed to assess safety and efficacy of masitinib versus placebo in severely symptomatic patients who were unresponsive to optimal symptomatic treatments.

Methods: In this randomised, double-blind, placebo-controlled, phase 3 study, we enrolled adults (aged 18-75 years) with indolent or smouldering systemic mastocytosis, according to WHO classification or documented mastocytosis based on histological criteria, at 50 centres in 15 countries. We excluded patients with cutaneous or non-severe systemic mastocytosis after a protocol amendment. Patients were centrally randomised (1:1) to receive either oral masitinib (6 mg/kg per day over 24 weeks with possible extension) or matched placebo with minimisation according to severe symptoms. The primary endpoint was cumulative response (≥75% improvement from baseline within weeks 8-24) in at least one severe baseline symptom from the following: pruritus score of 9 or more, eight or more flushes per week, Hamilton Rating Scale for Depression of 19 or more, or Fatigue Impact Scale of 75 or more. We assessed treatment effect using repeated measures methodology for rare diseases via the generalised estimating equation model in a modified intention-to-treat population, including all participants assigned to treatment minus those who withdrew due to a non-treatment-related cause. We assessed safety in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT00814073.

Findings: Between Feb 19, 2009, and July 15, 2015, 135 patients were randomly assigned to masitinib (n=71) or placebo (n=64). By 24 weeks, masitinib was associated with a cumulative response of 18·7% in the primary endpoint (122·6 responses of 656·5 possible responses [weighted generalised estimating equation]) compared with 7·4% for placebo (48·9 of 656·5; difference 11·3%; odds ratio 3·6; 95% CI 1·2-10·8; p=0·0076). Frequent severe adverse events (>4% difference from placebo) were diarrhoea (eight [11%] of 70 in the masitinib group vs one [2%] of 63 in the placebo group), rash (four [6%] vs none), and asthenia (four [6%] vs one [2%]). The most frequent serious adverse events were diarrhoea (three patients [4%] vs one [2%]) and urticaria (two [3%] vs none), and no life-threatening toxicities occurred. One patient in the placebo group died (unrelated to study treatment).

Interpretation: These study findings indicate that masitinib is an effective and well tolerated agent for the treatment of severely symptomatic indolent or smouldering systemic mastocytosis.

Funding: AB Science (Paris, France).
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http://dx.doi.org/10.1016/S0140-6736(16)31403-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5985971PMC
February 2017