Publications by authors named "Karl Sotlar"

136 Publications

COVID-19 vaccination in mastocytosis: recommendations of the European Competence Network on Mastocytosis (ECNM) and American Initiative in Mast Cell Diseases (AIM).

J Allergy Clin Immunol Pract 2021 Apr 5. Epub 2021 Apr 5.

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.

Mastocytosis is a neoplasm characterized by an accumulation of mast cells in various organs and increased risk for severe anaphylaxis in patients with concomitant allergies. Covid-19 is a pandemic that is associated with a relatively high rate of severe lung disease and mortality. The mortality is particularly high in those with certain comorbidities and increases with age. Recently, several companies have developed an effective vaccination against Covid-19. Although the reported frequency of severe side effects is low, there is an emerging discussion about the safety of Covid-19 vaccination in patients with severe allergies and mastocytosis. However, even in these patients, severe adverse reactions are rare. We therefore recommend the broad use of Covid-19 vaccination in patients with mastocytosis on a global basis. The only well-established exception is a known or suspected allergy against a constituent of the vaccine. Safety measures, including premedication and post-vaccination observation should be considered in all patients with mastocytosis, depending on the individual personal risk and overall situation in each case. The current article provides a summary of published data, observations and expert opinion that form the basis of these recommendations.
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http://dx.doi.org/10.1016/j.jaip.2021.03.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019658PMC
April 2021

Adverse Prognostic Impact of the D816V Transcriptional Activity in Advanced Systemic Mastocytosis.

Int J Mol Sci 2021 Mar 4;22(5). Epub 2021 Mar 4.

Department of Hematology and Oncology, University Hospital Mannheim, Heidelberg University, 68167 Mannheim, Germany.

In systemic mastocytosis (SM), qualitative and serial quantitative assessment of the D816V mutation is of diagnostic and prognostic relevance. We investigated peripheral blood and bone marrow samples of 161 patients (indolent SM (ISM), = 40; advanced SM, AdvSM, = 121) at referral and during follow-up for the D816V variant allele frequency (VAF) at the DNA-level and the D816V expressed allele burden (EAB) at the RNA-level. A round robin test with four participating laboratories revealed an excellent correlation ( > 0.99, > 0.98) between three different DNA-assays. VAF and EAB strongly correlated in ISM ( 0.91, coefficient of determination, 0.84) but only to a lesser extent in AdvSM ( 0.71; = 0.5). However, as compared to an EAB/VAF ratio ≤2 (cohort A, 77/121 patients, 64%) receiver operating characteristic (ROC) analysis identified an EAB/VAF ratio of >2 (cohort B, 44/121 patients, 36%) as predictive for an advanced phenotype and a significantly inferior median survival (3.3 vs. 11.7 years; = 0.005). In terms of overall survival, Cox-regression analysis was only significant for the EAB/VAF ratio >2 ( = 0.006) but not for VAF or EAB individually. This study demonstrates for the first time that the transcriptional activity of D816V may play an important role in the pathophysiology of SM.
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http://dx.doi.org/10.3390/ijms22052562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961551PMC
March 2021

Hsa-miR-375/RASD1 Signaling May Predict Local Control in Early Breast Cancer.

Genes (Basel) 2020 Nov 26;11(12). Epub 2020 Nov 26.

radART-Institute for Research and Development on Advanced Radiation Technologies, Paracelsus Medical University, Müllner Hauptstrasse 48, 5020 Salzburg, Austria.

Background: In order to characterize the various subtypes of breast cancer more precisely and improve patients selection for breast conserving therapy (BCT), molecular profiling has gained importance over the past two decades. MicroRNAs, which are small non-coding RNAs, can potentially regulate numerous downstream target molecules and thereby interfere in carcinogenesis and treatment response via multiple pathways. The aim of the current two-phase study was to investigate whether hsa-miR-375-signaling through RASD1 could predict local control (LC) in early breast cancer.

Results: The patient and treatment characteristics of 81 individuals were similarly distributed between relapse ( = 27) and control groups ( = 54). In the pilot phase, the primary tumors of 28 patients were analyzed with microarray technology. Of the more than 70,000 genes on the chip, 104 potential hsa-miR-375 target molecules were found to have a lower expression level in relapse patients compared to controls (-value < 0.2). For RASD1, a hsa-miR-375 binding site was predicted by an in silico search in five mRNA-miRNA databases and mechanistically proven in previous pre-clinical studies. Its expression levels were markedly lower in relapse patients than in controls (-value of 0.058). In a second phase, this finding could be validated in an independent set of 53 patients using ddPCR. Patients with enhanced levels of hsa-miR-375 compared to RASD1 had a higher probability of local relapse than those with the inverse expression pattern of the two markers (log-rank test, -value = 0.069).

Conclusion: This two-phase study demonstrates that hsa-miR-375/RASD1 signaling is able to predict local control in early breast cancer patients, which-to our knowledge-is the first clinical report on a miR combined with one of its downstream target proteins predicting LC in breast cancer.
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http://dx.doi.org/10.3390/genes11121404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759924PMC
November 2020

Mast cells as a unique hematopoietic lineage and cell system: From Paul Ehrlich's visions to precision medicine concepts.

Theranostics 2020 29;10(23):10743-10768. Epub 2020 Aug 29.

Departments of Pathology and of Microbiology and Immunology, and the Sean N. Parker Center for Allergy and Asthma Research, Stanford University School of Medicine, Stanford, USA.

The origin and functions of mast cells (MCs) have been debated since their description by Paul Ehrlich in 1879. MCs have long been considered 'reactive bystanders' and 'amplifiers' in inflammatory processes, allergic reactions, and host responses to infectious diseases. However, knowledge about the origin, phenotypes and functions of MCs has increased substantially over the past 50 years. MCs are now known to be derived from multipotent hematopoietic progenitors, which, through a process of differentiation and maturation, form a unique hematopoietic lineage residing in multiple organs. In particular, MCs are distinguishable from basophils and other hematopoietic cells by their unique phenotype, origin(s), and spectrum of functions, both in innate and adaptive immune responses and in other settings. The concept of a unique MC lineage is further supported by the development of a distinct group of neoplasms, collectively referred to as mastocytosis, in which MC precursors expand as clonal cells. The clinical consequences of the expansion and/or activation of MCs are best established in mastocytosis and in allergic inflammation. However, MCs have also been implicated as important participants in a number of additional pathologic conditions and physiological processes. In this article, we review concepts regarding MC development, factors controlling MC expansion and activation, and some of the fundamental roles MCs may play in both health and disease. We also discuss new concepts for suppressing MC expansion and/or activation using molecularly-targeted drugs.
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http://dx.doi.org/10.7150/thno.46719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7482799PMC
August 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

Diffuse midline glioma of the cervical spinal cord with H3 K27M genotype phenotypically mimicking anaplastic ganglioglioma: a case report and review of the literature.

Brain Tumor Pathol 2020 Jul 25;37(3):89-94. Epub 2020 May 25.

Institute of Pathology, University Hospital Salzburg, Paracelsus Medical University, Müllner Hauptstraße 48, 5020, Salzburg, Austria.

Here, we report on a 28-year old male patient presenting with neck and shoulder pain, dysesthesia of all four limbs and hypesthesia of both hands, without motor deficits. Magnetic resonance imaging showed an intradural, intramedullary mass of the cervical spinal cord of 6.4 cm length and 1.7 cm diameter. The patient underwent surgical resection. Histological and immunohistochemical evaluation showed pleomorphic glial tumor cells, mitoses, calcifications, and atypical ganglioid cells compatible with the morphology of anaplastic ganglioglioma (WHO Grade III). Extensive molecular workup revealed H3F3A K27M, TERT C228T and PDGFRα Y849C mutations indicating poor prognosis. The H3F3A K27M mutation assigned the tumor to the molecular group of diffuse midline glioma (WHO Grade IV). Epigenome-wide methylation profiling confirmed the methylation class of diffuse midline glioma. Thus, this is a very rare case of malignant glioma with H3 K27M genotype phenotypically mimicking anaplastic ganglioglioma. This case emphasizes the importance of comprehensive morphological and molecular workup including methylome profiling for advanced patient care.
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http://dx.doi.org/10.1007/s10014-020-00365-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7324431PMC
July 2020

Midostaurin improves quality of life and mediator-related symptoms in advanced systemic mastocytosis.

J Allergy Clin Immunol 2020 08 11;146(2):356-366.e4. Epub 2020 May 11.

University Medical Center Groningen, Department of Hematology, University of Groningen, Groningen, The Netherlands.

Background: Advanced systemic mastocytosis (advSM) is characterized by presence of the KIT D816V mutation and pathologic accumulation of neoplastic mast cells (MCs) in various tissues, leading to severe symptoms and organ damage (eg, cytopenias, liver dysfunction, portal hypertension, malabsorption, and weight loss). Treatment with midostaurin, an orally active multikinase/KIT inhibitor now approved for advSM in the United States and the European Union, resulted in a high rate of response accompanied by reduced MC infiltration of the bone marrow and lowered serum tryptase level.

Objective: We aimed to determine whether midostaurin improves health-related quality of life (QOL) and MC mediator-related symptoms in patients with advSM.

Methods: In 116 patients with systemic mastocytosis (89 patients with advSM fulfilling the strict inclusion criteria of the D2201 study [ClinicalTrials.gov identifier NCT00782067]), QOL and symptom burden were assessed during treatment with midostaurin by using the 12-Item Short-Form Health Survey (SF-12) and the Memorial Symptom Assessment Scale patient-reported questionnaires, respectively. MC mediator-related symptoms were evaluated by using a specific physician-reported questionnaire.

Results: Over the first 6 cycles of treatment with midostaurin (ie, 6 months), patients experienced significant improvements in total SF-12 and Memorial Symptom Assessment Scale scores, as well as in subscores of each instrument. These improvements were durable during 36 months of follow-up. Similarly, we found substantial improvements (67%-100%) in all MC mediator-related symptoms.

Conclusion: QOL and MC mediator-related symptoms significantly improve with midostaurin treatment in patients with advSM (ClinicalTrials.gov identifier, NCT00782067).
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http://dx.doi.org/10.1016/j.jaci.2020.03.044DOI Listing
August 2020

Importance of Adequate Diagnostic Workup for Correct Diagnosis of Advanced Systemic Mastocytosis.

J Allergy Clin Immunol Pract 2020 10 15;8(9):3121-3127.e1. Epub 2020 May 15.

Department of Hematology and Oncology, University Hospital Mannheim, Heidelberg University, Mannheim, Germany. Electronic address:

Background: Little is known about the epidemiology of advanced systemic mastocytosis (advSM).

Objectives: To investigate epidemiologic features and diagnostic pitfalls of advSM in Germany.

Methods: Therefore, 140 patients from a single German reference center of the European Competence Network on Mastocytosis between 2003 and 2018 were analyzed.

Results: The patients' median age was 68 years (range, 26-86 years), and male versus female ratio was 2:1. An elevated serum tryptase, a KIT D816 mutation, and additional somatic mutations, for example, in SRSF2, ASXL1, or RUNX1, were identified in 95%, 91%, and 74% of patients, respectively. Median overall survival was 3.5 years (range, 0.03-14.3 years; male vs female 2.6 vs 4.2 years; P = .02). Two categories of misdiagnoses were identified in 51 of 140 (36%) patients: First, systemic mastocytosis (SM) was overlooked in 28 of 140 (20%) patients primarily diagnosed with various subtypes of myeloid neoplasms. Second, 23 of 140 (16%) patients were diagnosed with supposed progression from indolent SM to advSM; however, combination of an elevated KIT D816V variant allele frequency in peripheral blood (n = 22), monocytosis (n = 9), eosinophilia (n = 6), and/or mutations in SRSF2, ASXL1, or RUNX1 (n = 10) suggest that distinct signs of potential advSM were overlooked in virtually all patients. Based on locally diagnosed patients in an area of 2.5 million inhabitants, but obviously without considering more, yet unrecognized cases, the incidence and prevalence of advSM is at least 0.8 and 5.2, respectively, per 1 million inhabitants.

Conclusions: Adequate analyses of tryptase levels, bone marrow morphology, and genetics in patients with myeloid neoplasms or SM would help to prevent the significant underdiagnosis of advSM.
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http://dx.doi.org/10.1016/j.jaip.2020.05.005DOI Listing
October 2020

Mesenchymal iron deposition is associated with adverse long-term outcome in non-alcoholic fatty liver disease.

Liver Int 2020 08 28;40(8):1872-1882. Epub 2020 May 28.

First Department of Medicine, Paracelsus Medical University, Salzburg, Austria.

Background & Aims: Approximately one-third of patients with non-alcoholic fatty liver disease (NAFLD) show signs of mild-to-moderate iron overload. The impact of histological iron deposition on the clinical course of patients with NAFLD has not been established.

Methods & Results: For this retrospective study, 299 consecutive patients with biopsy-proven NAFLD and a mean follow-up of 8.4 (±4.1; range: 0.3-18.0) years were allocated to one of four groups according to presence of hepatic iron in the reticuloendothelial system (RES) and/or hepatocytes (HC): 156 subjects (52%) showed no stainable iron (NONE), 58 (19%) exclusively reticuloendothelial (xRES), 19 (6%) exclusively hepatocellular (xHC) and 66 (22%) showed a mixed (HC/RES) pattern of iron deposition. A long-term analysis for overall survival, hepatic, cardiovascular or extrahepatic-malignant events was conducted. Based on multivariate Cox proportional hazards models any reticuloendothelial iron was associated with fatal and non-fatal hepatic events. Specifically, xRES showed a cause-specific hazard ratio (csHR) of 2.4 (95%-CI, 1.0-5.8; P = .048) for hepatic as well as cardiovascular fatal and non-fatal events combined (csHR 3.2; 95%-CI, 1.2-8.2; P = .015). Furthermore, the mixed HC/RES iron pattern showed a higher rate of combined hepatic fatal and non-fatal events (csHR 3.6; 95%-CI, 1.4-9.5; P = .010), while xHC iron deposition was not associated with any defined events.

Conclusions: The presence of reticuloendothelial-accentuated hepatic iron distribution patterns is associated with detrimental long-term outcomes reflected in a higher rate of both liver-related and cardiovascular fatal and non-fatal events.
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http://dx.doi.org/10.1111/liv.14503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496452PMC
August 2020

Tissue ACE phenotyping in lung cancer.

PLoS One 2019 26;14(12):e0226553. Epub 2019 Dec 26.

Department of Medicine, University of Arizona Health Sciences, Tucson, AZ, United States of America.

Background: Pulmonary vascular endothelium is the main metabolic site for Angiotensin I-Converting Enzyme (ACE)-mediated degradation of several biologically-active peptides (angiotensin I, bradykinin, hemo-regulatory peptide Ac-SDKP). Primary lung cancer growth and lung cancer metastases decrease lung vascularity reflected by dramatic decreases in both lung and serum ACE activity. We performed precise ACE phenotyping in tissues from subjects with lung cancer.

Methodology: ACE phenotyping included: 1) ACE immunohistochemistry with specific and well-characterized monoclonal antibodies (mAbs) to ACE; 2) ACE activity measurement with two ACE substrates (HHL, ZPHL); 3) calculation of ACE substrates hydrolysis ratio (ZPHL/HHL ratio); 4) the pattern of mAbs binding to 17 different ACE epitopes to detect changes in ACE conformation induced by tumor growth (conformational ACE fingerprint).

Results: ACE immunostaining was dramatically decreased in lung cancer tissues confirmed by a 3-fold decrease in ACE activity. The conformational fingerprint of ACE from tumor lung tissues differed from normal lung (6/17 mAbs) and reflected primarily higher ACE sialylation. The increase in ZPHL/HHL ratio in lung cancer tissues was consistent with greater conformational changes of ACE. Limited analysis of the conformational ACE fingerprint in normal lung tissue and lung cancer tissue form the same patient suggested a remote effect of tumor tissue on ACE conformation and/or on "field cancerization" in a morphologically-normal lung tissues.

Conclusions/significance: Local conformation of ACE is significantly altered in tumor lung tissues and may be detected by conformational fingerprinting of human ACE.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0226553PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6932779PMC
March 2020

New developments in the field of mastocytosis and mast cell activation syndromes: a summary of the Annual Meeting of the European Competence Network on Mastocytosis (ECNM) 2019.

Leuk Lymphoma 2020 05 26;61(5):1075-1083. Epub 2019 Dec 26.

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

Mastocytosis are a group of hematologic neoplasms characterized by an accumulation of atypical mast cells in one or several organs/tissues, often accompanied by mast cell activation. Whereas in children the disease manifestations are mostly limited to the skin, in adults the disease is usually systemic (systemic mastocytosis; SM) and involves the bone marrow and/or other internal organs. Several variants of SM have been defined. Whereas most patients have indolent SM, some patients have advanced SM, which underlines the complexity of SM. In 2002, a European consortium of clinicians and scientists initiated a multidisciplinary, multi-national cooperative network, termed the 'European Competence Network on Mastocytosis' (ECNM), with the aim to improve diagnosis and therapy of patients with mastocytosis and other mast cell activation disorders. Since then, members of the ECNM have organized Annual Meetings in several European countries. The present article provides a summary of advances in the field presented during the 17th Annual ECNM meeting held in Salzburg in October 2019.
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http://dx.doi.org/10.1080/10428194.2019.1703974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7115828PMC
May 2020

MARS: Mutation-Adjusted Risk Score for Advanced Systemic Mastocytosis.

J Clin Oncol 2019 11 11;37(31):2846-2856. Epub 2019 Sep 11.

University Hospital Mannheim, Heidelberg University, Mannheim, Germany.

Purpose: To develop a risk score for patients with advanced systemic mastocytosis (AdvSM) that integrates clinical and mutation characteristics.

Patients And Methods: The study included 383 patients with AdvSM from the German Registry on Disorders of Eosinophils and Mast Cells (training set; n = 231) and several centers for mastocytosis in the United States and Europe, all within the European Competence Network on Mastocytosis (validation set; n = 152). A Cox multivariable model was used to select variables that were predictive of overall survival (OS).

Results: In multivariable analysis, the following risk factors were identified as being associated with OS: age greater than 60 years, anemia (hemoglobin < 10 g/dL), thrombocytopenia (platelets < 100 × 10/L), presence of one high molecular risk gene mutation (ie, in , , and/or ), and presence of two or more high molecular risk gene mutations. By assigning hazard ratio-weighted points to these variables, the following three risk categories were defined: low risk (median OS, not reached), intermediate risk (median OS, 3.9 years; 95% CI, 2.1 to 5.7 years), and high risk (median OS, 1.9 years; 95% CI, 1.3 to 2.6 years; < .001). The mutation-adjusted risk score (MARS) was independent of the WHO classification and was confirmed in the independent validation set. During a median follow-up time of 2.2 years (range, 0 to 23 years), 63 (16%) of 383 patients experienced a leukemic transformation to secondary mast cell leukemia (32%) or secondary acute myeloid leukemia (68%). The MARS was also predictive for leukemia-free survival ( < .001).

Conclusion: The MARS is a validated, five-parameter, WHO-independent prognostic score that defines three risk groups among patients with AdvSM and may improve up-front treatment stratification for these rare hematologic neoplasms.
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http://dx.doi.org/10.1200/JCO.19.00640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823885PMC
November 2019

Autoimmune myocarditis is not associated with left ventricular systolic dysfunction.

Eur J Clin Invest 2019 Aug 14;49(8):e13132. Epub 2019 Jun 14.

Department of Cardiology, Clinic of Internal Medicine II, Paracelsus Medical University of Salzburg, Salzburg, Austria.

Background: Experimental autoimmune myocarditis (EAM) is a common animal model for the investigation of the pathophysiology of myocarditis. Because of diverging findings from previous studies, we performed serial echocardiographic examinations throughout the course of the disease and investigated the dimensions of the murine heart and left ventricular (LV) systolic function.

Materials And Methods: Experimental autoimmune myocarditis was induced in male Balb/c mice by subcutaneous injection of a fragment of the α-myosin heavy chain (MyHC-α 614-629: Ac-SLKLMATLFSTYASAD). Transthoracic echocardiography was performed on days 0, 7 and 21 in healthy animals and mice with EAM.

Results: Experimental autoimmune myocarditis was associated with a reduction in LV systolic function and an increase in LV internal diameter in diastole (LVIDd) and systole (LVIDs) 7 days postimmunization. After 21 days, EAM led to a significant increase in LV-thickness (1.3-fold increase in LV anterior wall diameter in diastole [LVAWDd]), but there was no difference in LV systolic function between immunized animals and healthy controls. LV-thickness correlated well with the severity of myocarditis in the histopathological examination (LVAWDd: rs = 0.603, P = 0.003, LV anterior wall diameter in systole (LVAWDs): rs = 0.718, P < 0.0001).

Conclusion: Our results indicate that EAM leads to an initial dilatation of the LV that is followed by ventricular "hypertrophy." On day 21, there was no significant difference in LV systolic function between immunized animals and controls. Furthermore, the ageing of the animals had a major impact on the echocardiographic parameters; therefore, the use of healthy age-matched controls seems warranted when echocardiography is performed in rodents.
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http://dx.doi.org/10.1111/eci.13132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6771695PMC
August 2019

Proposed diagnostic criteria for classical chronic myelomonocytic leukemia (CMML), CMML variants and pre-CMML conditions.

Haematologica 2019 10 2;104(10):1935-1949. Epub 2019 May 2.

Department of Pathology, Hematopathology Unit and James P Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA.

Chronic myelomonocytic leukemia (CMML) is a myeloid neoplasm characterized by dysplasia, abnormal production and accumulation of monocytic cells and an elevated risk of transforming into acute leukemia. Over the past two decades, our knowledge about the pathogenesis and molecular mechanisms in CMML has increased substantially. In parallel, better diagnostic criteria and therapeutic strategies have been developed. However, many questions remain regarding prognostication and optimal therapy. In addition, there is a need to define potential pre-phases of CMML and special CMML variants, and to separate these entities from each other and from conditions mimicking CMML. To address these unmet needs, an international consensus group met in a Working Conference in August 2018 and discussed open questions and issues around CMML, its variants, and pre-CMML conditions. The outcomes of this meeting are summarized herein and include diag nostic criteria and a proposed classification of pre-CMML conditions as well as refined minimal diagnostic criteria for classical CMML and special CMML variants, including oligomonocytic CMML and CMML associated with systemic mastocytosis. Moreover, we propose diagnostic standards and tools to distinguish between 'normal', pre-CMML and CMML entities. These criteria and standards should facilitate diagnostic and prognostic evaluations in daily practice and clinical studies in applied hematology.
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http://dx.doi.org/10.3324/haematol.2019.222059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6886439PMC
October 2019

A randomized trial comparing limited-excision conisation to Large Loop Excision of the Transformation Zone (LLETZ) in cervical dysplasia patients.

J Gynecol Oncol 2019 May;30(3):e42

Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Munich, Germany.

Objective: To show noninferiority of a limited-excision (resection of the dysplastic lesion only) vs. classical Large Loop Excision of the Transformation Zone (LLETZ).

Methods: In this prospective, randomized, multicenter trial, women with human papillomavirus (HPV) positive cervical intraepithelial neoplasia grade 3 were randomized into two groups (1:1). Primary outcome was the rate of negative HPV tests after 6 months, secondary outcomes included cone size, complete resection rates as well as cytological and histological results after 6 and 12 months. A sample size of 1,000 was calculated to show noninferiority of the limited-excision compared to the LLETZ group using a noninferiority margin of 5%. Enrollment was stopped after 100 patients due to slow accrual.

Results: Patients in the limited-excision group did not show a lower number of negative HPV tests (78% [LLETZ]-80% [limited-excision]=-2%; 90% confidence interval=-15%, 12%). The limited-excision resulted in a substantially lower cone size (LLETZ: 1.97 mL vs. limited-excision: 1.02 mL; p<0.001) but higher numbers of involved margins (LLETZ: 8% vs. limited-excision: 20%). Although postoperative cytological results slightly differed, histological results were similar in both groups. One limited-excision patient received immediate re-conisation, whereas one patient in each group was scheduled for re-conisation after 6 months.

Conclusion: The limited-excision could represent a promising option to reduce the surgical extent of conisations while maintaining oncological safety. The trial was not sufficiently powered to reach statistical significance due to early termination. Nevertheless, the study provides important insights in the feasibility of a limited-excision and could serve as a pilot study for future trials.

Trial Registration: German Clinical Trials Register Identifier: DRKS00006169.
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http://dx.doi.org/10.3802/jgo.2019.30.e42DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6424847PMC
May 2019

Clonal Hematopoiesis with Oncogenic Potential (CHOP): Separation from CHIP and Roads to AML.

Int J Mol Sci 2019 Feb 12;20(3). Epub 2019 Feb 12.

Institute of Pathology, Ludwig-Maximilians University, 80539 Munich, Germany.

The development of leukemia is a step-wise process that is associated with molecular diversification and clonal selection of neoplastic stem cells. Depending on the number and combinations of lesions, one or more sub-clones expand/s after a variable latency period. Initial stages may develop early in life or later in adulthood and include premalignant (indolent) stages and the malignant phase, defined by an acute leukemia. We recently proposed a cancer model in which the earliest somatic lesions are often age-related early mutations detectable in apparently healthy individuals and where additional oncogenic mutations will lead to the development of an overt neoplasm that is usually a preleukemic condition such as a myelodysplastic syndrome. These neoplasms may or may not transform to overt acute leukemia over time. Thus, depending on the type and number of somatic mutations, clonal hematopoiesis (CH) can be divided into CH with indeterminate potential (CHIP) and CH with oncogenic potential (CHOP). Whereas CHIP mutations usually create the molecular background of a neoplastic process, CHOP mutations are disease-related or even disease-specific lesions that trigger differentiation and/or proliferation of neoplastic cells. Over time, the acquisition of additional oncogenic events converts preleukemic neoplasms into secondary acute myeloid leukemia (sAML). In the present article, recent developments in the field are discussed with a focus on CHOP mutations that lead to distinct myeloid neoplasms, their role in disease evolution, and the impact of additional lesions that can drive a preleukemic neoplasm into sAML.
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http://dx.doi.org/10.3390/ijms20030789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6387423PMC
February 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

KIT D816 mutated/CBF-negative acute myeloid leukemia: a poor-risk subtype associated with systemic mastocytosis.

Leukemia 2019 05 11;33(5):1124-1134. Epub 2019 Jan 11.

Department of Hematology and Oncology, University Hospital Mannheim, Heidelberg University, Mannheim, Germany.

KIT D816 mutations (KIT D816) are strongly associated with systemic mastocytosis (SM) but are also detectable in acute myeloid leukemia (AML), where they represent an adverse prognostic factor in combination with core binding factor (CBF) fusion genes. Here, we evaluated the clinical and molecular features of KIT D816/CBF-negative (CBF) AML, a previously uncharacterized combination. All KIT D816/CBF cases (n = 40) had histologically proven SM with associated AML (SM-AML). Molecular analyses revealed at least one additional somatic mutation (median, n = 3) beside KIT D816 (e.g., SRSF2, 38%; ASXL1, 31%; RUNX1, 34%) in 32/32 (100%) patients. Secondary AML evolved in 29/40 (73%) patients from SM ± associated myeloid neoplasm. Longitudinal molecular and cytogenetic analyses revealed the acquisition of new mutations and/or karyotype evolution in 15/16 (94%) patients at the time of SM-AML. Median overall survival (OS) was 5.4 months. A screen of two independent AML databases (AML) revealed remarkable similarities between KIT D816/CBF SM-AML and KIT D816/CBF AML (n = 69) with regard to KIT D816 variant allele frequency, mutation profile, aberrant karyotype, and OS suggesting underlying SM in a significant proportion of AML patients. Bone marrow histology and reclassification as SM-AML has important clinical implications regarding prognosis and potential inclusion of KIT inhibitors in treatment concepts.
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http://dx.doi.org/10.1038/s41375-018-0346-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6756067PMC
May 2019

Lean Patients with Non-Alcoholic Fatty Liver Disease Have a Severe Histological Phenotype Similar to Obese Patients.

J Clin Med 2018 Dec 17;7(12). Epub 2018 Dec 17.

First Department of Medicine, Paracelsus Medical University, 5020 Salzburg, Austria.

A small proportion of lean patients develop non-alcoholic fatty liver disease (NAFLD). We aimed to report the histological picture of lean NAFLD in comparison to overweight and obese NAFLD patients. Biopsy and clinical data from 466 patients diagnosed with NAFLD were stratified to groups according to body mass index (BMI): lean (BMI ≤ 25.0 kg/m², confirmed to be appropriate = 74), overweight (BMI > 25.0 ≤ 30.0 kg/m², = 242) and obese (BMI > 30.0 kg/m², = 150). Lean NAFLD patients had a higher rate of lobular inflammation compared to overweight patients (12/74; 16.2% vs. 19/242; 7.9%; = 0.011) but were similar to obese patients (25/150; 16.7%). Ballooning was observed in fewer overweight patients (38/242; 15.7%) compared to lean (19/74; 25.7%; = 0.014) and obese patients (38/150; 25.3%; = 0.006). Overweight patients had a lower rate of portal and periportal fibrosis (32/242; 13.2%) than lean (19/74; 25.7%; = 0.019) and obese patients (37/150; 24.7%; = 0.016). The rate of cirrhosis was higher in lean patients (6/74; 8.1%) compared to overweight (4/242; 1.7%; = 0.010) and obese patients (3/150; 2.0% = 0.027). In total, 60/466; 12.9% patients were diagnosed with non-alcoholic steatohepatitis (NASH). The rate of NASH was higher in lean (14/74; 18.9% = 0.01) and obese (26/150; 17.3%; = 0.007) compared to overweight patients (20/242; 8.3%)). Among lean patients, fasting glucose, INR and use of thyroid hormone replacement therapy were independent predictors of NASH in a multivariate model. Lean NAFLD patients were characterized by a severe histological picture similar to obese patients but are more progressed compared to overweight patients. Fasting glucose, international normalized ratio (INR) and the use of thyroid hormone replacement may serve as indicators for NASH in lean patients.
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http://dx.doi.org/10.3390/jcm7120562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6306845PMC
December 2018

Progression-specific genes identified in microdissected formalin-fixed and paraffin-embedded tissue containing matched ductal carcinoma in situ and invasive ductal breast cancers.

BMC Med Genomics 2018 Sep 20;11(1):80. Epub 2018 Sep 20.

Department of Obstetrics and Gynaecology, Life-Science-Center, Heinrich-Heine University, Merowingerplatz 1A, 40225, Duesseldorf, Germany.

Background: The transition from ductal carcinoma in situ (DCIS) to invasive breast carcinoma (IBC) is an important step during breast carcinogenesis. Understanding its molecular changes may help to identify high-risk DCIS that progress to IBC. Here, we describe a transcriptomic profiling analysis of matched formalin-fixed and paraffin-embedded (FFPE) DCIS and IBC components of individual breast tumours, containing both tumour compartments. The study was performed to validate progression-associated transcripts detected in an earlier gene profiling project using fresh frozen breast cancer tissue. In addition, FFPE tissues from patients with pure DCIS (pDCIS) were analysed to identify candidate transcripts characterizing DCIS with a high or low risk of progressing to IBC.

Methods: Fifteen laser microdissected pairs of DCIS and IBC were profiled by Illumina DASL technology and used for expression validation by qPCR. Differential expression was independently validated using further 25 laser microdissected DCIS/IBC sample pairs. Additionally, laser microdissected epithelial cells from 31 pDCIS were investigated for expression of candidate transcripts using qPCR.

Results: Multiple statistical calculation methods revealed 1784 mRNAs which are differentially expressed between DCIS and IBC (P < 0.05), of which 124 have also been identified in the gene profiling project using fresh frozen breast cancer tissue. Nine mRNAs that had been selected from the gene list obtained using fresh frozen tissues by applying pathway and network analysis (MMP11, GREM1, PLEKHC1, SULF1, THBS2, CSPG2, COL10A1, COL11A1, KRT14) were investigated in tissues from the same 15 microdissected specimens and the 25 independent tissue samples by qPCR. All selected transcripts were also detected in tumour cells from pDCIS. Expression of MMP11 and COL10A1 increased significantly from pDCIS to DCIS of DCIS/IBC mixed tumours.

Conclusion: We confirm differential expression of progression-associated transcripts in FFPE breast cancer samples which might mediate the transition from DCIS to IBC. MMP11 and COL10A1 may characterize pure DCIS with a high risk developing IDC.
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http://dx.doi.org/10.1186/s12920-018-0403-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6147035PMC
September 2018

Subtyping Of Triple Negative Breast Carcinoma On The Basis Of RTK Expression.

J Cancer 2018 23;9(15):2589-2602. Epub 2018 Jun 23.

Institute of Pathology, Faculty of Medicine, LMU Munich, Germany.

"Triple-negative breast cancers" (TNBC) comprise a heterogeneous group of about 15% of invasive BCs lacking the expression of estrogen and progesterone receptors (ER, PR) and the expression of HER2 (ERBB2) and are therefore no established candidates for targeted treatment options in BC, i.e., endocrine and anti-HER2 therapy. The aim of the present study was to use gene expression profiling and immunohistochemical (IHC) characterization to identify receptor tyrosine kinase (RTK) profiles that would allow patient stratification for the purposes of target-oriented personalized tumor therapy in TNBC. Twenty-nine cases of TNBC selected according to routine diagnostic IHC/cytogenetic criteria were examined by reverse transcription polymerase chain reaction (RT-PCR). RTK mRNA expression profiles were generated for a total of 31 tumor-relevant biomarkers, mainly belonging to the IGF- and EGF-receptor families but also including biomarkers related to downstream signaling. Protein expression of selected biomarkers was investigated by IHC. Hierarchical cluster analysis revealed a dichotomous differentiation pattern amongst TNBCs. A significant difference in gene expression was observed for 16 of the 31 RTK-associated tumor relevant biomarkers between the two newly identified TNBC subgroups. The findings were verified at the posttranslational level by the IHC data. The RTKs HER4, IGF-1R and IGF-2R and the hormone receptors ER and PR below the IHC detection limit play a central role in the differentiation of the two TNBC subgroups. Observed survival was reported as Kaplan-Meier estimates and point towards an improved survival of patients with RTK-high with superior three-year survival rate of 100% compared to RTK-low gene signatures with superior three-year survival rate of 60% (log-rank test, p-value = 0.022). Gene-expression and IHC analysis of the EGF and IGF receptor families and biomarkers associated with downstream signaling point to the existence of two distinct TNBC subtypes. The RTKs HER4, IGF-1R, IGF-2R and the hormone receptors ER and PR appear to be of particular importance here. Based on survival analysis the differentiation of TNBC with RTK-high and RTK-low gene signatures seems to be of prognostic relevance. Additionally, correlation analysis of the relationship between RTKs and ER suggests co-regulatory mechanisms that may have potential significance in new therapeutic approaches.
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http://dx.doi.org/10.7150/jca.23023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6072816PMC
June 2018

Normal and pathological erythropoiesis in adults: from gene regulation to targeted treatment concepts.

Haematologica 2018 10 3;103(10):1593-1603. Epub 2018 Aug 3.

Imagine Institute, INSERM U 1163, CNRS 8654, Université Paris Descartes, Sorbonne, Paris Cité, France

Pathological erythropoiesis with consequent anemia is a leading cause of symptomatic morbidity in internal medicine. The etiologies of anemia are complex and include reactive as well as neoplastic conditions. Clonal expansion of erythroid cells in the bone marrow may result in peripheral erythrocytosis and polycythemia but can also result in anemia when clonal cells are dysplastic and have a maturation arrest that leads to apoptosis and hinders migration, a constellation typically seen in the myelodysplastic syndromes. Rarely, clonal expansion of immature erythroid blasts results in a clinical picture resembling erythroid leukemia. Although several mechanisms underlying normal and abnormal erythropoiesis and the pathogenesis of related disorders have been deciphered in recent years, little is known about specific markers and targets through which prognosis and therapy could be improved in anemic or polycythemic patients. In order to discuss new markers, targets and novel therapeutic approaches in erythroid disorders and the related pathologies, a workshop was organized in Vienna in April 2017. The outcomes of this workshop are summarized in this review, which includes a discussion of new diagnostic and prognostic markers, the updated WHO classification, and an overview of new drugs used to stimulate or to interfere with erythropoiesis in various neoplastic and reactive conditions. The use and usefulness of established and novel erythropoiesis-stimulating agents for various indications, including myelodysplastic syndromes and other neoplasms, are also discussed.
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http://dx.doi.org/10.3324/haematol.2018.192518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6165792PMC
October 2018

S2k-Leitlinie: HPV-assoziierte Läsionen der äußeren Genitalregion und des Anus - Genitalwarzen und Krebsvorstufen der Vulva, des Penis und der peri- und intraanalen Haut (Kurzfassung).

J Dtsch Dermatol Ges 2018 Feb;16(2):242-256

Klinik für Dermatologie, Venerologie und Allergologie, Division of Evidence Based Medicine in Dermatology (dEBM), Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin.

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http://dx.doi.org/10.1111/ddg.13441_gDOI Listing
February 2018

S2k guideline: HPV-associated lesions of the external genital region and the anus - anogenital warts and precancerous lesions of the vulva, the penis, and the peri- and intra-anal skin (short version).

J Dtsch Dermatol Ges 2018 Feb;16(2):242-255

Department of Dermatology, Venereology and Allergology, Division of Evidence-based Medicine in Dermatology (dEBM), Charité - Universitätsmedizin Berlin, corporate member of Free University Berlin, Humboldt University Berlin, and Berlin Institute of Health, Berlin, Germany.

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http://dx.doi.org/10.1111/ddg.13441DOI Listing
February 2018

Incidence and prognostic impact of cytogenetic aberrations in patients with systemic mastocytosis.

Genes Chromosomes Cancer 2018 05 19;57(5):252-259. Epub 2018 Feb 19.

Department of Hematology and Oncology, University Hospital Mannheim, Heidelberg University, Heidelberg, Germany.

The clinical behavior of systemic mastocytosis (SM) is strongly associated with activating mutations in KIT (D816V in >80% of cases), with the severity of the phenotype influenced by additional somatic mutations, for example, in SRSF2, ASXL1, or RUNX1. Complex molecular profiles are frequently associated with the presence of an associated hematologic neoplasm (AHN) and an unfavorable clinical outcome. However, little is known about the incidence and prognostic impact of cytogenetic aberrations. We analyzed cytogenetic and molecular characteristics of 109 patients (KIT D816V+, n = 102, 94%) with indolent (ISM, n = 26) and advanced SM (n = 83) with (n = 73, 88%) or without AHN. An aberrant karyotype was identified in SM-AHN (16/73, 22%) patients only. In patients with an aberrant karyotype, additional somatic mutations were identified in 12/16 (75%) patients. Seven of 10 (70%) patients with a poor-risk karyotype, for example, monosomy 7 or complex karyotype, and 1/6 (17%) patients with a good-risk karyotype progressed to secondary acute myeloid leukemia (n = 7) or mast cell leukemia (n = 1) within a median of 40 months (range 2-190, P = .04). In advanced SM, the median overall survival (OS) of poor-risk karyotype patients was significantly shorter than in good-risk/normal karyotype patients (4 vs 39 months; hazard ratio 11.7, 95% CI 5.0-27.3; P < .0001). Additionally, the shortened OS in patients with poor-risk karyotype was independent from the mutation status. In summary, a poor-risk karyotype is an independent prognostic variable in advanced SM. Cytogenetic and molecular analyses should be routinely performed in all patients with advanced SM ± AHN because these investigations greatly support prognostication and treatment decisions.
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http://dx.doi.org/10.1002/gcc.22526DOI Listing
May 2018

Proposed Terminology and Classification of Pre-Malignant Neoplastic Conditions: A Consensus Proposal.

EBioMedicine 2017 Dec 26;26:17-24. Epub 2017 Nov 26.

Institute of Pathology, Ludwig-Maximilian University, Munich, Germany.

Cancer evolution is a step-wise non-linear process that may start early in life or later in adulthood, and includes pre-malignant (indolent) and malignant phases. Early somatic changes may not be detectable or are found by chance in apparently healthy individuals. The same lesions may be detected in pre-malignant clonal conditions. In some patients, these lesions may never become relevant clinically whereas in others, they act together with additional pro-oncogenic hits and thereby contribute to the formation of an overt malignancy. Although some pre-malignant stages of a malignancy have been characterized, no global system to define and to classify these conditions is available. To discuss open issues related to pre-malignant phases of neoplastic disorders, a working conference was organized in Vienna in August 2015. The outcomes of this conference are summarized herein and include a basic proposal for a nomenclature and classification of pre-malignant conditions. This proposal should assist in the communication among patients, physicians and scientists, which is critical as genome-sequencing will soon be offered widely for early cancer-detection.
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http://dx.doi.org/10.1016/j.ebiom.2017.11.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5832623PMC
December 2017

Proposed minimal diagnostic criteria for myelodysplastic syndromes (MDS) and potential pre-MDS conditions.

Oncotarget 2017 Sep 5;8(43):73483-73500. Epub 2017 Jul 5.

Department of Pathology, Hematopathology Unit and James P Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA.

Myelodysplastic syndromes (MDS) comprise a heterogeneous group of myeloid neoplasms characterized by peripheral cytopenia, dysplasia, and a variable clinical course with about 30% risk to transform to secondary acute myeloid leukemia (AML). In the past 15 years, diagnostic evaluations, prognostication, and treatment of MDS have improved substantially. However, with the discovery of molecular markers and advent of novel targeted therapies, new challenges have emerged in the complex field of MDS. For example, MDS-related molecular lesions may be detectable in healthy individuals and increase in prevalence with age. Other patients exhibit persistent cytopenia of unknown etiology without dysplasia. Although these conditions are potential pre-phases of MDS they may also transform into other bone marrow neoplasms. Recently identified molecular, cytogenetic, and flow-based parameters may add in the delineation and prognostication of these conditions. However, no generally accepted integrated classification and no related criteria are as yet available. In an attempt to address this challenge, an international consensus group discussed these issues in a working conference in July 2016. The outcomes of this conference are summarized in the present article which includes criteria and a proposal for the classification of pre-MDS conditions as well as updated minimal diagnostic criteria of MDS. Moreover, we propose diagnostic standards to delineate between ´normal´, pre-MDS, and MDS. These standards and criteria should facilitate diagnostic and prognostic evaluations in clinical studies as well as in clinical practice.
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http://dx.doi.org/10.18632/oncotarget.19008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5650276PMC
September 2017

Response and progression on midostaurin in advanced systemic mastocytosis: D816V and other molecular markers.

Blood 2017 07 19;130(2):137-145. Epub 2017 Apr 19.

Department of Hematology and Oncology, Mannheim University Medical Center, Mannheim, Germany.

In advanced systemic mastocytosis (advSM), disease evolution is often triggered by mutations (D816V in >80% of cases) and by additional mutations (eg, in , , and/or [S/A/R in >60% of cases]). In a recently reported phase 2 study, midostaurin, a multikinase/KIT inhibitor, demonstrated an overall response rate (ORR) of 60% in advSM but biomarkers predictive of response are lacking. We evaluated the impact of molecular markers at baseline and during follow-up in 38 midostaurin-treated advSM patients. The median overall survival (OS) was 30 months (95% confidence interval, 6-54) from start of midostaurin. ORR and OS were significantly different between S/A/R (n = 12) and S/A/R (n = 23) patients (ORR: 75% vs 39%, = .04; OS: = .01, HR 4.5 [1.3-16.2]). Depending on the relative reduction of the D816V expressed allele burden (EAB) at month 6, patients were classified as responders (≥25%, n = 17) or nonresponders (<25%, n = 11). In univariate analyses at month 6, reduction of D816V EAB ≥25%, tryptase ≥50%, and alkaline phosphatase ≥50% were significantly associated with improved OS. In multivariate analysis, only D816V EAB reduction ≥25% remained an independent on-treatment marker for improved OS ( = .004, HR 6.8 [1.8-25.3]). Serial next-generation sequencing analysis of 28 genes in 16 patients revealed acquisition of additional mutations or increasing variant allele frequency in /, , , or associated with progression in 7 patients. In midostaurin-treated advSM patients, the complexity and dynamics of mutational profiles significantly affect response, progression, and prognosis.
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http://dx.doi.org/10.1182/blood-2017-01-764423DOI Listing
July 2017

Twelve-year survival and immune correlates in dendritic cell-vaccinated melanoma patients.

JCI Insight 2017 Apr 20;2(8). Epub 2017 Apr 20.

Department of Dermatology.

Background: Reports on long-term (≥10 years) effects of cancer vaccines are missing. Therefore, in 2002, we initiated a phase I/II trial in cutaneous melanoma patients to further explore the immunogenicity of our DC vaccine and to establish its long-term toxicity and clinical benefit after a planned 10-year followup.

Methods: Monocyte-derived DCs matured by TNFα, IL-1β, IL-6, and PGE2 and then loaded with 4 HLA class I and 6 class II-restricted tumor peptides were injected intradermally in high doses over 2 years. We performed serial immunomonitoring in all 53 evaluable patients.

Results: Vaccine-specific immune responses including high-affinity, IFNγ-producing CD4+ and lytic polyfunctional CD8+ T cells were de novo induced or boosted in most patients. Exposure of mature DCs to trimeric soluble CD40 ligand, unexpectedly, did not further enhance such immune responses, while keyhole limpet hemocyanin (KLH) pulsing to provide unspecific CD4+ help promoted CD8+ T cell responses - notably, their longevity. An unexpected 19% of nonresectable metastatic melanoma patients are still alive after 11 years, a survival rate similar to that observed in ipilimumab-treated patients and achieved without any major (>grade 2) toxicity. Survival correlated significantly with the development of intense vaccine injection site reactions, and with blood eosinophilia after the first series of vaccinations, suggesting that prolonged survival was a consequence of DC vaccination.

Conclusions: Long-term survival in advanced melanoma patients undergoing DC vaccination is similar to ipilimumab-treated patients and occurs upon induction of tumor-specific T cells, blood eosinophilia, and strong vaccine injection site reactions occurring after the initial vaccinations.

Trial Registration: ClinicalTrials.gov NCT00053391.

Funding: European Community, Sixth Framework Programme (Cancerimmunotherapy LSHC-CT-2006-518234; DC-THERA LSHB-CT-2004-512074), and German Research Foundation (CRC 643, C1, Z2).
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http://dx.doi.org/10.1172/jci.insight.91438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5396520PMC
April 2017