48 results on '"Thomas Kielsgaard Kristensen"'
Search Results
2. Next-generation sequencing and histological response assessment in peritoneal metastasis from pancreatic cancer treated with PIPAC
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Michael Bau Mortensen, Claus Wilki Fristrup, Signe Bremholm Ellebæk, Thomas Kielsgaard Kristensen, Martin Graversen, Malene Nielsen, Sönke Detlefsen, and Per Pfeiffer
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Male ,medicine.medical_specialty ,Peritoneal metastasis ,Biopsy ,medicine.medical_treatment ,Gastroenterology ,Pathology and Forensic Medicine ,Proto-Oncogene Proteins p21(ras) ,Peritoneum ,Internal medicine ,Pancreatic cancer ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Ascitic Fluid ,Humans ,pancreas ,Neoplasm Metastasis ,Grading (tumors) ,Peritoneal Neoplasms ,Aged ,Original Research ,Chemotherapy ,business.industry ,Peritoneal fluid ,High-Throughput Nucleotide Sequencing ,pancreatic neoplasms ,Oncogenes ,Sequence Analysis, DNA ,General Medicine ,Middle Aged ,peritoneum ,medicine.disease ,medicine.anatomical_structure ,Doxorubicin ,Mutation ,Female ,Lymph ,Cisplatin ,Pancreas ,business ,Injections, Intraperitoneal - Abstract
BackgroundPeritoneal metastasis from pancreatic cancer (PM-PC) may be treated with repeated pressurised intraperitoneal aerosol chemotherapy (PIPAC). Utility of next-generation sequencing (NGS) to detect cancer-related mutations in peritoneal quadrant biopsies (QBs) and peritoneal fluid (PF) after systemic and PIPAC treatment has not been evaluated. Around 90% of pancreatic cancers (PCs) harbour a KRAS mutation, making PC ideal for the evaluation of this aspect.AimsEvaluation of PM-PC in terms of (1) histological response to PIPAC using Peritoneal Regression Grading Score (PRGS), (2) clinical characteristics and (3) frequency of mutations in QBs and PF before and after PIPAC.MethodsPeritoneal QBs and PF were obtained prior to each PIPAC. NGS for 22 cancer-related genes was performed on primary tumours, QBs and PFs. Response was assessed by the four-tiered PRGS.ResultsSixteen patients treated with a median of three PIPAC procedures were included. The mean PRGS was reduced from 1.91 to 1.58 (p=0.02). Fifty-seven specimens (13 primary tumours, 2 metastatic lymph nodes, 16 PFs and 26 QB sets) were analysed with NGS. KRAS mutation was found in 14/16 patients (87.50%) and in QBs, primary tumours and PF in 8/12 (66.67%), 8/13 (61.53%) and 6/9 (66.67%). The median overall survival was 9.9 months (SE 1.5, 95% CI 4.9 to 13.9).ConclusionPIPAC induces histological response in the majority of patients with PM-PC. KRAS mutation can be found in PM-PC after PIPAC at a frequency similar to the primaries. NGS may be used to detect predictive mutations in PM-PC of various origins, also when only post-PIPAC QBs or PFs are available.
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- 2020
3. Impaired immune responses to herpesviruses and microbial ligands in patients with Mono <scp>MAC</scp>
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Maibritt Mardahl, Trine H. Mogensen, Mette Holm, Alon Schneider, Jens Erik Veirum, Mette Christiansen, Thomas Kielsgaard Kristensen, Sofie E. Jørgensen, Klas Raaschou-Jensen, Kristian Assing, and Isik Somuncu Johansen
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Adult ,Male ,herpesviruses ,Myeloid ,mycobacteria ,Ligands ,Germline ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,GATA2 ,medicine ,Humans ,Child ,haematological malignancy ,Transcription factor ,Herpesviridae ,MonoMAC ,Immunodeficiency ,Cytopenia ,business.industry ,Immunologic Deficiency Syndromes ,Hematology ,medicine.disease ,GATA2 Transcription Factor ,medicine.anatomical_structure ,innate immune responses ,030220 oncology & carcinogenesis ,Immunology ,Primary immunodeficiency ,Female ,business ,030215 immunology - Abstract
MonoMAC is a complex primary immunodeficiency caused by mutations in the myeloid transcription factor GATA2, characterized by multilineage cytopenia with malignant complications and severe infections, including mycobacteria and herpesviruses. We describe the clinical presentation, genetics and antiviral inflammatory responses in a small case series. Two patients presented in childhood with mycobacterial infection and were diagnosed with MonoMAC germline GATA2 variants; their healthy fathers with the same mutations were also studied. Three patients were elderly individuals with acquired GATA2 mutations and malignant haematological conditions. Overall, this study demonstrates the heterogeneous clinical presentation and variation in immunodeficiency caused by GATA2 mutations.
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- 2019
4. Genome-wide association study identifies novel susceptibility loci for KIT D816V positive mastocytosis
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Toshiko Tanaka, Gabriella Galatà, William J. Tapper, Sigurd Broesby-Olsen, Yvette Hoade, Ahmed A. Z. Dawoud, Carsten Bindslev-Jensen, Alessandro M. Vannucchi, Christian Gieger, Theresia M. Schnurr, Manja Meggendorfer, Javier I. Muñoz-González, Andreas Reiter, Paola Guglielmelli, Andrés C. García-Montero, Torsten Haferlach, Luigi Ferrucci, Iván Álvarez-Twose, Hanne Vestergaard, Michael Boe Møller, Nicholas C.P. Cross, Konstantin Strauch, Andrew Chase, Stefania Bandinelli, Alberto Orfao, Thomas Kielsgaard Kristensen, Deepti Radia, Wellcome Trust, Helmholtz-Zentrum Munich, Federal Ministry of Education and Research (Germany), Free State of Bavaria, Munich Center of Health Sciences, Ludwig Maximilians University Munich, Ministero della Salute, National Institute on Aging (US), Instituto de Salud Carlos III, European Commission, Associazione Italiana per la Ricerca sul Cancro, Novo Nordisk Foundation, University of Copenhagen, and Lady Tata Memorial Trust
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Male ,Amino Acid Transport System y+ ,TERT ,Receptors, Cytoplasmic and Nuclear ,Genome-wide association study ,Single-nucleotide polymorphism ,Disease ,Biology ,Quantitative trait locus ,Polymorphism, Single Nucleotide ,Germline ,Article ,Genetic variation ,CEBPA ,Genetics ,Humans ,TBL1XR1 ,Genetic Predisposition to Disease ,Gene ,Telomerase ,Genetics (clinical) ,Interleukin-13 ,KIT ,Introns ,Repressor Proteins ,Proto-Oncogene Proteins c-kit ,D816V ,Cebpa ,D816v ,Kit ,Mastocytosis ,Myeloid Cancer ,Tbl1xr1 ,Tert ,CCAAT-Enhancer-Binding Proteins ,DNA, Intergenic ,Female ,RNA, Long Noncoding ,Tryptases ,Myeloid cancer ,Genome-Wide Association Study - Abstract
Mastocytosis is a rare myeloid neoplasm characterized by uncontrolled expansion of mast cells, driven in >80% of affected individuals by acquisition of the KIT D816V mutation. To explore the hypothesis that inherited variation predisposes to mastocytosis, we performed a two-stage genome-wide association study, analyzing 1,035 individuals with KIT D816V positive disease and 17,960 healthy control individuals from five European populations. After quality control, we tested 592,007 SNPs at stage 1 and 75 SNPs at stage 2 for association by using logistic regression and performed a fixed effects meta-analysis to combine evidence across the two stages. From the meta-analysis, we identified three intergenic SNPs associated with mastocytosis that achieved genome-wide significance without heterogeneity between cohorts: rs4616402 (pmeta = 1.37 × 10−15, OR = 1.52), rs4662380 (pmeta = 2.11 × 10−12, OR = 1.46), and rs13077541 (pmeta = 2.10 × 10−9, OR = 1.33). Expression quantitative trait analyses demonstrated that rs4616402 is associated with the expression of CEBPA (peQTL = 2.3 × 10−14), a gene encoding a transcription factor known to play a critical role in myelopoiesis. The role of the other two SNPs is less clear: rs4662380 is associated with expression of the long non-coding RNA gene TEX41 (peQTL = 2.55 × 10−11), whereas rs13077541 is associated with the expression of TBL1XR1, which encodes transducin (β)-like 1 X-linked receptor 1 (peQTL = 5.70 × 10−8). In individuals with available data and non-advanced disease, rs4616402 was associated with age at presentation (p = 0.009; beta = 4.41; n = 422). Additional focused analysis identified suggestive associations between mastocytosis and genetic variation at TERT, TPSAB1/TPSB2, and IL13. These findings demonstrate that multiple germline variants predispose to KIT D816V positive mastocytosis and provide novel avenues for functional investigation., A full list of the investigators who contributed to the generation of the WTCCC data is available from the WTCCC website, funding for which was provided by The Wellcome Trust under award 07611. The KORA study was initiated and financed by the Helmholtz Zentrum München—German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Furthermore, KORA research was supported within the Munich Center of Health Sciences (MC-Health), Ludwig-Maximilians-Universität, as part of LMUinnovativ. The KORA Study Group consists of A. Peters (speaker), J. Heinrich, R. Holle, R. Leidl, C. Meisinger, K. Strauch, and their co-workers, who are responsible for the design and conduct of the KORA studies. We gratefully acknowledge the contribution of all members of field staff conducting the KORA study, and we are grateful to all study participants of KORA for their invaluable contributions to this study. The InCHIANTI study baseline (1998–2000) was supported as a “targeted project” (ICS110.1/RF97.71) by the Italian Ministry of Health and in part by the U.S. National Institute on Aging (263 MD 9164 and 263 MD 821336). The Spanish mastocytosis cohort and the Spanish National DNA Bank were supported by grants from the Instituto de Salud Carlos III and FEDER (PI16/00642 and PT17/0015/0044). The Italian cohort of mastocytosis-affected individuals was funded by the Associazione Italiana per la Ricerca sul cancro, Mynerva project, 21267. The Novo Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation. A.A.Z.D. was supported by a Lady Tata International Award; G.G., N.C.P.C., Y.H., A.J.C., and W.J.T. were supported by Blood Cancer UK (13002 and 18007).
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- 2021
5. Omalizumab prevents anaphylaxis and improves symptoms in systemic mastocytosis: Efficacy and safety observations
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Sigurd Broesby-Olsen, Anne Pernille Hermann, Bo Amdi Jensen, Michael Boe Møller, Thomas Kielsgaard Kristensen, Hanne Vestergaard, Troels Havelund, Carsten Bindslev-Jensen, Charlotte G. Mortz, and Frank Siebenhaar
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Male ,0301 basic medicine ,Omalizumab ,Anti-Allergic Agents/administration & dosage ,0302 clinical medicine ,Quality of life ,Anti-Allergic Agents ,Immunology and Allergy ,Systemic mastocytosis ,Skin ,mastocytosis ,Middle Aged ,mast cell disorders ,Omalizumab/administration & dosage ,Treatment Outcome ,Anesthesia ,Cohort ,Female ,Symptom Assessment ,KIT D816V ,Anaphylaxis ,Mastocytosis, Systemic/diagnosis ,medicine.drug ,Adult ,Skin/pathology ,medicine.medical_specialty ,Visual analogue scale ,Immunology ,tryptase ,systemic mastocytosis ,Young Adult ,03 medical and health sciences ,Mastocytosis, Systemic ,Internal medicine ,Journal Article ,anaphylaxis ,Anaphylaxis/etiology ,medicine ,Humans ,Adverse effect ,business.industry ,medicine.disease ,030104 developmental biology ,030228 respiratory system ,Concomitant ,Quality of Life ,omalizumab ,business ,Biomarkers - Abstract
BACKGROUND: Patients with systemic mastocytosis (SM) may suffer from mast cell (MC) mediator-related symptoms insufficiently controlled by conventional therapy. Omalizumab is an established treatment in other MC-driven diseases, but experiences in SM are limited.OBJECTIVE: To assess the efficacy and safety of omalizumab in SM.METHODS: In our patient cohort, we evaluated all SM patients treated with omalizumab. A physician global assessment of type and severity of symptoms was performed at baseline, at 3 and 6 months and at latest follow-up. Quality of life was assessed by visual analogue scale. S-tryptase and KIT D816V allele burden were monitored.RESULTS: A total of 14 adult SM patients (10 ISM, 2 BMM, 1 SSM, and 1 ASM-AHN) received omalizumab with a median duration of 17 months (range: 1-73 months). One patient was excluded due to concomitant cytoreductive therapy. In the remaining 13 patients, we observed a significant reduction in symptoms, with complete symptom control in five (38.5%), major response in three (23.1%), and a partial response in three (23.1%) patients, whereas two patients (15.4%) withdrew due to subjective side-effects at first dose. The treatment was most effective for recurrent anaphylaxis and skin symptoms, less for gastrointestinal, musculoskeletal, and neuropsychiatric symptoms. Patient-reported quality of life showed significant improvement. No significant changes in s-tryptase/KIT D816V allele burden were observed. No severe adverse events were recorded.CONCLUSIONS: Omalizumab appears to be a promising treatment option in SM, effectively preventing anaphylaxis and improving chronic MC mediator-related symptoms, insufficiently controlled by conventional therapy. Controlled studies are needed to substantiate findings.
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- 2017
6. Molecular characterization of sorted malignant B cells from patients clinically identified with mantle cell lymphoma
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Thomas Kielsgaard Kristensen, Niels Abildgaard, Oriane Cédile, Eigil Kjeldsen, Simone Valentin Hansen, Lene Hyldahl Ebbesen, Marcus Høy Hansen, Charlotte Guldborg Nyvold, Mads Thomassen, Torben A Kruse, Hans Herluf Nørgaard Bentzen, Jacob Haaber, Mia Koldby Blum, and Stephanie Kavan
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0301 basic medicine ,Adult ,Cancer Research ,Nonsense mutation ,DNA Mutational Analysis ,Lymphoma, Mantle-Cell ,Biology ,medicine.disease_cause ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,Genetics ,medicine ,Humans ,Splenic marginal zone lymphoma ,Molecular Biology ,B cell ,Mutation ,B-Lymphocytes ,Gene Expression Profiling ,Cell Biology ,Hematology ,medicine.disease ,Molecular diagnostics ,Flow Cytometry ,Lymphoma ,Neoplasm Proteins ,Gene expression profiling ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Cancer research ,Mantle cell lymphoma - Abstract
Mantle cell lymphoma (MCL) is a tumor with a poor prognosis. A few studies have examined the molecular landscape by next-generation sequencing and provided valuable insights into recurrent lesions driving this heterogeneous cancer. However, none has attempted to cross-link the individual genomic and transcriptomic profiles in sorted MCL cells to perform individual molecular characterizations of the lymphomas. Such approaches are relevant as MCL is heterogenous by nature, and thorough molecular diagnostics may potentially benefit the patient with more focused treatment options. In the work described here, we used sorted lymphoma cells from four patients at diagnosis and relapse by intersecting the coding DNA and mRNA. Even though only a few patients were included, this method enabled us to pinpoint a specific set of expressed somatic mutations, to present an overall expression profile different from the normal B cell counterparts, and to track molecular aberrations from diagnosis to relapse. Changes in single-nucleotide coding variants, subtle clonal changes in large-copy-number alterations, subclonal involvement, and changes in expression levels in the clinical course provided detailed information on each of the individual malignancies. In addition to mutations in known genes (e.g., TP53, CCND1, NOTCH1, ATM), we identified others, not linked to MCL, such as a nonsense mutation in SPEN and an MYD88 missense mutation in one patient, which along with copy number alterations exhibited a molecular resemblance to splenic marginal zone lymphoma. The detailed exonic and transcriptomic portraits of the individual MCL patients obtained by the methodology presented here could help in diagnostics, surveillance, and potentially more precise usage of therapeutic drugs by efficient screening of biomarkers.
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- 2019
7. Detection of free intraperitoneal tumour cells in peritoneal lavage fluid from patients with peritoneal metastasis before and after treatment with pressurised intraperitoneal aerosol chemotherapy (PIPAC)
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Trine Rennebod Larsen, Martin Graversen, Michael Bau Mortensen, Claus Wilki Fristrup, Sönke Detlefsen, Per Pfeiffer, and Thomas Kielsgaard Kristensen
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Adult ,Male ,Treatment response ,Peritoneal metastasis ,Pathology ,medicine.medical_specialty ,medicine.medical_treatment ,PIPAC ,Sensitivity and Specificity ,free intraperitoneal tumor cells ,Pathology and Forensic Medicine ,03 medical and health sciences ,chemistry.chemical_compound ,CEA ,0302 clinical medicine ,Carcinoembryonic antigen ,Ascites ,Antineoplastic Combined Chemotherapy Protocols ,Lavage fluid ,medicine ,Biomarkers, Tumor ,Ascitic Fluid ,Humans ,Peritoneal Lavage ,Prospective Studies ,CA-125 ,Peritoneal Neoplasms ,Aged ,Aged, 80 and over ,Chemotherapy ,biology ,business.industry ,Epithelial cell adhesion molecule ,General Medicine ,Middle Aged ,Treatment Outcome ,chemistry ,EpCAM ,peritoneal metastasis ,030220 oncology & carcinogenesis ,Chemotherapy, Cancer, Regional Perfusion ,biology.protein ,030211 gastroenterology & hepatology ,Female ,medicine.symptom ,business ,After treatment - Abstract
AimsIn this study, we investigated whether free intraperitoneal tumour cells (FITC) were detectable in ascites or peritoneal lavage fluid (PLF) from patients with peritoneal metastasis (PM) before and after treatment with pressurised intraperitoneal aerosol chemotherapy (PIPAC).MethodsAscites or PLF retrieved at the first and third PIPAC procedures was analysed by conventional cytology, carcinoembryonic antigen (CEA) and total protein concentration, and quantitative reverse transcriptase PCR (qRT-PCR) for mRNA expression of CEA, epithelial cell adhesion molecule (EpCAM) and cancer antigen 125 (CA-125). Conventional cytology and qRT-PCR were also performed in a negative control group (benign PLF specimens and inflammatory ascites). The treatment response was compared with the histological response based on repeated peritoneal biopsies evaluated by the Peritoneal Regression Grading Score (PRGS).ResultsThirty-five patients with PM of various origins were included from 2015 to 2016. At the first PIPAC procedure, FITC were detected by conventional cytology (sensitivity 0.58, specificity 1.00), CEA protein (cut-off 0.4 µg/L, sensitivity 0.71), CEA mRNA (sensitivity 0.75, specificity 1.00), EpCAM mRNA (sensitivity 0.71, specificity 1.00) and CA-125 mRNA (sensitivity 0.43, specificity 1.00). The combination of CEA/EpCAM mRNA had a sensitivity of 0.88 and a specificity of 1.00. The evaluation of ascites or PLF retrieved at the third PIPAC procedure failed to detect treatment response, when compared with the histological PRGS.ConclusionsThe evaluation of CEA and EpCAM mRNA detects FITC with a high sensitivity and an excellent specificity, but is not useful for response evaluation in patients treated with PIPAC.Trial registration numberNCT02320448.
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- 2018
8. Risk of solid cancer, cardiovascular disease, anaphylaxis, osteoporosis and fractures in patients with systemic mastocytosis: A nationwide population-based study
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Dóra Körmendiné Farkas, Henrik Frederiksen, Sigurd Broesby-Olsen, Carsten Bindslev-Jensen, Thomas Kielsgaard Kristensen, Henrik Toft Sørensen, Charlotte G. Mortz, Hanne Vestergaard, Michael Boe Møller, and Anne Pernille Hermann
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0301 basic medicine ,medicine.medical_specialty ,education.field_of_study ,Proportional hazards model ,business.industry ,Hazard ratio ,Osteoporosis ,Population ,Absolute risk reduction ,Hematology ,medicine.disease ,Surgery ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,030228 respiratory system ,Internal medicine ,Cohort ,medicine ,education ,business ,Stroke ,Cohort study - Abstract
In patients with systemic mastocytosis (SM), several aspects of morbidity remain poorly understood. We assessed the risk of solid cancers, cardiovascular disease, anaphylaxis, osteoporosis, and fractures in SM patients. Using Danish medical registries, we conducted a nationwide population-based cohort study including 687 adult (≥15 years) SM patients diagnosed during 1997-2012. A comparison cohort of 68,700 subjects from the general Danish population who were alive and without SM at the given SM subject's diagnosis were age- and gender-matched. Outcomes were a new diagnosis of solid cancer, venous thromboembolism (VTE), myocardial infarction (MI), stroke, anaphylaxis, osteoporosis, or fracture. For solid cancers the hazard ratio (HR) was 2.4 (95% confidence interval [CI] 1.9-2.8) with a 10-year absolute risk (AR) in the SM-cohort of 12.6% (95% CI 9.4-16.3). Specifically, we found a HR of 7.5 (95% CI 4.4-13.0) for melanoma and a HR of 2.5 (95% CI 1.7-3.5) for non-melanoma skin cancers (NMSCs). For VTE we found a HR of 1.9 (95% CI 1.2-3.0), with a 10-year AR of 3.9% (95% CI 2.3-6.1); for MI a nonsignificant increased HR of 1.4 (95% CI 0.9-2.3), with a 10-year AR of 1.8% (95% CI 0.9-3.2); and for stroke a HR of 1.6 (95% CI 1.1-2.3) with a 10-year AR of 4.6% (95% CI 2.8-6.9). The HR for anaphylaxis was 7.2 (95% CI 5.3-9.9), and the 10-year AR was 3.1% (95% CI 1.9-4.9). For osteoporosis the HR was 3.6 (95% CI 2.7-4.6) with a 10-year AR of 7.2% (95% CI 5.2-9.8). For fractures the HR was 1.2 (95% CI 0.9-1.6) and the 10-year AR was 5.9% (95% CI 3.9-8.4). SM patients are at increased risk of solid cancers - especially melanoma and NMSC-and cardiovascular disease. The risk of anaphylaxis and osteoporosis is clearly increased in SM, though absolute risk was low in this population-based study. The fracture-risk was only slightly increased. Am. J. Hematol. 91:1069-1075, 2016. © 2016 Wiley Periodicals, Inc.
- Published
- 2016
9. Erratum to 'Molecular characterization of sorted malignant B cells from patients clinically identified with mantle cell lymphoma' [Experimental Hematology 84 (2020) 7–18]
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Mads Thomassen, Simone Valentin Hansen, Oriane Cédile, Thomas Kielsgaard Kristensen, Lene Hyldahl Ebbesen, Eigil Kjeldsen, Jacob Haaber, Marcus Høy Hansen, Niels Abildgaard, Hans Herluf Nørgaard Bentzen, Torben A Kruse, Charlotte Guldborg Nyvold, Mia Koldby Blum, and Stephanie Kavan
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Cancer Research ,Pathology ,medicine.medical_specialty ,business.industry ,Experimental Hematology ,Genetics ,medicine ,Mantle cell lymphoma ,Cell Biology ,Hematology ,medicine.disease ,business ,Molecular Biology - Published
- 2020
10. Fatal anaphylaxis following a hornet sting in a yellow jacket venom-sensitized patient with undetected monoclonal mast cell activation syndrome and without previous history of a systemic sting reaction
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Heiko Methe, Sinan Pehlivanli, Martin Köberle, Knut Brockow, Yacine Amar, Hans-Peter Horny, Carsten B. Schmidt-Weber, Thomas Kielsgaard Kristensen, Simon Blank, Peter E. Stömmer, and Tilo Biedermann
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medicine.medical_specialty ,Injury control ,business.industry ,Accident prevention ,Wasps ,Insect Bites and Stings ,Poison control ,Fatal anaphylaxis ,Wasp Venoms ,Dermatology ,Bee Venoms ,Sting ,Monoclonal mast cell activation syndrome ,Yellow jacket venom ,Animals ,Humans ,Immunology and Allergy ,Medicine ,business ,Anaphylaxis ,Mastocytosis - Published
- 2020
11. Core-binding factor acute myeloid leukemia with t(8;21): Risk factors and a novel scoring system (I-CBFit)
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Sheeja T. Pullarkat, Jessica Kohlschmidt, Vinod Pullarkat, Michelle M Dolan, Joachim Deeg, Celalettin Ustun, Krzysztof Mrózek, David R. Czuchlewski, Gerwin Huls, Mark R. Litzow, Nam K. Ku, Jason L. Hornick, Guido Marcucci, Hans-Peter Horny, Erica E. M. Moodie, Dong Chen, Michael Boe Møller, Janie Coulombe, Wolfgang R. Sperr, Michael A. Linden, Young L. Kim, Hanne Vestergaard, Ryo Nakamura, Cecilia Arana Yi, Daniel J. Weisdorf, Robert S. Ohgami, Linda B. Baughn, Sigurd Broesby-Olsen, Jason Gotlib, Clara D. Bloomfield, Thomas Kielsgaard Kristensen, Miguel-Angel Perales, Ana Iris Schiefer, Elizabeth A. Morgan, Amandeep Salhotra, Lori Soma, J. R. Hilberink, Philip M. Kluin, Ryan Shanley, Christina Cho, Cem Akin, Cecilia Yeung, Gregor Hoermann, Peter Valent, Tracy I. George, Gautam Borthakur, Stem Cell Aging Leukemia and Lymphoma (SALL), and Guided Treatment in Optimal Selected Cancer Patients (GUTS)
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Male ,Myeloid ,Cancer Research ,Chromosomes, Human, Pair 21 ,Gene mutation ,Severity of Illness Index ,Translocation, Genetic ,0302 clinical medicine ,AML ,Stem Cell Research - Nonembryonic - Human ,Risk Factors ,80 and over ,FLT3 ,Child ,core-binding factor ,Cancer ,Pediatric ,Aged, 80 and over ,relapse ,Leukemia ,predictive value ,Myeloid leukemia ,Hematology ,Middle Aged ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,CANCER ,Kit d816v ,Leukemia, Myeloid, Acute ,Oncology ,030220 oncology & carcinogenesis ,Child, Preschool ,SURVIVAL ,Pair 8 ,Female ,GENE-MUTATIONS ,Chromosomes, Human, Pair 8 ,Human ,Adult ,Pediatric Research Initiative ,medicine.medical_specialty ,Scoring system ,C-KIT MUTATIONS ,Adolescent ,disease-free survival ,Childhood Leukemia ,Pediatric Cancer ,INV(16) ,PROGNOSTIC IMPACT ,Oncology and Carcinogenesis ,Translocation ,KIT mutation ,and over ,Acute ,acute myeloid leukemia ,lcsh:RC254-282 ,Chromosomes ,03 medical and health sciences ,Young Adult ,Rare Diseases ,Genetic ,Clinical Research ,Genetics ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,Preschool ,Core binding factor acute myeloid leukemia ,Aged ,Gynecology ,Hematopoietic cell ,business.industry ,Core Binding Factors ,scoring system ,Kit mutation ,ADULTS ,Stem Cell Research ,Transplantation ,GROUP-B ,core‐binding factor ,disease‐free survival ,Pair 21 ,Biochemistry and Cell Biology ,business ,030215 immunology - Abstract
Author(s): Ustun, Celalettin; Morgan, Elizabeth; Moodie, Erica EM; Pullarkat, Sheeja; Yeung, Cecilia; Broesby-Olsen, Sigurd; Ohgami, Robert; Kim, Young; Sperr, Wolfgang; Vestergaard, Hanne; Chen, Dong; Kluin, Philip M; Dolan, Michelle; Mrozek, Krzysztof; Czuchlewski, David; Horny, Hans-Peter; George, Tracy I; Kristensen, Thomas Kielsgaard; Ku, Nam K; Yi, Cecilia Arana; Moller, Michael Boe; Marcucci, Guido; Baughn, Linda; Schiefer, Ana-Iris; Hilberink, JR; Pullarkat, Vinod; Shanley, Ryan; Kohlschmidt, Jessica; Coulombe, Janie; Salhotra, Amandeep; Soma, Lori; Cho, Christina; Linden, Michael A; Akin, Cem; Gotlib, Jason; Hoermann, Gregor; Hornick, Jason; Nakamura, Ryo; Deeg, Joachim; Bloomfield, Clara D; Weisdorf, Daniel; Litzow, Mark R; Valent, Peter; Huls, Gerwin; Perales, Miguel-Angel; Borthakur, Gautam | Abstract: BackgroundAlthough the prognosis of core-binding factor (CBF) acute myeloid leukemia (AML) is better than other subtypes of AML, 30% of patients still relapse and may require allogeneic hematopoietic cell transplantation (alloHCT). However, there is no validated widely accepted scoring system to predict patient subsets with higher risk of relapse.MethodsEleven centers in the US and Europe evaluated 247 patients with t(8;21)(q22;q22).ResultsComplete remission (CR) rate was high (92.7%), yet relapse occurred in 27.1% of patients. A total of 24.7% of patients received alloHCT. The median disease-free (DFS) and overall (OS) survival were 20.8 and 31.2 months, respectively. Age, KIT D816V mutated (11.3%) or nontested (36.4%) compared with KIT D816V wild type (52.5%), high white blood cell counts (WBC), and pseudodiploidy compared with hyper- or hypodiploidy were included in a scoring system (named I-CBFit). DFS rate at 2 years was 76% for patients with a low-risk I-CBFit score compared with 36% for those with a high-risk I-CBFit score (P l 0.0001). Low- vs high-risk OS at 2 years was 89% vs 51% (P l 0.0001).ConclusionsI-CBFit composed of readily available risk factors can be useful to tailor the therapy of patients, especially for whom alloHCT is not need in CR1 (ie, patients with a low-risk I-CBFit score).
- Published
- 2018
12. Targeted ultradeep next-generation sequencing as a method forKITD816V mutation analysis in mastocytosis
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Hanne Vestergaard, Sigurd Broesby-Olsen, Carsten Bindslev-Jensen, Michael Boe Møller, and Thomas Kielsgaard Kristensen
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Adult ,Male ,0301 basic medicine ,DNA Mutational Analysis ,Gene Expression ,Biology ,Real-Time Polymerase Chain Reaction ,DNA sequencing ,03 medical and health sciences ,0302 clinical medicine ,Mastocytosis, Systemic ,medicine ,Humans ,Allele ,Systemic mastocytosis ,Alleles ,High-Throughput Nucleotide Sequencing ,Hematology ,General Medicine ,Kit mutation ,Ion semiconductor sequencing ,medicine.disease ,Molecular biology ,Kit d816v ,Proto-Oncogene Proteins c-kit ,030104 developmental biology ,Case-Control Studies ,030220 oncology & carcinogenesis ,Mutation ,Mutation (genetic algorithm) ,Mutation testing ,Female - Abstract
Next-generation sequencing (NGS) is becoming increasingly used for diagnostic mutation analysis in myeloid neoplasms and may also represent a feasible technique in mastocytosis. However, detection of the KIT D816V mutation requires a highly sensitive method in most patients due to the typically low mutation levels. In this study, we established an NGS-based KIT mutation analysis and analyzed the sensitivity of D816V detection using the Ion Torrent platform. Eighty-two individual NGS analyses were included in the study. All samples were also analyzed using highly sensitive KIT D816V mutation-specific qPCR. Measurements of the background level in D816V-negative samples supported a cutoff for positivity of 0.2% in three different NGS panels. Clinical samples from patients with SM that tested positive using qPCR with a D816V allele burden >0.2% also tested positive using NGS. Samples that tested positive using qPCR with an allele burden
- Published
- 2015
13. Comparison of gDNA-based versus mRNA-based KIT D816V mutation analysis reveals large differences between blood and bone marrow in systemic mastocytosis
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Sigurd Broesby-Olsen, Carsten Bindslev-Jensen, Hanne Vestergaard, Thomas Kielsgaard Kristensen, and Michael Boe Møller
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0301 basic medicine ,genomic DNA ,DNA Mutational Analysis ,Bone Marrow Cells ,systemic mastocytosis ,Biology ,Real-Time Polymerase Chain Reaction ,Sensitivity and Specificity ,03 medical and health sciences ,0302 clinical medicine ,Mastocytosis, Systemic ,blood ,medicine ,Humans ,RNA, Messenger ,Systemic mastocytosis ,Alleles ,Messenger RNA ,Blood Cells ,messenger RNA ,Reproducibility of Results ,KIT D816V mutation ,DNA ,Hematology ,medicine.disease ,Molecular biology ,Kit d816v ,Proto-Oncogene Proteins c-kit ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Mutation ,Cancer research ,Bone marrow ,human activities - Abstract
Keywords: systemic mastocytosis; KIT D816V mutation; blood; genomic DNA; messenger RNA
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- 2016
14. A child with mastocytosis and lymphomatoid papulosis
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Charlotte G. Mortz, Henriette Juel Lange, Thomas Kielsgaard Kristensen, Lone Agertoft, Hanne Vestergaard, Michael Boe Møller, Ole Clemmensen, Sigurd Broesby-Olsen, and Carsten Bindslev-Jensen
- Subjects
mastocytosis ,Pathology ,medicine.medical_specialty ,integumentary system ,CD30 ,business.industry ,Cutaneous Mastocytosis ,Lymphomatoid papulosis ,Case Report ,Case Reports ,General Medicine ,Disease ,medicine.disease ,Malignant lymphoma ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,030220 oncology & carcinogenesis ,Journal Article ,Medicine ,Urticaria pigmentosa ,business ,urticaria pigmentosa - Abstract
Key Clinical Message A change in clinical behavior of a disease should prompt search for differential diagnoses. Here, the appearance of ulcerated skin nodules in a preexisting cutaneous mastocytosis revealed a concurrent lymphomatoid papulosis – a CD30+ lymphoproliferative skin disease with histological features of a malignant lymphoma, but with a benign self‐healing course.
- Published
- 2016
15. Venom anaphylaxis can mimic other serious conditions and disclose important underlying disease
- Author
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Thomas Kielsgaard Kristensen, Sigurd Broesby-Olsen, Henrik Fomsgaard Kjaer, Carsten Bindslev-Jensen, Hanne Vestergaard, Charlotte G. Mortz, and Michael Boe Møller
- Subjects
0301 basic medicine ,Pulmonary and Respiratory Medicine ,Hypersensitivity, Immediate ,Male ,Immunology ,Venom ,Wasp Venoms ,Unconsciousness ,Bioinformatics ,Diagnosis, Differential ,03 medical and health sciences ,0302 clinical medicine ,Mastocytosis, Systemic ,medicine ,Immunology and Allergy ,Animals ,Humans ,Anaphylaxis ,business.industry ,Insect Bites and Stings ,Immunoglobulin E ,Middle Aged ,medicine.disease ,Hymenoptera ,Proto-Oncogene Proteins c-kit ,030104 developmental biology ,030228 respiratory system ,Underlying disease ,Tryptases ,business - Published
- 2017
16. Clinical Relevance of Sensitive and Quantitative STAT3 Mutation Analysis Using Next-Generation Sequencing in T-Cell Large Granular Lymphocytic Leukemia
- Author
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Thomas Kielsgaard Kristensen, Michael Boe Møller, Henrik Frederiksen, Mads Thomassen, Annika Rewes, and Martin Jakob Larsen
- Subjects
Adult ,Male ,STAT3 Transcription Factor ,Large granular lymphocytic leukemia ,DNA Mutational Analysis ,Biology ,Sensitivity and Specificity ,DNA sequencing ,Pathology and Forensic Medicine ,symbols.namesake ,medicine ,Humans ,Pentostatin ,Allele ,Aged ,Aged, 80 and over ,Genetics ,Sanger sequencing ,High-Throughput Nucleotide Sequencing ,Reproducibility of Results ,Middle Aged ,medicine.disease ,Molecular biology ,Leukemia, Large Granular Lymphocytic ,Leukemia ,Mutation ,Mutation (genetic algorithm) ,Mutation testing ,symbols ,Molecular Medicine ,Female ,medicine.drug - Abstract
Diagnosis of T-cell large granular lymphocytic leukemia (T-LGL) is often challenging because clinical and laboratory characteristics are overlapping with nonneoplastic conditions. Recently, mutation in the STAT3 gene has been identified as a recurrent genetic abnormality in T-LGL. STAT3 mutation, therefore, represents a promising marker in T-LGL diagnostics. We developed a new quantitative next-generation sequencing assay that allows sensitive analysis of the STAT3 gene. The assay was used to study the utility of STAT3 mutation analysis as a diagnostic tool in T-LGL. The study included 16 T-LGL patients. A total of 15 mutations, including 2 new mutations (G618R and K658R), were detected in 12 patients (75%), with mutation levels ranging from 2.5% to 45.6% mutation-positive alleles. Next-generation sequencing detected 50% more mutations than Sanger sequencing. Blood samples from 20 healthy blood donors all tested negative, thus demonstrating the specificity of the assay. The results also indicated that mutation levels in blood and bone marrow are not systematically different, and next-generation sequencing-based STAT3 mutation analysis represents a sensitive method for monitoring residual disease as demonstrated in a patient receiving pentostatin. We demonstrate the clinical relevance of next-generation sequencing-based STAT3 mutation analysis, which represents a sensitive and specific diagnostic marker in T-LGL that allows assessment of molecular residual disease, which may improve clinical decision making.
- Published
- 2014
17. Proposed diagnostic algorithm for patients with suspected mastocytosis: a proposal of the European Competence Network on Mastocytosis
- Author
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Knut Brockow, Cem Akin, Jason Gotlib, Peter Valent, H.-P. Horny, Thomas Kielsgaard Kristensen, Hanneke C. Kluin-Nelemans, J. J. Van Doormaal, Joseph H. Butterfield, Karin Hartmann, Lawrence B. Schwartz, Clive Grattan, Olivier Hermine, Bogusław Nedoszytko, Andreas Reiter, Dean D. Metcalfe, Marek Niedoszytko, Karl Sotlar, Iván Álvarez-Twose, Wolfgang R. Sperr, J. N. G. Oude Elberink, Michel Arock, Massimo Triggiani, Marcus Maurer, Mariana Castells, Luis Escribano, A. Orfao, Selim Yavuz, Deepti Radia, Sigurd Broesby-Olsen, Frank Siebenhaar, Austrian Science Fund, and National Institute of Allergy and Infectious Diseases (US)
- Subjects
KIT D816V MUTATION ,Urinary system ,Immunology ,tryptase ,INDOLENT SYSTEMIC MASTOCYTOSIS ,Tryptase ,Diagnostic algorithm ,mast cells ,Disease ,Biopsy ,Humans ,Immunology and Allergy ,Medicine ,TRYPTASE LEVELS ,CONSENSUS PROPOSAL ,OF-THE-ART ,CONSECUTIVE ADULTS ,biology ,medicine.diagnostic_test ,business.industry ,FUTURE PERSPECTIVES ,diagnostic algorithm ,Occult ,PROLIFERATIVE DISORDERS ,Kit d816v ,SERUM TRYPTASE ,medicine.anatomical_structure ,Mast cells ,biology.protein ,Bone marrow ,Differential diagnosis ,business ,Algorithm ,KIT D816V ,MAST-CELL ACTIVATION ,Algorithms ,Mastocytosis - Abstract
Mastocytosis is an emerging differential diagnosis in patients with more or less specific mediator-related symptoms. In some of these patients, typical skin lesions are found and the diagnosis of mastocytosis can be established. In other cases, however, skin lesions are absent, which represents a diagnostic challenge. In the light of this unmet need, we developed a diagnostic algorithm for patients with suspected mastocytosis. In adult patients with typical lesions of mastocytosis in the skin, a bone marrow (BM) biopsy should be considered, regardless of the basal serum tryptase concentration. In adults without skin lesions who suffer from mediator-related or other typical symptoms, the basal tryptase level is an important parameter. In those with a slightly increased tryptase level, additional investigations, including a sensitive KIT mutation analysis of blood leucocytes or measurement of urinary histamine metabolites, may be helpful. In adult patients in whom (i) KIT D816V is detected and/or (ii) the basal serum tryptase level is clearly increased (>25-30 ng/ ml) and/or (iii) other clinical or laboratory features suggest the presence of 'occult' mastocytosis or another haematologic neoplasm, a BM investigation is recommended. In the absence of KIT D816V and other signs or symptoms of mastocytosis or another haematopoietic disease, no BM investigation is required, but the clinical course and tryptase levels are monitored in the follow-up. In paediatric patients, a BM investigation is usually not required, even if the tryptase level is increased. Although validation is required, it can be expected that the algorithm proposed herein will facilitate the management of patients with suspected mastocytosis and help avoid unnecessary referrals and investigations., This work was supported in part by the Austrian Science Funds (FWF) Project SFB F4611 and SFB F4704-B20 and the Division of Intramural Research, NIAID.
- Published
- 2014
18. SensitiveKITD816V mutation analysis of blood as a diagnostic test in mastocytosis
- Author
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Thomas Kielsgaard Kristensen, Michael Boe Møller, Hanne Vestergaard, Sigurd Broesby-Olsen, and Carsten Bindslev-Jensen
- Subjects
biology ,Cutaneous Mastocytosis ,business.industry ,Case-control study ,Diagnostic test ,Tryptase ,Hematology ,medicine.disease ,Kit d816v ,Immunology ,Mutation (genetic algorithm) ,Mutation testing ,medicine ,biology.protein ,Systemic mastocytosis ,business - Abstract
The recent progress in sensitive KIT D816V mutation analysis suggests that mutation analysis of peripheral blood (PB) represents a promising diagnostic test in mastocytosis. However, there is a need for systematic assessment of the analytical sensitivity and specificity of the approach in order to establish its value in clinical use. We therefore evaluated sensitive KIT D816V mutation analysis of PB as a diagnostic test in an entire case-series of adults with mastocytosis. We demonstrate for the first time that by using a sufficiently sensitive KIT D816V mutation analysis, it is possible to detect the mutation in PB in nearly all adult mastocytosis patients. The mutation was detected in PB in 78 of 83 systemic mastocytosis (94%) and 3 of 4 cutaneous mastocytosis patients (75%). The test was 100% specific as determined by analysis of clinically relevant control patients who all tested negative. Mutation analysis of PB was significantly more sensitive than serum tryptase >20 ng/mL. Of 27 patients with low tryptase, 26 tested mutation positive (96%). The test is furthermore readily available and we consider the results to serve as a foundation of experimental evidence to support the inclusion of the test in diagnostic algorithms and clinical practice in mastocytosis.
- Published
- 2014
19. Genomic Profiling of a Phase III Clinical Trial of Interferon Versus Hydroxyurea in MPN Patients Reveals Mutation-Specific and Treatment-Specific Patterns of Response
- Author
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Hans Carl Hasselbalch, Mikael Frederiksen, Trine Alma Knudsen, Thomas Kielsgaard Kristensen, Lukas Frans Ocias, Ann Mullally, Bruce M. Wollison, Christina Ellervik, Ole Weis Bjerrum, Donna Neuberg, Torben A Kruse, Torben Mourits-Andersen, Karin de Stricker, Thomas Stauffer Larsen, Anwesha Nag, Aaron R. Thorner, Mads Thomassen, Mette Brabrand, Vibe Skov, Joern Starklint, Lillian Werner, Peter Møller, Daniel El Fassi, Jesper Stentoft, Christopher J. Gibson, R. Coleman Lindsley, William Duke, Ulrik Malthe Overgaard, Dennis Lund Hansen, Marianne Tang Severinsen, and Lasse Kjær
- Subjects
0301 basic medicine ,Oncology ,medicine.medical_specialty ,Mutation ,Myeloid ,business.industry ,Immunology ,Single-nucleotide polymorphism ,Cell Biology ,Hematology ,Gene mutation ,medicine.disease_cause ,Biochemistry ,IDH2 ,Loss of heterozygosity ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Germline mutation ,White blood cell ,Internal medicine ,Medicine ,business ,030215 immunology - Abstract
Background: To investigate the role of genomics in determining response and resistance to front line treatment in MPN, we performed somatic mutational profiling of the DALIAH trial, a randomized controlled phase III trial of interferon versus hydroxyurea in newly diagnosed MPN patients. Methods: We performed genomic analyses on 202 pre-treatment primary MPN samples obtained from patients enrolled on the DALIAH trial (NCT01387763) and 135 samples obtained after 24 months of treatment. Genomic profiling comprised targeted next generation sequencing (NGS) of 100 genes, selected on the basis of their known or suspected involvement in the pathogenesis of myeloid malignancies, and 1609 informative single nucleotide polymorphisms (SNPs) on chromosome 9p. Clinicohematological response was determined by central review using ELN 2009 (ET, PV and pre-MF) and EUMNET 2005 (PMF) criteria. We evaluated the association of somatic mutations with clinical parameters and with attainment of clinicohematological complete response (CR) at 24 months. Results: Prior to treatment, 191 of 202 (95%) patients had somatic mutations, including 93% with canonical MPN phenotypic drivers: JAK2 (74%), CALR (14%), and MPL (5%). Among those with JAK2 mutations 37% had JAK2 copy-neutral loss of heterozygosity (JAK2 CN-LOH). Patients with PV were more likely to have JAK2 CN-LOH (p = 0.0001) as compared with patients with other MPN subtypes. At baseline, patients with JAK2 CN-LOH had significantly higher hemoglobin (p = 0.0001), higher white blood cell count (WBC, p = 0.002) and lower platelet count (p=0.0001) than patients without JAK2 CN-LOH. Mutations in TET2 (24%), DNMT3A (16%), and ASXL1 (10%) were the most frequent co-occurring non-MPN phenotypic driver mutations and they occurred across all MPN subtypes. In addition, 5% of patients had spliceosome gene mutations, and 6% had mutations in genes involved in RAS/MAPK signaling. Patients with TET2, DNMT3A or ASXL1 mutations were significantly older than patients without these mutations (p= 0.0001) and there was a significant association between the presence of a TET2, DNMT3A or ASXL1 mutation and prior stroke (p = 0.004). There were no other significant associations between somatic mutation status and baseline clinical characteristics. The probability of attaining clinicohematological CR at 24 months was independent of baseline somatic mutations. Among patients with JAK2 mutations who remained on interferon treatment at 24 months, those with CR had a greater reduction in mean variant allele fraction (VAF) (28% to 8%, p Among patients who remained on treatment for 2 years, 44 mutations in 35 patients were newly detected or expanded on serial sampling. DNMT3A mutations were the most frequently acquired, accounting for 41% of new mutations. ASXL1, TET2, PPM1D, TP53, IDH2, and CBL mutations were also recurrently acquired. 97% of patients who acquired new mutations were JAK2-mutant. Among those with acquired DNMT3A mutations, 85% were treated with interferon, and 23% had CR at 24 months. Among those that acquired non-DNMT3A mutations, 38% were treated with interferon and 47% had CR at 24 months. The VAF of newly detected mutations was low (median 1.5%), and half of the patients with newly acquired mutations had at least 50% reduction in JAK2V617F VAF, suggesting that new mutations could either have arisen independently or be subclonal to the dominant JAK2-mutant clone. Conclusions: Using sequential genomic analyses of a phase III clinical trial of interferon versus hydroxyurea in MPN patients, we found mutation-specific and treatment-specific patterns of response. We uncovered distinct patterns of response to interferon in JAK2-mutant MPN as compared with CALR-mutant MPN. We found that DNMT3A mutations were the most frequent acquired mutations at 24 months and that these were enriched in patients treated with interferon. In aggregate, these results provide insights into molecular response and resistance to interferon and inform the clinical use of interferon in MPN patients. Disclosures Hansen: Alexion: Research Funding. Neuberg:Pharmacyclics: Research Funding; Madrigal Pharmaceuticals: Equity Ownership; Celgene: Research Funding. Hasselbalch:Novartis: Research Funding; AOP Orphan Pharmaceuticals: Other: Data monitoring board. Lindsley:Jazz Pharmaceuticals: Research Funding; Takeda Pharmaceuticals: Consultancy; Medlmmune: Research Funding. Mullally:Janssen: Research Funding.
- Published
- 2019
20. KIT D816V Mutation-Positive Cell Fractions in Lesional Skin Biopsies from Adults with Systemic Mastocytosis
- Author
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Carsten Bindslev-Jensen, Sigurd Broesby-Olsen, Hanne Vestergaard, Michael Boe Møller, and Thomas Kielsgaard Kristensen
- Subjects
Pathology ,medicine.medical_specialty ,integumentary system ,medicine.diagnostic_test ,Somatic cell ,Dermatology ,Biology ,Mast cell ,medicine.disease ,Real-time polymerase chain reaction ,medicine.anatomical_structure ,Immunology ,Mutation (genetic algorithm) ,Biopsy ,medicine ,Urticaria pigmentosa ,Bone marrow ,Systemic mastocytosis - Abstract
Background: Most adults with systemic mastocytosis (SM) carry the somatic KIT D816V mutation, but the occurrence of the mutation in lesional skin remains to be characterized. Objective: To assess the distribution and fraction of KIT D816V mutation-positive cells in lesional skin. Methods: Lesional skin biopsies from 29 adults with SM were analysed using sensitive and quantitative qPCR KIT D816V mutation analysis. Results: The KIT D816V mutation was detected in skin in all cases. Highly similar mutation levels were observed in all patients with a median of 5% mutation-positive cells in the skin (range 1-23%). Conclusion: The KIT D816V mutation is consistently present in lesional skin in adults with SM. The low variation in mutation levels detected in lesional skin contrasts blood and bone marrow where mast cell (MC) progenitor and non-MC lineage involvement causes the mutation-positive cell fraction to be highly variable.
- Published
- 2013
21. Risk of solid cancer, cardiovascular disease, anaphylaxis, osteoporosis and fractures in patients with systemic mastocytosis: A nationwide population-based study
- Author
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Sigurd, Broesby-Olsen, Dóra Körmendiné, Farkas, Hanne, Vestergaard, Anne Pernille, Hermann, Michael Boe, Møller, Charlotte Gotthard, Mortz, Thomas Kielsgaard, Kristensen, Carsten, Bindslev-Jensen, Henrik Toft, Sørensen, and Henrik, Frederiksen
- Subjects
Adult ,Aged, 80 and over ,Adolescent ,Middle Aged ,Risk Assessment ,Cohort Studies ,Fractures, Bone ,Young Adult ,Mastocytosis, Systemic ,Cardiovascular Diseases ,Neoplasms ,Humans ,Osteoporosis ,Registries ,Anaphylaxis ,Aged ,Netherlands ,Proportional Hazards Models - Abstract
In patients with systemic mastocytosis (SM), several aspects of morbidity remain poorly understood. We assessed the risk of solid cancers, cardiovascular disease, anaphylaxis, osteoporosis, and fractures in SM patients. Using Danish medical registries, we conducted a nationwide population-based cohort study including 687 adult (≥15 years) SM patients diagnosed during 1997-2012. A comparison cohort of 68,700 subjects from the general Danish population who were alive and without SM at the given SM subject's diagnosis were age- and gender-matched. Outcomes were a new diagnosis of solid cancer, venous thromboembolism (VTE), myocardial infarction (MI), stroke, anaphylaxis, osteoporosis, or fracture. For solid cancers the hazard ratio (HR) was 2.4 (95% confidence interval [CI] 1.9-2.8) with a 10-year absolute risk (AR) in the SM-cohort of 12.6% (95% CI 9.4-16.3). Specifically, we found a HR of 7.5 (95% CI 4.4-13.0) for melanoma and a HR of 2.5 (95% CI 1.7-3.5) for non-melanoma skin cancers (NMSCs). For VTE we found a HR of 1.9 (95% CI 1.2-3.0), with a 10-year AR of 3.9% (95% CI 2.3-6.1); for MI a nonsignificant increased HR of 1.4 (95% CI 0.9-2.3), with a 10-year AR of 1.8% (95% CI 0.9-3.2); and for stroke a HR of 1.6 (95% CI 1.1-2.3) with a 10-year AR of 4.6% (95% CI 2.8-6.9). The HR for anaphylaxis was 7.2 (95% CI 5.3-9.9), and the 10-year AR was 3.1% (95% CI 1.9-4.9). For osteoporosis the HR was 3.6 (95% CI 2.7-4.6) with a 10-year AR of 7.2% (95% CI 5.2-9.8). For fractures the HR was 1.2 (95% CI 0.9-1.6) and the 10-year AR was 5.9% (95% CI 3.9-8.4). SM patients are at increased risk of solid cancers - especially melanoma and NMSC-and cardiovascular disease. The risk of anaphylaxis and osteoporosis is clearly increased in SM, though absolute risk was low in this population-based study. The fracture-risk was only slightly increased. Am. J. Hematol. 91:1069-1075, 2016. © 2016 Wiley Periodicals, Inc.
- Published
- 2016
22. [Mastocytosis]
- Author
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Sigurd, Broesby-Olsen, Thomas Kielsgaard, Kristensen, Lone, Agertoft, Michael Boe, Møller, Anne Pernille, Hermann, Trine, Torfing, Troels, Havelund, Charlotte G, Mørtz, Carsten, Bindslev-Jensen, and Hanne, Vestergaard
- Subjects
Adult ,Humans ,Osteoporosis ,Child ,Anaphylaxis ,Algorithms ,Mastocytosis - Abstract
Mastocytosis is a heterogeneous disease with an increased number and activation of mast cells. Subtypes range from benign to rare aggressive forms, and the disease may affect people of all ages. The pathogenesis involves mutations in the KIT gene in both children and adult patients. Estimated prevalence is one per 10,000, but the disease is very likely underdiagnosed. The diagnosis may be challenging and patients may present to several medical specialties. This article presents an overview of clinical signs and symptoms as well as a diagnostic algorithm and treatment options of mastocytosis.
- Published
- 2016
23. Cutaneous manifestations in patients with mastocytosis: Consensus report of the European Competence Network on Mastocytosis; The American Academy of Allergy, Asthma & Immunology; And the European Academy of Allergology and Clinical Immunology
- Author
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Alberto Orfao, Cem Akin, Sigurd Broesby-Olsen, Peter Valent, Olivier Hermine, Frank Siebenhaar, Magdalena Lange, Clive Grattan, Anja Rabenhorst, Almudena Matito, Jason Gotlib, Michel Arock, Joanna N G Oude Elberink, Wolfgang R. Sperr, Melody C. Carter, Deepti Radia, Selim Yavuz, Knut Brockow, Roberta Zanotti, Karl Sotlar, Thomas Kielsgaard Kristensen, Hans Hägglund, Lawrence B. Schwartz, Bogusław Nedoszytko, Massimo Triggiani, Karin Hartmann, Hans-Peter Horny, Jason L. Hornick, Iván Álvarez-Twose, Patrizia Bonadonna, Marek Niedoszytko, Luis Escribano, Marcus Maurer, Dean D. Metcalfe, Hanneke C. Kluin-Nelemans, Antonio Torrelo, Andreas Reiter, Joseph H. Butterfield, Gunnar Nilsson, Mariana Castells, Jürgen Grabbe, Tracy I. George, Austrian Science Fund, European Academy of Allergy and Clinical Immunology, German Research Foundation, National Institute of Allergy and Infectious Diseases (US), Groningen Research Institute for Asthma and COPD (GRIAC), Stem Cell Aging Leukemia and Lymphoma (SALL), and Damage and Repair in Cancer Development and Cancer Treatment (DARE)
- Subjects
medicine.medical_specialty ,Allergy ,C-KIT MUTATIONS ,Mastocytosis, Cutaneous/classification ,Consensus ,Mastocytosis, Cutaneous ,Cutaneous mastocytosis ,Diagnostic criteria ,Solitary mastocytoma ,ONSET MASTOCYTOSIS ,DIAGNOSTIC-CRITERIA ,Diffuse cutaneous mastocytosis ,Immunology ,PEDIATRIC MASTOCYTOSIS ,Mast cell ,030207 dermatology & venereal diseases ,03 medical and health sciences ,Classification ,cutaneous mastocytosis ,diagnostic criteria ,mast cell ,mastocytosis ,standardization ,urticaria pigmentosa ,Allergy and Immunology ,Humans ,Societies, Medical ,Immunology and Allergy ,Medicine (all) ,0302 clinical medicine ,Medical ,MAST-CELL DISORDERS ,medicine ,TRYPTASE LEVELS ,ADULT PATIENTS ,Systemic mastocytosis ,GERMLINE MUTATION ,Asthma ,Urticaria pigmentosa ,Cutaneous Mastocytosis ,business.industry ,SYSTEMIC MASTOCYTOSIS ,medicine.disease ,Dermatology ,Standardization ,Telangiectasia macularis eruptiva perstans ,Cutaneous ,030228 respiratory system ,Societies ,business ,Mastocytosis - Abstract
Cutaneous lesions in patients with mastocytosis are highly heterogeneous and encompass localized and disseminated forms. Although a classification and criteria for cutaneous mastocytosis (CM) have been proposed, there remains a need to better define subforms of cutaneous manifestations in patients with mastocytosis. To address this unmet need, an international task force involving experts from different organizations (including the European Competence Network on Mastocytosis; the American Academy of Allergy, Asthma & Immunology; and the European Academy of Allergology and Clinical Immunology) met several times between 2010 and 2014 to discuss the classification and criteria for diagnosis of cutaneous manifestations in patients with mastocytosis. This article provides the major outcomes of these meetings and a proposal for a revised definition and criteria. In particular, we recommend that the typical maculopapular cutaneous lesions (urticaria pigmentosa) should be subdivided into 2 variants, namely a monomorphic variant with small maculopapular lesions, which is typically seen in adult patients, and a polymorphic variant with larger lesions of variable size and shape, which is typically seen in pediatric patients. Clinical observations suggest that the monomorphic variant, if it develops in children, often persists into adulthood, whereas the polymorphic variant may resolve around puberty. This delineation might have important prognostic implications, and its implementation in diagnostic algorithms and future mastocytosis classifications is recommended. Refinements are also suggested for the diagnostic criteria of CM, removal of telangiectasia macularis eruptiva perstans from the current classification of CM, and removal of the adjunct solitary from the term solitary mastocytoma., Supported by research grants from the German Research Council (DFG; HA 2393/6-1; CRC/SFB832, project A14; to K.H.); from the Division of Intramural Research, National Institute of Allergy and Infectious Diseases (to D.D.M.); and from the Austrian Science Funds (FWF; projects SFB F4611 and SFB F4707-B20; to P.V.). The Consensus Conference on Mastocytosis in Boston, Massachusetts (October 2012), was supported by the American Academy of Allergy, Asthma & Immunolog. A task force/consensus panel on mastocytosis between 2010 and 2012 was supported by the European Academy of Allergy and Clinical Immunology.
- Published
- 2016
24. Multidisciplinary Management of Mastocytosis: Nordic Expert Group Consensus
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Lene H. Garvey, Charlotte G. Mortz, Gunnar Nilsson, Peter Valent, Thomas Kielsgaard Kristensen, Ole Weis Bjerrum, Leena Ackermann, Trine Torfing, Theo Gülen, Maria Sääf, Eva Stylianou, Carsten Bindslev-Jensen, Ingunn Dybedal, Hanne Vestergaard, Birgitta Sander, Michael Boe Møller, Troels Havelund, Marie Bendix, Sigurd Broesby-Olsen, Anna Bergström, Maria A Karlsson, Lone Agertoft, Kim Brixen, Hans Hägglund, Pernille Hermann, Department of Dermatology, Allergology and Venereology, and Clinicum
- Subjects
Diagnostic criteria ,Disease ,BONE-MARROW HISTOPATHOLOGY ,030207 dermatology & venereal diseases ,0302 clinical medicine ,Multidisciplinary approach ,multidisciplinary management ,Prevalence ,TRYPTASE LEVELS ,Systemic mastocytosis ,CUTANEOUS-MASTOCYTOSIS ,Mast cell activation ,General Medicine ,Classification ,Expert group ,3. Good health ,classification ,030220 oncology & carcinogenesis ,Practice Guidelines as Topic ,GASTROINTESTINAL-TRACT ,MAST-CELL ACTIVATION ,Mastocytosis ,medicine.medical_specialty ,Consensus ,KIT D816V MUTATION ,INDOLENT SYSTEMIC MASTOCYTOSIS ,Dermatology ,systemic mastocytosis ,Scandinavian and Nordic Countries ,World Health Organization ,PEDIATRIC MASTOCYTOSIS ,Mast cell ,EUROPEAN COMPETENCE NETWORK ,Diagnosis, Differential ,03 medical and health sciences ,Multidisciplinary management ,medicine ,Humans ,Intensive care medicine ,RESPONSE CRITERIA ,Urticaria pigmentosa ,business.industry ,Cutaneous Mastocytosis ,Congresses as Topic ,medicine.disease ,3121 General medicine, internal medicine and other clinical medicine ,diagnostic criteria ,Immunology ,Differential diagnosis ,mast cell ,business ,urticaria pigmentosa - Abstract
Mastocytosis is a heterogeneous group of diseases defined by an increased number and accumulation of mast cells, and often also by signs and symptoms of mast cell activation. Disease subtypes range from indolent to rare aggressive forms. Mastocytosis affects people of all ages and has been considered rare; however, it is probably underdiagnosed with potential severe implications. Diagnosis can be challenging and symptoms may be complex and involve multiple organ-systems. In general it is advised that patients should be referred to centres with experience in the disease offering an individualized, multidisciplinary approach. We present here consensus recommendations from a Nordic expert group for the diagnosis and general management of patients with mastocytosis.
- Published
- 2015
25. NPM1 mutation is a stable marker for minimal residual disease monitoring in acute myeloid leukaemia patients with increased sensitivity compared to WT1 expression*
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Thomas Kielsgaard Kristensen, Lone S. Friis, Olav J. Bergmann, Birgitte Preiss, and Michael Boe Møller
- Subjects
NPM1 ,Myeloid ,Clone (cell biology) ,Wilms' tumor ,Karyotype ,Hematology ,General Medicine ,Biology ,medicine.disease ,Minimal residual disease ,Leukemia ,medicine.anatomical_structure ,hemic and lymphatic diseases ,Mutation (genetic algorithm) ,medicine ,Cancer research - Abstract
Mutation in the NPM1 gene occurs in 60% of acute myeloid leukaemia (AML) patients with normal karyotype. NPM1 mutation is potentially a superior minimal residual disease (MRD) marker compared to WT1 gene overexpression by being specific to the malignant clone, although experimental evidence published so far includes very limited numbers of relapsed cases. Also, the stability of the NPM1 mutation has been questioned by reports of the mutation being lost at relapse. In the present study we compared NPM1 mutation and WT1 overexpression as MRD markers in 20 cases of relapsed AML. The 20 patients experienced a total of 28 morphological relapses. Karyotypic evolution was detected in 56% of relapses. All relapses were accompanied by high levels of NPM1 mutation, along with high WT1 mRNA levels, thus demonstrating complete stability of both markers during relapse. Detectable NPM1 mutation following a period of morphological remission was accompanied by a morphological relapse in all cases. In contrast, WT1 expression was detected in 33% of the NPM1 mutation negative samples. This background WT1 expression produced by non-leukaemia cells was highly variable, both between and within patients, and limited the de facto sensitivity of the WT1 expression analysis. The present study therefore provides important experimental evidence demonstrating that NPM1 mutation is superior to WT1 overexpression as marker of MRD in NPM1-mutated AML, even in the presence of extensive karyotypic evolution.
- Published
- 2011
26. Seminal human papillomavirus originates from the body surface and is not a frequent aetiological factor in azoospermia
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Dorthe Ørnskov, Birte Engvad, Jens Fedder, Niels Marcussen, Marianne Waldstrøm, Thomas Kielsgaard Kristensen, and Mads Lomholt
- Subjects
Adult ,Male ,0301 basic medicine ,medicine.medical_specialty ,Cryptozoospermia ,Urology ,Vas deferens ,Semen ,Male infertility ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Vasectomy ,medicine ,Humans ,Sex organ ,Spermatogenesis ,human papillomavirus ,Papillomaviridae ,Skin ,Azoospermia ,Gynecology ,030219 obstetrics & reproductive medicine ,business.industry ,azoospermia ,virus diseases ,semen ,Original Articles ,General Medicine ,medicine.disease ,female genital diseases and pregnancy complications ,030104 developmental biology ,medicine.anatomical_structure ,male genital tract ,Papilloma ,Original Article ,business - Abstract
Human papillomavirus (HPV) DNA has been detected in the testis tissue of 6.5% of 185 men with non‐obstructive azoospermia (NOA). Others have suggested that seminal HPV originates from contamination from the genital skin and mucosa. One hundred unselected azoospermic men and 43 normal men undergoing vasectomy were recruited. Testicular biopsies for HPV examination were collected from all the men. Additionally, the normal men undergoing vasectomy delivered a semen sample and had a swab for HPV examination taken from the genital skin before vasectomy. A piece of each Vas deferens obtained during the vasectomy was examined for the presence of HPV. Two of the primarily azoospermic men were shown to have cryptozoospermia. It was not possible to detect HPV in the testis tissue of any of the included 98 azoospermic men or the 43 proven fertile men. In the proven fertile men, HPV DNA was detected in the semen of 15 men (35%), on the genital skin of 28 men (65%), and in the Vas deferens in three cases (7%). In 13 (87%) men with HPV‐positive semen samples, HPV DNA was also detected in the skin swabs, and in 11 men (73%), identical HPV genotypes were found in the two locations.
- Published
- 2018
27. [New disease markers within the chronic myeloproliferative neoplasms]
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Morten Orebo, Holmström, Lukas Frans, Ocias, Klaus, Kallenbach, Lasse, Kjær, Thomas Kielsgaard, Kristensen, Niels, Pallisgaard, Bodil Laub, Petersen, Vibe, Skov, Karin, de Stricker, Thomas Stauffer, Larsen, and Hans Carl, Hasselbalch
- Subjects
Thrombocytosis ,Myeloproliferative Disorders ,Primary Myelofibrosis ,Mutation ,Humans ,Calreticulin ,Polycythemia Vera ,Receptors, Thrombopoietin - Abstract
The chaperone and calcium storing protein calreticulin is coded by CALR, and newly identified mutations in CALR are found in respectively 49-70% and 56-88% of JAK2- and MPL-negative patients with essential thrombocytaemia (ET) and primary myelofibrosis (PMF). A total of 41 mutations have been identified, all located to exon 9 which codes the protein's C-terminal. CALR mutations are present only in myeloid malignancies and confer a more indolent disease than JAK2-mutated ET and PMF. CALR mutations as a diagnostic and prognostic tool are promising and the mutations are potential targets for immune therapy.
- Published
- 2015
28. Adult-onset systemic mastocytosis in monozygotic twins with KIT D816V and JAK2 V617F mutations
- Author
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Carsten Bindslev-Jensen, Sigurd Broesby-Olsen, Thomas Kielsgaard Kristensen, Hanne Vestergaard, and Michael Boe Møller
- Subjects
Adult ,Male ,Janus kinase 2 ,biology ,Immunology ,Twins, Monozygotic ,Janus Kinase 2 ,medicine.disease ,Kit d816v ,Proto-Oncogene Proteins c-kit ,Mastocytosis, Systemic ,Mutation ,Mutation (genetic algorithm) ,Diseases in Twins ,biology.protein ,medicine ,Humans ,Immunology and Allergy ,Systemic mastocytosis ,JAK2 V617F - Published
- 2012
29. High expression of PI3K core complex genes is associated with poor prognosis in chronic lymphocytic leukemia
- Author
-
Thomas Kielsgaard Kristensen, Mads Thomassen, Michael Boe Møller, Louise Kristensen, Niels Abildgaard, Torben Mourits-Andersen, and Mikael Frederiksen
- Subjects
Male ,Cancer Research ,Chronic lymphocytic leukemia ,medicine.medical_treatment ,Biology ,Disease-Free Survival ,Gene Expression Regulation, Enzymologic ,Pathogenesis ,Vacuolar Sorting Protein VPS15 ,immune system diseases ,hemic and lymphatic diseases ,medicine ,Autophagy ,PIK3C3 ,Humans ,Gene ,neoplasms ,PI3K/AKT/mTOR pathway ,Aged ,Chemotherapy ,Gene Expression Regulation, Leukemic ,Membrane Proteins ,Hematology ,BECN1 ,Middle Aged ,medicine.disease ,Prognosis ,Leukemia, Lymphocytic, Chronic, B-Cell ,PIK3R4 ,Survival Rate ,Leukemia ,Oncology ,Immunology ,Beclin-1 ,Female ,Apoptosis Regulatory Proteins - Abstract
a b s t r a c t Chronic lymphocytic leukemia (CLL) is the most common leukemia among adults in the Western world. Autophagy is a highly conserved process in eukaryotic cells. In CLL autophagy is involved in mediating the effect of chemotherapy but the role of autophagy in CLL pathogenesis remains unknown. In the present study, we used real-time RT-PCR to analyze expression of the PIK3C3, PIK3R4, and BECN1 genes. These genes encode the components of the PI3K core complex, which is central to initiation of autophagy. A consecutive series of 149 well-characterized CLL cases from Region of Southern Denmark were included in the study. All three genes were observed to be independent markers of prognosis in CLL with high expression being associated with more aggressive disease. With this clear association with outcome in CLL, these genes thereby represent promising candidates for future functional studies on the role of autophagy in CLL, and they may further represent targets of treatment.
- Published
- 2014
30. Relapse of myeloid neoplasm with eosinophilia and PDGFRA rearrangement after imatinib discontinuation in a pediatric patient
- Author
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Mathias, Rathe, Eckhard, Schomerus, Peder Skov, Wehner, Thomas Kielsgaard, Kristensen, and Michael Boe, Møller
- Subjects
Gene Rearrangement ,Myeloproliferative Disorders ,Receptor, Platelet-Derived Growth Factor alpha ,Antineoplastic Agents ,Prognosis ,Piperazines ,Pyrimidines ,Withholding Treatment ,Child, Preschool ,Benzamides ,Eosinophilia ,Imatinib Mesylate ,Humans ,Female ,Neoplasm Recurrence, Local - Published
- 2014
31. Epidemiology of systemic mastocytosis in Denmark
- Author
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Stine Skovbo, Thomas Kielsgaard Kristensen, Hanne Vestergaard, Jon P. Fryzek, Sarah S. Cohen, Michael Boe Møller, Sigurd Broesby-Olsen, and Carsten Bindslev-Jensen
- Subjects
Adult ,Male ,medicine.medical_specialty ,Adolescent ,Epidemiology ,Denmark ,Population ,Disease ,Young Adult ,Mastocytosis, Systemic ,Internal medicine ,medicine ,Humans ,Cumulative incidence ,Systemic mastocytosis ,education ,Indolent systemic mastocytosis ,Aggressive systemic mastocytosis ,Aged ,education.field_of_study ,Urticaria pigmentosa ,business.industry ,Retrospective cohort study ,Hematology ,Middle Aged ,medicine.disease ,Denmark/epidemiology ,Mastocytosis, Systemic/epidemiology ,Immunology ,Cohort ,Female ,business ,Epidemiologic Methods - Abstract
Mastocytosis is a heterogeneous group of diseases characterized by abnormal proliferation of mast cells. Systemic mastocytosis (SM), in which abnormal mast cells are present in tissues beyond the skin, is divided into seven subcategories with varying degrees of severity and prognosis. Very little is known about the epidemiology of SM and its subcategories. This retrospective cohort study of 548 adults with SM diagnosed 1997–2010 was constructed using linked Danish national health registries. The most common subtype of mastocytosis was indolent SM (including urticaria pigmentosa) (n = 450; 82%), followed by SM with subtype unknown (n = 61; 11%), SM with associated clonal haematological non-mast cell lineage disease (n = 24; 4%), aggressive SM (n = 8; 2%), and mast cell leukaemia (n = 5; 1%). The incidence rate for SM (all subtypes including urticaria pigmentosa) was 0_89 per 100 000 per year. Cumulative incidence was 12_46 per 100 000, and the 14-year limited-duration prevalence as of 1 January, 2011 was 9_59 per 100 000. This nationwide cohort from Denmark is the first population-based epidemiological study of mastocytosis. In this cohort of patients aged 15 years and older, SM was found to be overall relatively rare with notable variation by subtype for patient characteristics, survival and epidemiological measures. Keywords: aggressive systemic mastocytosis, indolent systemic mastocytosis, urticaria pigmentosa, epidemiology, Denmark. Mastocytosis is a heterogeneous group of diseases characterized by abnormal proliferation of mast cells. Systemic mastocytosis (SM), in which abnormal mast cells are present in tissues beyond the skin, is divided into seven subcategories with varying degrees of severity and prognosis. Very little is known about the epidemiology of SM and its subcategories. This retrospective cohort study of 548 adults with SM diagnosed 1997-2010 was constructed using linked Danish national health registries. The most common subtype of mastocytosis was indolent SM (including urticaria pigmentosa) (n = 450; 82%), followed by SM with subtype unknown (n = 61; 11%), SM with associated clonal haematological non-mast cell lineage disease (n = 24; 4%), aggressive SM (n = 8; 2%), and mast cell leukaemia (n = 5; 1%). The incidence rate for SM (all subtypes including urticaria pigmentosa) was 0·89 per 100 000 per year. Cumulative incidence was 12·46 per 100 000, and the 14-year limited-duration prevalence as of 1 January, 2011 was 9·59 per 100 000. This nationwide cohort from Denmark is the first population-based epidemiological study of mastocytosis. In this cohort of patients aged 15 years and older, SM was found to be overall relatively rare with notable variation by subtype for patient characteristics, survival and epidemiological measures.
- Published
- 2014
32. Myeloid neoplasm with prominent eosinophilia and PDGFRA rearrangement treated with imatinib mesylate
- Author
-
Niels Carlsen, Michael Boe Møller, Thomas Kielsgaard Kristensen, and Mathias Rathe
- Subjects
Receptor, Platelet-Derived Growth Factor alpha ,Myeloid ,PDGFRB ,PDGFRA ,Piperazines ,Myeloid Neoplasm ,hemic and lymphatic diseases ,Eosinophilia ,Humans ,Medicine ,Gene Rearrangement ,mRNA Cleavage and Polyadenylation Factors ,Myeloproliferative Disorders ,business.industry ,Imatinib ,Hematology ,Gene rearrangement ,digestive system diseases ,Pyrimidines ,medicine.anatomical_structure ,Imatinib mesylate ,Oncology ,Child, Preschool ,Benzamides ,Pediatrics, Perinatology and Child Health ,Imatinib Mesylate ,Cancer research ,Female ,medicine.symptom ,business ,medicine.drug - Abstract
The FIP1L1–PDGFRA fusion gene is the most frequent genetic aberration in myeloid neoplasms associated with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1. Affected patients in adult populations are very sensitive to imatinib therapy. Pediatric cases are rare and so far only one case of FIP1L1–PDGFRA positive disease has been reported. We report a 2-year-old female with a myeloid neoplasm associated with eosinophilia and rearrangement of PDGFRA. Treatment with imatinib resulted in complete and durable clinical, hematological, and molecular remission within 3 months after starting treatment. Pediatr Blood Cancer. 2010;55:730–732. © 2010 Wiley-Liss, Inc.
- Published
- 2010
33. KIT D816V mutation burden does not correlate to clinical manifestations of indolent systemic mastocytosis
- Author
-
Michael Boe Møller, Kim Brixen, Hanne Vestergaard, Thomas Kielsgaard Kristensen, Carsten Bindslev-Jensen, and Sigurd Broesby-Olsen
- Subjects
Adult ,Male ,medicine.medical_specialty ,Pathology ,Immunology ,Osteoporosis ,Bone Marrow Cells ,Gastroenterology ,Severity of Illness Index ,Young Adult ,Mastocytosis, Systemic ,Internal medicine ,Severity of illness ,medicine ,Immunology and Allergy ,Humans ,Young adult ,Systemic mastocytosis ,Anaphylaxis ,Dual-energy X-ray absorptiometry ,Aged ,medicine.diagnostic_test ,business.industry ,Middle Aged ,medicine.disease ,Osteopenia ,Proto-Oncogene Proteins c-kit ,medicine.anatomical_structure ,Mutation ,Female ,Bone marrow ,business - Abstract
Background Clinical manifestations of indolent systemic mastocytosis (ISM) comprise mediator-related symptoms, anaphylaxis, and osteoporosis. A new sensitive method for KIT D816V mutation detection allows quantification of the level of mutation-positive cells. Objective To investigate whether the fraction of KIT D816V positive cells in peripheral blood (PB) or bone marrow (BM) aspirate in adult patients with ISM correlates with clinical manifestations of the disease. Methods We included 48 adult patients with ISM (28 females/20 males) from our center in whom the KIT D816V mutation level in both BM aspirate and PB was analyzed. For each patient, the severity of mediator-related symptoms (skin, gastrointestinal, musculoskeletal, and neuropsychiatric) and episodes of anaphylaxis were evaluated by interview and medical record files. Bone mineral density was determined by using dual-energy x-ray absorptiometry. Results Median fraction (range) of KIT D816V positive cells was 0.6 (0.01%-90%) in BM and 0.3 (0.003%-49%) in PB. Mutation level did not differ between patients with none/mild symptoms and patients with moderate/severe symptoms, patients with and without anaphylaxis, or patients with osteoporosis/osteopenia and normal bone mineral density. No significant differences in clinical profile were detected in patients with different levels of mutation except for an indication of longer disease duration and age in patients with highest mutation levels. Conclusion To our knowledge, this is the first report on the clinical impact of the fraction of KIT D816V mutation positive cells in ISM, which in the present study does not seem to correlate with clinical manifestations of the disease.
- Published
- 2012
34. Low incidence of minor BRAF V600 mutation-positive subclones in primary and metastatic melanoma determined by sensitive and quantitative real-time PCR
- Author
-
Lise Hoejberg, Thomas Kielsgaard Kristensen, and Ole Clemmensen
- Subjects
Proto-Oncogene Proteins B-raf ,Mutant ,DNA Mutational Analysis ,Biology ,Real-Time Polymerase Chain Reaction ,Sensitivity and Specificity ,Pathology and Forensic Medicine ,medicine ,Humans ,Allele ,Neoplasm Metastasis ,neoplasms ,Melanoma ,Incidence (epidemiology) ,DNA, Neoplasm ,medicine.disease ,Molecular biology ,Real-time polymerase chain reaction ,Evaluation Studies as Topic ,Mutation (genetic algorithm) ,Mutation ,Cancer research ,Mutation testing ,Molecular Medicine ,Population study ,Switzerland ,Microsatellite Repeats - Abstract
BRAF V600 mutation is an important biological marker for therapeutic guidance in melanoma, where mutation-positive cases are candidates for therapy targeting mutant B-Raf. Recent studies showing intratumor variation in BRAF mutation status have caused concern that sensitive mutation analysis can lead to mutation-positive results in patients with melanomas with small subsets of mutation-positive cells who may not benefit from therapy targeting mutant B-Raf. Mutation analysis with high analytical sensitivity is generally preferred, to reduce the risk of false-negative results. In this study, sensitive and quantitative BRAF V600E and V600K mutation-specific real-time quantitative PCR was used to study the occurrence of small subsets of mutation-positive cells in primary melanomas and melanoma metastases. The BRAF V600E mutation was detected in 39 of 82 melanoma patients. We observed a highly dichotomous pattern, with most samples either testing mutation positive in a high fraction of alleles (median, 51%) or negative with a high sensitivity (median, 0.06%). This finding demonstrates that the occurrence of small subsets of mutation-positive cells was rare in our study population and indicates that sensitive mutation analysis can generally be expected to produce clinically relevant results in melanoma patients.
- Published
- 2012
35. Circulating KIT D816V mutation-positive non-mast cells in peripheral blood are characteristic of indolent systemic mastocytosis
- Author
-
Michael Boe Møller, Sigurd Broesby-Olsen, Hanne Vestergaard, Thomas Kielsgaard Kristensen, and Carsten Bindslev-Jensen
- Subjects
Adult ,Male ,Pathology ,medicine.medical_specialty ,medicine.disease_cause ,Flow cytometry ,Immunophenotyping ,Young Adult ,Mastocytosis, Systemic ,medicine ,Humans ,Mast Cells ,Systemic mastocytosis ,Aged ,Mutation ,medicine.diagnostic_test ,business.industry ,Interleukin-2 Receptor alpha Subunit ,Hematology ,General Medicine ,Middle Aged ,medicine.disease ,Neoplastic Cells, Circulating ,Peripheral blood ,Kit d816v ,Proto-Oncogene Proteins c-kit ,medicine.anatomical_structure ,Amino Acid Substitution ,Immunology ,Female ,Bone marrow ,business - Abstract
It is presently accepted that the KIT D816V mutation is detectable in tissues with neoplastic mast cells in most patients with indolent systemic mastocytosis. In this study, neoplastic mast cells were detected in bone marrow, but not in peripheral blood, by flow cytometry in all 25 included cases of indolent systemic mastocytosis. However, the KIT D816V mutation was detected using mutation-specific qPCR in both bone marrow and peripheral blood in all 25 cases, demonstrating for the first time that the KIT D816V mutation is consistently present in non-mast cells in indolent systemic mastocytosis and that these cells are circulating in peripheral blood.
- Published
- 2012
36. Systemic mastocytosis is uncommon in KIT D816V mutation positive core-binding factor acute myeloid leukemia
- Author
-
Hanne Vestergaard, Lone S. Friis, Sigurd Broesby-Olsen, Michael Boe Møller, Birgitte Preiss, and Thomas Kielsgaard Kristensen
- Subjects
Adult ,Male ,Cancer Research ,Adolescent ,Oncogene Proteins, Fusion ,Gene Expression ,Chromosomal translocation ,Translocation, Genetic ,RUNX1 Translocation Partner 1 Protein ,Mastocytosis, Systemic ,Medicine ,Humans ,Systemic mastocytosis ,Child ,Core binding factor acute myeloid leukemia ,Chromosomal inversion ,Aged ,business.industry ,Reverse Transcriptase Polymerase Chain Reaction ,Myeloid leukemia ,Hematology ,Middle Aged ,medicine.disease ,Molecular biology ,Leukemia ,Proto-Oncogene Proteins c-kit ,Oncology ,Amino Acid Substitution ,Leukemia, Myeloid ,Immunology ,Mutation (genetic algorithm) ,Acute Disease ,Chromosome Inversion ,Core Binding Factor Alpha 2 Subunit ,Mutation ,Female ,business - Abstract
The KIT D816V mutation is detected in the vast majority of adult cases of systemic mastocytosis (SM). The mutation is also frequently detected in core-binding factor acute myeloid leukemia (CBF AML) defined by the presence of t(8;21)(q22;q22); RUNX1-RUNX1T1 or inv(16)(p13.1;q22)/t(16;16)(p13.1;q22); CBFB-MYH11 chromosomal rearrangements, but whether the mutation is indicative of associated SM is unclear. In the present study, patients with CBF AML were therefore analyzed for the KIT D816V mutation and mutation positive cases subsequently analyzed for the presence of SM. The KIT D816V mutation was detected in eight of 20 cases of CBF AML, with the frequency in t(8;21)(q22;q22) and inv(16)(p13.1;q22) positive cases being 31% and 57%, respectively. The fraction of KIT D816V mutation positive cells was highly variable among the eight mutation positive patients, with levels ranging from 0.04 to 98% in a pretreatment blood sample. Five of the eight cases carried the mutation in a cell fraction below one-tenth of the blast cell fraction, thus suggesting that KIT mutation is often a late event in leukemogenesis. None of the eight KIT D816V mutation positive cases fulfilled the World Health Organization diagnostic criteria of SM. The presence of the KIT D816V mutation in the CBF AML subgroup can therefore not be considered indicative of associated SM.
- Published
- 2011
37. Improved detection of the KIT D816V mutation in patients with systemic mastocytosis using a quantitative and highly sensitive real-time qPCR assay
- Author
-
Hanne Vestergaard, Thomas Kielsgaard Kristensen, and Michael Boe Møller
- Subjects
Adult ,Male ,Pathology ,medicine.medical_specialty ,Biology ,Polymerase Chain Reaction ,Pathology and Forensic Medicine ,law.invention ,Mastocytosis, Systemic ,law ,medicine ,Humans ,Point Mutation ,Clinical significance ,Systemic mastocytosis ,Allele ,Polymerase chain reaction ,Aged ,Aged, 80 and over ,Point mutation ,Regular Article ,Sequence Analysis, DNA ,Middle Aged ,medicine.disease ,Mast cell ,Proto-Oncogene Proteins c-kit ,medicine.anatomical_structure ,Immunology ,Mutation (genetic algorithm) ,Molecular Medicine ,Female ,Bone marrow - Abstract
The vast majority of patients with systemic mastocytosis (SM) carry the somatic D816V mutation in the KIT gene. The KIT D816V mutation is one of the minor criteria for a diagnosis of SM according to the 2008 World Health Organization classification of myeloproliferative neoplasms. In the present study, we present a real-time qPCR assay that allows quantification of as little as 0.003% KIT D816V mutation-positive cells. A total of 61 samples from 31 cases of SM were included in the study. We detected the mutation in skin or bone marrow in 95% of the cases of SM. We demonstrate the clinical relevance of the assay by identifying as little as 0.03% mutation-positive cells in bone marrow aspirates from SM patients and calculate the analytical sensitivity of negative samples to determine the reliability of the result. We further demonstrate that this method also detects the KIT D816V mutation in peripheral blood in 81% of the mutation-positive cases with SM. The method also allows comparison of mutation-positive and mast cell fractions to determine whether the mutation is present in non-mast cells, a parameter that has recently been reported to be of prognostic importance in patients with indolent SM. Finally, the assay is suitable for use in prospective studies of the KIT D816V allele burden as a treatment endpoint in SM.
- Published
- 2010
38. Relapse of myeloid neoplasm with eosinophilia andPDGFRArearrangement after imatinib discontinuation in a pediatric patient
- Author
-
Eckhard Schomerus, Thomas Kielsgaard Kristensen, Peder Skov Wehner, Mathias Rathe, and Michael Boe Møller
- Subjects
Oncology ,medicine.medical_specialty ,Pathology ,business.industry ,Imatinib ,Hematology ,PDGFRA ,Myeloid Neoplasm ,Discontinuation ,Pediatric patient ,Internal medicine ,Pediatrics, Perinatology and Child Health ,medicine ,Eosinophilia ,medicine.symptom ,business ,medicine.drug - Published
- 2014
39. Anaphylaxis caused by mosquito allergy in systemic mastocytosis
- Author
-
Frank Siebenhaar, Sigurd Broesby-Olsen, Nadine Reiter, Martin Metz, Stefanie C. Becker, Thomas Kielsgaard Kristensen, Sabine Altrichter, Marcus Maurer, Martin K. Church, and Marielies Reiter
- Subjects
Male ,Allergy ,Omalizumab ,Immunoglobulin E ,Insect bites and stings ,Mastocytosis, Systemic ,parasitic diseases ,Animals ,Humans ,Medicine ,Systemic mastocytosis ,Anaphylaxis ,biology ,medicine.diagnostic_test ,business.industry ,Insect Bites and Stings ,General Medicine ,Middle Aged ,medicine.disease ,Bee stings ,Culicidae ,Immunology ,Skin biopsy ,biology.protein ,business ,medicine.drug - Abstract
In the summer of 1996, a 56-year-old man was bitten on his arm by a mosquito in his garden in Bavaria, Germany. About 15 min later he had diarrhoea, felt nauseous, and lost consciousness. He was bitten again by a mosquito in May, 2001, and August, 2001. Following the bite in August, 2001, the reaction developed rapidly, and he immediately lost consciousness and went into cardiac arrest before the ambulance arrived. Because of delayed resuscitation, he had hypoxic brain damage to the basal ganglia, resulting in spastic tetraplegia. Red-brown maculo papular skin lesions were seen on his upper legs and a skin biopsy showed increased mast cell numbers. In 2006, he was bitten a fourth time by a mosquito. Despite immediate adminis tration of rescue medi cation consisting of epinephrine, H1-antihistamine, and corticosteroid, he again had a severe reaction and cardiac arrest. In 2012, the patient was referred to the depart ment of dermatology and allergy, Charite—Universitatsmedizin Berlin, Germany, for further investigation. On the basis of the history of maculopopular skin lesions and increased mast cell numbers on skin biopsy, we suspected systemic mastocytosis. WHO diagnostic criteria for systemic mastocytosis were confi rmed. Despite having only slightly raised serum tryptase of 11·5 μg/L (normal range
- Published
- 2013
40. Mutation in the Nucleophosmin Gene (NPM1) Is a Stable Marker for Minimal Residual Disease Monitoring in Acute Myeloid Leukemia Patients with Increased Sensitivity and Specificity Compared to Expression of the Wilms Tumor (WT1) Gene
- Author
-
Birgitte Preiss, Lone S. Friis, Michael Boe Møller, and Thomas Kielsgaard Kristensen
- Subjects
NPM1 ,Immunology ,Myeloid leukemia ,Chromosomal translocation ,Wilms' tumor ,Cell Biology ,Hematology ,Biology ,medicine.disease ,Biochemistry ,Minimal residual disease ,Exon ,Leukemia ,hemic and lymphatic diseases ,Mutation (genetic algorithm) ,Cancer research ,medicine - Abstract
Abstract 1602 Poster Board I-628 Mutation in exon 12 of the nucleophosmin (NPM1) gene occurs in approximately 60% of acute myeloid leukemia (AML) patients with normal karyotype. To date, molecular minimal residual disease (MRD) monitoring in this patient group has primarily been based on expression of the Wilms tumor gene (WT1), although expression of WT1 in non-leukemia cells limits the specificity of this marker. Mutation in the NPM1 gene is potentially a superior MRD marker compared to WT1 gene expression by being specific to the malignant clone. The use of NPM1 mutation as a MRD marker would furthermore be in line with the widespread use of leukemia cell specific fusion-genes as MRD markers in AML patients with balanced translocations. In the present study, we therefore evaluated NPM1 mutation as a MRD marker with respect to stability, sensitivity and specificity in direct comparison to WT1 gene expression. A total of 13 relapsed AML patients with normal karyotype that were positive for mutation in NPM1 and WT1 gene expression at the time of diagnosis were included in the study. The NPM1 mutational load and WT1 gene expression was analyzed by real-time qPCR in up to 22 peripheral blood mononuclear cell samples per patient from the time of primary diagnosis to latest follow-up to compare the kinetics of the two markers during periods of morphological remission and relapse events. The 13 patients experienced a total of 18 morphological relapses which were all accompanied by high levels of NPM1 mutation, along with high WT1 mRNA levels, thus demonstrating complete stability of NPM1 mutation during relapse in the present material. During periods of complete morphological remission, the NPM1 mutational load was below detection limit (< 1/1000 cells) in all samples. In contrast, WT1 gene expression was detectable in 70% of these samples, thus demonstrating the limited specificity of this marker. This background WT1 expression in non-leukemia cells reached levels of up to 1% of the levels detected at the time of diagnosis thus limiting the de facto MRD marker sensitivity of WT1. All samples with detectable levels of NPM1 mutation after a period of complete molecular remission were followed by a morphological relapse within weeks. The present study therefore shows that mutation in NPM1 is a stable and more sensitive and specific, and therefore superior, molecular MRD marker than WT1. Disclosures No relevant conflicts of interest to declare.
- Published
- 2009
41. 1151 POSTER Fatigue in cancer patients at the time of rehabilitation
- Author
-
Anders Nielsen, J. Tofte, S.E. Larsen, M. Nielsen, C.B. Piester, U. Hjortebjerg, and Thomas Kielsgaard Kristensen
- Subjects
Cancer Research ,medicine.medical_specialty ,Physical medicine and rehabilitation ,Rehabilitation ,Oncology ,business.industry ,medicine.medical_treatment ,Physical therapy ,Medicine ,Cancer ,business ,medicine.disease - Published
- 2007
42. 8175 POSTER Side effects at the time of rehabilitation as reported by more than 600 cancer patients in response to an open question and a structered, closed questionaire
- Author
-
M. Munch Nielsen, Thomas Kielsgaard Kristensen, S.E. Larsen, U. Hjortebjerg, Anders Nielsen, J. Tofte, C. Bruun Pister, and K. Mark
- Subjects
Cancer Research ,medicine.medical_specialty ,Rehabilitation ,Oncology ,business.industry ,medicine.medical_treatment ,Physical therapy ,medicine ,Questionnaire ,Cancer ,medicine.disease ,business - Published
- 2007
43. Adult-onset systemic mastocytosis in monozygotic twins
- Author
-
Sigurd Broesby-Olsen, Thomas Kielsgaard Kristensen, Michael Boe Møller, Carsten Bindslev-Jensen, and Hanne Vestergaard
44. Molecular investigation of patients with chronic lymphocytic leukaemia (CLL) and ibrutinib resistance
- Author
-
Sólja Remisdóttir Veyhe, Oriane Cédile, Mh, Hansen, Michael Boe Møller, Thomas Kielsgaard Kristensen, Henrik Frederiksen, Karen Juul Jensen, and Charlotte Guldborg Nyvold
45. Molecular heterogeneity of mantle cell lymphoma
- Author
-
Oriane Cédile, Marcus Hansen, Lene Hyldahl Ebbesen, Hans Herluf Nørgaard Bentzen, Mads Thomassen, Kruse, Torben A., Stephanie Kavan, Michael Boe Møller, Thomas Kielsgaard Kristensen, Jacob Haaber Christensen, Niels Abildgaard, and Charlotte Guldborg Nyvold
46. Systemic mastocytosis--a systematic review
- Author
-
Christen Lykkegaard Andersen, Thomas Kielsgaard Kristensen, Marianne Tang Severinsen, Michael Boe Møller, Hanne Thang Vestergaard, Olav Jonas Bergmann, Hans Carl Hasselbalch, and Ole Weis Bjerrum
- Subjects
Mastocytosis, Systemic ,Histamine Antagonists ,Humans ,Mast Cells ,macromolecular substances ,Prognosis ,Glucocorticoids - Abstract
The mast cell lives a hidden life, but it is implicated in several physiological reactions. Its ability to react to different stimuli impacts a variety of conditions such as asthma, atopic dermatitis, urticaria and anaphylaxis. It is not until recent decades that the evolution of the cell has been described and its fascinating biology has only recently been depicted. We here give a review of systemic mastocytosis in regards to cell biology, diagnostic approaches and clinical practice.A search was made in PubMed in August 2011 entering the keywords: mastocytosis, (systemic, cutaneous, aggressive), mast cell leukaemia, mast cell sarcoma, chromosome, mutation, haematology and treatment.Mastocytosis is characterized by an abnormal proliferation of mast cells, which accumulate in one or several organ systems, primarily the skin and bone marrow. The disease is clinically heterogeneous and varies from a relatively benign condition with isolated cutaneous lesions to a very aggressive systemic condition with a grave prognosis. The condition affects men and women equally. Children are especially affected by the cutaneous form. In most children, the condition will improve or remit spontaneously before adulthood. Mastocytosis in adults, however, is more often systemic and tends to persist.Patients with mastocytosis represent a heterogeneous group in terms of clinical presentation, management and prognosis. Furthermore, a range of medical specialties serve as the primary entrance to health services, which can be a challenge in respect of achieving uniform management. In order to improve diagnostics and management of systemic mastocytosis, the European Competence Network on Mastocytosis has been established. Patients under suspicion of systemic mastocytosis should be conferred with or referred to a haematological and a dermatological/allergological department.
47. Circulating KIT D816V mutation positive non-mast cells in peripheral blood is characteristic of indolent systemic mastocytosis
- Author
-
Thomas Kielsgaard Kristensen, Sigurd Broesby-Olsen, Hanne Vestergaard, Carsten Bindslev-Jensen, and Michael Boe Møller
48. Nye sygdomsmarkører ved de kroniske myeloproliferative neoplasier
- Author
-
Morten Orebo Holmström, Lukas Frans Ocias, Klaus Kallenbach, Lasse Kjær, Thomas Kielsgaard Kristensen, Niels Pallisgaard, Bodil Laub Petersen, Vibe Skov, Karin de Stricker, Thomas Stauffer Larsen, and Hans Carl Hasselbalch
- Subjects
Myeloproliferative Disorders/diagnosis ,Polycythemia Vera/genetics ,Calreticulin/genetics ,Mutation ,Humans ,Receptors, Thrombopoietin/genetics ,Primary Myelofibrosis/genetics ,Thrombocytosis/genetics - Abstract
The chaperone and calcium storing protein calreticulin is coded by CALR, and newly identified mutations in CALR are found in respectively 49-70% and 56-88% of JAK2- and MPL-negative patients with essential thrombocytaemia (ET) and primary myelofibrosis (PMF). A total of 41 mutations have been identified, all located to exon 9 which codes the protein's C-terminal. CALR mutations are present only in myeloid malignancies and confer a more indolent disease than JAK2-mutated ET and PMF. CALR mutations as a diagnostic and prognostic tool are promising and the mutations are potential targets for immune therapy.
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