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1.
Blood ; 133(15): 1644-1651, 2019 04 11.
Article in English | MEDLINE | ID: mdl-30770395

ABSTRACT

Congenital thrombotic thrombocytopenic purpura (cTTP) is an ultra-rare thrombomicroangiopathy caused by an inherited deficiency of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13). There are limited data on genotype-phenotype correlation; there is no consensus on treatment. We reviewed the largest cohort of cTTP cases, diagnosed in the United Kingdom, over the past 15 years. Seventy-three cases of cTTP were diagnosed, confirmed by genetic analysis. Ninety-three percent were alive at the time of review. Thirty-six percent had homozygous mutations; 64% had compound heterozygous mutations. Two presentation peaks were seen: childhood (median diagnosis age, 3.5 years) and adulthood, typically related to pregnancy (median diagnosis age, 31 years). Genetic mutations differed by age of onset with prespacer mutations more likely to be associated with childhood onset (P = .0011). Sixty-nine percent of adult presentations were associated with pregnancy. Fresh-frozen plasma (FFP) and intermediate purity factor VIII concentrate were used as treatment. Eighty-eight percent of patients with normal blood counts, but with headaches, lethargy, or abdominal pain, reported symptom resolution with prophylactic therapy. The most common currently used regimen of 3-weekly FFP proved insufficient for 70% of patients and weekly or fortnightly infusions were required. Stroke incidence was significantly reduced in patients receiving prophylactic therapy (2% vs 17%; P = .04). Long-term, there is a risk of end-organ damage, seen in 75% of patients with late diagnosis of cTTP. In conclusion, prespacer mutations are associated with earlier development of cTTP symptoms. Prophylactic ADAMTS13 replacement decreases the risk of end-organ damage such as ischemic stroke and resolved previously unrecognized symptoms in patients with nonovert disease.


Subject(s)
ADAMTS13 Protein/genetics , Purpura, Thrombotic Thrombocytopenic/congenital , Purpura, Thrombotic Thrombocytopenic/drug therapy , ADAMTS13 Protein/deficiency , Adult , Child, Preschool , Factor VIII/therapeutic use , Female , Humans , Male , Mutation , Plasma , Pregnancy , Premedication/methods , Purpura, Thrombotic Thrombocytopenic/complications , Purpura, Thrombotic Thrombocytopenic/genetics , Stroke/prevention & control
2.
Genes Chromosomes Cancer ; 52(9): 785-93, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23720363

ABSTRACT

Multiple myeloma (MM) is a genetically heterogeneous disease with diverse clinical outcomes. Interphase fluorescence in situ hybridization (i-FISH) is the most commonly used approach to detect recurrent cytogenetic abnormalities in this malignancy. We aimed to assess the performance of multiplex ligation-dependent probe amplification (MLPA) to reveal copy number abnormalities (CNAs) in MM. Diagnostic bone marrow samples from 81 patients were analyzed using 42 MLPA probes for the following regions: 1p32-31, 1p21, 1q21.3, 1q23.3, 5q31.3, 12p13.31, 13q14, 16q12, 16q23, and 17p13. All samples were also screened by i-FISH for the presence of hyperdiploidy, deletion/monosomy of chromosome 13, deletion of TP53, disruption of the immunoglobulin heavy-chain gene, t(4;14), t(11;14), t(14;16), t(8;14), gain of 5q and abnormalities of chromosome 1. A total of 245 alterations were detected in 79 cases (98%). Investigating the same aberrations, the two methods showed a congruency of higher than 90%. A low proportion of cells with the relevant abnormality, focal CNAs and unmatched probes were responsible for the discrepancies. MLPA revealed 95 CNAs not detected by i-FISH providing additional information in 53 cases (65%). Scrutiny of CNAs on chromosome 1, using more than 20 probes, revealed significant heterogeneity in size and location, and variable intra-chromosomal and intra-clonal rates of loss or gain. Our results suggest that MLPA is a reliable high-throughput technique to detect CNAs in MM. Since balanced aberrations are key to prognostic classification of this disease, MLPA and i-FISH should be applied as complementary techniques in diagnostic pathology.


Subject(s)
Chromosome Aberrations , Cytogenetic Analysis/methods , In Situ Hybridization, Fluorescence , Multiple Myeloma/genetics , Multiplex Polymerase Chain Reaction , Chromosomes, Human, Pair 1/genetics , DNA Copy Number Variations , Humans , Multiple Myeloma/pathology
3.
Orv Hetil ; 151(34): 1365-74, 2010 Aug 22.
Article in Hungarian | MEDLINE | ID: mdl-20705551

ABSTRACT

A large proportion of hospitalized surgical and medical patients are at risk for venous thromboembolism. Depending on the type of surgical intervention, venous thrombosis develops in 15-60% of surgical patients without prophylaxis. Although venous thromboembolism is most often considered to be associated with recent surgery or trauma, 50 to 70% of symptomatic thromboembolic events and 70 to 80% of fatal pulmonary embolisms occur in nonsurgical patients. International and national registries show that the majority of at-risk surgical patients actually received the appropriate thromboembolic prophylaxis. However, despite of international and national recommendations, prophylaxis was not provided for a large proportion of at-risk medical patients. The rate of medical patients receiving prophylaxis should be increased, and appropriate thrombosis prophylaxis should be offered to at-risk medical patients. The thrombosis risk assessment is an important tool to identify patients at increased risk for venous thromboembolism, to simplify decision making on prophylaxis administration, and to improve the adherence to guidelines. When the risk is recognized, if there is no contraindication, prophylaxis should be ordered. The 4th Hungarian Antithrombotic Guideline entitled "Risk reduction and treatment of thromboembolism" calls attention to the importance of risk assessment and for the first time it includes and recommends risk assessment models for hospitalized surgical and medical patients. The risk assessment models are presented and the evidence based data for the different risk factors included in these models are reviewed.


Subject(s)
Hospitalization , Surgical Procedures, Operative/adverse effects , Surveys and Questionnaires/standards , Venous Thromboembolism/etiology , Venous Thromboembolism/prevention & control , Age Factors , Anticoagulants/therapeutic use , Autoimmune Diseases/complications , Body Mass Index , Contraceptives, Oral, Hormonal/adverse effects , Genetic Predisposition to Disease , Humans , Hungary , Infections/complications , Inflammatory Bowel Diseases/complications , Locomotion , Mutation , Neoplasms/complications , Nephrosis/complications , Obesity/complications , Practice Guidelines as Topic , Primary Prevention/methods , Pulmonary Disease, Chronic Obstructive/complications , Registries , Respiratory Insufficiency/complications , Risk Assessment , Risk Factors , Varicose Veins/complications , Venous Insufficiency/complications , Venous Thromboembolism/drug therapy , Venous Thromboembolism/genetics
4.
Blood ; 109(1): 61-4, 2007 Jan 01.
Article in English | MEDLINE | ID: mdl-16960151

ABSTRACT

Fusion genes derived from the platelet-derived growth factor receptor beta (PDGFRB) or alpha (PDGFRA) play an important role in the pathogenesis of BCR-ABL-negative chronic myeloproliferative disorders (CMPDs). These fusion genes encode constitutively activated receptor tyrosine kinases that can be inhibited by imatinib. Twelve patients with BCR-ABL-negative CMPDs and reciprocal translocations involving PDGFRB received imatinib for a median of 47 months (range, 0.1-60 months). Eleven had prompt responses with normalization of peripheral-blood cell counts and disappearance of eosinophilia; 10 had complete resolution of cytogenetic abnormalities and decrease or disappearance of fusion transcripts as measured by reverse transcriptase-polymerase chain reaction (RT-PCR). Updates were sought from 8 further patients previously described in the literature; prompt responses were described in 7 and persist in 6. Our data show that durable hematologic and cytogenetic responses are achieved with imatinib in patients with PDGFRB fusion-positive, BCR-ABL-negative CMPDs.


Subject(s)
Antineoplastic Agents/therapeutic use , Fusion Proteins, bcr-abl/blood , Myeloproliferative Disorders/drug therapy , Oncogene Proteins, Fusion/blood , Piperazines/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Pyrimidines/therapeutic use , Receptor, Platelet-Derived Growth Factor beta/blood , Adult , Aged , Aged, 80 and over , Benzamides , Biomarkers, Tumor/blood , Child , Child, Preschool , Drug Evaluation , Eosinophilia/etiology , Female , Follow-Up Studies , Humans , Imatinib Mesylate , Infant , Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative/blood , Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative/drug therapy , Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative/genetics , Male , Middle Aged , Myeloproliferative Disorders/blood , Myeloproliferative Disorders/genetics , Oncogene Proteins, Fusion/genetics , RNA, Messenger/blood , RNA, Neoplasm/blood , Receptor, Platelet-Derived Growth Factor beta/genetics , Retrospective Studies , Reverse Transcriptase Polymerase Chain Reaction , Translocation, Genetic , Treatment Outcome
5.
Orv Hetil ; 146(41): 2121-5, 2005 Oct 09.
Article in Hungarian | MEDLINE | ID: mdl-16304806

ABSTRACT

INTRODUCTION: In rare cases of thromboembolic diseases developing in young age, venous and arterial thromboembolism can occur simultaneously. AIMS: To detect the venous and the arterial risk factors in a severe thrombophilic family. A 47-years-old female with severe atherosclerosis and recurrent deep vein thrombosis, and 6 members of her family were analysed. METHODS: The following haemostatic and molecular genetic investigations were performed: besides the rutin haemostatic parameters, risk factors for venous thrombembolic disease, risk factors for venous and arterial thrombosis (plasma homocysteine level, MTHFR C677T polymorphism) were determined. This panel was completed with the measurement of lipoprotein (a), von Willebrand factor, plasminogen activator inhibitor-1 antigen, serum total cholesterin, HDL cholesterin, C reactive protein and PIA2 variant. The propositus was proven to have type I antithrombin deficiency, elevated homocysteine level, homozygous MTHFR C677T polymorphism, elevated Lp(a), vWF:Ag, and PAI-1:Ag levels. RESULTS: All family members had a combination of cardiovascular risk factors (in 4 cases elevated homocysteine level, in 3 cases elevated Lp(a), in 2 cases elevated vWF:Ag, in 4 cases increased PAI-1 level). These risk factors were combined in three cases with type I antithrombin deficiency. Despite of the presence of atherosclerotic risk factors in the family, arterial thrombotic disease could be detected only in two patients with antithrombin deficiency. CONCLUSIONS: The results of the investigated family indicate that in case of combination of venous and arterial thromboembolic risk factors, antithrombin deficiency may contribute to the manifestation of arterial thromboembolic diseases.


Subject(s)
Fibrin/deficiency , Thrombophilia/metabolism , Thrombosis/etiology , Adult , C-Reactive Protein/metabolism , Cholesterol/blood , Cysteine , Female , Genetic Predisposition to Disease , Homocysteine/blood , Humans , Male , Pedigree , Plasminogen Activator Inhibitor 1/immunology , Polymorphism, Genetic , Risk Factors , Threonine , Thrombophilia/genetics , Thrombosis/blood , Thrombosis/genetics , Thrombosis/metabolism , Venous Thrombosis/etiology , von Willebrand Factor/metabolism
6.
Orv Hetil ; 145(17): 901-7, 2004 Apr 25.
Article in Hungarian | MEDLINE | ID: mdl-15170967

ABSTRACT

BACKGROUND: Chronic myelogenous leukemia is characterised by the presence of Philadelphia translocation and consecutive expression of bcr-abl oncogene with enhanced tyrosine kinase activity, which is known to be the essential pathogenetic event in the disease. Imatinib (Glivec, formerly STI571) is a highly selective inhibitor of the bcr-abl tyrosine kinase which has shown a promising therapeutic activity in chronic myeloid leukemia as the first molecularly targeted antinoplastic treatment. METHODS: Between January 2001 and October 2001, 54 patients with chronic phase CML, resistant or intolerant to interferon-alpha were enrolled into the Novartis Expanded Access Study (Protocol 0113). Patients characteristics were as follows: male/female: 32/22, median age: 49 years (range: 22-75), median duration of disease: 44 months (range: 3-152). All patients received 400 mg imatinib orally. RESULTS: Complete hematologic response was obtained in 53 patients (96%) within 4 weeks. Major cytogenetic response (< 35% Ph+ metaphasis) was achieved after 6 months in 62.9%, and after 12 months in 64.8% of patients. Three patients progressed during the treatment (loss of complete hematologic response or cytogenetic response 1, blastic phase 2). The treatment was well tolerated, with mild side effects. Main non-hematologic side effects were weight gain and fluid retention. CONCLUSIONS: The results confirm that imatinib is highly active in inducing complete hematologic response and major cytogenetic response in most patients who failed interferon-alpha. Treatment was well tolerated with rare and mild adverse events and impressive improvement of quality of life.


Subject(s)
Antineoplastic Agents/therapeutic use , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Piperazines/therapeutic use , Pyrimidines/therapeutic use , Adult , Aged , Antineoplastic Agents/adverse effects , Benzamides , Female , Humans , Imatinib Mesylate , Interferon-alpha/therapeutic use , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/blood , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Male , Middle Aged , Piperazines/adverse effects , Pyrimidines/adverse effects , Quality of Life , Treatment Outcome
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