Gergely Szombath

Impact of polymorphic variation at 7p15.3, 3p22.1 and 2p23.3 loci on risk of multiple myeloma

whole of the UK. Wales has been a pioneer in the process of haematology harmonization, as a result of the introduction of a national laboratory information management system for Wales, and is represented on the Pathology Harmony Haematology Sub-Group. Scotland is represented on the Pathology Harmony Committee and the Scottish representatives have supported the earlier changes in Clinical Chemistry. The process to date has not been as easy as might be envisaged; it has taken much effort to reach this stage of the project. The haematology sub-group is also working closely with the DH advisor for the National Laboratory Medicine Catalogue (NLMC) on the incorporation of the changes of nomenclature and units into the NLMC, the standard for pathology test requests and results reporting, under collaborative development by the RCPath, the Department of Health and NHS Connecting for Health. The future challenges will be to move on to other areas of standardization including the development of consensus reference intervals for FBC and expansion to other areas of haematology, e.g., Hb A2, haematinic assays, coagulation factor assays and leucocyte immunophenotyping. The issue of harmonized reference intervals for the extended FBC is not expected to be straightforward, given the variation seen with age, ethnic differences and physiological state, e.g., pregnancy. For harmonized reference intervals to be effective, they must be widely adopted and this will not happen without a pragmatic approach and majority agreement within haematology.

Prognosis of acute myeloid leukemia transformed from myelodysplastic syndromes: A multicenter retrospective study

Myelodysplastic syndromes (MDS) often transform into acute leukemia (AL-MDS), although its prognostic details have not been examined thoroughly. We retrospectively analyzed the prognosis of 189 AL-MDS patients. Ninety-four patients received best supportive care (BSC), and 94 patients received disease-modifying therapies (DMT) that included chemotherapy (CHT) for 65 patients, allogeneic stem-cell transplantation (allo-SCT) for 21 patients, and other therapies for 8 patients. The median survival time was 142 days. In patients treated with BSC, platelet count alone was an independent prognostic factor. In younger patients treated with DMT (<60 years, N=25), allo-SCT was an independent prognostic factor associated with longer survival. In older patients treated with DMT (≥60 years, N=69), the therapy type did not affect survival, and performance status and MDS-specific comorbidity index were independent prognostic factors.

Progresszív kórlefolyást mutató szisztémás mastocytosis

Absztrakt: A szerzők egy kiterjedt bőrerintettseggel jaro szisztemas mastocytosisban szenvedő ferfi beteg esetenek bemutatasan keresztul rovid osszefoglalot adnak erről a ritka korformarol. A beteg eletminőseget megkeseritő kronikus hasmenes antihisztaminok, a mellkascsapolas utan korabban visszatermelődő folyadekgyulem alfa-interferon alkalmazasa mellett megszűnt. Mintegy 40 evvel a bőrtunetek jelentkezeset kovetően mind a „B” (30%-nal nagyobb mertekű csontvelő-infiltracio, dismyelopoesis, triptazszint >20 μg/L, maj- es lepmegnagyobbodas), mind pedig a „C” tunetek megjelenese (koros majfunkcio, cytopeniak, malabszorpcios tunetek, osteoporosis) jelezte a progressziot, es a beteg 87 eves koraban exitalt. A szerzők esetismertetesukkel felhivjak a figyelmet erre a ritka betegsegre es hangsulyozzak, hogy a betegek szamara tuneti, illetve egyedi meltanyossagi kerelem utjan elerhető szerekkel jobb eletminőseg erhető el. Orv Hetil. 2018; 159(5): 192–196.

Multiple Myeloma of the Central Nervous System: 13 Cases and Review of the Literature

Central nervous system involvement is a rare complication of multiple myeloma with extremely poor prognosis as it usually fails to respond to therapy. We present 13 cases diagnosed at two centers in Budapest and review the current literature. The majority of our cases presented with high-risk features initially; two had plasma cell leukemia. Repeated genetic tests showed clonal evolution in 3 cases. Treatments varied according to the era, and efficacy was poor as generally reported in the literature. Only one patient is currently alive, with 3-month follow-up, and the patient responded to daratumumab-based treatment. Recent case reports show promising effectivity of pomalidomide and marizomib.

Thalidomidkezelés relabált, diffúz nagy B-sejtes lymphomában idős betegekben. Három eset bemutatása

Absztrakt: A diffuz nagy B-sejtes lymphoma (DLBCL) a leggyakoribb malignus lymphomatipus, amely a non-Hodgkin-lymphomak (NHL) 31%-at teszi ki. A standard kemoterapias protokollok jelentős toxicitasuk miatt nem vagy nehezen alkalmazhatoak az idősebb betegpopulacioban, kulonosen a relabalt esetekben, ahol kurativ lehetőseget leginkabb a nagy dozisu kezeles es a ver-őssejtatultetes jelenthetne. Egyre tobb adat lat napvilagot a thalidomid es az ujabb IMiD-ek (lenalidomid, pomalidomid) kedvező hatasairol az NHL kezeleseben, amelyek reszei a standard kezelesnek myeloma multiplexben es myelodysplasias szindromaban. Az IMiD-ek kiterjedt anti-angiogenetikus, immunmodulans es gyulladasellenes hatasuknak koszonhetik az egyre szeleskorűbb alkalmazast. 2010-ben azonositottak az E3-ubiquitin-ligaz-komplex egyik komponenset, a cereblont, amely a thalidomid molekularis tamadasi pontja. Az irodalomban kozolt eredmenyek alapjan thalidomidkezelest inditottunk harom relabalt, idős DLBCL-es betegunknel. Ket esetben kozponti i...

Identification of miRSNPs associated with the risk of multiple myeloma.

Multiple myeloma (MM) is a malignancy of plasma cells usually infiltrating the bone marrow, associated with the production of a monoclonal immunoglobulin (M protein) which can be detected in the blood and/or urine. Multiple lines of evidence suggest that genetic factors are involved in MM pathogenesis, and several studies have identified single nucleotide polymorphisms (SNPs) associated with the susceptibility to the disease. SNPs within miRNA‐binding sites in target genes (miRSNPs) may alter the strength of miRNA–mRNA interactions, thus deregulating protein expression. MiRSNPs are known to be associated with risk of various types of cancer, but they have never been investigated in MM. We performed an in silico genome‐wide search for miRSNPs predicted to alter binding of miRNAs to their target sequences. We selected 12 miRSNPs and tested their association with MM risk. Our study population consisted of 1,832 controls and 2,894 MM cases recruited from seven European countries and Israel in the context of the IMMEnSE (International Multiple Myeloma rESEarch) consortium. In this population two SNPs showed an association with p < 0.05: rs286595 (located in gene MRLP22) and rs14191881 (located in gene TCF19). Results from IMMEnSE were meta‐analyzed with data from a previously published genome‐wide association study (GWAS). The SNPs rs13409 (located in the 3′UTR of the POU5F1 gene), rs1419881 (TCF19), rs1049633, rs1049623 (both in DDR1) showed significant associations with MM risk. In conclusion, we sought to identify genetic polymorphisms associated with MM risk starting from genome‐wide prediction of miRSNPs. For some mirSNPs, we have shown promising associations with MM risk.

Proteasome Subunit Beta Type 1 P11A Polymorphism Is a New Prognostic Marker in Multiple Myeloma

Background Proteasome subunit beta type 1 (PSMB1) rs12717 polymorphism, a single nucleotide polymorphism with unknown functional effect, was recently reported to influence response to bortezomib‐based therapy in follicular lymphoma. Patients and Methods We retrospectively analyzed the prognostic impact of this polymorphism in 211 consecutively diagnosed multiple myeloma cases, and performed in vitro experiments to look into its functional consequences. Results On univariate analysis, patients carrying the variant G allele showed significantly shorter progression‐free survival (PFS) with a pattern suggestive of a gene‐dose effect (PFS 26.4, 22.3, and 16.4 months in C/C, C/G, and G/G patients, respectively, P = .002). On multivariate analysis, carrying the G/G genotype was a significant independent risk factor for relapse (hazard ratio [HR] 2.29, P < .001) with a similar trend in C/G carriers (HR 1.33, P = .097) when compared with the major allele carrier C/C cohort. Our subsequent in vitro analyses demonstrated significantly reduced protease activity in proteasomes of individuals with G/G genotype compared with that of C/C carriers, despite that PSMB1 expression and proteasome assembly remained unaltered. Bortezomib exhibited a lower inhibitory capacity on the caspase‐ and trypsin‐like activity of proteasomes from G/G individuals. Conclusion Our results show that carriership of PSMB1 rs12717 minor allele is predictive for suboptimal response with bortezomib treatment, which could be explained by less active proteasomes that are less sensitive to bortezomib, and myeloma cells consequently relying on other escape mechanisms to cope with the abundance of misfolded proteins. Micro‐Abstract We retrospectively analyzed the prognostic impact of proteasome subunit beta type 1 rs12717 polymorphism in 211 consecutively diagnosed multiple myeloma cases. Patients carrying the variant G allele showed significantly shorter progression‐free survival. In proteasomes of individuals with G/G genotype, we found significantly reduced protease activity and lower inhibitory capacity of bortezomib on the caspase‐ and trypsin‐like activity.