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Background: The pathogenesis of Dupuytren's disease is unclear, but inflammatory mechanisms might be supposed in the background. Materials and methods: The ratios of the subsets of monocytes and lymphocytes in the peripheral blood were measured according to the stage of the disease of 39 Dupuytren's patients. They were compared with those of 29 healthy, age-matched controls. The measurements were accomplished by flow-cytometry. Results: In an active stage, the patients had significantly increased ratios of monocytes, NK-like T-cells, whereas significantly decreased ratio of B-lymphocytes, including CD5+ B-cells. The ratios of CD4+, CD8+ T-cells and NK-cells did not change significantly. In the advanced stage, the ratios of monocytes and B-lymphocytes remained constant, but the ratios of T-cells decreased significantly. In four cases among Dupuytren's patients, mature B- or T-cell lymphoid malignancies occurred. Conclusions: Our results support the previous considerations that lymphocytes are involved in the pathogenesis of Dupuytren's disease and enhance the role of monocytes, NK-like T-cells and the alteration of immune response between the stages of the disease. [ABSTRACT FROM AUTHOR]

Uvod: Patogeneza Dupuytrenove bolesti je nejasna, no mogu se pretpostaviti upalni mehanizmi u njenoj pozadini. Materijali i metode: Mjerili smo udjele različitih podvrsta monocita i lim-focita u perifernoj krvi prema stadiju bolesti kod 39 bolesnika oboljelih od Dupuytrenove bolesti. Rezultate smo usporedili s rezultatima 29 zdravih kontrolnih ispitanika iz iste dobne skupine. Mjerenja su napravljena pomoću protočne citometrije. Rezultati: U aktivnom su stadiju bolesnici imali bitno povišen udio monocita, NK-stanica sličnih T-limfocitima, dok je udio B-limfocita bio značajno snižen, uključujući CD5+ B-limfocite. Udjeli CD4+, CD8+ T-limfocita i B-limfocita nisu se znatno promijenili. U naprednom su stadiju bolesti udjeli monocita i B-limfocita ostali konstantnima, no značajno su se snizili udjeli T-limfocita. U četiri slučaja među bolesnicima koji boluju od Dupuytrenove bolesti pojavile su se limfoidne neoplazme zrelih B- ili T-limfocita. Zaključci: Naši rezultati podupiru prijašnja mišljenja da su limfociti povezani s patogenezom Dupuytrenove bolesti te pojačavaju ulogu monocita, NK-stanica sličnih T-limfocitima i promjenu imunosnog odgovora između stadija bolesti. [ABSTRACT FROM AUTHOR]

Background: Myelodysplastic neoplasms (MDS) are characterized by cytopenia, morphologic dysplasia, and genetic abnormalities. Multiparameter flow cytometry (FCM) is recommended in the diagnostic work-up of suspected MDS, but alone is not sufficient to establish the diagnosis. Our aim was to investigate the diagnostic power of FCM in a heterogeneous population of patients with cytopenia, excluding cases with increased blast count., Methods: We analyzed bone marrow samples from 179 patients with cytopenia (58 MDS, 121 non-MDS) using a standardized 8-color FCM method. We evaluated the sensitivity, specificity, and accuracy of several simple diagnostic approaches, including Ogata score, extended Ogata score, the WHO and ELN iMDSFlow recommended "3 aberrations in two cell compartments method," and the combination of the Ogata score and "3 aberrations in two cell compartments method." The patients were followed until the diagnosis was confirmed, with a median follow-up of 2 months (range 0.2-27)., Results: The combination of Ogata score and "3 aberrations in two cell compartments method" achieved the highest diagnostic accuracy (78%) with sensitivity and specificity 61% and 86%, respectively. When using only the "3 aberrations in two cell compartments method," the accuracy was 77% with a sensitivity of 72% and a specificity of 79%. The most frequently observed etiologies among the false positive cases were substrate deficiencies, inflammation/infection, or toxic effects. MDS can be excluded in all these cases after a thorough clinical evaluation and a relatively short follow-up., Conclusion: FCM remains an important but supplementary part in an integrated diagnostic process of MDS with low blasts. The combination of the Ogata score and the "3 aberrations in two cell compartments method" slightly improves accuracy compared to the detection of "3 aberrations in two cell compartments method" alone., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Plander, Kányási, Szendrei, Skrapits and Timár.)

TP53 aberrations predict chemoresistance and represent a contraindication for the use of standard chemoimmunotherapy in chronic lymphocytic leukaemia (CLL). Recent next-generation sequencing (NGS)-based studies have identified frequent low-burden TP53 mutations with variant allele frequencies below 10%, but the clinical impact of these low-burden TP53 mutations is still a matter of debate. In this study, we aimed to scrutinise the subclonal architecture and clinical impact of TP53 mutations using a sensitive, NGS-based mutation analysis in a 'real-world' cohort of 901 patients with CLL. In total, 225 TP53 mutations were identified in 17.5% (158/901) of the patients; 48% of these alterations represented high-burden mutations, while 52% were low-burden TP53 mutations. Low-burden mutations as sole alterations were identified in 39% (62/158) of all mutated cases with 82% (51/62) of these being represented by a single low-burden TP53 mutation. Patients harbouring low-burden TP53 mutations had significantly lower time to first treatment compared to patients with wild-type TP53. Our study has expanded the knowledge on the frequency, clonal architecture, and clinical impact of low-burden TP53 mutations. By demonstrating that patients with sole low-burden TP53 variants represent more than one-third of patients with TP53 mutations and have an increased risk for treatment initiation, our findings strengthen the need to redefine the threshold of TP53 variant reporting to below 10% in the routine diagnostic setting., (© 2023 The Authors. The Journal of Pathology: Clinical Research published by The Pathological Society of Great Britain and Ireland and John Wiley & Sons Ltd.)

Background: Ibrutinib is widely known as an effective and well-tolerated therapeutical choice of the chronic lymphocytic leukaemia (CLL). However, acquired resistance may occur during the treatment, causing relapse. Early detection of ibrutinib resistance is an important issue, therefore we aimed to find phenotypic markers on CLL cells the expression of which may correlate with the appearance of ibrutinib resistance. Methods: We examined 28 patients' peripheral blood (PB) samples (treatment naïve, ibrutinib sensitive, clinically ibrutinib resistant). The surface markers' expression (CD27, CD69, CD86, CD184, CD185) were measured by flow cytometry. Furthermore, the BTK C481S resistance mutation was assessed by digital droplet PCR. Moreover, the CLL cells' phenotype of a patient with acquired ibrutinib resistance was observed during the ibrutinib treatment. Results: The expression of CD27 ( p = 0.030) and CD86 ( p = 0.031) became higher in the clinically resistant cohort than in the ibrutinib sensitive cohort. Besides, we found that high CD86 and CD27 expressions were accompanied by BTK C481S mutation. Our prospective study showed that the increase of the expression of CD27, CD69 and CD86 was noticed ahead of the clinical resistance with 3 months. Conclusion: Our study suggests that the changes of the expression of these markers could indicate ibrutinib resistance and the examination of these phenotypic changes may become a part of the patients' follow-up in the future., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Takács, Kotmayer, Czeti, Szalóki, László, Mikala, Márk, Masszi, Farkas, Plander, Weisinger, Demeter, Fekete, Szerafin, Deák, Szaleczky, Sulák, Borbényi and Barna.)

Összefoglaló. Bevezetés: A myeloma multiplex mindmáig alapvetően gyógyíthatatlan betegség, ezért nagy klinikai jelentőségük van az eredményes mentő kezeléseknek. A szájon át adható első proteaszómagátlóval, az ixazomibbal kiegészített lenalidomid-dexametazon terápia jól tolerálható, csak orális szerekből álló kombináció, mely hazánkban 2015 áprilisától kezdődően a "Named Patient Program" keretén belül vált elérhetővé relabált, refrakter myeloma multiplexes betegek kezelésére. Célkitűzés: Kutatásunk célja az ixazomib-lenalidomid-dexametazon kezelés mellett a hosszú távon progressziómentes túlélők célzott vizsgálata. Módszer: A program keretében összesen 7 centrumban 80 visszaeső beteg részesült e triplet kezelésben, adataikat retrospektíven elemeztük. Leíró statisztikai és Kaplan-Meier-analízist végeztünk. Eredmények: A betegek nagyobb hányada reagált: 63,75%-os válaszarány mellett 14 (17,5%) betegnél nem volt terápiás válasz/stabil betegség alakult ki, és 15-nél (18,75%) a betegség a kezelés mellett is progrediált. A progressziómentes túlélés a teljes betegcsoportban 10,6 hónapnak adódott, ugyanakkor 16 beteg (18,75%) két éven túl progressziómentesnek bizonyult, sőt közülük 11-nél a betegség még 3 év után sem progrediált. Tanulmányunkban a fenti, hosszú távú túlélő betegcsoport tulajdonságait tárjuk fel. Megbeszélés: A folyamatos terápia a myeloma multiplex kezelésében meghatározóvá vált. Ezért fontos ismernünk, hogy kik lehetnek azok a betegek, akik különösen sokat profitálnak egy bizonyos terápiából. A hosszú távon progressziómentes túlélők között az immunglobulin-nehézláncot érintő transzlokációk vagy triszómiák közül (trend szintjén) az utóbbiak kedvezőbb progressziómentes túléléssel bírtak, de progressziómentes platót mindkét betegcsoportban észleltünk. A betegség tumortömegét mérő nemzetközi stádiumbeosztás (ISS) nem jelezte előre a hosszú túlélést. Gyógyszerelhagyáshoz vezető mellékhatást a hosszú távú túlélő csoportban egyet sem regisztráltunk; az észlelt mellékhatások nagy része enyhe volt. Következtetések: Munkánk során az ixazomib-lenalidomid-dexametazon kombinációt effektívnek és biztonságosnak találtuk relabált, refrakter myeloma multiplex kezelésére, mely a betegek mintegy hatodánál több éven át eredményesen alkalmazható. Cikkünkkel a hazai beteganyagon szerzett tapasztalatainkat szeretnénk megosztani a COVID-19-világjárvány alatt különösen aktuálissá vált, tisztán orális terápiás lehetőségről. Orv Hetil. 2021; 162(36): 1451-1458., Introduction: Despite great advances in therapy, multiple myeloma is still a largely incurable disease, therefore the importance of salvage therapies is paramount. The first oral proteasome inhibitor ixazomib in combination with lenalidomide-dexamethasone is a tolerable, orally administered regime, which has become available for Hungarian relapsed, refractory multiple myeloma patients from April 2015 in the Named Patient Program., Objective: Our goal was to investigate the long-time progression-free surviving patient population treated with the ixazomib-lenalidomide-dexamethasone triplet., Method: We retrospectively studied a total of 80 patients from 7 centers who received the triplet combination. Survival analyses were performed., Results: Two-third of the patients responded: the overall response rate was 63.75%. 14 patients (17.5%) did not respond/had stable disease and 15 patients (18.75%) outright progressed upon therapy. Although progression-free survival was only 10.6 months for the entire patient cohort, the disease in a subgroup of 16 patients did not progress within two years. In fact, 11 of them were still in sustained remission after 3 years of therapy. Our goal was to analyze the characteristics of this subgroup., Discussion: The idea of long-term therapy of multiple myeloma is gaining widespread acceptance. Therefore it is important to know which patients may benefit the most from certain therapies. Among these 16 long-term responder patients, reciprocal translocation of the immunoglobulin heavy chain seemed to lack an adverse impact on progression-free survival; comparable to trisomies, both curves had a progression-free plateau. The International Staging System (ISS) score at the start of therapy did not predict long-term survivorship. Most of the side effects in this subgroup were mild, manageable, none led to therapy discontinuation., Conclusion: Ixazomib-lenalidomide-dexamethasone was confirmed to be an effective and safe combination for relapsed, refractory multiple myeloma, and one-sixth of the treated patients were able to receive it for several years, effectively. This fully oral therapeutic option is at its best during the present COVID-19 pandemic. Orv Hetil. 2021; 162(36): 1451-1458.

The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib has revolutionised the therapeutic landscape of chronic lymphocytic leukaemia (CLL). Acquired mutations emerging at position C481 in the BTK tyrosine kinase domain are the predominant genetic alterations associated with secondary ibrutinib resistance. To assess the correlation between disease progression, and the emergence and temporal dynamics of the most common resistance mutation BTK C481S , sensitive (10 -4 ) time-resolved screening was performed in 83 relapsed/refractory CLL patients during single-agent ibrutinib treatment. With a median follow-up time of 40 months, BTK C481S was detected in 48·2% (40/83) of the patients, with 80·0% (32/40) of them showing disease progression during the examined period. In these 32 cases, representing 72·7% (32/44) of all patients experiencing relapse, emergence of the BTK C481S mutation preceded the symptoms of clinical relapse with a median of nine months. Subsequent Bcl-2 inhibition therapy applied in 28/32 patients harbouring BTK C481S and progressing on ibrutinib conferred clinical and molecular remission across the patients. Our study demonstrates the clinical value of sensitive BTK C481S monitoring with the largest longitudinally analysed real-world patient cohort reported to date and validates the feasibility of an early prediction of relapse in the majority of ibrutinib-treated relapsed/refractory CLL patients experiencing disease progression., (© 2021 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

In Hungary, the cost of lenalidomide-based therapy is covered only for relapsed multiple myeloma (MM) patients, therefore lenalidomide is typically used in the second-line either as part of a triplet with proteasome inhibitors or as a doublet. Lenalidomide-dexamethasone is a standard treatment approach for relapsed/refractory MM, and according to recent large randomized clinical trials (RCT, the standard arm of POLLUX, ASPIRE, TOURMALINE), the progression-free survival (PFS) is expected to be approximately 18 months. We surveyed ten Hungarian centers treating MM and collected data of 278 patients treated predominantly after 2016. The median age was 65 years, and patients were distributed roughly equally over the 3 international staging system groups, but patients with high risk cytogenetics were underrepresented. 15.8% of the patients reached complete response, 21.6% very good partial response, 40.6% partial response, 10.8% stable disease, and 2.5% progressed on treatment. The median PFS was unexpectedly long, 24 months, however only 9 months in those with high risk cytogenetics. We found interesting differences between centers regarding corticosteroid type (prednisolone, methylprednisolone or dexamethasone) and dosing, and also regarding the choice of anticoagulation, but the outcome of the various centers were not different. Although the higher equivalent steroid dose resulted in more complete responses, the median PFS of those having lower corticosteroid dose and methylprednisolone were not inferior compared to the ones with higher dose dexamethasone. On multivariate analysis high risk cytogenetics and the number of prior lines remained significant independent prognostic factors regarding PFS ( p < 0.001 and p = 0.005). Our results show that in well-selected patients Lenalidomide-dexamethasone can be a very effective treatment with real-world results that may even outperform those reported in the recent RCTs. This real world information may be more valuable than outdated RCT data when treatment options are discussed with patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Varga, Dávid Tóth, Réka Szita, Csukly, Hardi, Gaál-Weisinger, Nagy, Altai, Rencsik, Plander, Szendrei, Kórád, Radványi, Rottek, Deák, Szaleczky, Schneider, Kohl, Kosztolányi, Alizadeh, Lengyel, Modok, Borbényi, Lovas, Váróczy, Illés, Rajnics, Masszi and Mikala.)

Introduction: Prognostic impact of the detection of minimal residual disease (MRD) in multiple myeloma (MM) has been confirmed in numerous studies., Aim: Retrospective examination of our patient database (107 newly diagnosed multiple myelomas between 2007 and 2017). Flow cytometry (FCM) was performed as MRD assessment., Method: MRD assessment was performed in 56 patients (median age: 68 years), after induction treatment of multiple myeloma. The treatment contained bortezomib in 91%, autologous haematopoetic stem cell transplantation (ASCT) was perfomed in 50%. MRD detection was performed on bone marrow samples, predominantly in our hospital (BD FACScan, 3 colour, panel: CD38, CD138, CD19, CD45, CD56, CD28, CD117, cyKappa, cyLambda, 100 000 events)., Statistical Analysis: SPSS 13.0., Results: The progression-free survival (PFS) and the overall survival (OS) were significantly longer in MRD negative (n = 22) patients (PFS: 54 months, OS: 79% after 5 years) than MRD positive patients (n = 34, PFS: 22 months, OS 21% after 5 years, p = 0.001). Patients achieving complete response (CR) (n = 29) have different PFS (MRD negative CR: 60 months, MRD positive CR: 21 months, p<0.001). Patents achiving MRD negative very good partial response (n = 5) have similar PFS (54 months) as patients with MRD negative CR. The longest PFS (68 months) was observed in MRD negative patients, after ASCT (n = 11), while the PFS was significantly (p<0.001) shorter in patients who were MRD positive after ASCT (n = 18, PFS: 25 months), similarly in MRD positive patients without ASCT (n = 15, PFS 21 months). Cox regression analysis (stage, cytogenetic risk, ASCT) confirmed that MRD is an independent prognostic factor of PFS and OS. We did not find significant relationship between MRD and stage, cytogenetic risk, number of treatment cycles, ASCT., Conclusions: The depth of response after induction treatment of MM is an independent predictor of survival. MRD assessment with FCM is recommended to define response. Consideration of maintenance treatment in MRD positive patients and eradication of MRD are also recommended. Orv Hetil. 2019; 160(13): 502-508.

Introduction: In recent years much progress has been made in the therapy of chronic lymphocytic leukaemia, as the new innovative medicine proved to be effective in managing patients carrying TP53 abnormalities. To identify all these patients, it is essential to screen for both forms of TP53 defects, including both 17p deletions and TP53 mutations., Aim: The aim of this study was to determine the frequency of TP53 mutations and their association with 17p deletions in a large Hungarian cohort of 196 patients suffering from chronic lymphocytic leukaemia., Method: We performed mutation analysis of TP53 (exons 3-10) using Sanger sequencing., Results: TP53 mutations were present in 15.8% of patients, half of which were associated with 17p deletion. By analysing both forms, TP53 defect was identified in 25.4% of the patients., Conclusions: Our study demonstrates that by performing a TP53 mutation analysis, an additional 10% of high-risk patients can be detected. Orv. Hetil., 2017, 158(6), 220-228.

Introduction: Essential thrombocythemia is a Philadelphia chromosome-negative chronic myeloproliferative neoplasia with a risk of bleeding and thromboembolic complications during the course of illness. Cytoreductive drugs, such as non-selective hydroxyurea or interferon as first-line and specific, megakaryocyte-thrombocyte reductive anagrelide chosen as second-line treatment in cases of adverse, intolerable effects of hydroxyurea can lower the incidence of bleeding/thrombotic episodes in patients with essential thrombocythemia., Aim: In this observational survey the effect of anagrelide was investigated in patients with essential thrombocythemia, who were first treated with hydroxyurea but failed to have clinicopathologic reponse (resistant) or were intolerant (adverse effects)., Method: Between 2000 and 2014, 104 patients were diagnosed with essential thrombocythemia and treated first-line with hydroxyurea (weekly median dose of 7500 mg) in the haematologic outpatient department of the authors. Because of intolerance and/or resistance, hydroxyurea was changed to anagrelide (7.5 mg weekly median dose), the doses of hydroxyurea and anagrelide were adjusted to achieve clinicopathological response according to the updated criteria of the European LeukemiaNET. Effect of anagrelide as monotherapy (first- or second-line after hydroxyurea) or in combination with hydroxyurea was followed. Statistical analysis was performed using the Windows Statistical Package Program., Results: Of the 104 patients with essential thrombocythemia (according to the updated WHO-ET classifications 58 patients JAK2V617F mutation positive, 46 patients negative, 15 patients calreticulin mutation negative, 6 patients MPL-1 mutation negative) 87 patients received hydroxyurea in first line, 4 patients interferon, and 13 patients acetylsalycilic acid only. Seven patients who proved to be intolerant and 22 patients who were resistant to hydroxyurea received anagrelide in second line (in 18 patients monotherapy and in 11 patients in combination with hydroxyurea), while other 5 rather young patients in first line therapy (34/104, 32.6%). In the anagrelide first line group 5 patients (100%), in the second line anagrelide monotherapy group 16 patients (88,8%), and in the combined hydroxyurea plus anagrelide group 9 patients (82.1%) achieved complete remission. The 10-year overall survival was 82.1%. In 2 patients treated with anagrelide major bleeding and in one patient myocardial infarction occurred, other serious adverse events due to anagrelide treatment were not detected. Three elder patients died from non-hematologic diseases, but leukaemic transformation was not observed., Conclusions: First or second line anagrelide therapy, combined with hydroxyurea if necessary, was able to reduce the platelet-count and the rate of complications, and to control the course of essential thrombocythemia with tolerable adverse effects.

Introduction: Primary testicular lymphoma constitutes a rare subgroup among extranodal non-Hodgkin's lymphomas. Because of its aggressive clinical behaviour due to high grade histological features developing mainly in older population, patients with this disease usually have a poor prognosis. Orchidectomy followed by combination immunochemotherapy is a traditional treatment method with a rather inferior outcome., Aim: In this retrospective survey the authors analysed the clinical presentation, pathological features and treatment results of patients with primary testicular lymphoma diagnosed and treated in their haematology centre between 2000-2012 METHOD: During this period 334 patients with aggressive non-Hodgkin's lymphomas were treated, of whom 8 patients (2.39%; age between 23 and 86 years; median, 60 years) underwent semicastration for primary testicular lymphoma (7 patients had diffuse, large B-cell lymphoma and one patient had Burkitt-like lymphoma). According to the Ann Arbor staging system a limited stage I-IIE was diagnosed in 7 patients and advanced stage was found in one patient. All but one patients were treated with rituximab added to CHOP regimen (6 or 8 cycles in every 21 or 28 days), whereas one patient received radiotherapy only. Central nervous system intrathecal prophylaxis was used in one case and no preventive irradiation of the contralateral testis was used., Results: With a median follow-up of 50 months complete remission was observed in 7 patients. However, two patients died (one due to progression and one in remission from pulmonary solid tumour). Complete remission rate proved to be 87.5%, disease-free survival was between 13 and 152 months (median 38 months) and overall survival rates were between 17 and 156 months (median 43 months). The 5-year disease-free and overall survival rates were 37.5 %., Conclusions: The relatively favourable treatment outcome could be mainly explained by the high number of patients with early-stage of the disease, early surgical removal of testicular lymphomas and the use if immunochemotherapy. This therapeutic regimen was effective to prevent localized and distant relapses. Despite omission of regular prophylaxis of the central nervous system, no relapse was detected.