[Impact of minimal residual disease detection after treatment of multiple myeloma]. / A minimális residualis betegség vizsgálatának jelentosége myeloma multiplex kezelése után.

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.

[Treatment outcome of patients with essential thrombocythemia at our department in Hungary]. / Essentialis thrombocythaemiás betegek kezelési eredményei osztályunkon.

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.

[Changing times - changing diseases. Review of the neuropathological autopsy documentations at the Markusovszky University Teaching Hospital (1964-2014)]. / Változó idok - változó betegségek. A Markusovszky Egyetemi Oktatókórház neuropatológiai autopsziás anyagának áttekintése (1964-2014).

INTRODUCTION: Nearly 6000 autoptic studies were carried out during the last 50 years at the Laboratory of Neuropathology, Markusovszky University Teaching Hospital, Hungary. AIM: The aim of the authors was to present those previously frequent and often fatal conditions that can be prevented or treated today. METHOD: Retrospective analyses of the neuropathological documentations. RESULTS: Measles-related subacute sclerosing panencephalitis caused death in 13 cases, the last occurred in 1991. The mandatory vaccination against the causative virus has eliminated this severe neurological complication. Fourteen lives were lost due to herpes simplex encephalitis, including the last case seen in 1999. Feasibility of early diagnosis and the availability of acyclovir therapy resulted in better outcome without fatality. Tuberculous meningitis still occurred in most recent years, although only sporadically. Recognition of this condition is not straightforward due to its rarity, and considerations for this disease are often omitted from the routine differential diagnosis. The generally low mortality rates in tick borne encephalitis further dropped after the introduction of vaccination. Altogether only 8 such cases were documented. The last fatal cases of neurolues were seen in the 1990s. However, syphilis itself has not disappeared, and the number of cases with newly acquired infection continues to rise. The introduction of intrathecal methotrexate and radiotherapy made possible the prevention or effective treatment of meningeal leukosis. A careful coordination of these treatment modalities, however, is important as nervous system complications may develop in the form of disseminated necrotizing leukoencephalopathy that is also reflected in the records. CONCLUSIONS: The 50-year neuropathology documentation reflects changes in the occurrence of diseases, and it calls attention to those disorders which can be prevented or treated today, but may represent diagnostic challenges.

[Treatment outcome in primary testicular non-Hodgkin lymphoma]. / Primer herelymphomás betegek kezelésével szerzett tapasztalatok.

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.

[Treatment outcome of immune thrombocytopenia]. / Immun thrombocytopeniás betegek kezelésével szerzett tapasztalataink.

INTRODUCTION: Treatment of immune thrombocytopenia is sometimes difficult and needs personal setting. According to evidence-based guidelines, corticosteroids are suggested for first-line treatment. In case of corticosteroid ineffectiveness, second-line therapeutic options (splenectomy, immunosuppressive drugs and, recently, thrombopoietin-mimetics) may result in beneficial therapeutic effect. AIMS: The aim of the authors was to examine the clinicopathological data, disease course, treatment results, and the effectiveness of novel drugs in patients with immune thrombocytopenia. PATIENTS AND METHODS: The authors retrospectively analysed the files of 79 immune thrombocytopenic patients (26 males and 53 females) diagnosed and treated at the hematologic in- and outpatient units of the Markusovszky Hospital, County Vas, Hungary between January 1, 2000 and December 31, 2011. Remission rates, disease-free and overall survivals in response to corticosteroids (first-line treatment), after splenectomy (in cases when corticosteroids proved to be ineffective) and following second-line treatment were analysed. Survival curves were constructed using statistical software programs. RESULTS: Of the 79 patients during a median follow-up of 66 months (min. 3, max. 144 months), 28 patients receiving first-line corticosteroids achieved complete remission and remained in a prolonged disease-free condition (35.4%; median disease-free survival 75.5 months; min. 2, max. 140 months). Thirty-eight patients underwent splenectomy after ineffective treatment with corticosteroids or other immunosuppressive (48.0%; median disease-free survival 94.2 months; min. 6, max. 136 months). Surgical complications occurred in 2 cases, while postoperative and late infections were absent. Five patients died but death was not related to immune thrombocytemia. Second-line treatment was applied in 13 patients (16.4%) and among these patients relapse of immune thrombocytopenia after splenectomy was observed in 6 patients. Favourable effects of both conventional (immunosuppressive) and novel treatments (rituximab, thrombopoietin-mimetics) were also detected. CONCLUSIONS: More than two-thirds of patients with immune thrombocytopenia responded to corticosteroids or to splenectomy and achieved prolonged disease-free remission. Novel drugs (rituximab, thrombopoietin-mimetics) applied only in few cases produced also favourable results in patients not responding to corticosteroids and splenectomy.

[Detection and impact of minimal residual disease on outcome of chronic lymphocytic leukemia]. / Minimális residualis betegség vizsgálata és jelentosége a krónikus lymphocytás leukaemia kezelésében.

INTRODUCTION: Minimal residual disease is associated with longer overall survival in patients with chronic lymphocytic leukemia. AIM: The aim of the authors was to determine the clinical significance of remission and minimal residual disease on the survival of patients with chronic lymphocytic leukemia. METHODS: Data from 42 first-line treated patients with chronic lymphocytic leukemia were analyzed. Minimal residual disease was determined by flow cytometry. RESULTS: Overall response and complete remission was achieved in 91%, 86%, 100% and 87%, 0%, 60% of patients with fludarabine-based combinations, single-agent fludarabine and cyclophosphamide + vincristin + prednisolone regimen, respectively. Minimal residual disease eradication was feasible only with fludarabine-based combinations in 60% of these cases. The ratio of minimal residual disease was 0.5% on average. During a median follow-up period lasting 30 months, the overall survival of patients with fludarabine-resistant disease proved to be significantly shorter (p = 0.04), while complete remission without minimal residual disease was associated with significantly longer progression free survival (p = 0.02). CONCLUSION: Only fludarabine-based combinations were able to eradicate minimal residual disease in patients with chronic lymphocytic leukemia. Complete remission without minimal residual disease may predict longer progression free survival in these patients.

[Significance of the JAK2V617F mutation in patients with chronic myeloproliferative neoplasia]. / A JAK2V617F-mutáció jelentosége krónikus myeloproliferativ neoplasiás betegeinkben.

UNLABELLED: In Philadelphia chromosome-negative chronic myeloproliferative neoplasia, i.e. polycythemia vera, essential thrombocythemia and primary idiopathic myelofibrosis enhanced risk of thrombosis could be connected with Janus kinase 2 gene mutation occurring in various frequency in these diseases (JAK2V617F). Since 2002 the presence of JAK2 mutation in chronic myeloproliferative neoplasia has been regularly detected. AIMS: In a retrospective survey the possible connection between JAK2 mutation and thrombosis was analyzed in patients with chronic myeloproliferative neoplasia subgroups cared and treated in their hospital and outpatient departments. PATIENTS AND METHODS: Between 2007-2010 peripheral blood samples of 171 patients with chronic myeloproliferative neoplasia (68 patients of polycythemia vera, 84 of essential thrombocythemia and 19 ones with primary idiopathic myelofibrosis) were sent to several molecular biological laboratories, where V617F mutation from DNA specimens was detected by allele-specific polymerase chain reaction, as well. Thromboembolic complications (arterial, i.e. cerebro-and cardiovascular and venous thrombosis) occurred during course of illness of patients were registered. Statistical analysis was made by statistical software program for Windows. RESULTS: JAK2 mutation in 53 patients with polycythemia vera (77.9%) was detected, whilst in essential thrombocythemia 55 patients (65.4%) and in primary idiopathic myelofibrosis 7 patients (36.8%) proved to be JAK2 positive. In 18 JAK2 positive patients of polycythemia vera thromboembolic episodes were observed (18/53, 33.9%), whilst in essential thrombocythemia JAK2 mutational status was accompanied with thromboembolic events in 17/55 patients (30.9%). In the 7 JAK2 positive ones with primary idiopathic myelofibrosis thrombotic complication did not occurred. However, in JAK2 negative cases thrombotic events could also be detected (from 10 JAK2 negative patients with polycythemia vera in four ones, and in six with JAK2 negative 23 essential thrombocythemic patients. CONCLUSIONS: Incidence of the JAK2 mutation in their patients with chronic myeloproliferative neoplasia subgroups mainly corresponds to the literary data. Thrombosis ensued both in JAK positive polycythemia vera and essential thrombocythemia cases occurred nearly in the same number, but the incidence of thrombosis ensued in JAK2 negative cases did not differ significantly from the JAK2 positive patients. From these results it could be suggested that the presence or absence of JAK2 mutation in the development of thrombosis has no predictive value in patients with chronic myeloproliferative neoplasia.

Effects of isoflurane on Nfκb p65, Gadd45a and Jnk1 expression in the vital organs of CBA/CA mice.

BACKGROUND: Isoflurane is administered to patients during general anaesthesia to diminish the effects of surgical invasion. MATERIALS AND METHODS: CBA/CA mice were exposed to 2% isoflurane during general anaesthesia. Gene expressions were measured 6 and 12 hours later by quantitative real-time PCR on total RNA isolated from the lung, liver and kidneys of the animals. Expressions of growth arrest and DNA-damage-inducible 45 alpha (Gadd45 α), Jun N-terminal kinase 1 (Jnk1) and nuclear factor of kappa light polypeptide gene enhancer in B-cells p65 subunit (Nfκb p65) were analyzed. RESULTS: Gadd45α and Jnk1 showed significant inverse expression changes in the different tissues compared to the Nfκb p65. The length of anaesthesia also modified the gene induction. CONCLUSION: Isoflurane has significant modulatory effect on the transcription of genes regulating inflammation and apoptotic signalling.

[Therapeutic management of central nervous system lymphomas in a single hematological institute]. / Központi idegrendszeri lymphomás betegek kezelése osztályunkon.

UNLABELLED: Primary central nervous system lymphoma is defined as an extranodal lymphoma arising in the central nervous system in the absence of systemic disease. Because of their rare occurrence among lymphomas, optimal treatment could hardly be established. AIMS: In this retrospective survey we analyzed the result of combined treatment (systemic and intrathecal chemotherapy followed by consolidation radiotherapy) in patients with primary or relapsed central nervous system lymphomas diagnosed and treated in our hematological department between 1998-2009. PATIENTS AND METHODS: During this period (mean follow-up of 13.2 months) from 427 patients with newly diagnosed non-Hodgkin's lymphomas, 22 primary central nervous system lymphoma was diagnosed (5.15%, 16 cerebral and 6 spinal cord lymphoma cases). Significant male predominance (14:8) was registered with an age distribution of 34-77 years (mean = 60.7, median = 64 years). No patients were immunocompromised. All central nervous system lymphoma specimens taken with neurosurgical resection or stereotaxic biopsies were confirmed histopathologically. All cerebral lymphoma cases proved to be diffuse large B-cell of origin, while in epidural lymphomas low grade subtypes also occurred. Epidural lymphomas were treated with local radiotherapy (30-40 Gy), except for patients with follicular lymphomas getting rituximab-containing polychemotherapy (R + CHOP regimen) before irradiation. In cerebral lymphoma (every patients had supratentorial localization) the following combined therapy protocol was used: up to three courses of high dose methotrexate (HD MTX 3g/m 2 in a single dose for 4 hours lasting drop-infusion) were given at 4-week intervals, followed by leucovorin-rescue 24 hours after MTX infusion. Intrathecal combination of methotrexate, cytosin-arabinosid and dexamethasone was given three times after HD MTX infusion. In complete response after chemotherapy (evaluated by cranial MRI or CT, PET/CT), whole-brain irradiation was used in a total dose of 30 Gy. In case of partial response, boost irradiation for the tumor bed was also given. In relapse or resistant cases, salvage regimen was applied: HD MTX course combined with high dose cytosin-arabinosid (HD Ara-C) 3g/m 2 /dose b.i.d. over 4 h c.i., repeated in three cycles every four weeks. RESULTS: Complete remission has been achieved in 9 patients with cerebral and in 4 patients with spinal cord lymphoma (13/22; 59.0%), however, one relapsed patient became resistant and later expired, despite salvage therapy. Primarily 9 patients were not evaluable for response: 5 received only one or two HD MTX because of side effects, 4 patients died due to progression of the disease. Mean of the overall survival (OS) in cerebral lymphoma was 19.5 (3-46, median of 10) months, in epidural group 14.1 (2-76, median of 5) months, whilst mean time to progression (TTP) was 4.5 (2-6.5, median of 4 months). The 2-year survival for all patients was 50%. Acute toxicity of chemotherapy was usually hematological, moreover, in 8 patients impaired renal function and sepsis developed. No serious adverse effect of radiotherapy could be detected. CONCLUSION: In primary central nervous system lymphoma, basic treatment HD methotrexate together with intrathecal combination of methotrexate + cytosin-arabinosid + dexamethasone followed by whole-brain irradiation of at least 30 Gy could produce a medium response rate in our study. In case of relapse or progression, other salvage regimens containing HD Ara-C alternating with HD MTX could reduce the treatment failure, as well. After therapy PET/CT was negative in five patients with prolonged disease-free survival.

[Manifestations of systemic mycoses and related infections in the central nervous system]. / Szisztémás mycosisok és hasonló infekciók központi idegrendszeri manifesztációi.

UNLABELLED: In daily practice mycotic infections of the CNS have become more and more frequent. The main causes are the wide-ranging use of corticosteroids, immunosuppressive, cytostatic drugs and antibiotics, the spreading of AIDS, the increasing number of surviving immature newborns. To illustrate the diagnostic difficulties, the authors report several cases. CASE REPORTS: 1. Multifocal hemorrhagic infarcts of the brain, caused by generalized aspergillosis in mantle cell malignant lymphoma. 2. Cerebral microabscesses, caused by systemic candidiasis in a premature infant. 3. Fatal actinomycosis, mimicking a space occupying tumour in the thigh and with an abscess in the brain, radiologically indicated as a metastasis. The cause of death was actinomycotic pneumonia. 4. A successfully treated and recovered patient with recurrent pneumonia and multiplex brain abscesses, caused by filamentous microorganism of a Nocardia species revealed by histological examination of the neurosurgical specimen. DISCUSSION AND CONCLUSIONS: We have to be aware for the development of the mycotic and related infections of endangered patients. Aspergillosis and candidiasis play the most significant role in the involvement of the central nervous system. Actinomycosis and nocardiosis are more sensitive to treatment, so their diagnosis is of life-saving importance. The therapeutic chances of high risk patients with aspergillosis and candidiasis will be definitively better, if the infection is recognized and appropriately treated before the involvement of the CNS.

[Complex analysis of prognostic factors in chronic lymphocytic leukemia]. / Prognosztikai faktorok komplex vizsgálata krónikus lymphocytás leukémiában.

INTRODUCTION: Many new prognostic factors established in recent years in chronic lymphocytic leukemia. May help predicting survival. AIMS: The goal of the present study was to determine the frequency and the correlation of these novel prognostic factors in samples of 419 leukemia patients. METHODS: The mutation status of the IgH gene was evaluated in 160 cases. RESULTS: In 62% of cases, non-mutated IgH gene was found, the heavy chain family usage was different in mutated and non-mutated cases. The CD38 expression demonstrated 78% concordance with the mutation status, the ZAP-70 expression failed to show any correlation. Cytogenetic abnormalities were seen in 76% of cases, the most frequent were del(13q) (57%), trisomy 12 (15%), del(11q) (12%) and del(17p) (6%). 95% of cases with del(11q) harbored non-mutated, 74% of cases with del(13q) as the sole anomaly demonstrated mutated IgH genes. CONCLUSIONS: The parameters analysed are not independent of each other, utilization of them in the clinical routine needs careful planning.

[Cytogenetic and molecular monitoring of chronic myeloid leukemia]. / A krónikus myeloid leukaemia citogenetikai es molekuláris monitorozása.

The t(9;22) translocation, which results in a fusion protein with abnormal tyrosine-kinase activity, plays a central role in the pathogenesis of chronic myeloid leukemia. The selective inhibition of this chimeric protein with imatinib-mesylate is an efficient therapeutic option, haematologic and cytogenetic responses can be achieved in most of the patients. The primary goal of monitoring the disease is to assess the efficiency of the therapy, to highlight those patients, whose survival may be improved by modifying treatment. Three methods are widely used for the genetic monitoring of chronic myeloid leukemia. With karyotyping, the proliferating bone marrow cells can be evaluated. The use of fluorescent in situ hybridization makes the cytogenetic analysis of each cell within the sample possible. Real-time quantitative polymerase chain reaction is capable of quantifying residual leukemia far below the sensitivity of cytogenetics. The results of these three methods have different biological meanings, thus, for the interpretation of the results, the knowledge of the characteristics, the benefits and the draw-backs of the methods is required. The present study shows the most important characteristics of these methods based on the literature and data acquired from 1165 samples of 197 patients detected by the authors.