Gergely Varga

Inappropriate notch activity and limited mesenchymal stem cell plasticity in the bone marrow of patients with myelodysplastic syndromes

Myelodysplastic syndromes (MDSs) are a heterogeneous group of hematological disorders characterized by ineffective hematopoiesis, enhanced bone marrow apoptosis and frequent progression to acute myeloid leukemia. Several recent studies suggested that, besides the abnormal development of stem cells, microenvironmental alterations are also present in the MDS bone marrow. In this study, we have examined the relative frequencies of stem and progenitor cell subsets of MDS and normal hematopoietic cells growing on stromal cell layers established from MDS patients and from normal donors. When hematopoietic cells from MDS patients were co-cultured with normal stromal cells, the frequency of either early or late cobblestone area-forming cells (CAFC) was significantly lower compared to the corresponding normal control values in 4 out of 8 patients. In the opposite situation, when normal hematopoietic cells were incubated on MDS stromal cells, the CAFC frequencies were decreased in 5 out of 6 patients, compared to normal stromal layer-containing control cultures. Moreover, a soluble Notch ligand (Jagged-1 protein) was an inhibitor of day-35-42 CAFC when normal hematopoietic cells were cultured with normal or MDS stromal cells, but was unable to inhibit MDS stem and early progenitor cell growth (day-35-42 CAFC) on pre-established stromal layers. These findings suggest that in early hematopoietic cells isolated from MDS patients the Notch signal transduction pathway is disrupted. Furthermore, there was a marked reduction in the plasticity of mesenchymal stem cells of MDS patients compared with those of normal marrow donors, in neurogenic and adipogenic differentiation ability and hematopoiesis supporting capacityin vitro. These results are consistent with the hypothesis that when alterations are present in the myelodysplastic stroma environment along with intrinsic changes in a hematopoietic stem/progenitor cell clone, both factors might equally contribute to the abnormal hematopoiesis in MDS.

Early versus delayed autologous stem cell transplantation and interferon maintenance in multiple myeloma: Single-center experience of 18 years

BACKGROUND Autologous stem cell transplantation (ASCT) has become the mainstay of 1st-line treatment in younger patients with multiple myeloma (MM), but statistical confirmation of its superiority over other therapies, especially in the era of novel agents, is still lacking. METHODS We reviewed the results of all 548 myeloma ASCTs performed in our institute over the past 18 years. RESULTS More than one-half of the patients had access to novel agents before their transplantations. Although the age of the transplanted patients increased significantly over the years, treatment-related mortality (TRM) was remarkably low, especially in 1st-line transplanted patients (100-day TRM, 0.3%). The median overall survival (OS) of the entire cohort was 98.4 months. Patients transplanted within 12 months from the start of their therapy had significantly better responses than those having delayed ASCT (complete response rate, 58.1% vs 46.8%; P = .016) and significant post-ASCT progression-free survival (PFS) benefit (30.2 [26.1-34.3] mo vs 23.3 [16.8-29.8] mo; P = .036), but we found no significant overall survival difference. The results were similar in patients treated with or without novel agents before ASCT. During a period of time, interferon maintenance was our standard approach to post-ASCT maintenance. Our analysis showed not only a significant PFS advantage with interferon, but also a highly significant overall survival benefit (150.4 [105.1-195.8] mo vs 86.1 [72.5-99.7] mo; P = .003). CONCLUSIONS Our findings demonstrate that delayed ASCT can be feasible in selected patients.

NFKB1 −94ins/delATTG polymorphism is a novel prognostic marker in first line-treated multiple myeloma

Nuclear factor kappa B (NFKB) plays an important role in multiple myeloma (MM), and bortezomib affects this pathway. We retrospectively analysed the effect of the NFKB1 −94ins/delATTG polymorphism on the survival of 295 MM patients treated at a single centre. The median progression‐free survival (PFS) was 790 (659–921) d in patients with NFKB1 homozygous insertion genotype (I/I, n = 99) and 624 (515–733) d in deletion‐carriers (I/D&D/D, n = 196, P = 0·013). In multivariate analysis, I/I carriers showed a favourable PFS compared to I/D&D/D with a hazard ratio of 0·622 (0·457–0·847), P = 0·003, in addition to international staging system (ISS) score, fluorescence in situ hybridization (FISH) risk score, age and bortezomib treatment. I/I patients benefited more from bortezomib treatment [PFS 902 (703–1101) and 580 (343–817), P = 0·008] than I/D&D/D patients [PFS 659 (487–831) and 488 (323–653), P = 0·531]; in addition the beneficial effect of low ISS score was not observed in the I/D&D/D group [PFS 639 (454–824) and 650 (458–842), P = 0·226], while it was clear in I/I patients [PFS 1140 (803–1477) and 580 (408–752), P < 0·001]. We conclude that homozygous carriers of the insertion allele of the NFKB1 −94ins/delATTG polymorphism have a better prognosis and probably benefit more from bortezomib treatment than MM patients carrying the deletion allele.

Unicentric mixed variant Castleman disease associated with intrabronchial plasmacytoma

Castleman disease (CD), described as a heterogeneous lymphoproliferative disorder, can be divided into different subtypes according to clinical appearance (unicentric and multicentric form) and histopathological features (hyaline vascular, plasma cell, mixed type, human herpesvirus 8–associated and multicentric not otherwise specified). Unicentric CD is known to be usually of the hyaline vascular variant, plasma cell and mixed type of this form are quite uncommon. Malignancies are mainly associated with the multicentric form. We report a rare case of unicentric mixed variant CD evolving into intrabronchial, extramedullary plasmacytoma.Intrabronchial mass with consequential obstruction of the left main bronchus, left lung atelectasis and mediastinal lymphadenomegaly was detected by chest CT in our patient suffering from cough and hemoptysis. Pulmonectomy was performed, histopathological and immunhistochemical analysis of lymph nodes revealed mixed type of CD with interfollicular monotypic plasma cell proliferation. The intrabronchial mass consisted of monotypic plasma cells confirming plasmacytoma. Systemic involvement was not confirmed by further tests.Although malignancies more often present in multicentric CD that usually belongs to the plasma cell subtype, this case confirms the neoplastic potential of the rarest, unicentric mixed variant of CD.Virtual slidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2872096831190851

Recipient and donor JAK2 46/1 haplotypes are associated with acute graft-versus-host disease following allogeneic hematopoietic stem cell transplantation

Abstract Several genetic polymorphisms have been implicated to affect the outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT). The role of cytokines in acute graft-versus-host disease (aGvHD) is well established and many of the involved cytokines signal through the Janus kinase (JAK) pathways. In this study, we assessed the association of recipient and donor JAK2 46/1 haplotypes and allo-HSCT outcome in a cohort of 124 acute myeloid leukemia patients. Both, recipient and donor 46/1 haplotypes significantly affected aGvHD grades II–IV development (p = 0.006 and p = 0.031, respectively), furthermore the influence of the haplotypes seemed to be additive. In multivariate analyses the recipient haplotype remained independently related (p = 0.012) to aGvHD, while the donor not (p = 0.08). We observed significantly less relapses among haplotype carriers (p = 0.004), but overall survival did not differ (p = 0.732). Our findings suggest that recipient and donor JAK2 46/1 haplotypes might be involved in the regulation of aGvHD.

Agonists and Antagonists of Regulatory Peptides as Tools to Study Regulation of Pancreatic Exocrine Secretion, Cell Proliferation and Gene Expression

For more than two decades, our research group has been studying the pancreatic actions of three groups of regulatory peptides: members of the cholecystokinin/gastrin family, bombesin-like peptides and somatostatin. Investigating these peptides, our work has focused on three particularly interesting aspects: peptidergic regulation of pancreatic enzyme secretion and growth in adult rats, peptidergic control of pancreatic enzyme secretion and growth during postnatal development in rats, and peptidergic regulation of proliferation and differential gene expression in pancreatic adenocarcinoma cells. Our data confirmed that the control of the exocrine function of the pancreas is complex, and that it involves peptides such as the cholecystokinin/gastrin-like peptides, bombesin-like peptides and somatostatin. In these investigations, it became evident that selective peptide receptor agonists, antagonists and monoclonal antibodies raised against peptides are useful tools to identify the role of these bioactive peptides in pancreatic exocrine secretion and cell proliferation.

How long does a myeloma patient currently wait for the diagnosis in Hungary

INTRODUCTION Long delays with the diagnosis of myeloma are common. So far there has not been a comprehensive study on this issue in Hungary. AIM The aim of the authors was to analyze the waiting time from their first symptoms to the diagnosis of myeloma. METHOD 193 myeloma patients treated in one large tertiary referral hematology centre in Hungary were included. RESULTS The median time was 4.1 months (0-35.4) until diagnosis, and 5.2 months (0-35.4) until treatment. The delay was longer in patients with better prognosis (early stage, low cytogenetic risk), in nonsecretory disease and in 5 patients with amyloidosis. There was no significant relationship between the delay and the survival. CONCLUSIONS Considering the results of the present study and earlier literature data, the authors look for possibilities to improve the diagnostic delay. They think that the key to an earlier diagnosis is in the hands of the primary care physicians as they see the patients first and decide whether it is necessary to refer them to further test and to which specialty. Helping them with diagnostic algorithms, clear referring pathways, fast tracking patients with urgent problems, and making serum electrophoresis universally available in the primary care could help to reduce the time that myeloma patients spend waiting.

The adverse effect of FOPNL genomic variant is reversed by bortezomib-based treatment protocols in multiple myeloma

Abstract Fibroblast growth factor receptor 1 oncogene partner N-terminal like gene (FOPNL) rs72773978 polymorphism was identified as an adverse prognostic factor in multiple myeloma (MM). We aimed to investigate the associations of rs72773978 with clinical characteristics and treatment outcome in 373 Hungarian MM patients. In our cohort, FOPNL polymorphism showed differential prognostic effect that depended on the treatment applied. Among patients treated with non-proteasome inhibitor (PI)-based therapy, carriership of the minor allele was significantly associated with adverse overall survival (p=.022). In contrast, the adverse effect was overcome by the application of PI-containing treatment (p=.048). Multivariate analyses revealed the independent adverse effect of rs72773978 on survival in the non-PI-treated group (p=.045), but not in PI treatment (OS: p=.093). We confirmed the adverse prognostic effect of rs72773978 associated with non-PI-based treatment regimens. Our results point to the importance of genotypic prognostic information associated with complex clinical background MM.

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...