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Background and Objectives: Although left ventricular excessive trabeculation (LVET) can cause heart failure, arrhythmia and thromboembolism, limited literature is available on the ECG characteristics of primary LVET with preserved left ventricular function (EF). We aimed to compare the ECG characteristics and cardiac MR (CMR) parameters of LVET individuals with preserved left ventricular EF to a control (C) group, to identify sex-specific differences, and to compare the genetic subgroups of LVET with each other and with a C population. Methods: In our study, we selected 69 LVET individuals (EF > 50%) without any comorbidities and compared them to 69 sex- and age-matched control subjects (42% females in both groups, p = 1.000; mean age LVET-vs-C: 38 ± 14 vs. 38 ± 14 years p = 0.814). We analyzed the pattern and notable parameters of the 12-lead ECG recordings. We determined the volumetric and functional parameters, as well as the muscle mass values of the left and right ventricles (LV, RV) based on the CMR recordings. Based on the genotype, three subgroups were established: pathogenic, variant of uncertain significance and benign. Results: In the LVET group, we found normal but elevated volumetric and muscle mass values and a decreased LV_EF, wider QRS, prolonged QTc, higher RV Sokolow index values and lower T wave amplitude compared to the C. When comparing MR and ECG parameters between genetic subgroups, only the QTc showed a significant difference. Over one-third of the LVET population had arrhythmic episodes and a positive family history. Conclusions: The subclinical morphological and ECG changes and the clinical background of the LVET group indicate the need for follow-up of this population, even with preserved EF. [ABSTRACT FROM AUTHOR]

Background: Cardiac rotational parameters in primary symptomatic left ventricular noncompaction (LVNC) with preserved left ventricular ejection fraction (LVEF) are not well understood. We aimed to analyze cardiac rotation measured with cardiac magnetic resonance feature-tracking (CMR-FT) and speckle-tracking echocardiography (Echo-ST) in LVNC morphology subjects with preserved LVEF and different genotypes and healthy controls. Methods: Our retrospective study included 54 LVNC subjects with preserved LVEF and 54 control individuals. We evaluated functional and rotational parameters with CMR in the total study population and with echocardiography in 39 LVNC and 40 C individuals. All LVNC subjects were genotyped with a 174-gene next-generation sequencing panel and grouped into the subgroups: benign (B), variant of uncertain significance (VUS), and pathogenic (P). Results: In comparison with controls, LVNC subjects had reduced apical rotational degree (p = 0.004) and one-third had negative apical rotation. While the degree of apical rotation was comparable between the three genetic subgroups, they differed significantly in the direction of apical rotation (p<0.001). In contrast to control and B groups, all four studied cardiac rotational patterns were identified in the P and VUS subgroups, namely normal rotation, positive and negative rigid body rotation, and reverse rotation. When the CMR-FT and Echo-ST methods were compared, the direction and pattern of cardiac rotation had moderate to good association (p<0.001) whereas the rotational degrees showed no reasonable correlation or agreement. Conclusion: While measuring cardiac rotation using both CMR-FT and Echo-ST methods, subclinical mechanical differences were identified in subjects with LVNC phenotype and preserved LVEF, especially in cases with genetic involvement. [ABSTRACT FROM AUTHOR]

Copyright of Hungarian Medical Journal / Orvosi Hetilap is the property of Akademiai Kiado and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Hungarian Medical Journal / Orvosi Hetilap is the property of Akademiai Kiado and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Glioblastomas are the most common IDH-wildtype adult high-grade gliomas, frequently harboring mutations in the TERT gene promoter (pTERT) and utilizing the subsequent telomerase overexpression for telomere length maintenance. However, some rare cases show loss of ATRX and use alternative mechanisms of telomere lengthening. In this study, we performed the first complex genomic analysis specifically concentrating on the latter subgroup. Comprehensive genomic profiling of 12 ATRX-deficient and 13 ATRX-intact IDH-wildtype adult high-grade gliomas revealed that ATRX and pTERT mutations are mutually exclusive. DNMT3A alterations were confined to ATRX-deficient, while PTEN mutations to ATRX-intact cases. RAS–MAPK pathway alterations, including NF1 mutations, were more characteristic in the ATRX-deficient group. Variants of genes related to homologous recombination repair showed different patterns of affected genes. Two ATRX-deficient tumors with high tumor mutational burden and mismatch repair deficiency were found. One of these contained a novel fusion involving the NTRK2 and LRRFIP2 genes, while the other showed loss of MSH2 and MSH6 without genetic alterations in the encoding genes suggesting an epigenetic background. Genetic characteristics of ATRX-deficient IDH-wildtype adult high-grade gliomas suggest that these tumors are particularly intriguing targets of potential future therapeutic interventions including immunotherapies combined with MAPK pathway inhibition and DNA repair inhibitors. [ABSTRACT FROM AUTHOR]

The identification of novel drug targets is needed to improve the outcomes of heart failure (HF). G-protein-coupled receptors (GPCRs) represent the largest family of targets for already approved drugs, thus providing an opportunity for drug repurposing. Here, we aimed (i) to investigate the differential expressions of 288 cardiac GPCRs via droplet digital PCR (ddPCR) and bulk RNA sequencing (RNAseq) in a rat model of left ventricular pressure-overload; (ii) to compare RNAseq findings with those of ddPCR; and (iii) to screen and test for novel, translatable GPCR drug targets in HF. Male Wistar rats subjected to transverse aortic constriction (TAC, n = 5) showed significant systolic dysfunction vs. sham operated animals (SHAM, n = 5) via echocardiography. In TAC vs. SHAM hearts, RNAseq identified 69, and ddPCR identified 27 significantly differentially expressed GPCR mRNAs, 8 of which were identified using both methods, thus showing a correlation between the two methods. Of these, Prostaglandin-F2α-receptor (Ptgfr) was further investigated and localized on cardiomyocytes and fibroblasts in murine hearts via RNA-Scope. Antagonizing Ptgfr via AL-8810 reverted angiotensin-II-induced cardiomyocyte hypertrophy in vitro. In conclusion, using ddPCR as a novel screening method, we were able to identify GPCR targets in HF. We also show that the antagonism of Ptgfr could be a novel target in HF by alleviating cardiomyocyte hypertrophy. [ABSTRACT FROM AUTHOR]

Introduction: Donor‐derived cell‐free DNA (dd‐cfDNA) is a blood biomarker detecting graft injury with high negative predictive value. While non‐invasive strategies for heart transplant (HTx) rejection surveillance are widely adopted in the United States with centralized testing, data on the feasibility of dd‐cfDNA assay at the local level are lacking. Here, we report the first 6 months of experience with a local laboratory‐run dd‐cfDNA assay in the routine clinical surveillance setting. Methods: Twenty‐six HTx patients with stable graft function were transitioned from endomyocardial biopsy‐based (EMB) to dd‐cfDNA‐led rejection surveillance using a commercially available next‐generation sequencing‐based assay. Results: In the 90 samples analyzed, dd‐cfDNA fraction remained continuously low in most patients, thus 88% of surveillance EMBs could be safely avoided. In the case of ≥.25% dd‐cfDNA, EMB was performed. There was no missed rejection. Conclusion: Our data show the feasibility to analyze dd‐cfDNA at the local level and successful implementation of this non‐invasive surveillance method into clinical practice, thus considerably reducing the frequency of invasive surveillance EMBs. [ABSTRACT FROM AUTHOR]

Neurofibromatosis type 1 (NF1) is a clinically heterogeneous neurocutaneous disorder inherited in autosomal dominant manner. Approximately 5–10% of the cases are caused by NF1 microdeletions involving the NF1 gene and its flanking regions. Microdeletions, which lead to more severe clinical manifestations, can be subclassified into four different types (type 1, 2, 3 and atypical) according to their size, the genomic location of the breakpoints and the number of genes included within the deletion. Besides the prominent hallmarks of NF1, patients with NF1 microdeletions frequently exhibit specific additional clinical manifestations like dysmorphic facial features, macrocephaly, overgrowth, global developmental delay, cognitive disability and an increased risk of malignancies. It is important to identify the genes co-deleted with NF1, because they are likely to have an effect on the clinical manifestation. Multiplex ligation-dependent probe amplification (MLPA) and microarray analysis are the primary techniques for the investigation of NF1 microdeletions. However, based on previous research, optical genome mapping (OGM) could also serve as an alternative method to identify copy number variations (CNVs). Here, we present a case with NF1 microdeletion identified by means of OGM and demonstrate that this novel technology is a suitable tool for the identification and classification of the NF1 microdeletions. [ABSTRACT FROM AUTHOR]

The need for sensitive monitoring of minimal/measurable residual disease (MRD) in multiple myeloma emerged as novel therapies led to deeper responses. Moreover, the potential benefits of blood-based analyses, the so-called liquid biopsy is prompting more and more studies to assess its feasibility. Considering these recent demands, we aimed to optimize a highly sensitive molecular system based on the rearranged immunoglobulin (Ig) genes to monitor MRD from peripheral blood. We analyzed a small group of myeloma patients with the high-risk t(4;14) translocation, using next-generation sequencing of Ig genes and droplet digital PCR of patient-specific Ig heavy chain (IgH) sequences. Moreover, well established monitoring methods such as multiparametric flow cytometry and RT-qPCR of the fusion transcript IgH::MMSET (IgH and multiple myeloma SET domain-containing protein) were utilized to evaluate the feasibility of these novel molecular tools. Serum measurements of M-protein and free light chains together with the clinical assessment by the treating physician served as routine clinical data. We found significant correlation between our molecular data and clinical parameters, using Spearman correlations. While the comparisons of the Ig-based methods and the other monitoring methods (flow cytometry, qPCR) were not statistically evaluable, we found common trends in their target detection. Regarding longitudinal disease monitoring, the applied methods yielded complementary information thus increasing the reliability of MRD evaluation. We also detected indications of early relapse before clinical signs, although this implication needs further verification in a larger patient cohort. [ABSTRACT FROM AUTHOR]

A limited number of studies have focused on the mutational landscape of breast cancer in different ethnic populations within Europe and compared the data with other ethnic groups and databases. We performed whole-genome sequencing of 63 samples from 29 Hungarian breast cancer patients. We validated a subset of the identified variants at the DNA level using the Illumina TruSight Oncology (TSO) 500 assay. Canonical breast-cancer-associated genes with pathogenic germline mutations were CHEK2 and ATM. Nearly all the observed germline mutations were as frequent in the Hungarian breast cancer cohort as in independent European populations. The majority of the detected somatic short variants were single-nucleotide polymorphisms (SNPs), and only 8% and 6% of them were deletions or insertions, respectively. The genes most frequently affected by somatic mutations were KMT2C (31%), MUC4 (34%), PIK3CA (18%), and TP53 (34%). Copy number alterations were most common in the NBN, RAD51C, BRIP1, and CDH1 genes. For many samples, the somatic mutational landscape was dominated by mutational processes associated with homologous recombination deficiency (HRD). Our study, as the first breast tumor/normal sequencing study in Hungary, revealed several aspects of the significantly mutated genes and mutational signatures, and some of the copy number variations and somatic fusion events. Multiple signs of HRD were detected, highlighting the value of the comprehensive genomic characterization of breast cancer patient populations. [ABSTRACT FROM AUTHOR]

Simple Summary: Malignant melanoma of the skin develops primarily, but not exclusively, on UV-exposed skin, where the most frequent histological forms are superficial spreading and nodular melanomas. In these tumors in the vaste majority of cases (~80%), the driver oncogenes are mutant BRAF, RAS and KIT. The genetic makeup of the triple-wild-type melanoma (BRAF, NRAS and NF1) has been known for some time, but those studies grouped together rare histopathological versions with common ones, as well as mucosal and even uveal ones. Here we used whole genome sequencing to genetically characterize the triple-wild-type melanoma (TWM), termed here as BRAF, RAS and KIT wild type, using the most common histological forms and excluding rare ones. All these tumors except one were UV-induced. In this driverless setting, we revealed rare oncogenic drivers known from melanoma or other cancer types and identified rare actionable tyrosine kinase mutations in NTRK1/3, RET and VEGFR1. Mutations of TWM identified genes involved in antitumor immunity, Ca++ and BMP signaling. Even with this comprehensive genomic approach, cases remained driverless in several instances, suggesting that unrecognized drivers are hiding among passenger mutations. The genetic makeup of the triple-wild-type melanoma (BRAF, NRAS and NF1) has been known for some time, but those studies grouped together rare histopathological versions with common ones, as well as mucosal and even uveal ones. Here we used whole genome sequencing to genetically characterize the triple-wild-type melanoma (TWM), termed here as BRAF, RAS and KIT wild type (the most frequent oncogenic drivers of skin melanoma), using the most common histological forms and excluding rare ones. All these tumors except one were clearly induced by UV based on the mutational signature. The tumor mutational burden was low in TWM, except in the NF1 mutant forms, and a relatively high frequency of elevated LOH scores suggested frequent homologue recombination deficiency, but this was only confirmed by the mutation signature in one case. Furthermore, all these TWMs were microsatellite-stabile. In this driverless setting, we revealed rare oncogenic drivers known from melanoma or other cancer types and identified rare actionable tyrosine kinase mutations in NTRK1, RET and VEGFR1. Mutations of TWM identified genes involved in antitumor immunity (negative and positive predictors of immunotherapy), Ca++ and BMP signaling. The two regressed melanomas of this cohort shared a 17-gene mutation signature, containing genes involved in antitumor immunity and several cell surface receptors. Even with this comprehensive genomic approach, a few cases remained driverless, suggesting that unrecognized drivers are hiding among passenger mutations. [ABSTRACT FROM AUTHOR]

Significant improvements in the survival rates of paediatric cancer have been achieved over the past decade owing to recent advances in therapeutic and diagnostic strategies. However, disease progression and relapse remain a major challenge for the clinical management of paediatric angiosarcoma. Comprehensive genomic profiling of these rare tumours using high-throughput sequencing technologies may improve patient stratification and identify actionable biomarkers for therapeutic intervention. Here, we describe the clinical, histopathological, immunohistochemical and molecular profile of a novel and precision medicine-informed case where a KHDRBS1-NTRK3 fusion determined by next-generation sequencing-based comprehensive genomic profiling led to complete and sustained remission (clinical and radiological response) in an otherwise incurable disease. Our patient represents the first paediatric angiosarcoma harbouring a targetable NTRK3 fusion in the literature and demonstrates the first example of targeting this alteration in angiosarcoma using larotrectinib, an NTRK inhibitor. Clinical and radiological remission was achieved in under two months of therapy, and the patient is currently in complete remission, 4 month after stopping larotrectinib therapy, which was given over 17 months with only mild side effects reported. Therefore, this remarkable case exemplifies the true essence of precision-based care by incorporating conventional pathology with the why, when, and how to test for rare oncogenic drivers and agnostic biomarkers in paediatric angiosarcoma. [ABSTRACT FROM AUTHOR]

The group of histiocytic neoplasms affecting the central nervous system (CNS) includes rare entities with diverse clinicopathological features and variable prognosis. One single, larger, homogenously contrast-enhancing, dural-based lesion was described in the right cerebellar hemisphere and another intradural extramedullary lesion in the level of the dens axis (Fig. Magnetic resonance imaging (MRI) revealed multiple subcortical and periventricular white matter lesions also affecting the corpus callosum. 1 MR images (T1-weighted, contrast-enhanced) showing the soft-tissue lesion detected behind the maxillary sinus (a), the spinal extramedullary lesion in the level of dens axis (b) and a lumbo-sacral (S1-2) neuroforaminal lesion (c) (white arrowheads) Graph: Suppl. [Extracted from the article]

Summary: The importance of predisposition to leukaemia in clinical practice is being increasingly recognized. This is emphasized by the establishment of a novel WHO disease category in 2016 called "myeloid neoplasms with germline predisposition". A major syndrome within this group is GATA2 deficiency, a heterogeneous immunodeficiency syndrome with a very high lifetime risk to develop myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML). GATA2 deficiency has been identified as the most common hereditary cause of MDS in adolescents with monosomy 7. Allogenic haematopoietic stem cell transplantation is the only curative option; however, chances of survival decrease with progression of immunodeficiency and MDS evolution. Penetrance and expressivity within families carrying GATA2 mutations is often variable, suggesting that co‐operating extrinsic events are required to trigger the disease. Predictive tools are lacking, and intrafamilial heterogeneity is poorly understood; hence there is a clear unmet medical need. On behalf of the ERAPerMed GATA2 HuMo consortium, in this review we describe the genetic, clinical, and biological aspects of familial GATA2‐related MDS, highlighting the importance of developing robust disease preclinical models to improve early detection and clinical decision‐making of GATA2 carriers. [ABSTRACT FROM AUTHOR]

Ibrutinib (IBR) is an oral anticancer medication that inhibits Bruton tyrosine kinase irreversibly. Due to the high risk of adverse effects and its pharmacokinetic variability, the safe and effective use of IBR is expected to be facilitated by precision dosing. Delivering suitable clinical laboratory information on IBR is a prerequisite of constructing fit-for-purpose population and individual pharmacokinetic models. The validation of a dedicated high-throughput method using liquid chromatography–mass spectrometry is presented for the simultaneous analysis of IBR and its pharmacologically active metabolite dihydrodiol ibrutinib (DIB) in human plasma. The 6 h benchtop stability of IBR, DIB, and the active moiety (IBR + DIB) was assessed in whole blood and in plasma to identify any risk of degradation before samples reach the laboratory. In addition, four regression algorithms were tested to determine the optimal assay error equations of IBR, DIB, and the active moiety, which are essential for the correct estimation of the error of their future nonparametric pharmacokinetic models. The noncompartmental pharmacokinetic properties of IBR and the active moiety were evaluated in three patients diagnosed with chronic lymphocytic leukemia to provide a proof of concept. The presented methodology allows clinical laboratories to efficiently support pharmacokinetics-based precision pharmacotherapy with IBR. [ABSTRACT FROM AUTHOR]

Copyright of Hungarian Medical Journal / Orvosi Hetilap is the property of Akademiai Kiado and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Hungarian Medical Journal / Orvosi Hetilap is the property of Akademiai Kiado and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Chronic lymphocytic leukaemia (CLL) is the most common leukaemia in the western world. In previous studies, various proportion of patients was found to carry CD11b+ or CD11c+ B cells whose presence was an unfavourable prognostic factor. The exact mechanism however, how these receptors contribute to the pathogenesis of CLL has not been revealed so far. Here we analysed the role of CD11b and CD11c on B cells of CLL patients in the adhesion to fibrinogen and in the migration towards stromal cell derived factor-1 (SDF-1) and studied the role of CR4 in the adherence of the CD11c+ B cell line BJAB. We observed that both CR3 and CR4 mediate adhesion of the malignant B cells. Moreover, we found, that CR4 was strongly involved in the migration of the leukemic cells towards the chemoattractant SDF-1. Our data suggest that CR3 and CR4 are not only passive markers on CLL B cells, but they might contribute to the progression of the disease. Since the role of SDF-1 is prominent in the migration of CLL cells into the bone marrow where their survival is supported, our findings help to understand how the presence of CD11c on leukemic B cells can worsen the prognosis of chronic lymphocytic leukaemia. [ABSTRACT FROM AUTHOR]

Summary: 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 BTKC481S, 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, BTKC481S 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 BTKC481S mutation preceded the symptoms of clinical relapse with a median of nine months. Subsequent Bcl‐2 inhibition therapy applied in 28/32 patients harbouring BTKC481S and progressing on ibrutinib conferred clinical and molecular remission across the patients. Our study demonstrates the clinical value of sensitive BTKC481S 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. [ABSTRACT FROM AUTHOR]

Copyright of Orvosképzés is the property of Semmelweis Kiado and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Orvosképzés is the property of Semmelweis Kiado and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Orvosképzés is the property of Semmelweis Kiado and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Orvosképzés is the property of Semmelweis Kiado and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Orvosképzés is the property of Semmelweis Kiado and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Langerhans cell histiocytosis (LCH) is characterized by mutations of the RAS-RAF-MAPK signaling pathway. We analyzed MAP2K1, NRAS and KIT mutation incidence in skin lesions of BRAF wild-type (wt) LCH patients. We evaluated the occurrence of MAP2K1, NRAS and KIT mutations in seven LCH and one indeterminate cell histiocytosis (ICH) patients. MAP2K1 mutation frequency was found to be 3/7 (42.9%) in LCH and also found in ICH. Similarly, the KIT mutation frequency was found to be equally prevalent (4/7, 57.1%) in LCH and also occurred in ICH. Involvement of KIT exons in LCH-ICH indicated that exon 9/11/18 were equally prevalent followed by exon 13. This exploratory analysis on BRAF-wt LCH revealed a KIT mutation rate comparable to MAP2K1. Although the detected KIT mutations are different from activating mutations found in other KIT-dependent neoplasms, our data suggest that KIT-inhibitors might have a role in treating BRAF-wt LCH patients. [ABSTRACT FROM AUTHOR]

Complement receptors CR3 (CD11b/CD18) and CR4 (CD11c/CD18) of myeloid cells are known for long to participate in actin linked functions like phagocytosis, adhesion, and migration. The expression and role of these two β2-integrins however, in human B lymphocytes have only scarcely been studied so far, although it has been shown recently that CD11c+ B cells are mainly memory cells. In our systematic study we investigated B cells isolated from tonsils and peripheral blood of healthy donors. We found, that while only 5% of resting tonsillar B cells expressed CD11c, their number increased up to 26% after 3 days of BCR stimulation. Lower, but still remarkable percentage of B lymphocytes were positive for CD11c after stimulation via TLR9 alone or via TLR9 and BCR simultaneously. At the same time, we detected no significant expression of CD11b on resting or activated tonsillar B cells. Blood B lymphocytes showed a similar expression pattern of both β2-integrins. We demonstrated that CD11c molecules appearing on the surface of B cells are newly synthesized, reaching the number of 9,500 per activated B cell. We found that CR4 expressing B cells belong to the memory pool and the increase of CD11c expression on tonsillar B cells upon BCR mediated activation occurs parallel with class switching. Analysis of the function of CD11c revealed, that this β2-integrin contributes to the adhesion and migration of activated B lymphocytes. We also demonstrated that the CR4 mediated adhesion promotes the proliferation of the BCR activated cells. Our studies are the first to demonstrate that CD11c expressed on BCR-activated human B cells are not only passive markers but functional drivers of memory B cell responses. [ABSTRACT FROM AUTHOR]

The inclusion of familial myeloid malignancies as a separate disease entity in the revised WHO classification has renewed efforts to improve the recognition and management of this group of at risk individuals. Here we report a cohort of 86 acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) families with 49 harboring germline variants in 16 previously defined loci (57%). Whole exome sequencing in a further 37 uncharacterized families (43%) allowed us to rationalize 65 new candidate loci, including genes mutated in rare hematological syndromes (ADA, GP6, IL17RA, PRF1 and SEC23B), reported in prior MDS/AML or inherited bone marrow failure series (DNAH9, NAPRT1 and SH2B3) or variants at novel loci (DHX34) that appear specific to inherited forms of myeloid malignancies. Altogether, our series of MDS/AML families offer novel insights into the etiology of myeloid malignancies and provide a framework to prioritize variants for inclusion into routine diagnostics and patient management. Familial myeloid malignancies have recently been classified as separate disease entities. Here, using whole-exome sequencing of affected pedigrees - the authors highlight genetic variants associated with these conditions. [ABSTRACT FROM AUTHOR]

The Bruton tyrosine kinase (BTK) inhibitor ibrutinib provides effective treatment for patients with chronic lymphocytic leukemia (CLL), despite extensive heterogeneity in this disease. To define the underlining regulatory dynamics, we analyze high-resolution time courses of ibrutinib treatment in patients with CLL, combining immune-phenotyping, single-cell transcriptome profiling, and chromatin mapping. We identify a consistent regulatory program starting with a sharp decrease of NF-κB binding in CLL cells, which is followed by reduced activity of lineage-defining transcription factors, erosion of CLL cell identity, and acquisition of a quiescence-like gene signature. We observe patient-to-patient variation in the speed of execution of this program, which we exploit to predict patient-specific dynamics in the response to ibrutinib based on the pre-treatment patient samples. In aggregate, our study describes time-dependent cellular, molecular, and regulatory effects for therapeutic inhibition of B cell receptor signaling in CLL, and it establishes a broadly applicable method for epigenome/transcriptome-based treatment monitoring. Ibrutinib, a Bruton tyrosine kinase inhibitor, provides effective treatment for chronic lymphocytic leukemia (CLL). Here, the authors describe time-dependent molecular changes to malignant cells and to the immune system in patients undergoing ibrutinib therapy, with can be used for therapy monitoring. [ABSTRACT FROM AUTHOR]

Copyright of Hungarian Medical Journal / Orvosi Hetilap is the property of Akademiai Kiado and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Primary cutaneous follicle center lymphoma (PCFCL) is an indolent variant of follicular lymphoma (FL) with limited information available on the genetic background of the disease. The genetic hallmark of nodal FL, the t(14;18) translocation, affecting the BCL2 gene, is rare in PCFCL. Loss of 1p36, the most common secondary chromosomal abnormality in nodal FL, has been recently reported in 16.7% of PCFCL cases. In order to further characterize PCFCL, 21 cases were analyzed using interphase fluorescence in situ hybridization with BCL2 break apart and 1p36/1q25 dual color probes. Sanger sequencing was used to investigate TNFRSF14 and EZH2 mutations and immunohistochemistry to assess BCL2, EZH2 protein expressions.1p36 deletion occurred in 22% (5/21), BCL2 gene break in 10% (2/20) of the PCFCL cases. Mutations of the candidate tumor suppressor gene of the 1p36 region, TNFRSF14 mutations were detected in 4/17 (23.5%) cases with 2 cases presenting with concurrent 1p36 deletion. EZH2 hotspot mutations at Y641, A682, and A692 were not found. High EZH2 protein expression associated with a BCL2 negative phenotype was observed in 43% (9/21) of the cases. BCL2 gene break or 1p36 deletion did not impact the prognosis; however, they showed association with advanced stages at diagnosis (p = 0.016) and a tendency with shorter event free survival (p = 0.052).In conclusion, 1p36 deletion co-occurs with acquired TNFRSF14 mutations, suggesting a role of this tumor suppressor gene in the development of a subgroup of PCFCL. High EZH2 protein expression associated with BCL2 negative phenotype is common and might represent an ideal therapeutic target. [ABSTRACT FROM AUTHOR]

Copyright of Hungarian Medical Journal / Orvosi Hetilap is the property of Akademiai Kiado and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Hungarian Medical Journal / Orvosi Hetilap is the property of Akademiai Kiado and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Chronic lymphocytic leukemia (CLL) is characterized by a neoplastic B-cell population coexpressing CD5 and CD23; however, the expression of CD23 is variable. In human, two isotypes of CD23 have been identified and related to different functions. The aim of our study was to investigate the relative expression of the two CD23 isotypes in CLL and find possible correlation with other prognostic factors. The expression of CD23 isotypes was analyzed in 54 cases of CLL by polymerase chain reaction (PCR) and quantitative real-time PCR. The immunophenotype of CLL cells was characterized by flow cytometry. We demonstrated a higher CD23a than CD23b expression of CLL cells. Our results also revealed two subsets of CLL cases with a distinct CD23 isotype expression pattern. Thirty-two percent of the cases (group CLL1) showed both low mRNA level of CD23 isotypes and high protein levels of CD20 and CD38 in contrast to group CLL2 with high CD23 mRNA levels. By correlating these results to the presence of prognostic factors determined by fluorescence in situ hybridization, we found that the majority of the cases of group CLL1 (14/17) carried trisomy 12. In summary, our results confirm a high CD23a/CD23b ratio of the CLL cells and demonstrate that in a subset of CLL cases, low CD23 expression together with high CD20 and CD38 expressions may serve as a surrogate for trisomy 12. Copyright © 2015 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

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The recent application of next-generation sequencing technologies lead to significant improvements in our understanding of genetic underpinnings of non-Hodgkin lymphomas with identification of an unexpectedly high number of novel mutation targets across the different B-cell lymphoma entities. These recently discovered molecular lesions are expected to have a major impact on development of novel biomarkers and targeted therapies as well as patient stratification based on the underlying genetic profile. This review will cover the major discoveries in B-cell lymphomas using next-generation sequencing technologies over the last few years, highlighting alterations associated with relapse and progression of these diseases. [ABSTRACT FROM AUTHOR]

Follicular lymphoma is an incurable malignancy, with transformation to an aggressive subtype representing a critical event during disease progression. Here we performed whole-genome or whole-exome sequencing on 10 follicular lymphoma-transformed follicular lymphoma pairs followed by deep sequencing of 28 genes in an extension cohort, and we report the key events and evolutionary processes governing tumor initiation and transformation. Tumor evolution occurred through either a 'rich' or 'sparse' ancestral common progenitor clone (CPC). We identified recurrent mutations in linker histone, JAK-STAT signaling, NF-κB signaling and B cell developmental genes. Longitudinal analyses identified early driver mutations in chromatin regulator genes (CREBBP, EZH2 and KMT2D (MLL2)), whereas mutations in EBF1 and regulators of NF-κB signaling (MYD88 and TNFAIP3) were gained at transformation. Collectively, this study provides new insights into the genetic basis of follicular lymphoma and the clonal dynamics of transformation and suggests that personalizing therapies to target key genetic alterations in the CPC represents an attractive therapeutic strategy. [ABSTRACT FROM AUTHOR]

Genome wide association studies have identified single nucleotide polymorphisms (SNP) within fibroblast growth factor receptor 2 (FGFR2) as one of the highest ranking risk alleles in terms of development of breast cancer. The potential effect of these SNPs, in intron two, was postulated to be due to the differential binding of cis-regulatory elements, such as transcription factors, since all the SNPs in linkage disequilibrium were located in a regulatory DNA region. A Runx2 binding site was reported to be functional only in the minor, disease associated allele of rs2981578, resulting in increased expression of FGFR2 in cancers from patients homozygous for that allele. Moreover, the increased risk conferred by the minor FGFR2 allele associates most strongly in oestrogen receptor alpha positive (ERα) breast tumours, suggesting a potential interaction between ERα and FGFR signalling. Here, we have developed a human cell line model system to study the effect of the putative functional SNP, rs2981578, on cell behaviour. MCF7 cells, an ERα positive breast cancer cell line homozygous for the wild-type allele were edited using a Zinc Finger Nuclease approach. Unexpectedly, the acquisition of a single risk allele in MCF7 clones failed to affect proliferation or cell cycle progression. Binding of Runx2 to the risk allele was not observed. However FOXA1 binding, an important ERα partner, appeared decreased at the rs2981578 locus in the risk allele cells. Differences in allele specific expression (ASE) of FGFR2 were not observed in a panel of 72 ERα positive breast cancer samples. Thus, the apparent increased risk of developing ERα positive breast cancer seems not to be caused by rs2981578 alone. Rather, the observed increased risk of developing breast cancer might be the result of a coordinated effect of multiple SNPs forming a risk haplotype in the second intron of FGFR2. [ABSTRACT FROM AUTHOR]

The article focuses on acute myeloid leukemia (AML), reportedly the most common form of aggressive leukemia in adults. A review is provided covering the key molecular aberrations in adult AML for risk stratification and clinical management, next-generation sequencing (NGS) techniques that revolutionize the understanding of its molecular biology, and the potential for improving minimal residual disease (MRD) monitoring. Topics include clinically established mutations, and epigenetic mutations.

GATA2 mutations have recently been reported in acute myeloid leukaemia ( AML) patients with CEBPA-double mutations. To explore their impact on this favourable-risk disease, we determined GATA2 status in 153 sporadic AML patients and three members of a germ-line CEBPA-mutant family at AML presentation. Overall, 27% (15/55) CEBPA-double, 16% (7/43) CEBPA-single and 0% (0/55) normal karyotype/ CEBPA-wild-type patients were GATA2-mutant. All familial AML patients acquired both a second CEBPA and a GATA2 mutation. CEBPA and GATA2 mutant levels indicated that both mutations were likely to be early events in leukaemogenesis. GATA2 status did not impact on the favourable outcome of CEBPA-double/ FLT3-inernal tandem duplication-negative patients. [ABSTRACT FROM AUTHOR]