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Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin lymphoma (NHL) subtype characterized by overexpression of CCND1 and SOX11 genes. It is generally associated with clinically poor outcomes despite recent improvements in therapeutic approaches. The genes associated with the development and prognosis of MCL are still largely unknown. Through whole transcriptome sequencing (WTS), we identified mRNAs, lncRNAs, and alternative transcripts differentially expressed in MCL cases compared with reactive tonsil B-cell subsets. CCND1, VCAM1, and VWF mRNAs, as well as MIR100HG and ROR1-AS1 lncRNAs, were among the top 10 most significantly overexpressed, oncogenesis-related transcripts. Survival analyses with each of the top upregulated transcripts showed that MCL cases with high expression of VWF mRNA and low expression of FTX lncRNA were associated with poor overall survival. Similarly, high expression of MSTRG.153013.3, an overexpressed alternative transcript, was associated with shortened MCL survival. Known tumor suppressor candidates (e.g., PI3KIP1, UBXN) were significantly downregulated in MCL cases. Top differentially expressed protein-coding genes were enriched in signaling pathways related to invasion and metastasis. Survival analyses based on the abundance of tumor-infiltrating immunocytes estimated with CIBERSORTx showed that high ratios of CD8 + T-cells or resting NK cells and low ratios of eosinophils are associated with poor overall survival in diagnostic MCL cases. Integrative analysis of tumor-infiltrating CD8 + T-cell abundance and overexpressed oncogene candidates showed that MCL cases with high ratio CD8 + T-cells and low expression of FTX or PCA3 can potentially predict high-risk MCL patients. WTS results were cross-validated with qRT-PCR of selected transcripts as well as linear correlation analyses. In conclusion, expression levels of oncogenesis-associated transcripts and/or the ratios of microenvironmental immunocytes in MCL tumors may be used to improve prognostication, thereby leading to better patient management and outcomes.

Follicular lymphoma (FL) is the second most frequent non-Hodgkin lymphoma accounting for 10-20% of all lymphomas in western countries. As a clinically heterogeneous cancer, FL occasionally undergoes histological transformation to more aggressive B cell lymphoma types that are associated with poor prognosis. Here we evaluated the potential of circulating cell-free DNA (cfDNA) to improve the diagnosis and prognosis of follicular lymphoma patients. Twenty well-characterized FL cases (13 symptomatic and 7 asymptomatic) were prospectively included in this study. Plasma cfDNA, formalin-fixed paraffin-embedded (FFPE) tumor tissue DNA, and patient-matched granulocyte genomic DNA samples were obtained from 20 treatment-naive FL cases. Ultra-deep targeted next-generation sequencing was performed with these DNA samples by using a custom-designed platform including exons and exon-intron boundaries of 110 FL related genes. Using a strict computational bioinformatics pipeline, we identified 91 somatic variants in 31 genes in treatment-naive FL cases. Selected variants were cross-validated by using PCR-Sanger sequencing. We observed higher concentrations of cfDNA and a higher overlap of somatic variants present both in cfDNA and tumor tissue DNA in symptomatic FL cases compared to asymptomatic ones. Variants known to be associated with FL pathogenesis such as STAT6 p.D419 or EZH2 p.Y646 were observed in patient-matched cfDNA and tumor tissue samples. Consistent with previous observations, high Ki-67 staining, elevated LDH levels, FDG PET/CT positivity were associated with poor survival. High plasma cfDNA concentrations or the presence of BCL2 mutations in cfDNA showed significant association with poor survival in treatment-naive patients. BCL2 mutation evaluations in cfDNA improved the prognostic utility of previously established variables. In addition, we observed that a FL patient who had progressive disease contained histological transformation-associated gene (i.e. B2M and BTG1 ) mutations only in cfDNA. Pre-treatment concentrations and genotype of plasma cfDNA may be used as a liquid biopsy to improve diagnosis, risk stratification, and prediction of histological transformation. Targeted therapies related to oncogenic mutations may be applied based on cfDNA genotyping results. However, the results of this study need to be validated in a larger cohort of FL patients as the analyses conducted in this study have an exploratory nature., 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 Hatipoğlu, Esmeray Sönmez, Hu, Yuan, Danyeli, Şeyhanlı, Önal-Süzek, Zhang, Akman, Olgun, Özkal, Alacacıoğlu, Özcan, You and Küçük.)

Objective: Multiple myeloma (MM) is a malignant condition characterized by the accumulation of malignant plasma cells. Although MM remains incurable, the survival of MM patients has improved considerably due to the application of autologous stem cell transplantation, novel agents, and advanced treatment strategies. This study aimed to determine the cytogenetic characterization and bone marrow (BM) features of Turkish patients with MM., Materials and Methods: Eighty-five MM patients were admitted to Dokuz Eylül University Hospital in Turkey. BM samples of these MM patients were subjected to cytogenetic analyses at diagnosis and during therapy as a part of therapeutical and clinical evaluation. A complete cytogenetic study was performed using the G-banding technique. Fluorescence in situ hybridization (FISH) analysis was performed using cytoplasmic immunoglobulin. The degree of BM fibrosis was determined using reticulin histochemical staining. We determined the percentage of BM plasma cells based on the extent of CD38 staining., Results: Eighty-five MM patients were retrospectively identified between 2015 and 2021. The median age was 63 (38-90) years. Of the 85 patients, 60 (70.6%) were male and 25 (29.4%) were female. Seventy-two (84.7%) cases had BM fibrosis at the time of diagnosis. The most common was grade 2 fibrosis, recorded in 35 cases (41.2%). About 72.9% of the patients showed more than 50% plasma cells. FISH analysis indicated the presence of abnormal chromosomes in 37% (32/85) of the patients. The most frequent abnormality was Immunoglobulin heavy-chain (IGH) translocation (21.3%)., Conclusion: Subgroup analysis of IGH mutations is crucial in the identification of high-risk MM patients. We believe that our study will contribute to the determination of BM biopsy and cytogenetic features of MM patients in our country.

Objective: The aim of the present study was to evaluate the efficacy and safety of eltrombopag, an oral thrombopoietin receptor agonist, in patients with chronic immune thrombocytopenia (ITP)., Materials and Methods: A total of 285 chronic ITP patients (187 women, 65.6%; 98 men, 34.4%) followed in 55 centers were enrolled in this retrospective cohort. Response to treatment was assessed according to platelet count (/mm 3 ) and defined as complete (platelet count of >100,000/mm 3 ), partial (30,000-100,000/mm 3 or doubling of platelet count after treatment), or unresponsive (<30,000/mm 3 ). Clinical findings, descriptive features, response to treatment, and side effects were recorded. Correlations between descriptive, clinical, and hematological parameters were analyzed., Results: The median age at diagnosis was 43.9±20.6 (range: 3-95) years and the duration of follow-up was 18.0±6.4 (range: 6-28.2) months. Overall response rate was 86.7% (n=247). Complete and partial responses were observed in 182 (63.8%) and 65 (22.8%) patients, respectively. Thirty-eight patients (13.4%) did not respond to eltrombopag treatment. For patients above 60 years old (n=68), overall response rate was 89.7% (n=61), and for those above 80 years old (n=12), overall response rate was 83% (n=10). Considering thrombocyte count before treatment, eltrombopag significantly increased platelet count at the 1 st , 2 nd , 3 rd , 4 th , and 8 th weeks of treatment. As the time required for partial or complete response increased, response to treatment was significantly reduced. The time to reach the maximum platelet levels after treatment was quite variable (1-202 weeks). Notably, the higher the maximum platelet count after eltrombopag treatment, the more likely that side effects would occur. The most common side effects were headache (21.6%), weakness (13.7%), hepatotoxicity (11.8%), and thrombosis (5.9%)., Conclusion: Results of the current study imply that eltrombopag is an effective therapeutic option even in elderly patients with chronic ITP. However, patients must be closely monitored for response and side effects during treatment. Since both response and side effects may be variable throughout the follow-up period, patients should be evaluated dynamically, especially in terms of thrombotic risk factors.

Objective: Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma (NHL). The treatment of older NHL patients has always been a struggle; however, treatment statistics have begun showing favorable results similar to those of younger DLBCL patients thanks to newer treatment protocols. Here, we analyze the progress of our own elderly DLBCL patients who were followed between 2000 and 2016 in our center., Materials and Methods: Eighty-seven DLBCL patients, who were diagnosed and treated in the Dokuz Eylül University Department of Hematology between 2000 and 2016, were included in this study. Median age was 72 (65-89) years and 13 (14.9%) patients were older than 80 years., Results: Median follow-up time was 19 months and 45 patients (51.7%) died during the follow-up period. Median overall survival (OS) was 55 months and median progression-free survival was calculated as 27 months. Sixty-three patients (72.4%) received standard R-CHOP therapy. Complete response was seen in 46 (52.9%) patients. The median survival time for patients who had complete response was 136 months (p<0.001); however, OS was not statistically different between older (>80 years) and younger patients (p=0.236)., Conclusion: According to our findings, we think that being able to complete standard R-CHOP therapy is vital for the survival rate of elderly DLBCL patients.

Dyskeratosis congenita (DC) is a rare inherited syndrome characterized by classical mucocutaneous features and the presence of other clinical features including bone marrow failure, pulmonary fibrosis, liver cirrhosis, and a predisposition to cancer. The symptoms develop at various ages and may manifest over time. Gene mutations associated with DC, such as DC1, TERC, TERT, TINF2, NHP2, NOP10, ACD, CTC1, NAF1, PARN, POT1, RTEL1, STN1, and WRAP53, have been identified in about 70% of patients. Since the number of patients with DC is small and the effect of genetic pathogenic variant may affect the phenotype, we wanted to present the clinical features and course of illness in a patient with NHP2 gene mutation (compound heterozygote for the NHP2 mutations c.376G>A/c.460T>A; amino acid substitutions: p.Val126Met and p.X154Arg) that occurred as a compound heterozygous state., (© 2018 S. Karger AG, Basel.)

Objective: High-doses of melphalan treatment with autologous stem cell transplantation in multiple myeloma (MM) remains a major treatment modality in suitable patients. A minimal dose of 2x10 6 /kg CD34+ cells is preferred to achieve engraftment. Some patients need multiple leukapheresis procedures to achieve the necessary number of CD34+ cells, but this can cause a high volume of stem cell product that cannot be given in a single day. Whether or not the number of infusion days affects engraftment has not been studied before. We aimed to evaluate the impact of reinfusion of stem cells on multiple days on engraftment results., Materials and Methods: Demographic features, CD34+ cell doses, neutrophil and platelet engraftment days, hospitalization days, and number of infusion days of 149 autologous transplantations of 143 MM patients were evaluated retrospectively., Results: The data of 143 MM patients who were transplanted were analyzed retrospectively. Median age was 55±8.5 (range: 26-70) years with a male/female ratio of 91/58. Hospitalization days for all patients were 24±6 (range: 14-50) days. Mean CD34+ cell number was (7.5±5.3)x10 6 /kg (range: 1.5-31x10 6 /kg). CD34+ cells were reinfused in 1 day in 80.5% (n=120) of the patients, 2 days in 18.2% of the patients (n=27), and 3 days in 1.3% of the patients (n=2). For 29 patients, reinfusion was applied in more than 1 day because of the high volume of stem cell product. We did not see any dimethyl sulfoxide toxicity, cardiac arrhythmia, or volume overload complications. Hypertensive attacks during infusion were easily controlled by furosemide treatment. In the group with multiple infusions, the infused CD34+ cell numbers had a mean of (4.8±2.8)x10 6 /kg, and in the single infusion group the mean was (8.1±5.5)x10 6 /kg. There were no statistical differences between the two groups regarding platelet and neutrophil engraftment days (p=0.850, r=0.820 and p=0.500, r=0.440). There was no statistical difference between the two groups for hospitalization days (p=0.060, r=0.050)., Conclusion: In cases with a high volume of stem cell product to acquire adequate stem cells, reinfusion can be safely applied across multiple days without any delay in engraftment.

Bilateral non-granulomatous anterior uveitis with left vitritis and macular edema were detected in a 19-year-old woman presenting with blurred vision in her left eye. Light microscopic study of the pathologic mediastinal lymph node that was detected via contrast computed tomography imaging during etiologic study revealed nodular sclerosing and mixed cellularity Hodgkin's lymphoma (HL). Ocular findings completely resolved with adriablastin, bleomycin, vinblastine, dacarbazine chemotherapy treatment. Herein, it is emphasized that HL should be remembered as one of the differential diagnoses in patients with ocular inflammatory pathologies such as uveitis and vasculitis. The ocular findings of HL are discussed., Competing Interests: Conflict of Interest: No conflict of interest was declared by the authors.

Objective: Immune thrombocytopenia (ITP) is an immune-mediated disease characterized by transient or persistent decrease of the platelet count to less than 100x109/L. Although it is included in a benign disease group, bleeding complications may be mortal. With a better understanding of the pathophysiology of the disease, thrombopoietin receptor agonists, which came into use in recent years, seem to be an effective option in the treatment of resistant cases. This study aimed to retrospectively assess the efficacy, long-term safety, and tolerability of eltrombopag in Turkish patients with chronic ITP in the Aegean region of Turkey., Materials and Methods: Retrospective data of 40 patients with refractory ITP who were treated with eltrombopag in the Aegean region were examined and evaluated., Results: The total rate of response was 87%, and the median duration of response defined as the number of the platelets being over 50x109/L was 19.5 (interquartile range: 5-60) days. In one patient, venous sinus thrombosis was observed with no other additional risk factors due to or related to thrombosis. Another patient with complete response and irregular follow-up for 12 months was lost due to sudden death as the result of probable acute myocardial infarction., Conclusion: Although the responses to eltrombopag were satisfactory, patients need to be monitored closely for overshooting platelet counts as well as thromboembolic events.

Background: There have been concerns about the possible prothrombotic effects of nilotinib, especially in patients having cardiovascular risk factors. The potential mechanism behind the increased risk of thromboembolic events is still not clear., Objectives: In this study, we aimed to evaluate possible harmful effects of nilotinib on endothelial cells. To this aim, we examined proliferative capacity and secretory functions of healthy human carotid artery endothelial cells (HCtAECs) in response to nilotinib., Methods: 3-(4,5-Dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) cell proliferation method was used to determine antiproliferative effects of nilotinib on HCtAECs. The HCtAECs were incubated with 5, 10, and 100 nmol/L doses of nilotinib for 72 hours. Then, in order to assess the endothelial function, levels of nitric oxide (NO), von Willebrand factor (vWF), tissue plasminogen activator, plasminogen activator inhibitor 1 (PAI-1), and endothelin 1 (ET-1) were evaluated using enzyme-linked immunosorbent assay from tissue culture supernatants., Results: There were slight but statistically significant decreases in cell proliferation in response to nilotinib. Nilotinib increased the secretion of t-PA, PAI-1, and vWF in a dose-dependent manner when compared with the untreated control group. The ET-1 secretion was lower in 5 nmol/L and higher in 10 and 100 nmol/L nilotinib-treated cells as compared to untreated cells. Regarding NO secretion, lower levels were observed in 5 and 10 nmol/L, and higher levels were detected in 100 nmol/L nilotinib-treated cells as compared to untreated control group cells., Conclusion: Considering the results obtained in our study, nilotinib does not affect the functions of endothelial cells either in a prothrombotic or an antithrombotic fashion, despite a dose-dependent decline in cell viability., (© The Author(s) 2014.)

Transplantation-associated thrombotic microangiopathy (TA-TMA) is a challenge after allogeneic hematopoietic progenitor cell transplantation, considering the diagnostic uncertainties and lack of established treatment. We report a 43-year-old male patient who was diagnosed as TA-TMA after allogeneic progenitor cell transplantation for a progressive ALK negative anaplastic large cell lymphoma and responded to eculizumab with dramatically improving neurological status and renal function. Rapid neurological and renal recovery achieved after eculizumab could support a possible relationship between complement activation and TA-TMA. Eculizumab should be a reasonable treatment approach in patients with TA-TMA after allogeneic hematopoietic progenitor cell transplantation.

Langerhans cell sarcoma is a rare, high-grade neoplasm with overtly malignant cytological features and the Langerhans phenotype. Herein, we present a rare case of Langerhans cell sarcoma in a 65-year-old female that presented with a painless enlarging mass in her right axillary region, along with the histopathological features and diagnostic characteristics in the light of literature on Langerhans cell sarcoma.

Fludarabine-containing combinations have additive cell killing against leukemic blasts in vitro. It has also been shown that imatinib mesylate combined with fludarabine or cladribine had an additive effect on CML CFU-GM cells. In this regard, we aimed to investigate the effect of fludarabine-imatinib mesylate combination against CML blastic phase cell lines K562 and Meg-01. XTT test was performed for proliferation and inhibition assay. According to obtained data, five different effective concentrations of each drug in 25 different combinations were tested. Results of the combination studies were analyzed with isobologram. At IC20, imatinib mesylate and fludarabine combination showed synergism and strong synergism in K562 and Meg-01 cells, respectively. At IC50 and IC75, combination indexes (CI) indicated strong synergism and synergism. Based on our results, the fludarabine- based chemotherapy regimens can be used for those patients with CML blastic phase in combination with imatinib mesylate.

It has been shown that imatinib mesylate, a drug used in the treatment of chronic myelogenous leukemia, inhibits the effect of stem cell factor, which has a central role in erythropoiesis. In some polycythemia vera (PV) patients, it has inhibited autonomous erythroid colony growth in vitro and decreased the need for phlebotomy. In this study we have investigated the effect of insulin like growth factor (IGF)-I, stem cell factor (SCF) and erythropoietin (Epo) with interleukin (IL)-3, granulocyte macrophage-colony stimulating factor (GM-CSF) and granulocyte-colony stimulating factor (G-CSF) in the presence of imatinib mesylate on the erythroid progenitors derived from peripheral blood mononuclear cells of three patients with PV and four healthy controls in semisolid medium. Erythroid colony formation from hematopoietic progenitors obtained from healthy controls was observed only in the presence of all cytokines. However, the number of erythroid colonies could not reach that of patients with PV. Inhibition of imatinib mesylate on erythroid colony growth was evident. Hematopoietic progenitors of patients with PV displayed two types of colony formation: the first type was exogenous cytokine-independent and was hypersensitive to current cytokines, and the second displayed hypersensitivity to current exogenous cytokines, but was exogenous cytokine-dependent. For both types, the inhibitory effect of imatinib mesylate was striking in the presence of all cytokines including IL-3, GM-CSF and Epo. There is no direct evidence yet that imatinib mesylate could inhibit the effect of IL-3, G-CSF, GM-CSF, Epo and IGF-I on erythropoiesis. Considering former studies together with results of this study, it can be argued that imatinib mesylate is effective in PV on the intersecting signal transduction mechanisms in which stem cell factor and its receptor may have a part.

Background: The clinical course of patients with inflammatory bowel disease (IBD) is frequently complicated by thromboembolic events and may involve the arterial and venous systems. Although not uniformly documented, several studies document substantial alterations in markers of coagulation and fibrinolysis in patients with IBD., Methods: 45 patients with IBD (31 UC,14 CD) were included in the study. Age and sex matched 16 volunteers were used as a control group. TAFI antigen was determined using an ELISA kit VisuLiseTM for quantitative measurement., Results: Inflammatory parameters such as white blood cell, platelet levels, erythrocyte sedimentation rate, C-reactive protein were found to be significantly higher in active disease group compared to inactive patients. Coagulation parameters of prothrombin time, activated partial thromboplastin time and d-dimer levels showed no significant difference between active and inactive IBD. Fibrinogen levels were significantly higher in clinically active IBD patients. Plasma TAFI levels demonstrated no significant difference between active and control, inactive and control as well as active and inactive groups. We observed no significant changes in levels of β-TG and PF-4 between active and inactive disease group., Conclusions: We studied plasma TAFI levels in IBD. In conclusion, plasma TAFI levels does not appear to represent to be a marker of activation in IBD in contrast to literature. So further studies covering more patients with different clinic and disease activity status might improve the perspective on this issue.

t(1;3)(p36;p21) is a recurrent reciprocal translocation found in a subset of myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML) characterized by trilineage dysplasia, especially dysmegakaryopoiesis and poor prognosis. In the literature, some authors have suggested that this recurrent translocation is closely associated with prior chemotherapy including alkylating agents in various hematologic malignancies. We identified a recurring translocation, t(1;3)(p36;p21), in our patient with MDS/AML(M2), although she had not been given any kind of treatment previously.