Objective: Deleterious substitutions of the F8 gene are responsible for causing hemophilia A, which is an inherited bleeding disorder resulting from reduced or absent activity of the coagulant protein factor VIII (FVIII). The most important complication in treatment is inhibitor development toward therapeutic factor VIII. In this study, we aimed to analyze the effects of deleterious substitutions in the F8 gene upon protein structure and function.
Materials and Methods: All tests were conducted by computational methods from the CHAMP (CDC Hemophilia A Mutation Project) database. We performed an in silico analysis of deleterious variations using five software programs, Sift, PolyPhen-2, Align-GVGD, KD4v, and MutationTaster, in order to analyze the correlation between variation and the disease. We also studied the correlation between these variations and inhibitor formation.
Results: Our analysis showed that these in silico tools are coherent and that there are more variations in the A than the C domains. Moreover, we noticed that there are more deleterious variations than neutral variations in each of the A and C domains. We also found that 13.51% of the patients suffered from a severe form of hemophilia A and that carriers of missense variations developed inhibitors. Also, for the first time, we determined that variation nature is not associated with inhibitor formation. Furthermore, this analysis showed that the risk of developing inhibitors increases when the variation causes a change of amino acid class.
Conclusion: This study will help to correctly associate variations with inhibitor development and aid in early characterization of novel variants.

Objective: Chronic antigenic stimulation is frequently blamed in the pathogenesis of extranodal marginal zone lymphomas including splenic marginal zone lymphoma (SMZL). Chronic hepatitis C is frequently observed in SMZL patients in some geographical regions. However, these reports are largely from North America and Europe, and data from other countries are insufficient. In this multicenter study we aimed to identify the clinical characteristics of SMZL patients in Turkey, including viral hepatitis status and treatment details.
Materials and Methods: Data were gathered from participating centers from different regions of Turkey using IBM SPSS Statistics 23 for Windows. Hepatitis B virus surface antigen (HBsAg), anti-HBs antibody, anti-HB core antigen antibody (anti-HBcAg), HB viral load, anti-hepatitis C virus (HCV) antibody, HCV viral load results were analyzed.
Results: One hundred and four patients were reported. Hepatitis C virus positivity was observed in only one patient. However, hepatitis B virus surface antigen (HBsAg) positivity was observed in 11.2% and HBsAg and/or anti-HB core antigen antibody (anti-HBcAg) positivities were seen in 34.2% of the patients. The median age was 60 years (range=35-87). Median follow-up duration was 21.2 months (range=00.2-212; 23.2 months for surviving patients). Median overall survival was not reached. Estimated 3-year and 10-year survival rates were 84.8% and 68.9%, respectively. Older age, no splenectomy during follow-up, platelet count of <90x103/µL, lower albumin, higher lactate dehydrogenase, higher β2-microglobulin, and HBsAg positivity were associated with increased risk of death. Only albumin remained significant in multivariable analysis.
Conclusion: These results indicate that hepatitis B virus may be a possible risk factor for SMZL in our population. It may also be an indirect prognostic factor.

Objective: The management experience for plasma cell leukemia (PCL) is still limited by PCL’s rare incidence and aggressive course. The goal of this study was to further identify the efficacy of bortezomibcontaining regimens for PCL in Chinese patients.
Materials and Methods: In this study, 56 consecutive PCL patients [14 primary PCL (pPCL) and 42 secondary PCL (sPCL) cases] were retrospectively enrolled and 42/56 patients received bortezomibbased regimens (BBRs), including 10/14 pPCL and 32/42 sPCL patients. The patients’ survival data, clinical information, and safety data were collected and analyzed.
Results: In pPCL and sPCL patients, the overall response rate in the bortezomib group was 90.0% and 25.0%, respectively. The median progression-free survival from PCL diagnosis for pPCL and sPCL was 8.3 months vs. 2.9 months (p=0.043) and median overall survival (OS) from PCL diagnosis was 23.3 months vs. 4.0 months. The OS for patients receiving BBRs was significantly longer for both pPCL (8.3 vs. 1.2 months, p=0.002) and sPCL (4.3 vs. 1.1 months, p<0.001). In multivariate COX analysis, BBR treatment [p=0.008, hazard ratio (HR)=0.38, 95% confidence interval (CI)=0.19-0.77] and very good partial response or better (≥VGPR) (p=0.035, HR=0.19, 95% CI=0.040.74) were independent predictors of OS for sPCL patients. For pPCL patients, BBR predicted OS (p=0.029, HR=0.056, 95% CI=0.004-0.745) instead of ≥VGPR (p=0.272, HR=3.365, 95% CI=0.38-29.303).
Conclusion: It was found that BBRs could significantly improve OS for both pPCL and sPCL patients.

Objective: PTEN/AKT pathway deregulations have been reported to be associated with treatment response in acute leukemia. This study examined pediatric T-cell acute lymphoblastic leukemia (T-ALL) samples for PTEN and AKT1 gene variations and evaluated the clinical findings.
Materials and Methods: Fifty diagnostic bone marrow samples of childhood T-ALL cases were investigated for the hotspot regions of the PTEN and AKT1 genes by targeted next-generation sequencing.
Results: A total of five PTEN variations were found in three of the 50 T-ALL cases (6%). Three of the PTEN variations were first reported in this study. Furthermore, one patient clearly had two different mutant clones for PTEN. Two intronic single-nucleotide variations were found in AKT1 and none of the patients carried pathogenic AKT1 variations.
Conclusion: Targeted deep sequencing allowed us to detect both lowlevel variations and clonal diversity. Low-level PTEN/AKT1 variation frequency makes it harder to investigate the clinical associations of the variants. On the other hand, characterization of the PTEN/ AKT signaling members is important for improving case-specific therapeutic strategies.

Objective: Acute myeloid leukemia (AML) is a highly heterogeneous hematological malignancy, and drug resistance and relapse are key factors in the failure of leukemia treatment. Studies have increasingly shown that circRNA and LncRNA play important roles in the development of tumors, but their roles remain unclear in the mechanism of AML resistance.
Materials and Methods: Resistant AML cell line HL-60/ADM (adriamycin, ADM) was constructed and circRNA, LncRNA, and mRNA expression profiles were screened followed by high-throughput sequencing. Bioinformatics analysis was then carried out, and the circRNA-miRNA ceRNA network was constructed and confirmed using qRT-PCR analysis.
Results: A total of 1824 circRNAs, 2414 LncRNAs, and 5346 mRNAs were screened for differentially expressed genes. Enrichment analysis was performed utilizing Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes, which mainly involved protein domain specific binding, transforming growth factor-β (TGF-β) receptor, and cellular metabolism. The mTOR signaling pathway, MAPK signaling pathway, RAP1 signaling pathway, and Akt signaling pathway were closely related to drug resistance.
Conclusion: Our study provides a systematic outlook on the potential function of ncRNA in the molecular mechanisms of resistant AML cells. Hsa-circ-0000978 and hsa-circ-0000483 might serve as potential prognostic biomarkers and therapeutic targets of AML resistance.

Chemotherapy treatment and autologous and allogeneic cell transplantations are often complicated by the onset of metabolic and endocrine disorders. Autoimmune disorders, metabolic diseases, and hormonal dysfunctions are some of the endocrine complications observed during or after treatment with immunotherapy (mostly novel agents) and/or chemotherapy conditioning for transplantation. Although successful treatment of the underlying hematological condition often improves the dysfunction, endocrinopathies can have an impact on prognosis and are associated with poor survival; therefore, it is important to detect and treat them as early as possible. An increased incidence of cardiovascular diseases and metabolic syndrome has been observed after transplantation mostly in longterm survivors. In addition, chemotherapy and radiation along with the prolonged use of corticosteroids can contribute to the onset of thyroid and gonadal dysfunctions. The aim of this article is to describe metabolic dysfunctions occurring in patients who underwent allogeneic cell transplantation.

Objective: The prognosis of patients with acute myeloid leukemia (AML) is affected by factors that are both patient- and diseasespecific. The aim of this study is to evaluate the impact of early versus late platelet and neutrophil recovery after induction chemotherapy on survival outcomes of AML patients.
Materials and Methods: A total of 181 patients with AML who were treated in our tertiary center between 2001 and 2018 were evaluated. Neutrophil and platelet recovery times were accepted as the periods from the beginning of induction chemotherapy to a neutrophil count of ≥0.5x109/L and a platelet count of ≥20x109/L 3 days in a row, respectively. The median time to platelet recovery was 25 days (range=12-52) for all patients. Therefore, platelet recovery in the first 25 days was defined as early platelet recovery (EPR) and at ≥26 days it was defined as late platelet recovery (LPR). The median time to neutrophil recovery was 28 days (range=13-51) for all patients. Therefore, neutrophil recovery in the first 28 days was defined as early neutrophil recovery, and at ≥29 days it was defined as late neutrophil recovery.
Results: The 5-year overall survival (OS) rates for patients who had EPR and LPR after induction chemotherapy were 62% and 23%, respectively (p<0.001). The 5-year disease-free survival (DFS) rates for patients who had EPR and LPR after induction chemotherapy were 57% and 15%, respectively (p<0.001).
Conclusion: Short bone marrow recovery time may indicate better healthy hematopoiesis and marrow capacity associated with longer OS and DFS.