Prognostic Impact of IL17 A Gene Polymorphismson Egyptian Patients with Multiple Myeloma.

INTRODUCTION: Multiple myeloma (MM) is a B-cell lymphoproliferative disease in which the bone marrow microenvironment plays an important role in pathogenesis. The T helper (Th-17) cell plays an important role in the development of cancer by releasing pro-inflammatory cytokines such as IL-17A and IL-17F. Th-17 cells have been studied in a variety of solid tumors, as well as few hematological malignancies, including acute myeloid leukemia, non-Hodgkin lymphoma, and monoclonal gammopathy of unknown significance. AIM: Our study aimed to assess the association between IL-17A polymorphism and MM risk and other MM characteristics in Egyptian patients. PATIENTS & METHODS: a prospective study involving 77 patients with MM (mean age 54.6 years; males 53.2%; females 46.8%) and a healthy control group of same age and gender. It was performed at the Mansoura University Oncology Center (OCMU). The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) approach was used to detect IL17A 197 G/A (rs2275913) genotypes in genomic DNA from MM patients and healthy controls. RESULTS: The IL-17A polymorphism may not be associated to myeloma predilection in the Egyptians as a whole. There was also no significant correlation in statistical study between gender and the IL-17A polymorphism. (p 0.14), a number of clinical and laboratory characteristics, including hypercalcemia (p 0.28), hypoalbuminemia (p 0.49), renal impairment (p 0.13), high LDH (p 0.62), osteolytic bone lesions (p 0.26), and pathological fracture (p 0.96), are also present. Nevertheless, no statistically significant difference in the OS of MM patients was detected for the IL-17A polymorphism (p 0.83). CONCLUSION: Our research demonstrated that IL-17A polymorphism may not be linked to multiple myeloma susceptibility in our population and did not influence its different clinical and laboratory features. IL-17A polymorphism had no effect on OS in MM patients.

Angiogenic markers predict kidney injury and obstetric complications in women with preeclampsia and pregnancy-related acute kidney injury.

Pregnancy-related acute kidney injury (PRAKI) particularly on top of preeclampsia (PE) represents a major cause of maternal and fetal morbidity and mortality. Reliable diagnostic tools are needed to further evaluate the diagnosis and prognosis of PRAKI. Our objective was to study the diagnostic and prognostic value of angiogenic markers (e.g., stromal cell-derived factor 1 (SDF-1), vascular endothelial growth factor (VEGF), alarmins as uric acid) in women with PE and PRAKI. This prospective study included three groups; PRAKI, PE patients, and healthy controls that were compared regarding serum levels of the studied markers correlated to renal, maternal, and fetal outcomes. SDF-1, VEGF, and uric acid levels were significantly different between the three included groups and predicted PRAKI diagnosis. Patients with hemolysis, elevated liver enzymes, and low platelet (HELLP) syndrome exhibited the highest titers of SDF-1 and VEGF. A positive correlation was found between SDF-1 and renal recovery. Conclusively, serum assays of SDF-1, VEGF, and uric acid may add a diagnostic value in PRAKI and PE.

Acute kidney injury during pregnancy and puerperium: an Egyptian hospital-based study.

INTRODUCTION: While acute kidney injury (AKI) in pregnancy is currently a rare entity in developed countries, it is still a common occurrence in developing countries, representing a major cause of maternal and fetal morbidity and mortality. Scarce data are published regarding pregnancy-related acute kidney injury (PRAKI) in Middle Eastern and African countries. The aim of this work is to report on the frequency, the underlying causes, and the outcomes of patients with PRAKI in an Egyptian tertiary care hospital. METHODS: This is a prospective observational study that included 40 patients representing all women who presented to the Mansoura Nephrology and Dialysis Unit with PRAKI over two years. All patients were followed up for three months after hospital discharge to assess renal outcome, and till the end of pregnancy to assess the maternal and fetal outcomes. RESULTS: PRAKI was reported  in about 1% of women who presented to the obstetrics service, and accounted for 14% of all AKI patients who presented to the renal service in our hospital. Preeclampsia (PE) and obstetric hemorrhage were the commonest causes of PRAKI. Maternal mortality occurred in 22.5% of PRAKI patients. The majority of survivors (62.5%) fully recovered, while the remaining (37.5%) individuals became dialysis dependent. Unfavorable fetal events occurred in 24 pregnancies (60%). CONCLUSION: In our hospital in Mansoura, Egypt, PRAKI represents a relevant burden with potential ominous outcomes obstetric hemorrhage and preeclampsia were the major causes. Further research is needed to understand the causes and improve the outcomes of pregnancy-related AKI.

Association of SDF-1 Gene Polymorphism with Increased Risk of Acute Myeloid Leukemia Patients.

BACKGROUND: Acute myeloid leukemia (AML) is a heterogenous group of disorders that emerge from the malignant transformation of hematopoietic stem cells. Chemokine stromal cell-derived factor 1(SDF-1) and its receptor CXC receptor 4 (CXCR4) has an essential role in dissemination of blast cells. Study aimed to detect CXCR4 expression and the SDF-1 (rs1801157) gene polymorphisms and correlate them with prognosis and outcome in AML patients. SUBJECTS AND METHODS: The study was conducted on 60 de-novo AML patients, and 60 healthy controls. SDF-1 (rs1801157) gene polymorphisms were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), and CXCR4 expression was done using flow cytometry analysis. RESULTS: SDF-1 dominant model (AG+AA) had higher risk AML (p 0.002). CXCR4positive cases were associated significantly with toxic manifestations (p 0.019), lower CR rates (p 0.004), and unfavorable cytogenetics (p 0.027). Multivariate analysis showed that combined CXCR4positive with dominant SDF-1 considered as independent prognostic factor for shorter overall survival (OS) in AML patients (p 0.031). CONCLUSION: SDF-1 dominant model had a higher risk to develop AML, and CXCR4 positive expression predicts poor prognosis in AML patients and it could represent a targeted therapy in AML. In addition, CXCR4 could be easily integrated into the initial routine diagnostic work up of AML.
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Cyclin D1 G870A Polymorphism: Relation to the Risk of ALL Development, Prognosis Impact, and Methotrexate Cytotoxicity.

BACKGROUND: Cyclin D1 (CCND1) regulates cell cycle progression during the late G1 and S phase and takes part in methotrexate metabolism. It was hypothesized that CCND1 gene polymorphism affects acute lymphoblastic leukemia (ALL) development, prognosis and may relate to methotrexate cytotoxicity. SUBJECTS AND METHODS: This study included 50 ALL patients and 50 healthy controls, CCND1 G870A polymorphism was studied in all items using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and evaluated methotrexate cytotoxicity for ALL patients using liver function tests before and after methotrexate treatment. We followed up patients for one year to determine disease-free survival (DFS) and overall survival (OS) and its relation to the CCND1 genotype. RESULTS: We found that AA genotype and A allele have a higher risk of developing ALL compared to the control group. Additionally, we found no notable association between CCND1 variant and methotrexate cytotoxicity and no role of CCND1 polymorphism in ALL prognosis. CONCLUSION: Our results suggested that CCND1 G870A polymorphism is associated with a high risk of ALL development. However, it has no role in ALL prognosis or methotrexate cytotoxicity.

Accurate automatic detection of acute lymphatic leukemia using a refined simple classification.

An improved classification technique is presented to identify automatically the acute lymphatic leukemia (ALL) subtypes. An adaptive segmentation procedure is performed on peripheral blood smear images to extract the main features (10 geometric features) from the segmented images of white blood cell (WBC), nucleus, and cytoplasm. To show the importance of the different extracted features for the diagnostic accuracy, a comprehensive study is made on all the possible permutation cases of the features using powerful classifiers which are K-nearest neighbor (KNN) at different metric functions, support vector machine (SVM) with different kernels, and artificial neural network (ANN). This procedure enables us to construct a feature map depending only on least number of features which lead to the highest diagnostic accuracy. It is found that the features map regarding the vacuoles in the cytoplasm and the regularity of the nucleus membrane gives the highest accurate results. The automatic classification for ALL subtypes based only on these two effective features is assessed using the receiver operating characteristic (ROC) curve and F1 -score measures. It is confirmed that the present technique is highly accurate, and saves the effort and time of training.

The prevalence and prognostic significance of autoimmune cytopenias in a cohort of Egyptian patients with chronic lymphocytic leukemia.

OBJECTIVE/BACKGROUND: The impact of autoimmune cytopenias (AICs) on the chronic lymphocytic leukemia (CLL) clinical course and its prognostic significance remain a matter of controversial debate. This could be due to exclusion of patients with cytopenia from most clinical trials for this particular complication and the lack of standard diagnostic criteria and treatment approaches. We herein evaluate the prevalence and the prognostic significance of AICs among patients with CLL. METHODS: This is an observational retrospective study. Data on 101 patients with CLL were derived from the Oncology Center, Mansoura University, Egypt, database, which contains information on demographic and clinical characteristics at diagnosis and follow-up records. RESULTS: The prevalence of immune cytopenias was 11.9% among patients studied. Autoimmune hemolytic anemia was the most common autoimmune form in patients with cytopenia due to pure immune etiology (C immune group) with a prevalence of 6.9%. Patients with AICs and those in the C immune subgroup presented with more unfavorable parameters. Besides, patients with AICs showed lesser response to treatment and on restaging after initial treatment, significantly more patients without AICs moved to a more favorable stage. However, no parallel significant difference in the overall survival was found between patients without AICs and those with AICs or with immune and combined or infiltrative cytopenia. CONCLUSION: We have shown a prevalence of 11.8% for AIC among our CLL patients. AIC was associated with unsatisfactory normalization of the hematological parameters even with therapy and lower number of patients with CLL downstaging in comparison with patients without AIC. These results suggest that AIC is a fingerprint of a biologically more aggressive disease even if no significant impact on overall survival was found.

Expression and prognostic significance of livin/BIRC7 in childhood acute lymphoblastic leukemia.

Livin, a member of the inhibitor of apoptosis proteins has been considered to be a poor prognostic marker in malignancies. However, little is known about the clinical relevance of livin expression in childhood acute lymphoblastic leukemia (ALL). The aim of the present study was to assess the expression of livin on leukemic blasts of de novo childhood ALL and its relevance to clinical and hematological findings, and treatment outcome. The expression of livin was analyzed in 80 patients with newly diagnosed childhood ALL using quantitative reverse transcriptase-polymerase chain reaction. The results of the study revealed that the expression levels of livin were higher in patients with favorable prognostic factors. Furthermore, livin expression was associated with a favorable early response to chemotherapy (leukemic blast <25% day 7 bone marrow response) (P = 0.001). Patients with high livin expression were associated with significantly higher CR rate (P = 0.02) and lower mortality rate (P = 0.05) than those with low livin expression. Kaplan-Meier curves demonstrated that high livin expression was associated with significantly longer DFS (P = 0.004) and overall survival (P = 0.02). Multivariate analysis demonstrated that livin expression was independent favorable prognostic factor for OS and DFS (P = 0.05 and P = 0.01, respectively). This study suggests that livin expression could be a novel prognostic marker in childhood ALL thus it could be incorporated into patient stratification and treatment protocols.

Prognostic implications of NPM1 mutations and FLT3 internal tandem duplications in Egyptian patients with cytogenetically normal acute myeloid leukemia.

Nucleophosmin (NPM1) and fms-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) gene mutations represent the most frequent molecular aberrations in patients with cytogenetically normal-acute myeloid leukemia (CN-AML). We analyzed the prognostic impact of these mutations and their interactions in adults with CN-AML. NPM1 mutation (NPM1mut) and FLT3-ITD mutation (FLT3-ITD+) were analyzed by polymerase chain reaction and GeneScan assays of bone marrow samples obtained from newly diagnosed 104 CN-AML patients. FLT3-ITD+ and NPM1mut were detected in 36 (34.6%) and 30 (28.8%) out of 104 subjects, respectively, 16 cases (15.4%) had double NPM1mut/FLT3-ITD+. The incidence of FLT3-ITD+ was significantly higher in the NPM1mut group than in the NPM1 wild (NPM1wt) group (P = 0.018). Statistical analysis revealed that isolated NPM1mut group had a better clinical outcomes in terms of higher complete response (CR) rate (P = 0.01) and a trend towards favorable overall survival (OS) and disease-free survival (DFS) (P = 0.28, 0.40, respectively). In contrast, the isolated FLT3-ITD+ group had an unfavorable outcome in terms of lower CR rate (P = 0.12), shorter OS, and DFS (P < 0.0001 for both). The NPM1mut/FLT3-ITD-group had the best OS and DFS, while the NPM1wt/FLT3-ITD+ group had the worst OS and DFS than other groups (NPM1mut/FLT3-ITD+ or NPM1wt/FLT3-ITD-) (P < 0.0001 for both). Multivariate Cox regression analysis showed that age and FLT3/ITD+ were independent poor prognostic factors for OS (P = 0.006, <0.0001, respectively), while FLT3/ITD+ was independent predictor for DFS (P = 0.04). However, NPM1mut did not have a significant impact on OS and DFS. In conclusion, adult patients with CN-AML carrying isolated NPM1mut and isolated FLT3-ITD+ exhibit different clinical outcomes than those with NPM1mut/FLT3-ITD+ or NPM1wt/FLT3-ITD-. Patients with NPM1mut/FLT3-ITD- had the best prognosis in terms of higher CR, OS, and DFS, while those with NPM1mut/FLT3-ITD+ had the worst CR rate, and NPM1wt/FLT3-ITD+ had the lowest OS and DFS.

CEBPA gene mutations in Egyptian acute myeloid leukemia patients: impact on prognosis.

AIM: To assess the prognostic role of myeloid transcription factor gene CEBPA (CCAAT/enhancer binding protein-α), a novel gene involved in leukemia in Egyptian adults AML. MATERIALS AND METHODS: Screening for CEBPA mutations was assessed using PCR-single-strand conformation polymorphism (PCR-SSCP) in pretreatment bone marrow samples from 55 newly diagnosed adult AML. RESULTS: CEBPA mutations were found in 11 (20%) of 55 AML patients. They had significantly higher hemoglobin (P = 0.037), and lower LDH (P = 0.003) levels when compared to those without. CEBPA mutations were frequently detected in M4 (45.5%) and M2 (27.2%) subtypes, and significantly associated with normal karyotype (90.9%, P = 0.007). We distinguished six cases with two different mutations or one homozygous mutation (CEBPA(double-mut)) as well as five cases with only one single heterozygous mutation (CEBPA(single-mut)). Patients with CEBPA mutations had significantly higher complete remission (P = 0.047), lower mortality (p = 0.047). Double CEBPA mutant cases showed longer disease free survival (DFS) and overall survival (OS) when compared to wild type CEBPA (for DFS; median = 27 versus 24 months respectively; P = 0.009 and for OS; median = 28 versus 25 months respectively; p = 0.008). No significant differences were found between CEBPA(single-mut) cases and wild type cases regarding DFS and OS (for DFS; median = 13 versus 24 months respectively; P = 0.615 and for OS; median = 14 versus 25 months respectively; P = 0.703). CONCLUSION: CEBPA mutation status is known to be a prognostic factor for favorable outcome in AML patients. CEBPA(double-mut) is associated with favorable DFS and OS. In contrast, CEBPA(single-mut) AMLs survival studies did not differ significantly with wild-type cases. These results demonstrate significant underlying heterogeneity within CEBPA mutation positive AML with prognostic relevance. Based on these findings, we propose that CEBPA(double-mut) should be clearly defined from CEBPA(single-mut) AML and considered as a separate entity in the classification of AML. Furthermore, incorporation of CEBPA mutation status into novel risk-adapted therapeutic strategies in Egypt will improve the currently disappointing cure rate of this group of patients.

A study for evaluation of different diagnostic approaches in acute leukemia in Egypt.

Cytomorphology, cytochemistry, immunophenotyping, in addition to cytogenetic and molecular analyses have specific roles in the diagnosis and management of acute leukemias. This work was designed as a comparative study of different available methods for diagnosis of acute leukemia. The study comprised 47 cases with acute leukemia (21 cases with ALL and 26 cases with AML). Peripheral blood and bone marrow samples were subjected to through morphological examination of Leishman-stained smears, cytochemical analysis, immunophenotyping, conventional cytogenetic banding analysis, fluorescence in situ hybridization (FISH) for selected cases, and RT-PCR for detection of BCR-ABL rearrangement. The results of the study revealed that careful examination of Romanowsky-stained peripheral blood and BM films is fundamental in the diagnosis of acute leukemias, and when considered together with clinical and hematological features, indicates which of the more specialized techniques are most likely to be useful. The major role of cytochemistry was in the diagnosis of AML, while the major role of immunophenotyping was in the diagnosis of acute leukemia, which is not obviously myeloid. Apart from identification of chromosomal abnormalities unique to specific subtypes of leukemia, cytogenetic analysis had a salient impact on anticipating the prognosis and treatment outcome in acute leukemias. We could conclude that the techniques used in this study are considered complementary rather than alternatives and that stepwise employment of strategies is more cost effective than doing all the tests simultaneously.

P-glycoprotein (P-170) expression in acute leukemias.

Multidrug resistance (MDR) is still a major obstacle to chemotherapy success in acute myeloid leukemia (AML) and to a less extent acute lymphoblastic leukemia (ALL). Recent studies have shown that the expression of certain gene products mediate the development of resistance to chemotherapeutic agents. The most well characterized of these genes is the multidrug resistance gene MDR-1. This study was planned to study the expression of P-glycoprotein/170 in patients with acute leukemia and the effect of Cyclosporin A (CSA) as a modulator of P-glycoprotein functional activity. The study was carried out on 20 patients with acute leukemia (14 AML cases and 6 ALL cases). In addition, 6 normal individuals served as a reference group. Flow cytometric analysis of P-gp/170 surface expression was performed using UIC-2 MoAb together with the functional assay using Rhodamine 123 (Rh 123) and Cyclosporin A as a modulator.P-gp/170 was expressed on the leukemic cells of 37.5% of relapsed patients (40.0% of AML and 33.3% of ALL cases), whereas 27.2% of de novo patients expressed P-gp/170 (33.3% of AML cases and 0% of ALL cases). The functional activity of MDR-1 gp was 71.4% in AML and 33.3% in ALL patients compared with16.6% in normal lymphocytes. From this study, it is clear that P-gp/170 is expressed to a higher degree in leukemic cells and this is greater in relapsed compared to de novo cases and more in AML than ALL blasts. Functional activity is a more sensitive predictor of chemoresistance than P-gp/170 surface expression.