Implications of Glutathione Peroxidase 3 Expression in a Cohort of Egyptian Patients with Acute Myeloid Leukemia.

BACKGROUND: The impact of low expression of Glutathione peroxidase 3 (GPX3) on the clinical course of acute myeloid leukemia (AML) is poorly investigated. AIMS: To explore the status of GPX3 expression and analyze its clinical characteristics and prognosis in a cohort of Egyptian patients with AML. METHODS: GPX3 mRNA level was assessed by RT-q PCR in 40 newly diagnosed AML patients and 10 healthy controls. RESULTS: The gene expression level was significantly lower in AML patients than the control group (P < 0.001). A cut off value (0.1223) for the discrimination between AML and controls was obtained by ROC curve. According to this cutoff value; the patients were reassigned into 2 groups; 28 patients with lower GPX3 expression and 12 patients with high GPX3 expression. GPX3low expression was significantly associated with higher incidence of induction death (P= 0.037) and lower CR rate (P=0.048). Moreover, GPX3low expression was significantly associated with shorter cumulative 1-year overall survival (OS) (P = 0.001) and disease-free survival (DFS) (P=0.028). CONCLUSION: GPX3low expression status is considered a poor prognostic factor in AML predicting shorter OS and DFS. The study highlights the importance of targeting glutathione metabolism as a central component of the anti-leukemia therapy.

Multidetector computed tomography evaluation of synchronous lymphoma and other solid malignancies.

OBJECTIVE: The objective of this study is to review the multidetector computed tomography (MDCT) findings of synchronous lymphoma and other solid malignancies. PATIENTS AND METHODS: This retrospective study included 18 patients confirmed with diagnosis of lymphoma and other solid malignancies. They were 8 women and 10 men (mean age, 62.5 year; range, 44-73 years). CT scanning was performed on one of the two systems: 64 MDCT in 11 patients and 6 MDCT in 7 patients. All 36 malignancies were underwent pathological evaluation. RESULTS: All cases were confirmed pathologically. Lymphomas were Hodgkin disease ( n = 5 patients) and non-Hodgkin lymphoma ( n = 13 patients). Hepatocellular carcinoma was detected in five patients. Bronchogenic carcinoma was detected in two patients. Renal cell carcinoma was detected in two patients. Breast carcinoma was detected in two patients. Prostatic carcinoma was detected in two patients. Gastric carcinoma was detected in two patients. Endometrial carcinoma was detected in one patient. Colonic carcinoma was detected in one patient. Thyroid carcinoma was detected in one patient. CONCLUSIONS: MDCT scanning is accurately imaging modality for the evaluation of synchronous lymphoma and other solid malignancies. More reports and accumulation of such cases should help to clarify the mechanisms, contribute to a further understanding of this phenomenon, and may lead to a new treatment strategy for synchronous lymphoma and other solid malignancies.

Prognostic Significance of Absolute Lymphocyte Count, Absolute Monocyte Count, and Absolute Lymphocyte Count to Absolute Monocyte Count Ratio in Follicular Non-Hodgkin Lymphoma.

INTRODUCTION: Recently, the lymphocyte to monocyte ratio (LMR) has been proposed as an easily determinable prognostic factor in patients with cancer, including lymphomas. The objective of this study was the evaluation of the impact of baseline absolute lymphocyte count (ALC), absolute monocyte count (AMC), and the LMR on the treatment response and prognosis in follicular lymphoma (FL). PATIENTS AND METHODS: The data of 100 patients with a FL variant, admitted and treated between January 2009 and June 2018, were analyzed. RESULTS: The area under the receiver operator characteristic curve and cutoff values of ALC, AMC, and LMR for discrimination between survival times using receiver operating characteristic curves showed 0.57 × 109/L as the most discriminative ALC cutoff value, 1.235 ×109/L as the most discriminative AMC cutoff value, and 1.63 as the most discriminative LMR cutoff value. Progressive disease and stable disease after first-line therapy and mortality rate were significantly associated with lower ALC, higher AMC, and higher LMR. Shorter overall survival (OS) was significantly associated with patients with lower ALC when compared with those having higher ALC. Shorter OS and progression-free survival (PFS) were significantly associated with higher AMC when compared with those having lower AMC. Shorter OS and PFS were significantly associated with lower LMR when compared with those having higher LMR. High-risk Follicular Lymphoma International Prognostic Index as well as low LMR were considered as risk factors for prediction of OS in all the studied patients with FL in univariate analysis and multivariate analysis. CONCLUSION: ALC, AMC, and LMR at diagnosis are simple indices, which reflect the host systemic immunity and can predict the clinical outcomes in FL.

Unusual behavior of diffuse large B-cell lymphoma as cardiac invasion with rapid spontaneous regression after fine needle aspiration cytology.

OBJECTIVE: Spontaneous regression (SR) of lymphoma is a rare phenomenon. While the precise mechanism of SR remains unknown, apoptosis may be associated with its process. Here, we present a case of a 52-year-old woman was admitted to our hospital with cough and orthopnea for 2 weeks. Multi-detector computed tomography of whole body showed anterior and middle mediastinal soft tissue mass with multiple adjacent malignant lymphadenopathy. The mediastinal mass invaded right atrium and pericardium. Another left subphrenic retro-pancreatic mass was detected. This mass surrounded upper pole of left kidney. Fine needle aspiration cytology was done and revealed lymphocytic smear with advised tru-cut biopsy. CT guided tru-cut was taken after 8 days. During CT guided technique; marked regression of left subphrenic mass was detected. Post-contrast MDCT scan was done and revealed partial response of the masses after 8 days. The partial regressive course of this disease suggests the effectiveness of fine needle aspiration cytology in initiating spontaneous regression. Tru-cut biopsy revealed non-Hodgkin lymphoma (diffuse large B-cell type). We report a case of NHL with abnormal location and spontaneous regression.

Prevalence and Prognostic Impact of CEBPA Gene Mutation (Simplified Assay Technique) in Egyptian Acute Myeloid Leukemia Patients with Normal Cytogenetics.

Mutations of the CCAAT/enhancer binding protein alpha (CEBPA) gene have been associated with a favorable outcome in patients with acute myeloid leukemia (AML), especially in those with a normal cytogenetics. However, few studies were done on Egyptian AML patients and none of them look for easier and less expensive method for CEBPA mutation screening. This study is aimed to investigate the prevalence of CEBPA mutations and its clinical and prognostic impact in Egyptian patients with cytogenetically normal AML (CN-AML). This was done using fragment analysis to assess this method as a cheaper and less laborious screening method compared to sequencing. Fluorescent PCR was done to amplify CEBPA gene in DNA extracted from 40 CN-AML patients. This was followed by fragment analysis of post-PCR products using GeneMapper software for detection of CEBPA mutations. CEBPA gene mutations were found in 7/40 CN-AML patients (17.5 %) and it was significantly associated with lower LDH levels (p = 0.039). All patients with CEBPA mutations achieved clinical remission and none of them showed refractoriness, relapsed, or died by the end of the 2 years study period. Furthermore, those patients demonstrate significantly longer overall and disease free survival than those with wild type CEBPA gene (p = 0.001 and 0.004 respectively). CEBPA mutation has a favorable prognostic impact in CN-AML. Fragment analysis is a good, lees laborious and cheaper method that can be used for CEBPA mutation screening in patients with CN-AML.

High expression of LMO2 predicts a favorable outcome in adult patients with BCR/ABL negative B-cell acute lymphoblastic leukemia.

The LIM domain only protein 2 (LMO2) is a key regulator of hematopoietic stem cell development. Expression of LMO2 has been evaluated in B-cell lymphoma, T-cell acute lymphoblastic leukemia and acute myeloid leukemia; however, information concerning its role in breakpoint cluster region/Abelson murine leukemia viral oncogene homolog 1 (BCR/ABL) negative B-cell acute lymphoblastic leukemia (B-ALL) remains limited. The present study investigated LMO2 expression using quantitative polymerase chain reaction in 85 adult patients with BCR/ABL negative B-ALL, and associated the expression of LMO2 with established prognostic factors. LMO2 expression levels in patients with BCR/ABL negative B-ALL was not significantly different compared with control individuals (P=0.25). However, LMO2 expression levels were associated with the immunophenotypical features of the patients; a high LMO2 expression was associated with a higher incidence of complete remission (P=0.03) and lower rate of relapse (P=0.01), and patients with a high LMO2 expression had a significantly improved overall survival rate (P=0.01) and disease-free survival (P=0.01). The present results suggest that LMO2 expression is a favorable prognostic marker in adult patients with BCR/ABL negative B-ALL and may be used as a diagnostic marker and therapeutic target. However, additional studies regarding its prognostic role in patients with BCR/ABL negative B-ALL are required.

Prognostic Significance of Secreted Frizzled-Related Protein 2 Expression in Cytogenetically Normal Primary Acute Myeloid Leukemia.

BACKGROUND: Deregulation of secreted frizzled-related protein 2 (sFRP2) has been found in many types of cancer. However, the pattern of sFRP2 expression in acute myeloid leukemia (AML) is still unclear. METHODS: This study aimed to validate the prognostic significance of sFRP2 expression in 54 older patients with cytogenetic normal acute myeloid leukemia (CN-AML) using real-time quantitative polymerase chain reaction. RESULTS: sFRP2 expression was decreased markedly in patients compared with controls (P < 0.001). No correlation was found between sFRP2 gene expression and WBCs, hemoglobin, platelets, FAB type, NMP1 and FLT3/ITD mutations at diagnosis. All patients were treated with standard induction chemotherapy. Patients with high sFRP2 expression had higher incidence of complete remission rate (P = 0.04) and better overall survival (P = 0.026). Multivariate analysis revealed that high sFRP2 expression was a prognostic factor for older patients with CN-AML. CONCLUSIONS: This study demonstrated that sFRP2 gene expression at diagnosis had an impact on outcome of elderly CN-AML patients.

Influence of interleukin-15 polymorphism on the survival of adult patients with acute lymphoblastic leukemia in Egypt.

The aim of this study was to analyze the association of the rs10519612 and rs17007695 polymorphisms with the risk of acute lymphoblastic leukemia (ALL) and also to evaluate their impact on the survival of adult patients with ALL. The study included 164 adult patients with ALL and 158 healthy subjects as a control group who were genotyped for the interleukin-15 (IL-15) gene using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. We observed a higher risk of developing ALL for rs10519612 CC, rs17007695 TC and rs17007695 CC genotype carriers. There was increased risk for T-cell type in patients with the rs10519612 CC genotype. Notably, increased risk to develop B-cell type was found with rs17007695 TC and CC genotypes. There was no impact on overall survival or disease-free survival at 3 years. It is concluded that there is an association between both gene polymorphisms and the risk of ALL and with disease immunophenotype. However, there was no impact on the outcome of patients.

MTHFR A1298C and C677T gene polymorphisms and susceptibility to chronic myeloid leukemia in Egypt.

Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme regulating the intracellular folate metabolism which plays an important role in carcinogenesis through DNA methylation. We aimed to evaluate the association between MTHFR A1298C and C677T polymorphisms and the risks of chronic myeloid leukemia (CML). Eighty-five patients with CML and a control group containing 100 healthy, age and sex matched individuals were examined for MTHFR C677T and A1298C polymorphisms using polymerase chain reaction-restriction fragment-length (PCR-RFLP) method. The frequency of 677TT genotype in patients with CML was significantly higher compared to controls (OR=2.513, 95% CI: 0.722-4.086, P=0.025). No such association was shown for heterozygous 677CT (OR=1.010, 95% CI: 0.460-2.218, P=0.981). Moreover, for A1298C genotype, a statistically significant higher frequency of 1298CC was also detected in CML patients compared to control group (OR=1.1816, 95% CI: 0.952-3.573, P=0.036), 0.036). No such statistical significance was demonstrable for heterozygote 1298AC (OR=1.046, 95% CI: 0.740-1.759, P=0.092). In addition, patients with joint 677CT/1298AC or 677TT/1298CC genotypes showed an association with increased risk of CML (OR=1.849, 95% CI: 0.935-2.540, P=0.024; OR=1.915, 95% CI: 1.202-3.845, P=0.020 respectively). .A statistically significant increased risk of resistant to therapy was observed with 677CT and 1298AC genotypes (P=0.001, P=0.002 respectively). We conclude that both MTHFR 677TT and 1298CC polymorphisms have been associated with risk of CML and both 677CT and 1298AC genotypes are associated with higher risk of resistant to therapy.

DNMT3A R882 mutations in patients with cytogenetically normal acute myeloid leukemia and myelodysplastic syndrome.

Several molecular markers have been described that help to classify patients with acute myeloid leukemia (AML), a heterogeneous hematopoietic tissue neoplasm, into risk groups. We determined the frequency of DNMT3A mutations, their associations with clinical and molecular characteristics and outcome, in primary, cytogenetically-normal AML (CN-AML) and CN-myelodysplastic syndrome (MDS). A total of 63 CN-AML and 16 CN-MDS patients were analyzed for mutations in DNMT3A, codon R822 by direct sequencing and mutation of NPM1 and FLT3/ITD. DNMT3A mutations were found in 17/63 (27%) of CN-AML and in 1/16 (6.3%) of CN-MDS patients. Patients with DNMT3A mutations were older (p=0.047), had higher white blood cell (WBC) counts (p=0.046), more often belonged to FAB groups M4 and M5 (p=0.017), and were more associated with NPM1 mutations (p=0.017), than those with wild-type DNMT3A. DNMT3A-mutated patients had shorter overall disease survival (p<0.001) and disease-free survival (p=0.014) when the entire patient cohort was considered, which remained significant in multivariate analysis. We conclude that DNMT3A R882 mutations are recurrent molecular aberrations in CN-AML, less frequent in CN-MDS, and that testing for R882 mutations may provide a useful tool for refining risk classification of CN-AML.

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.