Associations of interleukin-10 gene polymorphisms with acute myeloid leukemia in human (Egypt).

BACKGROUND: Acute myeloid leukemia (AML) is a cytogenetically and molecularly heterogeneous diseases, and characterization of transforming genetic events is becoming increasingly important. Interleukins (ILs) are a diverse set of small cell signaling protein molecules. Single nucleotide polymorphisms (SNPs) of ILs alter their function, increasing susceptibility to different diseases. PATIENTS AND METHODS: We investigated the association between polymorphism in IL-10 -819T/C (rs1800871) and the risk of AML in the Egyptian population. DNA was isolated from bone marrow of 80 newly diagnosed adult AML patients, and 85 age- and sex-matched controls. Genetic analysis of IL-10 SNPs at -819T/C was assayed by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: Genetic analysis of IL-10 revealed that the Egyptians have high -819T allele frequencies in apparently healthy controls, whereas -819CC genotype and the -819C allele frequencies in the AML group were higher than in the controls (P = 0.000086). The study suggested that subjects carrying the rs1800871CC genotype and C allele had a significantly increased risk for AML. CONCLUSION: IL-10 SNP at -819 was associated with enhanced AML risk, suggesting that rs1800871 provides clue for future studies and early detection of AML.

The Meningioma 1 (MN1) Gene is an Independent Poor Prognostic Factor in Adult Egyptian Acute Myeloid Leukemia Patients

Aim: To determine the prognostic importance of meningioma 1 (MN1) gene expression levels in the context of other predictive markers for acute myeloid leukemia (AML) cases. Methods: MN1 expression was measured in 85 newly diagnosed adults younger than 60 years by real-time reverse-transcriptase polymerase chain reaction. Results: At diagnosis 67.4% of cases had elevated MN1 expression, this being associated with a worse prognosis, higher incidence of lymphadenopathy and CD34 transcript expression (p=0.02 and <0.001, respectively). No other molecular or clinical characteristics were significantly associated with MN1expression. Patients with high MN1 expression had lower complete response rate at day 15 compared to patients with low MN1 expression (p=0.09) and a significantly higher relapse rate (21.1% versus 7.7%, respectively, p=0.04). Patients with high MN1 expression had shorter TTP compared to those with low expression, p= 0.07. Conclusion: MN1 expression may predict outcome in AML patients. The MN1 gene and micro RNA expression suggest a biological feature that could be used as therapeutic targets.

Association of CYP3A5*3 and CYP1A1*2C Polymorphism with Development of Acute Myeloid Leukemia in Egyptian Patients

Aim: Cytochrome P450 (CYP) enzyme catalyzes the phase I metabolism reaction which metabolize endogenous and exogenous DNA-reactive chemical compounds and xenobiotics which could induce genotoxicity and increase the risk for leukemia. We aimed to detect frequency of CYP3A5*3 and CYP1A1*2C polymorphisms in Egyptian acute myeloid leukemia (AML) patients and to determine role of allele's variants as a risk factor for developing leukemia. Patients and Methods: A case-control study was conducted on seventy acute myeloid leukemia patients and thirty control subjects. Samples were analyzed for prevalence of CYP3A5*3 and CYP1A1*2C polymorphisms using PCR - restriction fragment length polymorphism method. Results: CYP3A5*3 polymorphism (3/3) and (1/3) genotype were significantly elevated in AML group compared to control group (p=0.002). However, no statistical significant differences were found between patients and control group as regard CYP1A1*2C polymorphism. Conclusion: Our results suggest that Egyptians carrying CYP3A5*3 polymorphism might have an increased risk of AML emphasizing the significance of effective phase I detoxification in carcinogenesis.

Prognostic Value of a CYP2B6 Gene Polymorphism in Patients with Acute Myeloid Leukemia.

BACKGROUND: The objectives of this study aimed to detect a CYP2B6 polymorphism in de novo cases of acute myeloid leukemia patients and identify any role in disease progression and outcome. MATERIALS AND METHODS: DNA was isolated from peripheral blood of 82 newly diagnosed acute myeloid leukemia cases and the CYP2B6 G15631T gene polymorphism was assayed by PCR restriction fragment length polymorphism (PCR-RFLP). RESULTS: The frequency of the GG genotype (wild type) was 48 (58.5%) and that of the mutant type T allele was 34 (41.9%). GT genotype heterozygous variants were found in 28 (34%), and TT genotype homozygous variants in 6 (7.3%) cases. We found no significant association between the CYP2B6 G15631T polymorphism and complete response (CR) (p-value=0.768), FAB classification (p-value=0.51), cytogenetic analysis (p-value=0.673), and overall survival (p-value=0.325). Also, there were no significant links with early toxic death (p-value=0.92) or progression- free survival (PFS) (p-value=0.245). CONCLUSIONS: Our results suggest that the CYP2B6 polymorphism has no role in disease progression, therapeutic outcome, patient free survival, early toxic death and overall survival in acute myeloid leukemia patients.

Gemcitabine and cisplatin as neoadjuvant chemotherapy for invasive transitional and squamous cell carcinoma of the bladder: effect on survival and bladder preservation.

BACKGROUND: Despite aggressive local therapy, patients with locally advanced bladder cancer have a significant risk of distant metastases. This study evaluated the role of neoadjuvant combination chemotherapy with gemcitabine/cisplatin (GC) in improving the outcome of this group of patients over radical cystectomy alone. PATIENTS AND METHODS: A total of 114 patients with newly diagnosed bladder cancer (T3-4, N0-2, M0) were randomized to radical cystectomy alone or initial 3 cycles of GC, then managed according to response. Patients who achieved complete response completed 6 cycles of GC followed by local radiation therapy (RT) only. If tumors were downstaged to T1, complete transurethral resection was done, followed by 3 cycles of GC and then RT. Patients with partial response underwent radical cystectomy followed by 3 cycles of GC. Patients with stable disease or disease progression underwent radical cystectomy. RESULTS: The overall response rate to GC was 55.1%, and complete response was achieved in 28.6%. The 3-year overall survival (OS) was 51.9% versus 51.2% in the chemotherapy and surgery arms, respectively (P = .399). The 3-year disease-free survival was 31.8% in the chemotherapy arm and 45.1% in the surgery arm (P = .06). Bladder preservation was achieved in 22.5% of patients in the neoadjuvant arm. OS was 78% in responding patients and 100% in patients with complete response. CONCLUSION: Neoadjuvant GC did not improve survival in locally advanced bladder cancer over radical cystectomy alone. However, bladder preservation was feasible, and OS in responding patients was impressive. Therefore, predictive models to select patients are needed. This is the largest prospective study of squamous cell carcinoma and transitional cell carcinoma using neoadjuvant GC.

Impact of PIVKA-II in diagnosis of hepatocellular carcinoma.

Liver cancer grows silently with mild or no symptoms until advanced. In the absence of an effective treatment for advanced stage of hepatic cancer hope lies in early detection, and screening for high-risk population. Among Egyptians viral hepatitis is the most common risk factor for hepatocellular carcinoma (HCC). The current work was designed to determine the level of prothrombin induced by vitamin K absence-II (PIVKA-II) in sera of patients suffering from HCC and hepatitis C virus (HCV) patients being the most common predisposing factor for HCC. Our ultimate goal is diagnosis of HCC at its early stage. The current study was carried out on 83 individuals within three groups; Normal control, HCV and HCC groups. Patients were subdivided into cirrhotic and non-cirrhotic. Complete clinicopathological examination was carried out for each individual to confirm diagnosis. Individuals' sera were subjected to quantitative determination of alpha-fetoprotein (AFP), PIVKA-II and other parameters. PIVKA-II proved to be superior to AFP for early detection of HCC patients being highly sensitive and specific. Furthermore it has the ability to discriminate between different histopathological grades of HCC and It has a powerful diagnostic validity to evaluate the thrombosis of portal vein and to differentiate between early and late stages of HCC. The direct relation between the level of PIVKA-II and the size of tumor makes it an attractive tool for early HCC diagnosis and surveillance. Using the best cut-off value of AFP (>28), showed a sensitivity of (44%) and specificity of (73.3%). While cut-off value of PIVKA-II (>53.7) showed 100% sensitivity and specificity.

CA 125, a New Prognostic Marker for Aggressive NHL.

PURPOSE: CA 125 was evaluated in the sera of patients with aggressive NHL, together with LDH and ß2m, in a trial to assess its value in the diagnosis and follow-up, and to compare it to some prognostic factors. SUBJECTS AND METHODS: The study included 78 newly diagnosed patients with diffuse large B cell non-Hodgkin's lymphoma (DLBCL), with age range 18-60 years, and a WHO performance status of 0, I or II, in addition to twenty apparently healthy controls. All patients received CHOP regimen for 6 cycles. RESULTS: The levels of CA 125 and LDH were significantly higher in DLBCL compared to the control group (p-value = 0.031 and = 0.009, respectively). Cutoff levels used were 20U/ml, 310 U/L, and 2mg/l for CA125, LDH and ß2m, respectively. CA125 serum level was high in 55%, LDH level in 72%, and ß2m level in 62% of patients. As regards the stage, CA 125 was elevated in 17%, 52%, 80%, and 100% of patients in stage I, II, III, and IV, respectively. CA 125 was elevated in 81.3% of patients with bulky disease, in 83.3% presenting with involvement of more than 1 extranodal site, and in 90% presenting with effusion. The highest levels of CA125, LDH, and ß2m were observed in stage IV, and lowest in stage I (p-value<0.001, 0.005, and 0.154, respectively). There was also a significant positive correlation between CA 125 and LDH (p-value <0.001). CA 125 showed specificity of 80% with 95% CI (56- 94), and LDH showed sensitivity of 72% with 95% CI (60-81). Complete response to treatment was achieved in 71.8% of our patients. Survival at 24 months was 78.2%. There was a statistically significant increase in survival in patients with CA125<20U/ml, patients with LDH<310U/L, and patients with ß2m<2mg/l (p-value = 0.006, 0.025, and 0.042, respectively). A shorter disease-free survival was associated with increased CA 125 (p<0.001). CONCLUSION: CA125 was found to correlate with stage, tumor bulk, involvement of more than 1 extranodal site, and presence of effusion. Elevated levels of CA 125 and LDH were found to predict decreased survival. Initial measurement of CA125 may, therefore, provide valuable prognostic information. KEY WORDS: CA125 - LDH - ß2m, NHL - DLBCL.