Spectrum of EGFR gene mutations and ALK rearrangements in lung cancer patients in Turkey.

The EGFR gene and ALK rearrangements are two genetic drivers of non-small cell lung cancer (NSCLC). The frequency of EGFR mutations and ALK rearrangement varies according to not only ethnicity but also gender, smoking status and the histological type of NSCLC. In the present study, we demonstrated the distribution of EGFR mutations in 132 NSCLC patients by using a pyrosequencing technique and the distribution of ALK rearrangements in 51 NSCLC patients by using fluorescent in situ hybridization technique in Turkey. Additionally, we compared the clinicopathological data of NSCLC patients with the mutation status of EGFR in their cancerous tissues. Both EGFR mutations and ALK rearrangements were identified in 19 (14.39 %) and 1 (1.96 %) patients, respectively. We found EGFR mutations in codon 861, 719 and 858 with the ratios of 10.52 % (2/19), 10.52 % (2/19) and 31.58 % (6/19), respectively, and deletion of exon 19 in 47.37 % (9/19) of the patients. We found the frequency of EGFR mutations to be significantly higher in female patients and nonsmokers (p = 0.043, p = 0.027, respectively). Consequently, we found EGFR mutations to be more frequent in female patients and nonsmokers. Future studies on larger patient groups would provide more accurate data to exhibit the relationship between EGFR mutations and ALK rearrangements and the clinicopathological status.

Qualitative and quantitative evaluation of the BCR-ABL fusion gene in chronic myelogenous leukemia by flourescence in situ hybridization and molecular genetic methods.

AIMS: Fluorescence in situ hybridization (FISH) and quantitative real-time polymerase chain reaction (QRT-PCR) were used to diagnose or screen for minimal residual disease (MRD) in Philadelphia (Ph) chromosome-positive leukemia. We compared the diagnostic utility of FISH and QRT-PCR at various time points in the course of chronic myelogenous leukemia (CML) and to determine the mean initial values for patients whose QRT-PCR results were not known at the time of diagnosis. RESULTS: We analyzed 135 results for 78 CML patients tested by FISH and QRT-PCR for the Ph chromosomal translocation. All newly diagnosed cases were positive by both methods. On follow-up following treatment, 1 case was FISH positive and QRT-PCR negative; 61 cases were FISH negative and QRT-PCR positive. Overall concordance was 54.1%. There was good concordance between QRT-PCR results and cytogenetic response categories. CONCLUSIONS: We confirmed that QRT-PCR allows precise measurement of low levels of BCR-ABL transcripts and can serve as a sensitive indicator of MRD. We also demonstrated 100% correlation between QRT-PCR and FISH in newly diagnosed CML.

Association of the ACE I/D gene polymorphisms with JAK2V617F-positive polycythemia vera and essential thrombocythemia.

The renin-angiotensin system contributes to cell growth, proliferation, and differentiation in the bone marrow. We investigated the role of the ACE I/D gene polymorphism in 108 polycythemia vera (PV) and essential thrombocytosis (ET) patients who were positive for the JAK2V617F mutation, with a thrombosis group (TG) of 95 patients who had a history of vascular events, but did not have a history of myeloproliferative neoplasms and compared these to a healthy control group (CG) of 72 subjects. In the patients, II genotype and I allele frequency (p=0.009, odds ratio [OR]=9.716, 95% confidence interval [CI]=1.242-76.00, p=0.004, OR=2.019, 95% CI=1.243-3.280, respectively) were found to be higher than those in the controls. The DD genotype (p=0.021, OR=0.491, 95% CI=0.268-0.899) and D allele (p=0.004, OR=0.495, 95% CI=0.305-0.805) were found to be correlated with a decreased risk of a myeloproliferative neoplasm. These findings support the hypothesis that the ACE II genotype and I allele may be related to increased risk of ET and PV. Conversely, the DD genotype and D allele may be related to decreased risk of ET and PV. The results also indicated that the ACE I/D gene polymorphism was independent of thrombosis formation.

MMP2 gene-735 C/T and MMP9 gene -1562 C/T polymorphisms in JAK2V617F positive myeloproliferative disorders.

BACKGROUND: Myeloproliferative disorders (MPDs) are clonal hematologic malignancies originating at the level of the pluripotent hematopoietic stem cell. Matrix metalloproteases (MMPs) are proteolytic enzymes that contribute to all stages of malignancy progression. Genetic variants in the MMP genes may influence the biological function of these enzymes and change their role in carcinogenesis and progression. To our knowledge, this is the first investigation of associations between the -735 C/T and -1562 C/T polymorphisms in the MMP2 and MMP9 genes, respectively, and the risk of essential thrombocytosis (ET), and polycythemia vera (PV). MATERIALS AND METHODS: The case-control study included JAK2V617F mutation positive 102 ET and PV patients and 111 controls. Polymorphisms were determined by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and electrophoresis. RESULTS: No statistically significant differences were detected between patient (ET+PV) and control groups regarding genotype distribution for MMP2 gene-735 C/T and MMP9 gene -1562 C/T polymorphisms and C/T allele frequency (p>0.050). Statistically borderline significance was observed between PV and control groups regarding genotype distribution for the MMP9 gene -1562 C/T polymorphism (p=0.050, OR=2.26, 95%Cl=0.99-5.16). CONCLUSIONS: Consequently this study supported that CC genotype of MMP9 gene -1562 C/T polymorphism may be related with PV even if with borderline significance.

Lack of genotoxicity in medical oncology nurses handling antineoplastic drugs: effect of work environment and protective equipment.

OBJECTIVE: In this study we aimed to investigate the genotoxic effects of antineoplastic agents in occupationally exposed oncology nurses. Genotoxic effects mean the disruptive effects in the integrity of DNA and they are associated with cancer development. Biomonitoring of health care workers handling antineoplastic agents is helpful for the evaluation of exposure to cytostatics. PARTICIPANTS: The study included an exposed and two control groups. The exposed group (n=9) was comprised of oncology nurses. The first (n=9) and second (n=10) control groups were comprised of subjects who did not come into contact with antineoplastic drugs working respectively in the same department with oncology nurses and in different departments. METHODS: Genotoxicity evaluation was performed using SCE analysis. After applying culture, harvest and chromosome staining procedures, a total of 25 metaphases were analyzed per person. Kruskal Wallis test was used to perform statistical analysis. RESULT: A statistically significant difference of sister chromatid exchange frequencies was not observed between the exposed and control groups. CONCLUSION: Lack of genotoxicity in medical oncology nurses might be due to good working conditions with high standards of technical equipment and improved personal protection.

Novel TSHR mutations in consanguineous families with congenital nongoitrous hypothyroidism.

OBJECTIVE: Nonsyndromic autosomal recessively inherited nongoitrous congenital hypothyroidism (CHNG) can be caused by mutations in TSHR, PAX8, TSHB and NKX2-5. We aimed to investigate mutational frequencies of these genes and genotype/phenotype correlations in consanguineous families with CHNG. DESIGN: Because consanguinity in individuals with a presumptive genetic condition is often an indicator of an autosomal recessive inheritance and allows firmer correlations to be established between genotype and phenotype, we planned to execute our study in consanguineous families. PATIENTS: Hundred and thirty-nine children with CHNG phenotype born to consanguineous families. MEASUREMENTS: First, we investigated cases for evidence of linkage to the four known CHNG genes by microsatellite marker analysis. Mutation analysis by direct sequencing was then performed in those cases in whom linkage to the relevant candidate gene could not be excluded. In addition, in silico analysis of the predicted structural effects of TSHR mutations was performed and related to the mutation-specific disease phenotype. RESULTS: Homozygous germline TSHR mutations were detected in six families (5%), but no mutations were detected in PAX8, TSHB and NKX2-5. Four of TSHR mutations had not previously been described. Genotype-phenotype correlations were established and found to be related to the predicted structural effects of the mutations. CONCLUSIONS: Known causative genes account for the development of CHNG only in a minority of cases, and our cohort should provide a powerful resource to identify novel causative genes and to delineate the extent of locus heterogeneity in autosomal recessively inherited CHNG.

AML1 amplification and 17q25 deletion in a case of childhood acute lymphoblastic leukemia.

We report a case of childhood acute lymphoblastic leukemia (ALL) with both acute myeloid leukemia 1 (AML1) amplification and 17q25 deletion. AML1 gene is located on 21q22 and encodes a transcription factor. AML1 amplification is a common finding in childhood ALL, and itis observed as an increase in gene copy number by the FISH analysis. The mechanism of AML1 amplification is not associated with AML1 gene mutations. The 17q25 is a gene-rich chromosomal location and distinct abnormalities of this region have been observed in previous cases of different kinds of leukemia. Deletion of the 17q25 region has been reported in two leukemia patients. Septin 9 (SEPT9) and survivin genes are located on 17q25. High expression of these genes and AML1 amplification are regarded as markers in tumorigenesis and disease progression; however, more data are needed for accurate prognostic evaluation.

Imatinib use during pregnancy and breast feeding: a case report and review of the literature.

INTRODUCTION: The development of imatinib as a therapeutic agent targeting BCR-ABL has increased the treatment options for chronic myeloid leukemia (CML) by significantly impacting outcomes, and imatinib is recommended by treatment guidelines as the first-line therapy. However, treatment of maternal CML with imatinib during gestation is not recommended because of the potential risk to the fetus. MATERIALS AND METHODS: We describe the clinical presentation, course and outcome of one pregnant patient with CML who was treated with imatinib. We review all pregnancies associated with imatinib documented in the literature. CASE PRESENTATION: A 27-year-old pregnant patient was diagnosed to have Philadelphia chromosome positive chronic phase CML in August 2007. Imatinib was administered (400 mg/day) between the 21st and 39th weeks of gestation. The patient tolerated the drug well and achieved complete hematological and cytogenetic remission. There were no imatinib-related maternal complications during the pregnancy. Fetal growth remained normal as well as amniotic fluid volume estimation. Labor was induced at the 39th gestational week, resulting in the uneventful vaginal delivery of a healthy male infant without any congenital anomaly. Umbilical cord blood and infant peripheral blood were collected at delivery. No postnatal complications occurred; however, imatinib was present in the umbilical cord blood (338 ng/mL) and in the infant's peripheral blood (478 ng/mL). Breast milk was collected on different postpartum days, and concentrations of imatinib were detected. At 10 months of age, the baby had normal growth and development. CONCLUSIONS: In light of reported cases and our experience, treatment of CML during the second and third trimesters of gestation and breast feeding seems to be safe, but the data are still limited and the effects of chronic exposure of infants to imatinib are not known. We think that each case should be examined and considered independently, and decisions should be individualized.

Chronic black tea administration protects plasma proteins, plasma, liver and kidney lipids against oxidation.

BACKGROUND: Black tea is known to have protective effects against plasma lipid and lipoprotein oxidation, but its influence on lipid peroxidation in tissue has been less studied. The effect of oral black tea consumption on protein oxidation has also not been demonstrated. The present study investigated the antioxidant effects of oral black tea consumption. MATERIAL/METHODS: Male Sprague-Dawley rats were fed a regular murine chow diet. The controls were supplied with water ad libitum, while the black tea group received aqueous black tea extract as the sole source of liquids. At the end of the ten-week experimental period, intestinal brush border, liver and kidney reduced-glutathione concentrations were evaluated as an index of cellular antioxidant defence. Plasma and tissue malondialdehyde concentrations and plasma protein carbonyl content were measured to evaluate lipid peroxidation and protein oxidation, respectively. RESULTS: The plasma malondialdehyde and protein carbonyl contents of rats consuming the black tea were significantly less than in controls. Similarly, liver and kidney malondialdehyde concentrations were significantly lower in the experimental group, while jejunoileal mucosa were not affected. Ten weeks of black tea administration caused significantly higher reduced-glutathione levels in the kidneys of black tea-administered rats, and a significant negative correlation was observed between kidney malondialdehyde and glutathione concentrations. CONCLUSIONS: These findings provide evidence that long term black tea supplementation is capable of protecting both plasma proteins and plasma lipids from oxidative injury, and demonstrate that chronic black tea administration protects both liver and kidney tissues - but not the jejunoileal mucosa - against oxidation.

Pregnancy under treatment of imatinib and successful labor in a patient with chronic myelogenous leukemia (CML). Outcome of discontinuation of imatinib therapy after achieving a molecular remission.

Because of the teratogenicity data in rats, it is recommended that women treated with imatinib should be aware of the potential teratogenicity of imatinib and effective contraception should be used during imatinib therapy to prevent pregnancy. We describe successful pregnancy and delivery, without any congenital anomaly, in a patient with CML under treatment of imatinib. The fetus had been exposed to imatinib for 8 weeks. The patient remained off treatment during gestation and cytogenetic relapse of CML (5 months after discontinuation of imatinib therapy) developed at seventh month of gestation.

Evaluation of the effects of Helicobacter pylori eradication therapy on gastric antral epithelial hyperproliferation: a prospective six-month follow-up study.

BACKGROUND/AIMS: H. pylori-induced hyperproliferation of the gastric epithelium may have a critical role in gastric carcinogenesis. H. pylori-related hyperproliferation and reversibility of hyperproliferation after eradication therapy is still controversial. Therefore, we have evaluated the effects of H. pylori and its eradication on gastric antral epithelial proliferation. METHODOLOGY: A total of 32 H. pylori-positive and 22 H. pylori-negative subjects were enrolled into the study. Triple eradication therapy was given to the H. pylori-positive group. Upper endoscopy was repeated one month after the therapy and six months later, antral biopsy specimens were taken in each endoscopy. Biopsy specimens from H. pylori-negative subject were taken at the beginning of the study and sixth months later also. RESULTS: Proliferative index was 40.2% in H. pylori-positive state; it regressed to 27.6% after eradication and six months later the proliferative index was 30.7%. H. pylori-negative group's proliferative index was 25.5% initially and six months later it was 25.6%. The difference between the H. pylori-positive and -negative group was statistically significant (p<0.0001). The difference between H. pylori-positive group's values at the beginning of the study and one month after the eradication was significant (p<0.0001). In addition, the difference between H. pylori-positive group's initial values and those six months after eradication was also significant (p<0.0001). CONCLUSIONS: H. pylori increased the gastric epithelial proliferation and after the eradication therapy proliferative index decreased to control values. H. pylori and the related factors inducing gastric antral hyperproliferation may have an important role in H. pylori-related gastric malignancies.