Tiraje Celkan

DNA repair gene XPD and XRCC1 polymorphisms and the risk of childhood acute lymphoblastic leukemia

Polymorphisms have been identified in several DNA repair genes. These polymorphisms may effect DNA repair capacity and modulate cancer susceptibility. In this study, we aimed to determine the four polymorphisms in two DNA repair genes, xeroderma pigmentosum complementation group D (XPD) and X-ray repair cross-complementing group 1 (XRCC1), in a sample of Turkish patients with childhood acute lymphoblastic leukemia (ALL), and evaluate their association with childhood ALL development. We used polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP), to analyze XPD Asp312Asn, XPD Lys751Gln, XRCC1 Arg194Trp, and XRCC1 Arg399Gln polymorphisms in 70 patients with childhood ALL and in 75 disease-free controls, who were of a similar age. No significant differences were observed among the study groups with regard to the XPD codon 312, XPD codon 751, XRCC1 codon 194, and XRCC1 codon 399 polymorphisms. However, the combined XRCC1 Arg194Trp/Trp194Trp variant genotypes were associated with increased risk for ALL in females (OR=5.47; 95% CI=1.49-20.10; p=0.008). This finding indicates that females carrying XRCC1 194Trp allele are at increased risk of developing childhood ALL. These results suggest that the risk of childhood ALL may be associated with DNA repair mechanisms, and understanding these mechanisms will help identify individuals at increased risk of developing childhood ALL, and also should be lead to improved treatment of ALL.

Antibody titers and immune response to diphtheria-tetanus-pertussis and measles-mumps-rubella vaccination in children treated for acute lymphoblastic leukemia.

The objective of this study was to investigate the diphtheria-tetanus-pertussis and/or measles-mumps antibody titers before and after vaccination at various time points of acute lymphoblastic leukemia (ALL) therapy and to suggest an appropriate vaccination approach for ALL patients. The authors studied 37 ALL patients and 14 healthy control subjects, divided into three groups. In group 1 (newly diagnosed patients), baseline anti-diphtheria, anti-tetanus, and anti-pertussis titers were determined. Patients in group 2 (on maintenance chemotherapy) and group 3 (patients not receiving therapy for 3-6 months) were vaccinated with diphtheria-tetanus with or without acellular pertussis; group 3 and control subjects were also given measles-mumps-rubella vaccine. Preimmunization and 1-month postimmunization titers were drawn. Preimmunization anti-diphtheria and anti-tetanus antibody titers between the groups and the controls were statistically similar. The seropositivity rate for anti-measles antibody in group 3 was significantly lower than controls. After vaccination, all of the patients developed protective anti-diphtheria and anti-tetanus antibody titers. The seroconversion rates of group 3 and controls for anti-measles and anti-mumps antibodies were statistically similar. The results showed that patients on maintenance therapy and after cessation of therapy made good antibody responses to diphtheria and tetanus toxoids, but response to measles and mumps vaccines was not as sufficient as toxoid vaccines. Children with ALL can receive the appropriate vaccines during and after maintenance treatment.

Retinoblastoma in Turkey: survival and clinical characteristics 1981 - 2004

Background: In this study, the authors aim to describe the survival and clinical characteristics of 141 retinoblastoma cases treated at Cerrahpasa Medical Faculty, University of Istanbul, Istanbul, Turkey, between 1981 and 2004.

NAD(P)H:quinone oxidoreductase 1 null genotype is not associated with pediatric de novo acute leukemia

NAD(P)H:quinone oxidoreductase1 (NQO1) is a two‐electron reductase that detoxifies quinones derived from the oxidation of phenolic metabolites of benzene. Exposure to benzene metabolites increases the risk of hematotoxicity and leukemia. NQO1 enzyme activity protects the cells against metabolites of benzene. C to T base substitution at nucleotide 609 of NQO1 cDNA (C609T) results in loss of enzyme activity. Low NQO1 activity may play a role in etiology of acute leukemia.

Syntaxin‐11 is expressed in primary human monocytes/macrophages and acts as a negative regulator of macrophage engulfment of apoptotic cells and IgG‐opsonized target cells

Syntaxin‐11 is a member of a family of membrane‐trafficking proteins referred to as soluble N‐ethylmaleimide‐sensitive factor attachment protein receptors (SNAREs). Recent studies have shown that syntaxin‐11 is expressed in natural killer cells and cytotoxic T cells and is likely to play a role in the granule exocytosis pathway. However, the biological role of syntaxin‐11 in other immune cells has remained elusive. This study found that stimulation with interferon‐γ upregulated syntaxin‐11 expression in primary monocytes. Experiments using monocytes from patients with familial haemophagocytic lymphohistiocytosis harbouring mutations in the gene encoding syntaxin‐11 (STX11), or monocytes from healthy individuals in which syntaxin‐11 was downregulated using specific short‐interfering RNA, demonstrated that syntaxin‐11 was not required for antibody‐dependent cellular cytotoxicity. On the other hand, silencing of syntaxin‐11 expression in primary macrophages enhanced the phagocytosis of apoptotic target cells with a concomitant increase in macrophage secretion of tumour necrosis factor‐α. Moreover, Fcγ‐receptor‐mediated uptake of target cells was also enhanced following silencing of syntaxin‐11 expression in macrophages. In addition, syntaxin‐11 localized to the plasma membrane in macrophages ingesting apoptotic cell corpses. Syntaxin‐11 thus appears to act as a negative regulator of human macrophage engulfment of apoptotic cells and IgG‐opsonized red blood cells.

Toxic Epidermal Necrolysis After the Use of High-Dose Cytosine Arabinoside

Abstract: We report a fatal case of toxic epidermal necrolysis (TEN) resulting from a high dose of cytosine arabinoside (ARA‐C). A 13‐year‐old girl with acute lymphocytic leukemia was treated according to the protocol of the BFM Group (BFM‐95, HRG). On the fifth day after administration of a high dose of ARA‐C (2 g/m2 intravenously every 12 hours), she developed bullous lesions on the hands and soles that disseminated, evolving to necrosis, sepsis, and death on the 22nd day. ARA‐C is frequently associated with dermatologic toxicity, but this is only the second case of toxic epidermal necrolysis described in connection with this drug.

Deregulated WNT signaling in childhood T-cell acute lymphoblastic leukemia

WNT signaling has been implicated in the regulation of hematopoietic stem cells and plays an important role during T-cell development in thymus. Here we investigated WNT pathway activation in childhood T-cell acute lymphoblastic leukemia (T-ALL) patients. To evaluate the potential role of WNT signaling in T-cell leukomogenesis, we performed expression analysis of key components of WNT pathway. More than 85% of the childhood T-ALL patients showed upregulated β-catenin expression at the protein level compared with normal human thymocytes. The impact of this upregulation was reflected in high expression of known target genes (AXIN2, c-MYC, TCF1 and LEF). Especially AXIN2, the universal target gene of WNT pathway, was upregulated at both mRNA and protein levels in ∼40% of the patients. When β-CATENIN gene was silenced by small interfering RNA, the cancer cells showed higher rates of apoptosis. These results demonstrate that abnormal WNT signaling activation occurs in a significant fraction of human T-ALL cases independent of known T-ALL risk factors. We conclude that deregulated WNT signaling is a novel oncogenic event in childhood T-ALL.

Bacteremia in childhood cancer.

Infection-related mortality affects the overall survival rates of children who are receiving treatment for cancer. The leading cause of mortality is bacteremia and sepsis related to it in febrile neutropenic patients. All positive blood cultures of febrile neutropenic patients treated in the Department of Pediatric Hematology-Oncology, Cerrahpasa Medical School, between January 1995 and January 2001 were reviewed. Cultures grew 159 micro-organisms, 95 (60 per cent) of which were Gram-positive bacteria, 56 (35 per cent) were Gram-negative bacteria and eight (5 per cent) were fungi. Coagulase-negative staphylococci (63, 40 per cent) and S. aureus (8, 5 per cent) were the most frequent Gram-positive pathogens. Klebsiella, E. coli, Enterobacter and Pseudomonas infections were the primary Gram-negative pathogens. Twenty cases were lost because of sepsis: in 11 cases (55 per cent) Gram-negative bacteria, in eight cases (40 per cent) Gram-positive bacteria, and in only one case a fungus were the causative organisms. Although vancomycin was not included in the first-line treatment, the mortality rate of Gram-positive bacteremia was 8 per cent. In Gram-negative bacteremia it was 20 per cent. Gram-negative pathogens, which were resistant to multiple antibiotics, caused the mortality. Drug resistance and mortality due to micro-organisms must be taken into consideration while febrile neutropenia protocols are prepared.

Prognostic significance of NOTCH1 and FBXW7 mutations in pediatric T-ALL.

The NOTCH signaling pathway plays important role in the development of multicellular organisms, as it regulates cell proliferation, survival, and differentiation. In adults, it is essential for the T- or B-lymphocyte lineage commitment. NOTCH1 and FBXW7 mutations both lead the activation of the NOTCH1 pathway and are found in the majority of T-ALL patients. In this study, the mutation analysis of NOTCH1 and FBXW7 genes was performed in 87 pediatric T-ALLs who were treated on the ALL-BFM protocols. In 19 patients (22%), activating NOTCH1 mutations were observed either in the heterodimerization domain or in the PEST domain and 7 cases (10%) demonstrated FBXW7 mutations (2 cases had both NOTCH1 and FBXW7 mutations). We also analyzed the relationship of the mutation data between the clinical and biological data of the patients. NOTCH1 and FBXW7, NOTCH1 alone were found correlated with lower initial leucocyte counts which was independent from the sex and T- cell immunophenotype. However, NOTCH1 and FBXW7 mutations were not predictive of outcome in the overall cohort of pediatric T-ALLs.

Fatal Trichoderma harzianum infection in a leukemic pediatric patient.

We report the repeated isolation for Trichoderma.harzianum, a rare opportunistic pathogen from three sets of each of the following clinical samples; blood serum, skin lesions, sputum and throat of a pediatric ALL patient with neutropenia. The definition of invasive fungal infection requires evidence of the presence of fungal elements in tissue samples, in addition to the isolation of suspected etiologic agent in culture. However, invasive procedures are not always applicable due to several factors, as for example in our case, the poor general status of the individual patient or thrombocytopenia. The present paper also emphasizes the problems encountered in obtaining appropriate samples and diagnosing invasive fungal disease in immunocompromised patient populations, including those with hematological malignancy. Three cases involving T. harzianum, including this one, have been described thus far in the literature. All were fatal and the fungus was resistant to antifungal therapy. A critical review of the other two cases of Trichoderma infections in humans is provided.