Alp Özkan

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.

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.

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.

ASSOCIATION BETWEEN GENETIC POLYMORPHISM IN DNA REPAIR GENES AND RISK OF B-CELL LYMPHOMA

Objectives: The authors evaluated the possible effect of DNA repair genes, XPD (Xeroderma pigmentosum group D) codon (312 and 751) and XRCC1 (X-ray repair cross-complementing group 1) codon (194 and 399) SNPs (single-nucleotide polymorphisms) on the risk of childhood B-cell lymphoma. Methods: The polymorphisms were analyzed in 33 patients with BL cases and in 52 healthy, age-matched controls using PCR-RFLP method. Results: The authors observed no association between variation in the XPD codon Asp312Asn, Lys751Gln, and XRCC1 codon Arg399Gln polymorphisms and B-cell lymphoma for any parameter. In contrast, tryptophan allele frequency in control and patient groups was 0.10 and 0.03 respectively (p = .04). The frequency of XRCC1 194Arg/Trp genotype in B-cell lymphoma was significantly lower than that in controls (p = .005). No significant relationship was found between genotypes and stage, lactate dehydrogenase, or bone marrow involvement. Conclusions: XRCC1 194Trp allele may be associated with a protective effect against development of childhood B-cell lymphoma. However, these results were based on a small number of case and further studies should be done.

Antiviral prophylaxis with continuous low dose acyclovir in childhood cancer

Having read the article ‘‘Oral valacyclovir as prophy-laxis against herpes simplex virus reactivation duringhigh dose chemotherapy for leukemia’’ by Orlowskiet al. [1], we wanted to write about our experiencewith acyclovir prophylaxis in children who weretreated for cancer [2]. Although the age of patientsand the medication used for prophylaxis inOrlowski’s and our study were different, an effectiveprophylaxis against reactivation of herpes simplexvirus or new infection in the respective patientpopulations was achieved in both papers.Children on chemotherapy have defects in cellularimmunity which predispose them to severe infectionswith certain viruses, particularly varicella zoster virus(VZV). Except relapse/underlying disease, the lead-ing cause of death in children with cancer is infection[3]. Prophylaxis against infection is a debatablesubject of cancer treatment. Only Pneumocystis cariniiprophylaxis in children receiving chemotherapy andantifungal prophylaxis in bone marrow transplanta-tion (BMT) units is recommended. Prophylaxis withacyclovir is only recommended in case of exposureVZV infections or to prevent the reactivation ofherpes infection in sero-positive patients. To ourknowledge, no pediatric cancer centers give acylovirfor viral prophylaxis, other than BMT. None of ourcases were transplanted, so the novelty of our data isthe critical element of this study.From January 1995 to December 2001, allchildren with cancer or leukemia were evaluated forherpes infections at the Hematology–Oncologydepartment of Cerrahpasa Medical University ofPediatrics. We used high dose acyclovir either in caseof exposure to VZV or for the treatment of varicella(chickenpox) or herpes zoster (shingles) infectionsuntil the end of 1997. From January 1995 to the endof December 1997, a total of 216 patients who werediagnosed with, and treated for, a malignancy havebeen evaluated retrospectively for VZV infections.Since January 1998, prophylactic acyclovir has beenadministered in our department to all patients withleukemia or solid tumor receiving chemotherapy,along with trimethoprim-sulphomethoxazole. Thedose has been determined empirically as 200 mg/day in two divided doses for young children and400 mg/day in two divided doses for older childrenand adolescents, contributing to a dose of approxi-mately 5–10 mg/kg/day. Prophylaxis was continuedfor 3 months after the end of chemotherapy for solidtumors and maintenance therapy of leukemia. Thesetwo periods (with or without prophylaxis) werecompared for frequency, morbidity and mortality ofthe VZV infections.Annually, 75–100 new patients are diagnosed andtreated for their cancer in our department. Duringthe periods with prophylaxis or not, there was nomajor difference in treatment regimens for cancerand supportive care. Before antiviral prophylaxis withcontinuous low dose acyclovir, 2–3 new chickenpoxand 2–4 shingles cases have been documentedyearly. There have even been two fatalities during1985–1990 due to severe varicella infection. Wehave collected the data of thirteen children with VZVinfection diagnosed during a 3-year period beforeprophylaxis. The incidence is 6% (13/216). The pati-ents who were diagnosed with VZV infections beforethe period of prophylaxis are shown in Table Ia. Nota single case of VZV infection has been diagnosed

Erythrocyte membrane protein defects in hereditary spherocytosis patients in Turkish population.

Abstract Hereditary spherocytosis (HS) is a congenital hemolytic anemia which is characterized by spherocytes in peripheral blood and increased osmotic fragility test. The disease is caused by defects in red cell membrane cytoskeleton. In this study, we investigated erythrocyte membrane protein defects in 50 Turkish HS patients and 42 controls. We used sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS–PAGE) to identify the protein defects causing HS. The patients were from 27 families (39 kindred and 11 unrelated patients). They were aged between 6 months and 53 years and the mean age was 18.75 (±14.70) years. Protein deficiencies related to HS were demonstrated in 42% of study group. There was not any statistically significant relation between the protein deficiency and hemoglobin levels. Isolated or combined spectrin deficiency was the most common protein abnormality among our patients. Spectrin deficiency was detected in 22% of cases (11/50), ankyrin deficiency in 8% (4/50), protein 4.2 deficiency in 8% (4/50), combined spectrin and protein 4.2 deficiency in 2% (1/50), combined spectrin and ankyrin deficiency in 2% (1/50). Fifty-eight percent of cases (29/50) showed normal protein contents.

Treatment of pediatric Burkitt lymphoma in Turkey.

This study aimed to assess the demographic data and treatment results of children who were diagnosed with Burkitt lymphoma and treated according to the Berlin-Frankfurt-Münster-95 (BFM) protocol in a single institution. A total of 48 patients (37 boys, 77%) with a median age of 8 years (range 2 to 16 years) at diagnosis, were evaluated. Primary tumor sites were abdomen (70.8%), head and neck (22.9%), peripheral lymph node (2%), bone (2%), and testis (2%). The 5-year overall survival (OS) and event-free survival (EFS) were 78.1±4% and 76.6±6%, respectively. In univariate analysis, hemoglobin level less than 10 g/dL, cerebrospinal fluid (CSF) positivity and dialysis requirement at diagnosis were found to be important reverse predictor factors for EFS (P; 0.001, 0.001, 0.004, respectively). In multivariate analysis, hemoglobin level less than 10 g/dL and dialysis at diagnosis were found to be important reverse predictor factors for EFS (P; 0.0001). The EFS of our patients was lower than the values achieved with BFM-95 protocol in other centers. This study provides evidence that low hemoglobin level, CSF positivity and dialysis at diagnosis were important predictor factors for EFS in children with Burkitt lymphoma.

The Role of Epstein-Barr Virus LMP-1 Immunohistochemical Staining in Childhood Hodgkin Lymphoma.

Background: There are a few published studies about prognostic markers of Epstein-B virus (EBV) related to outcomes in pediatric Hodgkin Lymphoma (HL). Objectives: We aimed to investigate the prognostic value and effect of EBV on survival by using biopsy materials in children and adolescents diagnosed with HL. Patients and Methods: EBV LMP-1 expression was examined using immunohistochemical methods in 58 tumor samples. Clinical features, overall survival (OS) and failure free survival time (FFS) were compared between EBV LMP-1 positive and negative patients. Results: In 20 (35%) patients tumors were LMP-1 positive. When compared with patients above 10 years old, EBV LMP-1 was often positive in patients under 10 years old (30% vs. 70%, P = 0.02). In our most cases having B symptoms and advanced stage, EBV positiveness in Hodgkin Reed-Stenberg cells (H-RS) was not a significant determinant for survival (P = 0.78). Half of the past clinical trials in childhood HL reported longer survival rates in EBV LMP-1 positive patients. In some trials similar to our results there was no significant relationship between EBV and prognosis. Conclusions: The reason of diminished EBV positiviness may be related to technical methods such as not using immunohistochemical and in situ hybridization for EBER antigen but in laboratory conditions painting of control tissues with EBV impair this probability. In addition, cases enrolled to our study were living in Istanbul where social and economical factors are improved rather than generally.

Severe factor X deficiency treated with heparin-added prothrombin complex concentrate

Factor X (FX) deficiency is a very rare coagulation disorder with autosomal recessive inheritance. It was first reported by Telper et al. [1] in 1956 in a female patient with the surname Prower and later described by Hougie et al. [2] in a patient named Stuart in 1957. It was proposed that this new factor be designated Stuart-Prower factor when experiments showed that mixing plasma from these two individuals did not result in correction of the partial thromboplastin time (PTT). This factor was later renamed factor X [3]. Clinical manifestations vary from severe bleeding disorder presenting in early life to a very mild bleeding tendency to asymptomatic individuals [4, 5, 6, 7]. These patients are treated with prolonged courses of fresh frozen plasma (FFP) or prothrombin-complex concentrates (PCC) [8, 9]. FFP has the risk of transmitting viral infections, whereas PCC have been associated with the thromboembolic complications and occasional episodes of disseminated intravascular coagulation [10, 11]. Therefore, its long-term prophylactic use is limited. We report a 7-month-old patient with FX deficiency who was diagnosed after vaccination that caused deep muscle hematoma and was successfully treated with heparinadded PCC (KASKADIL). A 5-month-old boy was born by spontaneous delivery to consanguineous parents, who have no family history of bleeding. Also, his 3-year-old sister had no signs of hemorrhage. Until his first vaccination at 5 months of age, he had no hemorrhagic problems. He was admitted to a hospital because of his subcutaneous bleeding at the injection site, where his prothrombin time (PT) and PTT estimations were prolonged, and Fibrin degradation products (FDP) were slightly elevated. FFP was transfused three times but with partial improvement of PT and PTT. FX level was found to be 1%. The mother’s FX level was 55%, the father’s 75%, and the sister’s 66%. He was treated with heparin-added PCC (KASKADIL). The hematoma disappeared and afterwards he was kept in a prophylactical replacement schedule. On several vaccinations, bleeding has not been a problem. Using the formula [body weight (kilogram) desired FX increase (%)]/ (1.5), his FX levels were raised to 50% before subsequent vaccinations. With this therapy, no further bleeding or thromboembolic complications due to PCC were recognized. FX deficiency occurs in fewer than one in 500,000 in the general population. FX is a glycoprotein of the intrinsic and extrinsic pathways of blood coagulation. It is a serine protease. The zymogene is activated by F-IXa or F-VIIa and converts prothrombin to thrombin [12]. The molecular genetics of FX deficiency include gene deletions, dysfunctional variants and variants that affect synthesis or function of FX [12]. A report of an Italian family with factor X deficiency showed a partial and heterozygous gene deletion, causing a defect of FX antigen and activity [12]. Although no genetic investigation is carried out in our case, the near normal FX levels of the parents supposed variations of genetic defects, but bimodal distribution of normal variants of FX cannot be excluded. Hemorrhage from the umbilical cord and later hemarthroses, central nervous system hemorrhage, menorrhagia, severe epistaxis and post-operative bleeding have been reported [4, 5, 6, 7]. A number of agents including vitamin K and danazol have been used to treat these patients, but only FFP and PCC have been reported to be effective [13]. PCC offers some advantages over FFP: (l) It is heat treated and therefore without viral contamination risk, (ll) The lyophilized form makes it convenient for home use, and (lll) Less volume is infused. However, it carries the risk for thromboembolic phenomena, especially with FX levels raised above 50%. Therefore, we preferred the heparinized form of PCC (KASKADIL). We have seen no thromboembolic complication with the use of this product. The half-life of FX H. Apak · T. Celkan · A. zkan · L. Y ksel · Z. Bilgi · İ. Yıldız Department Pediatric Hematology-Oncology, Cerrahpasa Medical School, Istanbul University, Istanbul, Turkey