Csongor Kiss

Comparison of PFA-100 Closure Time and Template Bleeding Time of Patients with Inherited Disorders Causing Defective Platelet Function

MINI REPORT Comparison of PFA-100 Closure Time and Template Bleeding Time of Patients with Inherited Disorders Causing Defective Platelet Function Adrienne Kerenyi1, Agota Schlammadinger2, Eva Ajzner1, Istvan Szegedi3, Csongor Kiss3, Zoltan Pap4, Zoltan Boda2 and Laszlo Muszbek1 1Department of Clinical Biochemistry and Molecular Pathology, 2Second Department of Medicine, 3Department of Pediatrics, University Medical School of Debrecen, Debrecen, 4City Health Service, Ophthalmology Unit, Debrecen, Hungary.

Overlapping Protective and Destructive Regulatory Pathways in Apical Periodontitis

INTRODUCTION Protective and destructive immunoreactions take place simultaneously in apical periodontitis. However, the same reactions defending the periapical area from infection-derived damage may also result in host tissue injury. METHODS The inflammatory reaction of the periapical tissues is self-limited. Regeneration of the injured tooth-supporting structures may follow elimination of the causative microbial irritation. RESULTS Recent experimental and clinical observations have identified important interplay between positive and negative regulatory pathways. A network of stimulatory and inhibitory feedback loops may influence the intensity of the defense and inflammatory responses and the balance between bone resorption and regeneration, resulting in lesion expansion or healing of apical periodontitis. CONCLUSIONS We critically discuss research data on regulatory mechanisms that control the activity of host effector cells and signaling molecules during interactions with pathogenic microbes.

Cystatin C is a suitable marker of glomerular function in children with cancer

Antineoplastic chemotherapy is associated with nephrotoxic side effects. Data on nephrotoxicity in childhood cancer are scanty, in part because of the difficulties in obtaining reliable markers of glomerular function. We used serum cystatin C (cysC) to assess glomerular function. CysC was compared with serum creatinine concentration (SCr), the endogenous creatinine clearence ( C Cr), and the calculated Counahan formula ( C Counahan) in children with leukemia and solid tumors. CysC was measured by particle-enhanced immunoturbidimetric assay. Serum and urinary creatinine concentrations were determined by the Jaffé method. Samples were obtained from 258 children, including 92 receiving anticancer chemotherapy, 108 long-term survivors, 40 children without any renal disease, and 18 patients with chronic renal insufficiency. CysC of patients on current chemotherapy was assessed both before and after treatment. Significant correlations were found between cysC and SCr and between 1/cysC and C Counahan. CysC increased significantly after cisplatin, methotrexate, cyclophosphamide, ifosfamide, and multimodality treatment. Our results suggest that cysC measurement can be used to characterize glomerular function in children with cancer.

Late effects on renal glomerular and tubular function in childhood cancer survivors

Late nephrotoxicity among childhood cancer survivors is poorly documented.

Significance of oral Candida infections in children with cancer

Candidiasis is common in children with cancer, particularly during periods of severe immunosuppression and neutropenia. Our aim was to study the microbiological changes in the oral cavity of children with newly diagnosed cancer. The study group consisted of 30 consecutive children and adolescents, 16 with acute lymphoblastic leukemia and 14 with solid tumors. Oral cultures to detect fungi and bacteria were conducted for all patients before treatment, during and after neutropenic episodes. In 23 patients developing fever simultaneous throat, urine and blood sampling was carried out. No pathogens were found in the cultures taken before the outset (30 cultures) or after recovery from (30 cultures) the neutropenic episodes. In the 45 oral cultures taken during the neutropenic episodes 38 (84.4%) proved positive. Fungi were the most frequently isolated oral pathogens: 33/38 yeast and 6/38 bacterial infections were identified. There was no association between the underlying malignancy and the occurrence of the positive cultures. Of the 30 patients, all 23 (76.7%) who have developed moderate-to-severe neutropenia, developed oral fungal colonization or clinically obvious fungal infection at least on one occasion during the study. In addition to oral samples, fungi were identified in 9/23 pharyngeal swabs, 6/23 urine and 1/23 blood cultures. The initial fungal pathogen was exclusively (33/33)Candida albicans. In extended severe neutropenic states,C. albicans was replaced by non-albicans species (C. kefyr, C. lusitaniae, C. sake, C. tropicalis) in 5 patients between 4 to 6 days of the neutropenic episodes. Four of the nonalbicansCandida strains were resistant to azole-type antifungal agents. Neutropenic episodes of children with cancer are associated with an increased risk of developing oral and even systemic infections withC. albicans that can be replaced by azole-resistant nonalbicans strains in prolonged neutropenia contributing to morbidity of these patients.

Identification of P‐selectin glycoprotein ligand‐1 as a useful marker in acute myeloid leukaemias

Immunophenotyping is considered to be less valuable in the diagnosis of acute myeloid leukaemias (AML) compared with acute lymphoid leukaemias. Here, we present data on the use of quantitative flow cytometry (QFC) of P‐selectin glycoprotein ligand 1 (PSGL‐1, CD162) and three‐colour immunophenotyping including CD162 staining in the identification of myeloid precursors in AML. Analysis of normal peripheral blood (n = 20) and normal bone marrow (n = 5) samples and on 20 samples from de novo M1, M2, M4 and M5 AML patients demonstrated that PSGL‐1 is differentially expressed on various mature and immature leucocyte subsets. It was found by QFC that neutrophils expressed 26500 ± 4500 and monocytes 47200 ± 9900 copies of PSGL‐1 on their surface, whereas AML blasts from M1 and M2 AML patients expressed significantly less PSGL‐1 (12 000 ± 5300) than mature neutrophils (P < 0·001). In M4 and M5 leukaemias, however, the amount of PSGL‐1 on monocytic precursors is displayed in a fairly broad range that is not significantly different from that of mature monocytes (P = 0·084). Using three‐colour immunophenotyping PSGL‐1‐dim staining was co‐expressed with CD7 and C34 positivity and PSGL‐1 staining intensity on immature myeloid cells paralleled with CD45 expression. This would imply a differential expression of PSGL‐1 during myeloid haematopoietic development and suggests that quantification of surface PSGL‐1 may aid in differentiating myeloblasts from monoblasts by immunophenotyping in different AML subsets.

Prevention and treatment of hyperuricemia with rasburicase in children with leukemia and non-Hodgkin's lymphoma

To prevent acute renal failure in children at risk for developing tumor lysis syndrome due to acute lymphoblastic leukemia or non-Hodgkin’s lymphoma treated according to international BFM protocols, we investigated recombinant urate oxidase (rasburicase) in the first Central European openlabeled, prospective, multicenter phase IV trial. Rasburicase was administered intravenously, at 0.2 mg/kg for 5 consecutive days to 36 patients. Blood levels of uric acid, creatinine, phosphorus, calcium, lactate dehydrogenase and complete blood count were measured daily during rasburicase treatment and on days 6, 7 and 12. Initial uric acid level decreased significantly by 4 hours (from 343 μmol/L to 58 μmol/L, p<0.001), except for one steroid-resistant patient who required hemodialysis on day 14 after having introduced combined cytostatic treatment. Comparing the data of a subgroup of 12 patients receiving rasburicase with that of a historic cohort of 14 patients treated with allopurinol indicated the superiority of rasburicase over allopurinol in prophylaxis and treatment of hyperuricemia in children with leukemia and lymphoma.

Anthracycline antibiotics induce acute renal tubular toxicity in children with cancer

Experimental evidence suggests that anthracyclines, widely used in cancer chemotherapy, may impair kidney function. We assessed kidney function by serum creatinine, urinary N-acetyl-β-D-glucosaminidase activity indices (NAGi) and microalbuminuria (MA) in 160 serum and urine samples obtained from 66 children with cancer. The effect of dexrazoxane was analyzed in 6 children on dexrazoxane supportive therapy in conjunction with daunorubicin (DNR) treatment, as compared with 6 children not receiving this agent. NAG; was significantly (p<0.05) elevated after treatment by DNR, doxorubicin, epirubicin (EPI) and idarubicin (IDA). MA proved to be a less sensitive indicator of kidney damage than NAGL DNR resulted in a progressive deterioration of proximal tubular function as determined by linear regression analysis. The mean NAG1 in the dexrazoxanetreated group was significantly (p<0.005) lower than in children not receiving dexrazoxane prior to DNR treatment. In conclusion, our study demonstrated that DNR, EPI and IDA induced an acute renal tubular damage similar to known tubulotoxic agents as cisplatin, carboplatin, cyclophosphamide and ifosfamide. The damage was clinically mild and only a minor proportion of patients can be expected to develop long-lasting tubulopathy with negative impact on the quality of life.

Activating braf V600E mutation in aggressive pediatric langerhans cell histiocytosis: Demonstration by allele-specific PCR/direct sequencing and immunohistochemistry

Langerhans cell histiocytosis (LCH) is a rare neoplastic disease originating from cells characterized by antigen-presenting Langerhans cell phenotype. The clinical spectrum of LCH is highly variable including localized and disseminated forms mostly occurring in children. Recently, about 60% of LCHs were reported to carry the activating BRAF mutation V600E. In our retrospective study, we evaluated the occurrence and prognostic impact of the V600E mutation in formaldehyde-fixed, paraffin-embedded samples from 15 pediatric LCH cases treated at our institution. Allele-specific polymerase chain reaction (PCR) and direct sequencing were used to demonstrate the presence of V600E mutation, and immunohistochemistry (IHC) using the mutant protein–specific VE1 antibody clone was performed to confirm mutant BRAF protein expression. Eight of 15 (53.3%) cases proved to be BRAF mutants by any of the methods applied, with a single case showing a discrepancy (PCR negative/IHC positive). Four of the BRAF-mutant cases (50.0%) showed refractory disease and progressed to death within 43 months, whereas the remaining mutant cases were stable and responded well to therapy. Wild-type BRAF cases (7/15, 46.6%) with generally comparable initial presentation were all treated successfully. In conclusion, activating V600E BRAF mutation can be frequently demonstrated in pediatric LCH by both allele-specific PCR and IHC. Unfavorable risk cases potentially also responding to BRAF-inhibitory therapy can be identified by mutation testing using archival formaldehyde-fixed, paraffin-embedded tumor samples.

Hungarian experience with Langerhans Cell Histiocytosis in childhood

The Langerhans cell histiocytosis (LCH) in children is relatively rare and the long-term analysis of therapy results has not been done yet in Hungary. The aim of this study was to investigate the incidence, clinical features, prognostic risk factors, and treatment results of childrens LCH in Hungary in a 20-year period. Children less than 18 years of age with newly diagnosed LCH in Hungary were entered in this study. Clinical data of all children with LCH were reported to the National Childhood Cancer Registry in Hungary from 1981 to 2000. The clinical files were collected and abstracted for information regarding age at diagnosis, gender, disease characteristics, treatment, and outcome of treatment. Median follow-up duration of surviving patients is 10.98 years. Between January 1981 and December 2000, 111 children under 18 years of age were newly diagnosed with LCH in Hungary. The annual incidence of LCH in children younger than 18 years of age was 2.24/million children. The male–female ratio was 1.36:1; the mean age was 4 years 11 months. Thirty-eight children had localized disease and in 73 cases systemic dissemination was found already at the time of diagnosis. Twenty-two patients were treated only by local surgery, 7 by surgery with local irradiation, and 5 children got only local irradiation. In 2 cases remission was achieved with local steroid administration. Seventy-five patients received chemotherapy. In the 20 years of the study 14 children died, 9 due to the progression of the disease. Sixteen patients had relapse with a mean of 2.16 ± 1.29 years after the first diagnosis. Three patients with relapse got chemotherapy generally used in lymphoma and remission was achieved. The overall survival of all patients (n = 111) was 88.3 ± 3.1% at 5 years and 87.3 ± 3.2% at 10 and 20 years. Childhood LCH is a well-treatable disease and the survival rate is high. Even disseminated diseases have a quite good prognosis in childhood.