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Krzysztof Czyzewski,1 Magdalena Dziedzic,1 Malgorzata Salamonowicz,2 Jowita Fraczkiewicz,2 Olga Zajac-Spychala,3 Agnieszka Zaucha-Prazmo,4 Jolanta Gozdzik,5 Przemyslaw Galazka,6 Natalia Bartoszewicz,1 Ewa Demidowicz,1 Jan Styczynski1 1Department of Pediatric Hematology and Oncology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Bydgoszcz, Poland; 2Department of Pediatric Transplantation, Oncology and Hematology, Medical University, Wroclaw, Poland; 3Department of Pediatric Oncology, Hematology and Transplantology, University of Medical Sciences, Poznan, Poland; 4Department of Pediatric Hematology, Oncology and Stem Cell Transplantation, Medical University, Lublin, Poland; 5Stem Cell Transplant Center, University Children’s Hospital, Department of Clinical Immunology and Transplantology, Jagiellonian University Collegium Medicum, Krakow, Poland; 6Department of General and Oncological Surgery for Children and Adolescents, Collegium Medicum, Nicolaus Copernicus University Torun, Bydgoszcz, PolandCorrespondence: Krzysztof CzyzewskiDepartment of Pediatric Hematology and Oncology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Ul. Sklodowskiej-Curie 9, Bydgoszcz 85-094, PolandTel +48 52 585 48 60Fax +48 52-585 4087Email k.czyzewski@cm.umk.plObjective: The analysis of epidemiology, risk factors and outcome of viral infections in children and adolescents after hematopoietic cell transplantation (HCT).Methods: In this multicenter nationwide study a total of 971 HCT procedures (741 allo-HCT; 230 auto-HCT) over a period of 6 years were analyzed.Results: During this period 801 episodes of viral infections were diagnosed in 442 patients. The incidence of viral infections was 57.9% in allo-HCT and 4.8% in auto-HCT patients. The most frequent infections after allo-HCT were caused by cytomegalovirus (CMV), polyoma BK virus (BKV) and Epstein–Barr virus (EBV). The majority of infections occurred within the first 4 months after allo-HCT and over 80% required pharmacotherapy or symptomatic therapy. The median time of treatment of specific viral infection ranged from 7 (for EBV) to 24 (for CMV) days. The highest mortality was observed in case of CMV infection. The risk factors for viral infections were allo-HCT, acute leukemia, acute and chronic graft versus host disease (a/cGVHD), and matched unrelated donor (MUD)/mismatched unrelated donor (MMUD)-HCT. The risk factor for death from viral infection were CMV-IgG seropositivity in acute lymphoblastic leukemia recipient, and MUD/MMUD-HCT. The incidence of EBV infection requiring pre-emptive treatment with rituximab in allo-HCT children was 19.3%. In 30.8% cases of EBV infection, these episodes were preceded by other viral infection and treated with antivirals, which did not prevent development of EBV-DNA-emia with need of rituximab treatment in 81.5% cases. In 47.7% of these cases, GVHD was a factor enabling development of significant EBV-DNA-emia during antiviral therapy of other infection.Conclusion: We have shown that antiviral drugs do not prevent EBV reactivation in allo-HCT pediatric patients.Keywords: children, EBV, HCT, infectious complications, risk factors analysis, viral infections

Krzysztof Czyzewski,1 Przemyslaw Galazka,2 Patrycja Zalas-Wiecek,3 Olga Gryniewicz-Kwiatkowska,4 Agnieszka Gietka,4 Katarzyna Semczuk,5 Liliana Chelmecka-Wiktorczyk,6 Iwona Zak,7 Malgorzata Salamonowicz,8 Jowita Fraczkiewicz,8 Olga Zajac-Spychala,9 Ewa Bien,10 Marcin Plonowski,11 Pawel Wawrykow,12 Filip Pierlejewski,13 Zuzanna Gamrot,14 Zofia Malas,15 Weronika Stolpa,16 Jakub Musial,17 Jan Styczynski11Department of Pediatric Hematology and Oncology, Collegium Medicum, Nicolaus Copernicus University Torun, Bydgoszcz, Poland; 2Department of General and Oncological Surgery for Children and Adolescents, Collegium Medicum, Nicolaus Copernicus University Torun, Bydgoszcz, Poland; 3Department of Microbiology, Collegium Medicum, Nicolaus Copernicus University Torun, Bydgoszcz, Poland; 4Department of Oncology, Children’s Memorial Health Institute, Warsaw, Poland; 5Department of Microbiology, Children’s Memorial Health Institute, Warsaw, Poland; 6Department of Pediatric Oncology and Hematology, University Children’s Hospital, Jagiellonian University, Collegium Medicum, Krakow, Poland; 7Department of Microbiology, University Children’s Hospital, Jagiellonian University, Collegium Medicum, Krakow, Poland; 8Department of Pediatric Stem Cell Transplantation, Hematology and Oncology, Medical University, Wroclaw, Poland; 9Department of Pediatric Oncology, Hematology and Transplantology, University of Medical Sciences, Poznan, Poland; 10Department of Pediatrics, Hematology and Oncology, Medical University, Gdansk, Poland; 11Department of Pediatric Oncology and Hematology, Medical University, Bialystok, Poland; 12Department of Pediatrics and Pediatric Oncology, Pomeranian Medical University, Szczecin, Poland; 13Department of Pediatric Oncology and Hematology, Medical University, Lodz, Poland; 14Division of Pediatric Hematology and Oncology, Chorzow City Hospital, Chorzow, Poland; 15Division of Pediatric Hematology and Oncology, Children Hospital, Olsztyn, Poland; 16Division of Pediatric Oncology, Hematology and Chemotherapy, Department of Pediatric, Silesian Medical University, Katowice, Poland; 17Department of Pediatric Oncohematology, Medical Faculty University of Rzeszow, Clinical Provincial Hospital No. 2, Rzeszow, PolandObjectives: The analysis of epidemiology, risk factors and outcome of infections in children with malignant bone tumors (MBT) undergoing chemotherapy.Methods: In this retrospective nationwide multicenter cross-sectional study, a total number of 126 children with MBT including 70 with Ewing sarcoma (ES) and 56 with osteosarcoma (OSA) were screened for infections over a period of 72 consecutive months.Results: The risk of infection was 7.15-fold higher in patients with ES as compared to the OSA group, especially concerning bacterial infections (4.1-fold increase risk). Bacterial infections occurred in 74.3% patients with ES and in 41.1% with OSA. The median time from diagnosis to first infection was 4.9 months. 33.0% of bacterial episodes were diagnosed as bloodstream (BSI), 31.1% as gastrointestinal tract, 30.1% as urinary tract infection. Infection-related mortality (IRM) from bacterial infection was 6% and 15% in ES and OSA patients, respectively. Cumulative incidence was 7.1% for invasive fungal disease and 6.3% for viral infections. The only significant risk factor for IRM was time to infection ≥5 months since the beginning of chemotherapy. All patients who have died from infection had BSI and were in neutropenia.Conclusions: Infections in the children with MBT in our study occurred with high frequency, especially in patients with ES. The most frequent were bacterial infections, while fungal and viral infections were episodic. Among the bacterial infections, bloodstream, urinary tract and gastrointestinal tract infections occurred with similar frequency. All deceased patients died due to BSI. Bacterial infection occurring ≥5 months since the beginning of chemotherapy was a risk factor for death.Keywords: infectious complications, risk factors analysis, Ewing sarcoma, osteosarcoma, malignant bone tumor, children

Abstract: Elevated levels of homocysteine have been observed in Parkinson''s disease (PD) patients treated with levodopa. However, it is not studied if duration of PD or PD per se is associated with hyperhomocysteinemia. In the present study, the levels of homocysteine in 99 levodopa-treated PD patients, 15 untreated PD patients and 100 controls were examined. We focused on the influence of levodopa dose, duration of therapy and disease as well as genetic (C677T methylenetetrahydrofolate reductase (MTHFR) polymorphism) and environmental factors. We found that levodopa-treated PD patients had elevated homocysteine plasma levels as compared to controls (p <0.05), but the levels did not depend on levodopa doses. Another factor influencing homocysteine level was the duration of PD (p <0.001). The frequency of allele C677T of MTHFR gene did not differ between PD and controls. In conclusion, hyperhomocysteinemia is associated with the duration of PD and levodopa treatment and possibly also with PD per se. [Copyright &y& Elsevier]

The p53 mutation spectrum can generate hypotheses linking carcinogen exposure to human cancer. Although it is well-documented that tobacco smoking is a major cause of lung cancer, the contribution of air pollution is less well-established. We determined the molecular and immunohistochemical changes (p53 gene mutations, p53 protein accumulation and WAF1 protein expression) and genetic polymorphisms of GSTM1, CYP1A1 and CYP2D6 genes in a case series of non-small-cell lung cancers from Silesia. This region of southern Poland is highly industrialized with considerable environmental pollution. More than 50% of lung cancers (90/164) contained p53 mutations and 75% showed the combined alteration of the p53 gene and protein accumulation. Males occupationally exposed to coal-derived substances showed a relatively high frequency of squamous and large-cell carcinomas, relatively frequent mutations in codon 298 of p53 and a low frequency of p53 immunohistochemically positive tumours. Codon 298 GAG-->TAG mutations have rarely been found in lung cancers in other populations. We found no correlation between WAF1 protein expression and mutations in the p53 gene or p53 protein accumulation. No statistically significant relationship was found between p53 mutations and GSTM1, CYP1A1, CYP2D6 genotypes. Never smokers with lung cancers from Silesia had a higher frequency of G:C-->T:A transversions than previously reported of the p53 mutation spectrum in never smokers (6/15 vs 4/34; P = 0.06 by chi2). These data are a tentative indication that occupational and environmental exposure to polycyclic aromatic hydrocarbons, such as benzo(a)pyrene, in polluted air contributes to the molecular pathogenesis of lung cancer in never smokers. [ABSTRACT FROM AUTHOR]

Aims and Objectives: A new pathomechanism of Parkinson's disease (PD) involving regulation of mitochondrial functions was recently proposed. Parkin complexed with mitochondrial transcription factor A (TFAM) binds mtDNA and promotes mitochondrial biogenesis, which is abolished by PARK2 gene mutations. We have previously shown that mitochondrial haplogroups/clusters and TFAM common variation influenced PD risk. We investigate the role of PARK2 polymorphisms on PD risk and their interactions with mitochondrial haplogroups/clusters as well as with TFAM variability.Methods: 104 early-onset PD patients (EOPD, age at onset ≤ 50 years) were screened for PARK2 coding sequence changes including gene dosage alterations. Three selected PARK2 polymorphisms (S167N, V380L, D394N) were genotyped in 326 PD patients and 315 controls using TaqMan allelic discrimination assay.Results: PARK2 screen revealed two heterozygous changes in two EOPD patients: exon 2 deletion and one novel synonymous variation (c.999C > A, P333P). In association study no differences in genotype/allele frequencies of S167N, V380L, D394N were found between analyzed groups. Stratification by mitochondrial clusters revealed higher frequency of V380L G/G genotype and allele G in PD patients, within HV cluster (p = 0.040; p = 0.022, respectively). Moreover, interaction between genotypes G/G V380L of PARK2 and G/G rs2306604 of TFAM, within HV cluster was significant (OR 2.05; CI 1.04-4.04; p = 0.038).Conclusions: Our results indicate that co-occurrence of G/G V380L PARK2 and G/G rs2306604 TFAM on the prooxidative HV cluster background can contribute to PD risk. We confirm low PARK2 mutation frequency in Polish EOPD patients. [ABSTRACT FROM AUTHOR]

A single nucleotide polymorphism in the promoter region of the dopamine beta-hydroxylase gene (DBH -1021C>T; rs1611115) is reported to regulate plasma enzyme activity levels. This variant has also been the focus of two large association studies in Parkinson's disease yielding conflicting results. We examined this association in four Caucasian patient-control series (n=2696). A modest protective association was observed in the Norwegian series (OR=0.81, p=0.03; n=1676), however, the effect was in the opposite direction in the Polish series (OR=2.01, p=0.01; n=224). No association was observed for DBH -1021C>T with disease susceptibility in the US and Irish series, or combining all four series (OR=0.91, p=0.16, n=2696). We observed a modest association between DBH -1021C>T and AAO in the combined series (p=0.01). Taken together, these findings indicate that DBH -1021C>T does not play a major role in the pathogenesis of Parkinson's disease. [ABSTRACT FROM AUTHOR]