Increased risk of infections and infection-related mortality in children undergoing haematopoietic stem cell transplantation compared to conventional anticancer therapy: a multicentre nationwide study.

This nationwide multicentre study analysed the epidemiology of bacterial, viral and fungal infections in paediatric haematopoietic stem cell transplantation (HSCT) and paediatric haematology and oncology (PHO) patients over a period of 24 consecutive months, including incidence, hazard risk and outcome of infections as well as occurrence of multidrug-resistant bacteria. During this period, 308 HSCTs were performed and 1768 children were newly diagnosed for malignancy. Compared to PHO, the risk in HSCT patients was significantly higher for all infections (hazard ratio (HR) 2.7), bacterial (HR 1.4), fungal (HR 3.5) and viral (HR 15.7) infections. The risk was higher in allo- than auto-HSCT for bacterial (HR 1.4), fungal (HR 3.2) and viral (HR 17.7) infections. The incidence of resistant bacteria was higher in HSCT than in PHO patients for both G-negative (72.5% vs. 59.2%) and G-positive (41.4% vs. 20.5%) strains. Cumulative incidence of bacterial, fungal and viral infections in HSCT patients was 33.9, 22.8 and 38.3%, respectively. Cumulative incidence of viral infections in allo-HSCT was 28.0% for cytomegalovirus, 18.5% for BK virus, 15.5% for Epstein-Barr virus, 9.5% for adenovirus, 2.6% for varicella zoster virus, 0.9% for influenza, 0.9% for human herpesvirus 6 and 0.3% for hepatitis B virus. Survival rates from infections were lower in HSCT than in PHO patients in bacterial (96.0 vs. 98.2%), fungal (75.5 vs. 94.6%) and most viral infections. In conclusion, the risk of any infections and the occurrence of resistant bacterial strains in allo-HSCT patients were higher than in auto-HSCT and PHO patients, while the outcome of infections was better in the PHO setting.

Second brain tumors following central nervous system radiotherapy in childhood.

OBJECTIVE: The second tumour (ST) occurrence is a relatively uncommon late complication of radiotherapy but represents one of the most significant issues, especially in childhood oncology. We describe our experience with patients who developed second brain neoplasm following cranial irradiation in childhood. METHODS: We identified nine patients who received radiotherapy owing to central nervous system tumour in childhood and subsequently developed the second brain tumour. The full clinical and radiological documentation and histopathological reports were reviewed. Risk factors such as age at irradiation, latency period to ST diagnosis, radiotherapy doses and volumes and other therapy methods were evaluated. We correlated the ST location with the three levels of irradiation dose (high, >40 Gy; medium, 25-40 Gy; and low <25 Gy). RESULTS: Five meningiomas and four gliomas occurred as the ST after the mean time of 11.7 years after radiotherapy. The average age of children during irradiation was 4.6 years. The shorter latency time to the ST induction was found in children treated with chemotherapy (9 years vs 17.2 years). Seven STs developed in the area of high and moderate dose (>25 Gy), only two low-grade gliomas appeared in the low-dose region. CONCLUSION: Our data suggest that the STs usually develop in the brain tissues that received doses >25 Gy in patients irradiated at a young age. ADVANCES IN KNOWLEDGE: The low-dose volume seems not to be so significant for second brain neoplasm induction. Therefore, the modern intensity-modulated radiotherapy technique could be safely applied in paediatric patients.

Liver transplantation in children with hepatocellular carcinoma. Do Milan criteria apply to pediatric patients?

HCC constitutes 25-30% of primary malignant liver tumors in children. Conventional surgical excision is not possible in more than 50% of patients. LTx has recently become an important therapeutic option for adults and children with primary liver tumors. The aim of this study was a retrospective analysis of the clinical and pathological data of children with HCC treated with LTx in relation to Milan criteria assessed at diagnosis and then immediately before transplantation, in comparison with a group of patients treated conventionally. Between 1990 and 2007 we have treated 21 children diagnosed with HCC. Patients were divided into two groups: group I, 10 children treated conventionally and group II, 11 children treated with LTx regardless of previous therapy. The outcome of our patients treated conventionally with resection and chemotherapy is very poor--the disease-free survival rate is 30%. In contrast, despite that only 3 children having fulfilled adult Milan criteria, early clinical results of LTx are much superior. Total hepatectomy followed by LTx is the main treatment option for the majority of children with HCC. Decisions on the type of surgical treatment is made individually, but very early in the course of treatment.

Postural sway in children and young adults, survivors of CNS tumours.

PURPOSE: Brain tumours are the most common solid tumours in children and adolescents. The increasing survival rate of these patients makes their follow-up and quality of life assessment an important task. The evaluation of the negative influence of anti-cancer treatment on their balance is the aim of this study. MATERIAL AND METHODS: The balance assessment was performed on patients who completed the treatment of CNS tumours and were disease-free at the time of the study. Eighty-eight patients aged 5 to 24 years participated in the study. Postural sway was recorded using Kistler force plate. Balance test parameters from two conditions: eyes open and eyes closed were calculated and compared with reference data. The severity of the balance disorders was scored for both conditions. RESULTS: The balance disorders were generally not dependent on the localisation of the tumour. Only patients treated for posterior fossa tumours had a higher score (indicating pronounced balance deficit) in eyes closed condition comparing to others. The patients treated for spinal cord tumours seemed to have increased total sway path in comparison to others. The severity of the balance deficits tended to diminish in time. CONCLUSIONS: These results suggest that the repair mechanisms of the CNS could overcome the problems inflicted by the illness and therapy.

A correlation of microvascular density and proliferative activity to clinical and histological characteristics in neuroblastoma.

Seventy-four neuroblastoma patients were analyzed according to the clinical data including age, stage, bone metastases, primary tumor localization, tumor diameter, LDH, and serum ferritin. Histological examination of tumor specimens comprised calculation of proliferative index (PI) on slides stained with anti Ki-67 antibody and assessment of microvascular density (MVD) on anti-CD34 stained sections. Wide range of PI (1.5-79; median 37.8%) and MVD (41-385; median 172/mm2) values was observed. Significant relationship between higher PI and tumor diameter more than 5 cm (40.3 vs 37.2%) was found. Lower PI was found more frequently in stroma-rich tumors. Significantly higher median MVD was found in infant tumors and in smaller tumors <5 cm. Tendency to inverse relationship between PI and MVD was observed. The high values of both PI and MVD were found in some aggressive tumors in patients >1-year old. We evaluated the new parameter: proliferative-vascular index (PVI) as PVI=PIxMVD which ranged from 213-18333. Among eleven patients >1 year old, with PVI >7000, seven (64%) had a poor outcome within the mean period of 22 months. Our results suggest that the simultaneous estimation of proliferative activity and vascularity of neuroblastomas could be studied as a prognostic indicator. Further investigations are needed to confirm this finding.

Screening for germline p53 mutations in pediatric and adult patients of high-risk groups in Poland.

Germline mutations of the p53 gene lead to cell transformation in various tissues. Such a complex cancer phenotype makes it difficult to recognize the carriers of the defective allele. Several studies undertaken to identify high-risk groups found germline p53 mutations in familial cancer aggregations and in patients with multiple tumors. We screened 189 pediatric and 48 adult patients. The high-risk groups comprised 41 patients with a family history of cancer and 35 with multiple neoplasms. Furthermore, 124 tumors were screened for somatic mutations. p53 exons 2 to 11 were analyzed by polymerase chain reaction and single strand conformation polymorphism (PCR-SSCP) followed by direct sequencing of abnormal DNA fragments. No germline p53 mutations were found and somatic mutations were detected in 5 of 59 sarcomas, globally, in 8 of 124 tumors. In conclusion, in Poland, p53 alterations do not seem very important for the predisposition to malignancy and development of sarcomas.

[High risk Wilms' tumor in children. Clinico-pathological correlation based on 320 patients registered in the Polish Paediatric Solid Tumor Study Group]. / Nerczak plodowy u dzieci z Wysokim ryzykiem zlosliwosci. Korelacje kliniczno-patologiczne u 320 dzieci zarejestrowanych w Polskiej Pediatrycznej Grupie ds. Leczenia Guzów Litych.

The records of 320 patients treated for Wilms' tumour in the first Wilms' Tumour Study (01-92 schedule) were reviewed and 42 children (13,86%) with unfavourable histology (UH) tumours were identified. There were 18 boys and 24 girls. Diffuse anaplasia was found in 26 patients (61,9%), focal anaplasia in 10 children (23,8%), CCSK and MRT were diagnosed in 3 patients each (7,1%). Clinical stages were: CS I - 5 (11,9%) patients, CS II N(-) - 7 (16,7%), CS II N(+) - 9 (21,4%), CS III - 15 (35,7%), CS IV - 5 (11,9%) and CS V - 1 patient (2,4%). Local and metastatic relapses of the disease occurred in 18 patients (43%). Seven of the 42 patients died, in 2 cases due to complications and in 5 from progression of the disease.

Risk factors of recurrence in 157 MB/PNET patients treated in one institution.

To evaluate the risk factors for recurrence of MB/PNET we analyzed the medical records of 157 patients treated at the Children's Memorial Health Institute between February 1981 and February 1997. The following factors were evaluated: age at diagnosis, gender, tumor size, tumor cells in the CSF, postoperative status, extent of resection and methods of treatment. We evaluated chemotherapy (CHT) doses, interval between courses, interval between surgery (S) and first course of CHT, interval between S and radiotherapy (RTX), and breaks during RTX. We divided patients into six groups: S alone, S+CHT, S+RTX, S+CHT+ RTX, S+RTX+CHT, S+CHT+RTX+ CHT. Age at diagnosis, gender, tumor size, extent of resection, postoperative status, intervals between courses of CHT, between S and the first course of CHT, and between S and RTX, and breaks during RTX had no statistical influence on relapse occurrence. Tumor cells in CSF were routinely checked for from January 1992 onward. In this group of 75 patients, 40 had tumor cells positive at surgery (28 relapsed), while in the group of 35 patients with negative tumor cells 14 relapsed (P=0.004). Out of 26 patients treated with S+RTX alone, 13 relapsed. Among 14 patients treated with S+RTX and prolonged CHT 6 relapsed. Out of 14 patients treated with S+CHT 13 relapsed; among 49 who received S+CHT+RTX 35 relapsed; and out of 51 patients treated with S+CHT+RTX+CHT 30 relapsed. In the multivariate analysis of treatment methods chemotherapy implemented after radiotherapy had a positive, though not statistically significant, influence on outcome (P=0.06). Among those receiving CHT the mean percentage of the ideal dose administered had a statistically significant influence on relapse: in the group of relapsed patients the mean dose was 76.1%, while in the group in continuous remission it was 83.7% (P=0.0013). On the basis of our data, we conclude that the presence of tumor cells in the CSF had a significant influence on the occurrence of relapse. Administration of appropriate doses of chemotherapy is extremely important for the occurrence of relapse and the final outcome of treatment. Prolonged adjuvant chemotherapy after radiotherapy seems to lower the risk of recurrence.

[The role of chemotherapy in treatment of nephroblastoma in children. Report of the Polish Pediatric Group re. treatments of solid tumors]. / Udzial chemioterapii w leczeniu nerczaka zarodkowego u dzieci. Raport Zespolu Polskiej Grupy Pediatrycznej ds. Leczenia Guzów Litych.

Retrospective analysis of chemotherapy results of children with nephroblastoma was performed in 220 patients aged from 1 yr to 14 yrs of live in 12 centers. Stage I nephroblastoma was documented in 24.5% but stage II--in 55.3%. Histologically 74.6% cases were diagnosed as medium malignant and 12.7%--high malignant. Therapy results were similar to observed in other centers.

[Progress in the treatment of children with Wilms' tumor in the Department of Pediatric Oncology at the Institute of Mother and Child]. / Postepy w leczeniu guzów Wilmsa u dzieci w Klinice Onkologii Dzieci i Mlodziezy Instytutu Matki i Dziecka.

A retrospective analysis of treatment results of 242 children with Wilms tumor treated in the years 1962-1989 is presented. The patients (pts) were divided into 4 groups according to methods of treatment that changed with the time. Group I consisted of patients treated between 1962-1965. Surgery followed by radiotherapy (RTX) and monochemotherapy (CHT) (ACTD) were the main treatment methods. Group II consisted of 68 patients treated between 1966-1974. In this group, surgery was followed by RTX and CHT (multiple courses of ACTD + VCR). Group III included 68 patients treated between 1975-1982. Preoperative RTX (20 Gy) and CHT (ACTD) were administered. RTX (total 35 Gy) and adjuvant CHT were continued after surgery. Group IV consisted of 62 patients treated in 1982-1989. Preoperative CHT (ACTD, VCR +/- ADR) was introduced. Adjuvant treatment depended on stage and histology of the tumor. The treatment results were as follows: 27, 66.1, 38.2 and 85.4% of survival, respectively. This points to the beneficial role of induction CHT, delayed surgery with adjusting the intensity of further adjuvant treatment to stage and tumor histology.

[Progress in the treatment of 155 children with rhabdomyosarcoma obtained in one center between 1962-1990]. / Postep w leczeniu rhabdomyosarcoma uzyskany w jednym osrodku u 155 dzieci w latach 1962-1990.

The results of treating 155 children with rhabdomyosarcoma using protocols that (RMS) changing over the years between 1962-1990 in reported to progress in chemotherapy (CHT), introduction of megavoltage radiotherapy (RTX) and conservative surgery with attempts to preserve vital organs are presented. In the first period between 1962-1980 when mainly surgery was applied with orthovoltage RTX and low intensity CHT, only 20 of 74 children (27%) survived. In the second period 1981-1985 systemic CHT containing new cytostatic, megavoltage RTX and limited surgery applied in advanced cases after induction of CHT were introduced. Nineteen of 46 children (41.3%) survived. In the last period a 1986-1990 more intensive CHT with an own modified protocol VACA/VAIA and intensification phases containing cisplatinum, etoposide and/or carboplatinum were introduced. Twenty seven of 35 patients (60%) survived. Comparative analysis of the last two periods pointed to significant progress in treatment in III clinical group (IRS classification), (20.7% vs 62.9%) and parameningeal RMS (0% vs 58%). Meaningful improvement concerned also young children below 5 years of age (42.8% vs 73.9%). The main prognostic factors and treatment failures of the recent years were analyzed.

[Blood antioxidant defense in children with malignant disease. I. Plasma antioxidant activity and level of ceruloplasmin and transferrin]. / Obrona przeciwutleniajaca we krwi dzieci z choroba nowotworowa. Czesc I. Aktywnosc przeciwutleniajaca osocza oraz stezenie ceruloplazminy i transferyny.

In this study we examined selected elements of the antioxidant defence system in the plasma of children with the most common solid tumors (nephroblastoma, neuroblastoma, rhabdomyosarcoma, osteosarcoma). We observed a significant increase of plasma antioxidant activity (AOA) in the majority of the examined children. This factor changed during clinical treatment, i.e. induction of chemotherapy, surgery and/or radiotherapy and during maintenance chemotherapy. We conclude that the elevated plasma antioxidant activity in children with malignancy may be due to the higher concentration of ceruloplasmin in affected children than in their healthy counterparts.

[Defense system antioxidants in blood of children with neoplasms. II. Antioxidant enzymes and lipid peroxidation in erythrocytes]. / Obrona przeciwutleniajaca we krwi dzieci z choroba nowotworowa. Czesc II. Enzymy przeciwutleniajace oraz peroksydacja lipidów w krwinkach czerwonych.

The aim of the work was to investigate selected parameters of antioxidant defence in red blood cells of children suffering from various types of solid tumors. In patients with these tumors, glutathione reductase and glutathione S-transferase activities were found to be reduced in comparison to healthy children.

[Preliminary evaluation of individualized use of large doses of methotrexate for treatment of osteosarcoma in children and adolescents]. / Wstepna ocena zastosowania indywidualizowanych duzych dawek metotreksatu w leczeniu miesaka kosciopochodnego u dzieci i mlodziezy.

To improve the final treatment results in children with osteosarcoma, we applied after French DD-11 protocol HD MTX increasing with the younger age of patients, modified next on the basis of maximal serum drug concentrations (Cmax) as feed-back dosing. Toxic side effects were analysed according to WHO grading correlated with MTX elimination. We administered 39 HD MTX courses in 13 patients with osteosarcoma: aged 7-20 yrs (median 12 yrs). We performed 301 measurements of MTX concentration using the method of fluorescence polarisation. Therapeutic Cmax of 1000 microM/L and higher were obtained in 20 courses, the mean of lower values was 770 microM/L. We modified the next MTX doses in 23.7% of courses. Drug elimination was good in the majority of cases: in 34 of 39 courses at 24 hrs, in 36 of 39 at 48 hrs. Nevertheless, III and IV degree toxic side-effects accompanied about half of the courses and could not be predicted by MTX serum level measurements. HD MTX therapy with monitoring MTX serum levels proved feasible with acceptable toxicity. Therapeutic MTX levels were obtained in about 60% of cycles in patients with a favourable course of the disease in comparison with 25% in patients with an unfavorable course but the beneficial effect of age-tailored MTX and feed-back dosing on the treatment results will be possible to assess in the next 3 years.

[Role of chemotherapy in treatment of osteosarcoma]. / Rola chemioterapii w leczeniu miesaka kosciopochodnego.

The paper is dedicated to various forms of chemotherapy used in osteosarcoma from the very beginning in '70-ties, when only one drug treatment was applied through the following 20 years full of assays and clinical trials, which finally proved the necessity of multidrug chemotherapy in all cases of osteosarcoma. The introduction of crucial neoadjuvant chemotherapy with exemplary Rosen programme T-10 which enabled the progress of conservative limb-salvage surgery and experience with this programme of many national groups are discussed.

[Langerhans Cell Histiocytosis in adults]. / Histiocytoza komórek Langerhansa u doroslych.

Five cases of Langerhans' cell histiocytosis in adult patients were reviewed. Signs, symptoms, the course of the disease and methods of treatment were presented. Results of tests, including results of organ biopsies that provided definitive diagnosis in most cases, were also analysed.

Urinary dopamine/noradrenaline and dopamine/vanillylmandelic acid ratios as a reflection of different biology of adrenergic clones in children's neuroblastic tumors.

The results of calculations of urinary dopamine/noradrenaline (DA/NAd) and dopamine/vanillylmandelic acid (DA/VMA) ratios in 54 untreated children with neuroblastic tumors are reported. Thirteen patients were in the prognostically favorable group (stages I, II, and IV-S and ganglioneuroma [GN]), and 41 had advanced neuroblastoma (stage III and IV). Among patients with ganglioneuroma and favorable neuroblastoma (n = 13), of whom all were survivors, the urinary DA/NAd and DA/VMA ratios exceeded 1.8 in only 2 cases of stage IV-S and stage I, respectively. In the advanced neuroblastoma group, the DA/NAd and DA/VMA ratios exhibited a wide range of values, but among the stage III and IV survivors (n = 10), DA/NAd ratios greater than 1.8 were noted in only 3 patients. The DA/VMA ratio was not greater than 1.8 in those 3 patients. The mean DA/NAd and DA/VMA proportions in the population comprising all survivors were 1.8 +/- 2.7 (mean +/- SD) and 1.1 +/- 0.4, respectively. The same computations carried out in patients who died showed higher values, ie, the mean DA/NAd and DA/VMA ratios were 5.2 +/- 6.3 and 5.6 +/- 10.5, respectively, showing the difference in DA/NAd and DA/VMA ratios between prognostically favorable and unfavorable groups. Of 23 survivors, only 4 had DA/NAd ratios greater than 1.8 (17%), while 24 of 31 children who died (77%) had DA/NAd ratios was greater than 1.8. The reported results suggest dissimilarity in the catecholamine metabolism of adrenergic clones with respect to the stage of advancement of neoplastic disease.