A randomized, controlled trial of oral propranolol in infantile hemangioma.

BACKGROUND: Oral propranolol has been used to treat complicated infantile hemangiomas, although data from randomized, controlled trials to inform its use are limited. METHODS: We performed a multicenter, randomized, double-blind, adaptive, phase 2-3 trial assessing the efficacy and safety of a pediatric-specific oral propranolol solution in infants 1 to 5 months of age with proliferating infantile hemangioma requiring systemic therapy. Infants were randomly assigned to receive placebo or one of four propranolol regimens (1 or 3 mg of propranolol base per kilogram of body weight per day for 3 or 6 months). A preplanned interim analysis was conducted to identify the regimen to study for the final efficacy analysis. The primary end point was success (complete or nearly complete resolution of the target hemangioma) or failure of trial treatment at week 24, as assessed by independent, centralized, blinded evaluations of standardized photographs. RESULTS: Of 460 infants who underwent randomization, 456 received treatment. On the basis of an interim analysis of the first 188 patients who completed 24 weeks of trial treatment, the regimen of 3 mg of propranolol per kilogram per day for 6 months was selected for the final efficacy analysis. The frequency of successful treatment was higher with this regimen than with placebo (60% vs. 4%, P<0.001). A total of 88% of patients who received the selected propranolol regimen showed improvement by week 5, versus 5% of patients who received placebo. A total of 10% of patients in whom treatment with propranolol was successful required systemic retreatment during follow-up. Known adverse events associated with propranolol (hypoglycemia, hypotension, bradycardia, and bronchospasm) occurred infrequently, with no significant difference in frequency between the placebo group and the groups receiving propranolol. CONCLUSIONS: This trial showed that propranolol was effective at a dose of 3 mg per kilogram per day for 6 months in the treatment of infantile hemangioma. (Funded by Pierre Fabre Dermatologie; ClinicalTrials.gov number, NCT01056341.).

The germline variants in DNA repair genes in pediatric medulloblastoma: a challenge for current therapeutic strategies.

BACKGROUND: The defects in DNA repair genes are potentially linked to development and response to therapy in medulloblastoma. Therefore the purpose of this study was to establish the spectrum and frequency of germline variants in selected DNA repair genes and their impact on response to chemotherapy in medulloblastoma patients. METHODS: The following genes were investigated in 102 paediatric patients: MSH2 and RAD50 using targeted gene panel sequencing and NBN variants (p.I171V and p.K219fs*19) by Sanger sequencing. In three patients with presence of rare life-threatening adverse events (AE) and no detected variants in the analyzed genes, whole exome sequencing was performed. Based on combination of molecular and immunohistochemical evaluations tumors were divided into molecular subgroups. Presence of variants was tested for potential association with the occurrence of rare life-threatening AE and other clinical features. RESULTS: We have identified altogether six new potentially pathogenic variants in MSH2 (p.A733T and p.V606I), RAD50 (p.R1093*), FANCM (p.L694*), ERCC2 (p.R695C) and EXO1 (p.V738L), in addition to two known NBN variants. Five out of twelve patients with defects in either of MSH2, RAD50 and NBN genes suffered from rare life-threatening AE, more frequently than in control group (p = 0.0005). When all detected variants were taken into account, the majority of patients (8 out of 15) suffered from life-threatening toxicity during chemotherapy. CONCLUSION: Our results, based on the largest systematic study performed in a clinical setting, provide preliminary evidence for a link between defects in DNA repair genes and treatment related toxicity in children with medulloblastoma. The data suggest that patients with DNA repair gene variants could need special vigilance during and after courses of chemotherapy.

Contrast enhancement pattern predicts poor survival for patients with non-WNT/SHH medulloblastoma tumours.

Recent studies revealed the biological heterogeneity of medulloblastoma, with the existence of at least four groups which are associated with several clinical and morphological features. We investigated for further correlations between molecular types, location of tumours, their contrast enhancement pattern and survival of patients. Altogether 76 tumours were analyzed and molecular subtypes were identified by immunohistochemistry using representative antibodies, detection of chromosome 6 monosomy and CTNNB1 mutation. The site of the tumour was assessed on diagnosis using Magnetic Resonance images and intra-operative surgical reports. In addition, the gadolinium enhancement pattern was also investigated in pre-treatment tumours. Cerebellar hemispheric location was associated with SHH tumours (p < 0.001), as opposed to midline location being typical for WNT and non-WNT/SHH tumours. Remarkably, for patients with non-WNT/SHH tumours, the extensive gadolinium enhancement pattern (present in >75% of tumour volume) predicted worse OS and EFS than for those with none/weak or heterogeneous enhancement (>10-75% of tumour volume), (both p < 0.001). Our analysis indicates that distribution of the medulloblastoma tumours location is related to the biological characteristics of tumour. Importantly, the enhancement pattern of the tumour may be a clinically useful prognostic marker for patients with non-WNT/SHH medulloblastomas.

DNA methylation profiling of medulloblastoma allows robust subclassification and improved outcome prediction using formalin-fixed biopsies.

Molecular subclassification is rapidly informing the clinical management of medulloblastoma. However, the disease remains associated with poor outcomes and therapy-associated late effects, and the majority of patients are not characterized by a validated prognostic biomarker. Here, we investigated the potential of epigenetic DNA methylation for disease subclassification, particularly in formalin-fixed biopsies, and to identify biomarkers for improved therapeutic individualization. Tumor DNA methylation profiles were assessed, alongside molecular and clinical disease features, in 230 patients primarily from the SIOP-UKCCSG PNET3 clinical trial. We demonstrate by cross-validation in frozen training and formalin-fixed test sets that medulloblastoma comprises four robust DNA methylation subgroups (termed WNT, SHH, G3 and G4), highly related to their transcriptomic counterparts, and which display distinct molecular, clinical and pathological disease characteristics. WNT patients displayed an expected favorable prognosis, while outcomes for SHH, G3 and G4 were equivalent in our cohort. MXI1 and IL8 methylation were identified as novel independent high-risk biomarkers in cross-validated survival models of non-WNT patients, and were validated using non-array methods. Incorporation of MXI1 and IL8 into current survival models significantly improved the assignment of disease risk; 46 % of patients could be classified as 'favorable risk' (>90 % survival) compared to 13 % using current models, while the high-risk group was reduced from 30 to 16 %. DNA methylation profiling enables the robust subclassification of four disease subgroups in frozen and routinely collected/archival formalin-fixed biopsy material, and the incorporation of DNA methylation biomarkers can significantly improve disease-risk stratification. These findings have important implications for future risk-adapted clinical disease management.

Adrenocortical carcinoma - 12-year observation period in a single centre. Case report with literature review.

BACKGROUND: Adrenocortical carcinoma (ACC) accounts for 0.2% of childhood malignancies. The most common symptom in children is rapidly progressive androgenization. Herein, we report a case of a patient with symptoms of hypercortisolaemia and androgenization, who was diagnosed with ACC. CASE PRESENTATION: In a 10-year-old patient with ACC the course of the disease was complicated by 3 recurrences. She was treated with surgery, chemo-, and radiotherapy. Currently, 8 years after the end of treatment, there have been no signs of recurrence. CONCLUSIONS: A patient after ACC treatment requires regular check-ups and long-term observation. Constant supervision enables early diagnosis of disease recurrence, and the use of treatment improves the prognosis.

Intraspinal mesenchymal chondrosarcoma in a 14-year-old patient: diagnostic and therapeutic problems in relation to the review of literature.

Mesenchymal chondrosarcoma (MC) is an infrequent, highly malignant neoplasm of the soft tissues and bone. It is very rare in the pediatric age group, especially in the intraspinal location. Only 24 cases have been reported to date. The authors present a case of a 14-year-old boy with an intraspinal MC who died of the disease 50 months from the initial diagnosis and after the third local recurrence. The patient was treated with a combination of chemotherapy, radiotherapy, and surgery. The authors review the clinical presentation, diagnostics, and the efficacy of treatment of pediatric patients with MC reported in the literature from 1978 to 2010.

Congenital brain tumors in a series of 56 patients.

INTRODUCTION: Central nervous system tumors diagnosed before the end of the first year of life differ from those found in older children and in adults. The differences include mode of clinical presentation, anatomical distribution, histopathological diagnoses, response to therapy, and outcome. MATERIALS AND METHODS: The material consists of 56 children (23 girls and 33 boys), aged at recognition 32 Hbd-12 months. We reviewed charts and MR exams according to age of the onset of symptoms, location of tumors, treatment, histopathology, and outcomes. Data of the outcome were analyzed using Kaplan-Meier plots and chi-square test. RESULTS: Eleven cases were recognized before 6 weeks of life, 24 before the age of 6 months, and 21 were diagnosed up to the end of 1 year of age. Thirty-eight tumors were located in the supratentorial compartment; 18 were infratentorial. Median age of tumors' recognition was 5.2 months; 4.3 months for supratentorial and 7.2 months for infratentorial tumors. We found 18 glial cell tumors (high and low grade), 15 embryonal tumors, and 12 choroid plexus tumors. CONCLUSIONS: The outcome of congenital CNS tumors depends on the size, location, time of diagnosis, histological type of the tumor, and therapeutic option. Neurosurgical procedures are necessary in most cases. Despite the notable advances in therapy, the outcome remains poor.

Incidental sonographic detection of mucosa-associated lymphoid tissue lymphoma of the urinary bladder found in a very young woman: report of a case.

We report a rare case of a mucosa-associated lymphoid tissue (MALT)-type lymphoma of the bladder, incidentally found on sonography in a 17-year-old girl during the workup of arterial hypertension. The diagnosis was established by a transurethral biopsy. Treatment consisted of transurethral resection of the bladder tumor and subsequent chemotherapy. To the best of our knowledge, this is the youngest patient with asymptomatic MALT-type lymphoma of the urinary bladder.

Reirradiation of relapsed brain tumors in children.

AIM: The aim of this study was to evaluate toxicity and response to fractionated reirradiation (FR) of relapsed primary brain tumors in children. BACKGROUND: The treatment options for recurrent brain tumors in children previously irradiated are limited. Reirradiation is performed with fear due to the cumulative late CNS toxicity and the lack of a significant chance of cure. MATERIALS AND METHODS: Between 2008 and 2009, eight children with a median age of 14.5 years with a diagnosis of a recurrent brain tumor underwent reirradiation. Initially, all patients were treated with surgery, chemotherapy and radiotherapy. The median time to the first recurrence after the initial treatment was 19.5 months. Intervals between radiotherapy courses were in the range of 5-51 mos. All retreatments were carried out with 3D image-based conformal methods. The total prescription dose was 40 Gy in a fraction of 5 × 2 Gy/week. The total cumulative dose ranged from 65 to 95 Gy (median: 75 Gy). The median cumulative biologically effective dose was 144 Gy (range: 126-181 Gy). RESULTS: The median overall survival and progression free survival measured from the beginning of reirradiation was 17.5 and 6.5 months, respectively. During the first evaluation, four patients showed a complete or partial response, two did not respond radiologically. Two children were progressive at the time of reirradiation. Among children with progression that occurred during the first year after reirradiation, only two progressed in the treatment area. The repeated irradiation was well tolerated by all patients. No late complications have been observed. CONCLUSION: In the absence of other treatment possibilities, the fractionated reirradiation with highly conformal three-dimensional planning could be a therapeutic choice in case of recurrent brain tumors in children. The control of craniospinal dissemination remains to be the main problem.

Prognostic significance of HER2 expression in neuroblastic tumors.

HER2 is essential for normal embryonic development and has a critical function in oncogenesis and progression of some types of cancer. Neuroblastic tumors create a heterogenous group of pediatric embryonal tumors of sympathoadrenal lineage. The biological and prognostic function of HER2 in these tumors is not well established. In this study, we evaluated the status of HER2, its prognostic significance, and clinicopathological correlations in series of 79 untreated neuroblastoma. The immunohistochemical assessment of HER2 and Ki-67 (proliferation index) as well as HER2 copy number status were performed on tissue microarrays. HER2 expression characterized 63 tumors, including 34 with low and 29 with high level, showing either membranous or mixed membranous-cytoplasmic pattern. Sixteen cases were HER2 immunonegative. The pattern of immunolabeling depended on the maturity of neuroblastic cells, being the most intense in differentiating neuroblasts. None of the tumors revealed HER2 amplification. In the examined group, 20% of patients died of disease from 4 to 107 months (median 18) from the diagnosis, and the survivors were followed up for 14-149 months (median 59). Patients' age, stage of disease, tumor location, mitosis/karyorrhexis index (MKI), and presence of HER2 expression were statistically significantly related to survival probability as detected by the Cox proportional hazard model. In the univariate analysis, Kaplan-Meier curves revealed significantly poorer outcome of HER2 negative than HER2-positive tumors (either low or high expression). The immunonegativity was associated with adverse clinicopathological parameters, including poor survival, metastatic stage of disease, un- or poorly differentiated histology, high MKI, and higher proliferation index. In conclusion, HER2 expression, not accompanied by gene amplification, is common in neuroblastic tumors. HER2 positivity seems to have a positive prognostic significance. HER2 expression with a variable pattern is a marker of the stage of neuroblastic cells differentiation.

Heterozygous germ-line mutations in the NBN gene predispose to medulloblastoma in pediatric patients.

The NBN (NBS1) gene belongs to a group of double-strand break repair genes. Mutations in any of these genes cause genome instability syndromes and contribute to carcinogenesis. NBN gene mutations cause increased tumor risk in Nijmegen breakage syndrome (NBS) homozygotes as well as in NBN heterozygotes. NBS patients develop different types of malignancies; among solid tumors, medulloblastoma (MB), an embryonal tumor of the cerebellum, has been reported most frequently. The majority of medulloblastomas occur sporadically, some of them manifest within familial cancer syndromes. Several signaling pathways are known to be engaged in hereditary and sporadic MB. The aim of our study was to identify mutations in selected exons of the NBN gene and to determine the frequency of the most common NBN gene mutations in pediatric patients with different types of medulloblastoma. We screened a total of 104 patients with MB and identified 7 heterozygous carriers (6.7%) of two different germ-line mutations of NBN gene; all of them had classic MB. Our results indicate that heterozygous carriers of the germ-line NBN gene mutations (c.511A>G and c.657_661del5) may exhibit increased susceptibility to developing MB. The risk of medulloblastoma is estimated to be 3.0 (for c.511A>G) and 4.86 (for c.657_661del5) times higher than in the general Polish population (p<0.05). These results suggest that heterozygous NBN germ-line mutations may contribute to the etiology of medulloblastoma.

The frequency of NBN molecular variants in pediatric astrocytic tumors.

Gliomas, particularly those of astrocytic origin, are the most frequent primary central nervous system tumors that develop in children. The majority of them are benign and slow growing, with relatively good prognosis. Several genomic and gene alterations are known to be involved in astrocytoma development, but the precise mechanisms remain poorly understood. The NBN gene, which participates in DNA double-strand break repair and maintenance of genome stability, has been postulated to be a susceptibility factor for a number of cancers. Here we report the results of NBN gene analyses performed in 127 children with various astrocytic tumors. PCR-SSCP analysis followed by DNA sequencing was used for molecular variant screening. Three carriers (2.37%) of different germline mutations on one NBN allele were found. The common Slavic deletion c.657_661del5 (p.K219fsX19) was detected in a patient with pilocytic astrocytoma; a known mutation, c.643C>T (p.R215W), and a new substitution, c.565C>G (p.Q189E), were identified in two patients with primary glioblastoma. The risk of developing astrocytic malignancies is estimated to be 1.33 times higher for c.657_661del5 and 3.2 times higher for c.643C>T than in the general Polish population (P > 0.05). Because of the low frequency of the mutations identified in the studied group, we were unable to determine the exact role of NBN in the development of astrocytoma in children. The presence of two potentially pathogenic NBN molecular variants among 16 glioblastoma cases (12.5%) could be a remarkable finding in our study. We thus cannot exclude a possible role of NBN in the tumorigenesis of a certain type of astrocytic tumors.

Analysis of PI3K/AKT/mTOR signalling pathway in high risk neuroblastic tumours.

Neuroblastoma (NB) represents one of the most common paediatric tumours. Despite advance in NB research and treatment, the outcome of the patients from the high-risk group remains poor. PI3K/AKT/mTOR signalling pathway which is involved in oncogenesis and cancer progression of many tumours, in parallel constitutes the target for the biologically based oncological therapy. In this study we analyzed the status of PI3K/AKT/mTOR signalling route in the primary tumour tissue samples from a group of 39 high-risk NB. The pathway activation state was assessed immunohistochemically using antibodies with specificity towards PI3Kp85, PI3Kp110, phospho-AKT, phospho-mTOR, phospho-p70S6K and phospho-4EBP1. Moreover, expression of PTEN, bcl2 and cyclin D1 was examined. We found that most of tumours were positive for PI3Kp85 and PI3Kp110, as well as for p-AKT, p-mTOR and its downstream effectors p-p70S6K and p-4EBPI. PTEN was expressed in all cases, bcl2 and cyclin D1 staining was found in more than 90% of examined NB. Statistical analysis revealed that p-AKT expression was correlated with p-mTOR and strong cyclin D1 labelling. Furthermore, high expression of p-4EBP1 was significantly associated with p-p70S6K expression, high cyclin D1 and lower differentiation of the tumour. PI3K/AKT/mTOR signalling pathway activation is a common event in high-risk NB and it seems that this group of patients may benefit from targeted therapy with kinase inhibitors.

[Treatment results of children with neuroblastoma: report of Polish Pediatric Solid Tumor Group]. / Wyniki leczenia dzieci ze zwojakiem zarodkowym wspólczulnym: wstepny raport Polskiej Pediatrycznej Grupy Guzów Litych.

Approximately 60 children aged 0-18 years are diagnosed of NBL each year in Poland. About 60% of all patients suffering from NBL have a chance for durable cure. Unfortunately the prognosis for patients within the high-risk group accounting for more than 50% of all NBL patients remains poor despite the introduction of more intensive chemotherapy regimens with radical surgery procedures and megachemotherapy with subsequent stem cell transplantation. Only one third of patients in this group can be cured. To improve the treatment results of the high-risk patient group and to decrease the rate of therapy related side effects current European treatment protocols have been introduced systematically in Poland. In February 2009 information about 389 patients (age 0.1-16.5 years) diagnosed between 2001 and 2008 were obtained. Results of therapy of 319 patients who started treatment from 2001 to 2007 were analyzed. Between 104 infants and 215 children over 1 year of age, stage 4 of disease was found in 25% and 54.5%, respectively. In this period additionally to European treatment protocols, two another protocols were used. Satisfactory treatment results were obtained in 104 infants (5-year event free survival /EFS/=82.6%), irrespective of the type of treatment protocol. Over 5-year EFS for children over 1 year of age in 1, 2 and 3 stage of disease was: 100%, 86.3% and 64.5%, respectively. On the contrary, 107 patients with 4 stage of disease achieved the 5-year EFS of 27% only. Treatment results obtained in patients treated according to the European HR-NBL-1/ESIOP protocol were better than for patients treated according to other treatment protocols (5-year EFS: 31.1% and 16.4%, respectively), but difference between these groups was not significant. Between 2001 and 2007 data reporting increased to 81% from 19% noted earlier. Unfortunately, results of treatment for children over 1 year of age remain still unsatisfactory. That is why there is a need of improvement of modern, unified treatment realization as well as better data reporting. For realization of these aims adequate financial support is essential.

c.1810C>T polymorphism of NTRK1 gene is associated with reduced survival in neuroblastoma patients.

BACKGROUND: TrkA (encoded by NTRK1 gene), the high-affinity tyrosine kinase receptor for neurotrophins, is involved in neural crest cell differentiation. Its expression has been reported to be associated with a favourable prognosis in neuroblastoma. Therefore, the entire coding sequence of NTRK1 gene has been analysed in order to identify mutations and/or polymorphisms which may alter TrkA receptor expression. METHODS: DNA was extracted from neuroblastomas of 55 Polish and 114 Italian patients and from peripheral blood leukocytes of 158 healthy controls. Denaturing High-Performance Liquid Chromatography (DHPLC) and Single-Strand Conformation Polymorphism (SSCP) analysis were used to screen for sequence variants. Genetic changes were confirmed by direct sequencing and correlated with biological and clinical data. RESULTS: Three previously reported and nine new single nucleotide polymorphisms were detected. c.1810C>T polymorphism present in 8.7% of cases was found to be an independent marker of disease recurrence (OR = 13.3; p = 0.009) associated with lower survival rates (HR = 4.45 p = 0.041). c.1810C>T polymorphism's unfavourable prognostic value was most significant in patients under 18 months of age with no MYCN amplification (HR = 26; p = 0.008). In-silico analysis of the c.1810C>T polymorphism suggests that the substitution of the corresponding amino acid residue within the conservative region of the tyrosine kinase domain might theoretically interfere with the functioning of the TrkA protein. CONCLUSIONS: NTRK1 c.1810C>T polymorphism appears to be a new independent prognostic factor of poor outcome in neuroblastoma, especially in children under 18 months of age with no MYCN amplification.

Non-Hodgkin lymphoma (NHL) in children with Nijmegen Breakage syndrome (NBS).

BACKGROUND: Due to small number of patients with Nijmegen Breakage Syndrome (NBS) and Non-Hodgkin lymphoma (NHL) experience in their treatment is limited. PROCEDURE: Since 1996, 17 patients with a median age of 9.5 years who had NBS, were treated for NHL. NHL type, stage, chemotherapy, dose modifications, chemotherapy delays, response to chemotherapy, toxicity, outcome and correlation of drug reduction with response to treatment and outcome were analyzed. RESULTS: Nine patients had TNHL, eight BNHL. TNHL patients received BFM and BNHL LMB type protocols. Doses of cytostatics were reduced in the first chemotherapy courses. Further modifications depended on severity of complications. None of the patients complied with timing of chemotherapy. Complete remissions after induction were achieved in 8 of 9 TNHL and 3 out 8 of BNHL patients. All patients experienced grade 4 toxicities. Two patients died from complications. Six of 17 patients are alive. All received more than 80% of recommended doses of chemotherapy. No differences in the type, number of responses or grade 3 and 4 toxicities between patients receiving less or more than 80% of drug doses were observed. Treatment related deaths concerned patients who received less than 80% of drug doses. CONCLUSIONS: Patients with NBS develop both T and B cell lymphomas. Treatment outcome is poor and might be improved by administering over 80% of drug doses. Although toxicity often depends upon drug doses, our patients experienced equal grade 3 and 4 toxicities whether they received more or less than 80% of the chemotherapeutic agents.

Ganglioglioma associated with alterations of NBN gene. A case report.

We report a case of a 13-year-old girl with a tumour of the right fronto-parietal region of the brain. The tumour consisted of two components: a well-differentiated astroglial component with Rosenthal fibres and a neoplastic neuronal component. The final histopathology established diagnosis of ganglioglioma WHO grade I. The patient was selected from a group of children with central nervous system (CNS) tumours screened for the most common molecular variants in the NBN gene (exons 5 and 6). Molecular analysis revealed the presence of c.511A>G (p.Ile171Val) substitution on one allele. This is the first patient with ganglioglioma and confirmed mutation in the NBN gene.

Infectious complications in children treated for hodgkin and non-hodgkin lymphomas in polish pediatric leukemia/lymphoma study group: incidence, epidemiology and etiology.

The objective of this nation-wide study was to evaluate the epidemiology and profile of bacterial (BI), viral (VI), and invasive fungal disease (IFD) in patients treated for non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL) between the years 2013-2015. In the analyzed period of time, within the studied group of 328 children diagnosed and treated for lymphomas, at least one infectious complication (IC) was diagnosed i.e. 39.3% children. In these patients there were 350 episodes of IC, therein 80.6% episodes of BI, 11.1% episodes of VI, and 8.3% episodes of IFD. In both groups, NHL and HL patients, a stable level of bacterial infections, with an increase in resistance rates, and increased levels of viral and fungal infections were observed. Profile of BI does not depend on lymphoma type, with predominance of Gram-negative bacteria and higher prevalence of MDR pathogens. The overall survival of lymphoma patients with IC was comparable for different types of infections.

Patterns of failure in children with medulloblastoma treated with 3D conformal radiotherapy.

BACKGROUND AND PURPOSE: Craniospinal irradiation for medulloblastoma is one of the most complex techniques employed in radiotherapy. Many reports stress the impact of irradiation quality on survival in these patients. Our report presents the outcome and patterns of failure for 95 patients treated with 3D conformal radiotherapy (3D-CRT). MATERIALS AND METHODS: From 1998 to 2003, 95 children with medulloblastoma received 3D conformal radiotherapy. All of them were previously treated with surgery and chemotherapy. The brain and upper spinal cord were treated with two lateral 6MV photon fields. In four patients, the cribriform plate was irradiated by the additional field. For primary tumour bed we applied two or three photon beams. Spinal cord was irradiated either with 18-20MeV electron fields or with a mixed beam. RESULTS: With a median follow-up of 48 months, 32/95 patients suffered a multifocal (21) or isolated (11) recurrence. We evaluated every primary site of failure. In all patients, the recurrence appeared within the isodose level of 95-100%. CONCLUSIONS: Patterns of failure in medulloblastoma patients treated with 3D conformal radiotherapy indicated that the relapse was mainly associated with poor response to pre-irradiation chemotherapy. We believe that 3D conformal radiotherapy allows avoiding failures, related to radiotherapy uncertainties.

Clinicopathological considerations on angiogenic potential in neuroblastoma Schwannian stroma - poor tumours.

The aim of the study was to determine microscopic angiogenic parameters of neuroblastoma (NB) Schwannian stroma-poor tumours. Furthermore the associations between vascular parameters and clinicopathological features of tumours and basic prognostic factors were analysed. Examined tissue samples from 62 NB came from 39 untreated and 23 chemotherapy pretreated tumours. The clinicopathological data comprised: patients' age, gender, survival, tumour site and stage, tumour histology and MYCN status.The morphological analysis of the angiogenic potential concentrated on examination of vascular patterns - classical type or pathological angiogenesis with mural microvascular proliferation (MVP). The quantitative study included semi-automatic assessment of vascular density (VD) in CD34 stained tumour sections. Pathologic angiogenesis with MVP, including simple and/or glomeruloid type, was encountered in 25 cases and was more frequent in differentiating histology subtype and extraadrenal tumours. VD value ranged from 56 to 385 vessels/mm2 (median 149). Higher VD was connected with younger patient's age. In untreated tumours VD was significantly higher in infants than in children over one year of age. Pathologic type angiogenesis and lower VD were found to be associated with shorter survival. Our study confirmed high vascularization of NB and revealed common occurrence of vascular pattern with MVP. Angiogenic potential in the analysed group showed diversity related to some clinicopathological tumour features. This points toward heterogeneity of NB tumours in vascular aspects, possibly affecting tumours' reactivity to antiangiogenic therapy.