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INTRODUCTION: Pineoblastoma is a rare, highly aggressive supratentorial tumour, more frequently diagnosed in young children. The prognosis remains poor. AIM: To present own experience with children with pineoblastoma. PATIENTS AND METHODS: 14 pts: 8 girls and 6 boys treated between 1998 and 2017 were analyzed. 5 pts (36%) were under 3 years of age. 7 pts underwent complete tumour resection, 2-partial resection and 5- biopsy. At the onset of treatment six patients had disseminated disease. 9 pts were treated according to protocol for MB HR group (with radiotherapy), 5 pts according to own baby protocol. RESULTS: 9 pts (64%) achieved good response to treatment (CCR-4 pts, CR-4 or PR-1). Four patients experienced tumour progression. 7 out of 14 patients are alive 3 ms to 17years from diagnosis (median 3years 4ms). Seven patients died (10ms to 8years from diagnosis). 1 pt died of long term post- radiotherapy sequelae. 5 yr EFS was 23 %, OS- 57%. 10 yr EFS and OS were 23 and 30,1% consecutively. 10 out of 14 pts relapsed 7ms to 4 years 3ms from diagnosis. 9 pts received second line treatment- 4 are alive. Children younger than 3 years of age treated without radiotherapy had worse outcome with 5 yrs OS estimated at 0% vs 74,1% in older children treated with chemotherapy and radiotherapy (p=0,014). CONCLUSION: Pineoblastoma is highly malignant CNS neoplasm of childhood with dismal prognosis. In our series children below 3 years of age treated without radiotherapy had poorer responses and worse outcome.

OBJECTIVES: Subependymal giant cell astrocytoma (SEGA) is a most common brain tumor in patients with tuberous sclerosis complex caused by mutation in TSC1 or TSC2 genes. Most of patients present the epilepsy and increased intracranial pressure. The aim of this work was provided a comprehensive analysis of SEGAs, including histopathological features, spectrum of molecular defects and clinical outcome. MATERIAL AND METHODS: The group of 33 SEGAs patients was included in this study. In all SEGAs microscopic pattern, results of immunohistochemical tests and spectrum of mutations were analyzed and correlated with clinical data, including response of the everolimus treatment. RESULTS: Microscopically SEGAs were composed of large pleomorphic cells with abundant cytoplasm and large nuclei with prominent nucleoli, spindle cells arranged within sweeping fascicles or ganglion-like cells. In four tumors foci of necrosis and mitotic figures were observed. In most of SEGAs focal calcifications were found, in two tumors calcifications were numerous and predominant. Tumors cells were positive for GFAP, S100 and present variable expression for neuronal markers. All of them displayed mTOR immunoreactivity. Most of SEGAs revealed mutations in TSC2 genes, including three tumors with large deletions involving the entire TSC2 and PKD1 region. No histopathological changes were observed in cases after everolimus treatment. CONCLUSIONS: SEGAs display heterogeneous histopathological pattern, in some cases with anaplastic features. Tumors in patients with TSC2/PKD1 deletion developed earlier in childhood and presented rapid growth. The response of mTOR inhibitor therapy was not noticed on microscopic level. The study was funding by CMHI project S152/2017.

OBJECTIVES: Previous analyses indicated that expression of ALK at the RNA level is correlated with the WNT-activated type of medulloblastoma. Therefore, we investigated if ALK expression at the protein level may serve as an useful marker for identification of this type of medulloblastoma. METHODS: Tumors from 134 patients were studied at diagnosis by immunohistochemistry using antibody ALK clone D5F3 #3633 (Cell Signaling). Consensus scoring was applied as the following: 0 (negative) for 0-10%, 1+ for >10-50%, 2+ for >50-100% of positive tumor cells. Transcriptional subtypes of medulloblastoma tumors were established in all cases. Thirty infratentorial ependymal tumors were also investigated to determine if ALK protein expression may serve as a marker for differential diagnosis. RESULTS: All 19 WNT tumors were positive for ALK expression and in all but one positive reaction was present in >50% of tumor cells (score 2+). Only four ALK positive tumors were detected among the remaining 85 tumors: one tumor with a score 2+ in Group 4 and three tumors with a score 1+ (one in Group 3 and two in SHH group). Therefore, expression of ALK is strongly associated with the WNT type of disease (p

Clostridium difficile infection (CDI) is one of the most common causes of nosocomial infectious diarrhea in children during anticancer therapy or undergoing hematopoietic stem cell transplantation (HSCT) in Europe. Immunosuppression in these patients is a risk factor for CDI. Malignant diseases, age, acute graft-versus-host disease (aGVHD), HLA mismatch, or use of total body irradiation may play an important role in CDI course. The aim of this study was to evaluate the incidence, course, and outcome of CDI in children treated for malignancy or undergoing HSCT. Between 2012 and 2015, a total number of 1846 patients were treated for malignancy in Polish pediatric oncological centers (PHO group) and 342 underwent transplantation (HSCT group). In PHO group, episodes of CDI occurred in 210 patients (14%). The incidence of CDI was higher in patients with hematological malignancies in comparison to that with solid tumors. Patients with acute myeloblastic leukemia had shorter time to episode of CDI than those with acute lymphoblastic leukemia. Patients over 5 years and treated for acute leukemia had more severe clinical course of disease in PHO group. In HSCT group, CDI occurred in 29 (8%) patients. The incidence of CDI was higher in patients transplanted for acute leukemia. The recurrence rate was 14.7% in PHO and 20.7% in HSCT patients. CDI incidence was highest in patients with hematological malignancies. Most of patients experienced mild CDI. Age

BACKGROUND AND OBJECTIVES: There is no consensus on optimal treatment duration for propranolol in infantile hemangioma (IH). We evaluated the efficacy and safety of oral propranolol solution administered for a minimum of 6 months up to a maximum of 12 months of age in high-risk IH. METHODS: This single-arm, open-label, phase 3 study was conducted in patients aged 35 to 150 days with high-risk IH in 10 hospitals between 2015 and 2017. The study comprised a 6-month initial treatment period (ITP) plus continuation up to 12 months of age if complete success was not achieved, a follow-up, and a retreatment period. Patients received oral propranolol twice daily (3 mg/kg per day). The primary end point was the success rate at the end of the ITP. Furthermore, the persistence of IH response and efficacy of retreatment was evaluated. RESULTS: The success rate after 6 months of treatment was 47%, increasing to 76% at the end of the ITP. Of the patients who achieved success, 68% sustained success for 3 months without treatment, and 24% required retreatment. Of the 8 patients who were retreated, 7 achieved success. Adverse events, reported by 80% of patients, were mild, which were expected in this population or known propranolol side effects. CONCLUSIONS: Oral propranolol administered beyond 6 months and up to 12 months of age meaningfully increases the success rate in high-risk IH. Success was sustained in most patients up to 3 months after stopping treatment. Retreatment was efficacious, and the safety profile satisfactory.

Desmoplastic infantile tumors are rare supratentorial brain lesions occurring in children under 18 months of age. We report characteristic neuroimaging with DWI and the histopathological features of these neoplasms.Magnetic resonance (MR) examinations of nine patients, aged 0-18 months (median age 3.5 months), were retrospectively analyzed. Analysis of MR images included location and tumor size, signal intensity, contrast enhancement, presence of edema, and hemorrhage. Minimum and mean value of apparent diffusion coefficient (ADC) in the solid component of the tumor and contralateral normal-appearing white matter (NAWM) were measured, and ADC/NAWM ratios were calculated. All patients underwent tumor resection, and diagnosis of grade I desmoplastic tumors was confirmed.The tumors were located in the temporal lobe in seven patients, the parietal lobe in three, and in the frontal lobe in one case (in two children, tumors invaded more than one lobe). Suprasellar localization was observed in two patients; one child had multifocal brain lesions. In five cases, signal intensity of the solid component was hypointense on T2-WI. The measured minimum ADC value of solid tumor varied from 0.606 to 1.020 × 10(-3) mm(2)/s, with a mean value of 0.921 × 10(-3) mm(2)/s. The mean ADC value of NAWM was 1.121 × 10(-3) mm(2)/s. The mean ADC ratio was 0.858 × 10(-3) mm(2)/s.From our series, we can assume that restricted diffusion is observed not only in malignant but also in benign brain tumors. Diffusion signals and ADC values in these neoplasms appear to depend on their cellularity and components of the extracellular matrix.

The aim of the study was to asses QoL in Medulloblastoma (MB) survivors according to risk groups. MATERIAL AND METHOD: Between 2005-2015 132 patients (40 girls, 92 boys aged 2 9/12 – 17 6/12) were treated of MB. 44 patients were standard risk and 88 high risk. Patients in SR group received radiotherapy to CNS 25Gy whereas HR - 36Gy. Age at analysis 6 1/12 to 29. Analysis included 5 year EFS/OS and assessment of: weight/height in percentiles according to risk groups and age at diagnosis, hearing loss, hearing aids, hair loss and occurrence of posterior fossa syndrome(PFS). Psychosocial assessment, including IQ, education, work, physical and social activities, interpersonal relationships was performed and compared in risk groups. RESULTS: 5 years EFS was 83% in SR and 76,6% HR (p=0,112), OS 89,7% and 82,3%. There was no significant difference in hearing loss between risk groups, but there was greater use of hearing aids in the latter (p=0,003), hair loss was markedly worse in HR (p=0,022). SR patients and those older than 10 years at diagnosis were higher as compared to other survivors. PFS occurred more often in HR group (p=0,005). IQ, educational achievements, physical and social activity and interpersonal relationships were significantly better in SR group (p

Background: Urolithiasis in the pediatric population is about 10 times less common than among adults. Adolescents present with similar symptoms to adult patients, among them renal colic (acute, severe flank pain, which radiates to the groin). This case report shows an atypical course of retromediastinal tumor, which mimicked symptoms of renal colic. Case presentation: A 15-year-old boy was admitted to Pediatric, Nephrology and Allergology Department, Military Institute of Medicine due to suspicion of urolithiasis. Patient presented left flank pain treated as renal colic. Before admission the boy was hospitalized in three centers during March 2016, July 2016 and September 2016. During those hospitalizations X-ray examination revealed a small calcification in the left kidney, however no renal calculi were detected in urography and repeated ultrasound examinations. Discussion: Patient was treated twice with antibiotics (cefuroxime, amikacin) due to increased inflammatory parameters. Analgesics and antispasmodic drugs were administered almost continuously, without any significant effect on reported symptoms. At admission no stones were visible in ultrasound examination, therefore abdominal computed tomography (CT) was performed. No signs of urolithiasis were observed in the scan, however abnormal mass on the left-side of the chest wall was found. The study was extended to thoracic CT scan, which revealed a mediastinal tumor. Patient was referred to an oncology department where Ewing sarcoma/ primitive neuroectodermal tumor (PNET) was diagnosed in pathologic analysis. Conclusion: Symptoms which mimic renal colic may not always be caused by urolithiasis. Even though posterior mediastinal tumors among children are significantly less common than renal stones, doctors should always consider all potential causes of symptoms that are reported by our patients. Ultrasonography remains the study of first choice, however CT should be recommended in patients with persistent symptoms of urolithiasis or nondiagnostic ultrasound examination.

The list of MSH2 and RAD50 gene germline variants detected in cohort of 102 MB patients. (DOC 92 kb)

BACKGROUND: Long-term brain tumor survivors present challenging neurocognitive problems, that limit their educational achievement and social independence. This motivates to seek effective ways of limiting the negative consequences of brain tumors and anticancer treatment, as well as increasing their quality of life. METHODS: Group of patients with posterior fossa tumor treated in our center, has been divided into two subgroups: with or without cognitive and physical stimulation during and after treatment. Next we randomly chose from each of group 30 patients, aged 8-14. Assessed groups did not differ on demographic or clinical variables. Three years after finishing treatment we assessed intelligence quotient, executive function, attention, visuospatial skills, processing speed, short-term memory and language in both groups. Social functioning were assessed according to definition of adaptive behavior (Vineland Adaptive Behavior Scales). All medical factors and treatment methods, especially the dose of irradiation, were also analyzed. Very important in these studies was the ecological aspect, which means bringing the forms of stimulation closer to the natural conditions and activities, typical for children in this group of age. RESULTS: We observed significant differences between neurocognitive outcome and educational achievement between subgroups, which allowed us prepare recommendation for stimulation of development pediatric brain tumors survivors. DISCUSSION: The most common objection to cognitive stimulation is the instability of effects. That’s why we studied patients three years after the end of treatment. In addition, we combined cognitive training with physical exercises.

Astroblastoma is a rare CNS tumor of glial origin distinguished from other gliomas in the recent International Classification of Tumors of the Central Nervous System proposed by the World Health Organization. We present our experience with 3 astroblastoma patients. Between 2003–2017 among 978 patients with tumors of glial origin treated at our Institution 3 patients (0,3 %) were diagnosed with astroblastoma. There were 2 girls and 1 boy aged 2.5, 3, 5.5 years. Two patients had supratentorial tumors, one tumor was located infratentorially. All patients underwent subtotal tumor resection received pre-irradiation chemotherapy, local irradiation (54Gy) and maintenance chemotherapy. All patients are alive 1, 5 yrs 8 m, 13 yrs2m from diagnosis. Our results as of other authors confirm favorable prognosis and rarity of astroblastoma in pediatric population.

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. Pediatr Blood Cancer 2009;52:186–190. © 2008 Wiley-Liss, Inc.

Focal cortical dysplasia (FCD) is one of the most important causes of drug-resistant epilepsy in paediatric patients, particularly in those below the age of 3. Even though over 40 years have passed since the first description of the entity by Taylor, the exact mechanisms causing these cortical abnormalities remain unelucidated. In this review, we summarise the current knowledge on clinical and histopathological aspects, taking into account the new classification system proposed by the International League Against Epilepsy. We focus on the clinicopathological associations and differences in post-surgical outcome among FCD subtypes, in particular isolated FCD vs. FCD associated with principal lesions, which have not been summarised to date. We also recapitulate genetic studies, pointing to the possible mechanisms of the cortical dysregulation and drug resistance, and summarise novel factors which may contribute to epileptogenesis in FCD. Furthermore, we compare FCD type IIB (FCDIIB) with brain tumours found in a neurocutaneous disorder, tuberous sclerosis, as we evaluate the hypothesis that FCD IIB may be a local form of this disease.

This analysis shows that the use of micafungin was successful in preemptive and targeted therapy in children with IFD in 85% pediatric hemato-oncology (PHO) and 60% allogeneic hematopoietic stem ce...

Background Ependymal tumors are the third most common group of brain tumors in children, accounting for about 10% of all primary brain neoplasms. According to the current WHO classification, they comprise four entities with the most frequent ependymoma and anaplastic ependymoma. The most of pediatric tumors are located within the posterior fossa, with a tendency to infiltrate the vital brain structures. This limits surgical resection and poses a considerable clinical problem. Moreover, there are no appropriate outcome prognostic factors besides the extent of surgical resection. Despite definition of molecular subgroups, the majority of childhood ependymomas present a balanced genome, which makes it difficult to establish molecular prognostic factors. Methods The purpose of our study was to explore whether miRNA expression could be used as prognostic markers in pediatric infratentorial ependymomas. We also performed a mRNA expression pattern analysis of NELL2 and LAMA2 genes, with immunohistochemical illustrations of representative cases. The miRNA and mRNA expression was measured in 53 pediatric infratentorial ependymomas using a real-time quantitative PCR. Results Three miRNAs were shown to efficiently differentiate between grade II and III ependymomas: miR-17-5p, miR-19a-3p, and miR-106b-5p. Survival analysis showed that the probabilities of overall (p = 0.036) and event-free survival (p = 0.002) were reduced with higher than median miRNA expression levels of miR-17-5p. Using multivariate analysis adjusted for patient's age, sex, tumor grade and localization, we showed statistically significant associations with event-free survival (p = 0004) and borderline statistical significance with overall survival (p = 0.057) for miR-17-5p. Correlation analysis of miR-19a, miR-17-5p, miR-106b revealed that their expression levels were significantly correlated with EZH2 expression, suggested marker of PFA ependymomas. Furthermore, lower expression level of LAMA2 mRNA was shown to be associated with an increased risk of death in covariate-adjusted analyses. Conclusions Our data provide a better understanding of pediatric ependymoma and suggests the presence of plausible molecular biomarkers connected with the outcome.

Objective To analyze the incidence and outcome of infections with Staphylococcus spp. in children with malignancies treated in pediatric hematology and oncology (PHO) centers or undergoing hematopoietic stem cell transplantation (HSCT) over a period of 24 months. Patients and methods A total number of 1768 patients with malignancies and 308 patients undergoing HSCT in 2012–2013 were analyzed for microbiologically documented infection with Staphylococcus spp. Results During 24 consecutive months the incidence of Staphylococcus spp. infection was 6.7% in children with malignancy and 8.4% in patients undergoing HSCT (p = 0.3). At least two episodes of infection occurred in 11/118 PHO and in 7/26 HSCT patients. The first episode of infection occurred much earlier in HSCT than in PHO patients (p Conclusions The first episode of infection occurred much earlier in HSCT than PHO patients. The incidence of Staphylococcus spp. infection was similar in both groups of patients. Favorable outcome of the infection reached 96.4% and 95.1% episodes in PHO and HSCT patients, respectively.

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. © 2011 Wiley Periodicals, Inc. J Clin Ultrasound, 2011

Background Undifferentiated embryonal sarcoma of the liver (UESL) represents less than 5% of all malignant hepatic tumors in childhood. It is considered an aggressive neoplasm with an unfavorable prognosis. The aim of this paper is to present a single center experience in the treatment of children with UESL. Materials and methods Ten children with UESL were treated between 1981 and 2012. Age at diagnosis ranged from 4 months to 17 years (median age, 6 years and 9 months). Surgery after neoadjuvant chemotherapy (CHT) was performed in 7 patients, and in 3 patients primary surgery was done. Adjuvant chemotherapy was administered in all 10 patients (CYVADIC, CAV, CAV/ETIF/IF + ADM, CDDP/PLADO). Right hemihepatectomy was performed in 1 patient, extended right hemihepatectomy in 6, and partial resection of the right lobe (segments V-VI, segment V) in 2 patients. One patient with unresectable tumor affecting both lobes was listed for liver transplantation (LTx). Results Follow-up from diagnosis ranged from 50 to 222 months (mean 138 months). Among 9 patients treated with partial liver resection, distant metastases/local recurrence was not observed in any, and disease-free survival in this group is 100% (9 patients alive). The patient that underwent liver transplantation died of multiorgan failure 4 months postoperatively. However, this patient was misdiagnosed as having hepatoblastoma (HBL) and received PLADO chemotherapy. The overall survival rate is 90%. Conclusion Excellent results with long-term survival can be achieved in children with UESL with conventional therapy, including a combination of neoadjuvant and adjuvant chemotherapy and surgery, even in large extensively growing tumors.

LG-49. LOW GRADE GLIOMA (LGG) OF THE SPINAL CORD. SPECIFIC LOCATION NEEDS SPECIFIC TREATMENT Marta Perek-Polnik, Iwona Filipek, Monika Drogosiewicz, Ewa Swieszkowska, Wieslawa Grajkowska, Elzbieta Jurkiewicz, Marcin Roszkowski, and Bozenna Dembowska-Baginska; The Children’s Memorial Health Institute, Warsaw, Poland INTRODUCTION: Spinal cord LGG constitute approximately 3,5% of all LGG locations. No specific therapeutic guidelines are available for this specific LGG site. AIM: Analysis of childhood spinal cord LGG. METHODOLOGY: 28 patients treated between2004-2015wereanalyzed for: sex, age, symptoms, pathology, treatment and outcome. RESULTS: There were 20 boys and 8 girls, aged 10 months-17 years, median 4.5 years. Paresis,scoliosis and pain were the most common symptoms. Pathology revealed Pilocytic astrocytoma in 21, Pilomyxoid astrocytoma in 4, LGG NOS in 3 patients. In 5 patients total or subtotal resections was performed, in 17 partial resection, in 6 biopsy were performed. In 13 pts neurological improvement was observed, in 7 – deterioration, the rest remained stable. 13 patients had no further treatment. 15 received chemotherapy: 7 following surgical treatment, 8 at tumor progression. 12 patients started with LGG protocol, 3 with VLB. In 10 patients stabilization, in 5 minimal tumor regression were observed. All patients are alive with median follow-up 3 years 8 months. 5 yr and 10 yr EFS are 52,1%, 27,7, respectively. 10 patients are walking without paresis, 9 with paresis, 2 have scoliosis, 6 pts use wheelchair, 1 is paralized. CONCLUSIONS: Spinal cord LGG have a good prognosis. Surgery improves neurological outcome, but radical resections are not mandated to achieve that. Some patients with tumor residual may not require further treatment, but at tumor progression chemotherapy is the treatment of choice. Quality of life should be the priority in choosing surgical strategy. Neuro-Oncology 18:iii78–iii96, 2016. doi:10.1093/neuonc/now075.49 #The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

We present two different cases of congenital intramedullary tumours, one of a patient in whom treatment was started without pathological confirmation of a malignant tumour and the other of a primitive neuroectodermal tumour. Magnetic resonance imaging is the most useful tool in the diagnosis of malignant intramedullary tumours and differentiation from other types of spinal cord lesions.

Nijmegen breakage syndrome (NBS) is a rare autosomal recessive syndrome of chromosomal instability mainly characterized by microcephaly at birth, combined immunodeficiency and predisposition to malignancies. Due to a founder mutation in the underlying NBN gene (c.657_661del5) the disease is encountered most frequently among Slavic populations. The principal clinical manifestations of the syndrome are: microcephaly, present at birth and progressive with age, dysmorphic facial features, mild growth retardation, mild-to-moderate intellectual disability, and, in females, hypergonadotropic hypogonadism. Combined cellular and humoral immunodeficiency with recurrent sinopulmonary infections, a strong predisposition to develop malignancies (predominantly of lymphoid origin) and radiosensitivity are other integral manifestations of the syndrome. The NBN gene codes for nibrin which, as part of a DNA repair complex, plays a critical nuclear role wherever double-stranded DNA ends occur, either physiologically or as a result of mutagenic exposure. Laboratory findings include: (1) spontaneous chromosomal breakage in peripheral T lymphocytes with rearrangements preferentially involving chromosomes 7 and 14, (2) sensitivity to ionizing radiation or radiomimetics as demonstrated in vitro by cytogenetic methods or by colony survival assay, (3) radioresistant DNA synthesis, (4) biallelic hypomorphic mutations in the NBN gene, and (5) absence of full-length nibrin protein. Microcephaly and immunodeficiency are common to DNA ligase IV deficiency (LIG4 syndrome) and severe combined immunodeficiency with microcephaly, growth retardation, and sensitivity to ionizing radiation due to NHEJ1 deficiency (NHEJ1 syndrome). In fact, NBS was most commonly confused with Fanconi anaemia and LIG4 syndrome. Genetic counselling should inform parents of an affected child of the 25% risk for further children to be affected. Prenatal molecular genetic diagnosis is possible if disease-causing mutations in both alleles of the NBN gene are known. No specific therapy is available for NBS, however, hematopoietic stem cell transplantation may be one option for some patients. Prognosis is generally poor due to the extremely high rate of malignancies. Zespół Nijmegen (Nijmegen breakage syndrome; NBS) jest rzadkim schorzeniem z wrodzoną niestabilnością chromosomową dziedziczącym się w sposób autosomalny recesywny, charakteryzującym się przede wszystkim wrodzonym małogłowiem, złożonymi niedoborami odporności i predyspozycją do rozwoju nowotworów. Choroba występuje najczęściej w populacjach słowiańskich, w których uwarunkowana jest mutacją założycielską w genie NBN (c.657_661del5). Do najważniejszych objawów zespołu zalicza się: małogłowie obecne od urodzenia i postępujące z wiekiem, charakterystyczne cechy dysmorfii twarzy, opóźnienie wzrastania, niepełnosprawność intelektualną w stopniu lekkim do umiarkowanego oraz hipogonadyzm hipogonadotropowy u dziewcząt. Na obraz choroby składają się także: niedobór odporności komórkowej i humoralnej, który jest przyczyną nawracających infekcji, znaczna predyspozycja do rozwoju nowotworów złośliwych (zwłaszcza układu chłonnego), a także zwiększona wrażliwość na promieniowanie jonizujące. Wyniki badań laboratoryjnych wykazują: (1) spontaniczną łamliwość chromosomów w limfocytach T krwi obwodowej, z preferencją do rearanżacji chromosomów 7 i 14, (2) nadwrażliwość na promieniowanie jonizujące lub radiomimetyki, co można wykazać metodami in vitro, (3) radiooporność syntezy DNA, (4) hipomorficzne mutacje na obu allelach genu NBN, oraz (5) brak w komórkach pełnej cząsteczki białka, nibryny. Małogłowie i niedobór odporności występują także w zespole niedoboru ligazy IV (LIG4) oraz w zespole niedoboru NHEJ1. Rodzice powinni otrzymać poradę genetyczną ze względu na wysokie ryzyko (25%) powtórzenia się choroby u kolejnego potomstwa. Możliwe jest zaproponowanie molekularnej diagnostyki prenatalnej jeżeli znane są obie mutacje będące przyczyną choroby. Nie ma możliwości zaproponowania specyficznej terapii, ale przeszczep szpiku może być alternatywą dla niektórych pacjentów. Generalnie prognoza nie jest pomyślna z uwagi na wysokie ryzyko rozwoju nowotworu.

Background/Purpose The aim of the study was to analyze changing management and survival of children with hepatoblastoma (HBL) treated in one center. Materials and Methods Over the last 20 years, 51 children with HBL were treated. Surgery was performed in 48 children (94.1%), conventional liver resection in 38 (of those, 2 received a rescue liver transplantation [LTx] for relapse), and total hepatectomy and primary LTx in 10 patients. The remaining 3 patients received only palliative treatment. Patient data were analyzed for survival with respect to PRETreatment EXTent of disease (PRETEXT), metastases, histopathology, conventional resection, and LTx. Results Survival of children with HBL treated with liver resection is 71% and 80% for primary LTx. Favorable prognostic factors for patient survival was tumor histology as epithelial-fetal subtype and mixed epithelial and mesenchymal type, without teratoid features, and good response to chemotherapy (necrosis, fibrosis). Unfavorable prognostic factors were small cells undifferentiated, transitional liver cell tumor, α -fetoprotein level above 1,000,000 IU/mL and below 100 IU/mL at diagnosis, lung metastases, and local recurrence after initial resection. Survival was related to PRETEXT stage. However, among patients with PRETEXT III and IV, LTx resulted in better survival. Conclusion Liver transplantation is a good option for children with advanced HBL. Early referral of children with potentially unresectable tumors to centers where combined treatment (chemotherapy, surgery including LTx) is available is crucial.

In 2000, regulation on orphan medicinal products was adopted in the European Union with the aim of benefiting patients who suffer from serious, rare conditions for which there is currently no satisfactory treatment. Since then, more than 850 orphan drug designations have been granted by the European Commission based on a positive opinion from the Committee for Orphan Medicinal Products (COMP), and more than 60 orphan drugs have received marketing authorization in Europe. Here, stimulated by the tenth anniversary of the COMP, we reflect on the outcomes and experience gained in the past decade, and contemplate issues for the future, such as catalysing drug development for the large number of rare diseases that still lack effective treatments.

The Nijmegen breakage syndrome (NBS) is a rare inherited condition, characterized by microcephaly, radiation hypersensitivity, chromosomal instability, an increased incidence of (mostly) lymphoid malignancies, and immunodeficiency. NBS is caused by hypomorphic mutations in the NBN gene (8q21). The NBN protein is a subunit of the MRN (Mre11-Rad50-NBN) nuclear protein complex, which associates with double-strand breaks. The immunodeficiency in NBS patients can partly be explained by strongly reduced absolute numbers of B lymphocytes and T lymphocytes. We show that NBS patients have a disturbed precursor B-cell differentiation pattern and significant disturbances in the resolution of recombination activating gene-induced IGH breaks. However, the composition of the junctional regions as well as the gene segment usage of the reduced number of successful immunoglobulin gene rearrangements were highly similar to healthy controls. This indicates that the NBN defect leads to a quantitative defect in V(D)J recombination through loss of juxtaposition of recombination activating gene-induced DNA ends. The resulting reduction in bone marrow B-cell efflux appeared to be partly compensated by significantly increased proliferation of mature B cells. Based on these observations, we conclude that the quantitative defect will affect the B-cell receptor repertoire, thus contributing to the observed immunodeficiency in NBS 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

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.

Objective The objective of this study was to assess the oral cavity status of patients with Nijmegen breakage syndrome (NBS), an inherited genetic disorder that belongs to the group of chromosome instability syndromes and is characterized by microcephaly, a distinct facial appearance, growth retardation, radiation sensitivity, and immunodeficiency. Study design Oral examination was conducted and immunological status assessed in 21 NBS patients (1.7-20.7 years old) and 21 healthy controls (5-21 years old). The differences between the frequency and severity of clinical manifestations and their correlation with immune parameters were analyzed by Student t test, the chi-square test, and Spearman's rank order correlation. Results Lesions of the oral mucosa and gingivitis were diagnosed more frequently in NBS patients than in controls. The mean Gingival Index was significantly higher in NBS subjects (P = 0.00043). Candidiasis was detected in 6 patients (28.6%) and in none of the healthy controls. Immune deficiency (humoral and/or cellular) was detected in 20 of 21 (95.2%) NBS patients. There was a significant association between severity of gingival inflammation and reduced number of B- and/or CD3+/CD4+ T cells combined with IgA+IgG4 deficiency. Conclusion Our study showed that oral manifestations diagnosed in NBS patients were associated with combined deficiencies of the humoral and cellular arms of the immune system. We postulate that periodical examination of the oral cavity is essential for early medical intervention.

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.

The aim of this study was to present acute hemodynamic failure as a rare indication for liver transplantation in neonates and infants with liver hemangiomatosis. We report four patients aged one to six months with giant liver hemangiomas, with huge arterio-venous shunting within these malformations. In three, many skin hemangiomas were found. All children developed right ventricular failure. In two, a trial of pharmacological reduction was attempted with corticosteroids and cyclophosphamide. In one patient, the arterio-venous fistulas were embolized without any improvement in hemodynamic status. Two children underwent rescue hepatic artery surgical ligation, which did not prevent heart and then multiorgan failure including liver failure. After unsuccessful conventional therapy, all infants were considered for urgent liver transplantation; in three cases, it was performed with a living-related donor, and in one case with a deceased donor. All patients are alive and well with the follow-up between nine and 37 months after transplantation. Liver transplantation should be considered as a rescue treatment in children with hepatic vascular malformations leading to hemodynamic insufficiency when conventional therapy is unsuccessful and multiorgan failure develops.

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.

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.

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 use of biomarkers within the procedures of the Committee of Orphan Medicinal Products (COMP) of the European Medicines Agency (EMA) is discussed herein. The applications for Orphan Medicinal Product designation in the EU are evaluated at two stages. At the time of orphan designation application, the file undergoes an assessment to establish whether the proposed condition is a distinct and serious condition affecting not more than 5 in 10,000 people in the EU, and whether the product is plausible as a therapy for that condition. In cases where therapies already exist, the significant benefit of the candidate product over existing therapies is also evaluated. The orphan criteria are reassessed at the time of marketing authorisation, so that marketing exclusivity for the product in the orphan medical condition can be granted. Within this context, biomarkers have been used in submissions in order to define an orphan condition and to justify that the criteria for orphan designation are met. The current work discusses specific examples from the experience of the COMP, where biomarkers have played a decisive role. Importantly, it identifies the proposal of sub-sets of non-rare conditions based on biomarkers as a challenging issue in the evaluation of applications. In particular two specific requirements for the candidate orphan medicines in relation to the biomarker-based subsets are highlighted: the “plausible link to the condition” and the “exclusion of effects outside the subset”.

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 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

Rearrangements involving the ALK gene were identified in a variety of cancers, including paediatric tumour neuroblastoma where presence of ALK expression is also associated with adverse prognosis. Microarrays data indicate that ALK is expressed in another paediatric tumour – medulloblastoma. Therefore, we investigated if the ALK gene is mutated in medulloblastoma and performed simultaneously the molecular profiling of tumours. Tumours from sixty-four medulloblastoma patients were studied for detection of ALK alterations in exons 23 and 25 using Sanger method. The molecular subtypes of tumours were identified by detection of mutations in the CTNNB1 gene, monosomy 6 and by immunohistochemistry using a panel of representative antibodies. Among three ALK variants detected two resulted in intron variants (rs3738867, rs113866835) and the third one was a novel heterozygous variant c.3595A>T in exon 23 identified in the WNT type of tumour. It resulted in methionine to leucine substitution at codon position 1199 (M1199L) of the kinase domain of ALK protein. Results of analysis using three in silico algorithms confirmed the pathogenicity of this single nucleotide variation. The same gene alteration was detected in both patient and maternal peripheral blood leukocytes indicating an inherited type of the detected variant. Presence of ALK expression in tumour tissue was confirmed by immunohistochemistry. The tumour was diagnosed as classic medulloblastoma, however with visible areas of focal anaplastic features. The patient has been disease free for 6 years since diagnosis. This is the first evidence of an inherited ALK variant in the WNT type of medulloblastoma, what altogether with presence of ALK expression may point towards involvement of the ALK gene in this type of tumours.

BACKGROUND Post-transplant lymphoproliferative disorder (PTLD) is a potential complication of solid organ or bone marrow transplants. The main PTLD risk factors are: the Epstein-Barr virus (EBV), transplant type, and use of immunosuppressants. It mainly consists of an uncontrolled growth of lymphocytes in transplant recipients under chronic immunosuppressive therapy. About 85% of PTLDs are EBV-containing B-cell proliferations; 14% are T-cell proliferations, of which only 40% contain EBV; and the remaining 1% is NK-cell or plasmocyte proliferations. PTLD may present various clinical manifestations, from non-specific mononucleosis-like syndrome to graft or other organ damage resulting from pathologic lymphocyte infiltration. PTLD may manifest in the oral cavity. CASE REPORT The objective of this study was to present the case of a 13-year-old female living-donor liver transplant recipient, resulting from biliary cirrhosis caused by congenital biliary atresia, with exophytic fibrous lesions on buccal mucosa and tongue. Exophytic and hyperplastic lesion of oral mucosa were removed and histopathological examination revealed polymorphic PTLD. The patient underwent 6 cycles of CHOP chemotherapy and all the oral lesions regressed completely. CONCLUSIONS All oral pathological lesions in organ transplant recipients need to be surgically removed and histopathologically examined because they present an increased risk of neoplastic transformations such as PTLD.