Results from a large multinational clinical trial (guardian™3) using prophylactic treatment with turoctocog alfa in paediatric patients with severe haemophilia A: safety, efficacy and pharmacokinetics.

Recombinant factor VIII (rFVIII) products provide a safe and efficacious replacement therapy for prophylaxis and treatment of bleeding episodes in patients with severe haemophilia A. This multinational, open-label, non-controlled trial investigated the safety, efficacy and pharmacokinetics (PK) of turoctocog alfa, a new rFVIII product, in a paediatric population. The primary objective was to evaluate safety. A total of 31 younger children (0-5 years) and 32 older children (6-11 years), with ≥ 50 exposure days to any factor VIII (FVIII) product and no history of inhibitors, received prophylaxis with turoctocog alfa (25-50 IU kg(-1) every second day or 25-60 IU kg(-1) three times weekly). PK assessments of turoctocog alfa and the patients' previous FVIII product were performed in 28 patients. Mean exposure to turoctocog alfa was 60 exposure days per patient. This corresponds to approximately 4.5 months in the trial. None of the patients developed inhibitors (≥ 0.6 BU) and no safety concerns were raised. A total of 120 bleeding episodes (95%) were controlled with 1-2 infusions of turoctocog alfa. Based on patient reports, the success rate (defined as 'excellent' or 'good' haemostatic response) for treatment of bleeding episodes was 92%. Overall, the median annualized bleeding rate was 3.0 (interquartile range: 8.5) bleeds patient(-1) year(-1) . PK parameters were comparable between the two age groups. In conclusion, the present large global clinical trial showed that turoctocog alfa was safe, effective in treatment of bleeding episodes and had a prophylactic effect in paediatric patients.

Glucocorticoid-resistant Evans' syndrome successfully controlled with low-dose cyclosporine.

OBJECTIVE: To present a patient suffering from Evans' syndrome (ES), whose bouts of severe cytopenia were prevented by low-dose cyclosporine maintenance therapy. CASE SUMMARY: A boy suffering from frequent mild respiratory infections, first time evaluated in a tertiary care pediatric center at age 4, was found to have lymphadenopathy and mild splenomegaly. The thrombocytopenia was first noted at age 6. He was diagnosed to have ES at the age of 8, during another bout of thrombocytopenia, this time associated with Coombs-positive hemolytic anemia. Immunoglobulin concentration in the plasma was measured repeatedly, and was in the normal range, or even increased. Lymphocyte subpopulation numbers were in the normal range, with decreased CD4+/ CD8+ ratio (0.6). Autoimmune lymphoproliferative syndrome was excluded by the absence of CD4-CD8- T lymphocytes. Since the patient failed to respond to standard therapy with prednisolon 2 mg/kg, high dose intravenous methylprednisolone (10 mg/ kg/d for 3 days) and high dose intravenous immunoglobulin (1 g/kg/d for 2 days), cyclosporine treatment was initiated (6 mg/ kg/d) and resulted in normalization of platelet count and resolution of hemolysis. Two attempts to withdraw cyclosporine therapy resulted in life-threatening hemolytic crisis with severe thrombocytopenia, requiring the re-institution of cyclosporine. The dose of cyclosporine was eventually tapered to the present 0.5 mg/kg, corresponding to drug serum levels of 5 - 8 mg/ml. The patient is now free of manifestations of Evans' syndrome but, after 20 years of cyclosporine treatment, has slightly impaired kidney function. CONCLUSION: Low-dose cyclosporine therapy given to our patient appears to have subdued the autoimmune process thought to underlie the manifestations of ES, albeit at the cost of some toxicity to the kidneys.

The state of research into children with cancer across Europe: new policies for a new decade.

Overcoming childhood cancers is critically dependent on the state of research. Understanding how, with whom and what the research community is doing with childhood cancers is essential for ensuring the evidence-based policies at national and European level to support children, their families and researchers. As part of the European Union funded EUROCANCERCOMS project to study and integrate cancer communications across Europe, we have carried out new research into the state of research in childhood cancers. We are very grateful for all the support we have received from colleagues in the European paediatric oncology community, and in particular from Edel Fitzgerald and Samira Essiaf from the SIOP Europe office. This report and the evidence-based policies that arise from it come at a important junction for Europe and its Member States. They provide a timely reminder that research into childhood cancers is critical and needs sustainable long-term support.

Congenital muscular torticollis in children: distribution, treatment duration and out come.

AIM: The aim of the study was to evaluate the proportion of left and right congenital muscular torticollis (CMT) in both genders and age groups of the patients as well as to evaluate the duration of physical therapy and treatment outcome in observed population. METHODS: In our study, 980 children with CMT without hematoma were treated at University children's Hospital of Belgrade (Serbia). They were divided into 2 groups: group with left torticollis and group with right torticollis. Boys and girls were separately evaluated. Patients were classified into 5 age groups: group of children less than one month of life, group above one to 3 months, group above 3 months to 6 months, group above 6 months to 12 months and group of children above 12 months of life. Optimal time for physical therapy was analyzed in every age group. RESULTS: We diagnosed 496 torticollis in boys and 484 torticollis in girls. There were 458 children with left torticollis and 522 children with right torticollis. In group of children less than one month of life median duration of physical therapy was 1.5+/-0.3 months, in group above one to 3 months of life 5.9+/-0.6, in group above 3 to 6 months 7.2+/-0.6, in group above 6 to 12 months 9.8+/-0.6 and in group of children above 12 months of life 10.3+/-0.8 months. CONCLUSION: Right torticollis is frequent in both genders and age groups. Younger children have lower treatment duration and better treatment outcome. Boys have longer treatment duration and not significantly better treatment outcome.

Clinical features of the most common fusion genes in childhood acute lymphoblastic leukemia.

Contemporary protocols ensure high-remission rate and long-term free survival in children with acute lymphoblastic leukemia (ALL), but small percentage of patients is still incurable. Molecular genetic methods helped to establish submicroscopic classification as well as minimal residual disease follow-up, considered to be responsible for relapse. Our study enrolled 70 pediatric patients with de novo ALL, analyzed using reverse transcriptase-polymerase chain reaction for the presence of four major risk-stratifying translocations (BCR/ABL, MLL/AF4, TEL/AML1, and E2A/PBX1). Bone marrow samples were collected at diagnosis, at the end of induction phase, and after intensive chemotherapy with the aim to establish the correlation between chromosomal aberration, clinical features, and treatment response. Presenting the results of this study, we offer another evidence of variable incidence and clinical characteristics of ALL subtypes.

[Successful treatment of second hepatoblastoma relapse--case report].

INTRODUCTION: The prognosis of hepatoblastoma has changed since effective adjuvant chemotherapy had been introduced in 1980's. There is a general agreement that complete resection is the cornerstone of treatment for children with hepapatoblastoma and the only way for eventual cure. CASE REPORT: We describe a boy with relapsed hepatoblastoma presenting with elevated -fetoprotein (AFP) and no visible tumor by ultrasound and computed tomography (CT). The relapse was treated with chemotherapy. Second relapse occurred shortly after therapy was completed, but this time we waited for tumor mass to appear. Combined surgery and chemotherapy resulted in remission status with 48 months of follow up. CONCLUSION: Hepatoblastoma relapse without evidence of tumor is not unusual but its treatment remains controversial. Radiological investigations should be repeated until site of relapse is identified. Based on our experience it seems of no benefit to treat isolated elevation of AFP.

Molecular basis of thalassemia syndromes in Serbia and Montenegro.

This study reports the molecular characterization of thalassemia syndromes in Serbian and Montenegrin populations. We identified eight beta-thalassemia mutations [codon 39 (C-->T), IVS-I-110 (G-->A), IVS-II-745 (C-->G), codon 44 (-C), -87 (C-->G), IVS-II-1 (G-->A), IVS-I-6 (T-->C), IVS I-1 (G-->A)] in 70 members of 29 families using polymerase chain reaction, reverse dot blot, amplification refractory mutation system and direct sequencing analysis. Hemoglobin (Hb) Lepore was found to be the most common cause of the thalassemia phenotype. Hb Sabine and alpha-thalassemia were detected as well. We also studied beta-globin gene cluster haplotypes and their association with the most common mutations. A novel haplotype associated with the Hb Lepore gene was identified. The results presented herein allowed the implementation of a prenatal diagnosis program in Serbia and Montenegro.

Stress-induced Cushing's syndrome in fur-chewing chinchillas.

One of the most serious problems in the chinchilla industry is 'fur-chewing', when the chinchilla bites off areas of its own or some other animal's fur. The condition generally develops in both genders at the age of 6-8 months. In chinchilla farms in Croatia an incidence of 15-20% has been observed. A pathomorphological, microbiological and parasitological investigation was conducted on eleven 6- to 11-month-old chinchillas of both sexes with clinical symptoms of 'fur-chewing' and three chinchillas without such signs. Histopathology of the adrenal glands and of the chewed skin revealed changes typical of Cushing's syndrome in 'fur-chewed' chinchillas, such as hyperkeratinisation of the epidermis, epidermal atrophy, pronounced follicular and sebaceous gland atrophy, hyperkeratinisation of the follicles with comedo formations and the presence of calcium salts in subcutis.

Nuclear lamin expression reveals a surprisingly high growth fraction in childhood acute lymphoblastic leukemia cells.

In an attempt to better characterize leukemic bone marrow cells of children with ALL in G0/G1, we studied the variation of the nuclear projection area (NPA) during the cell cycle. Approximately half of the increase of the nuclear volume during the cell cycle occurred before DNA synthesis. Next, we assessed by in situ hybridization (ISH) the expression of nuclear envelope type A/C and type B lamins in leukemic lymphoblast and unstimulated as well as stimulated normal peripheral blood mononuclear cells (PBMC). It was found that 82.0 +/- 16.0% of the ALL cells expressed B-type and 5.8 +/- 3.1% A/C-type lamins. The in vitro 3HdT pulse-labeling index (3HdT LI) of ALL cells varied from 1.3 to 16.8%. Of unstimulated PBMC 2.9 and 1.2% expressed lamin type B and A/C, respectively. The 3HdT LI was 0.8%. In conA-stimulated PBMC, the corresponding values were 95.3 and 74.8% and 31.0%, respectively. In view of the current concepts regarding G1 events and regulation of cell proliferation, we considered B-type lamin expression an early marker for the commitment to proliferation and used it for growth fraction (GF) determinations. By this method, a surprisingly high GF was found in ALL cell populations; there was no correlation between GF and the 3HdT LI, as seen in normal cells.

[Child trauma in Vojvodina]. / Traumatizam dece u Vojvodini.

Trauma represents for quite a long period a significant problem in child health care in Vojvodina. For better understanding of the trends of trauma in overall registrated child morbidity and mortality includingoutpatient and hospital cases we used the data derived from retrospective study fora period from 1979 to 1988. Analyzing the structure of ten leading groups of illnesses in the outpatient groups of children by the age of 6 years, injuries and intoxications were on the sixth position with the frequency of 2% and for the same period had a progressive increase with the dynamic index of 105.30. The percentage of the injuries and intoxications in the registrated outpatient morbidity of children from 6 to 14 years was 5-5.5% which put them on the fifth position at the list of ten leading groups of illnesses. During the same period of time trauma registered in the hospital morbidity showed decrease with the dynamic index of 86.12 and was on the fourth position with 7-8% of overall morbidity. There are on the average 74 child deaths annually in Vojvodina caused by injuries and intoxications.

[Hodgkin's lymphoma in children--histopathological and clinical features a 10-year experience (1978-1987)]. / Hockinov (Hodgkin) limfom kod dece--histopatoloske i klinicke karakteristike. Analiza za desetogodisnji period (1978-1987).

Hodgkin's lymphoma (HL) is a common neoplasm in children. In a 10-year period HL was found in 41% of all malignant lymphomas. Clinical and morphological features of 22 cases of HL are presented. HL was clinically manifested as an painless unilateral cervical lymphadenopathy. Males were slightly more affected, and the majority of the patients were from 5 to 15 years old. The most frequent histological types of HL were nodular sclerosis (45%) and mixed cellularity (40%). Although modern chemotherapy altered prognosis of HL and contributed to a favourable outcome of the disease in children, 36% of our patients died.

[Response to histamine in the skin prick test in children]. / Reaktivnost na histamin u prick koznom testu kod dece.

Allergen skin reactivity to histamine assessed by Prick testing was studied in 183 children with different allergic symptoms, aged from 4 months to 15 years. No significant difference was noted in male children versus female in different parts of the arm (antecubital fossa of the left arm, wrist of both arms) and in different allergic disorders (respiratory, pollen and skin allergy). The volume of reaction was not significantly changed in repeated applications of histamine. The peak reaction to histamine appeared 5 minutes after the application of histamine in the majority of children; it gradually declined after 10 and 15 minutes.