Cerebral sinus venous thromboses in children with acute lymphoblastic leukaemia - a multicentre study from the Nordic Society of Paediatric Haematology and Oncology.

We present a prospective multicentre cohort of 20 children with acute lymphoblastic leukaemia (ALL) and cerebral sinus venous thrombosis (CSVT). The study covers a period of 5 years and comprises 1038 children treated according to the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL 2008 protocol. The cumulative incidence of CSVT was 2%. Sixteen of the thromboses were related to asparaginase and 16 to steroids. Most CSVTs occurred in the consolidation phase. Nearly all were treated with low molecular weight heparin without bleeding complications. Mortality related to CSVT directly or indirectly was 10%, emphasizing the importance of this complication.

Very late relapse of PTLD 10 yr after allogeneic HSCT and nine yr after stopping immunosuppressive therapy.

We present a very late onset relapse of PTLD 10 yr after allogeneic HSCT in a patient in third remission for ALL, nine yr after the first episode of PTLD. The recipient was conditioned with fractionated TBI 12 Gy, cyclophosphamide, and horse ATG. The first episode of PTLD with a large retroperitoneal tumor occurred one yr after transplantation; a residual tumor infiltrating spleen and colon was resected one yr later. Due to continual pathological signals in liver and lungs, persistent fever, and an M-component in peripheral blood, a new course of four rituximab doses was given, after which the fever settled, the PET scan normalized, and the M-component disappeared. Without any ongoing immunosuppressive therapy, PTLD relapsed nine yr later with large intra-abdominal lymph node masses causing ureteric obstruction with bilateral hydronephrosis. Pathological features were identical to the primary PTLD tumor: EBV related, of donor origin, positive for CD138 and CD79 alpha, but negative for CD20 and CD19. The transcription factor PAX5 was negative but BOB1 and OCT2 were positive, consistent with plasmablastic lymphoma. The relapse was successfully treated with a combination of low dose chemotherapy and rituximab. Five yr after end of treatment, the girl has moderately reduced renal function but otherwise remains well without evidence of disease.

[Homozygous mutation in the intrinsic factor gene in a child with severe vitamin B12 deficiency]. / Homozygot mutation i intrinsic factor-genet hos et barn med svær vitamin B 12-mangel.

A 28 month-old boy was hospitalized with pallor and weight stagnation. He had macrocytic anaemia and pancytopenia due to cobalamin deficiency and a rare homozygous mutation in the intrinsic factor gene. His sister showed similar symptoms at the age of 15 months. The heterozygous father had no symptoms, but did have a low cobalamin level. Gastroscopy with biopsies showed no pathology. All were given monthly cyanocobalamin injections which, however, caused leg cramps. Replacement with monthly hydroxocobalamin was successful.

Pediatric venous and arterial noncerebral thromboembolism in Denmark: a nationwide population-based study.

OBJECTIVE: To assess the incidence rate (IR), changes in IR over time, risk factors, treatment, and outcomes of pediatric noncerebral thromboembolism (TE). STUDY DESIGN: The study included all patients aged 0 to 18 years diagnosed with first-ever noncerebral venous thromboembolism (VTE) and/or arterial TE in Denmark between 1994 and 2006. Patients were identified in national registries, followed by validation of diagnoses by medical records review. RESULTS: We confirmed 331 cases of VTE and 46 cases of arterial TE during 15.8 million person-years of observation, with corresponding IRs of 2.09 and 0.29 per 100 000 person-years. The IR peaked in infancy (age <1 year) for both VTE and arterial TE, with an additional peak among adolescents (age 15 to 18 years) for VTE. Boys predominated in IR of VTE in infancy, whereas girls did so in adolescence (P < .01). The IRs of VTE and arterial TE remained stable during the study period, but with an trend toward increasing VTE in 2001 to 2006 (P = .064). Underlying diseases/external triggers were present in 86.6% of the patients, and thrombophilia was present in 47.9% of the VTE cases. All-cause and TE-related 30-day case fatalities were 4.0% and 1.6%, respectively. CONCLUSIONS: We found age- and sex-related disparities in the IRs of pediatric VTE and arterial TE, but insignificant changes in IR from 1994 to 2006.

Bone marrow aspiration technique may have an impact on therapy stratification in children with acute lymphoblastic leukaemia.

BACKGROUND: Morphological evaluation of early response to chemotherapy and measurement of minimal residual disease by flow cytometry or PCR are being used for evaluation of prognosis and treatment stratification in children with acute lymphoblastic leukaemia (ALL). PROCEDURE: In a series of 14 consecutive bone marrow investigations from children with precursor B-cell ALL, morphological evaluations of smears and flow cytometric measurements of minimal residual disease in sequentially aspirated small (2 ml) and large (5-10 ml) volumes of bone marrow were compared, at various time points during therapy. RESULTS: The density of nucleated cells was markedly reduced in the large volume aspirate. The percentage of erythroblasts measured by flow cytometry was smaller, indicating dilution with peripheral cells. Similarly, the blast percentage was reduced with 54% in large aspirates, and in four instances with minimal residual disease of >0.1% in the small volume, the level of blasts in the large aspirate was below this limit. CONCLUSIONS: The amount of minimal residual disease should be measured in the first 2.5 ml of bone marrow aspirated from one puncture site. The procedure should be performed by experienced and carefully instructed doctors. In large aspirates, minimal residual disease will be underestimated, which may lead to failure to undertake a required intensification of therapy and a lower fraction of high risk patients in the trial.

Predictive value of pediatric thrombosis diagnoses in the Danish National Patient Registry.

Data on the validity of pediatric thrombosis diagnoses are missing. We aimed to examine the predictive value of a diagnosis of venous and arterial thrombosis using the Danish National Patient Registry (DNPR). We identified all first-time diagnoses among children and adolescents (aged 0-18 years) between 1994 and 2006 in DNPR. In total, 1138 potential cases of thrombosis were identified; the medical records were retrieved for 1112 (97.7%) and the positive predictive value (PPV) computed. Overall, the diagnosis of thrombosis was verified in 598 of the 1112 cases, corresponding to a PPV of 53.7% (95% confidence interval [CI]: 50.8-56.7). Diagnoses from wards had the PPV of 62.5% (95% CI: 59.4-65.6). The predictive value of a thrombosis diagnosis from wards was age-dependent, with a higher PPV (77.4%, 95% CI: 68.7-84.7) in neonates (<28 days) and adolescents (15-18 years) (68.2%; 95% CI: 63.2-72.5)) than in children (28 days-14 years) (51.2%; (95% CI: 46.0-56.4)). The PPV of a thrombosis diagnosis was improved by restricting the analysis to diagnoses from wards, primary diagnoses, and admissions with a length of stay of three or more days. The results indicate that an interpretation of nonvalidated hospital discharge data for pediatric thrombosis in a registry like DNPR should be made with caution.

[Herpes zoster-associated morbidity in children undergoing chemotherapy for acute lymphoblastic leukaemia]. / Herpes zoster-associeret morbiditet hos børn i kemoterapi for akut lymfoblastaer leukaemi.

INTRODUCTION: Herpes zoster rarely occurs in healthy children, but may occur frequently and may take a complicated course in children receiving chemotherapy. We aimed to assess morbidity from herpes zoster in children with acute lymphoblastic leukemia (ALL). MATERIAL AND METHODS: Reviewing records, treatment and course of zoster eruptions were registered in a cohort of 67 children with newly diagnosed ALL. Of these, 45 had had varicella at the time of diagnosis and 15 contracted varicella or were vaccinated during the course of therapy. RESULTS: Eleven children had a total of 17 eruptions while receiving chemotherapy. All eruptions were treated with acyclovir, in eight cases intravenously, and in six cases chemotherapy was interrupted. Cutaneous dissemination occurred in two cases, visceral dissemination in none. One child had postherpetic trigeminal neuralgia for two months. The eruption rate was higher among small children than among school-aged children (0.22 vs. 0.13 per year of chemotherapy) and was related to the intensity of chemotherapy (0.30 per year of consolidation treatment vs. 0.13 for maintenance therapy). Three children on prolonged intensive chemotherapy had recurrent zoster episodes. CONCLUSION: Chemotherapy causes zoster eruptions in approximately one quarter of children with ALL, and with intensive protocols recurrent zoster can cause significant morbidity. Attempts to improve immunity by vaccine boosting after attaining remission seems warranted.

[Varicella-associated morbidity in children undergoing chemotherapy for acute lymphoblastic leukaemia]. / Varicel-associeret morbiditet hos børn i kemoterapi for akut lymfoblastaer leukaemi.

INTRODUCTION: In children with cancer, varicella can be complicated by visceral dissemination with a risk of fatal outcome, especially in children with acute lymphoblastic leukaemia (ALL). Immunoprophylaxis and antiviral therapy have reduced the mortality, but the morbidity remains significant and is explored here in a cohort of children with ALL. MATERIAL AND METHODS: Among 67 children diagnosed with ALL during 1992-2007, 22 were seronegative for varicella-zoster virus (VZV) at the time of diagnosis. Patient records were reviewed to describe varicella exposures, eruptions and vaccinations during chemotherapy (24-30 months) and the following six months of immune recovery. RESULTS: Fifteen exposures were recognised in eight children and were managed with oral acyclovir prophylaxis; three resulted in clinical infection. Adoption of brief prophylaxis in the second week of incubation has not - so far - increased the infection rate (one in six versus two in nine). A further six varicella cases occurred without recognised exposure. All nine eruptions (in eight children) were uncomplicated but entailed hospitalisation days for intravenous therapy with acyclovir and loss of chemotherapy days. Seven children were VZV-vaccinated during maintenance chemotherapy; none developed varicella or zoster later in the course. CONCLUSION: Despite protective isolation and prophylactic treatment, seronegative children with ALL have a high risk of varicella during or shortly after chemotherapy. We recommend that susceptible siblings should be vaccinated at the time of diagnosis and the child should receive vaccination once oral maintenance chemotherapy has been initiated.

[Infantile haemangioma and intracranial vascular malformation]. / Et barn med infantile haemangiomer og malformationer.

A two-week-old female infant presented with a large haemangioma in the left superior palpebra, preventing her from opening the eye. Cerebral magnetic resonance imaging with angiography revealed another two facial haemangiomas and agenesia of the left internal carotid artery. The combination of facial haemangiomas and intracranial vascular malformation is diagnostic for the PHACES syndrome. When given oral prednisolone, the haemangioma regressed, allowing her to open the eye. She was treated for 29 weeks with slow tapering. Growth stagnation occurred during treatment, but otherwise her development was normal.

[Venous thromboembolism in children]. / Venøse tromboser hos børn.

Venous thromboembolism is a rare condition in children, but the incidence appears to be increasing. Newborns and teenagers are at the highest risk of thrombosis, which is often triggered by a combination of risk factors, in particular: infection, central venous line or chemotherapy. The impact of thrombophilia is uncertain. International guidelines recommend screening for thrombophilia as part of the diagnostic set-up in children with thrombosis. Treatment of paediatric thrombosis with low-molecular-weight heparin appears safe, but the effectiveness remains to be established.

[Childhood acute lymphoblastic leukemia in Norway 1992-2000]. / Akutt lymfatisk leukemi hos barn i Norge 1992-2000.

BACKGROUND: Acute lymphoblastic leukemia is the most common malignancy in childhood. The survival rate has increased steadily over the last 40 years. MATERIAL AND METHODS: All children aged 0-15 years and diagnosed in Norway in the period 1992-2000, were included in the study (n = 301). The patients were followed up until 1.1. 2005. RESULTS AND INTERPRETATION: The diagnosis was made in 301 children, 33 new cases per year (range 24 to 40) on average. The peak incidence was between 2 and 5 years. Four of 6 infants with acute lymphoblastic leukemia and all 4 with mature B-cell leukemia are alive. Two of the remaining 291 children died before treatment was started. 289 were all treated according to the common Nordic NOPHO-ALL 1992 protocol. All children achieved remission (99.7%), except for one who died before remission was achieved. 55 children (19%) relapsed. Radiation to the brain as part of central nervous system prophylaxis was given to just 10% of the children. The 10-year event-free survival (p-EFS) was 76%, and 244 of 289 (84%) were alive 4-13 years after the diagnosis was made. The data are comparable with the best international results.

[Survival of children with cancer]. / Kreftoverlevelse hos barn.

Survival data for all consecutive paediatric cancer patients (age 0-15) diagnosed between 1 January 1992 and 31 December 2001 are presented. The patients came from a catchment area in Norway with a population of approximately 1 million. During the period under review, the most intensive paediatric cancer treatment regimen up until now was given. There were 280 patients 128/280 (45.7%) girls and 152/280 (54.3%) boys; mean age at diagnosis was 6. Overall survival 3-13 years after diagnosis was 219/280 (78%). Over this ten-year period we treated 65 (23%) children with central nervous system tumours, 98 (35%) children with leukaemia, including acute myeloid leukaemia, and 117 (42%) children with solid tumours including lymphomas. Overall survival in these three subgroups was 49/65 (75%) for patients with central nervous system tumours, 80/98 (82%) for those with leukaemia, and 92/117 (79%) for those with solid tumours. Compared to previous data, survival increased with the intensity of treatment and resources used. Saved years of life for our 280 children are estimated to be a total of 14,000; the cost per saved year of life to be on average USD 2400. Our former patients will, through their future taxes, pay this back to the community many times over.

Cerebral atypical teratoid/rhabdoid tumor of infancy: long-term survival after multimodal treatment, also including triple intrathecal chemotherapy and gamma knife radiosurgery--case report.

Cerebral atypical teratoid/rhabdoid tumors (AT/RT) of infancy are highly malignant and have a poor prognosis. The authors report on one case with long-term survival. The patient was a 1 year-old boy presenting with a large AT/RT in the right temporal lobe. He was treated with complete surgery, followed by multiagent chemotherapy. Later he had a second resection and intrathecal chemotherapy and Gamma knife radiosurgery was added to the treatment. Except for a well-controlled temporal epilepsy, the boy is doing well after 6 years follow-up. AT/RT should be treated in a multimodal way. Intrathecal chemotherapy and Gamma knife radiosurgery of single recurrent or residual tumors might increase survival.

Gamma-knife radiosurgery in pediatric cerebral and skull base tumors.

BACKGROUND: This retrospective study of 12 children with cerebral or skull base tumors was undertaken to evaluate morbidity and outcome after gamma-knife surgery. PROCEDURE: Twelve consecutive children treated with stereotactic radiosurgery in a curative intent were reviewed. There were five girls and seven boys. The mean age at diagnosis was 5.8 years and at radiosurgical treatment 8.4 years. There were four pilocytic astrocytomas, two craniopharyngeomas, two pineoblastomas, two ependymomas, and two other tumors of high malignancy. We used a 201-source Co60 Leksell gamma knife and all children were treated in general anesthesia. RESULTS: The mean tumor volume was 3.7 cm(3) and the mean tumor margin dose was 13.8 Gy. Seven patients remained stable after gamma-knife treatment with a mean follow- up of 78.6 months. One patient died during follow-up. The remaining four patients had progressive disease, two within and two outside the irradiated field, and have received further treatment. They are still alive with and without disease with a mean follow-up of 96.8 months. CONCLUSION: Gamma-knife surgery is an effective treatment in some non-resectable cerebral and skull base pediatric tumors. In most cases, it is used in combination with other therapeutic modalities. It is safe and well tolerated.