Embryonal tumors in Canadian children less than 36 months of age: results from the Canadian Pediatric Brain Tumor Consortium (CPBTC).

Embryonal tumors are a heterogeneous group of central nervous system (CNS) tumors whose subgroups have varying incidence and outcome. Despite these differences, they are often grouped as a single entity for study purposes. To date, there are no Canadian multi-institutional studies examining the incidence and outcome of all embryonal subtypes. The current study is an observational study reviewing embryonal tumors in all patients less than 36 months of age diagnosed with a CNS tumor in Canada from 1990 to 2005. Embryonal tumors accounted for 26.9% of all CNS tumors. Medulloblastomas were the highest proportion of the embryonal tumors at 61.5%. Atypical teratoid/rhabdoid tumors (AT/RT) had the second highest proportion of embryonal tumors at 18%. The proportion of primitive neuroectodermal tumors (PNET) was 16%, with 2.6 and 1.9% for congenital medulloepithelioma and ependymoblastoma tumors, respectively. AT/RT and PNET were more common in younger age groups. Medulloblastoma became more prevalent with increasing age, with its highest prevalence in the 25 to 36 month age group. Survival rates for our Canadian population at 18 and 24 months were 0.74 and 0.68 for medulloblastoma, 0.64 and 0.60 for PNET, and 0.36 and 0.29 for AT/RT, respectively. Overall, our data are comparable with published international rates for embryonal tumors. These incidence and outcome figures can guide future research into these rare tumors.

Status Report ­ The Cancer in Young People in Canada surveillance system.

TITRE: Rapport d'étape - Le système de surveillance Cancer chez les jeunes au Canada. INTRODUCTION: Même si le cancer infantile demeure la principale cause de décès lié à la maladie chez les enfants de moins de 14 ans, il est relativement rare. Chaque année au Canada, environ 910 enfants reçoivent un diagnostic de cancer et 139 meurent de la maladie. Sur le plan biologique, les cancers infantiles diffèrent de ceux habituellement observés chez les adultes. Chez ces derniers, la majorité des cancers sont des carcinomes du tissu épithélial qui tapisse les organes comme le sein, le poumon, le colon et la prostate. Chez les enfants, les carcinomes sont rares, et les tumeurs pédiatriques sont le plus souvent d'origine embryonnaire ou hématopoïétique. Les groupes de diagnostic les plus nombreux sont ceux de la leucémie, du lymphome et des cancers du système nerveux central. Comparativement aux cancers chez les adultes, les cancers chez les enfants ont des périodes de latence plus courtes et sont généralement plus agressifs, envahissants et avancés au moment du diagnostic. Malgré le rang élevé qu'occupe le cancer comme cause de décès chez les enfants, le taux de survie s'est grandement amélioré au cours des vingt dernières années, de sorte que les enfants survivent au cancer plus que jamais auparavant. Toutefois, plus de 60 % des survivants d'un cancer infantile sont confrontés aux effets secondaires physiques et psychologiques à long terme de la maladie et de son traitement, et presque 30 % d'entre eux éprouvent des effets tardifs graves ou potentiellement mortels. Les survivants d'un cancer infantile présentent un risque 11 fois plus élevé de décès, un risque accru de développer un second cancer jusqu'à 30 ans après le traitement ainsi qu'un large éventail de problèmes chroniques d'ordres physique, psychosocial et cognitif. La prise en compte de la nature particulière des cancers dans ce groupe d'âge et des effets tardifs à long terme d'ampleur considérable ont incité de nombreux pays à mettre sur pied des systèmes spécialisés de surveillance et de suivi du cancer chez les enfants. En 2009, l'Agence de la santé publique du Canada (ASPC) a lancé à l'échelle du pays un système spécialisé de surveillance du cancer chez les enfants qui assure un suivi actif des enfants de 14 ans et moins ayant été traités dans l'un des 17 centres d'oncologie pédiatrique du Canada. En fait, le programme Cancer chez les jeunes au Canada (CCJC) est le renouvellement du Programme canadien de surveillance et de lutte contre le cancer chez les enfants (PCSLCE) du gouvernement fédéral. Créé en 1992 dans le cadre de l'initiative Grandir ensemble, ce programme recueille des données exhaustives sur le diagnostic de cancer chez les enfants, les traitements, l'issue de la maladie et l'utilisation des services de santé. Dans cet article, nous décrivons les forces et les réussites de CCJC en mettant en lumière la rigueur appliquée dans les méthodes de collecte et de contrôle de la qualité des données, ses dernières réalisations et ses orientations futures.

Central nervous system atypical teratoid rhabdoid tumours: the Canadian Paediatric Brain Tumour Consortium experience.

BACKGROUND: Atypical teratoid rhabdoid tumours (ATRT) are aggressive brain tumours mostly occurring in early childhood. Largest published series arise from registries and institutional experiences (1-4). The aim of this report is to provide population-based data to further characterise this rare entity and to delineate prognostic factors. PATIENTS AND METHODS: A national retrospective study of children ⩽18years diagnosed with a central nervous system (CNS) ATRT between 1995 and 2007 was undertaken. All cases underwent central pathology review. RESULTS: There were 50 patients (31 males; median age at diagnosis of 16.7months). Twelve patients were >36months. Infratentorial location accounted for 52% of all cases. Nineteen patients (38%) had metastatic disease. Fifteen (30%) underwent gross total resection (GTR). Ten patients (20%) underwent palliation. Among the 40 remaining patients, 22 received conventional chemotherapy and 18 received high dose chemotherapy regimens (HDC); nine received intrathecal chemotherapy and 15 received adjuvant radiation. Thirty of the 40 treated patients relapsed/progressed at a median time of 5.5months (0-32). The median survival time of the entire cohort was 13.5months (1-117.5months). Age, tumour location and metastatic status were not prognostic. Patients with GTR had a better survival (2years overall survival (OS): 60%±12.6 versus 21.7%±8.5, p=0.03). HDC conferred better outcome (2years OS 47.9%±12.1 versus 27.3%±9.5, p=0.036). Upfront radiation did not provide survival benefit. Six of the 12 survivors (50%) did not receive radiation. CONCLUSION: The outcome of CNS ATRT remains poor. However, the use of HDC provides encouraging results. GTR is a significant prognostic factor. The role of adjuvant radiation remains unclear.

Pituitary choriocarcinoma in an adolescent male: tumor-derived CG and GH delay diagnosis.

BACKGROUND: Primary intracranial germ cell tumors usually present in the first two decades of life, often with precocious puberty. The most common location is in the pineal gland; suprasellar germ cell tumors are rare. We present an additional case of a suprasellar choriocarcinoma producing GH, and review the literature. CASE: This French Canadian, 17 year-old male presented to the ER with a history of mild weight loss and an episode of syncope while hiking in Mexico, but with no other neurological symptoms. Puberty began at age 13 years (growth spurt: 15-16 years), and he attained an adult height within genetic target by age 16 years. Past medical history was negative except for myopia diagnosed during childhood. System review revealed increased thirst and nocturia. The mother was treated for an oligo-astrocytoma in 2007. Clinical examination showed a euthyroid, well-looking young man with 20 ml testicles. Endocrine evaluation revealed elevated testosterone, mildly elevated PRL, borderline low FT4, and decreased IGF-I, morning cortisol and urine osmolality; tumor markers were positive in serum and CSF (hCG>50 IU/L, AFP>10 ng/mL). A transphenoidal biopsy of a 4.5 cm, homogeneous, non-calcified, suprasellar mass was compatible with the diagnosis of choriocarcinoma and stained intensely for hCG and hGH, presumably the placental variant (GH-V) as previously found in vitro in choriocarcinoma cell lines. Combined chemotherapy and irradiation led to tumor regression and undetectable serum hCG to 36 months of follow-up. He is doing well with no evidence of tumor progression and is on complete hormone replacement therapy. CONCLUSIONS: Choriocarcinomas can have a hormonal profile that delays the development of symptoms, due to hCG stimulation of both the gonadal and thyroid axes. This report corroborates previous in vitro evidence that choriocarcinoma cells are able to make GH-V. To what extent the patient's tumor-derived GH contributed to his normal growth is not known. Prognosis for this intracranial neoplasm is very reserved, although combined radiotherapy and chemotherapy has been successful in our patient now 36 months post-diagnosis.

Treatment-related morbidity in atypical teratoid/rhabdoid tumor: multifocal necrotizing leukoencephalopathy.

BACKGROUND: Atypical teratoid/rhabdoid tumor (AT/RT) is an aggressive malignant brain tumor that, since it was first identified, has been treated with aggressive treatment regimens, e.g. high-dose chemotherapy with stem cell rescue and early radiotherapy. We reviewed our experience because of concerns with respect to treatment-related toxicity in our patients. METHODS: Seven patients with a median age at presentation of 18 months were diagnosed with AT/RT between 1996 and 2006. Tumor location was supratentorial in 2 patients, in the posterior fossa in 4 and spinal in 1. Gross total resection was performed in 1 patient, subtotal resection in 5 and biopsy only in 1. Adjuvant treatment consisted of chemotherapy and radiotherapy in 5 patients. RESULTS: Median progression-free survival was 4 months, and median overall survival was 7 months. Two children are alive at 44 and 102 months. Significant surgical and chemotherapy-related morbidity was seen. Biopsy-proven multifocal necrotizing leukoencephalopathy (MNL) was seen in one patient who is alive 44 months after diagnosis. Another patient who was thought to have recurrent tumor in the brainstem 9 months after diagnosis had imaging findings compatible with MNL. CONCLUSION: Although improving results are reported for AT/RT using intensive treatment regimens, treatment-related morbidity is considerable in this young patient population.

The use and effectiveness of temozolomide in children with central nervous system tumours: a survey from the Canadian Paediatric Brain Tumour Consortium.

OBJECTIVE: To describe the use of temozolomide (tmz) in Canadian children treated for brain tumours and to evaluate survival and predictors of survival for children treated with this agent. METHODS: A survey was conducted within the Canadian Paediatric Brain Tumour Consortium (cpbtc), a group of tertiary care centres in pediatric neuro-oncology (n = 16) in Canada that are involved in the treatment of children with central nervous system tumours. RESULTS: In 10 of the 16 participating pediatric oncology centres of the cpbtc, 137 children with brain tumours were treated with tmz between January 2000 and March 2006. Although 33% of the children were enrolled into a clinical trial, 67% were treated outside open studies. Most patients (72%) received tmz treatment on recurrence of their brain tumour (first or subsequent). The most commonly administered regimen was single-agent tmz 150-200 mg/m(2) administered on 5 consecutive days every 28 days. The median duration of tmz treatment was 141 days (range: 4-1102 days). Response data were provided for 127 of the 137 patients, of whom 6 showed a complete response. Sixteen patients experienced a minor or partial response, 53 had stable disease, and 52 had progressive disease. Of 32 patients alive at last follow-up, 19 had a diagnosis of low-grade glioma. CONCLUSIONS: Temozolomide is used in a variety of pediatric brain tumours, often at the time of recurrence. The lack of insight into clear indications for this agent in pediatric brain tumours-used either alone or in combination therapy-may be a result of suboptimal design of phase i and ii studies and a lack of phase iii trials in the pediatric brain tumour population.

Epidemiological survey of central nervous system germ cell tumors in Canadian children.

OBJECTIVES: To determine the incidence and characteristics of pediatric patients with central nervous system (CNS) germ cell tumors (GCT) in Canada. METHOD: A national retrospective review of hospital charts was done on all patients with CNS GCT diagnosed between 1990 and 2004. Patients had to be under age 18 years at the time of diagnosis of a CNS germ cell tumor and be a resident of Canada. Information extracted included age and year of diagnosis, pathological diagnosis, location of tumor, evidence of disseminated disease at time of diagnosis and biological markers. RESULTS: One hundred and twenty-one cases were identified (83 germinoma; 38 non-germinoma germ cell tumor). The mean annual incidence of CNS GCT was 1.06 per million children (0.7 per million for germinoma; 0.3 per million for NGGCT). Though yearly incidences varied, there was no clear trend to increased incidence. Male predominance was noted (2.4:1 for germinoma; 11:1 for NGGCT). The primary locations were the pineal and suprasellar regions. At the time of diagnosis, disseminated disease was not uncommon (22% germinoma; 32% NGGCT). Beta human gonadotrophin was elevated in the serum, cerebrospinal fluid (CSF) or both in 7% of patients with germinoma and 36% of patients with NGGCT. Elevation of alpha-fetoprotein in serum, CSF or both was seen in 34% of patients with NGGCT. CONCLUSION: The incidence of CNS germ cell tumors in Canadian children is similar to that observed in other Western countries.

Chimaeric anti-CD20 monoclonal antibody (rituximab) in post-transplant B-lymphoproliferative disorder following stem cell transplantation in children.

Post-transplant lymphoproliferative disorder (PTLD) after haemopoietic stem cell transplantation is a serious complication that occurs in 8-22% of patients with high-risk factors. We retrospectively investigated tolerance and efficacy of humanized anti-CD20 monoclonal antibody (rituximab) as first-line treatment in 12 children with B-cell PTLD. At diagnosis, eight patients had tumoral involvement. The other four patients had fever, associated with raised Epstein-Barr virus (EBV) viral load and monoclonal gammopathy. Rituximab was given at the dose of 375 mg/m2 once a week by intravenous infusion (1-9 infusions). Only 1/48 infusions was associated with a grade 2 clinical adverse event. Eight out of 12 (66%) patients responded to the treatment and were in complete remission. All patients without tumoral involvement responded to the treatment. A rapid decrease in fever within 1 week was observed in all responders. Non-responders did not show any clinical response during the first week. Tumoral involvement and immunodepression seemed to be more marked in non-responders. Rituximab was an effective and well-tolerated treatment of B-cell PTLD. Early treatment before tumoral involvement seemed to be the most effective approach. Lack of rapid response should lead to intensification of PTLD treatment. Pre-emptive treatment should be considered and evaluated in further longitudinal multicentre studies.

Infection due to acyclovir resistant herpes simplex virus in patients undergoing allogeneic hematopoietic stem cell transplantation.

Over an eight-month period from October 1997 to May 1998, four patients who had received bone marrow transplant (BMT) from unrelated donor presented with severe mucosal cutaneous infections involving acyclovir resistant herpes simplex virus 1 (HSV-1). The four isolates were acyclovir (ACV) resistant, three of which were also foscarnet resistant as determined by the dye uptake method. The sequencing of the thymidine kinase (TK) gene did not permit to establish a relation between mutations and resistance to ACV. Three patients were considered as clinically cured of their HSV infection by replacement of ACV or foscarnet with either valacyclovir (one case) or cidofovir (two cases) but eventually two of them died of graft vs host disease. One patient died of extensive HSV infection despite administration of cidofovir. This study emphasizes the importance of monitoring the herpes virus resistance to antiviral drugs in bone marrow transplant recipients and the usefulness of the evaluation of novel antiviral drug for treatment of infections due to strains of HSV resistant to ACV and foscarnet that occur in about 5% of immunocompromised patients.

Treatment of adenovirus infections in patients undergoing allogeneic hematopoietic stem cell transplantation.

Retrospective analysis of 303 patients who underwent allogeneic hematopoietic stem cell transplantation identified 35 (11.5%) with adenovirus infection. Among them, 22 received specific therapy. As first-line therapy, 18 were treated with intravenous ribavirin, 3 with cidofovir, and 1 with vidarabine. Moreover, 2 received donor leukocyte infusion in combination with ribavirin, and 1 received it after failing to respond to other therapies. Seven survived (31.8%; 3 of 13 who received ribavirin alone and 2 of 3 who received cidofovir). Among the 5 patients treated with combined strategies, 2 who received donor leukocyte infusions showed clearance of all symptoms. Acute graft-versus-host disease grade > or = 3 (P = .01) and a long delay between infection and treatment (P = .05) correlated with a greater risk of treatment failure. In conclusion, ribavirin and vidarabine are ineffective options, particularly for patients at who are high risk of acquiring disseminated adenovirus disease. Conversely, cidofovir or donor leukocyte infusions seem to be encouraging approaches if initiated early.

Investigation of aciclovir-resistant herpes simplex virus I infection in a bone marrow transplantation unit: genotyping shows that different strains are involved.

Over an eight-month period from October 1997 to May 1998, four patients who had received a bone marrow transplant (BMT) from an unrelated donor presented with severe mucosal cutaneous infections involving aciclovir resistant herpes simplex virus 1 (HSV-1). The emergence within a short period of resistant HSV-1 strains in the bone marrow transplantation unit raised fears of hospital-acquired infections. The hypothesis was investigated by restriction fragment length polymorphism (RFLP), sequencing of the thymidine kinase (TK) gene and genotyping of hypervariable regions of these four strains. Restriction fragment length polymorphism proved to be poorly discriminant and the TK sequence did not rule out transmission between these patients. Amplification of reiterating hypervariable genomic HSV-1 regions designated Re IV and Re VII clearly differentiated patients' strains. Thus, in this study, there was no evidence of nosocomial transmission of HSV-1 strains between the four patients.

A convenient semi-quantitative method for the diagnosis of Epstein-Barr virus reactivation.

A semi-quantitative determination of Epstein-Barr virus (EBV) viremia has been devised. Peripheral blood mononuclear cells are recovered by Ficoll gradient and numerated. Five microl aliquots of recovered cell suspension and 5 microl of two standard dilutions (containing 500 and 100 cells, respectively) are subjected to a nested polymerase chain reaction (PCR). This technique has been evaluated over 3 years for the follow-up of 45 patients attending the Bone Marrow Transplantation Unit of the "Centre Hospitalier et Universitaire de Nancy". EBV reactivation was diagnosed in 13 patients (28%). Positivity of PCR for 100 cells was found in 9 patients of whom 6 developed lymphoma or lymphoproliferative disorder. This technique is easy to perform and doesn't necessitate any specific material besides the one necessary for routine genic amplification.

Long-term results of CD34(+) cell transplantation in children with neuroblastoma.

BACKGROUND: This is the first report of the long-term results of CD34(+) cell transplantation in children with neuroblastoma. We investigated the hematologic and immune recovery, posttransplant morbidity, and clinical outcome of these children. PROCEDURE: Twenty-three children with advanced neuroblastoma had PBPCs (20 patients) or BM (3 patients) collected, followed by CD34(+) cell selection on Ceprate column. The purge of residual neuroblastoma cells was evaluated using an RT-PCR for tyrosine hydroxylase (TH) mRNA assay. Reinfusion of CD34(+) cells followed busulfan + melphalan myeloablative chemotherapy. RESULTS: A median of 2.9 x 10(6) CD34(+) cells/kg was reinjected. Median days to achieve ANC > 0.5 x 10(9)/liter and platelets > 50 x 10(9)/liter were 13 (range 9-33) and 59 (range 22-259), respectively. Circulating T cells were primarily CD4(-)/CD8(+) with fewer than 0.2 10(9)CD4(+) cells/liter throughout the first 6 months. CD19(+) cells and CD56(+) cells were not detectable up to day +35 posttransplant. At 1 year posttransplant, 16 evaluable patients had stable hematopoiesis with 2.3 x 10(9) ANC/liter (range 0.8-4.1), 1.4 x 10(9) lymphocytes/liter (range 0.5- 2.0) and 251 x 10(9) PLT/liter (range 35-490). After the completion of hematopoietic reconstitution, six events of severe septicemia/septic shock were noted. Six children had severe VZV infections, and 2 had EBV-associated lymphoproliferation. Thirteen patients are alive with a median follow-up of 40 months (range 2-54). Ten patients have died; 8 relapsed or developed progressive disease, 1 died from nondocumented pneumopathy at day 56, and 1 developed AML-M4 at 3 years posttransplant. CONCLUSIONS: In children, CD34(+) cell transplantation can be accomplished with a reduction of neuroblastoma cell inoculum in the selected graft as assessed by RT-PCR analysis. CD34(+) cell grafts provide successful neutrophil reconstitution. However, delayed platelet recovery, persistent decrease in CD4(+) lymphocyte levels and a high incidence of serious and life-threatening late infections were observed in these children. There remains a critical need to evaluate any real clinical benefit of CD34(+) cell autografts in neuroblastoma patients.

Humanized anti-CD20 monoclonal antibody (Rituximab) in post transplant B-lymphoproliferative disorder: a retrospective analysis on 32 patients.

BACKGROUND: B-lymphoproliferative post-transplant disorder (BLPD) is a severe complication of organ and bone marrow transplantation. The reduction of immuno-suppressive therapy or surgery for localized disease may cure some BLPDs. Other therapeutic approaches such as chemotherapy and antiviral drugs are toxic and of limited efficacy. Adoptive immunotherapy with donor T-cell infusions has yielded promising results but is, at the present time, easily applicable only in bone marrow-transplanted patients. Anti-B-cell Murine monoclonal antibodies (MoAbs) have proven effective but are no longer available for human use. We report the activity of a humanized anti CD 20 Mo Ab (Rituximab-MABTHERA Roche) in 32 episodes of BLPD treated in 14 French centers. PATIENTS AND METHODS: Between November 1997 and September 1998, 32 patients were diagnosed with BLPD. Twenty-six patients had undergone solid organ transplants (liver 8, kidney 8, heart 4, lung 3, heart lung 1, kidney-pancreas 1, liver-kidney 1) and six patients had received bone marrow transplantations. The median age of the patients was 34 years (3-67 years) and the median delay between graft and tumor 5 months (1-156 months). In organ recipients, tumors were classified as polymorphic and monomorphic in 10 and 15 cases, respectively; 4 of 6 bone marrow transplant recipients were treated without pathology documentation because of a rise in EBV load, fever and lymph node enlargement. Tumors were associated with EBV in 22 of 26 tested cases. Rituximab was used as first-line therapy in 30 patients (after reduction of immunosuppressive treatment in 27 patients) and as salvage therapy in 2 patients (after failure of chemotherapy). The median time from diagnosis of BLPD to treatment with Rituximab was 14 days (1-110 days). Two patients received eight infusions, twenty-six patients four infusions, one patient three infusions and three patients two infusions of 375 mg/m2. RESULTS: The tolerance of rituximab was good. The overall response rate was 69%, with 20 complete responses and 2 partial responses. In solid organ transplant the response rate was 65% (15 CR and 2 PR) while it was 83% in bone marrow-transplanted patients (5 CR). With a median follow-up of 8 months (1-16 months) 24 patients are still alive. The one-year projected survival is 73%. Of the 22 patients who achieved response, 15 patients (11 solid organ transplant and 4 bone marrow transplant) are alive with no evidence of disease, 4 patients relapsed a median of 7 months (3-10 months) after treatment and 3 died while in CR of concurrent diseases. Of the 10 patients who did not respond to Rituximab 5 are alive with no evidence of disease after salvage therapy. CONCLUSIONS: The use of rituximab appears to be a safe and relatively efficient therapy in BLPDs. The results need to be confirmed in a prospective multicentric trial.

Bone marrow transplantation as treatment for X-linked immunodeficiency with hyper-IgM.

We report a 10-year-old boy with a severe form of immunodeficiency with hyper-IgM who underwent successful bone marrow transplantation with his HLA-matched sister as donor. Busulfan (20 mg/kg) and cyclophosphamide (200 mg/kg) were used as conditioning. The post-transplant course was uneventful. He is alive 25 months later with full hematological and immunological reconstitution.

[Isolated persistent thrombocytopenia after autologous bone marrow grafting]. / Thrombopénie isolée persistante après autogreffe de moelle.

An 11 year-old boy was treated for acute promyelocytic leukemia (ALM3) with chemotherapy according to the LAME 86 protocol (aracytin and rubidomycin). The first complete remission was consolidated by two autologous bone marrow transplantations. Following autologous graft, a persistent thrombocytopenic purpura appeared. Autoimmune origin was indicated by a decrease in platelet survival time and by the presence of high levels of antiplatelet antibodies.