Risk-adapted therapy for young children with medulloblastoma (SJYC07): therapeutic and molecular outcomes from a multicentre, phase 2 trial.

BACKGROUND: Young children with medulloblastoma have a poor overall survival compared with older children, due to use of radiation-sparing therapy in young children. Radiotherapy is omitted or reduced in these young patients to spare them from debilitating long-term side-effects. We aimed to estimate event-free survival and define the molecular characteristics associated with progression-free survival in young patients with medulloblastoma using a risk-stratified treatment strategy designed to defer, reduce, or delay radiation exposure. METHODS: In this multicentre, phase 2 trial, we enrolled children younger than 3 years with newly diagnosed medulloblastoma at six centres in the USA and Australia. Children aged 3-5 years with newly diagnosed, non-metastatic medulloblastoma without any high-risk features were also eligible. Eligible patients were required to start therapy within 31 days from definitive surgery, had a Lansky performance score of at least 30, and did not receive previous radiotherapy or chemotherapy. Patients were stratified postoperatively by clinical and histological criteria into low-risk, intermediate-risk, and high-risk treatment groups. All patients received identical induction chemotherapy (methotrexate, vincristine, cisplatin, and cyclophosphamide), with high-risk patients also receiving an additional five doses of vinblastine. Induction was followed by risk-adapted consolidation therapy: low-risk patients received cyclophosphamide (1500 mg/m2 on day 1), etoposide (100 mg/m2 on days 1 and 2), and carboplatin (area under the curve 5 mg/mL per min on day 2) for two 4-week cycles; intermediate-risk patients received focal radiation therapy (54 Gy with a clinical target volume of 5 mm over 6 weeks) to the tumour bed; and high-risk patients received chemotherapy with targeted intravenous topotecan (area under the curve 120-160 ng-h/mL intravenously on days 1-5) and cyclophosphamide (600 mg/m2 intravenously on days 1-5). After consolidation, all patients received maintenance chemotherapy with cyclophosphamide, topotecan, and erlotinib. The coprimary endpoints were event-free survival and patterns of methylation profiling associated with progression-free survival. Outcome and safety analyses were per protocol (all patients who received at least one dose of induction chemotherapy); biological analyses included all patients with tissue available for methylation profiling. This trial is registered with ClinicalTrials.gov, number NCT00602667, and was closed to accrual on April 19, 2017. FINDINGS: Between Nov 27, 2007, and April 19, 2017, we enrolled 81 patients with histologically confirmed medulloblastoma. Accrual to the low-risk group was suspended after an interim analysis on Dec 2, 2015, when the 1-year event-free survival was estimated to be below the stopping rule boundary. After a median follow-up of 5·5 years (IQR 2·7-7·3), 5-year event-free survival was 31·3% (95% CI 19·3-43·3) for the whole cohort, 55·3% (95% CI 33·3-77·3) in the low-risk cohort (n=23) versus 24·6% (3·6-45·6) in the intermediate-risk cohort (n=32; hazard ratio 2·50, 95% CI 1·19-5·27; p=0·016) and 16·7% (3·4-30·0) in the high-risk cohort (n=26; 3·55, 1·66-7·59; p=0·0011; overall p=0·0021). 5-year progression-free survival by methylation subgroup was 51·1% (95% CI 34·6-67·6) in the sonic hedgehog (SHH) subgroup (n=42), 8·3% (95% CI 0·0-24·0%) in the group 3 subgroup (n=24), and 13·3% (95% CI 0·0-37·6%) in the group 4 subgroup (n=10). Within the SHH subgroup, two distinct methylation subtypes were identified and named iSHH-I and iSHH-II. 5-year progression-free survival was 27·8% (95% CI 9·0-46·6; n=21) for iSHH-I and 75·4% (55·0-95·8; n=21) for iSHH-II. The most common adverse events were grade 3-4 febrile neutropenia (48 patients [59%]), neutropenia (21 [26%]), infection with neutropenia (20 [25%]), leucopenia (15 [19%]), vomiting (15 [19%]), and anorexia (13 [16%]). No treatment-related deaths occurred. INTERPRETATION: The risk-adapted approach did not improve event-free survival in young children with medulloblastoma. However, the methylation subgroup analyses showed that the SHH subgroup had improved progression-free survival compared with the group 3 subgroup. Moreover, within the SHH subgroup, the iSHH-II subtype had improved progression-free survival in the absence of radiation, intraventricular chemotherapy, or high-dose chemotherapy compared with the iSHH-I subtype. These findings support the development of a molecularly driven, risk-adapted, treatment approach in future trials in young children with medulloblastoma. FUNDING: American Lebanese Syrian Associated Charities, St Jude Children's Research Hospital, NCI Cancer Center, Alexander and Margaret Stewart Trust, Sontag Foundation, and American Association for Cancer Research.

Relevance of Molecular Groups in Children with Newly Diagnosed Atypical Teratoid Rhabdoid Tumor: Results from Prospective St. Jude Multi-institutional Trials.

PURPOSE: Report relevance of molecular groups to clinicopathologic features, germline SMARCB1/SMARCA4 alterations (GLA), and survival of children with atypical teratoid rhabdoid tumor (ATRT) treated in two multi-institutional clinical trials. MATERIALS AND METHODS: Seventy-four participants with newly diagnosed ATRT were treated in two trials: infants (SJYC07: age < 3 years; n = 52) and children (SJMB03: age 3-21 years; n = 22), using surgery, conventional chemotherapy (infants), or dose-dense chemotherapy with autologous stem cell rescue (children), and age- and risk-adapted radiotherapy [focal (infants) and craniospinal (CSI; children)]. Molecular groups ATRT-MYC (MYC), ATRT-SHH (SHH), and ATRT-TYR (TYR) were determined from tumor DNA methylation profiles. RESULTS: Twenty-four participants (32%) were alive at time of analysis at a median follow-up of 8.4 years (range, 3.1-14.1 years). Methylation profiling classified 64 ATRTs as TYR (n = 21), SHH (n = 30), and MYC (n = 13), SHH group being associated with metastatic disease. Among infants, TYR group had the best overall survival (OS; P = 0.02). However, outcomes did not differ by molecular groups among infants with nonmetastatic (M0) disease. Children with M0 disease and <1.5 cm2 residual tumor had a 5-year progression-free survival (PFS) of 72.7 ± 12.7% and OS of 81.8 ± 11%. Infants with M0 disease had a 5-year PFS of 39.1 ± 11.5% and OS of 51.8 ± 12%. Those with metastases fared poorly [5-year OS 25 ± 12.5% (children) and 0% (infants)]. SMARCB1 GLAs were not associated with PFS. CONCLUSIONS: Among infants, those with ATRT-TYR had the best OS. ATRT-SHH was associated with metastases and consequently with inferior outcomes. Children with nonmetastatic ATRT benefit from postoperative CSI and adjuvant chemotherapy.

Fanconi anemia and biallelic BRCA2 mutation diagnosed in a young child with an embryonal CNS tumor.

Medulloblastoma, the most common pediatric malignant brain tumor often arises sporadically; however, in a subgroup of patients, there exist familial conditions such as Fanconi anemia with biallelic BRCA2 mutation that predispose patients to developing medulloblastoma. Biallelic inactivation of BRCA2 in Fanconi anemia has been previously described in only 11 patients with medulloblastoma in the literature to date. Here we report two siblings diagnosed with central nervous system embryonal tumors at an early age in association with biallelic BRCA2 inactivation, including the first reported case of a spinal cord primitive neuroectodermal tumor (PNET) in a BRCA2/FANCD1 kindred.

Novel Combined Immune Deficiency and Radiation Sensitivity Blended Phenotype in an Adult with Biallelic Variations in ZAP70 and RNF168.

With the advent of high-throughput genomic sequencing techniques, novel genetic etiologies are being uncovered for previously unexplained Mendelian phenotypes, and the underlying genetic architecture of disease is being unraveled. Although most of these "mendelizing" disease traits represent phenotypes caused by single-gene defects, a percentage of patients have blended phenotypes caused by pathogenic variants in multiple genes. We describe an adult patient with susceptibility to bacterial, herpesviral, and fungal infections. Immunologic defects included CD8+ T cell lymphopenia, decreased T cell proliferative responses to mitogens, hypogammaglobulinemia, and radiation sensitivity. Whole-exome sequencing revealed compound heterozygous variants in ZAP70. Biallelic mutations in ZAP70 are known to produce a spectrum of immune deficiency that includes the T cell abnormalities observed in this patient. Analyses for variants in genes associated with radiation sensitivity identified the presence of a homozygous RNF168 variant of unknown significance. RNF168 deficiency causes radiosensitivity, immunodeficiency, dysmorphic features, and learning difficulties syndrome and may account for the radiation sensitivity. Thus, the patient was found to have a novel blended phenotype associated with multilocus genomic variation: i.e., separate and distinct genetic defects. These findings further illustrate the clinical utility of applying genomic testing in patients with primary immunodeficiency diseases.

Telomerase expression predicts unfavorable outcome in osteosarcoma.

PURPOSE: Osteosarcoma is distinct from most cancers in that the majority of osteosarcomas lack telomerase expression and use the alternative lengthening of telomeres (ALT) mechanism to maintain telomeres. Laboratory studies suggest that compared with ALT, telomerase expression is associated with increased tumor aggressiveness. We evaluated the clinical significance of telomerase expression in human osteosarcoma. PATIENTS AND METHODS: Fifty-six osteosarcomas from 51 patients treated at St Jude Children's Research Hospital between 1982 and 2003 were evaluated for telomerase enzyme activity, mRNA expression of the catalytic component of telomerase (TERT), and presence of the ALT pathway. RESULTS: Outcome analysis was based on TERT mRNA expression in the primary tumor samples from 44 patients. Fourteen primary tumors expressed TERT mRNA (32%; eight TERT only, six TERT and ALT) and 30 did not express TERT mRNA (68%; 29 ALT, one no ALT). Progression-free survival (PFS) was inferior in the TERT-positive group compared with the TERT-negative group (3-year estimates, 21.4% +/- 9.5% v 63.7% +/- 11.1%; P =.014). Likewise, overall survival was inferior in the TERT-positive group compared with the TERT-negative group (3-year estimates, 42.9% +/- 12.2% v 70.0% +/- 9.9%; P =.031). Among 31 patients with nonmetastatic disease at diagnosis, PFS was lower in the TERT-positive group compared with the TERT-negative group (3-year estimates, 33.3% +/- 13.6% v 72.0% +/- 11.5%; P =.092). CONCLUSION: Telomerase expression in primary tumor samples is associated with decreased PFS and OS in patients with osteosarcoma. Additional studies are warranted to better define the clinical utility of this molecular marker.

Young age may predict a better outcome for children with diffuse pontine glioma.

BACKGROUND: Because diffuse pontine glioma (DPG) is rare among young children, the outcome of affected patients is unknown. METHODS: The authors reviewed clinical and radiologic characteristics of all children aged <3 years with DPG who were evaluated at their institution. Inclusion followed standard magnetic resonance imaging criteria for the diagnosis of DPG. RESULTS: The median age at diagnosis in 10 patients was 2.2 years (range, 0.8-2.7 years). The median interval between the onset of symptoms and diagnosis was 2.5 months. All patients presented with cranial nerve palsy with (n = 7) or without (n = 3) other neurologic deficits attributable to brainstem involvement. All patients had pons-based tumors involving >50% of this brainstem segment. Histologic confirmation was attempted in 2 patients who had atypical radiologic features at diagnosis. Four patients initially were observed only. All patients received therapy, which consisted of radiation therapy (RT) (n = 2), RT and chemotherapy (n = 6), or chemotherapy only (n = 2). Four patients died of tumor progression after a median of 0.7 years (range, 0.5-3.7 years). Six patients have survived for a median of 2.3 years (range, 0.9-8 years). The 3-year progression-free and overall survival rates were 45% +/- 19% and 69% +/- 19%, respectively. CONCLUSIONS: Children aged <3 years with DPG potentially may fare better than older patients with the same diagnosis despite the use of similar therapy. The current results suggested that DPG in younger children may be distinct biologically from similar tumors in older age groups.

M1 Medulloblastoma: high risk at any age.

BACKGROUND: The prognosis for children with M1 medulloblastoma (positive CSF cytology) has not been well-defined. METHODS: We retrospectively reviewed the records of 285 newly diagnosed medulloblastoma patients treated between 1984 and 2006. Older children received post-operative craniospinal and tumor bed irradiation; radiotherapy for younger children depended on treatment era and physician/family preference. RESULTS: 55 patients were <3 years old and 230 patients were >or= 3 years old at diagnosis. We detected significant (P < 0.0001) associations between M1 disease and EFS for the entire cohort and for both younger and older patients. Among younger children, M1 patients had lower EFS than M0 (P = 0.0044). CONCLUSIONS: Children <3 years old with M1 medulloblastoma fared poorly in our small series. Survival for older children with M1 disease treated with higher-dose CSI was better than that of M2/M3 patients, but still less than optimal; our findings do not support reduction in therapy for either cohort.

Endocrine outcomes for children with embryonal brain tumors after risk-adapted craniospinal and conformal primary-site irradiation and high-dose chemotherapy with stem-cell rescue on the SJMB-96 trial.

PURPOSE: To estimate the cumulative incidence of specific hormone deficiencies and the influence of hypothalamic-pituitary (HP) axis radiation dose in a cohort of children with embryonal brain tumors treated with risk-adapted craniospinal irradiation (CSI), conformal primary site irradiation, and high-dose chemotherapy. PATIENTS AND METHODS: Clinical data and HP axis radiation dosimetry data were obtained from 88 eligible children. All patients received regular endocrine follow-up that included screening tests of thyroid function and stimulation testing for growth hormone deficiency (GHD), and adrenocorticotropin hormone deficiency. RESULTS: The cumulative incidence of GHD, thyroid-stimulating hormone (TSH) deficiency, adrenocorticotropic hormone deficiency, and primary hypothyroidism at 4 years from diagnosis was 93% +/- 4%, 23% +/- 8%, 38% +/- 6%, and 65% +/- 7%, respectively. Radiation dosimetry to the HP axis was associated only with the development of TSH deficiency; the 4-year cumulative incidence was 44% +/- 19% and 11% +/- 8% (P = .014) for those receiving more or less than the median dose to the hypothalamus (>or= 42 v < 42 Gy), respectively. The median dose of CSI for the average-risk (AR) patients was 23.4 and 39.6 Gy (36 to 40.5 Gy) for the high-risk patients. The estimated mean decline in height Z-score after radiation therapy was greater in high-risk patients (-0.65 units/yr) when compared with AR patients (-0.54 units/yr; P = .039). CONCLUSION: Pediatric patients with CNS embryonal tumors are at high risk for treatment-related hormone deficiencies. GHD and primary hypothyroidism were diagnosed in a majority of subjects relatively soon after the completion of therapy. Radiation dose to the hypothalamus in excess of 42 Gy was associated with an increase in the risk of developing TSH deficiency.

Reinduction of relapsed acute promyelocytic leukemia with ATRA and low dose antimetabolite-based chemotherapy.

While the disease-free survival of acute promyelocytic leukemia (APML) now approaches 75%, some children continue to experience relapses, and questions remain as to the optimal management of these patients. We describe two young children who experienced combined relapses in the bone marrow and extramedullary locations following hematopoietic stem cell transplantation (HSCT). An induction regimen, consisting of all-trans retinoic acid (ATRA), methotrexate, and 6-mercaptopurine (6MP), successfully and safely achieved hematologic remission in one patient and molecular remission in the other. These cases demonstrate that there is a role for ATRA plus differentiating chemotherapy other than arsenic trioxide in the treatment of relapsed APML.

A revised classification scheme for acute transfusion reactions.

BACKGROUND: Although the standard classification system for acute transfusion reactions adequately describes the general features associated with the various types of reactions, it was not designed to provide strict criteria for diagnosis and classification. Consequently, its use to classify individual reactions can result in significant inter- and intraobserver variability, which can complicate patient management and clinical research. STUDY DESIGN AND METHODS: A total of 595 transfusion reactions that occurred at a single institution between January 1, 1996, and December 31, 2003, were reviewed and were initially classified according to the established conventions of the AABB. Each reaction was then reclassified with a revised system that refines and clarifies reaction categories, adds severity grades in the format of the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE), and includes terminology to indicate the attribution or likelihood that the adverse event is related to the transfusion. RESULTS: Comparison of the two approaches as applied to these 595 transfusion reactions showed clear advantages for the revised system. Of 128 reactions classified by AABB criteria as inconclusive, a mixture of reaction types, or otherwise qualified, all but 5 were accommodated by discrete categories within our revised scheme. In each case with a classifiable reaction, the severity of the reaction could be readily graded. CONCLUSION: The advantages of this revised classification scheme for acute transfusion reactions warrant prospective evaluation and ultimately consideration of its incorporation into clinical practice.

High-grade astrocytoma in very young children.

BACKGROUND: High-grade astrocytomas are rare in young children, but have been reported to have a better prognosis than similar tumors in older patients. PROCEDURE: We retrospectively reviewed the clinical characteristics, survival, and long-term sequelae for patients younger than 3 years old with high-grade astrocytoma, treated at a single institution between 1984 and 2005. RESULTS: Sixteen patients were included. Histology included anaplastic astrocytoma (n = 9), glioblastoma multiforme (n = 5), and malignant glioma (n = 2). All patients underwent biopsy or resection, followed by chemotherapy. Six patients received scheduled irradiation and six were irradiated at the time of disease progression. Ten patients are alive at a median follow-up of 11.6 years (range, 1.7-21.6 years). 5-year overall survival (OS) was 66.3% (SE 12.2%), and 5-year event-free survival (EFS) was 28.6% (SE 12.1%). Age at diagnosis was a significant predictor of the hazard of death in a Cox model (HR 2.871, 95%CI 1.015-8.123). Gender and histology did not predict OS or EFS. Trends toward improved OS were detected for patients with hemispheric tumors and those undergoing complete resection. All evaluable survivors (n = 9) had some neurocognitive impairment, with estimated overall cognitive ability ranging from significantly delayed to average; all survivors attending school (n = 5) performed below grade level on achievement testing. Seven of nine evaluable survivors had endocrine dysfunction. CONCLUSIONS: Young children with high-grade astrocytoma have better long-term overall survival than older patients, but recurrence is common, and most children require irradiation. Long-term complications are frequent and often severe.

Familial adenomatous polyposis in two brothers with hepatoblastoma: implications for diagnosis and screening.

Two brothers with hepatoblastoma were noted to have a family history of early onset colon cancer. Genetic testing of the younger brother revealed a deletion in exon 15 of the adenomatous polyposis coli (APC) gene (2710-2711delAG), consistent with a diagnosis of familial adenomatous polyposis (FAP). We review the clinical and molecular aspects of the relationship between hepatoblastoma and FAP, and the implications for diagnostic testing and cancer screening in affected patients.

Premedication with acetaminophen or diphenhydramine for transfusion with leucoreduced blood products in children.

Febrile non-haemolytic or allergic reactions occur in 0.1-30% of transfusions; physicians often premedicate patients with acetaminophen or diphenhydramine to prevent these reactions. The effectiveness of this practice has not been demonstrated. In this retrospective review of all transfusions at our institution during 2002, 385 patients received 7900 evaluable leucoreduced, irradiated blood products (4280 single-donor apheresis platelets and 3620 packed red blood cells). Febrile reactions occurred in 0.95% of 4108 transfusions with, and 0.53% of 3792 transfusions without, acetaminophen premedication. Allergic reactions occurred in 0.90% of 4315 transfusions with, and 0.56% of 3585 transfusions without, diphenhydramine premedication. In a multivariate analysis that adjusted for age, patient category, transfusion location, product, transfusion history, and reaction history, premedication with acetaminophen was associated with a statistically non-significant increase in the odds of a febrile reaction (odds ratio 1.74; 95% confidence interval 0.71-4.23; P = 0.22), and diphenhydramine with a non-significant increase in allergic reactions (odds ratio 1.74; 95% confidence interval 0.99-3.06; P = 0.054). Reactions occurred in only 1.3% of the 518 transfusions to patients with a history of two or more prior reactions. Febrile and allergic transfusion reactions were rare in paediatric patients transfused with leucoreduced, irradiated blood products, whether premedication was used or not.