Stergios Zacharoulis

Intensive chemotherapy followed by consolidative myeloablative chemotherapy with autologous hematopoietic cell rescue (AuHCR) in young children with newly diagnosed supratentorial primitive neuroectodermal tumors (sPNETs): report of the Head Start I and II experience.

Children with newly diagnosed supratentorial primitive neuroectodermal tumors (sPNET) have poor outcomes compared to medulloblastoma patients, despite similar treatments. In an effort to improve overall survival (OS) and event‐free survival (EFS) and to decrease radiation exposure, the Head Start (HS) protocols treated children with newly diagnosed sPNET utilizing intensified induction chemotherapy (ICHT) followed by consolidation with myeloablative chemotherapy and autologous hematopoietic cell rescue (AuHCR).

The Treatment of High Grade Gliomas and Diffuse Intrinsic Pontine Tumors of Childhood and Adolescence: A Historical – and Futuristic – Perspective

SummaryPediatric high grade gliomas represent a heterogeneous group of tumors with poor prognoses despite the use of multimodal treatment. Very little progress has been made over the past decades in identifying efficacious therapeutic modalities against both high grade gliomas and diffuse brainstem gliomas in children. The degree of surgical resection is the most important clinical prognostic factor for children with high grade gliomas, and a complete resection should be attempted whenever feasible. The role of radiation therapy in the treatment of older children with high grade gliomas and diffuse brain stem gliomas is undisputed; however the benefit of using radiation for patients less than 6 years of age (with high grade gliomas) might be questionable. Despite the absence of solid evidence to support its use, chemotherapy is routinely used against these tumors. Currently temozolomide is being investigated due to its activity in adult trials and based on preliminary data regarding recurrent disease. A small subgroup of patients can be successfully treated with high dose chemotherapy followed by autologous stem cell rescue. Early trials using this modality in the past had been associated with high morbidity and mortality. High dose chemotherapy with autologous stem cell rescue in selected patients with minimal residual disease, angiogenesis inhibitors, radiosensitizers and other biological modifiers are being currently investigated in phase I/II trials.

Ependymoma: An Update

The authors provide an update on most issues related to biology, diagnosis, and treatment of children with ependymoma based on a literature review. Ependymoma is the third most common brain tumor in children and overall survival ranges from 24% to 75% at 5 years. The extent of surgical resection remains the principal risk factor that clearly influences outcome. The influence of age, location, grade, or stage has proved to be more controversial. Current standard therapy includes surgical resection and radiotherapy. Chemotherapy has a role in infants to avoid/delay radiotherapy and can be helpful to improve resectability. About half of patients will experience relapse, and outcome is dismal. New radiation modalities, reirradiation, chemotherapy, or targeted agents have been tested with promising results. Results of multi-institutional clinical trials are awaited to determine the best first-line treatment, while results of early phase I/ II trials will explore directed therapies based on new biologic factors.

Does chemotherapy affect the visual outcome in children with optic pathway glioma? A systematic review of the evidence

INTRODUCTION Overall prognosis for optic pathway glioma (OPG) in children is excellent. Little is known, however, about the effect of chemotherapy on visual outcome of these patients. MATERIAL AND METHODS A systematic review of the literature was carried out to identify all studies published in PubMed, EMBASE and Cochrane Library between 1990 and 2008 reporting visual outcome in children with OPG after chemotherapy. Studies were included when they included 10 or more children with OPG, main treatment was chemotherapy and visual outcome was described. Cochrane guidelines for meta-analysis of non-randomised clinical trials were followed and levels of quality were assigned. RESULTS Eighty-five potentially relevant publications were retrieved for detailed evaluation and only 8 were included. The review revealed 0 randomised controlled trials, 0 non-randomised controlled trials, 3 (37.5%) single-arm trials (1 multi-institutional and 2 single institution trials) and 5 (62.5%) retrospective series. All studies achieved a level of evidence of 4 according to CEBM classification (case-series and poor quality cohort and case-control studies). Only 25 of 174 children experienced improvement in vision after chemotherapy (14.4%), responses ranged from 0% to 45.5%. Vision was stable in 82 children (47.1%, range 27-100%). No study documented the duration of the visual response. DISCUSSION Published studies on childhood low grade gliomas have not shown satisfactorily whether chemotherapy improves outcome of vision in children with OPG. Based on our systematic review it appears that treatment with chemotherapy does not improve resulting vision in the majority of children with OPG. The data available does not allow us to assess whether vision is stabilised sufficiently prior to treatment with radiotherapy.

Metastatic ependymoma: A multi‐institutional retrospective analysis of prognostic factors

Metastatic ependymoma is exceedingly rare at diagnosis with variable prognosis reported in the literature. The purpose of this study was to identify prognostic factors in children with metastatic ependymoma.

Serum angiogenic profile of patients with glioblastoma identifies distinct tumor subtypes and shows that TIMP-1 is a prognostic factor

Angiogenesis plays a key role in glioblastoma biology and antiangiogenic agents are under clinical investigation with promising results. However, the angiogenic profiles of patients with glioblastoma and their clinical significance are not well understood. Here we characterize the serum angiogenic profile of patients with glioblastoma, and examine the prognostic significance of individual angiogenic factors. Serum samples from 36 patients with glioblastoma were collected on admission and simultaneously assayed for 48 angiogenic factors using protein microarrays. The data were analyzed using hierarchical cluster analysis. Vessel morphology was assessed histologically after immunostaining for the pan-endothelial marker CD31. Tumor samples were also immunostained for tissue inhibitor of metalloproteinase-1 (TIMP-1). Cluster analysis of the serum angiogenic profiles revealed 2 distinct subtypes of glioblastoma. The 2 subtypes had markedly different tumor microvessel densities. A low serum level of TIMP-1 was associated with significantly longer survival independent of patient age, performance status, or treatment. The serum angiogenic profile in patients with glioblastoma mirrors tumor biology and has prognostic value. Our data suggest the serum TIMP-1 level as an independent predictor of survival.

Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma

Summary We collated data from 157 unpublished cases of pediatric high-grade glioma and diffuse intrinsic pontine glioma and 20 publicly available datasets in an integrated analysis of >1,000 cases. We identified co-segregating mutations in histone-mutant subgroups including loss of FBXW7 in H3.3G34R/V, TOP3A rearrangements in H3.3K27M, and BCOR mutations in H3.1K27M. Histone wild-type subgroups are refined by the presence of key oncogenic events or methylation profiles more closely resembling lower-grade tumors. Genomic aberrations increase with age, highlighting the infant population as biologically and clinically distinct. Uncommon pathway dysregulation is seen in small subsets of tumors, further defining the molecular diversity of the disease, opening up avenues for biological study and providing a basis for functionally defined future treatment stratification.

Pediatric CNS tumors: current treatment and future directions

Pediatric CNS tumors are the most common solid tumor of childhood and are the leading cause of cancer-related death in this age group. Improving prognosis is not the only challenge facing physicians managing these young patients as it is vital to consider the quality of survival. Current management strategies rely on surgery, radiotherapy and conventional cytotoxic chemotherapy, and although ongoing clinical trials continue to refine these treatments, newer approaches are required. This article will discuss current treatment standards for the most common pediatric CNS tumors: astrocytomas (low- and high-grade glioma), ependymoma and primitive neuroectodermal tumors (medulloblastoma), as well as future biological-based novel therapies.

Toxicity and Outcome of Children and Adolescents Participating in Phase I/II Trials of Novel Anticancer Drugs: The Royal Marsden Experience

Early phase trials are crucial in developing new therapies for poor prognosis childhood malignancies. Outcomes and toxicities of children treated on phase I/II trials at the Royal Marsden, one of the largest pediatric oncology early phase trial units in Europe, were examined to provide a baseline dataset and generate hypotheses. All patients recruited over a 10-year period to December 2011 were included. Variables including baseline characteristics, time on study, survival, toxicities, and admissions were collected. Seventy-two patients were recruited to 21 trials (5 phase I, 16 phase II; overall 12 involved molecularly targeted agents). Median age at consent was 12.4 years. Dose-limiting toxicities were rare in phase I trial participants (2 of 15 evaluable patients, 13%); the most common reason for leaving trials was disease progression (76%), rather than drug toxicity (1.7%). Median time on trial was 1.3 months (phase I patients) and 3.3 months (phase II). Early phase trials in children are safe and unexpected toxic side effects are infrequent. Patients and their families are willing to travel to access novel therapies, although the overall prognosis for these individuals is poor. Continued expansion of the portfolio is needed ultimately to improve the outcomes for those with resistant disease.

Pediatric neuro-oncology: current status and future directions.

Tumors of the central nervous system (CNS) are the most common solid malignancies in childhood and are the leading cause of cancer‐related death in this age group. While an ongoing improvement in overall prognosis has been achieved in the last few decades, current therapeutic approaches still confer significant morbidities, especially for the very young. The traditional strategies of surgery, radiotherapy and conventional cytotoxic chemotherapy need to be further refined while newer approaches, including molecularly targeted agents, hold the promise of better responses, improved outcomes and reduced toxicities. This article discusses treatment standards, the focus of current clinical investigations and the future promise of novel, biologically based approaches for the most common pediatric CNS tumors: primitive neuroectodermal tumors including medulloblastomas, ependymomas and astrocytomas (both low‐grade and high‐grade glioma).