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Abhaya V. Kulkarni, Janine Piscione, Iffat Shams, and Eric Bouffet

Object

In the face of increasing survival, quality of life (QOL) has become an important indicator of treatment success in children with posterior fossa brain tumors (PFBTs). The authors' objective was to assess the long-term QOL in survivors of PFBT.

Methods

The authors conducted a cross-sectional study of children who, between birth and age 18 years at diagnosis, had previously been treated at their institution for a PFBT. At the time of assessment for this study, children were between 5 and 19 years old and had received standard treatment for PFBT ending at least 6 months before the assessment. The QOL was measured with the Pediatric Quality of Life Inventory (PedsQL) generic score scales and the Health Utilities Index Mark 3 (HUI3). Multivariate analyses were used to assess several variables (patient related, treatment related, and socioeconomic) for association with QOL.

Results

A total of 62 children participated in the study (median age at assessment 11.9 years, interquartile range [IQR] 7.8–14.8, and median age at tumor diagnosis of 4.9 years, IQR 2.5–6.9). Median time since active treatment for their PFBT was 5.2 years (IQR 2.4–10.1). Tumor types included cerebellar pilocytic astrocytoma (45.2%), medulloblastoma (30.6%), ependymoma (11.3%), and brainstem astrocytoma (11.3%). Adjuvant therapy included chemotherapy (40.3%) or radiotherapy (14.5% focal and 21.0% craniospinal radiotherapy). Permanent treatment for hydrocephalus was required in 38.7% of the patients. Tumors recurred in 11.3%, requiring repeat treatment in these patients. The median HUI3 utility score was 0.91 (IQR 0.71–1.00) and the median PedsQL total score was 78.3 (IQR 64.1–92.4). Only the following variables were significantly associated with decreased QOL in multivariable model testing (all p < 0.05): need for permanent hydrocephalus treatment, large ventricle size, decreased family functioning, and lower family income.

Conclusions

As a group, long-term survivors of pediatric PFBT appear to have QOL indicators that are similar to those of the general population, although a reasonable minority of patients experience poor outcomes. Although several confounding variables likely remain in this retrospective study, important associations with QOL include the presence of hydrocephalus and socioeconomic factors. The study sample size, however, was limited and the presence of other important factors cannot be excluded.

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Mei Hua Li, Eric Bouffet, Cynthia E. Hawkins, Jeremy A. Squire, and Annie Huang

The supratentorial primitive neuroectodermal tumors (PNETs) are a group of highly malignant lesions primarily affecting young children. Although these tumors are histologically indistinguishable from infratentorial medulloblastoma, they often respond poorly to medulloblastoma-specific therapy. Indeed, existing molecular genetic studies indicate that supratentorial PNETs have transcriptional and cytogenetic profiles that are different from those of medullo-blastomas, thus pointing to unique biological derivation for the supratentorial PNET. Due to the rarity of these tumors and disagreement about their histopathological diagnoses, very little is known about the molecular characteristics of the supratentorial PNET. Clearly, future concerted efforts to characterize the molecular features of these rare tumors will be necessary for development of more effective supratentorial PNET treatment protocols and appropriate disease models. In this article the authors review existing molecular genetic data derived from human and mouse studies, with the aim of providing some insight into the putative histogenesis of these rare tumors and the underlying transforming pathways that drive their development. Studies of the related but distinct pineoblastoma PNET are also reviewed.

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Christian Schneider, Vijay Ramaswamy, Abhaya V. Kulkarni, James T. Rutka, Marc Remke, Uri Tabori, Cynthia Hawkins, Eric Bouffet, and Michael D. Taylor

OBJECT

While medulloblastoma was initially thought to comprise a single homogeneous entity, it is now accepted that it in fact comprises 4 discrete subgroups, each with its own distinct demographics, clinical presentation, transcriptomics, genetics, and outcome. Hydrocephalus is a common complication of medulloblastoma and not infrequently requires CSF diversion. The authors report the incidence of CSF diversion surgery in each of the subgroups of medulloblastoma (Wnt, Shh, Group 3, and Group 4).

METHODS

The medical and imaging records for patients who underwent surgery for medulloblastoma at The Hospital for Sick Children were retrospectively reviewed. The primary outcome was the requirement for CSF diversion surgery either before or within 60 days of tumor resection. The modified Canadian Preoperative Prediction Rule for Hydrocephalus (mCPPRH) was compared among subgroups.

RESULTS

Of 143 medulloblastoma patients, treated from 1991 to 2013, sufficient data were available for 130 patients (15 with Wnt, 30 with Shh, 30 with Group 3, and 55 with Group 4 medulloblastomas). Of these, 28 patients (22%) ultimately underwent CSF diversion surgery: 0% with Wnt, 29% with Shh, 29% with Group 3, and 43% with Group 4 tumors. Patients in the Wnt subgroup had a lower incidence of CSF diversion than all other patients combined (p = 0.04). Wnt patients had a lower mCPPRH score (lower risk of CSF diversion, p = 0.045), were older, had smaller ventricles at diagnosis, and had no leptomeningeal metastases.

CONCLUSIONS

The overall rate of CSF diversion surgery for Shh, Group 3, and Group 4 medulloblastomas is around 30%, but no patients in the present series with a Wnt medulloblastoma required shunting. The low incidence of hydrocephalus in patients with Wnt medulloblastoma likely reflects both host factors (age) and disease factors (lack of metastases). The absence of hydrocephalus in patients with Wnt medulloblastomas likely contributes to their excellent rate of survival and may also contribute to a higher quality of life than for patients in other subgroups.

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Mustafa Nadi, Navid Khezri, Tahani Ahmad, Michael Ellis, Eric Bouffet, James T. Rutka, and Michael D. Taylor

Medulloblastoma is a highly malignant brain tumor of childhood. Although craniospinal dissemination within the subarachnoid space is common, invasion of the dural sinuses is rare. Here, the authors report on a 15-year-old girl who presented with a right cerebellar mass, obstructive hydrocephalus, and radiographic evidence of tumor invasion into the right transverse–sigmoid sinus junction. The patient underwent posterior fossa craniotomy, gross-total resection of the intraparenchymal component of the right cerebellar tumor, and coagulation of the tumor invading the transverse sinus. After pathological confirmation of anaplastic medulloblastoma, the patient underwent craniospinal radiation therapy and high-dose chemotherapy. At 2 years posttreatment, the child was neurologically intact with no radiographic evidence of residual disease or recurrence. The implications for disease prognosis and management are discussed.

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Machiel van den Akker, Paul Northcott, Michael D. Taylor, William Halliday, Ute Bartels, and Eric Bouffet

A 9-year-old boy with known Duchenne type muscular dystrophy (DMD) presented with signs of increased intracranial pressure. Radiological investigations revealed a lesion in the midline of the posterior fossa. Subtotal resection was performed. Pathology findings were consistent with the diagnosis of anaplastic medulloblastoma. The postoperative lumbar CSF was positive for malignant cells. Postoperatively, the patient showed severe neurological deterioration and lost his capacity to walk. He was treated with craniospinal radiation followed by nonintensive chemotherapy. At 30 months postsurgery, he was still in complete remission but had not recovered his walking ability. This is the second report of a malignant brain tumor in a boy with DMD. The possible link between the 2 conditions is discussed, as are ethical considerations regarding the management of medulloblastoma in children with DMD.

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Lucie Lafay-Cousin, Gillian Lindzon, Michael D. Taylor, Walter Hader, Cynthia Hawkins, Robert Nordal, Normand Laperriere, Suzanne Laughlin, Eric Bouffet, and Ute Bartels

OBJECT

Primary CNS sarcomas are very rare pediatric tumors with no defined standard of care.

METHODS

This study was a retrospective review of children diagnosed with a primary CNS sarcoma and treated at 2 Canadian tertiary care centers between 1995 and 2012. This report focuses on patients with cerebral hemispheric tumor location due to their specific clinical presentation.

RESULTS

Fourteen patients with nonmetastatic primary CNS sarcoma were identified; in 9 patients, tumors were located in the cerebral hemisphere and 7 of these patients presented with intratumoral hemorrhage. One infant who died of progressive disease postoperatively before receiving any adjuvant therapy was not included in this study. The final cohort therefore included 8 patients (4 males). Median patient age at diagnosis was 11.8 years (range 5.8–17 years). All tumors were located in the right hemisphere. Duration of symptoms prior to diagnosis was very short with a median of 2 days (range 3–7 days), except for 1 patient. Three (37.5%) patients had an underlying diagnosis of neurofibromatosis Type 1 (NF1). Gross-total resection was achieved in 5 patients. The dose of focal radiation therapy (RT) ranged between 54 Gy and 60 Gy. Concomitant etoposide was administered during RT. ICE (ifosfamide, carboplatin, etoposide) chemotherapy was administered prior to and after RT for a total of 6–8 cycles. Seven of the 8 patients were alive at a median time of 4.9 years (range 1.9–17.9 years) after treatment.

CONCLUSIONS

In this retrospective series, patients with primary CNS sarcomas located in the cerebral hemisphere most commonly presented with symptomatic acute intratumoral hemorrhage. Patients with NF1 were overrepresented. The combination of adjuvant ICE chemotherapy and focal RT provided encouraging outcomes.

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Ute Bartels, Cynthia Hawkins, Jing Ma, Michael Ho, Peter Dirks, James Rutka, Derek Stephens, and Eric Bouffet

Object

The authors’ aim in conducting this study was to investigate retrospectively the prognostic significance of angiogenic features in optic pathway/hypothalamic gliomas (OPHGs) in children.

Methods

Patients were identified in whom a diagnosis of OPHG was made using pathological analysis at the Toronto Hospital for Sick Children between 1985 and 2002. Tumor specimens were reviewed for diagnostic accuracy and adequacy of the specimen. Sections were immunostained with factor VIII to assess microvessel density (MVD). A ratio of α–smooth muscle actin to factor VIII immunostaining was calculated to arrive at a vascular maturity index (VMI). Vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) immunostaining were performed to evaluate angiogenic factors. In addition, the MIB-1 labeling index (LI) was used to assess proliferation. These factors were evaluated with respect to progression-free survival (PFS).

Forty-one of 60 patients originally identified had adequate samples and follow up for inclusion in the study. Of these, eight patients had coexisting neurofibromatosis Type 1. Twenty-eight patients experienced tumor progression after the initial treatment (surgery with or without adjuvant treatment). Thirty-eight patients are still alive. A high MVD (> 21 vessels/1.2 mm2) was associated with a significantly higher rate of progression compared with a low MVD (< 21 vessels/1.2 mm2; p = 0.017). Microvessel density was also predictive of reduced PFS on multivariate analysis stratified for extent of resection (p = 0.04), and VMI as well as intensity and distribution of VEGF and VEGFR staining and the MIB-1 LI were not significantly associated with PFS.

Conclusions

These findings suggest that MVD is the best current predictor of PFS in incompletely resected OPHGs. This information highlights the importance of angiogenesis in regard to low-grade gliomas.

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Eric Bouffet, Jeffrey C. Allen, James M. Boyett, Allen Yates, Floyd Gilles, Peter C. Burger, Richard L. Davis, Laurence E. Becker, Ian F. Pollack, and Jonathan L. Finlay

OBJECT

The impact of central pathology review on outcome has been described in pediatric patients with high-grade glioma (HGG). The objective of this report was to analyze the impact of the central pathology review on outcome in the subgroup of patients with institutional diagnosis of HGG of the spinal cord enrolled in the Children's Cancer Group 945 cooperative study.

METHODS

Five neuropathologists centrally reviewed the pathology of the 18 patients with HGG of the spinal cord who were enrolled in the study. These reviews were independent, and reviewers were blinded to clinical history and outcomes. A consensus diagnosis was established for each patient, based on the outcome of the review.

RESULTS

Of 18 patients, only 10 were confirmed to have HGG on central review. At a median follow-up of 12 years, event-free and overall survival for all 18 patients was 43.2% ± 13.3% and 50% ± 13.4%, respectively. After central review, 10-year event-free and overall survival for confirmed HGGs and discordant diagnoses was 30% ± 12.5% versus 58.3% ± 18.8% (p = 0.108) and 30% ± 12.5% versus 75% ± 14.2% (p = 0.0757), respectively.

CONCLUSIONS

The level of discordant diagnoses in children and adolescents with institutional diagnosis of HGG of the spinal cord was 44% in this experience. However, there was no significant difference in outcome between patients with confirmed and discordant diagnosis. This group of tumor deserves a specific attention in future trials.

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Michael J. Ellis, Samuel Cheshier, Sunjay Sharma, Derek Armstrong, Cynthia Hawkins, Eric Bouffet, James T. Rutka, and Michael D. Taylor

Among the neoplastic conditions that affect patients with neurofibromatosis Type 1 (NF1) are malignant peripheral nerve sheath tumors (MPNSTs), which typically arise from peripheral nerves of the limbs, trunk, and lumbar and brachial plexuses. Ionizing radiation is an established risk factor for MPNST development, especially in susceptible patients such as those with NF1. Patients with NF1 are also at risk for intracranial aneurysms, which are increasingly being successfully managed with endovascular therapies. The authors describe the case of a 9-year-old, previously healthy girl who presented in extremis with a right frontal intracerebral hemorrhage resulting from a ruptured right middle cerebral artery (MCA) trifurcation aneurysm. Following urgent decompressive craniectomy, the patient underwent endovascular coil embolization of the MCA aneurysm without complication. Given her mother's history of NF1, the child underwent genetic testing, which disclosed signs positive for NF1. The patient recovered well, but follow-up MR imaging and MR angiography performed at 14 months demonstrated a large frontotemporal mass encasing the right MCA trifurcation. The patient underwent frontotemporal craniotomy and subtotal resection of the mass, which was histologically found to be an intracranial MPNST. The patient received chemotherapy and focal radiation therapy and remains alive at 6 months postresection. To the authors' knowledge, this represents the only known case of intracranial neoplasm arising in the region of an intracranial aneurysm repaired by endovascular coil embolization. While patients with NF1 represent a population with genetic susceptibility to radiation-induced tumors, the pathogenesis of intracerebral MPNSTs remains poorly understood.