Katrin Scheinemann

Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations

Diffuse intrinsic pontine glioma (DIPG) is a fatal brain cancer that arises in the brainstem of children, with no effective treatment and near 100% fatality. The failure of most therapies can be attributed to the delicate location of these tumors and to the selection of therapies on the basis of assumptions that DIPGs are molecularly similar to adult disease. Recent studies have unraveled the unique genetic makeup of this brain cancer, with nearly 80% found to harbor a p.Lys27Met histone H3.3 or p.Lys27Met histone H3.1 alteration. However, DIPGs are still thought of as one disease, with limited understanding of the genetic drivers of these tumors. To understand what drives DIPGs, we integrated whole-genome sequencing with methylation, expression and copy number profiling, discovering that DIPGs comprise three molecularly distinct subgroups (H3-K27M, silent and MYCN) and uncovering a new recurrent activating mutation affecting the activin receptor gene ACVR1 in 20% of DIPGs. Mutations in ACVR1 were constitutively activating, leading to SMAD phosphorylation and increased expression of the downstream activin signaling targets ID1 and ID2. Our results highlight distinct molecular subgroups and novel therapeutic targets for this incurable pediatric cancer.

BRAF-KIAA1549 Fusion Predicts Better Clinical Outcome in Pediatric Low-Grade Astrocytoma

Purpose: Recent studies have revealed that the majority of pediatric low-grade astrocytomas (PLGA) harbor the BRAF-KIAA1549 (B-K) fusion gene resulting in constitutive activation of the RAS/MAPK pathway. However, the clinical significance of this genetic alteration is yet to be determined. We aimed to test the prognostic role of the B-K fusion in progression of incompletely resected PLGA. Experimental Design: We retrospectively identified 70 consecutive patients with incompletely resected “clinically relevant” PLGA. We added 76 tumors diagnosed at our institution between 1985 and 2010 as controls. We examined BRAF alterations by reverse transcriptase PCR, FISH, and single-nucleotide polymorphism array analysis and correlated that with progression-free survival (PFS). Results: Overall, 60% of tumors were B-K fusion positive. All patients with B-K fused PLGA are still alive. Five-year PFS was 61% ± 8% and 18% ± 8% for fusion positive and negative patients, respectively (P = 0.0004). B-K fusion resulted in similarly significant favorable PFS for patients who received chemotherapy. Multivariate analysis revealed that B-K fusion was the most significant favorable prognostic factor in incompletely resected PLGA and was independent of location, pathology, and age. In vitro, BRAF overexpression resulted in growth arrest associated with DNA damage (γH2AX expression). Five-year PFS was 68% ± 15% and 0% for patients with B-K fused and γH2AX-expressing PLGA versus negative tumors (P = 0.001). Conclusion: These data suggest that B-K fusion confers a less aggressive clinical phenotype on PLGA and may explain their tendency to growth arrest. Combined analysis of B-K fusion and γH2AX expression can determine prognosis and may be a powerful tool to tailor therapy for these patients. Clin Cancer Res; 17(14); 4790–8. ©2011 AACR.

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.

Is There a Benefit of Preoperative Meningioma Embolization

OBJECTIVETo evaluate the effect of preoperative embolization of meningiomas on surgery and outcomes. METHODSIn a prospective study, 60 consecutive patients with intracranial meningiomas who were treated in two neurosurgical centers were included. In Center A, embolization was performed for none of the patients (n = 30). In Center B, 30 consecutive patients with embolized meningiomas were treated. Preoperatively, tumor size and location, neurological status, and Barthel scale score were recorded. In Center B, the extent of tumor devascularization was evaluated using angiography and postembolization magnetic resonance imaging. Intraoperatively, blood loss, the numbers of blood units transfused, and the observations of the neurosurgeon concerning hemostasis, tumor consistency, and intratumoral necrosis were recorded. Postoperatively, the neurological status and duration of hospitalization were recorded. Six months after surgery, the outcomes were assessed using the Barthel scale and neurological examinations. RESULTSThe mean tumor sizes were 22.9 cc in Center A and 29.6 cc in Center B (P > 0.1). The mean blood losses did not differ significantly (646 ml in Center A versus 636 ml in Center B;P > 0.5). However, for a subgroup of patients with subtotal devascularization (>90% of the tumor) on postembolization magnetic resonance imaging scans in Center B, blood loss was less, compared with the entire group in Center A (P < 0.05). The observations of the neurosurgeon regarding hemostasis, tumor consistency, and intratumoral necrosis did not differ significantly. There were no surgery-related deaths in either center. The rates of surgical morbidity, with permanent neurological worsening, were 20% (n = 6) in Center A and 16% (n = 5) in Center B. There was one permanent neurological deficit (3%) caused by embolization. CONCLUSIONIn this preliminary study, only complete embolization had an effect on blood loss. The value of preoperative embolization for all meningiomas must be reconsidered, especially in view of the high costs and risks of embolization.

Medulloblastoma stem cells: where development and cancer cross pathways

Brain tumors are the leading cause of childhood cancer mortality, with medulloblastoma (MB) representing the most frequent malignant tumor. The recent molecular classification of MB has reconceptualized the heterogeneity that exists within pathological subtypes by giving context to the role of key developmental signaling pathways in MB pathogenesis. The identification of cancer stem cell (CSC) populations, termed brain tumor-initiating cells (BTICs), in MB has provided novel cellular targets for the study of these aberrantly activated signaling pathways, namely, Sonic hedgehog (Shh) and Wingless (Wnt), along with the identification of novel BTIC self-renewal pathways. In this review, we discuss recent evidence for the presence of a MB stem cell that drives tumorigenesis in this malignant childhood tumor. We focus on evidence from cerebellar development, the recent identification of BTICs, the presence of activated developmental signaling pathways in MB, the role of epigenetic stem cell regulatory mechanisms, and how these developmental and epigenetic pathways may be targeted for novel therapeutic options.

FoxG1 Interacts with Bmi1 to Regulate Self‐Renewal and Tumorigenicity of Medulloblastoma Stem Cells

Brain tumors represent the leading cause of childhood cancer mortality, of which medulloblastoma (MB) is the most frequent malignant tumor. Recent studies have demonstrated the presence of several MB molecular subgroups, each distinct in terms of prognosis and predicted therapeutic response. Groups 1 and 2 are characterized by relatively good clinical outcomes and activation of the Wnt and Shh pathways, respectively. In contrast, groups 3 and 4 (“non‐Shh/Wnt MBs”) are distinguished by metastatic disease, poor patient outcome, and lack a molecular pathway phenotype. Current gene expression platforms have not detected brain tumor‐initiating cell (BTIC) self‐renewal genes in groups 3 and 4 MBs as BTICs typically comprise a minority of tumor cells and may therefore go undetected on bulk tumor analyses. Since increasing BTIC frequency has been associated with increasing tumor aggressiveness and poor patient outcome, we investigated the subgroup‐specific gene expression profile of candidate stem cell genes within 251 primary human MBs from four nonoverlapping MB transcriptional databases (Amsterdam, Memphis, Toronto, Boston) and 74 NanoString‐subgrouped MBs (Vancouver). We assessed the functional relevance of two genes, FoxG1 and Bmi1, which were significantly enriched in non‐Shh/Wnt MBs and showed these genes to mediate MB stem cell self‐renewal and tumor initiation in mice. We also identified their transcriptional regulation through reciprocal promoter occupancy in CD15+ MB stem cells. Our work demonstrates the application of stem cell data gathered from genomic platforms to guide functional BTIC assays, which may then be used to develop novel BTIC self‐renewal mechanisms amenable to therapeutic targeting. STEM Cells2013;31:1266–1277

Survival and functional outcome of childhood spinal cord low-grade gliomas: Clinical article

OBJECT Intramedullary spinal cord low-grade gliomas (LGGs) are rare CNS neoplasms in pediatric patients, and there is little information on therapy for and outcome of these tumors in this population. Furthermore, most patient series combine adult and pediatric patients or high- and low-grade tumors, resulting in controversial data regarding optimal treatment of these children. To clarify these issues, the authors performed a regional population-based study of spinal cord LGGs in pediatric patients. METHODS All pediatric patients with LGGs treated during the MR imaging era (1985-2007) were identified in the comprehensive database of the Hospital for Sick Children in Toronto. Data on demographics, pathology, treatment details, and outcomes were collected. RESULTS Spinal cord LGGs in pediatric patients constituted 29 (4.6%) of 635 LGGs. Epidemiological and clinical data in this cohort were different than in patients with other spinal tumors and strikingly similar to data from pediatric patients with intracranial LGGs. The authors observed an age peak at 2 years and a male predominance in patients with these tumors. Histological testing revealed a Grade I astrocytoma in 86% of tumors. Although 5-year progression-free survival for the entire group was 48 +/- 9%, all patients were alive at a median follow-up of 8.2 years. Five-year progression-free survival was 88 +/- 13% for patients undergoing gross-total resection and 34 +/- 11% for those undergoing all other therapies, respectively (p = 0.02). Chemotherapy and radiation therapy showed similar efficacy, achieving sustained tumor control in most patients. However, this excellent survival rate was associated with an 83% rate of significant neurological and orthopedic sequelae. CONCLUSIONS This study provides basic data on the incidence, clinical course, and outcome of spinal cord LGGs in pediatric patients. The similarities between spinal and intracranial LGGs in pediatric patients showing excellent survival but high morbidity suggest that a less aggressive approach may be the preferable treatment option for these patients.

Phase II Weekly Vinblastine for Chemotherapy-Naïve Children With Progressive Low-Grade Glioma: A Canadian Pediatric Brain Tumor Consortium Study

Purpose Vinblastine monotherapy has shown promising activity and a low-toxicity profile in patients with pediatric low-grade glioma (PLGG) who experienced treatment failure after initial treatment with chemotherapy and/or radiation. The aim of this study was to assess the activity of vinblastine in therapy-naïve children. Patients and Methods Patients < 18 years old with unresectable and/or progressive therapy-naïve PLGG were eligible. Vinblastine was administered once per week at a dose of 6 mg/m2 intravenously over a period of 70 weeks. Vision, quality of life, neurofibromatosis type 1 (NF1) status, and BRAF mutation/fusion status were also determined and correlated with outcome. Results Fifty-four patients were enrolled onto the study, with a median age of 8 years (range, 0.7 to 17.2 years). Most patients had chiasmatic/hypothalamic tumors (55.5%), and 13 patients (24.1%) had NF1. The most common histology was pilocytic astrocytoma (46.3%). Seventeen patients were diagnosed using radiologic criteria alone. Best response to chemotherapy was centrally reviewed with a response rate (complete, partial, or minor response) of 25.9%. Disease stabilization (complete, partial, or minor response or stable disease) was achieved in 47 patients (87.0%). Visual improvement was observed in 20% of patients with optic pathway glioma. Five-year overall survival and progression-free survival (PFS) rates were 94.4% (95% CI, 88.5% to 100%) and 53.2% (95% CI, 41.3% to 68.5%), respectively, for the entire cohort. Patients with NF1 had a significantly better PFS (85.1%; 95% CI, 68.0% to 100%) when compared with patients without NF1 (42.0%; 95% CI, 29.1% to 60.7%; P = .012). Age< 3 years or > 10 years was not associated with poor outcome. Treatment was well tolerated, and quality of life was not affected during treatment. In this trial, there was no correlation between BRAF alterations and outcome. Conclusion Vinblastine administered once per week is well tolerated in children with treatment naïve PLGG. Overall survival and PFS are comparable to current therapies, with a favorable toxicity profile and a maintained quality of life.

Utility of peripheral blood cultures in bacteremic pediatric cancer patients with a central line

PurposeThe utility of peripheral blood cultures in febrile neutropenic children with cancer and central venous catheters (CVC) is controversial. Our primary objective was to describe true bloodstream infections detected only by peripheral culture. Our secondary objectives were to describe true bloodstream infections detected only by CVC culture and to describe probable contaminants detected in both types of blood cultures.MethodsWe included children with cancer who had peripheral and CVC cultures obtained on the same day in which at least one culture was positive. Only cultures obtained prior to the initiation of broad-spectrum antibiotics were included. We defined true bloodstream infections due to common contaminants (such as coagulase-negative Staphylococcus) as occurring if multiple cultures were positive for the same organism or if sepsis was present.ResultsBetween January 2002 and July 2007, 318 episodes of bloodstream infection from 224 children were included. Of these, 228/318 (71.7%) were classified as true bloodstream infections while 90/318 (28.3%) were classified as contaminants. Importantly, 28/228 (12.3%) true bloodstream infections were detected only in peripheral culture while 85/228 (37.3%) true bloodstream infections were detected only by CVC cultures. Contaminants were identified in peripheral culture in 45/318 (14.2%) of episodes and in CVC culture in 45/318 (14.2%) episodes.ConclusionsTrue bloodstream infections frequently are only detected in the peripheral culture. These data support continuation of the practice of routine peripheral cultures in addition to CVC cultures at the onset of fever for children with cancer who are not already receiving broad-spectrum antibiotics.

Considering quality of life for children with cancer: a systematic review of patient-reported outcome measures and the development of a conceptual model

ObjectivesAn appraisal of pediatric cancer-specific quality-of-life (QOL) instruments revealed a lack of clarity about what constitutes QOL in this population. This study addresses this concern by identifying the concepts that underpin the construct of QOL as determined by a content analysis of all patient-reported outcome (PRO) instruments used in childhood cancer research.MethodsA systematic review was performed of key databases (i.e., MEDLINE, CINAHL, PsychINFO) to identify studies of QOL in children with cancer. A content analysis process was used to code and categorize all items from generic and cancer-specified PRO instruments. Our objective was to provide clarification regarding the conceptual underpinnings of these instruments, as well as to help inform the development of theory and contribute to building a conceptual framework of QOL for children with cancer.ResultsA total of 6,013 English language articles were screened, identifying 148 studies. Ten generic and ten cancer-specific PRO instruments provided 957 items. Content analysis led to the identification of four major domains of QOL (physical, psychological, social, and general health), with 11 subdomains covering 98 different concepts. While all instruments reflected items relating to the broader domains of QOL, there was substantial heterogeneity in terms of the content and variability in the distribution of items.ConclusionsThis systematic review and the proposed model represent a useful starting point in the critical appraisal of the conceptual underpinnings of PRO instruments used in pediatric oncology and contribute to the need to place such tools under a critical, yet reflective and analytical lens.