PD-L1 and PD-1 expression in pediatric central nervous system germ cell tumors.

Central nervous system (CNS) germ cell tumors (GCTs) represent 2-3% of all primary CNS tumors. The majority are germinomas, which are radiosensitive and have an excellent prognosis. Contrarily, CNS non-germinomatous GCTs (NGGCTs) have less favorable prognosis and require more aggressive treatment. The expression of checkpoint/immune markers in CNS GCTs, particularly NGGCTs, is unknown. We previously reported a case of a patient whose intracranial NGGCT (predominantly choriocarcinoma) responded to immune checkpoint inhibition therapy. This case led us to evaluate our archive of intracranial GCTs for expression of PD-L1 and PD-1. With IRB approval, we searched the pathology archives at our institution for CNS GCTs. Demographic, radiologic, clinical, and histologic information was extracted from the medical records. Immunohistochemistry for lymphocytic markers (CD4, CD8, CD20), PD-1, and PD-L1 was performed. PD-L1 was considered positive if greater than 1% of tumor cells were positive and PD-1 was reported as a percentage of positive inflammatory cells. Fifty cases were identified, including 28 germinomas (mean age at diagnosis: 15.5 years; 17 males, 11 females), and 22 NGGCTs (mean age at diagnosis: 12.0 years, 21 males, 1 female). Germinomas were mostly suprasellar (17/28) and NGGCTs were predominantly pineal (17/22). Twenty-two germinomas (79%) were positive for PD-L1 expression, and 13 NGGCTs (57%) were positive for PD-L1. Cases of choriocarcinoma showed the most diffuse PD-L1 expression. PD-1 expression was seen in lymphocytes among 27/28 of the germinomas and 20/23 of the NGGCTs (ranging from 1-40% of lymphocytes). As expected, larger quantities of inflammatory cells were present in cases of germinoma. We demonstrate immune activity in CNS GCTs, and our results suggest that immune checkpoint inhibitors may be efficacious in the treatment of intracranial GCTs. Among NGGCTs, cases of choriocarcinoma showed the highest expression of PD-L1 in tumor cells, suggesting that this subtype may have the greatest benefit from checkpoint blockade.

An international study evaluating the epidemiology of intracranial germ cell tumors in the native versus immigrant Japanese populations: the need for an international registry.

BACKGROUND: Pediatric intra-cranial germ cell tumors (iGCTs) occur at an incidence of 0.6-1.2 cases/million/year in Western countries. The incidence is reported up to 5 times higher in Japan. It is unknown whether this increased incidence is due to genetic predisposition or environment. METHODS: The incidence of iGCTs in children ages 0-19 years was evaluated from December 1st, 1996-December 1st, 2016 in stable Japanese immigrant populations living abroad and compared to current native Japanese registry data. The incidence of medullobblastoma was used as a control to account for assumptions in the data. Sites were identified based on historical and population data of known large scale emigration from Japan during a period of industrialization from 1868-1912 which resulted in large, stable Japanese immigrant populations abroad. These three representative sites included Lima, Peru, San Paolo, Brazil, and Vancouver, Canada. Data was collected from registry and hospital-based resources within each region. RESULTS: A review of the Brain Tumor Registry of Japan from 1984-2004 revealed an incidence of 2.5 cases/million/year, lower than previously reported, and a lower incidence of medulloblastoma at 1.2 cases/million/year. Data from Vancouver, Canada, Lima, Peru, and San Paolo, Brazil included a total population of 731,174 Japanese persons. The ratio of all medulloblastoma to iGCT cases in Japan was identified as 1:2 while the ratio was 2:1, 6.5:1, and 5:1, respectively, in the other three locations. The data suggests increased incidence in native Japan may not translate to higher incidence in immigrant Japanese populations abroad and a clear genetic component was not found in our data set. CONCLUSIONS: A more precise and comprehensive study is needed to determine the cause of this difference in incidence. This study also emphasizes the importance of national and state registries and is a call to collaborate on state and country level epidemiology studies.

DICER1 mutations in primary central nervous system tumors: new insights into histologies, mutations, and prognosis.

PURPOSE: We sought to characterize clinical outcomes for adult and pediatric patients with primary CNS tumors harboring DICER1 mutations or loss of DICER1. METHODS: We conducted a retrospective cohort study of 98 patients who were treated between 1995 and 2020 for primary CNS tumors containing DICER1 mutations or loss of DICER1 on chromosome 14q, identified by targeted next generation sequencing. Kaplan-Meier plots and log rank tests were used to analyze survival. Cox proportional-hazards model was used for univariate and multivariable analyses for all-cause mortality (ACM). RESULTS: Within our cohort, the most common malignancies were grade 3/4 glioma (61%), grade 1/2 glioma (17%), and CNS sarcoma (6%). Sarcoma and non-glioma histologies, and tumors with biallelic DICER1 mutations or deletions were common in the pediatric population. Mutations occurred throughout DICER1, including missense mutations in the DexD/H-box helicase, DUF283, RNaseIIIa, and RNaseIIIb domains. For patients with grade 3/4 glioma, MGMT methylation (Hazard ratio [HR] 0.35, 95% Confidence Interval [CI] 0.16-0.73, p = 0.005), IDH1 R132 mutation (HR 0.11, 95% CI 0.03-0.41, p = 0.001), and missense mutation in the DexD/H-box helicase domain (HR 0.06, 95% CI 0.01-0.38, p = 0.003) were independently associated with longer time to ACM on multivariable analyses. CONCLUSION: DICER1 mutations or loss of DICER1 occur in diverse primary CNS tumors, including previously unrecognized grade 3/4 gliomas as the most common histology. While prior studies have described RNaseIIIb hotspot mutations, we document novel mutations in additional DICER1 functional domains. Within the grade 3/4 glioma cohort, missense mutation in the DexD/H-box helicase domain was associated with prolonged survival.

Comparison of toxicity following single versus tandem autologous transplant regimens for pediatric medulloblastoma.

BACKGROUND: Medulloblastoma outcomes have improved with craniospinal irradiation and chemotherapy, but such therapy has resulted in poor neurocognitive outcomes for young patients. Chemotherapy-only regimens with autologous transplant have been implemented with the intention of avoiding radiation. It is not yet known whether single or tandem transplantation is superior with respect to efficacy and/or safety. METHODS: We performed a retrospective review of children with medulloblastoma treated at Dana-Farber Cancer Institute from 1996 to 2016 who received either single or tandem autologous transplantation after completion of induction chemotherapy. We compared safety and outcome data between the two groups. RESULTS: Among 23 patients, 12 received tandem transplants. Median follow-up was 6.4 years (IQR = 0.8-10.5). There was no statistically significant difference in 5-year EFS or OS between the single (70.7 ± 14%, 80.2 ± 13%) and tandem transplant groups (57.1 ± 15%, 79.6 ± 13%). Seven tandem transplant patients received subsequent radiation while only four required radiation in the single transplant group (p = .41). In the single transplant regimen, patients experienced longer antibiotic duration (p = .03) and LOS (p = .01) and a trend toward increased number of transfusions (p = .06). Four cases of veno-occlusive disease were reported in the single transplant group (p = .04). CONCLUSIONS: Outcomes were similar between regimens, but the single transplant regimen had more hepatic complications. These data suggest that tandem transplant regimens may have reduced toxicity compared to the single transplant regimen with similar outcome measures.

Outcomes after first relapse of childhood intracranial ependymoma.

BACKGROUND: Ependymoma is the third most common malignant CNS tumor in children. Despite multimodal therapy, prognosis of relapsed ependymoma remains poor. Approaches to therapy for relapsed ependymoma are varied. We present a single-institution retrospective review of the outcomes after first relapse of intracranial ependymoma in children. PROCEDURE: We performed a retrospective, IRB-approved chart review of patients with recurrent intracranial ependymoma treated at Dana-Farber/Boston Children's Cancer and Blood Disorders Center from 1990 to 2019. RESULTS: Thirty-four patients with relapsed intracranial ependymoma were identified. At initial diagnosis, 11 patients had supratentorial disease, 22 with posterior fossa disease and one with metastatic disease. Median time-to-first relapse was 14.9 months from initial diagnosis (range 1.4-52.5). Seven patients had metastatic disease at first relapse. Gross total resection (GTR) was associated with improved 5-year progression-free survival (PFS) relative to subtotal resection (STR) and no surgery (p = .005). Localized disease at relapse was associated with improved 5-year overall survival (OS) when compared to metastatic disease (p = .02). Irradiation at first relapse seemed to delay progression but was not associated with statistically prolonged PFS or OS. Tumor location, histology, and chromosomal 1q status did not impact outcome at first relapse, although available molecular data were limited making definitive conclusions difficult. Median time-to-second relapse was 10 months (range 0.7-124). Five-year PFS and OS after first relapse were 19.9% and 45.1%, respectively. Median PFS and OS were 10.0 and 52.5 months after first relapse, respectively. CONCLUSIONS: Relapsed intracranial ependymoma has a poor prognosis despite multimodal therapy. Novel therapeutic strategies are desperately needed for this disease.

A POETIC Phase II study of continuous oral everolimus in recurrent, radiographically progressive pediatric low-grade glioma.

BACKGROUND: To evaluate efficacy, pharmacokinetics (PK) and pharmacodynamics of single-agent everolimus in pediatric patients with radiographically progressive low-grade glioma (LGG). METHODS: Everolimus was administered at 5 mg/m2 once daily as a tablet or liquid for a planned 48-week duration or until unacceptable toxicity or disease progression. Patients with neurofibromatosis type 1 were excluded. PK and pharmacodynamic endpoints were assessed in consenting patients. RESULTS: Twenty-three eligible patients (median age 9.2 years) were enrolled. All patients received prior chemotherapy (median number of prior regimens two) and/or radiotherapy (two patients). By week 48, two patients had a partial response, 10 stable disease, and 11 clinical or radiographic progression; two discontinued study prior to 1 year (toxicity: 1, physician determination: 1). With a median follow up of 1.8 years (range 0.2-6.7 years), the 2-, 3-, and 5-year progression-free survivals (PFS) were 39 ± 11%, 26 ± 11%, and 26 ± 11%, respectively; two patients died of disease. The 2-, 3-, and 5-year overall survival (OS) were all 93 ± 6%. Grade 1 and 2 toxicities predominated; two definitively related grade 3 toxicities (mucositis and neutropenia) occurred. Grade 4 elevation of liver enzymes was possibly related in one patient. Predose blood levels showed substantial variability between patients with 45.5% below and 18.2% above the target range of 5-15 ng/mL. Pharmacodynamic analysis demonstrated significant inhibition in phospho-S6, 4E-BP1, and modulation of c-Myc expression. CONCLUSION: Daily oral everolimus provides a well-tolerated, alternative treatment for multiple recurrent, radiographically progressive pediatric LGG. Based on these results, everolimus is being investigated further for this patient population.

Trametinib for the treatment of recurrent/progressive pediatric low-grade glioma.

PURPOSE: Pediatric low-grade gliomas (pLGGs) are the most common CNS tumor of childhood and comprise a heterogenous group of tumors. Children with progressive pLGG often require numerous treatment modalities including surgery, chemotherapy, rarely radiation therapy and, more recently, molecularly targeted therapy. We describe our institutional experience using the MEK inhibitor, trametinib, for recurrent/progressive pLGGs. METHODS: We performed a retrospective, IRB-approved, chart review of all pediatric patients treated with trametinib for recurrent/progressive pLGGs at Dana-Farber/Boston Children's Cancer and Blood Disorder Center between 2016 and 2018. RESULTS: Eleven patients were identified, of which 10 were evaluable for response. Median age at commencement of trametinib treatment was 14.7 years (range 7.3-25.9 years). Tumor molecular status included KIAA1549-BRAF fusion (n = 4), NF1 mutation (n = 4), FGFR mutation (n = 1) and CDKN2A loss (n = 1). Median number of prior treatment regimens was 5 (range 1-12). Median duration of treatment with trametinib was 19.2 months (range 3.8-29.8 months). Based on modified RANO criteria, best responses included partial (n = 2), minor response (n = 2) and stable disease (n = 6). Two patients remain on therapy (29.8 and 25.9 months, respectively). The most common toxicities attributable to trametinib were rash, fatigue and gastrointestinal disturbance. Five patients required dose reduction for toxicities. Two patients experienced significant intracranial hemorrhage (ICH) while on trametinib. While it is unclear whether ICH was directly attributable to trametinib, therapy was discontinued. CONCLUSION: Trametinib appears to be an effective treatment for patients with recurrent/progressive pLGG. The toxicities of this therapy warrant further investigation, with particular attention to the potential risk for intracranial hemorrhage. Early phase multi-institutional clinical trials are underway.

Increasing value of autopsies in patients with brain tumors in the molecular era.

BACKGROUND: Pediatric brain tumors are associated with high morbidity and mortality, in part due to insufficient understanding of tumor biology. With limited tissue allocation for research from surgical specimens, a key barrier to improving biological understanding, brain tumor autopsies have become an increasingly valuable resource. This study reviews the brain tumor autopsy practice at our institution and describes specific emerging research utilization patterns beyond the clinical autopsy report. METHODS: We performed a retrospective analysis of brain tumor autopsies at Boston Children's Hospital (BCH) between 2007 and 2017 and reviewed their consents, neuropathology reports and final diagnoses. We reviewed the method of tissue triaging for research consented autopsies (bioregistry, frozen and fresh tissue) and documented their specific uses. RESULTS: Ninety-six deaths at BCH were due to brain tumors; 56 autopsies were performed (58.3%), of which 49 (87.5%) were consented for research. Tumor mapping was performed on all cases and tissue was allocated for DNA- and RNA-based sequencing studies (published and ongoing). Three tissue allocations with a postmortem interval of 8 h or less resulted in successful cell lines. Tissue from 14 autopsies was contributed to the National DIPG Registry. CONCLUSION: Our institutional pediatric brain tumor autopsy clinical experience demonstrates the increased utility and wide utilization of autopsy-derived tissue for multiple types of research. These results support the increased efforts to obtain research consent for brain tumor autopsy and active collection of unfixed autopsy material in the molecular era.

Cutaneous reactions to targeted therapies in children with CNS tumors: A cross-sectional study.

BACKGROUND: MAPK (RAS-RAF-MEK-ERK-MAP) and mTOR inhibitors are novel treatments for pediatric central nervous system (CNS) tumors. The literature on common cutaneous adverse reactions to these therapies is sparse in the pediatric population. The aim of this study was to describe common cutaneous adverse reactions to BRAF, MEK, and mTOR inhibitors in children with CNS tumors. METHODS: In this cross-sectional study, patients younger than 21 years of age receiving BRAF, MEK, and mTOR inhibitor monotherapy for a CNS tumor were enrolled over a one-year period. Full body skin examination, photographs of dermatologic findings, and initial treatment recommendations were included at the initial visit, and follow-up skin examinations were recommended every three months. RESULTS: Twenty-two patients were enrolled in the study. Fifty percent (11/22) received trametinib, a MEK inhibitor, 27.3% (6/22) received dabrafenib, a BRAF inhibitor, and 22.7% (5/22) received everolimus, an mTOR inhibitor. Median age at visit was 11 years (range, 3-19). Median time from treatment initiation to skin examination was 4.5 months (range, 0-43). Ninety-six percent (21/22) of all patients had at least one skin reaction. The most common reactions across treatment groups included follicular/acneiform eruptions and xerosis. Two patients on MEK inhibitors and one patient on a BRAF inhibitor required therapy cessation due to severe cutaneous reactions. CONCLUSIONS: Cutaneous reactions to targeted anticancer therapy in children are common, treatable, and rarely require drug dose reduction or discontinuation. Routine surveillance and early intervention may improve quality of life and facilitate continuation of life-saving therapy.

Improvement of hereditary palmoplantar keratoderma with oral trametinib.

We report a child with a past medical history notable for congenital deafness, palmoplantar keratoderma (PPK), and hypothalamic glioma who initiated a MEK inhibitor trametinib for cancer-directed therapy at 11 years of age and was incidentally noted to have marked improvement in his PPK. Trametinib withdrawal led to worsening in the patient's PPK. We speculate that the patient's PPK improved because of trametinib, given the temporal relationship between trametinib therapy and PPK severity, observed both after introduction and withdrawal of trametinib therapy. The upregulation of MAPK signaling may be involved in the pathogenesis of keratinocyte proliferation in at least some forms of PPK, given that downstream inhibition of MAPK signaling led to an improvement in the patient's PPK.

A phase 1/2 dose-finding, safety, and activity study of cabazitaxel in pediatric patients with refractory solid tumors including tumors of the central nervous system.

BACKGROUND: This phase 1/2 study (NCT01751308) evaluated cabazitaxel in pediatric patients. Phase 1 determined the maximum tolerated dose (MTD) in patients with recurrent/refractory solid tumors, including central nervous system (CNS) tumors. Phase 2 evaluated activity in pediatric recurrent high-grade glioma (HGG) or diffuse intrinsic pontine glioma (DIPG). PROCEDURE: In phase 1, a 3 + 3 dose-escalation study design was followed. Cabazitaxel was administered at a starting dose of 20 mg/m2 . Dose-limiting toxicities (DLTs) during cycle 1 were assessed to determine the MTD. Tumor response and cabazitaxel pharmacokinetics were also assessed. In phase 2, patients received cabazitaxel at the MTD determined in phase 1. Tumor responses were assessed every 9 weeks (modified Response Assessment in Neuro-oncology criteria). Progression-free survival and cabazitaxel pharmacokinetics were evaluated, and overall survival was estimated. RESULTS: In phase 1, 23 patients were treated, including 19 with CNS tumors. One patient had a partial response; five had stable disease for >3 cycles. Common adverse events included fatigue, diarrhea, nausea and vomiting, febrile neutropenia, and hypersensitivity reactions. Two of three DLTs (febrile neutropenia) occurred with a dose of 35 mg/m2 ; the MTD was 30 mg/m2 . Slightly higher cabazitaxel clearance was observed compared with adult trials. In phase 2, 16 patients (eight HGG and eight DIPG) were enrolled; 11 were evaluable for response and five withdrew (three due to anaphylaxis). All 11 patients progressed within four cycles. No responses were observed; the study was stopped due to futility. CONCLUSIONS: The safety profile of cabazitaxel was consistent with previous studies. The MTD (30 mg/m2 ) was higher than the adult MTD. Cabazitaxel did not demonstrate activity in recurrent/refractory HGG or DIPG.

Rethinking childhood ependymoma: a retrospective, multi-center analysis reveals poor long-term overall survival.

Ependymoma is the third most common brain tumor in children, but there is a paucity of large studies with more than 10 years of follow-up examining the long-term survival and recurrence patterns of this disease. We conducted a retrospective chart review of 103 pediatric patients with WHO Grades II/III intracranial ependymoma, who were treated at Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Chicago's Ann & Robert H. Lurie Children's Hospital between 1985 and 2008, and an additional 360 ependymoma patients identified from the Surveillance Epidemiology and End Results (SEER) database. For the institutional cohort, we evaluated clinical and histopathological prognostic factors of overall survival (OS) and progression-free survival (PFS) using the log-rank test, and univariate and multivariate Cox proportional-hazards models. Overall survival rates were compared to those of the SEER cohort. Median follow-up time was 11 years. Ten-year OS and PFS were 50 ± 5% and 29 ± 5%, respectively. Findings were validated in the independent SEER cohort, with 10-year OS rates of 52 ± 3%. GTR and grade II pathology were associated with significantly improved OS. However, GTR was not curative for all children. Ten-year OS for patients treated with a GTR was 61 ± 7% and PFS was 36 ± 6%. Pathological examination confirmed most recurrent tumors to be ependymoma, and 74% occurred at the primary tumor site. Current treatment paradigms are not sufficient to provide long-term cure for children with ependymoma. Our findings highlight the urgent need to develop novel treatment approaches for this devastating disease.

Long-term neuropsychological follow-up of young children with medulloblastoma treated with sequential high-dose chemotherapy and irradiation sparing approach.

High-dose chemotherapy (HDC) strategies were developed in brain tumor protocols for young children to prevent neuropsychological (NP) impairments associated with radiotherapy. However, comprehensive NP evaluations of these children treated with such strategies remain limited. We examined the long-term neurocognitive outcomes of young children (<6 years) with medulloblastoma, treated similarly, with a HDC strategy "according to" the chemotherapy regimen of the protocol CCG 99703. This retrospective study included young children less than 6 years of age at diagnosis of medulloblastoma treated from 1998 to 2011 at 7 North American institutions. Twenty-four patients who had at least one NP assessment post-treatment are the focus of the current study. Of 24 patients in this review, 15 (63%) were male and the mean age at diagnosis was 29.4 months (SD = 13.5). Posterior fossa syndrome (PFs) was reported in five patients (21%). Nine (37.5%) received radiotherapy (5 focal, 4 craniospinal). On average, children were assessed 3.5 years (SD = 1.8) post-diagnosis, and full-scale intellectual quotient (FSIQ) scores ranged from 56 to 119 ([Formula: see text]= 92; SD = 16.8). The majority of children (74%) had low-average to average NP functioning. Very young children treated with radiotherapy, who needed hearing support or with PFs had worse neurocognitive outcomes. Clinically significant deficits (<10th percentile) in at least one area of NP functioning were found in 25% of the children. NP data obtained from this sample of survivors of medulloblastoma in early childhood, all treated with sequential HDC and 1/3 with radiotherapy, describe NP functioning within average normal limits overall. However, almost 25% of children had significant deficits in specific domains.

A pediatric trial of radiation/cetuximab followed by irinotecan/cetuximab in newly diagnosed diffuse pontine gliomas and high-grade astrocytomas: A Pediatric Oncology Experimental Therapeutics Investigators' Consortium study.

BACKGROUND: Diffuse intrinsic pontine gliomas (DIPGs) and high-grade astrocytomas (HGA) continue to have dismal prognoses. The combination of cetuximab and irinotecan was demonstrated to be safe and tolerable in a previous pediatric phase 1 combination study. We developed this phase 2 trial to investigate the safety and efficacy of cetuximab given with radiation therapy followed by adjuvant cetuximab and irinotecan. METHODS: Eligible patients of age 3-21 years had newly diagnosed DIPG or HGA. Patients received radiation therapy (5,940 cGy) with concurrent cetuximab. Following radiation, patients received cetuximab weekly and irinotecan daily for 5 days per week for 2 weeks every 21 days for 30 weeks. Correlative studies were performed. The regimen was considered to be promising if the number of patients with 1-year progression-free survival (PFS) for DIPG and HGA was at least six of 25 and 14 of 26, respectively. RESULTS: Forty-five evaluable patients were enrolled (25 DIPG and 20 HGA). Six patients with DIPG and five with HGA were progression free at 1 year from the start of therapy with 1-year PFS of 29.6% and 18%, respectively. Fatigue, gastrointestinal complaints, electrolyte abnormalities, and rash were the most common adverse events and generally of grade 1 and 2. Increased epidermal growth factor receptor copy number but no K-ras mutations were identified in available samples. CONCLUSIONS: The trial did not meet the predetermined endpoint to deem this regimen successful for HGA. While the trial met the predetermined endpoint for DIPG, overall survival was not markedly improved from historical controls, therefore does not merit further study in this population.

Myxopapillary ependymomas in children: imaging, treatment and outcomes.

Myxopapillary ependymomas (MPEs) are rare spinal tumors in children. The natural history and clinical course of pediatric MPEs are largely unknown and the indication for adjuvant therapy remains to be clarified. We performed an IRB-approved, retrospective review of children with MPEs treated at the Dana-Farber/Boston Children's Cancer and Blood Disorder Center between 1982 and 2013. Eighteen children (age range 8-21 years, median age 14 years) met inclusion criteria. We reviewed the histopathology, magnetic resonance imaging, tumor location and stage, surgical management, adjuvant therapy, and clinical outcomes. The median follow-up duration was 9.4 years (range 1-30 years). Children most commonly presented with pain, scoliosis, and urinary symptoms. All primary tumors were located in the lower thoracic or lumbar spine. Nine children (50%) had leptomeningeal tumor seeding at presentation, most commonly located within the distal thecal sac. A gross-total resection was achieved in nine children (50%). Three children were treated with irradiation following initial surgery. No child received adjuvant chemotherapy at diagnosis. The 10-year event-free survival (EFS) was 26% ± 14.8. Children with disseminated disease trended towards inferior EFS compared to those with localized disease (10-year EFS 12.7% ± 12 vs. 57 ± 25%, p value 0.07). The 10-year overall survival was 100%. The efficacy of adjuvant irradiation could not be assessed due to the small sample size. Although children with MPEs frequently present with disseminated tumor and/or develop recurrent or progressive disease, their overall survival is excellent. Treatment should aim to minimize both tumor- and therapy-related morbidity.

Pediatric malignant germ cell tumors: A comparison of the neuro-oncology and solid tumor experience.

Malignant germ cell tumors (GCT) arise from abnormal migration of primordial germ cells and are histologically identical whether they occur inside or outside the central nervous system (CNS). However, the treatment strategy for GCTs varies greatly depending on the location of the tumor. These differences are in part due to the increased morbidity of surgery in the CNS but may also reflect differential sensitivity of the tumors to chemotherapy and radiation therapy (RT) or not-yet-understood biologic differences between these tumors. Historically, specialists caring for extracranial and intracranial GCT in the United States have practiced separately without much cross communication. The focus of this review is a discussion of differences between the management of CNS and extra-CNS GCTs and opportunities for collaboration and future research.

Clinical, Pathological, and Molecular Characterization of Infant Medulloblastomas Treated with Sequential High-Dose Chemotherapy.

BACKGROUND: High-dose chemotherapy (HDC) strategies were developed to avoid unacceptable neurotoxicity associated with craniospinal irradiation in infants with embryonal brain tumors. However, the impact of molecular and pathological characterizations in such approaches and long-term outcome have not been widely described in young children. METHODS: We retrospectively collected information from seven North American institutions, on young children with medulloblastoma (MB) treated with sequential HDC, as per the CCG 99703 protocol. Data collection included clinical presentation, histology, molecular subgroup, irradiation, ototoxicity, and neurocognitive evaluations. RESULTS: The cohort included 53 patients diagnosed at a median age of 24 months (2.9-63.2). Seventeen patients (32.1%) had nodular desmoplatic MB, all belonging to the sonic Hedgehog (SHH) subgroup, as did 30% of classic MB. The 5-year progression-free survival (PFS) and overall survival (OS) was 69.6% (±6·9%) and 76.1% (±6.5%), respectively. Seventeen (32.1%) patients received irradiation (nine adjuvant radiotherapy [RT]). Patients with SHH and group 3 MB had a 5-year PFS of 86·2% (±7.4%) and 49·1% (±14%), respectively (P = 0.03). The 5-year PFS radiation free for group 3 MB was 46.4%. Patients with macroscopic metastasis (M2 and M3) had a worst survival. Fifteen (45.5%) patients had significant ototoxicity. Mean Full Scale Intellectual Quotient (FSIQ) for 24 survivors was 91.6 (range 52-119). CONCLUSIONS: This HDC strategy led to an encouraging OS while only 20% of the patients received adjuvant RT. SHH MB, irrespective of histological subgroup, had an excellent outcome. Such intensive therapy may not be needed for this subgroup. Patients with classic histology or group 3 had an encouraging PFS of 58% and 46.4%, respectively, in the absence of adjuvant RT. The neurocognitive profile of the survivors appears to be within the normal range.

Central Versus Extraventricular Neurocytoma in Children: A Clinicopathologic Comparison and Review of the Literature.

BACKGROUND: Central neurocytomas (CN) are rare pediatric CNS tumors most often with a benign clinical course. Occasionally, these tumors occur outside the ventricles and are called extraventricular neurocytomas (EVN). We present a retrospective institutional analysis of children with neurocytoma with prolonged follow-up. PROCEDURE: Twelve patients were diagnosed with neurocytoma at our institution between 1993 and 2004. RESULTS: Six patients were male and the median age at diagnosis was 12 years (1.5 to 16 y). Seven patients had CN and 5 had EVN. Presenting symptoms included headaches (67%), vomiting (50%), nausea (33%), seizures (33%), and mental status changes (25%). Obstructive hydrocephalus was present at diagnosis in 42% of the cases. Younger age and seizures were more common in patients with EVN. Gross total resection (GTR) was achieved in 42% (5/12) of the patients. Patients with GTR received no adjuvant therapy upfront; 1 patient subsequently had recurrence with leptomeningeal disease. Patients with subtotal resection received additional treatment: 1 underwent reoperation (GTR), 2 patients received focal radiation, 2 patients received adjuvant chemotherapy, and 2 patients received craniospinal irradiation followed by chemotherapy. The 20-year overall survival for this cohort was 83% with event free survival of 56%. Overall survival for CNs was 100%, versus 40% for EVN. Event free survival for CNs was 57% and 53% for the EVNs. An MIB-1 fraction >2% was associated with worse prognosis. CONCLUSIONS: Neurocytomas are rare brain tumors in children usually cured with GTR. Adjuvant focal radiation therapy and/or chemotherapy may improve disease control in cases with subtotal resection, but case-by-case analysis should be done. EVNs might be associated with worse outcome due to a higher proliferative index.

Classification of treatment-related mortality in children with cancer: a systematic assessment.

Treatment-related mortality is an important outcome in paediatric cancer clinical trials. An international group of experts in supportive care in paediatric cancer developed a consensus-based definition of treatment-related mortality and a cause-of-death attribution system. The reliability and validity of the system was tested in 30 deaths, which were independently assessed by two clinical research associates and two paediatric oncologists. We defined treatment-related mortality as death occurring in the absence of progressive cancer. Of the 30 reviewed deaths, the reliability of classification for treatment-related mortality was noted as excellent by clinical research associates (κ=0·83, 95% CI 0·60-1·00) and paediatric oncologists (0·84, 0·63-1·00). Criterion validity was established because agreement between the consensus classifications by clinical research associates and paediatric oncologists was almost perfect (0·92, 0·78-1·00). Our approach should allow comparison of treatment-related mortality across trials and across time.

Long-term outcome of 4,040 children diagnosed with pediatric low-grade gliomas: an analysis of the Surveillance Epidemiology and End Results (SEER) database.

BACKGROUND: Children with pediatric low-grade gliomas (PLGG) are known to have excellent 10-year survival rates; however the outcomes of adult survivors of PLGG are unknown. We identified patients diagnosed with PLGG diagnosed between 1973 and 2008 through the Surveillance Epidemiology and End Results (SEER) database to examine outcomes of adult survivors of PLGG. PROCEDURE: Four thousand and forty patients with either WHO grade I or II PLGG were identified and outcome data retrieved. Two analyses were performed to assess survival and risk of death from tumor. Competing risks analysis was conducted and cumulative incidence curves of death due to disease were generated. Cox proportional hazards regression was performed, with adjustment for non-disease death. Kaplan-Meier curves for overall cancer specific survival (OS) were also generated. RESULTS: The 20-year OS was 87% ± 0.8% and the 20-year cumulative incidence of death due to glioma was 12% ± 0.8%. The incidence of death after transition to adulthood (age greater than 22 years) was slightly lower, with 20-year cumulative incidence of disease death of 7% ± 1.8%. Year of diagnosis, age of diagnosis, histology, WHO grade, primary site, radiation, and degree of initial resection were prognostic in univariate analysis, while the administration of radiation was the greatest risk of death in multivariate analysis of OS (hazard ratio = 3.9). CONCLUSIONS: PLGGs are associated with an excellent long-term survival, with a low likelihood of PLGG related death in adult survivors. Treatment strategies for pediatric tumors should therefore aim for disease control during childhood and adolescence with an emphasis on minimizing long-term treatment induced toxicities.