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BACKGROUND: Central nervous system (CNS) germinomas are treatment-sensitive tumors with excellent survival outcomes. Current treatment strategies combine chemotherapy with radiotherapy (RT) in order to reduce the field and dose of RT. Germinomas originating in the basal ganglia/thalamus (BGTGs) have proven challenging to treat given their rarity and poorly defined imaging characteristics. Craniospinal (CSI), whole brain (WBI), whole ventricle (WVI), and focal RT have all been utilized; however, the best treatment strategy remains unclear. METHODS: Retrospective multi-institutional analysis has been conducted across 18 institutions in four countries. RESULTS: For 43 cases of non-metastatic BGTGs, the 5- and 10-year event-free survival (EFS) were 85.8% and 81.0%, respectively, while the 5- and 10-year overall survival (OS) were 100%, and 95.5%, respectively (one patient fatality from unrelated cause). Median RT doses were as follows: CSI: 2250 cGy/cGy(RBE) (1980 to 2400 cGy/cGy[RBE]), WBI: 2340 (1800 to 3000 cGy/cGy[RBE]), WVI: 2340 cGy/cGy(RBE) (1800 to 2550 cGy/cGy[RBE]), focal: 3600 cGy (3060 to 5400 cGy). Thirty-eight patients (90.5%) received chemotherapy. There was no statistically significant difference in the EFS based on initial field extent (p=0.84). Nevertheless, no relapses were reported in patients who received CSI or WBI. Chemotherapy alone had significantly inferior EFS compared to combined therapy (p=0.0092), but patients were salvageable with RT. CONCLUSION: Patients with BGTGs have excellent outcomes and RT proved to be an integral component of the treatment plan. This group of patients should be included in future prospective clinical trials and the best RT field should be investigated further.

Outcomes for children with high-grade gliomas (HGG) remain dismal despite aggressive treatment strategies. The use of targeted therapy for BRAFV600E mutated malignancies including HGG is being explored as a potentially well tolerated and effective therapeutic option. The results of adult melanoma studies demonstrating that combination therapy with BRAF inhibitors and MEK inhibitors results in prolonged survival led us to employ this treatment strategy in children with BRAFV600E mutated HGG. In this case series, we describe three pediatric patients with HGG with confirmed BRAFV600E mutation who demonstrated responses to combination therapy with dabrafenib and trametinib.

Isocitrate dehydrogenase (IDH) mutations are rare in pediatric and adolescent gliomas. We recently identified three adolescent/young adult (AYA) patients with IDH‐mutant low grade gliomas of the brainstem with several key clinicopathologic and molecular features in common. We discuss these three cases and review the current literature.

Background Recent large-scale genomic studies have revealed a spectrum of genetic variants associated with specific subtypes of central nervous system (CNS) tumors. The aim of this study was to determine the clinical utility of comprehensive genomic profiling of pediatric, adolescent and young adult (AYA) CNS tumors in a prospective setting, including detection of DNA sequence variants, gene fusions, copy number alterations (CNAs), and loss of heterozygosity. Methods OncoKids, a comprehensive DNA- and RNA-based next-generation sequencing (NGS) panel, in conjunction with chromosomal microarray analysis (CMA) was employed to detect diagnostic, prognostic, and therapeutic markers. NGS was performed on 222 specimens from 212 patients. Clinical CMA data were analyzed in parallel for 66% (146/222) of cases. Results NGS demonstrated clinically significant alterations in 66% (147/222) of cases. Diagnostic markers were identified in 62% (138/222) of cases. Prognostic information and targetable genomic alterations were identified in 22% (49/222) and 18% (41/222) of cases, respectively. Diagnostic or prognostic CNAs were revealed by CMA in 69% (101/146) of cases. Importantly, clinically significant CNAs were detected in 57% (34/60) of cases with noncontributory NGS results. Germline cancer predisposition testing was indicated for 27% (57/212) of patients. Follow-up germline testing was performed for 20 patients which confirmed a germline pathogenic/likely pathogenic variant in 9 cases: TP53 (2), NF1 (2), SMARCB1 (1), NF2 (1), MSH6 (1), PMS2 (1), and a patient with 47,XXY Klinefelter syndrome. Conclusions Our results demonstrate the significant clinical utility of integrating genomic profiling into routine clinical testing for pediatric and AYA patients with CNS tumors.

Intradural extramedullary peripheral primitive neuroectodermal tumor (pPNET) with t(11;22) is a rare clinical finding in the pediatric population with few published cases in the literature. The authors report 3 cases of intradural primary pPNET and discuss the clinical presentation, treatment, and survival of the patients. Clinicians should be vigilant in considering pPNET in the differential diagnosis of extradural masses. The authors also compare the clinical course and outcome of therapy with primary PNET of the central nervous system and Ewing sarcoma family of tumors. In addition, this report highlights the risk for leptomeningeal dissemination at recurrence and discusses the importance of central nervous system-targeted therapy for durable disease control.

Children diagnosed with high grade gliomas (HGG) have dismal prognoses and treatment options remain limited. Tumor treating fields (TTFields) in combination with temozolomide (TMZ) is approved for the treatment of newly diagnosed and recurrent glioblastoma (GBM) in adult patients. However, clinical experience with TTFields in the pediatric HGG population is lacking. This retrospective review of four clinical cases was undertaken to evaluate the feasibility of treating children diagnosed with HGG off-label with TTFields. Patients were evaluated for device compliance, safety, and outcome. Treatment with TTFields was delivered via four transducer arrays placed on the shaved scalp, which were connected to a portable device generating 200 kHz alternating electric fields. One female and three male patients (ages 4-16 years) with heavily pretreated HGG were treated with TTFields off-label from March 2015 to December 2016. In three of these cases, TTFields were administered in combination with TMZ. Across all four patient cases, average wear compliance rates ranged between 53% and 92%. No device-related toxicities were reported during treatment with TTFields delivered for up to four months. All patients eventually died of the disease. TTFields was well tolerated in our limited cohort of patients. Compliance times were similar to what has been reported in adults without significant toxicity. Further studies of the efficacy and safety of TTFields in children with HGG are underway in a clinical trial setting.

Breast cancer is the most frequently occurring type of cancer among the female population. As a result, it poses a serious social problem, being subject to various scientific research and analysis. The topic of this thesis is an assessment o f a c o m p l e x r e h a b i l i t a t i o n o f lymphedema that occurs among females after mastectomy, which is the most frequent postoperative complication in this group of patients. The purpose of this thesis is an assessment of the quality of rehabilitation of patients and its effectiveness but also a recognition of the preferences concerning types of treatment. The analysis was divided into two parts: theoretical and explanatory. The research was conducted among m e m b e r s o f “ B i ł g o r a j s k i e Stowarzyszenie Amazonek” (The Amazons' Association in Biłgoraj) and Stowarzyszenie “Rzeszowski Klub Amazonek” (The Amazons' Club in Rzeszów). The first part includes an outline of cancer disease, its risk factors and methods of treatment. The explanatory part includes an answer to the hypothesis concerning the level of complex rehabilitation, its accessibility and effectiveness. The research shows that complex rehabilitation is a crucial element of the holistic treatment of cancer patients because it reduces the risk of complications, improves psychophysical conditions of patients and increases the chances of full recovery. The research outcomes demonstrate that the most frequently used treatment in the therapy of lymphedema is lymphatic drainage but also physiotherapy and kinesiotherapy treatments.

BACKGROUND: For several types of cancer, biological differences and outcome disparities have been documented in adolescents/young adults (AYAs, 15–39 years old) versus children. This study compared clinicopathological features and survival between younger AYAs and children with low-grade glioma (LGG), a common brain tumor among AYAs. METHODS: This was a secondary analysis of Children’s Oncology Group legacy study CCG-9891/POG-9130, which enrolled participants 0–21 years of age with newly-diagnosed LGG treated with surgery alone. For analysis, participants were categorized as children (0–14 years old) or early AYAs (eAYAs, 15–21 years old) and compared on demographics, clinical presentation, tumor characteristics, surgical outcomes, progression-free survival (PFS) and overall survival (OS). RESULTS: Among 468 children and 50 eAYAs, more eAYAs presented with seizures (34.0% vs 19.2%; p=0.015), without other significant differences in clinicopathological features. Five-year PFS rates for children and eAYA were 80.2% (95% Confidence Interval [95%CI], 76.1–83.7) and 83.0% (95%CI, 68.8–91.1), respectively; 5-year OS rates were 97.3% (95%CI, 95.2–98.5) and 95.4% (95%CI, 82.7–98.8), respectively. Multivariable analysis including all participants showed presence of residual tumor to be an independent predictor of PFS (

Atypical teratoid rhabdoid tumor (ATRT) is a central nervous system tumor with poor outcome. ACNS0333, a Children’s Oncology Group phase 3 trial, enrolled 65 evaluable patients who received two cycles of induction chemotherapy, three cycles of consolidative high-dose chemotherapy (HDCT), and focal radiation therapy (RT) pre- or post-consolidation. Craniospinal irradiation (CSI) was left to clinician discretion. We retrospectively analyzed medical records of 27 children treated at our institutions according to ACNS0333. Median age at diagnosis was 14 months (range 4–165); 13 (48%) were male. M-stage was M0, M2, and M3 for 18 (66%), 5 (19%), and 4 (15%), respectively. Tumor location was supratentorial (n=14, 52%), infratentorial (n=12, 44%), or both (n=1, 4%). Complete resection was achieved for 17 (63%). All but one completed induction. Of 13 (51%) with residual disease at diagnosis, 5 (36%) and 7 (50%), respectively, exhibited complete and partial response to induction. Three patients progressed on therapy, and six progressed after completion of therapy at a median of 9.7 months. In all, 18 patients completed RT (16 focal/4 CSI and 6 pre-/12 post-consolidation). Three died of therapy-related toxicity (two in primary therapy and one in relapse therapy), and 8 died of disease. Sixteen patients (59%) are alive at a median follow up of 53 months (range 9–114). Of 17 with germline testing, eight (47%) had rhabdoid predisposition syndrome of whom three are alive. At the time of presentation, data for approximately 50 patients is expected, and we will compare outcomes to soon-to-be published data from ACNS0333.

A 12 year-old male presented with a 2-month history of intermittent headaches, nausea, and vomiting. Magnetic resonance imaging (MRI) of the brain revealed a 2.2 x 3.5 x 2.6 cm lobulated, sellar/suprasellar mass, mildly T1/T2 hyperintense, with mild homogeneous enhancement and diffusion restriction. He underwent transsphenoidal and right craniotomies for gross total resection of the mass. Pathology demonstrated a hypercellular neoplasm with spindled to ovoid tumor cells arranged in fascicles and tight whirls, consistent with a spindle cell oncocytoma. OncoKids, a DNA- and RNA-based next generation sequencing panel, demonstrated an in-frame EML4 exon 2-ALK exon 19 fusion with a total of 179,872 supporting reads. The EML4-ALK fusion gene is predicted to encode a chimeric tyrosine kinase that facilitates multimerization and autophosphorylation of ALK, and activates its downstream targets, such as RAS/ERK, PI3K/AKT, and JAK/STAT pathways. This fusion is found in approximately 5% of patients with non-small cell lung cancer, a subset of inflammatory myofibroblastic tumors, as well as single cases of pulmonary atypical carcinoid, cholangiocarcinoma, and high-grade glioma. However, it has not been previously described in oncocytoma. Chromosomal microarray analysis demonstrated two interstitial non-contiguous deletions in 2p, and an interstitial deletion in 18q that does not include any known cancer-related genes. The deleted segment in 2p23.3p23.2 includes DNMT3A, which mediates DNA methylation and functions in modification of gene expression. DNMT3A mutations are frequent in hematological malignancies, however their role in oncocytoma is currently unknown. The proximal breakpoint of the deletion in 2p23.3p23.2 is in close proximity to but does not reside within ALK. Spindle cell oncocytoma is rarely reported in the pediatric population, with only one case described in the literature. This is the first case report of an oncocytoma with an EML4-ALK fusion. Additional studies are warranted to confirm its functional effect.

INTRODUCTION Irradiation-sparing approaches are used in young children with medulloblastoma (MB) given the vulnerability of the developing brain to neurocognitive impairment. Limited data are available following relapse for these patients. We aimed to describe the management and outcomes of young children with MB who relapsed after initial treatment without craniospinal irradiation (CSI). METHODS International retrospective study including patients with MB diagnosed between 1995-2017, ≤ 72 months old, initially treated without CSI, who subsequently relapsed. RESULTS Data are available for 66 patients. The median age at initial diagnosis was 27 months (range, 6-72). At diagnosis, 27 patients had metastatic disease. Initial therapy included conventional chemotherapy or with high-dose chemotherapy (HDC) in 30 and 36 patients, respectively. Eight (12.1%) received upfront focal irradiation. Molecular subgrouping was available for 27 (41%) patients. Ten were SHH, five group 3, six group 4 and six others were non-WNT/non-SHH. The median time from initial diagnosis to relapse was 13 months (range, 3-63). Relapse was local, disseminated, or combined in 39%, 32%, and 29%, respectively. The median time to death from relapse was 18 months. Curative intent therapy was given in 53 patients with irradiation (81%), conventional chemotherapy without HDC (40%), and HDC (25%). For patients who received irradiation, 85% received CSI (median dose 33 Gy, 18-41.4) and 15% focal irradiation. Ten patients received chemotherapy without salvage irradiation. The median follow-up time was 44 months (range, 4-255), 33 (62%) patients who underwent curative-intent therapy were alive, including 8/10 SHH, 2/3 group 3, 2/6 group 4, and 4/5 non-WNT/non-SHH. Three of four patients with SHH and treated without salvage radiotherapy are survivors. The 5-year OS for curative intent was 70%. CONCLUSION A substantial proportion of young children who relapse following irradiation-sparing strategies can be salvaged. A proportion of children with SHH MB can be salvaged without salvage radiotherapy.

PURPOSE: Irradiation-avoiding strategies have been used with relative success in the treatment of infants and young children with medulloblastoma. While advances in cancer genomics have significantly improved our understanding of the tumor biology of medulloblastoma allowing for improved prognostication and risk-stratification, the molecular subgroup-specific outcomes of infants and young children with medulloblastoma treated with irradiation-avoiding strategies remains unknown. METHODS: Molecular and clinical features of children with medulloblastoma treated with irradiation-avoiding strategies at Children’s Hospital Los Angeles were analyzed. Molecular subgrouping of these patients was determined using a 31-gene TaqMan Low Density Array signature. Survival analyses were conducted based on 3 molecular subgroups (SHH, Group 3, and Group 4). RESULTS: Twenty-eight patients with medulloblastoma received irradiation-sparing regimens and were included in this analysis. Patients were divided into SHH (n = 16), Group 3 (n = 3) and Group 4 subgroups (n = 9). Subgroup specific 5-year progression-free and overall survival was 81.2% (95% CI 52.5–93.5) and 93.7% (95% CI 63.2–99.1) for SHH, 0% and 0% for Group 3 and 0% and 44.4% (95% CI 13.6–71.9) for Group 4. CONCLUSION: The majority of young children with SHH-subgroup medulloblastoma can be treated effectively with irradiation-sparing regimens. Our results support the use of chemotherapy-only strategies for upfront treatment of young children with SHH medulloblastoma, while demonstrating the urgent need for intensification/augmentation of treatment for patients with group 3/4 medulloblastoma.

BACKGROUND Germ cell tumors (GCT) arising from non-midline structures (basal ganglia, thalamus, and posterior fossa) are rare. Although patients with midline (pineal and suprasellar) germinoma have excellent survival with chemotherapy and whole ventricular irradiation (WVI), germinoma in non-midline locations have traditionally been treated with craniospinal irradiation (CSI) or whole brain irradiation (WBI) to achieve similar outcomes. However, CSI and WBI are associated with significant long-term neuropsychological sequelae. METHODS We describe the clinical and neuropsychological outcomes of patients with non-midline germinoma treated at the Children's Hospital Los Angeles between 1990 and 2015. RESULTS Nine patients had basal ganglia/thalamic germinoma and one patient had a cerebellar primary. Eight patients received chemotherapy followed by reduced dose/volume irradiation, whereas two patients received chemotherapy alone as upfront therapy. One patient in the chemotherapy alone group relapsed after 4.3 years and was salvaged with CSI plus boost. The overall survival for the entire cohort was 100% at a median follow-up of 8.5 years. Neuropsychological data were available for six patients at a median of five months (baseline) and 4.2 years (follow-up) post-diagnosis. At four-year follow-up, data available revealed intact overall cognitive ability, verbal memory, and executive functioning, but persistent deficits in fine motor function. Comparison of baseline to follow-up suggests a downward trend in working memory, planning/problem-solving, verbal memory, and visuospatial integration. CONCLUSION Chemotherapy followed by reduced dose/volume of irradiation is an effective strategy resulting in long-term survival in patients with non-midline germinoma. Neuropsychological data suggest relatively minimal morbidity over time.

BACKGROUND AND PURPOSE: Atypical teratoid/rhabdoid tumors are rare, aggressive central nervous system tumors that are predominantly encountered in very young children. Our aim was to determine whether in vivo metabolic profiles correlate with molecular features of central nervous system pediatric atypical teratoid/rhabdoid tumors. MATERIALS AND METHODS: Twenty confirmed patients with atypical teratoid/rhabdoid tumors who underwent MR spectroscopy were included in this study. In vivo metabolite levels of atypical teratoid/rhabdoid tumors were compared with molecular subtypes assessed by achaete-scute homolog 1 expression. Additionally, brain-specific creatine kinase levels were determined in tissue samples. RESULTS: In vivo creatine concentrations were higher in tumors that demonstrated achaete-scute homolog 1 expression compared with those without achaete-scute homolog 1 expression (3.42 ± 1.1 versus 1.8 ± 0.8 IU, P < .01). Additionally, levels of myo-inositol (mI) (9.0 ± 1.5 versus 4.7 ± 3.6 IU, P < .05) were significantly different, whereas lipids approached significance (44 ± 20 versus 80 ± 30 IU, P = .07) in these 2 cohorts. Higher brain-specific creatine kinase levels were observed in the cohort with achaete-scute homolog 1 expression (P < .05). Pearson correlation analysis showed a significant positive correlation of brain-specific creatine kinase with absolute creatine (P < .05) and myo-inositol (P < .05) concentrations. CONCLUSIONS: In vivo MR spectroscopy may predict key molecular features of atypical teratoid/rhabdoid tumors at initial diagnosis, leading to timely patient risk stratification and accelerating the development of targeted therapies.

Medulloblastoma (MB) is the most common malignant brain tumor in children. Currently, "one-size-fits-all" radiation and chemotherapy treatment regimen is employed for treating MB patient, causing at least some children to undergo highly aggressive and in some cases, inadequate radiation therapy. Consequently, there is a need for prognostic and predictive tools for identifying disease aggressiveness and ultimately which patients with MB may be able to benefit from de-escalation of therapy. Genomic characterization of MB has recently identified 4 distinct molecular subgroups: Sonic Hedgehog (SHH) , Wingless (WNT) , Group 3, Group 4 each exhibiting different clinical behavior. The molecular sub-types have unique risk-profiles and outcomes, and patients could potentially benefit from sub-group specific treatments. However, the transition of these molecular MB subtypes into clinical practice has been limited due to challenges in availability of molecular profiling in most hospitals, as well as variability in clinical assessment. In this work, we present a radiomic feature that captures subtle tissue deformations caused due to the impact of tumor growth on the normal-appearing brain around tumor (BAT), to distinguish molecular sub-types of MB. First, we obtain voxel-wise deformation magnitude from the deformation orientations, after registering Gadolinium (Gd)-enhanced T1-w MRI scan for every study to a normal age-specific T1w MRI template. Deformation statistics are then computed within every 5mm annular BAT region, 0 < d < 60mm, where d is the distance from the tumor infiltrating edge, to capture subtle localized deformation changes around the tumor. Our results using multi-class comparison via one-way ANOVA and post-hoc comparison showed significant differences across deformation magnitudes obtained for Group 3, Group 4, and SHH molecular sub-types, observed up to 15-mm outside the infiltrating edge. Our feasibility results suggest that the subtle deformation features in BAT observed on routine Gd-T1w MRI may potentially serve as surrogate markers to non-invasively characterize molecular sub-types of pediatric MB.

BACKGROUND Central nervous system (CNS) germinomas are radiotherapy (RT)-sensitive tumors with excellent survival. Current treatment strategies combine chemotherapy with RT to reduce the field and dose of RT. There is no standard treatment for germinomas originating in the basal ganglia/thalami (BGTG) given their rarity and poorly-defined imaging characteristics. Craniospinal (CSI), whole brain (WBI), whole ventricle (WVI), and focal RT have been previously utilized; however, the optimal strategy remains unclear. METHODS Retrospective multi-institutional analysis was conducted across 18 institutions in four countries. RESULTS For 46 cases with non-metastatic BGTG, the event-free survival (EFS) was 86.9% at both 5 and 10 years, while overall survival (OS) was 100%, and 95.7% respectively at 5 and 10 years. Median RT dose and range for the various treatment volumes were as follows: CSI (n=10): 2340 cGy (1980–3060 cGy), WBI (n=8): 2340 (1800–3000 cGy), WVI (n=14): 2340 cGy (1800–2550 cGy), focal (n=9): 3600 cGy (3060–5400 cGy). There was no statistically significant difference in the EFS based on RT modality (p=0.57), but EFS for subjects with CSI and WBI were both 100%. The three subjects who received chemotherapy alone had significantly lower EFS than those who received chemotherapy and RT (p=0.001), but were salvageable with RT. CONCLUSION In the largest study to date for BGTG, there were no significant differences in outcomes between patients who received CSI, WBI, WVI or focal RT. This group of patients should be included in future prospective clinical trials, and a more limited RT field may be considered.

IDH-mutant astrocytomas are well-recognized in the adult population and while increasingly identified, are rare in children and young adults. These tumors typically arise in cortical locations, however cases of these tumors occurring in the brainstem have been reported in the adult literature. Here we present two cases of young adults with IDH-mutant astrocytomas of the brainstem. Patient 1 was initially diagnosed with an infiltrative low grade glioma (LGG) of the brainstem at 19 years of age based on conventional magnetic resonance imaging and magnetic resonance spectroscopy characteristics. She was treated with LGG therapy and had stable disease for over three years. At the time of disease progression she underwent biopsy and pathology was consistent with an anaplastic astrocytoma, IDH1 R132S mutant. Despite treatment she experienced rapid disease progression and died six months later. Patient 2 is a 17-year-old male who underwent up-front biopsy of an infiltrating brainstem lesion; pathology was consistent with diffuse astrocytoma, IDH1 R132H mutant. He was treated with focal irradiation and chemotherapy and continues to have stable disease 26 months post diagnosis. To our knowledge, this is the first report of IDH-mutant astrocytomas occurring the brainstem in young adult patients. Both patients’ tumors harbored accompanying TP53 mutations, but not ATRX mutations. These two cases reveal the importance of obtaining biopsies for brainstem tumors to perform molecular characterization and appropriate prognostication.

Objectives: The aims of this study were: to evaluate the prevalence of abdominal wall defects in the Polish population, to analyze temporal trends in the prevalence, to identify areas (clusters) of high risk of abdominal wall defects, and to characterize, with respect to epidemiology, children with abdominal wall defects and their mothers in the area defined as a cluster. Material and Methods: We used isolated congenital malformations (gastroschisis Q79.3 and omphalocele Q79.2 according to the International Statistical Classification of Diseases and Related Health Problems, 10th revision (ICD-10, the extended version)) data reported to the Polish Registry of Congenital Malformations (PRCM) over the years 1998– 2008 based on the population of 2 362 502 live births. We analyzed 11 administrative regions of Poland with complete epidemiologic data. Results: Of 11 regions, 2 had a significantly higher standardized prevalence of isolated gastroschisis: Dolnośląskie (1.7/10 000 live births, p = 0.0052) and Śląskie (1.9/10 000 live births, p < 0.0001). Furthermore, within the region of Dolnośląskie, we defined a clear prevalence of the isolated gastroschisis cluster (p = 0.023). We comprehensively examined demographic and socio-economic risk factors for abdominal wall defects in this area, and we found that these factors failed to account for the cluster. Conclusions: We identified a distinct prevalence cluster for isolated gastroschisis, although a precise reason for the disease clustering in this region remains unknown. Cluster identification enables more focused research aimed at identification of specific factors with teratogenic effects.

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.

Avoiding irradiation in infants/young children with malignant brain tumors has been associated with inferior survival. We reviewed medical records of infants/young children with malignant brain tumors diagnosed at our institution between 1991–2015 that completed intensive induction followed by myeloablative chemotherapy/AuHCR and either did or did not receive XRT post-AuHCR. Ninety-nine patients were identified (55 medulloblastoma, 21 PNET, 15 AT/RT, and 8 choroid plexus carcinoma). Twenty-seven of 99 patients received irradiation post-AuHCR and 72 did not. XRT group had 41% of patients with residual tumor post-induction and 44% with disseminated disease versus 18% and 26%, respectively, in no-XRT group. 5-year event-free survival (EFS) and overall survival (OS) for all patients was 63 + 5% and 73 + 5%. 5-year EFS and OS rates for patients receiving XRT post-AUHCR were 69 + 9% and 78 + 8% versus 60 + 6% and 71 + 6%for no-XRT group (p=0.26 and 0.64). For patients with residual tumor post-induction, 5-year EFS was 65 + 14% for XRT group versus 34 + 14% for no-XRT group (p=0.12). For patients with localized disease at diagnosis, 5-year EFS was 86 + 9% in XRT group versus 65 + 7% in no-XRT group (p=0.12). 5-year EFS for patients with disseminated disease in XRT and no-XRT groups was 47%. For medulloblastoma patients, 5-year EFS and OS rates were 65 + 7% and 89 + 10% in XRT group and 67 + 16% and 82 + 6% in no-XRT group. 5-year EFS was 80 + 13% for AT/RT patients in XRT group versus zero in no-XRT group. For infants/young children with malignant brain tumors completing AuHCR, administration of XRT did not provide significant survival advantage, with the exception of AT/RT.

INTRODUCTION: Children with diffuse intrinsic pontine glioma (DIPG) have a dismal prognosis. Checkpoint blockade has revolutionized treatment of some resistant cancers. METHODS: Pembrolizumab, a PD-1 inhibitor, was administered to children with progressive DIPG (Stratum A) and results are reported here. Children aged 1-18yrs with progressive DIPG were eligible with functional scores >60 and physiologic or less steroid usage, among standard eligibility criteria. Pembrolizumab was administered at 2mg/kg IV every three weeks. Tumor tissue (if available), serum and MRI studies were collected for correlative analysis. RESULTS: Five patients with progressive DIPG were enrolled from June-July 2015. The median age at diagnosis was 3.5yrs (range,2.8-6.9), and median time from diagnosis to study entry was 14.6 months (range,8.7-20.7). Progression-free survival (PFS) was 1.02 months (range,0.5-1.7); overall survival from initial treatment was 1.7 months (range,0.5-6.2). All patients clinically and/or radiographically worsened after one (n=1) or two (n=4) doses of pembrolizumab. Grade 3 or greater treatment-related adverse events included fatigue (n=2) and new or increased grade neurologic symptoms. Correlative analysis is ongoing. CONCLUSIONS: Checkpoint inhibition holds potential for CNS cancer treatment; however, special consideration is required in the CNS with limited space and large disease burdens. In our study, patients rapidly deteriorated neurologically after initiation of checkpoint blockade, with a shorter median PFS than expected by analogous historical trials; pembrolizumab protocols were amended to exclude recurrent DIPG patients after these events. Our findings suggest caution when utilizing immunotherapy in actively progressing tumor in the brain stem.

BACKGROUND: Rhabdoid Tumors (RTs) are rare heritable cancers with bi-allelic SMARCB1/A4 alterations, arising in the brain (Atypical Teratoid/Rhabdoid Tumors/ATRTs) and in various extra-cranial locations (Malignant Rhabdoid Tumors/MRTs). Recent studies uncovered molecular sub-types of ATRTs and MRTs, however, the molecular relationship and clinico-pathologic implications of MRTs and ATRTs sub-types remain unclear. METHODS: To inform clinical understanding of ATRTs and MRTs, 450/850K methylation array profiles generated from 202 ATRTs and 57 MRTs were used to define molecular categories of ATRTs/MRTs and examine their clinical significance. RESULTS: ATRTs segregated into 3 known molecular subgroups, group 1/SHH (n=87), group 2A/TYR (n=69), group 2B/MYC (n= 46); 13 and 44 MRTs respectively segregated with group 2A/TYR and 2B/MYC ATRTs. Median patient age was 19.1 months for group 1/SHH, 12.3 months for group 2A/TYR and 22.3 months for group 2B/MYC Rhabdoid tumors. Complete clinical information and treatment information available for 162 patients (n=125 ATRTs and n=37 MRTs), indicated only 65 patients received a combined chemo-radiation therapy. 24-month PFS was 30%,38% and 28% and the 24-month OS was 43%,48% and 43% for subgroups 1/SHH, 2A/TYR and 2B/MYC tumors respectively. CONCLUSION: MRT and ATRT comprise a biological spectrum with overlapping molecular features. Clinicopathologic analysis suggest ATRT/MRT molecular subtypes have different therapeutic response to chemo-radiotherapeutic regimens.

BACKGROUND: Radiation therapy, while a mainstay of medulloblastoma treatment, is associated with significant age-dependent neurocognitive morbidity in children. Relatively little is known about the subgroup-specific outcome of infants and young children with medulloblastoma treated with irradiation-sparing regimens. METHODS: Infants and young children

Introduction Substantial resources are required to provide lifelong postoperative care to people with cochlear implants. Most patients visit the clinic annually. We introduced a person-centred remote follow-up pathway, giving patients telemedicine tools to use at home so they would only visit the centre when intervention was required. Objectives To assess the feasibility of comparing a remote care pathway with the standard pathway in adults using cochlear implants. Design Two-arm randomised controlled trial. Randomisation used a minimisation approach, controlling for potential confounding factors. Participant blinding was not possible, but baseline measures occurred before allocation. Setting University of Southampton Auditory Implant Service: provider of National Health Service care. Participants 60 adults who had used cochlear implants for at least 6 months. Interventions Control group (n=30) followed usual care pathway. Remote care group (n=30) received care remotely for 6 months incorporating: home hearing in noise test, online support tool and self-adjustment of device (only 10 had compatible equipment). Main outcome measures Primary: change in patient activation; measured using the Patient Activation Measure. Secondary: change in hearing and quality of life; qualitative feedback from patients and clinicians. Results One participant in the remote care group dropped out. The remote care group showed a greater increase in patient activation than the control group. Changes in hearing differed between the groups. The remote care group improved on the Triple Digit Test hearing test; the control group perceived their hearing was worse on the Speech, Spatial and Qualities of Hearing Scale questionnaire. Quality of life remained unchanged in both groups. Patients and clinicians were generally positive about remote care tools and wanted to continue. Conclusions Adults with cochlear implants were willing to be randomised and complied with the protocol. Personalised remote care for long-term follow-up is feasible and acceptable, leading to more empowered patients. Trial registration number NCT14644286.

Posterior fossa ependymomas (EPN_PF) in children comprise two morphologically identical, but biologically distinct tumor entities. Group-A (EPN_PFA) tumors have a poor prognosis and require intensive therapy. In contrast, group-B tumors (EPN_PFB) exhibit excellent prognosis and the current consensus opinion recommends future clinical trials to test the possibility of treatment de-escalation in these patients. Therefore, distinguishing these two tumor subtypes is critical. EPN_PFA and EPN_PFB can be distinguished based on DNA methylation signatures, but these assays are not routinely available. We have previously shown that a subset of poorly prognostic childhood EPN_PF exhibits global reduction in H3K27me3. Therefore, we set out to determine whether a simple immunohistochemical assay for H3K27me3 could be used to segregate EPN_PFA from EPN_PFB tumors. We assembled a cohort of 230 childhood ependymomas and H3K27me3 immunohistochemistry was assessed as positive or negative in a blinded manner. H3K27me3 staining results were compared with DNA methylation-based subgroup information available in 112 samples [EPN_PFA (n=72) and EPN_PFB tumors (n=40)]. H3K27me3 staining was globally reduced in EPN_PFA tumors and immunohistochemistry showed 99% sensitivity and 100% specificity in segregating EPN_PFA from EPN_PFB tumors. Moreover, H3K27me3 immunostaining was sufficient to delineate patients with worse prognosis in two independent, non-overlapping cohorts (n=133 and n=97). In conclusion, immunohistochemical evaluation of H3K27me3 global reduction is an economic, easily available and readily adaptable method for defining high-risk EPN_PFA from low-risk posterior fossa EPN_PFB tumors to inform prognosis and to enable the design of future clinical trials.

Ependymomas in children occur most commonly in the posterior fossa of the brain and cause significant morbidity and mortality. The pathogenesis of these tumors remains obscure as recent whole genome and whole exome sequencings have not yielded recurrent genetic alterations. These tumors are classified into PFA and PFB groups based on abnormal CpG island methylation suggesting that epigenetic alterations may be a significant driver. To gain insights into the epigenetics of childhood ependymomas, we performed mass spectroscopy for histone modifications to discover that H3K27me3 was globally reduced in PFA tumors, similar to that observed in H3K27M diffuse intrinsic pontine gliomas (DIPGs). Despite global reduction in H3K27me3, ChIP-sequencing for H3K27me3 revealed genomic enrichment at several loci important for neurodevelopment. Comparison of DNA methylation and genome-wide H3K27me3 enrichment from both H3K27M mutant DIPGs and PFAs showed many similarities and pointed to factors that regulate radial glial (neuronal stem cells) development. Moreover, radial glia in the developing human posterior fossa were negative for H3K27me3. To assess the clinical utility of this finding, H3K27me3 immunohistochemistry was assessed as positive or negative in a blinded manner in a cohort (n=112) of previously defined childhood PFA (n=72) and PFB tumors (n=40). Next, H3K27me3 immunohistochemistry status in two independent, non-overlapping cohorts of childhood EPN (n=133 and n=98) was determined and risk stratification was assessed retrospectively using univariate and multivariate Cox proportional hazards analyses. H3K27me3 immunohistochemistry showed 99% sensitivity and 100% specificity in delineating PFA from PFB tumors and was sufficient to delineate patients with worse prognosis (P

BACKGROUND: Single agent studies targeting the tumor microenvironment in central nervous system (CNS) tumors have largely been disappointing. Combination therapies targeting various pathways and cell types may be a more effective strategy. In this phase I study, we evaluated the combination of dasatinib, lenalidomide, and temozolomide in children with relapsed or refractory primary CNS tumors. METHODS: Patients 1–21 years old with relapsed or refractory CNS tumors were eligible. Starting doses of dasatinib and lenalidomide were 65 mg/m(2)/dose twice daily and 55 mg/m(2) once daily, respectively, while temozolomide was constant at 75 mg/m(2) daily. The study followed a 3+3 phase I design, with a 4-week dose-limiting toxicity (DLT) evaluation period. Serial peripheral blood lymphocyte subsets were evaluated in consenting patients. RESULTS: Fifteen patients were enrolled and thirteen were DLT-evaluable. DLTs occurred in 5 patients, including somnolence and confusion (1 patient), hypokalemia (1 patient) and thrombocytopenia (3 patients). The maximum tolerated dose for the combination was dasatinib 65 mg/m(2) twice daily, lenalidomide 40 mg/m(2) daily, and temozolomide 75 mg/m(2) daily, for 21 days followed by 7 days rest in repeating 28-day cycles. Transient increases in natural killer effector cells and cytotoxic T-cells were seen after 1 week of treatment. One out of 6 response-evaluable patients showed a partial response. CONCLUSIONS: The combination was feasible and relatively well tolerated in this heavily pre-treated population. The most common toxicities were hematologic. Preliminary evidence of clinical benefit was seen.

Diffuse intrinsic pontine gliomas (DIPGs) are rare but devastating brain tumors that occur primarily in children. These gliomas have poor prognoses and present options focus on palliation of symptoms and prolongation of life. Here, we present a case of a 16-year-old female diagnosed with a DIPG whose age group has been mostly left out of discussions regarding psychosocial support options. This report is meant to start a conversation about the different support options available at our institution that have shown promising results in the literature for palliative care applications. These options can include camps for patients with brain tumors, psychological counseling, the Ronald McDonald House, and other psychosocial programs. Many of these programs can be tailored to meet the specific needs of adolescent and young adult (AYA) patients and will hopefully be integrated into a comprehensive palliative care regimen in future studies.

Genetic analysis of familial forms of Alzheimer's disease (AD) causally links the proteolytic processing of the amyloid precursor protein (APP) and AD. However, the specific type of amyloid and mechanisms of amyloid pathogenesis remain unclear. We conducted a detailed analysis of intracellular amyloid with an aggregation specific conformation dependent monoclonal antibody, M78, raised against fibrillar Aß42. M78 immunoreactivity colocalizes with Aß and the carboxyl terminus of APP (APP-CTF) immunoreactivities in perinuclear compartments at intermediate times in 10. month 3XTg-AD mice, indicating that this represents misfolded and aggregated protein rather than normally folded APP. At 12. months, M78 immunoreactivity also accumulates in the nucleus. Neuritic plaques at 12. months display the same spatial organization of centrally colocalized M78, diffuse chromatin and neuronal nuclear NeuN staining surrounded by peripheral M78 and APP-CTF immunoreactivity as observed in neurons, indicating that neuritic plaques arise from degenerating neurons with intracellular amyloid immunoreactivity. The same staining pattern was observed in neuritic plaques in human AD brains, showing elevated intracellular M78 immunoreactivity at intermediate stages of amyloid pathology (Braak A and B) compared to no amyloid pathology and late stage amyloid pathology (Braak 0 and C, respectively). These results indicate that intraneuronal protein aggregation and amyloid accumulation is an early event in AD and that neuritic plaques are initiated by the degeneration and death of neurons by a mechanism that may be related to the formation of extracellular traps by neutrophils. © 2014 Elsevier Inc.

BACKGROUND: Vemurafenib is an orally administered inhibitor of BRAF-V600E kinase approved for the treatment of BRAF-V600E mutated melanoma. We have previously presented favorable radiographic response and safety data for vemurafenib in children with BRAF-V600E mutated brain tumors and report here an update on outcomes of this cohort, as well as pharmacokinetic (PK) data of patients taking whole (n=18) or crushed (n=6) tablets. METHODS: Vemurafenib was given orally, either as crushed or whole tablets, beginning at the adult dose equivalent of 550 mg/m2, twice daily. Toxicity, PK, and response were assessed. Doses of 420 mg/m2 and 550 mg/m2 were assessed by a 3 + 3 design in a dose de-escalation study. PK plasma samples were analyzed using HPLC at Covance Inc and modeled by standard PK methods using Phoenix v8 (Certera, Princeton, New Jersey). RESULTS: PK analyses demonstrated a significant accumulation factor (approximately six-fold) over time with each vemurafenib dose. In the “crushed” tablet cohort, bioavailability was approximately 96% of that seen in patients receiving whole tablets. The steady-state area-under-the-curve (AUC(ss)) median (range) was 754mg*h/L (464–920) in the whole tablet cohort and 621mg*h/L (184–1043) in the crushed tablet cohort. Updated best radiographic objective responses are: one complete response (CR), eleven partial responses (PR), and seven with stable disease (SD). Sustained responses were observed for over 50 months. Patients with SD had 30% lower AUC(ss) compared PR+CR. However, a logistic regression model using AUCss as a predictor of PR+CR was not significant given the observed variability. CONCLUSIONS: Children with BRAF-V600E mutated brain tumors treated with vemurafenib have durable responses. PK modeling confirmed similar PK paramaters in children as compared to adults treated for melanoma. Using crushed tablets to administer a liquid suspension of drug resulted in similar drug exposure to whole tablets.

© The Authors, some rights reserved;. Childhood posterior fossa (PF) ependymomas cause substantial morbidity and mortality. These tumors lack recurrent genetic mutations, but a subset of these ependymomas exhibits CpG island (CpGi) hypermethylation [PF group A (PFA)], implicating epigenetic alterations in their pathogenesis. Further, histological grade does not reliably predict prognosis, highlighting the importance of developing more robust prognostic markers. We discovered global H3K27me3 reduction in a subset of these tumors (PF-ve ependymomas) analogous to H3K27M mutant gliomas. PF-ve tumors exhibited many clinical and biological similarities with PFA ependymomas. Genomic H3K27me3 distribution showed an inverse relationship with CpGi methylation, suggesting that CpGi hypermethylation drives low H3K27me3 in PF-ve ependymomas. Despite CpGi hypermethylation and global H3K27me3 reduction, these tumors showed DNA hypomethylation in the rest of the genome and exhibited increased H3K27me3 genomic enrichment at limited genomic loci similar to H3K27M mutant gliomas. Combined integrative analysis of PF-ve ependymomas with H3K27M gliomas uncovered common epigenetic deregulation of select factors that control radial glial biology, and PF radial glia in early human development exhibited reduced H3K27me3. Finally, H3K27me3 immunostaining served as a biomarker of poor prognosis and delineated radiologically invasive tumors, suggesting that reduced H3K27me3 may be a prognostic indicator in PF ependymomas. 2016

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 (

Ependymomas in children occur most commonly in the posterior fossa of the brain and cause significant morbidity and mortality. The pathogenesis of these tumors remains obscure as recent whole genome and whole exome sequencing efforts have not yielded recurrent genetic mutations. These tumors exhibit abnormal CpG island methylation, suggesting that epigenetic alterations may be a significant driver. To gain insights into the epigenetics of childhood ependymomas, we performed mass spectroscopy for histone modifications to discover that H3K27 trimethylation was globally reduced in these tumors. Despite global reduction in H3K27me3, ChIP-sequencing for H3K27me3 revealed genomic enrichment at several loci important for neurodevelopment. In a cohort of 195 childhood posterior fossa ependymoma samples, reduction in H3K27me3 was associated with worse prognosis (p

Molecularly targeted therapies, such as MEK, BRAF, and EGFR inhibitors, are prescribed in pediatric neuro-oncology practice with increasing frequency. Although these targeted medications have demonstrated inhibition of tumor growth without traditional chemotherapy side effects, they are not without associated toxicities. Dermatologic findings are among the most commonly reported toxicities. Collaboration between providers, patients and families through prevention, early recognition, and promptly initiated treatment of associated skin toxicities can decrease strain and avoid interruption and/or early termination of these therapeutic agents resulting in overall increased treatment compliance. After an extensive review of the available published literature, a skin care teaching tool was created, in collaboration with nurse practitioners and physicians. The handout was implemented into practice to educate patients and families on preventative and early interventional measures to identify and treat skin toxicities related to treatment with targeted therapies. The fact sheet outlined the most common skin side effects including dry, itchy, scaly scalp and skin, cracked lips, dermatitis, acneiform rash, hair thinning, photosensitivity, ingrown and infected nails, and development of new moles. This introduction of skin care guidelines into a clinical neuro-oncology program represents a feasible and effective strategy for providing educational and supportive care to patients and families and preventing and treating skin toxicities associated with innovative targeted treatments. These guidelines can easily be initiated at other pediatric neuro-oncology practices, demonstrate adaptation in provider practice to newer oncology therapies, and exemplifies an evidence based collaborative team approach together with patients and families.

Li–Fraumeni syndrome (LFS) is an autosomal dominant cancer predisposition syndrome caused by germline alterations in the tumor suppressor gene TP53. LFS is associated with numerous malignancies including astrocytoma. Sanger sequencing and chromosomal microarray studies of blood and tumor tissue from a 4-yr-old boy with glioblastoma demonstrated a germline TP53 mutation with loss of heterozygosity for the short arm of Chromosome 17 as the second inactivating event in the tumor. There was no family history of LFS, but the child's mother had recently died from metastatic choriocarcinoma after antecedent normal term delivery of a then 6-mo-old daughter. The choriocarcinoma contained the same TP53 mutation detected in the proband and the 6-mo-old daughter was confirmed to be a carrier. Unexpectedly, the germline TP53 mutation was found to be inherited from the unaffected father. We report here the second genetically confirmed case of TP53-mutated choriocarcinoma in the partner of an LFS patient. Based on this case and recent literature, female partners of LFS patients may have increased risk of choriocarcinoma due to transmission of germline TP53 mutation from male carriers. Although the Toronto protocol has established an effective approach to detect tumors and improve survival in children and adults with LFS, there is a need to expand the current criteria to include surveillance of female partners of LFS patients for choriocarcinoma and other gestational trophoblastic disease. Recognition of this unique mode of transmission of TP53 mutations should be considered in genetic counseling for cancer risk assessment and family planning.

Background: The defining molecular feature of rhabdoid tumors, epithelioid sarcoma (ES), and poorly differentiated chordomas is the absence of tumor expression of INI1 (SMARCB1), a subunit of the SWI/SNF chromatin remodeling complex. INI1 loss impairs SWI/SNF activity and induces a dependence on the activity of EZH2, the catalytic subunit of PRC2, a separate complex responsible for chromatin remodeling and transcriptional repression through trimethylation of lysine 27 on histone H3 (H3K27me3). Tazemetostat, a potent and selective EZH2 inhibitor, has demonstrated tumor regressions in INI1-negative preclinical malignant rhabdoid tumor (MRT) models and durable objective responses in adults with certain INI1-negative ES or chordoma. Interim results from dose escalation (DEsc) cohorts of a Phase (Ph) 1 pediatric study are reported. Methods: EZH-102 (NCT02601937) is a Ph 1, multicenter study of tazemetostat dosed continuously as an oral suspension administered twice daily (BID) in patients (pts) aged 6 months to 21 years with synovial sarcoma, or INI1-negative tumors including atypical teratoid rhabdoid tumors (ATRT), MRT, ES, chordoma, and others. A “Rolling 6” design was used for DEsc. Objective response was assessed every 8 weeks using disease-appropriate response criteria, i.e., RANO or RECIST 1.1. Primary endpoints included identification of dose-limiting toxicities (DLT) and recommended Ph 2 dose (RP2D). Secondary endpoints included characterization of safety/tolerability, pharmacokinetics (PK), and duration of response. Exploratory endpoints included assessing the relationship between tazemetostat exposure and the pharmacodynamic (PD) marker H3K27me3 in peripheral blood. Results: Forty-six pts have been treated in 7 dose cohorts: 240 (n=8), 300 (n=6), 400 (n=6), 520 (n=7), 700 (n=6), 900 (n=6), and 1200 mg/m2 BID (n=7). One pt at 300 mg/m2 had DLTs of dyspnea (grade 4)/hypoxia (grade 3), but no DLTs were observed in any other cohort. Adverse events were generally mild to moderate, consistent with the safety profile observed in adults. Plasma concentrations were generally dose-proportional across the dose range studied and were lower at steady-state on Day 15 vs. those measured on Day 1. Mean systemic exposure in the 1200 mg/m2 cohort was ~ 4-fold greater than that at the adult RP2D of 800 mg BID. A PK:PD relationship between C1D15 tazemetostat exposure and H3K27me3 levels in peripheral blood monocytes and granulocytes was observed with consistent and significant post-dose reductions in H3K27me3 at the 900 and 1200 mg/m2 doses. Confirmed complete or partial responses (CR/PR) per RECIST/RANO were observed in pts with ES (n=1), chordoma (n=2), and ATRT (n=1) at dose levels ranging from 520 to 900 mg/m2. Conclusion: Tazemetostat was generally well tolerated in children and showed promising antitumor activity including CRs in pts with INI1-negative tumors. The RP2D of 1200 mg/m2 BID was defined on the basis of PK, PD, and clinical safety, and resulted in higher systemic exposure than in adults. Dose expansion cohorts are currently enrolling. Citation Format: Susan Chi, Maryam Fouladi, Neerav Shukla, Franck Bourdeaut, Ashley Margol, Guy Makin, Geoff McCowage, Cynthia Wetmore, Margaret Macy, Ted Laetsch, Darren Hargrave, Navin Pinto, Joanna Yi, Dave Ebb, Giles Robinson, Maria Roche, Benjamin Suttle, Alicia Clawson, Peter Ho, Jill Rodstrom, Scott Daigle, Karsten Nysom. Phase 1 study of the EZH2 inhibitor, tazemetostat, in children with relapsed or refractory INI1-negative tumors including rhabdoid tumors, epithelioid sarcoma, chordoma, and synovial sarcoma [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A175.

PURPOSE: Bifocal presentation of central nervous system (CNS) germinomas, with synchronous pineal and suprasellar involvement, is common, and associated with favorable outcome. However, the incidence and outcome of bifocal presentation of non-germinomatous germ cell tumors (NGGCT) is less well described. METHODS: Medical records of patients with CNS NGGCT treated at Children's Hospital Los Angeles between 1993 and 2014 were reviewed for clinical characteristics, treatment and outcome. RESULTS: Seven (24.1%) of 29 patients diagnosed with CNS NGGCT between 1993 and 2014 had bifocal involvement. The mean age at diagnosis was 13.1 years (range: 8-22 years). Diagnosis was made on tumor marker elevation in seven patients, and confirmed on histopathology on one patient. Seven patients had elevated AFP and one patient had elevated βHCG in serum and/or CSF. Two patients are still undergoing therapy and have not been included in the survival analyses. Four of remaining five patients are long term survivors at 41, 56, 57, and 97 months. Patient #1 received initial chemotherapy without irradiation, relapsed in the 3rd ventricle at 10 months, and was successfully salvaged with high-dose chemotherapy (HDCx) with autologous hematopoietic stem cell rescue (AuHCR) and 3600cGy craniospinal irradiation (CSI) with local boost. Patient #2 had partial response to chemotherapy, underwent HDCx and AuHCR, followed by 3600cGy CSI with boost. Patients #3 and #4 received chemotherapy with a complete response, followed by whole ventricular irradiation with a local boost. Patient #5 received chemotherapy only, developed ventricular relapse at 75 months, was treated with cyclophosphamide and vinblastine followed by CSI with boost, but died at 87 months. CONCLUSIONS: Our experience suggests that bifocal NGGCT may be more common than previously thought, and may be more likely to have yolk-sac component given elevated AFP, and therefore have a better prognosis than other NGGCT.

Medulloblastoma, the most common malignant brain tumor in children, occurs with increased frequency in individuals with Fanconi anemia who have biallelic germline mutations in BRCA2. We describe an 8 year old child who had disseminated anaplastic medulloblastoma and a deleterious heterozygous BRCA2 6174delT germline mutation. Molecular profiling was consistent with Group 4 medulloblastoma. The posterior fossa mass was resected and the patient received intensive chemotherapy and craniospinal irradiation. Despite this, the patient succumbed to a second recurrence of his medulloblastoma, which presented eight months after diagnosis as malignant pleural and peritoneal effusions. Continuous medulloblastoma cell lines were isolated from the original tumor (CHLA-01-MED) and the malignant pleural effusion (CHLA-01R-MED). Here we provide their analyses, including in vitro and in vivo growth, drug sensitivity, comparative genomic hybridization and next generation sequencing analysis. In addition to the BRCA2 6174delT, the medulloblastoma cells had amplification of MYC, deletion at Xp11.2 and isochromosome 17, but no structural variations or overexpression of GFI1 or GFI1B. To our knowledge, this is the first pair of diagnosis/recurrence medulloblastoma cell lines, the only medulloblastoma cell lines with BRCA2 6174delT described to date, and the first reported case of a child with medulloblastoma associated with a germline BRCA2 6174delT who did not also have Fanconi anemia.

BACKGROUND: Medulloblastomas in children can be categorized into four molecular subgroups with differing clinical characteristics such that subgroup determination aids in prognostication and risk-adaptive treatment strategies. Magnetic resonance spectroscopy (MRS) is a widely available, non-invasive tool used to determine metabolic characteristics of tumors providing diagnostic information without the need for tumor tissue. In this study we investigated the hypothesis that metabolite concentrations measured by MRS would differ between molecular subgroups of medulloblastoma allowing for accurate subgroup determination. METHODS: Magnetic resonance spectroscopy was used to measure metabolites in medulloblastomas across molecular subgroups (SHH = 12, Groups 3/4 = 17, WNT = 1). Levels of fourteen metabolites were analyzed to determine those which were most discriminant for medulloblastoma subgroups in order to construct a multivariable classifier to distinguish between combined Group 3/4 and SHH tumors. RESULTS: Medulloblastomas across molecular subgroups revealed distinct spectral features. A five metabolite subgroup classifier inclusive of creatine, myo-inositol, taurine, aspartate and lipid 13a was developed that could discriminate between Group 3/4 and SHH medulloblastomas with excellent accuracy (cross-validated Area Under the Curve AUC = 0.88). Group 3 and Group 4 tumors demonstrated metabolic profiles with readily detectable taurine, lower levels of lipids and high levels of creatine. SHH tumors showed prominent choline and lipid with low levels of creatine and little or no evidence of taurine. CONCLUSIONS: The data show that medulloblastomas of different molecular subgroups differ metabolically as measured using MRS. MRS is a potentially useful and accurate tool to determine medulloblastoma molecular subgroups.

Despite the documented benefit of voriconazole therapeutic drug monitoring, nonlinear pharmacokinetics make the timing of steady-state trough sampling and appropriate dose adjustments unpredictable by conventional methods. We developed a nonparametric population model with data from 141 previously richly sampled children and adults. We then used it in our multiple-model Bayesian adaptive control algorithm to predict measured concentrations and doses in a separate cohort of 33 pediatric patients aged 8 months to 17 years who were receiving voriconazole and enrolled in a pharmacokinetic study. Using all available samples to estimate the individual Bayesian posterior parameter values, the median percent prediction bias relative to a measured target trough concentration in the patients was 1.1% (interquartile range, −17.1 to 10%). Compared to the actual dose that resulted in the target concentration, the percent bias of the predicted dose was −0.7% (interquartile range, −7 to 20%). Using only trough concentrations to generate the Bayesian posterior parameter values, the target bias was 6.4% (interquartile range, −1.4 to 14.7%; P = 0.16 versus the full posterior parameter value) and the dose bias was −6.7% (interquartile range, −18.7 to 2.4%; P = 0.15). Use of a sample collected at an optimal time of 4 h after a dose, in addition to the trough concentration, resulted in a nonsignificantly improved target bias of 3.8% (interquartile range, −13.1 to 18%; P = 0.32) and a dose bias of −3.5% (interquartile range, −18 to 14%; P = 0.33). With the nonparametric population model and trough concentrations, our control algorithm can accurately manage voriconazole therapy in children independently of steady-state conditions, and it is generalizable to any drug with a nonparametric pharmacokinetic model. (This study has been registered at ClinicalTrials.gov under registration no. NCT01976078.)

Introduction: For many forms of cancers, survival improvement in the AYA population has lagged behind that of younger patients. One contributing factor could be differences in drug metabolism and tolerance of cancer treatment. Although previous studies have documented greater vincristine-related neurotoxicity (VRNT) in AYA vs. younger patients, comparative vincristine PK studies have yielded mixed results with no clear difference in PK related to age. One limitation of these studies is that age, rather than a more physiological assessment of developmental maturity, was used for the comparison. The primary aim of this study was to determine whether developmental differences in vincristine PK related to Tanner Stage could be detected in a sample of children and AYAs undergoing treatment for ALL. Our hypothesis was that vincristine PK would be related to Tanner Stage. Methods: From September 2014-March 2015, a purposeful sample of 30 patients with a diagnosis of ALL treated at Children9s Hospital of Los Angeles were recruited to this IRB-approved study either prior to starting Induction phase or during Maintenance phase. Tanner Stage was classified as ≤2 or ≥4, excluding Tanner Stage 3. Vincristine blood levels were obtained around the first dose during Induction or any single monthly dose during Maintenance at pre-specified time points: 0 min, 10 min, 30 min, 1 hour, 12 hour (Induction only), and 24 hours. For all patients, the vincristine dose was 1.5 mg/m 2 (max 2 mg). Vincristine levels were determined by high performance liquid chromatography. Mean vincristine clearance was compared using the independent T-test. Univariate and multivariate linear regression analysis via backward selection was performed using Tanner Stage, age, sex, BMI, fluconazole exposure, and treatment phase as predictors. P-values were two-sided with significance set at Results: The age range was 1-24 yrs ( 2 , respectively (p=0.71). As summarized in Tables 1 and 2, in both univariate and multivariate analyses no predictors, including Tanner Stage, were associated with vincristine clearance. Conclusions: In this pilot study, we were unable to detect an association between vincristine clearance and Tanner Stage. These data suggest that even when using a measure more reflective of physiological maturity than age, substantial developmental differences in vincristine clearance appear to be lacking. This calls into question the potential explanation of altered clearance for the increased VRNT observed in AYAs, and suggests that future investigations should be directed toward potential developmental differences in vincristine pharmacodynamics. Our data may have implications for understanding other differences in chemotherapy toxicity observed in AYAs. Disclosures No relevant conflicts of interest to declare.

Pediatric posterior fossa ependymomas are poorly understood childhood brain tumors and have no effective treatments. The biology of these tumors is obscure as recent sequencing efforts suggest that they lack recurrent genetic alterations. A subset of these tumors termed PF-A ependymomas exhibits CpG-island hypermethylation implicating epigenetic alterations in their pathogenesis. Through comprehensive analyses of histone modification, we discovered global H3K27me3 reduction in a subset of these tumors. Tumors with lowered H3K27me3 showed many clinical and biologic similarities with PFA-ependymomas. Global reduction in H3K27me3 is likewise observed in pediatric gliomas that bear histone H3K27M mutations termed diffuse intrinsic pontine gliomas (DIPG) that also arise in the posterior fossa of young children. Analyses of ependymomas with reduced H3K27me3 and H3K27M mutant DIPGs showed many similarities in DNA methylation and enrichment of H3K27me3 in many genomic loci important for neuroglial specification. Combined integrative analysis of both tumor types uncovered common epigenetic deregulation of select factors that control radial glial biology and radial glia in the developing posterior fossa showed reduced H3K27me3. Finally, PF ependymomas with lowered H3K27me3 were more invasive radiologically and exhibited poor prognosis in three independent cohorts (P300). These data have clinical implications for biomarker development and to inform epigenetic approaches to treat PF ependymomas. Citation Format: Sriram Venneti, Jill Bayliss, Piali Mukherjee, Chao Lu, Siddhant Jain, Chan Chung, Daniel Martinez, Benjamin Sabari, Ashley Margol, Pooja Panwalkar, Abhijit Paroloia, Melike Pekmezci, Richard Mc Eachin, Marcin Cieslik, Benita Tamrazi, Benjamin Garcia, Gaspare La Rocca, Mariarita Santi, Peter Lewis, Cynthia Hawkins, Ari Melnick, C David Allis, Craig B. Thompson, Arul Chinnaiyan, Alexander R. Judkins. A subset of poorly prognostic pediatric posterior fossa ependymomas exhibit lowered H3K27me3 and DNA hypomethylation and show epigenetic similarities with H3K27M mutant diffuse intrinsic pontine gliomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3863. doi:10.1158/1538-7445.AM2017-3863

Background: Transvaginal sonography (TVS) is a new diagnostic technique used for the evaluation of the female pelvis. The objective of the present study was to study the role of TVS and to assess the diagnostic accuracy in gynecological disorders.Methods: Total number of 100 patients attending OPDs with various complaints was selected by random technique of the study. All the patients have informed consent and thorough clinical examination including general, systemic and pelvic examination was conducted after taking a detailed history then the patients underwent TVS followed by one of the procedures like fractional curettage, dilatation and curettage and abdominal hysterectomy (with or without conservation of ovaries) or conservative management with regular follow up.Results: The sensitivity of TVS in diagnosing dysfunctional uterine bleeding (DUB) and pelvic inflammatory diseases (PID) was 100% and specificity was 85.1% and 95% respectively. For fibroids and ovarian mass diagnosis, sensitivity was 68.9% and 80.9% respectively and specificity was 100%. Diagnostic accuracy of clinical diagnosis was 70.0% whereas TVS had 94.0% of diagnostic accuracy in diagnosing various gynecological disorders.Conclusions: The final outcome is that TVS examination is an important non-invasive investigation, can be used as important diagnostic method in various gynecological disorders as it has got a high diagnostic accuracy.