bluuebunny/crossref_metadata_2025 huggingface dataset:
QOL-18. A LONGITUDINAL STUDY OF NEUROCOGNITION IN CHILDREN TREATED FOR A BRAIN TUMOR
Authors: Lemiere Jurgen , Van den Wyngaert Linde , Vandereydt Josefien , Vandenabeele Karen , Vercruysse Trui , Sleurs Charlotte , Jacobs Sandra
Published: December 2020

It is well known that neurocognition in children treated for a brain tumor can be affected. However, studies on the trajectory of these neurocognitive problems are scarce. In the present study we investigated the evolution of neurocognition between timepoints of diagnosis, 2, 4 and 6 years later. A total of 53 children diagnosed with a brain tumor were recruited in this study, of which all completed a comprehensive neuropsychological test battery at three successive timepoints and 30 at 4 timepoints. The first assessment was conducted as soon as possible after diagnosis and before initiation of chemo- and/or radiotherapy. Mean age at diagnosis was 8.06 years. The most common diagnoses were pilocytic astrocytoma (n=28) and medulloblastoma (n=10). 24.5% and 18.9% of these patient groups received focal or craniospinal irradiation, respectively. A repeated measures analysis with cranial irradiation (no, focal, craniospinal) as between-subjects factor demonstrated a significant interaction effect between time and type of irradiation for overall intelligence (p=0.02) for children with three assessments. The same interaction effect was found for overall intelligence and processing speed for children with four assessments (p=.005 and p=.002, respectively). The group who received craniospinal irradiation demonstrated the most pronounced decline. Interestingly, no main time effect or interaction effect was found for general memory functioning. Our results demonstrate that not all neurocognitive functions in children treated for a brain tumor decline after treatment. Overall IQ and processing speed are the most vulnerable outcomes in our cohort, especially for the children treated with craniospinal irradiation.
QOL-27. SWALLOWING ASSESSMENT IN PEDIATRIC PATIENTS WITH BRAIN TUMOR
Authors: Machado Natalia Oliveira , Duarte Ana Paula , dos Santos Aline Azevedo , Mançano Bruna Minniti , Almeida Carlos
Published: December 2020

BACKGROUND

Neurosurgical intervention is the initial modality of treatment for the vast majority of pediatric brain tumors. However, studies on the swallowing process in pediatric patients with brain tumors are scarce, especially comparing changes that can be identified before and after surgery. In clinical practice, it is possible to observe that these patients may present modifications in the swallowing phases both before and after surgery. Therefore, we conducted a longitudinal study with a cohort of 20 patients ranging in age from 0 to 17 years, in order to characterize the swallowing disorders.

RESULTS

30% of the patients presented some change in orofacial motricity in the organs related to initiation, coordination, and maintenance of swallowing at the time of hospital admission, and 65% of the patients exhibited these changes after surgery. Due to worsening in swallowing after surgery, 40% of the patients required modification of the consistence of oral diet or required the use of an alternative route of feeding.

CONCLUSIONS

There is a high prevalence of swallowing disorders in pediatric patients with brain tumors, mainly regarding the proper functioning of organs related to initiation, coordination, and maintenance of swallowing even before the surgical intervention, and these changes increase after surgery - especially in patients with posterior fossa tumors. The role of the speech/language pathologist is of paramount importance, given their role in the assessment and adequacy of the feeding route, identifying patients at risk of pulmonary aspirations, minimizing swallowing complications, and also facilitating communication with patients and their families.
QOL-31. USE OF PATIENT-REPORTED OUTCOMES TO IDENTIFY YOUTH AT RISK FOR IMPAIRED OVERALL HEALTH
Authors: Ingerski Lisa , Lewis Rebecca Williamson , Mertens Ann , MacDonald Tobey
Published: December 2020

Pediatric brain tumor survivors often experience persistent and clinically significant late-effects following treatment. Critical to understanding morbidity is utilization of patient-reported outcomes (PROs). The current study evaluated PROs of individuals previously diagnosed with a pediatric brain tumor and identified risk factors for less optimal overall health. Participants included 127 youth 10.59±4.81 (M±SD) years old at survey completion and 4.45±3.82 years from diagnosis of a brain tumor (34.6% Pilocytic Astrocytoma, 9.4% Medulloblastoma, 9.4% Ependymoma, 7.9% Craniopharyngioma, 38.6% Other). Outcomes were assessed via Patient-Reported Outcomes Measurement Information System (PROMIS) parent-proxy measures. Overall health was assessed via PROMIS Global Health (i.e., a measure of general, physical, mental, and social health). Univariate and logistic regression analyses examined potential demographic, medical, and psychosocial factors (e.g., age, race, diagnosis, treatment) related to poor global health. Initial descriptive analyses suggested that most youth experienced anxiety symptoms (T-score M±SD=50.71±11.54), depressive symptoms (47.96±10.34), cognitive functioning (46.52±9.10), and fatigue (55.14±10.62) similar to their peers. However, 31.0% of youth experienced impaired global health (T-score<40). After adjusting for other potential covariates, the final model suggested that youth with significant anxiety (OR=6.20, CI=1.56–24.65), youth with significant fatigue (OR=3.96, CI=1.26–12.41), and youth who did not undergo a gross total resection (OR=0.25, CI=0.07–0.96) were at risk for impaired global health. Identifying those at-risk for impaired health is essential to reducing survivor morbidity and optimizing overall quality of life following treatment. Current data suggest potentially modifiable factors that may improve long-term outcomes for survivors of pediatric brain tumors.
QOL-36. USE OF CANNABINOIDS IN THE PEDIATRIC CENTRAL NERVOUS SYSTEM TUMOR POPULATION
Authors: Dorris Kathleen , Channell Jessica , Mettetal Ashley , Hemenway Molly , Briones Natalie , Tran Alexander , Griesinger Andrea , Donson Andrew , Vibhakar Rajeev , Green Adam , Nellan Anandani , Levy Jean Mulcahy , Ambruso Daniel , Foreman Nicholas
Published: December 2020

BACKGROUND

Cannabinoids, including cannabidiol (CBD) and tetrahydrocannabinol (THC), are a class of compounds found in marijuana. Numerous studies in adults have examined cannabinoid use in management of cancer-related symptoms such as nausea, anorexia, and pain. Less is known about the use in the pediatric oncology population.

METHODS

A prospective observational study has been ongoing since 2016 at Children’s Hospital Colorado to evaluate cannabinoids’ impact using PedsQL™ modules on quality of life of pediatric patients with central nervous system (CNS) tumors who are 2–18 years old. Laboratory assessments of T-cell activity and pharmacokinetics of CBD, THC and associated metabolites are in process. Diaries with exploratory information on cannabinoid use patterns are being collected.

RESULTS

Thirty-three patients (14:19; male:female) have been enrolled with a median age of 6.4 years (range, 2.9–17.7 years). The most common tumor type in enrolled patients is embryonal tumors (13/33; 39%). Nine (27%) patients have low-grade glial/glioneuronal tumors, and eight (24%) had high-grade/diffuse midline gliomas. The remaining patients had ependymoma or craniopharyngioma. The median time on cannabinoids is 9 months. Most (n=20) patients have used oral products with CBD and THC. One patient continues on cannabinoid therapy in follow up. Preliminary immune function analyses identified impaired neutrophil superoxide anion production and chemotaxis in patients taking cannabinoids at early time points on therapy.

CONCLUSIONS

Families of children with various CNS tumors are pursuing cannabinoid therapy for both antitumor and supportive care purposes. Analysis of the impact of cannabinoids on patients’ quality of life is ongoing.
QOL-37. USE OF COMPUTERIZED NEUROPSYCHOLOGICAL MEASURES TO ASSESS COGNITIVE MORBIDITY IN CHILDREN UNDERGOING ACTIVE RADIATION THERAPY
Authors: Kais Lorri , Roesser Kellie , Kleman Michelle , Wilkening Greta , Liu Arthur , Hankinson Todd , Foreman Nicholas , Hutaff-Lee Christa
Published: December 2020

Cognitive late effects of brain tumors and related treatments are well-established; however, limited information regarding changes in cognition during radiation therapy (RT) is available. Recent advances in computerized neuropsychological assessments for monitoring of acute and late treatment effects have been developed, though the feasibility of using these tools in a population undergoing active RT has limited empirical evidence. This study investigated performance of pediatric patients with brain tumors actively undergoing RT on the NIH Toolbox (N = 10; M age = 11.29 ± 3.35 years; 86% Caucasian; 86% female). Given significant individual variability, one-sample proportion tests were calculated to assess whether the proportion of patients with performances >1 standard deviation below the mean significantly differed from normative expectations. Of the 12 participants that were enrolled in the study, 10 completed the NIH Toolbox during active RT. Compared to normative expectations, a greater proportion of participants undergoing active RT exhibited deficits on measures of processing speed, working memory, and response inhibition (p=<.01). Differences between participants and normative expectations were not seen on measures of visual memory and vocabulary (p=>.05). Seventy-seven percent of recruited participants completed computerized assessment during active RT, suggesting reasonable feasibility within the small cohort recruited. Consistent with the literature regarding late effects of RT, performance on computerized measures of cognitive functioning mediated by processing speed and aspects of executive functioning were lower for patients undergoing active RT. Further investigation will focus on clarifying the trajectory of deficits across treatment course and comparing computerized measures to traditional neuropsychological measures.
QOL-40. THE IMPACT OF TASK COMPLEXITY ON INFORMATION PROCESSING SPEED AND NEURAL COMMUNICATION IN PAEDIATRIC BRAIN TUMOUR SURVIVORS
Authors: Cox Elizabeth , Atton Juanita , Tseng Julie , Bells Sonya , de Medeiros Cynthia , Laughlin Suzanne , Bouffet Eric , Mabbott Donald J
Published: December 2020

Paediatric brain tumour survivors (PBTS) experience slower information processing speed (IPS) that contributes to difficulty performing tasks of minimal (MC) and greater complexity (GC), and is related to aberrant neural communication. It is still unknown whether deficient IPS exists during increasing complexity. We aim to determine if PBTS experience deficient IPS and neural communication relative to typically developing children (TDC) during an increasingly complex visual-motor reaction time (RT) task. During magnetoencephalography recording, participants (n=58, 12.69 ±3.24 years) pressed a button with their left or right thumb after an arrow pointing in the corresponding direction appeared on a screen. During two MC conditions, the arrow pointed in a single direction. During a GC condition, the arrow alternated direction randomly. Mean RT >3SD and signal artifacts were removed prior to analyses. The phase lag index (PLI) estimated neural communication between 90 cortical sources. Linear regression and Network Based Statistics assessed group differences in mean RT and the PLI. PBTS demonstrated increased RT relative to TDC during the GC condition (p=0.04, MPBTS=354.00s, MTDC=326.00s). Group differences in mean RT during MC conditions and the PLI during all conditions were not detected (p>0.05). These results suggest PBTS experience slower IPS during GC. Reduced IPS is thought to contribute to difficulty recruiting cognitive resources needed to perform more complex tasks. Subtle deficits in neural communication may underlie slower IPS. The weighted PLI is superior to the PLI when estimating small differences in neural communication. We will now use the weighted PLI to assess task-related neural communication.
QOL-44. ASSESSMENT OF NEUROCOGNITIVE FUNCTION AND MRI PARAMETERS IN LONG-TERM SURVIVORS WITH POSTERIOR FOSSA TUMORS: A COMPARISON BETWEEN MEDULLOBLASTOMAS TREATED BY REDUCED-DOSE CRANIOSPINAL IRRADIATION AND OTHER TUMORS
Authors: Kagawa Naoki , Miyamura Takako , Hirayama Ryuichi , Yokota Chisato , Nakagawa Tomoyoshi , Kijima Noriyuki , Kinoshita Manabu , Hashii Yoshiko , Okada Keiko , Hara Jyunichi , Kishima Haruhiko
Published: December 2020

BACKGROUND

Children with medulloblastoma cannot avoid chemoradiotherapy including craniospinal radiation, although prognosis of medulloblastoma has improved and previous studies have reported a significant risk of intellectual disturbance by these treatments. We retrospectively analysed neurocognitive functions, clinical MRI parameters of patients with posterior fossa tumors, especially medulloblastomas.

MATERIALS AND METHODS

Twenty-two patients (12 medulloblastomas, 5 ependymomas, 5 astrocytomas) treated in our institution were enrolled in this study. Mean age was 7.8 years and 6.5 years, percentage of hydrocephalus at onset was 66.7% and 60%, respectively in medulloblastoma group and in other tumor group (ependymoma and astrocytoma). Postoperative chemoradiotherapy including reduced-dose craniospinal irradiation (18Gy) was done for medulloblastoma group and local radiation or operation only was done for other group. Version 3 or 4 of Wechsler Intelligent Scale for Children (WISC) was used by neurocognitive function analysis. Ventricular size, white matter volume and other parameters were also was estimated based on MRI. Follow-up duration was 6–17 years (mean: 10.5 years).

RESULTS

Evaluations of neurocognitive functions based on WISC pointed out lower performance IQ than verbal IQ in long term survivor of both group, especially working memory (P=0.05). Both hydrocephalus and cranial nerve complications was influenced lower scores of WISC, but age at onset did not influence WISC scores. Comparison between both group showed there was no significant difference about cognitive function and white matter volume.
QOL-54. HEIGHT, WEIGHT AND CARDIOVASCULAR EFFECTS OF STIMULANTS ON CHILDREN WITH BRAIN TUMOR
Authors: Khan Raja , Bano Maha , Mirman Igal , Wang Fang , Haitao Pan , Smith Jessica , Andrea Simmons , Greene William , Christensen Anthony , Sadighi Zsila
Published: December 2020

INTRODUCTION

Children with brain tumors may develop inattention, slow processing, and hypersomnia. Stimulant medications improve these problems but their effect on growth, heart rate, and blood pressure are inadequately explored.

METHODS

We retrospectively studied children with brain tumors treated at our institution that had data available for one-year pre and two year post stimulant treatment. Tumor location, gender, radiation treatment (RT), age at RT, drug type, and hormone therapy were variables of interest.

RESULTS

We identified 65 children (35 males) that fulfilled eligibility criteria. Focal RT was utilized in 58; 11 additionally received whole brain RT. Thirty were treated for hypersomnia and inattention, 8 for hypersomnia alone, and rest for inattention. Modafinil was the first drug in 18 (27.7%) and methylphenidate in the others. Forty-seven (72.3%), 40 (61.5%) and 49 (75.4%) were on thyroxine, cortisone and growth hormone respectively. There was no difference in pre and post stimulant BMI, heart rate, and blood pressure. There was also no difference between modafinil and methylphenidate groups. Rate of increase in height slowed on stimulants (p=0.0096). Thyroxine treatment correlated with increase in BMI after stimulants (p=0.0434). Younger age (p=0.0003) and higher BMI (p=0.0063) pre stimulants correlated with increased heart rate on stimulants, while higher age at RT (0.0159) correlated with elevated systolic BP on stimulants. No association of studied variables was found with height and diastolic BP.

CONCLUSION

Stimulants are well tolerated by children with brain tumors that are appropriately managed for endocrine deficiencies but may reduce the trajectory of height attainment.
RARE-01. MANAGEMENT AND OUTCOMES OF PAEDIATRIC CRANIOPHARYNGIOMA: A 15-YEAR EXPERIENCE IN SINGAPORE
Authors: Lim Mervyn Jun Rui , Liu Sherry Jiani , Ho Cindy Wei Li , Teo Kejia , Lwin Sein , Chou Ning , Yeo Tseng Tsai , Kimpo Miriam , Nga Vincent Diong Weng
Published: December 2020

BACKGROUND

Craniopharyngiomas are rare embryonic malformations of the sellar region with high survival rates but high morbidity due to long-term sequelae caused by the location of the tumour. We summarise our institution’s experience on the management and outcomes of paediatric craniopharyngiomas in Singapore.

METHODS

This was a retrospective review of all paediatric patients (18 years and below) with histologically diagnosed craniopharyngioma managed by the National University Hospital, Singapore from January 2002 to June 2017. Data on clinical presentation, imaging, treatments, and outcomes were extracted from the electronic medical records using a standardized data collection form. Data analysis was conducted using RStudio (Version 1.2.5033). Institutional ethics approval was obtained for the study.

RESULTS

We identified 12 cases of paediatric craniopharyngiomas. The majority of cases were male (8, 66.7%) and the median age at presentation was 6.0 (IQR 3.8 – 9.5). Initial surgical management was tumour excision (11, 91.7%) or insertion of a reservoir into the cyst cavity (1, 8.3%). All cases had diabetes insipidus, 10 (83.3%) had endocrine dysfunction, and 8 (66.7%) had visual impairment on long term follow up. 7 (58.3%) cases had recurrence, and 3 (25.0%) had demised. Cox-regression showed that females (HR=33.9, p=0.049), and Chinese race (HR=13.3, p=0.034) were at higher risk for recurrence, but age at diagnosis and residual tumor on post-operative MRI was not significant.

CONCLUSION

The management of craniopharyngioma is complex as it is complicated by high recurrence rates and significant long-term morbidity. Further research on treatment strategies focusing on maintaining quality of life is important.
RARE-07. THE LANDSCAPE OF GENOMIC ALTERATIONS IN ADAMANTINOMATOUS CRANIOPHARYNGIOMAS
Authors: Khadka Prasidda , Prince Eric , Lu Sophie , Santagata Sandro , Ligon Keith , Manley Peter , Beroukhim Rameen , Hankinson Todd , Bandopadhayay Pratiti
Published: December 2020

INTRODUCTION

Adamantinomatous craniopharyngiomas (ACPs) are characterized by activating mutations in the CTNNB1 gene. Here we perform a comprehensive genomic analysis of 23 ACPs to define the landscape of genomic alterations in this disease.

METHODS

We performed whole-genome sequencing of 24 ACPs and their matched normal tissues. We used Mutect 2.0 to detect mutations and indels in these samples and MutSig2CV to identify significant mutations. Copy numbers were called using the GATK4 pipeline and GISTIC 2.0 was applied to identify significant alterations. Finally, SvABA was applied to identify genome-wide structural variants and rearrangements.

RESULTS

18/24 (75%) of the sequenced ACPs harbored activating mutations in exon 3 of CTNNB1 gene with an average variant allele fraction (VAF) of 0.4±0.1. These mutations have previously been shown to activate the WNT signaling pathway in these tumors. No other significantly recurrent mutations were detected in our samples. The ACPs were quiet with regard to copy number alterations and no recurrent amplifications or deletions were detected. 528 structural variations and rearrangements were detected in total in all 24 samples with an average of 22 variants per sample. Gene-Set Enrichment Analysis (GSEA) of the RNAseq data revealed upregulation of WNT/B-catenin (FDR q-value <0.25) in the CTNNB1 mutant samples compared to CTNNB1 WT samples.

CONCLUSION

Our study identified previously described activating CTNNB1 mutations in the majority of ACPs. In addition, we identified several rearrangements and structural variations in these tumors that could play an important role in the pathogenesis of the disease.
RARE-08. CYST FLUID CYTOKINES MAY PROMOTE EPITHELIAL-TO-MESENCHYMAL TRANSITION IN PEDIATRIC ADAMANTINOMATOUS CRANIOPHARYNGIOMA
Authors: Vijmasi Trinka , Prince Eric , Hengartner Astrid , Agwu Chibueze , Staulcup Susan , Pavlova Maryna , Griesinger Andrea , Donson Andrew , Dorris Kathleen , Handler Michael , Hankinson Todd
Published: December 2020

BACKGROUND

Despite poor clinical outcomes, no targeted therapies have been established for the treatment of Adamantinomatous Craniopharyngioma (ACP). The only known genetic aberration is a mutation in CTNNB1 that results in the nuclear accumulation of beta-catenin. Nuclear beta-catenin is an established inducer of Epithelial-to-Mesenchymal Transition (EMT). ACP cyst fluid is enriched with pro-inflammatory and SASP cytokines, many of which are also directly implicated in EMT. We sought to investigate the role of EMT in ACP pathology.

METHODS

Normal human epithelial cells were cultured and treated with ACP cyst fluid (10%) for 1, 2, 4 and 8 days. Cell morphology was monitored by live cell brightfield microscopy. The expression of EMT associated genes, ZEB1, ZEB2, SNAI-1, SLUG, TWIST, E-Cadherin, Beta-Catenin and Vimentin was determined by RT-qPCR.

RESULTS

ACP cyst fluid treated epithelial cells were markedly transformed into long, spindle-shaped cells. ACP cyst fluid treatment resulted in the progressive up-regulation of ZEB2 over 8 days (RQ=12.0; P<0.01), the progressive up-regulation of SNAI-1 over 4 days (RQ=5.1; P<0.05) and up-regulation of Vimentin (RQ=2.2; p<0.01), identified only on Day 8.

CONCLUSION

ACP cyst fluid can induce EMT-like changes in normal human epithelial cells. In conjunction with the frequency of beta-catenin mutation in ACP, it is possible that EMT plays a crucial role in the pathology of ACP. Understanding ACP pathology in the context of the EMT paradigm may aid the development of new targeted therapeutics.
RARE-14. DEVELOPMENT OF ANAPLASTIC ASTROCYTOMA AS A THIRD MALIGNANCY IN A PEDIATRIC PATIENT WITH CONSTITUTIONAL MISMATCH REPAIR DEFICIENCY (CMMRD): A CASE REPORT AND EVALUATION OF TUMOR GENOMICS IDENTIFYING BIALLELIC MSH6 MUTATIONS
Authors: Wright Erin , Judd Alexis , Stanke Jennifer , Rush Sarah , Pettee Daniel
Published: December 2020

Congenital mismatch repair deficiency (CMMRD) is a pediatric cancer predisposition syndrome secondary to biallelic mutations in mismatch repair genes including MLH1, MSH2, MSH6, and PMS2. Due to the resulting lack of repair mechanisms, these patients develop a high intracellular mutational burden and have a high risk of development of multiple malignancies at a young age. Similar to patients with Lynch Syndrome (monoallelic mutations in MMR genes), these patients are at risk for development of central nervous system (CNS) tumors including high grade gliomas. Forty-eight percent of patients with CMMRD are diagnosed with a CNS malignancy. In this interesting case, a patient developed three metachronous malignancies prior to the age of 13, including Burkitt lymphoma, T-Cell lymphoma and anaplastic astrocytoma. Genomic analysis revealed a high mutational burden in his initial tumors, with multiple oncogenic mutations, as well as a previously unreported germline compound heterozygous MSH6 E744fs*12 and R248fs*8 alteration. He received a gross total resection of the tumor which in previous studies has been shown to have the highest impact on survival. Surgery was followed by radiation and ongoing treatment with an immune checkpoint inhibitor with stable disease at 6 months. The purpose of this case report is to describe the interesting presentation of CMMRD and discuss the previously unreported biallelic MSH6 mutations.
RARE-16. SEVEN CASES OF RETINOBLASTOMA WITH CNS INVOLVEMENTS
Authors: Kiyotani Chikako , Sugawa Masahiro , Matsukawa Yukihiro , Gocho Yoshihiro , Sakamoto Kenichi , Azuma Noriyuki , Yoshioka Takako , Tsutsumi Yoshiyuki , Fuji Hiroshi , Usami Kenichi , Ogiwara Hideki , Terashima Keita , Matsumoto Kimikazu
Published: December 2020

Treatment strategy for trilateral retinoblastoma (TRb: very rare RB with brain tumor) or retinoblastoma with central nervous system (CNS) involvement is not established yet. We retrospectively reviewed our seven cases of these rare almost fatal tumors. Their ages at diagnosis are 0y3m-1y10m (median 1y3m) (Male 4, Female 3). Only one had RB family history. Their affected eyes were bilateral 3, unilateral 3 and no 1. Their CNS involvements were suprasellar tumor 4, pineal tumor 1 and cerebrospinal fluid (CSF) cytology positive 2. Three of the suprasellar tumor patients had spinal metastasis. Four of the seven patients were TRb and one were genetically classified suprasellar retinoblastoma. All of them were treated with chemotherapy and four received high-dose chemotherapy. Three brain tumors of four TRb almost disappeared with chemotherapy. Two of them also received radiotherapy but relapsed. Although one radiation-free long-term TRb survivor developed secondary osteosarcoma, he got remission again and live 5 more years. One CSF positive Rb patient with chiasm invasion died of disease 11 months later. The other patient had no chiasm invasion nor CSF involvement at diagnosis, but his CSF cytology turned to positive after his second cycle of chemotherapy. He got remission with radiotherapy and high-dose chemotherapy, and alive without disease for 4 years. 2-year RFS and 2-year OS of all patients were 40% and 60%. Although our TRb patients responded to chemotherapy, it was difficult to avoid radiotherapy except one. Data accumulation is necessary for better treatment of these cancer-predisposed patients.
RARE-18. GENETIC EVALUATION IN PATIENTS WITH CHOROID PLEXUS TUMORS
Authors: Oliveira Milena , Silva Nasjla , Cappellano Andrea , Almeida Daniela , Cavalheiro Sergio , Dastoli Patrícia , Silva Frederico , Lima Fernanda
Published: December 2020

INTRODUCTION

Choroid plexus tumors (CPT) are rare intraventricular neoplasms of epithelial origin. They usually occur in the 2nd year of life, corresponding to 0.4–0.6% of intracranial tumors in this age group. They are sub classified, according to WHO 2016, in choroid plexus carcinoma (CPC), atypical choroid plexus papilloma (ACPP) and choroid plexus papilloma (CPP). Li-Fraumeni syndrome (LFS) is present in 50% of patients with CPC. In Brazil, the TP53 p.R337H mutation affects 0.3% of the population in the South/Southeast.

OBJECTIVE

Evaluate the incidence of genetic mutations in patients with choroid plexus tumors and therefore the importance of genetic evaluation.

PATIENTS AND METHODS

Between 1992–2019, 38 patients were diagnosed with CPT in our institution, 23 with CPC. From 2012, 21 patients were referred for genetic evaluation, 16 of which had CPC (2 had previously CPP). Positive family history for neoplasms was present in 87.5%; 37.5% compatible with LFS, 50% of them with mutations. All the patients with positive, but unspecific, family history of neoplasms, had pathogenic mutation. The molecular investigation of the TP53 gene in patients with CPC was performed and positive in 56.2%: R337H (5 patients), R110C, R158H, H179R, R196* (1 patient each). Of those with R337H, p53 protein immunohistochemistry resulted in 90–100% positivity. One of the patients with CPP that evolved to CCP had the H179R mutation. Clinical course was similar among them, and with those without mutations.

CONCLUSION

These results confirm the need for genetic evaluation in patients with choroid plexus tumors for adequate therapeutic management and long-term follow-up.
RARE-21. CANCER SPECTRUM IN GERMLINE SUFU MUTATION CARRIERS: A COLLABORATIVE PROJECT OF THE SIOPE HOST GENOME WORKING GROUP
Authors: Guerrini-Rousseau Léa , Waszak Sebastian , Bourdeaut Franck , Delattre Olivier , Dikow Nicola , Dufour Christelle , Gajjar Amar , Grill Jacques , Hirsch Steffen , Hopman Saskia , Jones David , Jongmans Majoline , Korshunov Andrey , Kratz Christian , Lafay-Cousin Lucie , Masliah Julien , Milde Till , Northcott Paul , Pajtler Kristian , Pfister Stefan , Puget Stéphanie , Collonge Marie Agnès Rame , Robinson Giles , Sariban Eric , Sevenet Nicolas , Smith Miriam , Sturm Dominik , Zattara Hélène , Varlet Pascale , Evans Gareth , Brugières Laurence
Published: December 2020

BACKGROUND

Little is known about cancer risk associated with pathogenic germline SUFU variants.

METHODS

Data of all previously published and 25 still unpublished patients with a pathogenic germline SUFU mutation were compiled.

RESULTS

124 patients in 67 families were identified, most of them ascertained after the occurrence of a medulloblastoma (MB) or as part of Gorlin syndrome cohorts. Overall, 30 patients were healthy carriers and 94 patients developed a total of 129 tumors (up to 4 tumors/patient): 68 MBs, always as first tumor (median age at diagnosis: 1.5yr [0.1–5]), 22 patients with at least 1 basal cell carcinoma (BCC) (median 10/patient) (median age at first BCC: 43yr, [17–52]), 15 meningiomas (median age 43yr, [13–72]), 7 ovarian stromal/fibrous tumors (median age 12yr [5–34]), and 17 other tumors including 5 sarcomas (median age: 50yr [7–79]). Median age at last follow-up was 30yr. Nineteen patients died, including 11 from MB. Second malignancies were diagnosed in 21 patients including 13 in MB survivors. Mutations were inherited in 58/66 (88%) of cases in which inheritance could be tested and de novo in 8. In 6/67 families (9%), >2 children were diagnosed with a MB.

CONCLUSION

In this large cohort of germline SUFU mutation carriers, MB in infants is the most frequent tumor but the spectrum also includes typical Gorlin syndrome tumors (BCC, meningiomas, and ovarian stromal/fibrous tumors) either as first tumors or as second malignancies. This broad tumor spectrum and the high risk of second malignancies justify the implementation of specific cancer surveillance programs.
RARE-22. GERMLINE PATHOGENIC VARIANT c.1552G>A;p.E518K IN DGCR8 CONFERS SUSCEPTIBILITY FOR SCHWANNOMATOSIS AND THYROID TUMORS
Authors: Chong Anne-Sophie , Nadaf Javad , Grau Elia , Apellaniz-Ruiz Maria , Fahiminiya Somayyeh , Saskin Avi , Han HyeRim , Turcotte Robert , Muchantef Karl , Thomas Christian , Wagener Rabea , Bassenden Angelia , Mete Ozgur , Pusztaszeri Marc , Paulus Werner , Berghuis Albert , Siebert Reiner , Albrecht Steffen , Hasselblatt Martin , Lazaro Conxi , Teule Alexander , Fabian Marc , Brunet Joan , Foulkes William , Rivera Barbara
Published: December 2020

Germline mutations in DICER1 cause a pleiotropic susceptibility syndrome characterized by the development of pediatric or early-onset tumors including pleuropulmonary blastoma, Wilms tumors, pineoblastomas, multinodular goiter (MNG) and thyroid cancers. Somatic mutations in the other two microprocessors DROSHA and DGCR8 have been found in Wilms Tumors and pineoblastomas. We present here two families with peripheral schwannomatosis and thyroid tumors carrying a germline variant c.1552G>A;p.E518K in DGCR8. Family one had six affected members with early-onset MNG and five of them developed schwannomatosis. All five members were heterozygous for the variant. One of the carriers had also been diagnosed with a choroid plexus papilloma at 7 years old. The common second event in all tumors tested was the loss of chromosome 22 at the somatic level. In family two, a 35-year-old male was diagnosed with a peripheral schwannoma at the age of 12. Since then, he has developed seven extra peripheral schwannomas (one of which was an ancient schwannoma) and papillary thyroid cancer. DGCR8 lies on chromosome 22q, adjacent to the three schwannoma genes: LZTR1, SMARCB1 and NF2. The variant, c.1552G>A;p.E518K localizes to the first RNA-binding domain of DGCR8 and structural modelling predicts that it abolishes proper binding of RNA. It is also a hotspot somatic mutation in Wilms tumors. Using miRNA profiling, we show that this variant disrupts global microRNA production and DGCR8 mutated tumors show a specific miRNA profile different from DGCR8 wild type tumors. These findings reinforce DGCR8 as a novel susceptibility gene for schwannomatosis and thyroid tumors.
RARE-23. NOVEL NF1 MUTATIONS IN TWO OCCURRENCES OF GLIOBLASTOMA MULTIFORM IN A PATIENT WITH CONSTITUTIONAL MISMATCH REPAIR DEFICIENCY SYNDROME
Authors: Utley Kaylyn , Reuter Jens , Li Lei , Evans Devon , Florman Jeffrey , Chaleff Stanley
Published: December 2020

Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare cancer predisposition syndrome in children. Its main associated tumor types include brain and CNS tumors, hematologic malignancies, intestinal polyps and colorectal tumors, and other malignancies. Tumor genesis within this population is highly complex and poorly understood. We describe a case of a patient with two occurrences of glioblastoma multiforme (GBM), each with unique NF1 mutations. The patient is a female with CMMRD who was first diagnosed with GBM of the right frontal lobe in 2015. She subsequently underwent gross total resection, radiation to the field and concomitant and maintenance therapy with Temozolomide and Everolimus, due to high suspicion for NF-1. Genetic studies didn’t show NF-1, instead revealing a diagnosis of CMMRD. Molecular testing of the GBM showed a high mutational burden and an NF1 mutation. Later, screening revealed stage IV colon cancer, for which she underwent subtotal colectomy, partial liver resection and chemotherapy. Molecular testing from the colon cancer found a hypermutant malignancy without mutations in NF1. Surveillance imaging detected a mass at the original site of her GBM, for which she had a resection. Notably, the genetic profile of the second tumor substantially different from the original tumor and the colon cancer sample, but had new mutations in NF-1. These findings highlight the significant variability in the genetic profiles of tumors in the context of CMMRD. It is also worth considering that NF1 is one of the first in a cascade of mutations leading to GBM in these patients.
RARE-24. LARGE CONGENITAL MELANOCYTIC NEVI AND NEUROCUTANEOUS MELANOCYTOSIS: A RETROSPECTIVE CASE SERIES
Authors: Sener Ugur , Ennin Elsie , Suser Stephanie , Marghoob Ashfaq , Haque Sofia , Khakoo Yasmin
Published: December 2020

Neurocutaneous melanocytosis (NCM) is a rare disease characterized by excessive proliferation and deposition of melanocytes in the leptomeninges and brain parenchyma, occurring in children with large congenital melanocytic nevi (LCMN). Manifestations of NCM range from asymptomatic CNS melanin deposition to cranial neuropathies, seizures, and hydrocephalus. Patients with NCM are at risk for malignant melanoma. We conducted a retrospective, single-institution study of patients with LCMN evaluated at Memorial Sloan Kettering Cancer Center from June 2000 to January 2020. Of 55 patients studied, 15 had no radiographic NCM, and 40 had radiographic NCM at initial evaluation. MRI findings included: focal melanocytosis (33), diffuse leptomeningeal disease (4), solid melanoma (3). Malformations were identified in 13, including arachnoid cyst (4), congenital hydrocephalus (4), Dandy-Walker malformation (3), and tethered cord (1). Twenty-one patients completed imaging once and were followed clinically. Seventeen with serial imaging (10 with focal melanocytosis, 7 with normal MRI) remained stable over a median 24-month follow up (range: 1–124). Six had suspected radiographic progression of NCM without melanoma. Malignant melanoma developed in 11 patients, 5 with focal melanocytosis on initial imaging. Median time from focal melanocytosis identification to melanoma diagnosis was 80 months (range: 18–200). Median age at melanoma diagnosis was 9.9 years (range: 1.1–25.3). Median survival from melanoma diagnosis was 9.1 months (range: 1–60.4). Focal NCM on neuroaxis imaging does not predict time to transformation to malignant melanoma. Serial imaging is not indicated in absence of disease-modifying treatment. Clinical follow up of at-risk individuals is essential in early identification of complications.
RARE-29. PRIMARY CENTRAL NERVOUS SYSTEM NON-HODGKIN LYMPHOMA IN AN 11-YEAR-OLD BOY: A CASE REPORT
Authors: Ramírez-Melo Jorge Luis , del Campo Regina M Navarro-Martin , Martinez-Albarran Manuel D , Sánchez-Zubieta Fernando , Orozco-Alvarado Ana L , Arredondo-Navarro Luis A , Gutierrez-Oliva Lorelai
Published: December 2020

BACKGROUND

Primary central nervous system lymphoma (PCNSL) are very rare in children. CLINICAL CASE: An 11-year-old male presented with a 2 months history with myoclonic movements in the upper right limb, and a sudden frontal headache, gait disturbance due to right hemiparesis and an ipsilateral convulsive episode. Upon admission he had critical condition, with hypertensive skull syndrome, Glasgow of 12, Karnofsky 40%, right hemiparesis, swallowing disorder, facial paralysis, and loss of photo motor reflex and unilateral amaurosis. A CT and MRI showed a huge tumor mass in the left tempo-parietal region, infiltrating the white matter and shifting the midline. A Tumor biopsy was done, and reported diffuse small cell non-Hodgkin lymphoma of high-grade, Burkitt type. Systemic lymphoma workup was negative. He received six cycles of chemotherapy based on high dose methotrexate, rituximab and triple intrathecal.After the second cycle an ophthalmologic evaluation was done, and found infiltration to the right retina, for which 6 cycles of intra vitreous chemotherapy with methotrexate were applied, he showed an excellent response, and recovered all his neurological functions except that right hemianopia persist. Control MRI showed partial response at 2nd cycle and complete response after the 4th cycle. No Radiation was performed.

CONCLUSION

This report highlights the fact that pediatric PCNSL may be effectively treated by a combination of HDMTX and rituximab-based chemoimmunotherapy without irradiation. Lack of awareness of this rare entity may lead to extense resections of brain, and potential permanent secuelae that were avoided in this illustrative case.
RARE-31. RECURRENT CHOROID PLEXUS CARCINOMA IN THE SETTING OF LI-FRAUMENI SYNDROME: REPORT OF TWO CHILDREN MANAGED WITH INTENSIVE RE-INDUCTION AND MARROW-ABLATIVE CONSOLIDATION CHEMOTHERAPY WITHOUT IRRADIATION FOLLOWED BY MOLECULARLY-TARGETED BIOLOGICAL THERAPY
Authors: Shatara Margaret , Filipek Iwona , Ciołkowski Maciej , Kowalczyk Paweł , Osorio Diana S , AbdelBaki Mohamed S , Varga Elizabeth A , Abu-Arja Rolla , Heinerich Claire , Boué Daniel R , Pierson Christopher R , Jones Jeremy , Cottrell Catherine E , Mardis Elaine R , Wilson Richard K , Leonard Jeffrey R , Finlay Jonathan L
Published: December 2020

BACKGROUND

The optimal management for children with recurrent choroid plexus carcinoma (CPC), is not established. We report two children with germline TP53 mutations, whose CPC relapses were managed with marrow-ablative chemotherapy and oral biologically-targeted therapies. PATIENTS: Patient A: A 17 months old male presented with non-metastatic bilateral CPC. A de novo mosaic germline TP53 mutation was identified. After near-total resections, 16 months of standard chemotherapy were administered; 18 months later, localized tumor growth developed, again near-totally resected. Two cycles of re-induction chemotherapy were administered followed by three cycles of thiotepa/carboplatin with autologous hematopoietic cell rescue (AuHCR) and subsequently 21 months of sirolimus and thalidomide, continuing without residual or recurrent disease. Patient B: A 30 months old male presented with left lateral ventricular non-metastatic CPC. A de novo TP53 germline mutation was identified. Following sub-total resection, craniospinal irradiation with boost was administered followed by eight cycles of standard chemotherapy; 18 months later, localized recurrence developed; gross total resection was followed by 15 months of standard dose chemotherapies; four months thereafter, a second local recurrence developed, again gross totally resected. He then received one cycle of high-dose cyclophosphamide followed by three cycles of thiotepa/carboplatin with AuHCR. Subsequently he received sirolimus and thalidomide for 12 months, complicated by progressive pancytopenia. A small localized CPC recurrence was noted, gross totally resected, concomitant with myelodysplastic syndrome; he underwent an allogeneic matched unrelated donor marrow transplantation.

CONCLUSIONS

Marrow-ablative chemotherapy with post-transplant targeted biological therapy may afford durable survival for select children with recurrent CPC.
RARE-35. PINEOBLASTOMA IN CHILDREN SIX YEARS OF AGE OR LESS: FINAL REPORT OF THE HEAD START I, II AND III EXPERIENCE
Authors: AbdelBaki Mohamed S , Abu-Arja Mohammad H , Davidson Tom B , Fangusaro Jason R , Stanek Joseph R , Dunkel Ira J , Dhall Girish , Gardner Sharon L , Finlay Jonathan L
Published: December 2020

BACKGROUND

We report the outcomes of patients with pineoblastoma enrolled on the Head Start I-III trials.

METHODS

Twenty-three children were enrolled between 1991–2009. Treatment included maximal surgical resection followed by five cycles of intensive-chemotherapy and consolidation with marrow-ablative chemotherapy and autologous hematopoietic cell rescue (HDCx/AuHCR). Irradiation following consolidation was reserved for children over six years of age or those with residual tumor at the end of induction.

RESULTS

The median age was 3.12 years (range:0.44–5.72). Three patients withdrew from the protocols and two patients experienced chemotherapy-related mortality. Eight patients experienced progressive disease (PD) during induction chemotherapy. Ten patients received HDCx/AuHCR; eight experienced PD post-consolidation. Seven patients received craniospinal irradiation (CSI) with a median dose of 20.7 Gy (range:18–36 Gy) with boost(s) (median dose 27 Gy, range:18–36 Gy); three received CSI as adjuvant therapy (2 post-HDCx/AuHCR) and four upon progression/recurrence. The 5-year progression-free survival (PFS) and overall survival (OS) were 9.7% (95%,CI:2.6–36.0%) and 13% (95%,CI:4.5–37.5%), respectively. Three patients survived beyond five years. Nineteen patients relapsed in the following sites: local site (n=4), distal site (n=6), local and distal sites (n=9). Favorable OS prognostic factors were CSI (hazard ratio (HR)=0.30 (0.11–0.86), p=0.025), and HDCx/AuHCR (HR=0.40 (0.16–0.99), p=0.047).

CONCLUSION

CSI and HDCx/AuHCR were statistically associated with improved survival. The overall poor outcomes and high PD rate during later induction cycles and following consolidation chemotherapy warrants consideration of fewer induction cycles before consolidation and the intensification of consolidation with multiple cycles of marrow-ablative chemotherapy.
RARE-42. PRIMARY INTRACRANIAL SARCOMA WITH DICER1-MUTATION - TREATMENT RESULTS OF A NEW MOLECULAR ENTITY
Authors: Diaz Rosdali , Mynarek Martin , Casavilca Sandro , Aptomizer Antonio Wachtel , Mora Pamela , Koelsche Christian , Von Deimling Andreas , Schüller Ulrich , Sernaque Raymundo , Sarria Gustavo , Negreiros Tatiana , Ojeda Luis , Garcia-Corrochano Pamela , Campos Danny , Ponce Jimena , Rutkowski Stefan , Garcia Juan
Published: December 2020

OBJECTIVE

An unexpectedly high incidence of sarcomas of the Central Nervous System (SCNS) was recently observed in Peru. We describe clinical and biological characteristics of the disease.

METHODS

Seventy pediatric patients with primary SCNS diagnosed between January 2005 and June 2018 were analyzed. DNA methylation profiling and gene panel sequencing was available from 28 and 27 tumors, respectively.

RESULTS

Median age was 6 years (range 2–17.5), 66/70 patients had supratentorial tumors, 56 patients intratumoral hemorrhage at diagnosis. Three patients fulfilled clinical criteria of NF1; 35 had café-au-lait spots and/or freckling. DNA-methylation profiling classified 28/28 as “intracranial spindle cell sarcoma with rhabdomyosarcoma-like features and DICER1 mutations”. DICER1 mutations were found in 26/27, TP53 mutations in 22/27, and RAS-pathway gene mutations (NF1, KRAS, NRAS) in 19/27 tumors, all of which were somatic (germline control available in n=19 cases). Survival was analyzed in 57 patients with non-metastatic disease who received adjuvant therapy. Two patients had metastatic disease, eleven did not receive or abandoned treatment. Two-year OS was 66.3% (95%-CI: 54–81%), 2-year PFS 51% (38–67%). PFS was highest in patients treated with postoperative ICE chemotherapy followed by radiotherapy and ICE (2y-EFS 79% [59–100%], n=18) and worse after upfront radiotherapy followed by ICE (40% [19–85%]; n=10) or VAC (50% [28–88%], n=12) and radiotherapy only (21% [6–71%], n=11; p=0.008).

CONCLUSION

Primary SCNS with DICER1 mutation have an aggressive clinical course. A combination of chemotherapy and radiotherapy seems beneficial. A link to a cancer predisposition syndrome could not be established so far.
RARE-46. A THIRTEEN YEAR PATIENT JOURNEY OF INFANT GIANT CLIVAL CHORDOMA: CASE REPORT AND LITERATURE REVIEW
Authors: Apps John , Neumann Eloise , Afshari Fardad , Solanki Guirish , English Martin
Published: December 2020

In 2006 we reported the youngest case of a large clival chordoma, a 15-week old baby, the second case to present without skull base involvement and the fourth case of chordoma in a patient with tuberous sclerosis. This unusually rare case (surgically un-resect able) underwent endoscopic skull-base diagnostic biopsy and a novel chemotherapy regime that aimed to control his disease[i]. Initial tumour control was achieved with chemotherapy (Ifosfamide, doxorubicin with dexrazonane, intrathecal hydrocortisone, methotrexate, cytarabine). Carboplatin and etoposide were later given for a further year. Following this, Sirolimus and imatinib were used for another twelve months due to primary tumour regrowth and three new skull-vault lesions. Sirolimus alone was continued for an additional year, but stopped due to optic neuritis. Imatinib was given until further progression two years later, leading to a change to everolimus. Surgery for the ventral foramen magnum was performed a year later. The patient received further surgery and radiotherapy for tumour recurrence. Sadly the tumour metastasised and he succumbed at age 13. Chordomas are aggressive and recur frequently. Complete primary resection followed by radiotherapy/proton beam therapy offers the best chance of cure but is not an option in infants with giant lesions, as in our case. We inform on alternative targeted treatment strategies and review the literature on these rare lesions. [i] Kambogiorgas D, St George EJ, Chapman S, English M, Solanki G: Infantile Clivus chordoma without clivus involvement: Case report and review of the literature, Childs Nerv System (2006) 22:1369–1374