BIOM-42. IMMUNOHISTOCHEMICAL ASSESSMENT OF MEMBRANOUS SOMATOSTATIN TYPE 2A RECEPTOR (SST2A) EXPRESSION ACROSS HIGH-RISK PEDIATRIC CENTRAL NERVOUS SYSTEM (CNS) TUMORS

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi20-vi20
Author(s):  
Margot Lazow ◽  
Andrew Trout ◽  
Christine Fuller ◽  
Jaime Reuss ◽  
Brian Turpin ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Somatostatin Receptor ◽  
High Grade Glioma ◽  
Staining Intensity ◽  
Cns Tumors ◽  
Embryonal Tumors ◽  
Therapeutic Implications ◽  
Variable Expression ◽  
Cell Percentage ◽  
Pediatric Cns Tumors

Abstract INTRODUCTION 77Lu-DOTATATE, a radionuclide therapy which binds SST2A, has demonstrated efficacy in neuroendocrine tumors and evidence of CNS penetration, supporting potential expansion within pediatric neuro-oncology. Understanding the prevalence of SST2A expression across pediatric CNS tumors is essential to identify patients who may benefit from somatostatin receptor-targeted therapy and to further elucidate the oncogenic role of SST2A. METHODS SST2A immunohistochemistry (IHC) was performed on tumor specimens and interpreted by two experienced pathologists (blinded), utilizing semi-quantitative scoring of membranous expression within viable tumor. Immunoreactive cell percentage was visually scored as 0 (none), 1 (< 10%), 2 (10-50%), 3 (51-80%), or 4 (>80%). Staining intensity was scored as 0 (none), 1 (weak), 2 (moderate), or 3 (strong). Combined scores for each specimen were calculated by multiplying percent immunoreactivity and staining intensity values (range=0-12). RESULTS A total of 117 tumor samples from 113 patients were analyzed. Significant differences in SST2A IHC scores were observed across histopathologic diagnoses, with consistently high scores in medulloblastoma (mean±SD=7.6±3.6 [n=36]) and meningioma (5.7±3.4 [n=15]), compared to minimal or absent expression in ATRT (0.3±0.6 [n=3]), ETMR (1.0±0 [n=3]), ependymoma (grades I-III; 0.2±0.7 [n=26]), and high-grade glioma (grades III-IV; 0.4±0.7 [n=22]). Pineoblastoma (3.8±1.5 [n=4]) and other embryonal tumors (2.3±3.8 [n=8]) exhibited intermediate, variable expression. Among expressors, there was no association between SST2A IHC score and patient age, sex, presence of metastases, likelihood of relapse, or prior treatment. In a subset of paired primary and recurrent specimens from 3 patients, SST2A IHC scores remained largely unchanged. Among medulloblastomas, SST2A IHC scores were higher in non-SHH (8.6±3.2) than SHH (5.0±3.3) molecular subgroups (p=0.033). CONCLUSIONS High membranous SST2A expression was demonstrated in medulloblastoma, meningioma, and some rarer embryonal tumors with potential diagnostic, biologic, and therapeutic implications. Somatostatin receptor-targeted therapy such as 177Lu-DOTATATE deserves further investigation in these highly SST2A-expressing pediatric CNS tumors.

scholarly journals EXTH-16. TREATMENT OF THREE DIFFERENT BRAF-V600E POSITIVE BRAIN TUMORS WITH VEMURAFENIB AND DABRAFENIB/TRAMETINIB: A CASE SERIES

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii90-ii90
Author(s):  
Nikita Dhir ◽  
Sheila Chandrahas ◽  
Chibuzo O’Suoji ◽  
Mohamad Al-Rahawan
Keyword(s):  
Targeted Therapy ◽  
Brain Tumors ◽  
Tumor Regression ◽  
Case Series ◽  
Pediatric Brain Tumors ◽  
Braf V600e ◽  
Cns Tumors ◽  
Braf Inhibitors ◽  
Pediatric Brain ◽  
Pediatric Cns Tumors

Abstract BACKGROUND The BRAF-V600E gene is a protein kinase involved in regulation of the mitogen activated protein kinase pathway (MAPK/MEK) and downstream extracellular receptor kinase (ERK). The BRAF-V600E mutation has a significant role in the progression of pediatric brain tumors. 85% of pediatric CNS tumors express the BRAF mutation. Thus, BRAF targeted therapy in pediatric CNS malignancies has potential to become the standard of care for tumors expressing this mutation. OBJECTIVE Current pediatric CNS brain tumor treatment focuses on chemotherapy and radiation, causing significant toxic side effects for patients. The significance of this case series lies in relaying our experience using targeted therapy in BRAF-V600E positive CNS pediatric brain tumors. METHODS We followed the disease course, progression, and treatment of three pediatric patients with three different CNS tumors. Each of these individuals was treated with surgical resection, chemotherapy, and/or radiation as per standard protocol. When that modality failed to reduce tumor progression, we found that each of their different tumors was BRAF-V600E positive and they were all started on targeted therapy. DISCUSSION Vemurafenib, Dabrafenib, and Trametinib are BRAF-V600E/MEK inhibitors that were initially used to treat melanomas. However, more research has shown that various pediatric CNS tumors are BRAF-V600 positive. Therapy with these BRAF inhibitors has been shown to slow tumor progression, but toxicity can be severe. This case series shows one patient with successful tumor regression, one patient with prolonged disease stabilization, and one patient with initial response but subsequent progression and ultimate death. It has been shown that using BRAF inhibitors in lower grade CNS tumors are more effective than higher grade CNS tumors. CONCLUSION The success of Vemurafenib and Dabrafenib/Trametinib in causing pediatric CNS tumor regression is promising, but further studies are needed to solidify their role in pediatric CNS cancers.

scholarly journals EPID-13. A POPULATION-BASED ANALYSIS OF CNS TUMOR DIAGNOSES, TREATMENT, AND SURVIVAL IN CONGENITAL AND INFANT AGE GROUPS

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii321-iii321
Author(s):  
Muriel Hart ◽  
Amy Mellies ◽  
Alina Beltrami ◽  
Ahmed Gilani ◽  
Adam Green
Keyword(s):  
Age Groups ◽  
Young Patients ◽  
High Grade Glioma ◽  
Population Based ◽  
Cns Tumors ◽  
Low Grade ◽  
Tumor Type ◽  
Older Children ◽  
Embryonal Tumors ◽  
Chi Square

Abstract BACKGROUND Congenital (<3 months) and infant (3 to 11 months) brain tumors are biologically different from tumors in older children, but epidemiology of these tumors has not been studied comprehensively. Insight into epidemiological differences could help tailor treatment recommendations by age and increase overall survival (OS). METHODS Population-based data from the SEER 18 registries was obtained for 14,493 0-19-year-olds diagnosed with CNS tumors between 1990 and 2015. Incidence, treatment, and survival were analyzed using Chi-square and Kaplan-Meier analyses. RESULTS Between the <3 month, 3–5 month, 6–11 month, and 1–19 year age groups, tumor type distribution differed significantly (p<0.001); high-grade glioma (HGG) was most common in the <3-month-olds, while low-grade glioma (LGG) was most common in the other groups. 5-year OS for all tumors was 36.7% (<3 months), 56.0% (<3–5 months), 63.8% (6–11 months), and 74.7% (1–19 years) (log rank p<0.001). OS by tumor type was worst for <3-month-olds with LGG, medulloblastoma, and other embryonal tumors; OS was worst for 3-5-month-olds with ependymoma, <1-year-olds collectively with atypical teratoid-rhabdoid tumor, and 1-19-year-olds with HGG (log rank p<0.02 for all tumor types). <3-month-olds were least likely to receive any treatment for each tumor type and least likely to undergo surgery for all except HGG. <1-year-olds were far less likely than 1-19-year-olds to undergo radiation for embryonal tumors, as expected, but were also less likely to undergo chemotherapy. CONCLUSIONS Congenital/infant CNS tumors differ pathologically, therapeutically, and prognostically from those in older children. Treatment changes could help address poorer outcomes for these young patients.

scholarly journals EPID-06. DIAGNOSTIC INTERVAL TIME OF PEDIATRIC CNS TUMORS: A REPORT OF THE CANCER IN YOUNG PEOPLE IN CANADA (CYP-C) DATABASE

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii319-iii320
Author(s):  
Mohammad AlNajjar ◽  
Divya Goel ◽  
Valerie Larouche ◽  
Craig Erker ◽  
Sylvia Cheng ◽  
...  
Keyword(s):  
Cns Tumors ◽  
Medical Attention ◽  
Embryonal Tumors ◽  
Interval Time ◽  
Tertiary Center ◽  
Time To Diagnosis ◽  
Diagnostic Interval ◽  
Canadian Provinces ◽  
First Contact ◽  
Pediatric Cns Tumors

Abstract INTRODUCTION CNS tumors are the second most common neoplasm in children and have historically been associated with longer time to diagnosis. Data on the time-to-diagnosis for Canadian children with CNS tumors are limited and outdated. We aimed at evaluating the diagnostic interval time(DIT) for Canadian children, and identifying factors possibly associated with prolonged DIT. METHODS Using the CYP-C database, we analyzed data from children <15 years, diagnosed with CNS tumors between 2001–2015. DIT was defined as time in weeks, elapsed from the first contact with a healthcare provider to confirming diagnosis. We described DIT according to patient’s demographics, socioeconomic, geographic factors as well as tumor-related criteria. RESULTS Patients from all Canadian provinces, except Ontario, had available timepoints to calculate DIT. The cohort included 842 patients. Mean DIT for all patients was 11.7 weeks(median 1.4). Gliomas had the longest mean DIT and embryonal tumors had the shortest(14.6 and 3.6 weeks p<0.01). ATRT and medulloblastoma had a mean DIT of 1.3 and 4.3 weeks respectively. DIT for HGG was shorter than for LGG (6.4 versus 16.1 weeks, p<0.01). Metastatic disease, infratentorial tumors, or age £36 months had significantly shorter DIT (5.6 vs 12.4 vs 18.4, 7.4 vs 13.1 and 8.6). Sex, annual income(QAIPPE), and distance from tertiary center did not influence DIT. CONCLUSION The current diagnostic interval time for pediatric CNS tumors in Canada is 11.7 weeks(median 1.4weeks). These results only reflect the healthcare system’s contribution toward diagnosis confirmation, but not the patient interval before seeking medical attention.

Preirradiation chemotherapy with carboplatin and etoposide in newly diagnosed embryonal pediatric CNS tumors.

1995 ◽  
Vol 13 (9) ◽  
pp. 2247-2254 ◽  
Author(s):  
R L Heideman ◽  
E H Kovnar ◽  
S J Kellie ◽  
E C Douglass ◽  
A J Gajjar ◽  
...  
Keyword(s):  
Confidence Interval ◽  
Complete Response ◽  
Cns Tumors ◽  
Comparable Efficacy ◽  
Newly Diagnosed ◽  
Embryonal Tumors ◽  
Future Studies ◽  
Rate Of Progression ◽  
Drug Regimens ◽  
Pediatric Cns Tumors

PURPOSE We evaluated the clinical efficacy of preirradiation carboplatin (CARBO) and etoposide (VP-16) in 25 patients with newly diagnosed embryonal CNS tumors. PATIENTS AND METHODS Sixteen patients with high-risk medulloblastoma and nine with other embryonal tumors were treated with two daily doses of CARBO 350 mg/m2 and VP-16 100 mg/m2 (CARBO/VP) every 21 days for four cycles before standard craniospinal irradiation. Patients with disease progression (PD) before radiation therapy were additionally treated with intensive postirradiation cyclophosphamide (CYCLO) and vincristine (VINC). RESULTS Among 23 assessable patients, 48% (95% confidence interval, 27% to 69%) had a complete response (CR) or partial response (PR) to CARBO/VP; eight had PD. Among the subgroup of 15 assessable patients with medulloblastoma, 53% had a CR or PR (95% confidence interval, 27% to 79%) and five PD. The toxicity of CARBO/VP was predominantly hematologic; although grade IV neutropenia was common, only five episodes of febrile neutropenia occurred. Only thrombocytopenia was a more common toxicity than in other reported chemotherapy regimens; ototoxicity was less common than in cisplatin (CDDP) regimens. CONCLUSION The responses and survival associated with neoadjuvant CARBO/VP are similar to those with CDDP-containing and other neoadjuvant drug regimens. Although the rate of progression with this regimen may be higher than with similar CDDP-containing regimens, the numbers of patients in other published studies of these agents are too small to detect meaningful statistical differences. Future studies must balance the apparently comparable efficacy of CARBO and CDDP with their differing toxicities.

scholarly journals LGG-16. TO BE PRECISE - KNOW YOUR TARGETS: INSTITUTIONAL EXPERIENCE WITH TUMOR TARGETED THERAPY FOR RECURRENT/PROGRESSIVE PEDIATRIC LOW-GRADE GLIOMA AND PLEXIFORM NEUROFIBROMA

2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i35-i35
Author(s):  
Mackenzie Silverman ◽  
Joseph Piatt ◽  
Andrew Walter ◽  
Rahul Nikam ◽  
Gurcharanjeet Kaur
Keyword(s):  
Targeted Therapy ◽  
Targeted Therapies ◽  
Progressive Disease ◽  
Plexiform Neurofibroma ◽  
Cns Tumors ◽  
Low Grade ◽  
Therapy Initiation ◽  
Community Oncology ◽  
Institutional Experience ◽  
Pediatric Cns Tumors

Abstract Introduction The oncogenic drivers of pediatric CNS tumors are rapidly being identified with the implementation of high throughput genetic screening. Precision medicine approaches to treatment have shown promising results, but data remains limited in the community oncology setting. We aim to describe our institutional experience using targeted therapies for plexiform neurofibroma and recurrent/progressive pediatric low-grade glioma (pLGG). Methods We performed a retrospective chart review of all patients treated with tumor targeted therapies for recurrent/progressive pLGG and plexiform neurofibroma over the past 5 years. Results Ten patients treated with tumor targeted therapies were identified. Regimens included combination Dabrafenib and Trametinib (n=3), Trametinib monotherapy (n=2), Selumetinib (n=3), Vemurafenib (n=1), and Larotrectinib (n=1). Median age at therapy initiation was 11.5 years (range 1.1 - 18 years). Tumor molecular status included BRAFV600E mutation (n=4), NF1 mutation (n=2), KIAA1549-BRAF fusion (n=1), NACC-NTRK fusion (n=1), and FGFR1 mutation (n=1). Patients trialed an average of 2 treatment regimens prior to targeted therapy initiation (range 0–5). Mean duration of therapy was 14.5 months (range .5–33 months) with 8 patients remaining on treatment. Based on modified RANO criteria, responses included partial (n=1), stable disease (n=8), and progressive disease (n=1). Progressive disease was noted after 4 months of treatment with Dabrafenib and Trametinib combination therapy, but rate of tumor growth was decreased. Subjective functional improvement was seen in 50% of patients. The most common toxicities included rash (n=5) and pyrexia (n=2). Trametinib was discontinued in one patient due to intra-tumoral hemorrhage of unclear etiology. Conclusion Treatment of pediatric CNS tumors with targeted agents appears to be feasible and efficacious in the community oncology setting. Multi-institutional clinical trials are currently ongoing for each of these therapies. There remains a need for community oncology institutional data regarding their use.

scholarly journals PATH-31. THE IMPACT OF MOLECULAR PROFILING OF PEDIATRIC CNS TUMORS ON TUMOR DIAGNOSIS AND MANAGEMENT - A SINGLE CENTER EXPERIENCE

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii431-iii431
Author(s):  
Kazuhiro Sabet ◽  
Marike Zwienenberg ◽  
Mirna Lechpammer ◽  
Lee-Way Jin ◽  
David Solomon ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Clinical Diagnosis ◽  
Therapeutic Targets ◽  
Cns Tumors ◽  
Low Grade ◽  
Diagnosis And Management ◽  
Shh Pathway ◽  
Oncology Research ◽  
The Impact ◽  
Pediatric Cns Tumors

Abstract BACKGROUND Next generation sequencing (NGS) plays a role in neuro-oncology research and in clinical diagnosis and management. Here, we describe how NGS for pediatric CNS tumors impacted clinical diagnosis and therapy at a single institution. METHODS NGS was performed using the UCSF 500 Gene Panel (targeted sequencing platform covering about 500 cancer associated genes). Patients were selected for NGS based on tumor pathology /need to identify therapeutic targets. We collected data on patient demographics, tumor histology/pathway alterations/therapeutic targets/therapy and used descriptive statistics for data analysis. RESULTS Between January 2016 and July 2019, about one-third of patients with CNS tumors seen at our institution (N=29) were interrogated. NGS revealed pathway alterations in 20/29 patients. Treatment recommendations/modifications based on pathway alterations/therapeutic targets impacted the therapy of 18 patients. Patient groups: Medulloblastoma (N=6), alterations in WNT, SHH, and TP53 pathways (Vismodegib recommended for SHH pathway alteration but not used). High-grade glioma (N=4), alterations (with treatment changes) included, NF1(Trametinib, Everolimus); MSH2/MLH1(Nivolumab); CDKN2A/CDKN2B/CDKN2C(Abemaciclib); EGFR (Osimertinib, Afatinib); H3K27M (Panobinostat/ONC201); BRAFV600 (Dabrafenib, Trametinib); ATRT (N=1) SMARCB1; Low Grade Glioma (N=10), BRAFV600(Vemurafenib) /BRAFKIAA1549 fusion (Trametinib)/ PIK3CA; DIPG (N=5), H3K27M/BCOR/ P53/ACVR/PIK3CA (LY3023414, Everolimus)/PDGFR(Dasatinib); Ependymoma (N=3), PFA/PFB/RELA Fusion. Seven patients were treated with targeted therapy + conventional therapy. In 8 patients targeted therapy remains an option but not yet needed. CONCLUSIONS NGS of pediatric brain tumors is widely available and contributes to the diagnosis/therapy of pediatric CNS tumors. Optimal chemotherapy/targeted therapy combinations are areas of study.

scholarly journals EPCO-23. COMPARATIVE TRANSCRIPTOMICS TO IDENTIFY TARGETED THERAPY CANDIDATES IN HIGH GRADE GLIOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii74-ii74
Author(s):  
Kelsey Hundley ◽  
Olena Vaske ◽  
Geoff Lyle ◽  
Katrina Learned ◽  
Holly Beale ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Therapeutic Targets ◽  
High Grade Glioma ◽  
Comparative Transcriptomics ◽  
Potential Candidate ◽  
High Grade ◽  
Illumina Hiseq ◽  
Li Fraumeni Syndrome ◽  
Statistical Framework ◽  
Genomic Characterization

Abstract Genomic characterization is often used for the identification of therapeutic targets in tumors. Recently, comparative transcriptomics has begun to be utilized for this purpose. In this pilot, we compare the transcriptome of a patient with recurrent high grade glioma (HGG) to our cohort to identify potential therapies. We reviewed transcriptomic profiles from patients who had resection of HGG at our institution over the past year as well as the UCSC cancer compendium. Briefly, tumor RNA was extracted from embedded tumor tissue sections with tumor cellularity higher than 20%. RNA libraries were sequenced to obtain approximately 65 million reads on an Illumina HiSeq 4000 System utilizing patterned flow cell technology. The RNA profile of a 24 male with Li-Fraumeni syndrome and recurrent HGG with leptomeningeal spread underwent comparative transcriptomics to identify targets. A Bayesian statistical framework for gene expression outlier detection was used. These comparisons allowed for the identification of genes and pathways that are significantly overexpressed. Our internal HGG cohort consisted of 44 adult patients and was evenly distributed among the 4 HGG Verhaak subtypes. Our patient of interest had druggable outlier expression in HDAC1, STAT1 and STAT2 in comparison to our internal cohort indicating vorinostat and ruxolitinib as potential therapies, respectively. We then compared our patient of interest to 12,747 patients in the cancer compendium and STAT2 expression was high but not an outlier. In comparison to 738 glioma samples, STAT1 and STAT2 were outliers but not HDAC1 again indicating ruxolitinib as a potential targeted therapy. The patient did not have outlier expression in notch transcriptional targets or immune checkpoint biomarkers when compared to all cohorts. In conclusion, comparative Transcriptomics can identify therapeutic targets in a patient with recurrent HGG even in small cohorts. In our pilot, we identified ruxolitinib as a potential candidate to treat leptomeningeal recurrence.

scholarly journals LINC-42. EPIDEMIOLOGICAL OVERVIEW OF CHILDHOOD CNS TUMORS IN THE NEUROSURGICAL UNIT IN YEREVAN, ARMENIA

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii386-iii386
Author(s):  
Nune Karapetyan ◽  
Samvel Danielyan ◽  
Gevorg Tamamyan ◽  
Armen Tananyan ◽  
Liana Safaryan ◽  
...  
Keyword(s):  
Medical Center ◽  
Survival Rates ◽  
Developed Countries ◽  
Cns Tumors ◽  
Malignant Neoplasms ◽  
Low Grade ◽  
Embryonal Tumors ◽  
Low Grade Gliomas ◽  
Neurosurgical Treatment

Abstract BACKGROUND Central nervous system (CNS) tumors are the second most common malignant neoplasms among children worldwide. The current paper aims to analyze the situation in pediatric neuro-oncology in Armenia from the neurosurgical perspective. METHODS We have collected data of pediatric patients with CNS tumors treated in the Neurosurgery department of “Surb Astvasamayr” Medical Center from 01.01.2010 till 01.12.2019. Incidence by gender, age at diagnosis, and histopathology results were calculated. Survival rates were calculated based on the follow-up results performed until 30.12.2019. RESULTS Hospital-based data showed that during the previous 10 years 47 patients with CNS tumors received neurosurgical treatment in the unit, among them 66% were females. 38.3%, 31.9% and 29.8% of diagnosed patients were aged 0–4, 5–9, and 10–18 respectively. In 41 cases, the disease was not disseminated at diagnosis. The most common observed malignancies were low-grade gliomas (21.3%) and embryonal tumors (19.1%), followed by high-grade gliomas (14.9%) and ependymal tumors (8.5%). Follow-up information only for 33 patients is available. From them, 14 are dead and 19 alive. Survival rates in most common groups were 62.5%, 80%, 50%, and 50% respectively. The median follow-up time was 18 months (range 1–113 months). CONCLUSION Similar to the data reported in the literature, low-grade gliomas, and embryonal tumors are the most frequent pediatric CNS tumors in Armenia. On the other hand, the pediatric CNS tumor survival rates are lower compared to those reported in developed countries.

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