bluuebunny/crossref_metadata_2025 huggingface dataset:
HGG-40. EXCEPTIONAL SYNCHRONOUS OCCURENCE OF A BRAF V600E MUTANT GLIOBLASTOMA AND A H3.3K27M MUTANT DIFFUSE INTRINSIC PONTINE GLIOMA: A CASE REPORT
Authors: De Carli Emilie , Boisselier Blandine , Fournier Luc Le , Supiot Stéphane , Mallebranche Coralie , Proust-Houdemont Stéphanie , Duplan Mylène , Pellier Isabelle , Rousseau Audrey
Published: December 2020

We report herein the case of a 17-year-old female who presented with intracranial hypertension and diplopia. Magnetic resonance imaging showed a large left cystic and solid temporoparietal lesion, associated with an infiltrating lesion of the brainstem, hypointense in T1 and hyperintense in FLAIR sequences, without enhancement after injection of gadolinium. Complete resection of the parietal mass and biopsy of the brainstem lesion were performed. Histopathological analysis of the parietal mass showed glioblastoma (WHO grade IV) with no IDH1/2 or H3.3/H3.1 gene mutation detected by Sanger sequencing. Immunohistochemistry found the expression of the proteins of mismatch repair system. Whole exome and RNA sequencing identified a BRAF-V600E mutation. The brainstem lesion was a diffuse midline glioma, H3K27M-mutant (grade IV) according to the 2016 WHO classification. Pan-genomic SNP arrays of the 2 tumors showed distinct genetic alterations. The parietal glioblastoma displayed complex genomic alterations whereas the brainstem glioma harbored chromosome 7q gain, chromosome 9p and 10 losses, and RB, TP53 and CDKN2A homozygous deletions. The patient was treated by concomitant radiochemotherapy (according to Stupp protocol). After 12 cycles of temozolomide, there was complete remission persistant in the parietal lobe. The brainstem tumor was stable but progressed after 3 months of temozolomide discontinuation. Treatment with mTOR inhibitors was initiated. At 21-month follow-up, the patient remains with few symptoms. No predisposition syndrome was identified in the patient or her family. Concurrent glioblastomas with distinct driver gene mutations are exceptional.
HGG-56. EXTENSIVE MOLECULAR HETEROGENEITY WITHIN H3-/IDH-WILDTYPE PEDIATRIC GLIOBLASTOMA
Authors: Blattner-Johnson Mirjam , Sahm Felix , Sill Martin , Sturm Dominik , Kramm Christof M , Pfister Stefan M , Jones David
Published: December 2020

About half of all pediatric high-grade gliomas (HGG) harbor mutations in histone 3 or IDH genes. The remaining HGG are currently broadly classified as H3-/IDH-wild-type. Since the introduction of a uniform approach to DNA methylation-based classification of CNS tumors in 2018, DNA methylation data from over 45,000 CNS tumor samples have been generated. From this large cohort, a number of smaller yet distinct subgroups start to emerge within H3-/IDH-wild-type HGG. Three such subgroups are enriched for focal gene amplifications and have been provisionally termed pedGBM_MYCN, pedGBM_RTK1 and pedGBM_RTK2. Since a significant subset of samples in each subgroup is lacking characteristic alterations, we further investigated the molecular and transcriptional composition of H3-/IDH-wild-type HGG. We evaluated DNA methylation and copy-number profiles in >1000 tumors classified as H3-/IDH-wild-type HGG. Tumors classified pedGBM_MYCN showed a focal MYCN amplification in 25%, with a similar fraction showing amplification of EGFR (8% of samples harbored both alterations) compared to 4% and 4% in pedGBM_RTK1 and 14% and 22% in pedGBM_RTK2. Deletion of CDKN2A/B was much more prevalent in the pedGBM_RTK2 subgroup (~50% compared to 27% in pedGBM_RTK1 and <10% in the pedGBM_MYCN group). We defined a pedGBM_MYCN transcriptional signature, which will be helpful in identifying subgroup-defining mechanisms and alterations. Initial results suggest an involvement of the sonic hedgehog pathway and genes controlling stem-cell pluripotency. Patient-derived xenograft models and murine neural stem cells are now being used for functional characterization and pre-clinical testing of potential drug targets in these molecularly defined subgroups.
IMMU-08. reMATCH PROTOCOL: PHASE II STUDY OF EX-VIVO EXPANDED AUTOLOGOUS TUMOR SPECIFIC LYMPHOCYTE TRANSFER (X-ALT) + TOTAL TUMOR RNA DC VACCINE (TT-RNA DC) DURING RECOVERY FROM MYELOABLATIVE CHEMOTHERAPY (MAC) AND PERIPHERAL BLOOD STEM CELL (PBSC) RESCUE OR NON-MYELOABLATIVE CHEMOTHERAPY (NMAC) AND PBSC IN PATIENTS (PTS) WITH RECURRENT PNET (R-PNET)
Authors: Gururangan Sridharan , Hwang Eugene , Dhall Girish , Yegorov Oleg , Governale Lance , Blatt Jason , Horn Biljana , Mitchell Duane
Published: December 2020

A phase II study was performed to assess vaccine-related toxicities and efficacy of x-ALT+tt-RNA DC following MAC +PBSC (group A) or NMAC +PBSC (group B) in pts with r-PNET. METHODS: Eligible pts underwent biopsy to confirm r-PNET and obtain tumor for vaccine preparation. Pts with local (group A) or metastatic (group B) disease received cytoreductive induction chemotherapy prior to either MAC (carboplatin+ thiotepa+ etoposide) or NMAC (cyclophosphamide + fludarabine) respectively and then received one dose of x-ALT (3 x 107cells/kg), PBSC, and 3 doses of bi-weekly intradermal tt-RNA DCs (107cells each). Patients were followed for survival and vaccine-related toxicities. Correlative studies included TCR RNA sequencing and measurement of serum cytokines. RESULTS: 20 evaluable pts (75% males) [Medulloblastoma 17, PNET 3; unifocal 40%] were treated on protocol (group A 7, group B 13). There were no significant vaccine-related toxicities. At a median follow-up of 8.5 months, 5 patients (all with medulloblastoma) are alive following vaccine therapy; 2 pts with SD (3.5+ and 6.5+ months) and 3 pts with PD that stabilized with salvage therapies (26+, 31+, and 46+ months respectively). One patient with medulloblastoma and bone marrow involvement who had PD despite MAC, had an almost complete response one month following x-ALT + tt-RNA DCs and TCR RNA sequencing demonstrated massive clonal expansion of T cells. Correlative studies are ongoing. CONCLUSIONS: x-ALT+tt-RNA DC following either MAC or NMAC is safe and shows signs of biologic and possible clinical activity in some pts with r-PNET.
IMMU-10. INTERIM ANALYSIS OF THE HIT-HGG REZ IMMUNVAC STUDY - DENDRITIC CELL VACCINATION WITH PARTIAL TREG DEPLETION IN CHILDREN, ADOLESCENTS, AND ADULTS WITH RELAPSED HIGH-GRADE GLIOMAS
Authors: Eyrich Matthias , Krauss Jürgen , Rachor Johannes , Monoranu Camelia , Bison Brigitte , Löhr Mario , Rückriegel Stefan , Wölfl Matthias , Miller Elisabeth , Schlegel Paul G , Kramm Christof
Published: December 2020

Efficacy of therapeutic dendritic cell vaccines (DCV) can be limited by immunosuppressive mechanisms in the micromilieu of high-grade gliomas. In the HIT-HGG-Rez Immunovac trial (Eudra-CT 2013-000419-26), we investigate whether a reduction of Treg with metronomic cyclophosphamide (metrCyc) might be a feasible option to improve vaccine efficacy. 10 pediatric (mean age 11.4±4.2y) and 5 adult patients (mean age 39.5±19.9y) with relapsed glioblastoma were treated according to the HIT-HGG-Rez Immunovac protocol so far. 2 children were treated within the trial, the other 13 in the pilot phase. Patients received upfront oral metrCyc for 2–4 weeks. After reoperation and monocyte-apheresis, patients received 4 weekly intradermal doses of autologous, TNFa/IL-1ß matured DCs pulsed with tumor lysate in imiquimod-prepared skin. Thereafter, tumor lysate boosts were given. All patients received at least 5 vaccines (4xDCs, 1xlysate boosts). MetrCyc was well tolerated and led to a reduction in Treg-frequency of 35.6±17.8% followed by a rebound after cessation of metrCyc. Importantly, 13/14 analyzed patients showed a positive IFNg-T-cell response against autologous tumor lysate with a tendency to decrease over time. 6-month overall survival was 100%, compared to 65% in a historical control. Mean PFS and OS were 5.7 and 21.1 months with no difference between adults and children. We conclude that DCV in combination with partial Treg depletion is feasible, safe, and related with a high rate of tumor-specific IFNg-responses. As the clinically and immunologically beneficial effects seem to diminish over time, we aim to combine our approach with checkpoint inhibition in the next amendment.
IMMU-21. INVESTIGATION OF WHITE BLOOD CELL CHARACTERISTICS IN CSF SAMPLES AT PEDIATRIC BRAIN TUMOR DIAGNOSIS
Authors: Greer Hunter , Campbell Kristen , Samay Sadaf , Green Adam
Published: December 2020

BACKGROUND

There has been a recent surge in investigation of immunity and immunotherapy, but their role in pediatric brain tumors is incompletely defined. We hypothesized that investigating an understudied dataset, WBC and differential results in CSF drawn at the time of pediatric brain tumor diagnosis to look for microscopic metastases, would provide insight into the role of immunology and potential for immunotherapy in these diseases and correlate with prognosis and/or metastasis.

METHODS

We conducted a retrospective comparison analysis of CSF values in 349 patients at our institution from samples drawn within 60 days of initial CNS tumor diagnosis from 1998–2018. We examined total nucleated cell count, absolute counts and percentages for WBC subtypes. We compared CSF values by tumor cell presence, patient vital status, and disease group: atypical teratoid rhabdoid tumor, ependymoma, germinoma, high-grade glioma (HGG), low-grade glioma (LGG), medulloblastoma, non-germinomatous germ cell tumor, and other embryonal tumors (OET). We used Wilcoxon and Kruskal-Wallis tests for comparisons.

RESULTS

Overall, higher lymphocyte percentage (p=0.002) and lower monocyte percentage (p=0.007) were associated with survival. WBC characteristics did not differ significantly based on tumor cell presence. Compared to medulloblastoma, ependymoma showed a more active CSF immune response, while LGG, HGG, and OET showed a less active response, based on total WBC and/or absolute neutrophil count (p=0.001–0.007).

CONCLUSIONS

Higher lymphocyte and lower monocyte percentages in CSF correlated with better prognosis overall; causality requires further investigation. Tumor subtypes varied in their immune stimulation, offering potential insight into which will be amenable to immunotherapy.
LGG-05. MOLECULAR GUIDED THERAPY FOR A PEDIATRIC LOW GRADE GLIOMA: A CASE REPORT
Authors: VonBergen Jayne , Armstrong Beth , Schmitt Morgan
Published: December 2020

Low grade gliomas are the most common type of central nervous system tumors among children. Despite the fact that they are not typically life threatening, low grade gliomas remain a significant clinical challenge. Case Study: Patient is a 4-year-old male who presented at 20 months of age with several weeks of ataxia, emesis, and head tilt. Imaging revealed a right temporal lobe lesion; he was subsequently taken to surgery, where a gross total resection was achieved. Imaging 9 months post resection revealed recurrent disease within the right temporal region with leptomeningeal involvement. Four months later imaging revealed progression of multifocal disease and new growth within the sella. At this time the patient started standard treatment, Carboplatin and Vincristine, per CCG 9952A. Persistent slow progression was observed despite receiving standard therapy. The patient developed a grade 3 reaction to carboplatin, worsening with each subsequent dose. At this time, he was referred to our Precision Genomics Neuro Oncology program for tumor molecular characterization. Somatic tumor testing revealed an ETV6-NTRK3 fusion, at which time standard treatment was stopped, and patient began targeted therapy, Larotrectinib. Imaging was preformed 2 months post start of targeted therapy and revealed interval decrease in size of previously enhancing nodular lesions; findings consistent with treatment response. Disease burden continues to decrease with therapy. This case illustrates a clear benefit of using molecular guided therapy in low grade gliomas.
LGG-13. THE CLINICAL AND MOLECULAR LANDSCAPE OF GLIOMAS IN ADOLESCENTS AND YOUNG ADULTS
Authors: Bennett Julie , Fang Karen , Sheth Javal , Ryall Scott , Martin Komosa , Nunes Nuno , Nobre Liana , Perry James , Sahgal Arjun , Mason Warren , Das Sunit , Gao Andrew , Tsang Derek , Nguyen Lananh , Laperriere Normand , Keith Julia , Munoz David , Tabori Uri , Hawkins Cynthia
Published: December 2020

OBJECTIVE

Pediatric low grade gliomas are typically driven by MAPK upregulation with excellent long-term survival. In contrast, adult lower grade gliomas commonly harbor IDH-1 mutations and undergo malignant transformation. Gliomas in adolescents and young adults (AYA) are an orphan group of tumors that have been poorly described. We aim to determine the clinical and molecular landscape of AYA gliomas.

METHODS

A multi-institutional population based cohort of 839 patients diagnosed with glioma between 15–40 years has been identified. Complete molecular analysis, long term outcome and therapeutic data are being collected.

RESULTS

Of 364 AYA gliomas analyzed, the prevalence of WHO grade I tumors was highest in those <21 years (54%), while the prevalence of higher grade tumors increased with age. Interestingly, only 38% harbor IDH-1 mutations while 23% harbor pediatric mutations, including 8% with BRAF p.V600E, and 4% with KIAA1549:BRAF fusion. The median age for IDH-1 mutation is 32 years, with highest frequency in WHO grade II and III tumors. In contrast, BRAF alterations were most frequently observed in WHO grade I and II tumors and enriched in those less than 20 years. Five-year progression-free survival for BRAF fusion, p.V600E and IDH-1 p.R132H were 81%, 78% and 26% respectively. No survivors were observed in H3 p.K27M and p.G34R gliomas (p<0.0001).

CONCLUSIONS

Gliomas in AYA overlap pediatric and adult classification and exhibit enrichment for pediatric alterations. As the latter are associated with improved PFS and are amenable to targeted therapies, this should be considered in the work up of these tumors.
LGG-17. SYNERGISTIC ACTIVITY OF MAPK INHIBITOR CLASSES REVEALED BY A NOVEL CELL-BASED MAPK ACTIVITY PEDIATRIC LOW-GRADE GLIOMA ASSAY
Authors: Usta Diren , Sigaud Romain , Buhl Juliane L , Selt Florian , Marquardt Viktoria , Pauck David , Pusch Stefan , Ecker Jonas , Hielscher Thomas , Vollmer Johanna , Sommerkamp Alexander C , Rubner Tobias , Hargrave Darren , van Tilburg Cornelis M , Pfister Stefan M , Jones David T W , Remke Marc , Brummer Tilman , Witt Olaf , Milde Till
Published: December 2020

Pilocytic astrocytomas (PAs) and other pediatric low-grade gliomas (pLGGs) exhibit aberrant activation of the MAPK signaling pathway caused by genetic alterations, most commonly KIAA1549:BRAF fusions, BRAF V600E and NF1 mutations. In such a single-pathway disease, novel drugs targeting the MAPK pathway (MAPKi) are prime candidates for treatment. We developed an assay suitable for pre-clinical testing of MAPKi in pLGGs, aiming at the identification of novel MAPK pathway suppressing synergistic drug combinations. We generated a reporter plasmid (pDIPZ) expressing destabilized firefly luciferase driven by a MAPK-responsive ELK-1-binding element, packaged in a lentiviral vector system. We stably transfected pediatric glioma cell lines with a BRAF fusion (DKFZ-BT66) and a BRAFV600E mutation (BT-40) background, respectively. Measurement of MAPK pathway activity was performed using the luciferase reporter. pERK protein levels were detected for validation. We performed a screen of a MAPKi library and calculated Combination Indices of selected combinations. The MAPKi library screen revealed MEK inhibitors as the class inhibiting the pathway with the lowest IC50s, followed by ERK and second generation RAF inhibitors. Synergistic effects in both BRAF-fusion and BRAFV600E mutation backgrounds were observed following combination treatments with different MAPKi classes (RAFi/MEKi, > RAFi/ERKi > MEKi/ERKi). We have generated a novel reporter assay for medium- to high-throughput pre-clinical drug testing of MAPKi in pLGG cell lines. MEK, ERK and next-generation RAF inhibitors were confirmed as potential treatment approaches for KIAA1549:BRAF and BRAFV600E mutated pLGGs. Synergistic suppression of MAPK pathway activity upon combination treatments was revealed using our assay in addition.
LGG-23. EXCELLENT CLINICAL / RADIOLOGICAL RESPONSE TO BRAF INHIBITION IN A YOUNG CHILD WITH IN-OPERABLE SUPRA-SELLAR PILOCYTIC ASTROCYTOMA
Authors: Chapman Stacy , Serletis Demitre , Kazina Colin , Rafay Mubeen , Krawitz Sherry , Rozovsky Katya , Vanan Magimairajan Issai
Published: December 2020

In-operable low grade gliomas (LGG) in the pediatric population continue to present a treatment dilemma. Due to the low-grade nature of these tumors, and variable response to chemotherapy / radiation, the choice of adjuvant treatment is difficult. Overall survival is directly related to the degree of surgical resection, adding complexity to these inoperable tumors. Current chemotherapeutic regimen for these inoperable tumors includes vincristine (VCR) and carboplatin (Carbo). With advancements in the molecular characterization of gliomas, the role of targeted therapy has come into question. We present a 2-year-old female with biopsy proven Pilocytic Astrocytoma (positive BRAF-V600E mutation) involving the hypothalamic/optic chiasm region. She presented with ataxic gait, bi-temporal hemianopia, obstructive hydrocephalus and central hypothyroidism, which progressed to altered consciousness, and right hemiparesis due to location/mass effect of the tumor. She was initially treated with chemotherapy (VCR/Carbo) but her tumor progressed at 6 weeks of treatment. As her tumor was positive for BRAF-V600E mutation, she was started on Dabrafenib monotherapy, resulting in dramatic improvement in her clinical symptoms (able to stand, improved vision), and a 60% reduction in tumor size at 3-months. At 6-months, follow up MRI showed slight increase in the solid portion of the tumor, with no clinical symptoms. We plan to add MEK inhibitor (Trametinib) and continue with Dabrafenib. Our experience and literature review suggests that LGG with BRAF-V600E mutations may benefit from upfront targeted therapy. Prospective clinical trials comparing the efficacy of BRAF inhibitors versus standard chemotherapy in LGG with BRAF mutations are urgently needed.
LGG-25. A PHASE 2 STUDY OF TRAMETINIB FOR PATIENTS WITH PEDIATRIC GLIOMA WITH ACTIVATION OF THE MAPK/ERK PATHWAY. TRAM-01
Authors: Perreault Sébastien , Larouche Valérie , Tabori Uri , Hawkins Cynthia , Lippé Sarah , Ellezam Benjamin , Décarie Jean-Claude , Théoret Yves , Métras Marie-Élaine , Sultan Serge , Cantin Édith , Routhier Marie-Ève , Caru Maxime , Legault Geneviève , Bouffet Eric , Lafay-Cousin Lucie , Hukin Juliette , Erker Craig , Jabado Nada
Published: December 2020

BACKGROUND

Pediatric low-grade gliomas (PLGG) are the most frequent brain tumors in children. It is now known that the majority of PLGG have activation of the MAPK/ERK pathway. We hypothesize that we will observe responses in recurrent/refractory PLGG treated with trametinib.

METHODS

This is a multicenter phase II including three progressing/refractory PLGG groups: NF1 patients, KIAA1549-BRAF fusion patients and patients with other activation of the MAPK/ERK pathway (excluding V600E). Patients will receive daily oral trametinib for a total of 18 cycles of 28 days. A total of 104 patients will be enrolled in seven Canadian centers. Secondary objectives include the assessment of progression-free survival, tolerability of trametinib, serum levels of trametinib and evaluation of quality of life during treatment.

RESULTS

As of January 7 2020, 28 patients have been enrolled (NF1: 6 patients, KIAA1549-BRAF fusion: 17, other: 5 including 3 patients FGFR1 alteration). Median age is 8.5 years (range 2.5–25.4 years). Median follow-up is currently 4.6 months (range 0.16–14.7 months). Twenty patients are currently evaluable. Best response includes: 1 complete response (5%), 3 partial response (15%), 4 minor response (20%), 8 stable disease (40%), 4 progressive disease (20%). 8 patients (28,5%) discontinued treatment: 4 for progressive disease, 3 adverse event (alanine aminotransferase increase), 1 withdrew.

CONCLUSION

Trametinib is potential effective targeted therapy for patients with recurrent/refractory PLGG. Overall treatment is well tolerated. This ongoing trial will continue to gather data on response rate, duration of response and safety of trametinib for PLGG.
LGG-38. GENETIC ANALYSIS OF NEUROEPITHELIAL TUMORS IN THE PEDIATRIC AND ADOLESCENT AND YOUNG ADULT AGE IN A SINGLE INSTITUTE
Authors: Makino Yasuhide , Kawauchi Takeshi , Arakawa Yoshiki , Shofuda Tomoko , Yoshioka Ema , Tanji Masahiro , Mineharu Yohei , Kanemura Yonehiro , Miyamoto Susumu
Published: December 2020

Molecular diagnosis in brain tumors has been widely spread after the publication of WHO 2016 classification. But it become a major problem that there are some tumors not to be classified on its criteria, especially in pediatric neuroepithelial tumors. To clarify the characteristics of gliomas in pediatric and adolescent and young adult age (AYA), we picked up 131 neuroepithelial tumors under 30-year-old at Kyoto University and analyze their molecular profiles. Hot spot mutations in IDH1/2, H3F3A, HIST1H3B, TERT promoter, and BRAF were analyzed by Sanger sequencing, and 1p/19q codeletion was examined by FISH or MLPA. With the pathohistological diagnosis and genetic information, all tumors were classified based on WHO 2016 classification. The terms “not otherwise specified” (NOS) and “not elsewhere classified” (NEC) were used based on cIMPACT-NOW. There were 25 glioblastomas and 34 pilocytic astrocytomas, which accounted for a larger percentage than in adult tumors. IDH-wild type gliomas accounted for 55% in diffuse astrocytomas and 69% in anaplastic astrocytomas. The percentages of gliomas with NEC were 50% of oligodendrogliomas and 20% in anaplastic oligodendrogliomas, respectively. Most pilocytic astrocytomas were under 20-year-old (27 patients) and located in infratentorial area (21 patients). Based on WHO 2016 classification, not a few neuroepithelial tumors in pediatric and AYA ages could be classified clearly. These tumors had more different genetic abnormalities than those in adult. Therefore, it may be important to evaluate these tumors with comprehensive genetic analysis.
LGG-42. BEVACIZUMAB-ASSOCIATED SECONDARY AMENORRHEA AND PREMATURE OVARIAN FAILURE IN ADOLESCENT FEMALE PATIENTS WITH LOW-GRADE CNS DISEASE
Authors: Zhukova Nataliya , Chan Kiri , Walshe Kathryne , Downie Peter A , Wood Paul
Published: December 2020

Compelling body of evidence exists to use bevacizumab, a humanized monoclonal anti-VEGF antibody, in selected paediatric patients with low-grade CNS tumours. Common toxicities of bevacizumab, hypertension, proteinuria, epistaxis, mucosal perforation, decreased wound healing are well reported. However, the effect of bevacizumab on female ovarian function and long-term fertility is still being documented. Current evidence for bevacizumab-associated decline in ovarian function is largely from breast and colon cancer cohorts where exposure to multimodal chemotherapy confounds causative relationships. Fertility counseling and oocyte cryopreservation is currently offered as standard of care to post-pubertal females at high risk of infertility due to high-dose radiation and chemotherapy. Adolescent females with low-grade CNS tumours on bevacizumab represent a unique population which could potentially be at high risk for infertility. We report 2 cases of adolescent girls treated with bevacizumab as a single agent and in combination with vinblastine for NF2-associated vestibular schwannomas and brainstem glioma respectively. Both patients were post-pubertal with established menstrual cycles and normal baseline FSH/LH/oestradiol/AMH values prior to commencement of therapy. They became amenorrhoeic shortly after starting of therapy with levels of FSH/LH/oestradiol suggestive of premature ovarian failure. One patient has remained asymptomatic, whereas the other has developed profound post-menopausal symptoms interfering with quality of life which necessitated commencement of hormone-replacement therapy. Appropriate pretreatment fertility investigation and consultation should be offered to all post-pubertal females starting on bevacizumab. Further research into the long-term effects of gonadal toxicity in both females and males with drugs inhibiting angiogenesis is needed.
LINC-04. POSSIBLE ROLE OF NEOADJUVANT CHEMOTHERAPY IN METASTATIC PURE GERMINOMA IN LOW AND MIDDLE INCOME COUNTRIES. A PRO POS OF A CASE
Authors: Leal-Cavazos Carlos , Escamilla-Luna Paola , Luna Marissa Fernandez-De , Vidal-Gutierrez Oscar
Published: December 2020

BACKGROUND

CNS germ cell tumors represent about 3–5 % of pediatric brain tumors, 60% are pure germinomas. Germinomas are very sensitive to chemotherapy which has helped to reduce volume and dose of radiotherapy in localized disease while maintaining excellent survival. In metastatic disease the SIOP GCT-96 trial showed no benefit with addition of chemotherapy to craniospinal irradiation alone. Radiotherapy maybe not readily available in Low/Middle Income Countries (LMIC).

METHOD

We describe a patient in which the use of neoadjuvant chemotherapy helped to rescue vision. The patient is a 9 year old female with a 3 months history of morning headaches and vomits. Visual decline was noticed a month before admission when the child had completely loss vision of the right eye and left eye was partially affected. MRI showed a large suprasellar mass with ventricular nodules. Beta-hGC in CSF was mildly elevated. Patient received 2 cycles of carboplatin/etoposide. After first cycle there was a complete vision recovery in both eyes. After the second course the MRI showed complete response in primary and metastatic disease. Patient received CSI (24Gy + 16 Gy Boost) after 2 cycles of chemotherapy. Chemotherapy was very well tolerated without side effects. Patient vision is 20/20 in both eyes without deficit in visual fields.

CONCLUSION

Although the addition of chemotherapy in metastatic germinoma has no clear role in reducing radiotherapy it could possible help selected patients in attempt to rescue vision when radiotherapy is not readily available.
LINC-10. SIOP PODC ADAPTED TREATMENT GUIDELINES FOR CRANIOPHARYNGIOMA IN LOW- AND MIDDLE-INCOME SETTINGS
Authors: amayiri Nisreen , Spitaels Ariane , Zaghloul Mohamed , Figaji Anthony , Cavalheiro Sergio , Muller Hermann L , Elhassan Moawia , Parkes Jeannette , Mushtaq Naureen , El Beltagy Mohamed , Yousef Yacoub , Esiashvili Natia , Sullivan Michael , da Costa Marcos Devanir , Dastoli Patricia , Mubarak Fatima , Bartels Ute , Chamdine Omar , Davidson Alan , Musharbash Awni , Alcasabas Patricia , Bouffet Eric , Bailey Simon
Published: December 2020

Pediatric craniopharyngioma is a rare tumor with excellent survival but significant long-term morbidities due to the loco-regional tumor growth or secondary to its treatment. Visual impairment, panhypopituitarism, hypothalamic damage and behavioral changes are amongst the main challenges. This tumor should be managed under the care of a multidisciplinary team to determine the optimum treatment within the available resources. This is particularly important for low middle-income countries (LMICs) where resources are variable. We provide a risk-stratified management guideline for children diagnosed with craniopharyngioma in a resource limited setting based on the service levels describing the facilities and personnel required for management as previously specified by the Pediatric Oncology in Developing Countries (PODC) committee of The International Society of Pediatric Oncology (SIOP). A multi-disciplinary group of neurosurgeons, radiation and pediatric oncologists, radiologists, pediatric endocrinologists and an ophthalmologist with experience in managing children with craniopharyngioma in LMIC setting was formed and carried online meetings to form a consensus guideline. The clinical characteristics (including the visual and endocrine presentations), suggestive radiological features as well as potential treatment options including surgery, radiotherapy and intra-cystic therapies were discussed in depth and in relation to available resources. In addition, hormonal management, pre- and post-operative PICU care and expected future complications related to craniopharyngioma and to follow up these children were discussed and documented in the guideline. We believe this guideline is a useful reference for health care providers in LMIC.
LINC-15. OUTCOME OF CHINESE CHILDREN WITH MEDULLOBLASTOMA: A MULTI-CENTER EXPERIENCE WITH RISK-ADAPTED THERAPY
Authors: Sun Xiaofei , Liu Anthony Pak-Yin , Yang Qunying , Wang Jian , Wu Shaoxiong , Zhen Zijun , Wang Jingsheng , Guo Haixia , Jiang Lian , Ma Xiaoli , Weng Wenjun , Yang Lihua , Huang Libin , Li Juan , Chan Godfrey Chi-Fung
Published: December 2020

BACKGROUND

Medulloblastoma is the commonest brain tumor in young children but literature on Chinese is scarce. We hereby present the outcome of children with medulloblastoma managed according to a risk- and age-stratified guideline from ten institutions across China.

METHODS

Patients <18 years of age diagnosed with medulloblastoma between January 2016 and April 2019 were reviewed. Patients ≥3 years, stratified into average-risk (≤1.5cm2 residual tumor, non-metastatic, non-anaplastic histology) and high-risk (others) groups, were treated with risk-adapted craniospinal irradiation (average-risk: 23.4Gy, high-risk: 36Gy), tumor boost, and chemotherapy (lomustine/cisplatin/vincristine). Patients <3 years (considered high-risk, other than patients with localized and desmoplastic/nodular histology) received chemotherapy (cyclophosphamide/vincristine, high-dose methotrexate, carboplatin/etoposide) with/without delayed irradiation.

RESULTS

112 patients were included with a median age at diagnosis of 6.5 years (range: 0.5–16.7). 16 patients (14.3%) had residual tumor >1.5cm2 and 36 (32%) had metastasis. Available data on histological subtype (n=87) were classic in 56 (64%), desmoplastic/nodular or extensive nodularity in 23 (26%), and large cell/anaplastic in 8 (9%). Molecular subgrouping (n=55) assigned tumors as WNT-activated (n=8, 15%), SHH-activated (n=17, 31%), Group 3 (n=12, 22%) and Group 4 (n=18, 33%). Respective 2-year EFS/OS for patients ≥3 and <3 years were 86.0±4.0%/96.4±2.1% and 57.8±12.6%/81.4±9.8% (EFS/OS p<0.001/p=0.009). Significant difference in outcome was also observed between patients with average-risk and high-risk disease (EFS/OS p=0.006/p=0.018).

CONCLUSION

We demonstrated feasibility in protocolizing the inter-disciplinary treatment for medulloblastoma in China. This will serve as a prototype for the standardization of pediatric neuro-oncology care in the country.
LINC-30. A CLINICOPATHOLOGICAL STUDY OF IMMUNOGENICITY AND IMMUNE EVASION MECHANISMS AMONG MOLECULAR SUBGROUPS OF MEDULLOBLASTOMA
Authors: Kaur Kavneet , Suri Vaishali , Sharma Mehar C , Suri Ashish , Sarkar Chitra
Published: December 2020

INTRODUCTION

Medulloblastomas have been well characterised in terms of genomics, epigenomics, transcriptomics and recently proteomics. However, there is limited knowledge regarding immunogenicity, immune-microenvironment and immune evasion mechanisms in different molecular subgroups of medulloblastoma. It is important to analyze these parameters to understand tumor progression, prognostic stratification as well as treatment response to available immunotherapeutic drugs.

MATERIALS AND METHODS

Molecular subgrouping performed by immunohistochemistry(IHC), Nanostring and 850k-methylation array. Immune profile by IHC for CD3, 20, CD8 [tumor infiltrating lymphocytes (TILs)], CD163 [tumor-associated macrophages (TAMs)], and PD-L1 and CTLA-4 [immune checkpoint proteins].

RESULTS

A total of 35 cases were analyzed with age-range from 1 to 54 years (77% pediatric and 23% adult). 82% cases were located in midline, while rest in cerebellar hemispheres. On molecular subgrouping, MBs were subdivided into 8 WNT, 10 SHH, 8 Group 3 and 9 Group 4. Twenty four cases had follow up, 12 with no evidence of disease while 12 with progressive disease or death. PD-L1 expression ranged from 0% to 20% and included 5SHH, 2WNT and 1Group 3. CTLA4 positive lymphocytes ranged from 0 to 33 in 4 cases: 1WNT, 3 SHH, 1Group4. TILs ranged from 0–220/mm2 with a median of 3. TAMs ranged from 0–60/mm2 with a median of 18. Both TILs and TAMs were significantly higher in SHH subgroup.

CONCLUSION

PD-L1 positivity and number of TILs and TAMs were significantly more in SHH-subgroup tumors followed by WNT tumors. CTLA-4 expression did not correlate with subgroups. All parameters showed a positive trend with increasing age.
MBCL-01. METHYLATION PROFILING OF PEDIATRIC MEDULLOBLASTOMA IN SAUDI ARABIA IN A CLINICAL SETTING PERMITS SUB-CLASSIFICATION AND REVEALS NEW OUTCOME PREDICTIONS
Authors: Alharbi Musa , Mobark Nahla , Balbaid Ali Abdullah O , Bashawri Yara , Safieh Leen Abu , Alowayn Albandary , Alaljelaify Rasha , AlSaeed Mariam , Almutairi Amal , Alqubaishi Fatmah , Alsolm Ebtehal , Ahmad Maqsood , Al-Banyan Ayman , Alotabi Fahad E , Snuderl Matija , Abedalthagafi Malak
Published: December 2020

Medulloblastoma (MB) is the most common childhood malignant brain tumor. DNA methylation profiling has rapidly advanced our understanding of MB pathogenesis at the molecular level, MBs can be sub-grouped according to methylation patterns from FPPE samples into Wingless (WNT-MB), Sonic Hedgehog (SHH-MB), Group 3 (G3) and Group 4 (G4) WNT-MB and SHH-MB subgroups are characterized by gain-of function mutations that activate oncogenic cell signalling whilst G3/G4 tumors show recurrent chromosomal alterations. each subgroup has distinct clinical outcomes, the ability to subgroup SA-FPPE samples holds significant prognostic and therapeutic value. We performed the first assessment of MB-DNA methylation patterns in Saudi Arabian SA cohort using archival biopsy materials (FPPE n=49). Of the 41 materials available for methylation assessments, 39 could be classified into the major DNA methylation subgroups (SHH, WNT, G3 and G4). Methylation analysis was able to reclassify tumors that could not be sub-grouped through NGS testing, highlighting its improved accuracy for MB molecular classifications. Independent assessments demonstrate clinical relationships of the subgroups, exemplified by the high survival rates observed for WNT tumors. Surprisingly, the G4 subgroup did not conform to previously identified phenotypes, with a high prevalence in females, high metastatic rates and a large number of tumor-associated deaths. DNA methylation profiling enables the robust sub-classification of four disease sub-groups in SA-MB patients. Moreover, the incorporation of DNA methylation biomarkers can significantly improve current disease-risk stratification schemes, particularly concerning the identification of aggressive G4 tumors. These findings have important implications for future clinical disease management in MB cases across the Arab world.
MBCL-17. METASTATIC MEDULLOBLASTOMA CAN BE CURED WITHOUT EXCISION OF THE PRIMARY TUMOR: A SINGLE CENTER EXPERIENCE
Authors: Dvir Rina , Constantini Shlomi , Roth Jonathan , Rosenfeld-Keidar Hila , Ospovat Inna , Elhasid Ronit
Published: December 2020

INTRODUCTION

Metastatic medulloblastoma is a challenging disease The current clinical approach advocates removal of the primary tumor in the posterior fossa despite evidence of metastatic disease and administer oncologic treatment within several weeks: Infants of 3–4 years are treated by tandem high dose chemotherapy with stem cell support (ACNS0334 protocol), while older children are given radiotherapy and tandem high dose chemotherapy with stem cell support (SJMB03 protocol). We postulate that a resection of the primary tumor is not obligatory, and a biopsy may suffice in order to enable prompt oncological treatment without affecting the long-term survival.

PATIENTS AND METHODS

Between 2010-2019 7 patients with metastatic medulloblastoma (median age 4.5, age 1–10) were treated with biopsy only, five spinal and two from the primary tumor. Six children had a concurrent VP shunt. Four presented with cord compression, and two with neurological deterioration. Four needed emergency radiotherapy. Two infants received protocol ACNS0334, five patients received protocol SJMB03.

RESULTS

Six patients (85%) survived; .3 patients are long term survivors (> 5 years), 2 patients are in remission for 2–3 years, one patient is on active therapy. Only 1 patient died after a late (4 years) metastatic relapse not in the posterior fossa.

CONCLUSIONS

Metastatic medulloblastoma can be cured without excision of the primary tumor and without mutilating surgery. Long term prognosis is probably more attributable to disease subtype and prompt oncologic treatment. This approach merits further studies and may have implications on treatment of non-metastatic tumors.
MBCL-20. DETECTION OF SOMATIC MUTATIONS BY USING RNA-SEQ DATA IN CHILDHOOD MEDULLOBLASTOMA AND ITS POTENTIAL CLINICAL APPLICATION: A COHORT SERIES OF 52 CASES STUDY IN TAIWAN
Authors: Wong Tai-Tong , Wu Kuo-Sheng , Ho Donald Ming-Tak , Lin Shih-Chieh , Huang Wen-Chang , Laing Muh-Lii , Chen Hsin-Hung
Published: December 2020

BACKGROUND

In 2016, a project was initiated in Taiwan to adopt molecular diagnosis of childhood medulloblastoma (MB). Part of our aim was to explore the clinical application for drug target identification and finding clues to genetic predisposition.

METHODS

In total, 52 frozen tumor tissues of childhood MBs were collected. RNA-Seq and DNA methylation array data were generated. Molecular subgrouping was performed. We selected 51 clinically relevant genes for somatic variant calling using RNA-Seq data. Correlated clinical findings to genetic predisposition were defined. Potential drug targets and genetic predispositions were explored.

RESULTS

Four core molecular subgroups (WNT, SHH, Group 3, and Group 4) were identified. Potential drug targets were detected in the pathways of DNA damage response. Five patients with relevant clinical findings to genetic predisposition clustered in SHH MBs. The corresponding somatic driver mutations involved TP53, MSH6, PTEN, PTCH1, and TERT promoter (suspicious). For validation, whole exome sequencing (WES) of blood and tumor tissue was used in 10 patients with SHH MBs in the cohort series. This study included the five patients with potential genetic predispositions. Four patients exhibited relevant germline mutations named as TP53, MSH6, PTEN, and SUFU.

CONCLUSION

The findings of this study provide valuable information for personalized care of childhood MB in our cohort series and in Taiwan.
MBCL-34. EFFICACY OF METHOTREXATE (MTX) ACCORDING TO MOLECULAR SUB-TYPE IN YOUNG CHILDREN WITH MEDULLOBLASTOMA (MB): A REPORT FROM CHILDREN’S ONCOLOGY GROUP PHASE III TRIAL ACNS0334
Authors: Mazewski Claire , Kang Guolian , Kellie Stewart , Gossett Jeffrey , Leary Sarah , Li Bryan , Aridgides Paul , Hayes Laura , Reddy Alyssa , Shaw Dennis , Burger Peter , Judkins Alexander , Geyer Jeffrey Russell , Fouladi Maryam , Huang Annie
Published: December 2020

ACNS0334, a Phase 3 trial, compared outcomes of children <36 months treated with intensive chemotherapy +/-high-dose methotrexate. Nodular-desmoplastic M0-stage MB were excluded. Treatment included 3 induction cycles (cyclophosphamide/etoposide/vincristine/cisplatin+/-mtx) and 3 consolidation cycles (carboplatin/thiotepa with stem cell rescue). Radiation (RT) was at physician discretion. Molecular sub-typing was by DNA-methylation. Log-rank testing was used to compare survival differences. Molecular sub-typing of 38 MB identified 11 Sonic Hedgehog (SHH), 25 Group 3 (GP3), 2 Group 4 (GP4). Five-year survival (OS) was 100% for 5 SHH with MTX and 4 SHH without MTX; 80% for 10 GP3 with MTX, 40% for 15 GP3 without MTX (p=0.025). Only 6/14 survivors received RT: 4 for residual following therapy (1 SHH and 3 GP3) and 2 GP3 salvaged after progression. Two GP3 deaths were associated with toxicity; all others were due to disease. Histology among SHH was nodular-desmoplastic (8) or classic (3); GP3 histology was classic (17) or anaplastic (7). Whole-exome sequencing identified 6 somatic PTCH1 and 1 germline SUFU alteration(s) among 9 SHH. Among GP3, no p53 mutations were found; copy-number analysis identified 5/25 with myc-amplification, 5/25 iso17q, 11/25 with 8 loss, 14/25 with loss of 11. Among GP3, 14/19 had no significant germline mutation. ACNS0334 achieved 100% survival for metastatic SHH. Benefit of methotrexate was observed in GP3 MB supporting incorporation of methotrexate into standard therapy for GP3. Upfront central pathology review and molecular sub-typing are critical for future clinical trial risk stratification of young children with embryonal tumors.
MBCL-52. ENDOCRINE PROFILE AFTER MEDULLOBLASTOMA TREATMENT
Authors: Pavon-Mengual Miriam , Curry Helen , Saraff Vrinda , Mohamed Zainaba , Benghiat Helen , Ford Daniel , Peet Andrew , Adamski Jenny , English Martin
Published: December 2020

BACKGROUND

Treatment of medulloblastoma has evolved substantially with more chemotherapy, risk-adapted dosing of radiotherapy (RT) and new RT techniques. We present the endocrine profile for our patients treated over a 20-year period.

METHODS

The charts of patients treated for medulloblastoma between 1/1/00 and 31/12/19 were reviewed. 105 were available. Group 1 received chemotherapy alone, Group 2 received 23.4 Gy whole CNS RT with a posterior fossa (PF) boost to 54 Gy, Group 3 received > 35 Gy whole CNS RT with PF boost to 54–59 Gy, Group 4 received PF RT to 54 Gy. All received chemotherapy according to national guidelines or clinical trials relevant at the time.

RESULTS

Group 1 (M:F 11:6, 7 survivors mean age 2 years range 1–7) had no endocrinopathies. At 5 years from diagnosis Group 2 (M:F 15:13) and Group 3 (M:F 35:14) had the following %

RESULTS

Survival 77:61; Growth Hormone deficiency 92:100; Thyroid deficiency 75:81; ACTH deficiency 42:33. Girls were more likely to need sex hormone replacement than boys. Group 4 (M:F 7:5 mean age 2) were all treated in the first decade. 3 survivors, one GH deficiency, one thyroxine deficiency, one both.

CONCLUSIONS

There is a trend to earlier endocrinopathies in the group 3 vs group 2 patients, but it does not reach statistical significance. Girls are more likely to need sex hormone replacement than boys. This investigation provides a contemporary profile of endocrinopathy after treatment for medulloblastoma that can be used for future comparisons.
MBRS-01. DISSECTING REGULATORS OF THE ABERRANT POST-TRANSCRIPTIONAL LANDSCAPE IN MYC-AMPLIFIED GROUP 3 MEDULLOBLASTOMA
Authors: Kameda-Smith Michelle , Zhu Helen , Luo EnChing , Venugopal Chitra , Xella Agata , Brown Kevin , Fox Raymond , Yee Brian , Xing Sansi , Tan Frederick , Bakhshinyan David , Adile Ashley , Subapanditha Minomi , Picard Daniel , Moffat Jason , Fleming Adam , Hope Kristin , John Provias , Remke Marc , Lu Yu , Reya Tannishitha , Reimand Juri , Wechsler-Reya Robert , Yeo Gene , Singh Sheila
Published: December 2020

Medulloblastoma (MB) is the most common solid malignant pediatric brain neoplasm, with Group 3 (G3) MB representing the most aggressive subgroup. MYC amplification is an independent poor prognostic factor in G3 MB, however, therapeutic targeting of the MYC pathway remains limited and alternative therapies for G3 MB are urgently needed. Here we show that an RNA-binding protein, Musashi-1 (MSI1) is an essential mediator of G3 MB in both MYC-overexpressing mouse models and patient-derived xenografts. Unbiased integrative multi-omics analysis of MSI1 function in human G3 MB suggests a paradigm shift beyond traditional gene-based profiling of oncogenes. Here we identify MSI1 as an oncogene in G3 MB driving stem cell self-renewal through stabilization of HIPK1 mRNA, a downstream context-specific therapeutic target for drug discovery.
MBRS-06. Gli3 INDUCES NEURONAL DIFFERENTIATION IN WNT- AND SHH- ACTIVATED MEDULLOBLASTOMA
Authors: Natsumeda Manabu , Miyahara Hiroaki , Yoshimura Junichi , Tsukamoto Yoshihiro , Oishi Makoto , Wataya Takafumi , Eberhart Charles , Kakita Akiyoshi , Fujii Yukihiko
Published: December 2020

BACKGROUND

We have previously investigated the expression of Gli3, a downstream target of the Sonic Hedgehog pathway, which main function is to suppress Gli1/2 in medulloblastomas. We found that Gli3 is associated with neuronal and glial differentiation in desmoplastic / nodular (D/N) type medulloblastomas (Miyahara et al., Neuropathology, 2013). In the present study, we investigated the expression of Gli3 in molecular subgroups.

METHOD

Thirty-one medulloblastomas treated at Niigata University between 1982 and 2013 were studied. Molecular classification into 4 subgroups (WNT-activated, SHH-activated, Group 3 and Group 4) using Nanostring and immunohistochemistry was performed. Furthermore, Gli3 and Gli1 expression in molecular subgroups was assessed using public data bases.

RESULTS

Nanostring was considered reliable (confidence > 0.9) in 28 cases. Four cases were classified as WNT-, 5 cases as SHH-activated, 4 cases as Group 3 and 16 cases as Group 4. Gli3 was positive in 7 out of 9 (78%) WNT-/SHH- cases, but positive in only 8 out of 19 (42.1%) non-WNT-/SHH- subgroup cases (p = 0.1145, Fisher’s exact test). R2 database analysis confirmed that Gli3 was significantly elevated in WNT- and SHH-activated medulloblastoma. Gli1 was elevated in SHH-activated cases but suppressed in WNT-activated cases. IHC analysis revealed that Gli3 was elevated inside nodules showing neuronal differentiation in D/N type medulloblastoma. Results of single cell RNA analyses were consistent with those of IHC, Nanostring and R2.

CONCLUSION

These results suggest that Gli3 is elevated inside the nodules of SHH-activated medulloblastoma, whereas in WNT-activated cases, Gli3 diffusely suppresses HH signaling.
MBRS-16. MYC REGULATED LONG NONCODING RNA LNC-HLX-2–7 IS A PUTATIVE MOLECULAR MARKER AND A THERAPEUTIC TARGET FOR GROUP 3 MEDULLOBLASTOMAS IN CHILDREN
Authors: Katsushima Keisuke , Joshi Piyush , Stapleton Stacie , Garancher Alexandra , Vibhakar Rajeev , Raabe Eric , Eberhart Charles , Wechsler-Reya Robert , Jallo George , Perera Ranjan
Published: December 2020

Medulloblastoma (MB), a central nervous system tumor that predominantly affects children, requires aggressive therapy. Recent advances in the noncoding RNA genome could contribute to the sub-classification of medulloblastoma. The focus of this study is to identify novel long noncoding RNAs (lncRNAs) as molecular markers and potential therapeutic targets within each subgroup of MBs, in particular within Group 3. We analyzed publicly available 175 RNA-seq datasets to identify a group of putative lncRNA signatures that may be able to differentiate medulloblastoma subgroups accurately. Among those, lncRNA lnc-HLX-2–7 was highly upregulated in Group 3 MB cell lines, patient-derived xenografts, FFPE samples compared to other groups. CRISPR/Cas9 deletion of the lnc-HLX-2–7 followed by the fluorescence-activated sorting and generating monoclonal Group 3 MB cells significantly reduced the cell growth and 3-D colony formation together with the induction of apoptosis. Intracranial injection to mouse cerebellum using lnc-HLX-2–7 deleted cells resulted in reduced tumor growth compared to parental cells, and tumors were further characterized by single-cell sequencing. We identified that oncogene MYC regulates lnc-HLX-2–7 and its expression can be controlled by the small molecule JQ1, a BET-bromodomain (BRD4) inhibitor that disrupts interactions with MYC. RNA-FISH analysis using FFPE, PDX, and tissue microarrays revealed that lnc-HLX-2–7 expression is specific to Group 3 MB compared to other groups. We present supporting evidence that lnc-HLX-2–7 is a novel molecular marker and a potential therapeutic target for Group 3 MBs in children.