bluuebunny/crossref_metadata_2025_split huggingface dataset:
OTHR-13. Effectivity and toxicity of off-label treatment with Trametinib monotherapy or in combination with Dabrafenib in children with relapsed or refractory brain tumor
Authors: Bregonje S (Selena) , de Vos-Kerkhof E (Evelien) , Engels F K (Frederike) , van Veelen M L C (Marie-Lise) , van der Lugt J (Jasper) 
Published: June 2022

Abstract
INTRODUCTION: Most pediatric low grade gliomas, and a substantial part of PXAs, have a BRAF alteration/activated MAPK pathway. This group often requires several lines of therapy, which coincides with significant morbidity. There is growing evidence that molecular targeted treatment may be beneficial for this population. Here we report the toxicity and efficacy of patients treated off-trial with either trametinib monotherapy or in combination with dabrafenib. METHODS: We performed a single-center retrospective chart review of all neuro-oncological patients who received trametinib monotherapy or in combination with dabrafenib (compassionate-use) in the Princes Maxima Center between April 1st, 2018 and December 31st, 2021. RESULTS: 22 patients (ages 1-21 years) were included of whom 14 received trametinib monotherapy (BRAF-KIAA fusion, n=10) and eight received trametinib/dabrafenib combination therapy (BRAFV600 mutation, n=8). All patients on trametinib monotherapy (n=14) developed skin problems such as rash (100%), dry skin (86%), paronychia (71%) and eczema (64%). Eight patients (57%) had at least one adverse event (AE) ≥grade 3. Patients on trametinib and dabrafenib showed similar toxicity, although with lower prevalence and no paronychia. One patient (13%) had an AE ≥grade 3. Median treatment time of trametinib was 514 days (IQR 455) and for trametinib and dabrafenib 360 days (IQR 512). Five patients (36%) on trametinib are still on treatment and nine patients (64%) stopped treatment due to e.g. tumor progression or toxicity. All patients on trametinib and dabrafenib are still on treatment. Best overall response of trametinib monotherapy (n=14 evaluated) was observed as partial response (50%), stable disease (33%) and progressive disease (17%). Combination therapy (n=7 evaluated) brought 100% partial response. CONCLUSION: Dermatological toxicities are mostly seen in trametinib monotherapy or in combination with dabrafenib. Despite moderate toxicity patients seem to benefit from treatment. Results suggest that combination therapy has a more favorable toxicity profile than monotherapy.
OTHR-14. Responding to the COVID Challenge: evaluating a new method of adverse event recording in response to remote working.
Authors: Reiners Stephanie , Barnwell Alison , Murray Lisa , Abdelbaki Mohamed , Jones Sally , Lluka Brunilda , Roemerman Heather 
Published: June 2022

Abstract
BACKGROUND: The SARS-COV2 pandemic had huge impact on how clinical research is conducted when clinical research coordinators (CRC) transitioned to working remotely. An urgent transition of paper documentation into electronic formats had to occur without compromising participant safety or data integrity. Adverse event (AE) reporting had previously been captured in various paper formats with wet signature. AEs, attribution, severity, and clinical significance had to be changed into being electronically captured and incorporated into the medical record that captures the events in real time. METHOD: We assessed the satisfaction of the new method of AE recording amongst pediatric hematology oncology physicians and staff in a large academic institution during the COVID pandemic through a REDCap survey. The survey assessed the time, effort, perceived efficacy and overall acceptability of the paper-based and electronic methods of AE documentation. RESULTS: Seventy-one staff members were surveyed. Fifty (65%) responded, including 6 participants who were not involved in the AE reporting process and did not complete the survey. Of the remaining 44 participants, 43 (98%) preferred an electronic documentation method. Secondary results and further analysis will be presented at the meeting. CONCLUSIONS: The COVID pandemic has changed how CRC report AEs and electronic documentation seems to be the preferred method of documentation.
PATH-01. Infant-Type Hemispheric Glioma: New Molecular Alterations and Precision-Medicine Treatment
Authors: Hu Wanming , Yuan Li , Zeng Jing 
Published: June 2022

Abstract
BACKGROUND: Infant-type hemispheric glioma, harboring alterations in the receptor tyrosine kinases ALK, ROS1, NTRK and MET, is a new subtype of Pediatric-type diffuse high-grade gliomas in the 2021 WHO classification of CNS tumors. It has important clinical therapeutic value with specialized therapeutic drugs. Here, we presented 3 cases of infant-type hemispheric glioma. Patient1 with EML4-ALK fusion which often appeared in lung cancer, the other 2 patients have new molecular alterations which has not been reported before (Patient2 has both NTRK1-TP53/TP53-NTRK1 fusions and p53 protein showed characteristic cytoplasm positive; Patient3 presented a brand-new ALK-QKI fusion combined with ALK mutation and focal SMARCB1 deletion. All these 3 cases received corresponding targeted therapy and have a good recovery and normal neurologic function till now.
METHOD: Immunohistochemistry, fluorescent in situ hybridization and whole-transcriptome sequencing. RESULTS: Case 18 months, male, right semiovale center occupation. Histopathology: High-grade neuroepithelial neoplasm. IHC: GFAP(only few cells+), Olig2(-), S100(+), CD56(+), Syn(-), NSE(focal+), NeuN(-), CD34(-), INI-1(+), Ki67(10%+). Characteristic Molecular Information: EML4-ALK fusion. Follow-up: 15 months, alive. Case 2: 3 years, female, insular lobe occupation.Histopathology: Gliosarcoma. IHC: GFAP(partly+), Olig2(partly+), Vimentin(+), P53(cytoplasm+), pan-TRK(+), Ki67(25%+). Reticular fiber staining showed biphasic tissue pattern with reticulin-rich sarcomatous and reticulin-free gliomatous elements. Characteristic Molecular Information: NTRK1-TP53 and TP53-NRTK1 fusion. Follow-up: 27 months, alive. Case 3: 3 years, male, left parietal occipital lobe occupation. Histopathology: GBM and AT/RT. IHC: GFAP(partly+), Olig2(partly+), INI-1(partly-), BRG1(+), SYN(-), CD34(-), BRAF(-), S100(-), CK(-), H3K27M(-), IDH1(-), P53(40%+), ATRX(+), pan-TRK(-), ALK(+), Ki67(30%+). Characteristic Molecular Information: ALK mutation, ALK-QKI fusion, RAD51C mutation and focal SMARCB1(INI-1) deletion. Follow-up: 14 months, alive. CONCLUSION: Infant-type hemispheric glioma is a special kind of glioma, which is particularly suitable for precision-medicine treatment approaches. Their overall survival is good compared with other three pHGG subtype.
PATH-08. DNA methylation profiling improves routine diagnostics of paediatric CNS tumours: a prospective population-based study
Authors: Schepke Elizabeth , Löfgren Maja , Pietsch Torsten , Bontell Thomas Olsson , Kling Teresia , Wenger Anna , Vega Sandra Ferreyra , Danielsson Anna , Dosa Sandor , Holm Stefan , Öberg Anders , Nyman Per , Eliasson-Hofvander Marie , Sandström Per-Erik , Pfister Stefan M , Lannering Birgitta , Sabel Magnus , Carén Helena 
Published: June 2022

Abstract
AIMS: Paediatric brain tumours are rare and establishing a precise diagnosis can be challenging. Analysis of DNA methylation profiles has been shown to be a reliable method to classify central nervous system (CNS) tumours with high accuracy. We aimed to prospectively analyse CNS tumours diagnosed in Sweden, to assess the clinical impact of adding DNA methylation-based classification to standard paediatric brain tumour diagnostics in an unselected cohort. Methods: All CNS tumours diagnosed in children (0-18 years) during 2017-2020 were eligible for inclusion provided sufficient tumour material was available. Tumours were analysed using genome-wide DNA methylation profiling and classified by the MNP brain tumour classifier. The initial histopathological diagnosis was compared to the DNA methylation-based classification. For incongruent results, a blinded re-evaluation was performed by an experienced neuropathologist. Results: 240 tumours with a histopathology-based diagnosis were profiled. A high-confidence methylation score of 0.84 or more was reached in 78% of the cases. In 69%, the histopathological diagnosis was confirmed and for some of these also refined, 6% were incongruent and the re-evaluation favoured the methylation-based classification. In the remaining 3% of cases, the methylation class was non-contributory or could not be predicted. The change in diagnosis would have had a direct impact on the clinical management in 5% of all patients.Conclusions: Integrating DNA methylation-based tumour classification into routine clinical analysis improves diagnostics and molecular information important for treatment decisions. The results from methylation profiling should be interpreted in the context of clinical and histopathological information.
PATH-14. Alteration of histopathological diagnoses by molecular profiling
Authors: Knirsch Stephanie , Milde Till , Pfister Stefan M , Blattmann Claudia 
Published: June 2022

Abstract
Here, we present a 4.5 year old patient presented with disturbed vision (double vision) and nausea over 2 weeks. Cerebral MRI revealed a tumor mass (6.5 x 6 x 5cm) located in the left temporal lobe. A macroscopical complete resection was achieved in May 2020. Conventional histopathology diagnosed a glioblastoma multiforme WHO IV° locally as well upon central review. A pleomorphic xanthoastrocytoma was considered to be unlikley due to the lack of eosinophile granular corpuscules, CD34-positive cells and dense reticulin fibres. The patient received treatment according to the SIOP HGG protocol with a postsurgical radiotherapy (total dosage of 54 Gy) accompanied by oral chemotherapy with temozolomide and valproic acid. After completion of radiotherapy, another 12 cycles of oral temozolomide were applied resulting in 1 year of consolidation treatment. In parallel, the tumor tissue was examined molecularly through the INFORM precision oncology platform (INdividualized Therapy FOr Relapsed Malignancies in Childhood). The results revealed an NTRK1-fusion as possible treatment target. Furthermore, methylation profiling of the tumor classified it as a pleomorphic xanthoastocytoma. The molecular results were completed during treatment of the patient and were discussed interdisciplinary. Finally, the diagnosis was changed integrating histopathology and molecular results, but the treatment was completed. In about 10% of the brain tumor cases within molecular diagnostic studies such as INFORM or PTT, the histopathological diagnosis differs from the molecular results leading to reconsideration of the initial diagnosis and potential impact on clinical management. These results demonstrate the importance of molecular profiling in brain tumors (and sarcomas) to complement conventional histopathology and select appropriate risk adapted treatment, especially in young patients.
PATH-15. Molecular and clinical landscape of CNS tumors arising among adolescents and young adults (AYA) at Memorial Sloan Kettering Cancer Center (MSKCC): a single-institutional experience
Authors: Li Bryan K , Miller Alexandra , Bouvier Nancy , Hill Katherine , Berger Michael F , Sait Sameer Farouk , Karajannis Matthias 
Published: June 2022

Abstract
BACKGROUND: The management of CNS tumors arising among AYA represents an unmet challenge. Treatment may be split between pediatric and adult centers, often with conflicting approaches. Biology also appears to be distinct compared to younger/older age groups but has yet to be fully characterized. Such features would have important implications for prognostication and informing vulnerabilities for targeted therapies.METHODS: To establish the clinical and molecular landscape of these tumors, we analyzed all cases in patients aged 15-39 years old who were treated at MSKCC between 2018-2021. RESULTS: 302 patients with accompanying MSK-IMPACT targeted sequencing, copy number analysis, Archer fusion panel, and clinical data were found. 239/302 cases (79%) were gliomas, with the remaining consisting mainly of neuro-epithelial tumors (n=15; 5%), meningiomas (9; 3%), ependymomas (10; 3%), and embryonal tumors (7; 2%). Among gliomas, 163/239 (68%) had IDH1/2 mutations, which were significantly more enriched for TP53 (121/163; 74%) and ATRX (90/163; 55%) co-mutations compared to IDH-wild type (IDH-WT) (q&lt;0.0001). In comparison, IDH-WT gliomas (n=76) were enriched for alterations in BRAF (16/76 with SNV, 9/76 fusion; q&lt;0.0001), H3F3A (14/76; q&lt;0.0001), PTEN (10/76; q=0.038), and CDKN2A (16/76; q=0.038). Among 113 patients with high-grade gliomas (WHO grade 3/4), those with IDH-WT tumors (n=34) had a poorer prognosis that those with IDH-mutant tumors (n=79) (1 and 5-year OS of 68% and 28% vs. 97% and 76%, respectively) (p&lt;0.0001). Further, a lower frequency of alterations in TERT (26/113; 23%), EGFR (6/113; 5%), and PDGFRA (4/113; 4%) were observed compared to previous studies for adult-only cohorts (~50-70%, 40%, and 10%, respectively). CONCLUSIONS: IDH-mutant gliomas were the most common tumor type seen in this AYA cohort. However, some alterations characteristic of adult high-grade gliomas (TERT, EGFR, PDGFRA) were not as frequently observed. Additional identification of molecular features that predict response to conventional and targeted therapies is underway.
LINC-07. Challenges in management of paediatric CNS tumors in low- and middle-income countries: experience from a tertiary center in Pakistan.
Authors: Zia Nida , Kaleem Bushra , Hamid Ahmer , Moreira Daniel 
Published: June 2022

Abstract
BACKGROUND: The cure rate of children with central nervous system (CNS) tumors in low- and middle-income countries (LMICs) is lower than high-income countries due to under diagnosis, treatment abandonment, lack of appropriate radiological, histopathologic, neurosurgical, radiotherapeutic, and pediatric oncologic services. The present study aimed to evaluate the treatment challenges observed in a tertiary center in Pakistan. MATERIALS AND METHODS: Patients younger than 17 years-of-age with CNS tumors either diagnosed at or referred to Indus Hospital from January 2015 to December 2021 were included. RESULTS: A total of 235 patients were included with a median age of 10.0 years and male preponderance (60.8%). The three most frequent CNS malignancies observed were glioma (105; 44.3%), medulloblastoma (63;26.6%), and ependymoma (34;14.3%). Of 235 patients, 45(19%) received palliative treatment upfront, 37(15.6%) were referred to other institutions for care, and 33 (13.9%) abandoned prior to treatment initiation. Of the 120 (51.0%) patients who started curative treatment, 74(61.6%) completed treatment, 22(18.3%) continue on treatment, 19(15.8%) abandoned treatment, and 5(4.2%) died during treatment . Overall survival in patients on curative treatment at the time of analysis was close to 80%. CONCLUSION: This study describes the outlook of care for children with CNS tumors in a tertiary center of Pakistan.It is observed that high rate of patients with upfront palliation and abandonment lead to poor outcomes. Stigma cancer, financial toxicity, delayed referral and burden of neurosurgeries in government sectors could be contributing to these outcomes. Further work must be done to clarify the barriers to quality care. Futhermore, a conscious effort to increase integrated care for these patients is of utmost importance.
LINC-12. Encouraging early outcomes with image guided pencil beam proton therapy for cranio-spinal irradiation and unique considerations for paediatric population – First report from India
Authors: Gaikwad Utpal , Sudarsan Rishan Thimma , Noufal M P , Jacinthlyn Sylvia , Reddy Ashok K , Panda Pankaj Kumar , Chilukuri Srinivas , Sharma Dayananda , Jalali Rakesh 
Published: June 2022

Abstract
BACKGROUND: To report our experience with image guided pencil beam proton beam therapy (PBT) for craniospinal irradiation (CSI). MATERIALS AND METHODS: Between January 2019 to Dec 2021, we carried out a detailed audit of the first forty patients treated with PBT. All patients were carefully selected after approval from our institutional multidisciplinary tumour and proton board meetings. Median age of the patient cohort was 8 years, and histologies include 20 medulloblastoma, 7 recurrent ependymoma, 3 pineoblastoma, 3 were germ cell tumors and remaining 7 constituted other diagnoses. Forty percent patients received concurrent chemotherapy. We had recorded acute toxicities on a prospectively maintained database. We also report early outcomes in this cohort and discuss limitations of current contouring guidelines during CSI PBT planning. RESULTS: Median CSI dose was 23.4 GyE (Gray Equivalent; range 21.6 - 35). Thirty-five patients (87.5%) completed their CSI without interruption as an outpatient procedure. Five patients required hospital admission during treatment, while one developed grade 3 mucosal toxicity, requiring plan adaptation and treatment break. No patient had grade 2 or more weight loss during the treatment. Forty-five percent (18) developed grade 1 hematological toxicities and 20% (8) developed grade 2 or 3 toxicities; none had grade 4 toxicities. At median follow up of 12 months, 90 % patients are alive of whom 88.9 % are having local control. Special consideration with modification in standard contouring used at our institute helped in limiting acute toxicities in paediatric CSI patients. CONCLUSION: Our preliminary experience with modern contemporary PBT using pencil beam technology and daily image guidance in a range of tumours suitable for CSI is encouraging. Patients tolerated the treatment well with acceptable acute toxicity and expected short-term survival outcome. In paediatric CSI patients, modification in standard contouring guidelines required to achieve better results with PBT
MODL-02. A novelCre-conditionalcMYC-driven MB Group 3 transgenic mouse model shows traceable leptomeningeal dissemination.
Authors: Morcavallo Alaide , Barker Karen , Kwok Colin , Boult Jessica K R , da Silva Patricia Benites Goncalves , Okonechnikov Konstantin , Zuckermann Marc , Gorrini Chiara , Jacques Thomas S , Robinson Simon P , Clifford Steven C , Weiss William A , Pfister Stefan M , Kawauchi Daisuke , Chesler Louis 
Published: June 2022

Abstract
Medulloblastoma (MB), the most common embryonal tumour of the Central Nervous System, occurs in the cerebellum. Treatment regimens involve surgery, craniospinal radiotherapy, and chemotherapy. The greatest mortality is associated with disseminated disease, almost exclusively found in the leptomeningeal space. Unfortunately, knowledge about the aetiology of MB spread is limited and the need for kinder and efficacious therapy remains an unmet goal. Of the four molecular classified MB groups, Group3 (Gr3) MB presents with a high frequency of metastasis at diagnosis, with the worst overall survival. Gr3 MB tumours are dominated by primitive progenitor-like cells and cMYC deregulation; often, p53 deficiency is observed at relapse. To dissect the biology of primary and metastatic Gr3 MB, we have developed a new germline genetically engineered mouse model (GEMM), harbouring cMYC amplification in a Tamoxifen-inducible p53 functional background (Trp53ERTAM strain). A novel LSL-cMYC-CopGFP-Luciferase transgene was integrated into the Rosa-26 locus of the mouse genome. Transgenic mice were crossed with a strain expressing Cre recombinase under the Blbp promoter targeting embryonic neural progenitors, and subsequently bred to Trp53ERTAM mice. As result, the cMYC overexpression was sufficient to generate tumours. Tumour penetrance was observed in all the expected tumour bearing genotypes, with increased aggressiveness in a non-functional p53 background. Bioluminescence imaging demonstrated tumour onset in the brain and dissemination along the spinal cord. CopGFP positive tumour cells were isolated from primary and metastatic tumours. Pathological interrogation confirmed that tumours present large cell/anaplastic (LCA) histology. Analysis of preliminary transcriptional profiling data proved that tumours cluster with human Gr3 MB. Ongoing methylation profiling and multi-omics approaches will inform on the tumour cells of origin and clonal divergence of primary tumour versus metastasis. In conclusion, we have successfully developed a novel immunocompetent mouse model of metastatic Gr3 MB with which we can investigate therapeutic vulnerabilities of MB.
MODL-08. Cellular yield and xenograft creation from probe washing after stereotactic biopsy of deep-seated CNS tumors in children
Authors: DeCuypere Michael , Xiao Sophie , Du Yuchen , Lam Sandi , Li Xiao-Nan 
Published: June 2022

Abstract
Intracranial tumors located in otherwise difficult-to-resect regions of the brain are routinely biopsied to obtain tissue diagnosis and guide clinical decision making. However, tissue yield from these stereotactic biopsy samples is limited and leaves little remaining for research purposes or tumor banking. Given the importance of molecular diagnostics and rise of targeted therapies, research into the genetic and immune landscape of these lesions is of paramount importance, especially for inoperable and deep-seated tumors. We sought to obtain viable cellular material from otherwise discarded biopsy probes without visible tumor sample within the probe. Cells were obtained from clinically challenging pediatric tumors of the brainstem, thalamus, and pineal region by washing biopsy probes in FBS media immediately after completion of a stereotactic biopsy. The wash was then filtered and re-suspended in media before evenly distributing in a 24 well plate for culture purposes. A total of 15 samples were collected from probe washes, including 6 diffuse midline gliomas of the brain stem, 7 supratentorial diffuse midline gliomas, and 2 tumors in the pineal region. Viable tumor cells were obtained from 9/15 samples, ranging from 500 to approximately 525,000 cells per sample wash (219,222 ± 181,951). Orthotopic implantation into matching locations was completed with 7 tumor samples. Formation of a patient-derived orthotopic xenograft was confirmed in one thalamic high-grade glioma (165,000 cells). Three of the five diffuse midline gliomas of the brainstem showed early signs of tumor formation (yielding &gt;2 million cells) and will be validated. In conclusion, viable tumor cells can be collected from biopsy probe washes after stereotactic biopsy, without visible tumor within the probe. Tumor cells can be used for patient-derived orthotopic xenograft tumor formation, which allows for new avenues in the development of animal models of difficult to resect brain tumors.