tbuckley/cabot-search huggingface dataset:
Analysis of 10,478 cancer genomes identifies candidate driver genes and opportunities for precision oncology
Authors: Ben Kinnersley, Amit Sud, Andrew Everall, Alex J. Cornish, Daniel Chubb, Richard Culliford, Andreas J. Gruber, Adrian Lärkeryd, Costas Mitsopoulos, David Wedge, Richard Houlston
Journal: Nature Genetics (2024)

Tumor genomic profiling is increasingly seen as a prerequisite to guide the treatment of patients with cancer. To explore the value of whole-genome sequencing (WGS) in broadening the scope of cancers potentially amenable to a precision therapy, we analysed whole-genome sequencing data on 10,478 patients spanning 35 cancer types recruited to the UK 100,000 Genomes Project. We identified 330 candidate driver genes, including 74 that are new to any cancer. We estimate that approximately 55% of patients studied harbor at least one clinically relevant mutation, predicting either sensitivity or resistance to certain treatments or clinical trial eligibility. By performing computational chemogenomic analysis of cancer mutations we identify additional targets for compounds that represent attractive candidates for future clinical trials. This study represents one of the most comprehensive efforts thus far to identify cancer driver genes in the real world setting and assess their impact on informing precision oncology.
Plasma extracellular vesicle tau and TDP-43 as diagnostic biomarkers in FTD and ALS
Authors: Madhurima Chatterjee, Selcuk Özdemir, Christian Fritz, Wiebke Möbius, Luca Kleineidam, Eckhard Mandelkow, Jacek Biernat, Cem Doğdu, Oliver Peters, Nicoleta Carmen Cosma, Xiao Wang, Luisa-Sophia Schneider, Josef Priller, Eike Spruth, Andrea A. Kühn, Patricia Krause, Thomas Klockgether, Ina R. Vogt, Okka Kimmich, Annika Spottke, Daniel C. Hoffmann, Klaus Fliessbach, Carolin Miklitz, Cornelia McCormick, Patrick Weydt, Björn Falkenburger, Moritz Brandt, René Guenther, Elisabeth Dinter, Jens Wiltfang, Niels Hansen, Mathias Bähr, Inga Zerr, Agnes Flöel, Peter J. Nestor, Emrah Düzel, Wenzel Glanz, Enise Incesoy, Katharina Bürger, Daniel Janowitz, Robert Perneczky, Boris S. Rauchmann, Franziska Hopfner, Olivia Wagemann, Johannes Levin, Stefan Teipel, Ingo Kilimann, Doreen Goerss, Johannes Prudlo, Thomas Gasser, Kathrin Brockmann, David Mengel, Milan Zimmermann, Matthis Synofzik, Carlo Wilke, Judit Selma-González, Janina Turon-Sans, Miguel Angel Santos-Santos, Daniel Alcolea, Sara Rubio-Guerra, Juan Fortea, Álvaro Carbayo, Alberto Lleó, Ricardo Rojas-García, Ignacio Illán-Gala, Michael Wagner, Ingo Frommann, Sandra Roeske, Lucas Bertram, Michael T. Heneka, Frederic Brosseron, Alfredo Ramirez, Matthias Schmid, Rudi Beschorner, Annett Halle, Jochen Herms, Manuela Neumann, Nicolas R. Barthélemy, Randall J. Bateman, Patrizia Rizzu, Peter Heutink, Oriol Dols-Icardo, Günter Höglinger, Andreas Hermann, Anja Schneider
Journal: Nature Medicine (2024)

Minimally invasive biomarkers are urgently needed to detect molecular pathology in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Here, we show that plasma extracellular vesicles (EVs) contain quantifiable amounts of TDP-43 and full-length tau, which allow the quantification of 3-repeat (3R) and 4-repeat (4R) tau isoforms. Plasma EV TDP-43 levels and EV 3R/4R tau ratios were determined in a cohort of 704 patients, including 37 genetically and 31 neuropathologically proven cases. Diagnostic groups comprised patients with TDP-43 proteinopathy ALS, 4R tauopathy progressive supranuclear palsy, behavior variant FTD (bvFTD) as a group with either tau or TDP-43 pathology, and healthy controls. EV tau ratios were low in progressive supranuclear palsy and high in bvFTD with tau pathology. EV TDP-43 levels were high in ALS and in bvFTD with TDP-43 pathology. Both markers discriminated between the diagnostic groups with area under the curve values >0.9, and between TDP-43 and tau pathology in bvFTD. Both markers strongly correlated with neurodegeneration, and clinical and neuropsychological markers of disease severity. Findings were replicated in an independent validation cohort of 292 patients including 34 genetically confirmed cases. Taken together, the combination of EV TDP-43 levels and EV 3R/4R tau ratios may aid the molecular diagnosis of FTD, FTD spectrum disorders and ALS, providing a potential biomarker to monitor disease progression and target engagement in clinical trials.
Circ6834 suppresses non-small cell lung cancer progression by destabilizing ANHAK and regulating miR-873-5p/TXNIP axis
Authors: Maoye Wang, Xiaoge Ding, Xinjian Fang, Jing Xu, Yanke Chen, Yu Qian, Jiahui Zhang, Dan Yu, Xiaoxin Zhang, Xiuqin Ma, Taofeng Zhu, Jianmei Gu, Xu Zhang
Journal: Molecular Cancer (2024)

Abstract Background Circular RNAs (circRNAs) play important roles in cancer progression and metastasis. However, the expression profiles and biological roles of circRNAs in non-small cell lung cancer (NSCLC) remain unclear. Methods In this study, we identified a novel circRNA, hsa_circ_0006834 (termed circ6834), in NSCLC by RNA-seq and investigated the biological role of circ6834 in NSCLC progression in vitro and in vivo. Finally, the molecular mechanism of circ6834 was revealed by tagged RNA affinity purification (TRAP), western blot, RNA immunoprecipitation, dual luciferase reporter gene assays and rescue experiments. Results Our results showed that circ6834 was downregulated in NSCLC tumor tissues and cell lines. Circ6834 overexpression inhibited NSCLC cell growth and metastasis both in vitro and in vivo, while circ6834 knockdown had the opposite effect. We found that TGF-β treatment decreased circ6834 expression, which was associated with the QKI reduction in NSCLC cells and circ6834 antagonized TGF-β-induced EMT and metastasis in NSCLC cells. Mechanistically, circ6834 bound to AHNAK protein, a key regulator of TGF-β/Smad signaling, and inhibited its stability by enhancing TRIM25-mediated ubiquitination and degradation. In addition, circ6834 acted as a miRNA sponge for miR-873-5p and upregulated TXNIP gene expression, which together inactivated the TGF-β/Smad signaling pathway in NSCLC cells. Conclusion In conclusion, circ6834 is a tumor-suppressive circRNA that inhibits NSCLC progression by forming a negative regulatory feedback loop with the TGF-β/Smad signaling pathway and represents a novel therapeutic target for NSCLC.
SURG-01. ULTRA-FAST DEEP-LEARNED CNS TUMOR CLASSIFICATION USING STURGEON; THE IMPACT ON STRATEGY FOR THE PEDIATRIC NEUROSURGEON
Authors: Eelco Hoving, Oscar Eelkman Rooda, Mariska Sie, Carlo Vermeulen, Marc Pages-Gallego, Lennart Kester, Mariette Kranendonk, Pieter Wesseling, Jasper van der Lugt, Bastiaan Tops, Jeroen de Ridder
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Central nervous system tumors still represent one of the most challenging fields to create curation in pediatric oncology. The primary treatment always starts with a neurosurgical intervention to obtain tumor tissue for diagnosis. In most cases this intervention is a maximal safe resection of the tumor. The oncological prognostic value of extent of resection is determined by the precise molecular diagnosis and per-operative ultra-fast molecular classification of central nervous tissue provides the neurosurgeon relevant information for choosing the right strategy. This per-operative molecular diagnosis determines the balance between the need of radicality versus the prevention of neurological morbidity in the individual patient. We shall report on our neurosurgical experiences with the per-operative use of Sturgeon in our national practice of pediatric neuro-oncology in the Netherlands. METHODS The ultra-fast AI-based nanopore sequencing method, Sturgeon, has been implemented as per-operative diagnostic in most neurosurgical tumor resections in our center (1). An overview of our nanopore sequencing pipe- and timeline will be presented and its impact on neurosurgical strategies will be shared. RESULTS Reliable and accurate diagnoses can be obtained within 40 minutes after starting sequencing in 45 out of 50 retrospectively sequenced samples (while abstaining from diagnosis of the other 5 samples). The implementation in real time surgery results in a turnaround time between taking out sample material to diagnosis in less than 90 minutes. The most important result is that there is a high sensitivity and virtually no false positives since it is refraining from diagnosis when there is too much uncertainty. Several illustrative cases with impact on the neurosurgical strategy have been collected. CONCLUSION Ultra-fast deep-learning CNS tumor classification using Sturgeon is feasible. Results of per-operative implementation illustrate the impact on neurosurgical strategy. 1. Ultra-fast deep-learned CNS tumour classification during surgery. Vermeulen C et al. Nature. 2023 Oct;622(7984):842-849.
LMIC-25. EXPANDING THE PEDIATRIC NEURO-ONCOLOGY TELECONFERENCE EXPERIENCES, A LUXURY, OR A NECESSITY?
Authors: Essra’ Al Badarin, Omar Chamdine, Moatasem El-Ayadi, Abeer Al-Battashi, Mohammed Al Nuaimi, Emam Alshamsi, Laila Hessissen, Hiba Al-Tarrah, Eslam Maher, Roula farah, Ata Ur Rehman Maaz, Waleed Saed, Ruba Haziemeh, Maher Khader Mustafa, Khadra Salami, Cynthia Hawkins, Mohamed Abdelbaki, Ute Bartels, Uri tabori, Eric Bouffet, Nisreen Amayiri
Journal: Neuro-Oncology (2024)

Abstract INTRODUCTION Videoteleconference in neurooncology is feasible and sustainable. The well-established 20 years’ Sickkids/KHCC teleconferencing is an example. Since 2018, several regional centers joined these meetings to discuss their patients’ management plans. We aimed to evaluate the impact of this experience. METHODS We retrospectively reviewed the 56 meetings’ minutes (9/2018-12/2023) and compared the pre-conference suggested plans with the post-conference recommendations. We recorded if the recommendations were implemented and the impact perceived. RESULTS In total, 251 patients were discussed: KHCC (137) and non-KHCC (114). Four of the regional participating oncologists had dedicated pediatric neuro-oncology training. Patients were selected for discussion due to challenges in their management (i.e. with relapsed tumors, rare diagnoses, unexpected tumor behavior). Main diagnoses were: Low-grade-glioma (28%), High-grade-glioma (21%), and Medulloblastoma (17%). Of the 227 patients where the local team suggested a care plan, the teleconference recommendations concurred with the proposed plan in 50% of the cases, agreed on but provided an alternative plan option in 18% and disagreed on in 32% of the cases. The difference in recommendations mostly affected the proposed treatment modality (15%). In 64% of the discordant plans and 50% of the alternative plans, the treating team applied the recommendations. Challenges to apply the recommendations were mainly linked to patients’ factors (53%, plan refusal, traveling abroad, clinical deterioration), local multidisciplinary team consensus on a different plan (29%) or logistic difficulties (18%, e.g. drug access). CONCLUSIONS Improvement in patients’ care was likely achieved with the continuous effort of the local teams to implement the recommendations. Participating oncologists valued the shared educational experience learned from each other’s case discussions, especially those related to molecular-testing and implications on treatment. Joining such regional teleconferences is of particular importance to small-volume centers or those lacking a pediatric neurooncologist. Regional and international collaborations are a necessity when it comes to improving the care of children with CNS tumors.
LMIC-22. TOWARD A COMPREHENSIVE PEDIATRIC BRAIN TUMOR REGISTRY: ESTABLISHING FUNDAMENTAL VALUE IN INDONESIA TERTIARY HOSPITAL
Authors: Ludi Dhyani Rahmartani, Michael Nathaniel Budiarso, Ganda Ilmana, Riski Muhaimin, Eka Susanto, Mohamad Yanuar Amal, Endang Nuryadi, Achmad Rafli, Kevin Gunawan
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Systematic documentation and research on pediatric brain tumor (PBT) have been underreported in Indonesia. Precise and readily available epidemiological data hold significant value in enhancing the PBT service of any center, each with its own distinctive characteristics. We aim to evaluate our PBT registry and service after Cipto Mangunkusumo National General Hospital utilized the St. Jude (SJ) Cares Registry program. METHODS A retrospective observational longitudinal study, carried out at Cipto Mangunkusumo National General Hospital, utilizing primary registry data encompassing patients’ profiles, diagnoses, and follow-up issues from January 2022 to December 2023, was performed. An evaluative review was then carried out to delineate our center’s unique problems and solutions to improve the overall PBT health services. RESULTS A total of 103 patients participated, dominated by females (55.3%), with a median age of 8 (IQR 4-12). The most identified diagnoses were gliomas (48.6%), germ cells (16.5%), and medulloblastomas (8.7%), with high-grade gliomas contributing to the most death (48.4%). The main symptoms contributing to the most extended diagnosis delay (from onset to diagnosis) were puberty issues, motoric paresis, vertigo, macrocephaly, proptosis, disequilibrium, and headache. Some critical findings from this registry evaluation were the mapping of patients’ key clinical symptoms and most diagnoses to be anticipated, factors related to diagnosis delay, and the numerous ineffective yet revisable health service systems that led to incomplete patient data and loss of follow-up. These led to our team’s effort to implement more effective multidiscipline communication (through regular synchronous and asynchronous meetings), orbit the pediatrician to become the St. Jude virtual fellow and recruit more trained data registry specialists. CONCLUSION In conclusion, as each center has unique problems in its own PBT health services, it is essential to have accurate registry data to be the fundamental value and starting point for comprehensively delineating and improving PBT service.
LMIC-20. REAL-WORLD EXPERIENCE IN DEALING WITH CHILDREN WITH SUSPECTED CENTRAL NERVOUS SYSTEM (CNS) TUMORS AT THE CHILDREN’S HOSPITAL LAHORE (UCHS), PAKISTAN
Authors: Rahat Ul Ain, Laeeq Ur Rehman, Rabia Aqeel Qaiser, Mahwish Hussain, Amber Goraya, Samina Zaman, Alia Ahmad, Shazia Riaz, Mahwish Faizan, Zeena Salman, Ibrahim Qaddoumi, Naureen Mushtaq, Eric Bouffet
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND CNS tumors are the leading cause of cancer-related deaths in children in HICs, but data from LMICs are scarce. The objectives of this study were to document the trajectory of children with CNS tumors at a tertiary-care hospital in Pakistan. METHODS This prospective, analytic, cohort study recorded all new cases of suspected CNS tumors (birth to 16 years) presented from 2023/01/01 to 2023/12/31 at UCHS, Lahore. RESULTS A total of 145 cases were included. Median age at presentation was 7.0 years (1.5 months–15 years); male-to-female ratio was 1.4:1. Median time to presentation was 2 months (0.1 – 96 months); delay of &amp;gt;6 months was observed in 30.5% cases due to delayed presentation to medical facility (74%) and healthcare delay (26%). Headaches and vomiting (56%), focal neurological deficit (23%), and seizures (15%) were the most common presenting complaints. Consanguinity (46%), and family history of cancers (19%) were frequent; café au lait macules were observed in 9.7%. 50% tumors were infratentorial, 46% supratentorial and 4% spinal. Tumor excision was done in 45%, VP-shunts in 42%, and upfront chemotherapy in 2%. Only 60% had a final diagnosis. Tissue diagnosis in 39% cases showed Medulloblastoma (18 patients, 32%), Pilocytic Astrocytoma (27%), and High-grade glioma (16%) as the commonest diagnoses, while 21% had a radiological diagnosis based on CT/MRI features: DIPG/DMG (12%), Craniopharyngioma (7.6%), and Optic Pathway Glioma (1.4%). Of 18 medulloblastoma patients, only 7 received postoperative radiotherapy. Seventy (48%) patients expired (including 38 before surgery), 27% are on follow-up and 25% are LAMA/LTFU/defaulted treatment. One-year survival was 36% with median survival of 4 months (0.07-96 months). CONCLUSION Less than half of the patients with CNS tumors undergo active treatment, a large proportion leave treatment/follow-up and have poor overall survival. Considerable cases with cancer predisposition syndromes were suspected.
SURG-02. INTRAOPERATIVE APPLICATION OF A POLYMER-BASED HYDROGEL AGAINST MEDULLOBLASTOMA GROUP 3 AND ATYPICAL TERATOID/RHABDOID TUMOURS
Authors: Cara Moloney, Amr ElSherbeny, Phoebe McCrorie, Harry Porter, Chiara Bastiancich, Hulya Bayraktutan, Umut Can Oz, Richard G Grundy, Karin Forsberg Nilsson, Henry Brem, Cameron Alexander, Betty Tyler, Stuart J Smith, Ruman Rahman
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Local drug delivery systems (LDDSs) applied during neurosurgery offer a means of overcoming poor blood brain barrier (BBB) permeability and have been extensively investigated for the treatment of adult gliomas. To the best of our knowledge, they have not been investigated for the treatment of paediatric cerebellar tumours, including medulloblastoma group 3 (MB3) and atypical teratoid/rhabdoid tumours (ATRT), both of which are associated with poor prognoses. METHODS We prepared and characterised an injectable and biodegradable poly(ethyleneglycol)-poly(caprolactone)-poly(ethyleneglycol) (PECE) hydrogel, which has been investigated broadly throughout the literature with an array of therapeutic agents against numerous cancer types. Here, we loaded the PECE hydrogel with chemotherapeutics previously identified as being effective against primary MB3 and ATRT in vitro, but which do not cross the BBB in vivo, namely CHIR99021, ribavirin and PG545. Biocompatibility and cytotoxicity of drug loaded hydrogels was assessed in vitro. LDDSs safety and efficacy was evaluated using patient derived MB3 and ATRT intracranial xenograft resection models. RESULTS The hydrogel was both biocompatible and effected cytotoxicity following drug release. In vivo efficacy experiments against MB3 indicated a comparable median survival in treatment arms receiving radiotherapy or CHIR99021 and PG545 loaded LDDS. However, combined radiotherapy and LDDS conferred a significant survival enhancement including long-term survivors. Against ATRT, the median survival of arms receiving radiotherapy was comparable to that of the CHIR99021 and ribavirin loaded LDDS, with long-term survivors observed only in the latter arm. CONCLUSIONS The application of LDDSs against cerebellar brain tumours offers a promising novel therapeutic alternative. For MB3, the combination of radiotherapy and a LDDS significantly enhances survival compared to radiotherapy alone. For ATRT, the comparable survival of the LDDS and radiotherapy alone is encouraging and indicates the possibility of circumventing radiation-induced adverse effects for young children impacted by this disease.
NURS-11. NEURO-ONCOLOGIC EMERGENCY MANAGEMENT
Authors: Caroline Fitzgerald, Alison Phelan
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Due to disease location, neuro-oncology patients experience emergencies that are infrequently encountered in general oncology and require unique interventions. Paramount among these emergencies is vasogenic cerebral edema (CE). Urgent and accurate interventions are needed to decrease associated morbidity and mortality. In an educational institution, access to knowledge of next steps is crucial. This prompted further inquiry of best practice into recognition of increasing intracranial pressure (ICP) and management of cerebral edema using a literature review and reflection on institutional experience. METHODS A literature review was conducted using pubmed to identify articles through January 2014. The Key words used in the search included “neuro-ongologic emergencies” “brain herniation management” “cerebral edema. RESULTS The searched yielded 3237 results. Of these, 3236 were excluded. Ten full text articles were relevant and included in the review. In combination with the literature and institutional experience of neuro-oncological emergencies, interventions and outcomes were evaluated to provide recommendations for treatment in the event of an emergency. CONCLUSION CE is not an uncommon finding with malignant brain tumors given disrupted blood brain barrier. This subsequently increases ICP and left unmanaged, can lead to brain herniation. Signs and symptoms can vary depending on tumor location and extent of edema. Most common exam findings to be aware of include headache, nausea, vomiting, altered pupil exam, abnormal eye movements, and altered consciousness. Ultimately surgical intervention may be the definitive treatment, non-surgical management is important. Literature review supported the use of both high dose dexamethasone and hyperosmolar solutions are temporizing measures to decrease CE. Additional measures such as positioning, treatment of pain or fever, are also recommended. Prompt recognition and intervention of CE are crucial to improved patient outcomes. An educational poster with recommendations for best practice when encountering neuro-oncological emergencies will be created. Dissemination of findings will be done at local, national and international levels.
SURG-03. VIRTUAL REALITY ASSISTANCE IN THE MANAGEMENT OF PEDIATRIC BRAIN TUMORS
Authors: Andrea Carai, Roberto Premuselli, Matteo Barba, Alessandra Marasi, Eleonora Piccirilli, Antonella Bua, Giada Del Baldo, Alessandro De Benedictis, Claudia D’Orazio, Antonella Cacchione, Alessandra Savioli, Carlo E Marras, Giovanna S Colafati, Angela Mastronuzzi
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Virtual reality (VR) solutions are emerging as a useful adjunct to the armamentarium of the neurosurgeon. Surprisingly, little data is available in the literature regarding its utility in pediatric neurosurgical oncology. We hereby report our preliminary Institutional experience on the application of VR to surgical rehearsal in a series of pediatric brain tumors. METHODS Virtual models were obtained by the Surgical Planner (Surgical Theatre, Inc) in a series of 50 consecutive brain tumor cases treated at Bambino Gesù Children’s Hospital. Utility of VR was scored based on operators’ perception. Explored items included: planning, execution, resection, sparing of eloquent tissue, and overall surgical management. Scoring was performed using a customized Likert scale. RESULTS We prospectively collected 100 consecutive questionnaires from surgeons participating to brain tumor resection procedures. In a multivariate analysis VR was found to be significantly more beneficial in specific surgical settings. Leading surgeons (LS) judged VR significantly more useful in supratentorial tumors, in children younger than 10 years, and in planned partial resections. Assistant surgeons (AS) found VR more useful in supratentorial lesions, particularly in deep seated tumors. Both LS and AS perceived VR to be less useful for in embryonal tumors and epilepsy-associated gliomas (LEAT). CONCLUSIONS Our data suggest that VR technology is useful in the surgical management of children with brain tumors. There might be specific clinical scenarios in which the advantage of VR availability might have a significant clinical impact in planning and performing surgical resection.