tbuckley/cabot-search huggingface dataset:
CP-08. THE CLINICAL CHARACTERISTICS OF CHILDREN WITH CRANIOPHARYNGIOMA AND THEIR MANAGEMENT IN UGANDA: A RETROSPECTIVE REVIEW
Authors: Victoria Mwebe Katasi, Deogratius Munube, Murali Chintagumpala, Ronald Naitala, Phillip Kasirye, Peter Wasswa Muwonge, Joseph Lubega, Jennifer Zungu, Cathy Nabbagala, Anne Akullo, Annet Nakirulu, Ruth Namazzi, Julie Ssekabunga, Peter Ssenyonga, Justin Onen, Emmanuel Wegoye
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Craniopharyngiomas are benign brain tumors that mostly arise in the sellar/suprasellar region. Histologically though benign, these tumors can locally infiltrate with involvement of surrounding structures. They have a 5-year survival rate of above 80% in High Income Countries (HIC). Craniopharyngioma management includes surgery, radiotherapy and intracystic treatments and requires a multi-disciplinary team. The morbidity associated with treatment must be weighed against tumor recurrence and quality of life after treatment. Endocrine deficiencies, especially growth hormone deficiency and visual deficits are common presenting features. OBJECTIVE To describe the clinical characteristics and management of children with craniopharyngioma managed at Mulago National Referral Hospital from March 2019 to December 2023. METHODOLOGY A retrospective descriptive study was conducted among patients&amp;lt; 18 years of age, admitted to the Mulago National Referral Hospital (MNRH) from March 2019 to December 2023 with a radiological diagnosis of a craniopharyngioma. RESULTS A total of 151 children with a diagnosis of a brain tumor during this period were identified and of these 40 (26%) were diagnosed with craniopharyngioma. The median age was 8.4 years and 22 (55%) were males. Only 2 children had maximal safe resection (sub-total resection), one of whom later received adjuvant external beam radiotherapy. Thirty-eight patients had insertion of ommaya reservoirs as their tumors were predominantly cystic. Two patients received intracystic bleomycin and 11 received radical external beam radiotherapy. Twenty-seven patients had no additional therapy after ommaya reservoir placement. Fifteen (39%) of the patients had endocrine deficits with hypothyroidism, hypocortisolism and growth hormone deficiency being the most common. The median follow-up time was 1.45 years. The overall survival was 67.5%, 95%CI(42.5-83.5). CONCLUSION Management of patients with craniopharyngioma in Uganda is mostly conservative with the aim of intervention to preserve quality of life. Limited access to radiation therapy contributed to the poorer survival compared to HIC.
DIPG-20. SURGICAL INTERVENTION’S CORRELATION WITH SUBSEQUENT METASTASIS DEVELOPMENT IN CHILDREN WITH DIFFUSE INTRINSIC PONTINE GLIOMAS (DIPG)
Authors: SHOAIB BASHIR, Jiangfen Zhou, Mingyao Lai, Linbo Cai
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive pediatric brain tumor with a poor prognosis. Currently, there is no curative treatment option available for these patients. These patients often undergo surgery to confirm the diagnosis pathologically. However, the relationship between surgery and dissemination is to be confirmed. This retrospective cohort determines if surgical intervention increases the risk of dissemination and what other factors may also be associated. METHODS The final analysis included 142 pediatric (age ≤ 12) DIPG patients treated at Sanjiu Brain Hospital between January 2017 and June 2023. The data were retrospectively collected following the initial diagnosis. The diagnosis was established based on imaging studies. Three radiologists analyzed the imaging data. The endpoint was the occurrence of subsequent metastasis. Univariable and multivariable logistic regressions were performed to identify predictors of subsequent dissemination. All statistical assessments were two-tailed; only P &amp;lt; 0.05 was considered statistically significant. RESULTS Of 142 patients, 28 (19.7%) developed metastasis, and 114 (80.3%) had no evidence of metastasis. There were 77 (54.2%) males and 65 (45.8%) females. The patients’ median age was 7 years (1-12 yrs.). Patients were followed up for at least 6 months or until they developed subsequent metastasis or died without developing metastasis. Univariate logistic regression analysis demonstrated that surgery (OR 4.277, 95%CI 1.753 - 11.607, P=0.002), adjuvant temozolomide (OR 2.891, 95%CI 1.097 - 9.106, P=0.045), and adjuvant bevacizumab (OR 10.278, 95%CI 3.759 - 9.444, P=0.003) were the potential predictor of metastasis development. Multivariate logistic regression analysis showed that surgery (OR 5.061, 95%CI 1.966 - 14.508, P=0.001) and administration of adjuvant bevacizumab (OR 3.020, 95%CI 1.196 - 8.065, P=0.022) were the independent predictors of dissemination. CONCLUSION Surgery and adjuvant bevacizumab may increase the risk of subsequent metastasis in the pediatric DIPG population.
DIPG-15. NOVEL CNS SENSING SYNNOTCH-CAR T CELLS FOR TARGETING DIFFUSE MIDLINE GLIOMA
Authors: Senthilnath Lakshmanachetty, Milos Simic, Jeffrey Haegelin, Payal Watchmaker, Haoyu Long, Jason Deucker, Robert Zhu, Chanelle Sheperd, Wei Yu, Ben Ng, Yuan Wang, Olga Troyanskaya, Lia Cardarelli, Sachdev Sidhu, Wendell Lim, Hideho Okada
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Diffuse midline glioma (DMG), including Diffuse intrinsic pontine glioma (DIPG), is an aggressive brain tumor in children with limited treatment options. Recent developments of phase 1 clinical trials have shown early promise for chimeric antigen receptor (CAR) T cells in patients with DMG/DIPG. However, several barriers such as the absence of tumor-specific antigens, restricted trafficking to the tumor site, and poor persistence hinder the full therapeutic potential of CAR T cell therapy in DMG/DIPG. METHODS To safely target the glioma-associated antigens (GAAs) without attacking nomal tissues expressing the same antigens, we adopted a novel synthetic Notch (synNotch) receptor system and engineered T cell circuits employing a “prime-and-kill” strategy. In this system, a synNotch receptor recognizing the priming antigen, Brevican (BCAN), exclusively expressed on cells in the central nervous system (CNS) but not on non-CNS cells, locally induces the expression of a tandem CAR against GAAs, ephrin type A receptor (EphA2) and interleukin-13 receptor a2 (IL13Ra2), there by homogenously eliminating DMG/DIPG cells. RESULTS The α-BCAN synNotch⋄α-EphA2/IL-13Rα2 CAR (B-SYNC) T cells efficiently killed DMG/DIPG (BT-245, SF8628, SU-DIPGXIII, and SU-DIPGXVII) cells in vitro in the presence of priming cells (K562 cells expressing BCAN). Moreover, a single intravenous infusion of B-SYNC T cells significantly (P&amp;lt; 0.001) prolonged the survival of immunodeficient mice bearing aggressive, orthotopic SF8628 DIPG xenografts and completely eradicated the tumor in more than 50% (4/7) of mice. Strikingly, we observed excellent homing, priming, activation, and persistence of B-SYNC T cells in the brain stem of mice bearing SF8628 xenografts. In contrast, constitutively active α-EphA2/IL-13Rα2 CAR T cells or untransduced T cells demonstrated a failure to migrate to the brain stem and improve the survival of mice. CONCLUSIONS Collectively, our findings strongly support the development of clinical trials evaluating the efficacy of B-SYNC T cells in DMG/DIPG patients.
DIPG-46. TOTAL THERAPY FOR DIFFUSE MIDLINE GLIOMAS: A SEQUENTIAL, INTENSIVE, MULTI-AGENT COMBINATION PLATFORM IS A POTENT TREATMENT STRATEGY
Authors: Aaminah Khan, Dannielle Upton, Anjana Gopalakrishnan, Yongjuan Chen, Maria Tsoli, David S Ziegler
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Diffuse Midline Glioma (DMG) has a dire prognosis, with a mortality rate nearing 100%. In the past, children diagnosed with Acute Lymphoblastic Leukemia (ALL) faced a similar prognosis until multi-agent chemotherapy revolutionized their survival rates. We hypothesized that implementing a comprehensive treatment strategy for DMG could yield similar efficacy. This study aimed to test the safety and efficacy of sequential, intensive, multi-agent combinations targeting epigenetic/chromatin modification (CBL0137-Panobinostat, CP), polyamine metabolism (DFMO-AMXT1501, DA), and the NF-κB pathway (ACT001) in preclinical DMG models. METHODS/RESULTS Maximum tolerated dose studies, which integrated comprehensive biochemical and hematological analyses with clinical data, tested different treatment durations and drug sequences. Tolerable doses and drug sequences were assessed in the aggressive patient-derived SU-DIPGVI orthotopic model for activity. In total six different drug combination sequences were tested for impact on survival. One particular sequence – DA/ACT001/CP – was significantly more effective compared with both vehicle and other regimens. This specific sequential regimen resulted in a 50% tumour regression rate with surviving animals maintaining tumor-free status &amp;gt; 1 year, compared with 81-day survival in controls. This 5-agent treatment sequence (DA/ACT001/CP) was next tested in the HSJD-DIPG007 orthotopic model with a significant extension of survival (119 days) compared with single or two-agent treatments (vehicle-59 days, DA-86 days, ACT001-66 days, CP-62 days, DA/ACT001-93 days). Further enhancement of this treatment regimen through addition of radiotherapy significantly extended survival to 130 days, with one-third of the cohort showing sustained tumor regression and remaining tumor-free (by Xenogen imaging) for &amp;gt; 220 days. CONCLUSIONS There are no effective therapies for DMG. Single and combination regimens in vivo often extend survival by days or weeks but do not generally eliminate tumors. Our “Total Therapy” strategy, inspired by successful ALL therapies, suggests that multi-agent sequential combination therapy can induce profound responses and unprecedented long-term survival in DMG animal models.
ETMR-10. DEVELOPMENT AND CHARACTERIZATION OF A NOVEL IMMUNOCOMPETENT ORTHOTOPIC MOUSE MODEL FOR THE STUDY OF EMBRYONAL TUMORS WITH MULTILAYERED ROSETTES (ETMRS)
Authors: Irati Hervás-Corpión, Marta Zalacain, Marisol González-Huarriz, David A Largaespada, Marta M Alonso
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND ETMRs are highly aggressive CNS embryonal tumors with a median survival of &amp;lt;12 months. They are characterized by the presence of multilayered rosettes, amplification of the C19MC microRNA cluster, and high expression of LIN28A; all which are used as diagnostic markers of ETMR. To understand more deeply the mechanisms involved in ETMR pathogenesis, as well as to test immune therapies, it is necessary to develop appropriate immunocompetent murine models that resemble human ETMRs, which are currently scarce. Thus, the aim of our study is the generation and characterization of a novel preclinical ETMR mouse model. METHODS The murine PNET cell line DF1-MYC, produced using a MYC overexpressing RCAS model on a C57BL/6J background, and corresponding allografts were implanted into the supratentorial region of 4-week-old NSG and immunocompetent NTV-a p53floxed mice. Mice were monitored and sacrificed. For efficacy studies, the survival curves were plotted according to the Kaplan-Meier method. For tumor histological analysis and immunohistochemistry, FFPE brain sections were stained with H&amp;E or antibodies against Ki67, c-Myc and Lin28a. Transcriptional profile was characterized by RNA-seq. RESULTS DF1-MYC-bearing NP53 mice did not develop tumors except one mouse that showed a small tumor with multilayered rosettes. With the goal of achieving complete penetrance, we injected DF1-MYC cells orthotopically in NSG mice and allografts subsequently in NP53 mice. Specifically, our MYC384 allograft ETMR mouse model show a penetrance of 70% with a median survival of 36 days. Importantly, the MYC384 allograft model recapitulates histopathologic features of human ETMR, including the presence of highly proliferative undifferentiated cells with multilayered rosettes. Moreover, we are working on overexpressing Lin28a and c-Myc in MYC384 to create a more realistic molecular model of ETMR while allowing us to achieve 100% penetrance. CONCLUSION We describe MYC384 as a potential relevant immunocompetent mouse model of ETMR with almost complete penetrance.
BIOM-08. CDKN2A --AN INDEPENDENT CYCLIN-DEPENDENT KINASE INHIBITOR VARIANT ASSOCIATED WITH MALIGNANCY AND WITH SMALL VESSEL STROKE, AS A POTENTIAL MARKER FOR RISK OF LARGE-VESSEL STROKE COMPLICATING BENIGN TERATOMA
Authors: Krupesh B Patel, Stacie Stapleton, Matthew D Smyth, Valerie A Crus-Florez, Ignacio Gonzonlaz-Gomez, Claudia Luckas, Thomas J Geller
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Cyclin-dependent kinase inhibitor variants, particularly those of CDKN2A are known to be associated with autosomal dominant Familial Atypical Multiple Mole/Melanoma Syndrome and pancreatic cancer predisposition. These variants are associated with risk of small vessel stroke in African/ African-American populations, and are risk factors for stroke in Nordic populations with hypertension, independent of cardiovascular risk factors. METHODS We performed a case review of a female presenting in late infancy with a central nervous system teratoma, that later was complicated by a right hemispheric middle cerebral artery (MCA)stroke, associated with a CDKN2A germline mutation. RESULTS This 14month old female presented with transient alterations of consciousness and apparent abdominal migraine events with pernicious vomiting. Neuroimaging revealed a right heterogeneous para- suprasellar mass and bilateral complex arachnoid adjacent cysts. She was observed closely for any progression, as the lesion was immediately adjacent to the optic chiasm. One year after presentation, she developed an acute ischemic right middle cerebral artery (MCA) stroke and had radiographic evidence of severe stenosis and decreased flow primarily within the right supra-clinoid internal carotid artery, the M1 segment and portion of the right A1 segment of cerebral vessels, with decreased enhancement and number of vessels in the distal right MCA territory. The vessels did not appear to be compressed by any mass effect. The radiologic appearance was consistent with vasospasm. The patient upon stoke recovery, underwent near- complete resection of the mass with no evidence of disruption of the capsule surrounding it and no vascular infiltration. Pathology revealed the expected teratoma with prominence of pancreatic acinar structures, and molecular evidence of a variant of CDKN2A, which was present in the patient and mother in the germline. CONCLUSION We propose that the imaging evidence of a vasculopathy was related to the genotype at the cyclin- dependent kinase site.
MDB-89. DETERMINING THE IMMUNOMODULATORY POTENTIAL OF PI3KΓ IN AGGRESSIVE MEDULLOBLASTOMA AND THE TUMOR MICROENVIRONMENT
Authors: Rita M Yazejian, Kirsten Moziak, Natalia Munoz Perez, Juliana Pensabene, Allison Martin
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Medulloblastoma (MB) is the most common pediatric embryonal brain tumor arising in the cerebellum. It has a “cold” tumor microenvironment (TME) characterized by an abundance of immunosuppressive Tumor Associated Macrophages (TAMs) and low T-cell infiltration. TAMs include tissue resident microglia and migrating bone marrow derived macrophages. While microglia play important roles in the central nervous system through their immune surveillance and ability to activate other immune cells, they can be polarized by tumor cells toward an anti-inflammatory state which allows for maintained tumor growth and proliferation. A potential new target to combat the immunosuppressed TME of MB is the class IB isoform PI3Kγ. Inhibiting this isoform has been attributed to controlling a critical switch between immune suppression and immune stimulation in TAMs but has yet to be examined in MB and its TME. We hypothesize that inhibiting PI3Kγ in TAMs and MB tumor cells will induce an anti-tumorigenic immune response within the MB TME and promote tumor clearance. METHODS Engineered murine MB cells, mCB DNp53 MYC, are treated with a pan-PI3K or specific PI3Kγ inhibitor for 48 hours before being co-cultured with naïve splenic CD4 T-cells from C57BL/6J mice for 5 days. Proliferation of the T cells is measured using Cell Trace Violet through flow cytometry on a Cytek Aurora. RESULTS Pan-PI3K inhibition revealed that tumor cells treated with the inhibitor prior to co-culturing did not suppress T-cell proliferation as drastically when compared to untreated tumor cells. Treatment with a selective inhibitor is on-going. CONCLUSIONS These results suggest that inhibition of the PI3K pathway in our MB tumor cells dampens their ability to suppress T cell proliferation. The PI3K pathway may play an active role in tumor cell’s ability to induce immunosuppression. Inhibiting this pathway may be a new avenue for therapeutic intervention for relapsed/refractory MB.
ETMR-06. PNOC031 - INTERNATIONAL TRIAL FOR EMBRYONAL TUMOR WITH MULTILAYERED ROSETTES
Authors: Derek Hanson, Susan Chi, Steve Braunstein, Hesham Elhalawani, Marcel Kool, Mariella Filbin, Johannes Gojo, Sabine Plasschaert, Katja Von Hoff, Ashley Margol, Cassie Kline, Annette Molinaro, Michael Prados, Sabine Mueller
Journal: Neuro-Oncology (2024)

Abstract Embryonal tumors with multilayered rosettes (ETMR) are aggressive central nervous system neoplasms with unfavorable prognosis, exhibiting rapid disease progression and frequent post-therapeutic relapse. The rarity of ETMR necessitates global collaboration to advance therapies. Radiotherapy (RT) has been associated with improved survival outcomes in ETMR with case series revealing that nearly half of ETMR patients treated without RT relapse within six months of diagnosis. However, RT is often withheld due to young patient age and neurodevelopmental considerations. This high-rate of on-treatment relapse is unique to ETMR and suggests that radiation-sparing regimens may be suboptimal. PNOC031 is an international collaboration, establishing a global clinical trial to innovate and improve therapeutic interventions for children with ETMR. Eligible patients with newly-diagnosed ETMR are stratified into three cohorts: Cohort 1 - gross total resection/RT-eligible patients to receive early focal radiotherapy (RT); Cohort 2 – gross total resection/not RT-eligible to receive high-dose chemotherapy with autologous stem cell rescue; and Cohort 3 – less than gross total resection or with metastatic disease to receive RT or high-dose chemotherapy per RT eligibility, based on age and tumor location. Cohort 1 will test the hypothesis if early RT improves outcomes in a pilot cohort of 20 patients. Patients will receive six weeks of induction chemotherapy, followed by focal irradiation and an additional six weeks of chemotherapy. Six-month progression-free survival will be assessed to determine the impact of radiotherapy on the rate of early relapse. Cohorts 2 and 3 will allow collection of uniform prospective clinical data using a common treatment backbone, to inform future clinical trial design for ETMR. Incorporating a myriad of correlative studies, including next-generation sequencing, cerebrospinal fluid analyses, microbiome profiles, and evaluations of social determinants of health alongside cognitive outcomes, will enhance comprehensive understanding of clinical responses and advance therapeutic options for this high risk disease.
ETMR-05. DEVELOPMENT OF NOVEL PRECLINICAL MODELS AND THERAPEUTIC STRATEGIES FOR ETMR
Authors: Carolina Cocito, Esteban Uceda Arias-Stella, Christopher C Padilla, Xiaohu Zhang, Crystal McKnight, Zina Itkin, Carleen Klumpp-Thomas, David Holland, Erin Beck, Gustavo Alencastro Veiga Cruzeiro, Susan N Chi, David J Pisapia, Mariella G Filbin, Mark M Souweidane, Nadia Dahmane, Craig J Thomas, Jeffrey P Greenfield
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Embryonal Tumor with Multilayered Rosettes (ETMR) is a very rare, aggressive pediatric brain tumor with a dismal 5-year overall survival rate. Few genetic aberrations in miRNA clusters and processing machinery have been detected in ETMRs with 90% of ETMR patients having the C19MC amplification. ETMRs show unique histopathological features which, together with the detection of C19MC or DICER alterations, are necessary for diagnosis. The cellular and molecular mechanisms underlying ETMR development are poorly understood, and targeted therapeutics have not been developed due to scarcity of preclinical models. To expand knowledge of ETMR biology and accelerate the design of novel and therapies, it is thus essential to develop preclinical models. METHODS We have generated two novel patient-derived ETMR cell lines from resected patient derived tumor samples (CTBP-03A and CBTP-139) and created three patient-derived xenograft (PDX) models (CTBP-03A, CBTP-139 and CBTP-38). We have used these unique patient-derived cell lines to identify mechanisms driving ETMR development and progression. To identify novel therapeutic targets, we conducted high-throughput drug screening (HTDS) utilizing 2480 approved and investigational drugs, against the CBTP-03A and CBTP-139 lines. RESULTS Among the candidate drugs showing an inhibitory effect on both lines, compounds were selected based on their activity, CNS penetration ability, mechanism of action, and bioavailability, if known. The top selected hits were screened in an all-versus-all format, totaling 1953 combinations. The rapidity of action and efficacy of the top choice compounds used as single agent or in double and triple combination was assessed by caspase glow and cell titer glow assays. This initial combination screen identified DNA replication stress, retinoid receptor agonist and FGF signaling as potential combinatorial targets. Data are currently being validated in vivo. CONCLUSIONS This is the first combinatorial HTDS on two novel patient-derived cell lines which highlighted potential drug combination strategies for the treatment of ETMR.