tbuckley/cabot-search huggingface dataset:
EPID-08. PEDIATRIC GLIOMA IN INDONESIA: CLINICAL PROFILES AND OUTCOMES
Authors: Ludi Dhyani Rahmartani, Michael Nathaniel Budiarso, Eka Susanto, Mohamad Yanuar Amal, Endang Nuryadi, Kevin Gunawan
Journal: Neuro-Oncology (2024)

Abstract BACKGROUNDS Gliomas are the most common form of pediatric brain tumor. The primary obstacle to optimizing pediatric brain tumor health services, particularly in LMICs, is the lack of comprehensive epidemiological data. We aim to compile comprehensive data on pediatric gliomas, focusing on clinical profiles and outcomes within a national general hospital in Indonesia. METHODS A retrospective observational longitudinal study was performed at Cipto Mangunkusumo National General Hospital, focusing on glioma patients’ profiles and outcomes, registered under the pediatric CNS tumor service from January 2022 to December 2023. RESULTS Out of 50 suspected glioma patients, 28 patients (56%) underwent biopsy, 28% underwent other modalities (brainstem location), 12% were scheduled for surgery but had already died, 2% were in a watchful waiting mode, and 2% were scheduled for surgery but were lost to follow-up. Glioma-confirmed patients were predominantly female (57.1%), with a mean age of 7.11 ± 4.98. Low-grade gliomas predominated at 57.1%, a trend we attribute to Cipto Mangunkusumo’s status as a referral national hospital, where low-grade glioma cases may have been managed more frequently at lower-level hospitals. The majority of tumors were supratentorial (53.6%) compared to infratentorial (39.3%) and supra-infratentorial (7.1%). The most common symptoms were seizures (25%), followed by headaches (21.4%), disequilibrium (14.3%), and vomiting (10.7%). Moreover, the latter three symptoms exhibited a longer mean delay between symptom onset and medical consultation, potentially impacting prognosis. In the last follow-up, higher-grade gliomas demonstrated a significantly higher mortality rate at 28.6% compared to low-grade gliomas at 3.6% (P &amp;lt; 0.001). CONCLUSION Given the variable clinical characteristics of glioma tumors, these results underscore the urgent need for comprehensive epidemiological data on pediatric gliomas in Indonesia, particularly regarding prognosis-related factors. Such data could serve as a crucial step towards future research and clinical strategies aimed at improving outcomes for children with gliomas.
ATRT-12. EXPLORING FGFR INHIBITION AND COMBINATION THERAPIES FOR ATYPICAL TERATOID/RHABDOID TUMORS
Authors: Daniel Senfter, Julia Freund, Leah Mager, Katharina Bruckner, Natalia Stepien, Lisa Mayr, Carola N Jaunecker, Anna Laemmerer, Dominik Kirchhofer, Peter Kuess, Franziska Eckert, Christian Dorfer, Marcel Kool, Christine Haberler, Walter Berger, Daniela Lötsch-Gojo, Sibylle Madlener, Johannes Gojo
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Atypical teratoid/rhabdoid tumors (ATRTs) are aggressive pediatric brain neoplasms characterized by an inactivation of the SWI/SNF chromatin remodeling complex members SMARCB1 or SMARCA4. Based on epigenetic profiling ATRTs can be divided into four different molecular subgroups. Despite improvements in treatment strategies, the prognosis for ATRT patients remains dismal. The FGF/FGFR signaling pathway plays a crucial role in many physiological processes, including embryonic development, tissue repair, angiogenesis. Dysregulation of the signaling axis is driving tumorigenesis. Targeted therapeutic approaches, particularly FGFR inhibitors, have demonstrated potential in enhancing treatment outcomes for various tumors, including pediatric brain tumors. METHODS We used bulk and single-cell RNA sequencing (scRNA-seq) data to examine the expression patterns of FGF family members in ATRTs. Subsequently, we conducted in vitro analysis on a panel of FGFR inhibitors and combination treatments. RESULTS Transcriptomic analysis of more than 130 ATRT tissues samples, revealed a widespread expression of FGFR1 and FGFR2 across all ATRT subtypes. Notably, FGFR1 displayed distinctly elevated expression in ATRT-SHH, surpassing levels seen in other ATRT subtypes and brain tumor types. Utilizing scRNA-seq data of murine ATRT models, we elucidated an autocrine FGFR signaling loop. To assess the therapeutic feasibility of targeting FGFR, we evaluated a panel of FGFR inhibitors, currently in clinical development, across 10 in house established patient-derived cell models (6 ATRT-MYC, 3 ATRT-SHH, 1 ATRT-TYR), revealing sensitivity in a nanomolar to a low-micromolar range. We further explored combination therapies, demonstrating that Erdafitinib, the most effective inhibitor when combined with Abemaciclib and radiation, exhibited enhanced synergistic effects in 2D as well as in 3D tumoroid models. Investigations towards testing these combinations in an organoid co-culture system, along with in vivo models are ongoing. CONCLUSIONS This study emphasizes the prospect of combining FGFR inhibition with radiation and CDK4/6 inhibition as a therapeutic target for ATRTs.
DIPG-66. MULTIPLEXED IMMUNOFLUORESCENCE MAPPING AND AI MODEL PREDICTION OF TUMOR MICROENVIRONMENT IN DIFFUSE MIDLINE GLIOMAS
Authors: Sandra Laternser, Andrea Joseph De Micheli, Antonela Petrovic, Sarah Brüningk, Elizabeth McDonough, Christine Surrette, Fiona Ginty, Augustine Eze, Susanne Dettwiler, Fabiola Prutek, Noelia Casares Lagar, Denise Morinigo, Miriam Bornhorst, Elisabeth Jane Rushing, Michael Grotzer, Ana Sofia Guerreiro Stücklin, Sabine Müller, Roger Packer, Marta Maria Alonso Rodan, Javad Nazarian
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Diffuse midline glioma (DMG) is a fatal childhood brain cancer with a survival rate of less than one year from diagnosis. Pharmacological approaches and immunotherapy have failed to make a clinical impact. Incomplete understanding of the tumor microenvironment (TME) and tumor associated antigens have contributed to the observed poor prognosis. Therefore, mapping TME is urgently needed. METHODS Whole brains were collected at autopsy from 80 pediatric subjects, including patients diagnosed with DMG (n=50), GBM (n=9), non-malignant controls (n=10), ependymoma (n=5), ATRT (n=2). Up to four brain anatomical sites were selected: primary tumor, metastatic and adjacent healthy control sites, and processed for staining with hematoxylin and eosin (H&amp;E). After reviewing the tumor and healthy regions, three punch cores were obtained resulting in a total of 918 core punches and two TMA blocks. Multiplexed immunofluorescence (MxIF) technology was used to probe 43 biomarkers on a single TMA slide, focusing on immune cell types and activation thereof. Clinical data including genomics alterations were obtained from each patient for downstream analyses. RESULTS Highest expressed immune markers across all patients were CD8 and CD3 (T-cells), CD68, Iba1 and CD163 (microglia). In DMGs, T-cells were mostly detected and increased in ONC201 and immunotherapy treated patients compared to only immunotherapy treated patients. Analysis of Iba1 confirmed a higher difference in activation in primary tumor compared to metastatic and adjacent healthy tissue, whereas in contrast, CD68 was significantly increased in metastatic sites. Patient plasma and RNA transcriptome analysis confirmed biomarkers and immune related pathways. Further, immune competent murine models were used to validate immune cell infiltration. AI deep learning technology modeling is ongoing now to, in future, be able to predict cell type composition and neighborhoods mapping. CONCLUSION We posit that this comprehensive data and characterization of the DMG TME will help to identify biology-informed targeted treatments.
IMMU-06. CAR DESIGN SHAPES THE BRAIN TUMOR IMMUNE MICROENVIRONMENT: IMPACT ON ACTIVITY AND PERSISTENCE OF ANTI-GLIOMA ADOPTIVE T CELL IMMUNOTHERAPY
Authors: Dalia Haydar, Jorge Ibañez-Vega, Jeremy Crawford, Zhongzhen Yi, Chris DeRenzo, Stephen Gottschalk, Martine Roussel, Paul Thomas, Giedre Krenciute
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND B7-H3 CAR T-cells effectively eradicate brain tumors in xenograft models and have proven safe in clinical trials, yet no objective responses were observed in patients. The limited efficacy is partly attributed to the immunosuppressive tumor microenvironment (TME), a characteristic not fully recapitulated in investigations using xenograft models. In this study, we set to optimize B7-H3 CAR structure and examine the effects of CAR design on the brain TME using an immunocompetent glioma model. METHODS We generated a panel of fully murine B7-H3 CARs with variations in transmembrane, co-stimulatory, and activation domains. This enabled us to comprehensively investigate their effector functions within the intact immune system. High-dimensional flow cytometry and single-cell RNA sequencing were then used to investigate changes in the brain TME following CAR T-cell therapy. RESULTS While five out of six B7-H3 CARs with single co-stimulatory domains exhibited potent functionality in vitro, optimizing co-stimulation and signaling failed to enhance their anti-glioma efficacy in vivo. To further enhance therapeutic effectiveness and persistence, we incorporated 4-1BB and CD28 co-stimulation through transgenic expression of 4-1BBL on CD28-based CAR T-cells. Although this design significantly improved anti-glioma efficacy in vitro, it conferred no additional benefits in vivo. Analysis of the TME revealed that CAR T-cell therapy influenced the immune composition of the brain TME. Successful anti-tumor responses were dictated by the recruitment, activation, and spatial localization of unique inflammatory ‘immune hubs’ containing specific subsets of macrophages and endogenous T-cells. Interestingly, depletion of brain macrophages using CSF1R inhibitor markedly inhibited CAR T-cell anti-tumor activity. CONCLUSION Our study highlights the critical role of CAR structural design and its modulation of the TME in mediating the efficacy of CAR T-cell therapy in brain tumors. Yet, more specific targeting and/or reprogramming of the TME is warranted for the successful design of effective adoptive immunotherapies for high-grade glioma.
IMMU-04. THE ROLE OF CHECK POINT INHIBITORS IN PEDIATRIC PRIMARY DIFFUSE LEPTOMENINGEAL MELANOMATOSIS: REPORT OF TWO CASES
Authors: Liat Oren, Evgeni Vlodavsky, Michal Raz, Zoar Yaniv, Mony Benifla, Shlomi Constantini, Myriam Ben Arush, Gadi Adebe Campino
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Primary diffuse leptomeningeal melanomatosis (PDLM), a subtype of malignant melanomas of CNS, is rare, especially in children. PDLM is defined by diffuse invasiveness of the leptomeninges with or without nodules. Clinical manifestations of PDLM are nonspecific, mimicking the diagnosis of meningitis. As PDLM is neither sensitive to chemotherapy nor radiotherapy, the prognosis is extremely poor. Recently, some new therapeutic aspects like immunotherapy, especially immune check point inhibitors (ICI) are emerging. Cases report: First case: A 13 years old boy presented with 4 months of weakness, dysphasia and vomiting. MRI demonstrated diffuse leptomeningeal enhancement of the brain and spine. Brain biopsy confirmed the diagnosis of PDLM, with low PDL1 stains in immunohistochemistry, without targetable alterations on NGS. PET FDG normal. Treatment with ICI (Nivolumab 1 mg/kg/dose and Ipilimumab 3 mg/kg/dose, 4 courses every 21 days) was started. He developed severe complications after the 1st course (ICI enterocolitis, pancreatitis) and progressive disease after 2 courses. Craniospinal radiotherapy was delivered at a dose of 30 Gy. The disease continued to progress; the patient died nine months after diagnosis. Second case: A 7-year-old boy presented with diplopia, headache and vomiting. MRI demonstrated a cranial leptomeningeal enhancement and hypo-intense T1 and hyper-intense T2 signal at bilateral medial frontal cortex area. PET FDG normal. Brain biopsy confirmed the diagnosis of PDLM, with TMB 1.9, NRAS mutation and wild type BRAF by NGS. He started combination of ICI therapy. Three weeks after 1st course of Ipilimumab-Nivolumab he was admitted to PICU with prolonged status epilepticus. MRI demonstrated progression of leptomeningeal disease. Trametinib was deferred by parents and the child succumbed a year from diagnosis. CONCLUSIONS We report two cases of pediatric patients with PDLM treated unsuccessfully by immune check point inhibitors, emphasizing the diagnostic and therapeutic challenges in such a rare disease.
LGG-37. A PHASE III STUDY COMPARING TWO CARBOPLATIN CONTAINING REGIMENS FOR CHILDREN AND YOUNG ADULTS WITH PREVIOUSLY UNTREATED LOW-GRADE GLIOMA
Authors: Alicia Lenen, Angela J Waanders, Latifa Bazzi, Hui Zhang, Jin-Shei Lai, Ashley S Plant-Fox, Andrew Cluster, John Crawford, Ken Cohen, David Dickens, Mukund Dole, Jessica Goodman, Lindsey Hoffman, Carl Koschmann, Margot Lazow, Asher Marks, Diane Puccetti, Mary M Skrypek, Ryuma Tanaka, Lauren Weintraub, Karen Wright, Sarah Zieber Rush, Jason Fangusaro, Rishi Lulla, Stewart Goldman, Natasha Pillay-Smiley
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Low-grade glioma (LGG) is the most common childhood central nervous system tumor. Carboplatin/vincristine (CV) is a standard of care regimen used for incompletely resected tumors. Monthly carboplatin is an alternative regimen that has not been prospectively compared to CV previously in untreated patients. METHODS Patients ≤ 21 years with LGG and no treatment besides surgery were eligible. Patients were stratified according to NF1 status and randomized to Arm A (carboplatin/vincristine) or Arm B (carboplatin monthly). The primary endpoint was 3-year progression-free survival (PFS). Secondary endpoint analysis is underway and includes quality of life, tumor response rates, toxicity and association of molecular alterations on outcomes. Analyses included log-rank test and descriptive statistics. RESULTS There were 95 evaluable patients with a median age of 5 (range 0-18) years; 67 non-NF1 subjects (32 Arm A, 35 Arm B) and 28 NF1 subjects (14 Arm A, 14 Arm B). Three-year PFS was superior for patients without NF1 treated on Arm A (58%; 95% CI: 38%, 74%) versus Arm B (33%; 95% CI: 18%, 49%) (p=0.04). In patients with NF1, there was no statistical difference in PFS between those treated on Arm A (71%; 95% CI: 41%, 88%) and Arm B (93%; 95% CI: 59%, 99%) (p=0.08). Grade 3/4 toxicity neutropenia was more commonly seen in Arm A patients compared to Arm B for both NF and non-NF1 patients. Peripheral neuropathy was also more commonly seen in non-NF1 patients (Grade 1-4; 32%) compared to NF1 patients (7%) for patients treated on Arm A. There were 15 carboplatin reactions (Grade 1-4); 7 non-NF1 on Arm A, 3 non-NF1 on Arm B, and 5 NF1 on Arm A. CONCLUSIONS Non-NF1 patients treated with carboplatin and vincristine show statistically significant improved PFS compared to monthly carboplatin. Patients with NF1 are statistically underpowered due to low accrual.
IMMU-01. PIONEERING QUAD-TARGETING CAR T CELL THERAPY IN PEDIATRIC CNS TUMORS – ANALYSIS FROM THE INITIAL PATIENTS TREATED ON THE FIRST-IN-HUMAN PHASE 1 TRIAL BRAINCHILD-04
Authors: Rebecca Ronsley, Michelle Choe, Kristy Seidel, Prabha Narayanaswamy, Sowmya Pattabhi, Jason Wendler, On Ho, Stephanie Rawlings-Rhea, Juliane Gust, Wenjun Huang, Erin Crotty, Sarah Leary, Jason Hauptman, Catherine M Albert, Rebecca A Gardner, Julie R Park, Colleen Annesley, Michael C Jensen, Nicholas A Vitanza
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND BrainChild-04 is a first-in-human clinical trial of quad-chimeric antigen receptor (CAR) T cell therapy for children and young adults with central nervous system (CNS) tumors. This trial administers repeated locoregional CAR T cells targeting B7-H3, EGFR, HER2, and IL-13Ralpha2 (“quad-CAR T cells”), leveraging multi-antigen targeting to address the tumor heterogeneity of high-grade CNS tumors. METHODS The primary endpoints are feasibility and safety, and secondary endpoints are disease response and correlative studies of CAR T cell activity. The trial utilized a Bayesian Optimal Interval (BOIN) design with three dose regimens (DR). There are 2 arms with weekly delivery for 3 weeks of a 4-week cycle:(A) –diffuse intrinsic pontine glioma (DIPG), (B) –non-pontine diffuse midline glioma (DMG) or other relapsed CNS tumors. RESULTS Enrolled patients include DMG N=6, DIPG N=5, other CNS tumors N=4. Of the 15 enrolled patients, 7 have been infused with 8 awaiting infusions. A total of 33 intracranial CAR T doses have been delivered, including Arm A DR 1 (N=1), Arm B DR 1 (N=3), DR2 (N=3). The most common adverse events have been grade 1-2 fever (7/7 patients), grade 1-3 headache (6/7), and grade 1-2 nausea/vomiting (6/7). There have been no DLTs and no cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity(ICANS). CTCAE and tumor inflammation-associated neurotoxicity are both being captured. All treated patients are alive with median follow up time post-initial infusion of 93(14-198) days. CAR T cells were detected by flow cytometric analysis of CSF post-infusion in 14/24 CSF samples. Radiographic response, CSF ct-DNA, targeted mass spectrometry, and cytokine analysis will be presented. CONCLUSIONS Our preliminary experience suggests tolerability of locoregional quad-CAR T therapy at doses evaluated. The trial remains ongoing and these data support continued evaluation of this product to better assess anti-tumor activity in patients with CNS tumors, including DIPG/DMG.
Availability of drugs and resistance testing for bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaL(M)) regimen for rifampicin-resistant tuberculosis in Europe: author's response
Authors: Christoph Lange, Yousra Kherabi, Lorenzo Guglielmetti, Raquel Duarte, Gunar Günther
Journal: Clinical Microbiology and Infection (2024)
Nonexposed endoscopic wall inversion surgery with sentinel node mapping for a high risk gastric lesion
Authors: Alanna Ebigbo, Dmytro Vlasenko, Markus W. Scheppach, Sandra Nagl, Matthias Anthuber, Helmut Messmann
Journal: Endoscopy (2024)

Endoscopic submucosal dissection (ESD) is the standard approach for the management of early gastric cancer (EGC) [1]. However, in some situations, such as in borderline lesions, a combined laparoscopic-endoscopic technique may be a valid option [2]. We report the case of an 85-year-old man with multiple comorbidities who presented to us for further management of an EGC in the gastric body.
Cholangioscopy-assisted extraction of choledocholithiasis through novel papillary support: the protective effect on the sphincter of Oddi
Authors: Zixin Wang, Enqiang Linghu, Longsong Li, Wengang Zhang, Nan Ru, Bo Zhang, Ningli Chai
Journal: Endoscopy (2024)

A 78-year-old man with choledocholithiasis underwent cholangioscopy-assisted extraction for multiple stones with a maximum diameter of 10 mm ([Fig. 1]). Considering the potential loss of sphincter of Oddi (SO) function associated with endoscopic sphincterotomy and endoscopic papillary balloon dilation, we used novel papillary support to provide an adequate exit for the extraction of the stones [1] [2]. The papillary support (12 mm in diameter, 25 mm in length) is a metal-covered membrane stent with a unique single dumbbell-style design on the papillary side, serving to protect the support from entering the common bile duct (CBD) during stone removal procedures [3].
Neoadjuvant and Adjuvant Treatments for Early Stage Resectable NSCLC: Consensus Recommendations From the International Association for the Study of Lung Cancer
Authors: Jonathan D. Spicer, Tina Cascone, Murry W. Wynes, Myung-Ju Ahn, Sanja Dacic, Enriqueta Felip, Patrick M. Forde, Kristin A. Higgins, Mark G. Kris, Tetsuya Mitsudomi, Mariano Provencio, Suresh Senan, Benjamin J. Solomon, Ming Sound Tsao, Masahiro Tsuboi, Heather A. Wakelee, Yi-Long Wu, James Chih-Hsin Yang, Caicun Zhou, David H. Harpole, Karen L. Kelly
Journal: Journal of Thoracic Oncology (2024)
Peroral endoscopic myotomy using a novel thin therapeutic scope
Authors: Hiroshi Tanabe, Hiroya Sakaguchi, Hirofumi Abe, Hitomi Hori, Chise Ueda, Shinwa Tanaka, Yuzo Kodama
Journal: Endoscopy (2024)

Peroral endoscopic myotomy (POEM) has been gaining in popularity as an effective minimally invasive treatment for achalasia [1]. However, submucosal fibrosis and thicker esophageal mucosa in patients with achalasia can complicate scope insertion into the submucosa. Furthermore, passing the scope through the esophago-gastric junction can be challenging when the lower esophageal sphincter (LES) is tight. A thinner therapeutic scope may be desirable for such challenging POEM-based procedures. POEM with a nasoendoscope is a potential solution for such situations and has shown short-term outcomes comparable to those of conventional POEM [2]. However, only certain types of endoknives can be passed through the smaller working channels of nasoendoscopes, and a lack of scope stiffness may make their manipulation difficult. A novel thin therapeutic endoscope (EG-840TP; Fujifilm Co., Tokyo, Japan), with a diameter of 7.9 mm, a wide (3.2-mm) working channel, a wide-ranging downward angle of 160°, and enhanced stiffness compared to a nasoendoscope may overcome these challenges ([Fig. 1]).
Efficacy of underwater endoscopic intermuscular dissection in the management of a rectal neuroendocrine tumor
Authors: Suhuan Liao, Silin Huang, Guang Yang, Bo Li, Huizhao Deng, Yi Tan, Guifa He
Journal: Endoscopy (2024)

Endoscopic intermuscular dissection (EID), which is emerging as a therapeutic modality, has garnered recent attention for its efficacy in reducing positive vertical margins, particularly in the management of neuroendocrine tumors (NETs) [1] [2] [3]. EID procedures are intricate, requiring precise differentiation of the intermuscular space. Herein, we endeavor to employ underwater EID (U-EID) techniques to enhance procedural efficacy.
Transformation of Natural Resin Resina Draconis to 3D Functionalized Fibrous Scaffolds for Efficient Chronic Wound Healing
Authors: Shijie Guo, Pengyu Wang, Yu Sun, Can Cao, Junwei Gao, Shihao Hong, Ning Li, Ruodan Xu
Journal: Advanced Healthcare Materials (2024)

Chronic wound healing is a major challenge in clinical practice. Secondary dressing damage and antibiotic resistance are the main obstacles for traditional wound dressings. Resina draconis (RD), a natural resin traditionally used in powder form for wound care, is now considered unsuitable due to the lack of gas permeability and moist environment required for wound healing. Here, RD is incorporated in situ by constructing a 3D coiled fibrous scaffold with polycaprolactone/polyethylene oxide. Due to the high porosity of 3D scaffold, the RD-3D dressings have a favorable swelling capacity, providing permeability and moisture for wound repair. Meanwhile, the transformation of RD powder into 3D dressings fully demonstrates capabilities of RD in rapid hemostasis, bactericidal, and inflammation-regulating activities. In vivo evaluations using pressure ulcer and infected wound models confirm the high efficacy of RD-3D dressing in early wound healing, particularly beneficial in the infected wound model compared to recombinant bovine FGF-basic. Further biological analysis shows that resveratrol, loureirin A, and loureirin B, as potentially bioactive components of RD, individually contribute to different aspects of wound healing. Collectively, RD-3D integrated dressings represent a simple, cost-effective, and safe approach to wound healing, providing an alternative therapy for translating medical dressings from bench to bedside.
Capsule endoscopy emissions: less than expected and largely influenced by patient transport
Authors: Vicente Lorenzo-Zúñiga
Journal: Endoscopy (2024)

Small-bowel capsule endoscopy (SBCE) is a common noninvasive method, based on a single-use consumable, which has transformed the way we track gastrointestinal diseases since its introduction in 2000 [1]. However, as with any other medical supplies, it is crucial to consider the environmental footprint using a standardized approach to assessment of the net greenhouse gas (GHG) emission profile of each procedure, following the current ESGE Green Endoscopy Position Statement [2].