tbuckley/cabot-search huggingface dataset:
QOL-24. TREATMENT- AND TIME-RELATED IMPACT ON LONG-TERM NEUROCOGNITIVE OUTCOMES IN ADULT SURVIVORS OF A PEDIATRIC BRAIN TUMOR
Authors: Kristien Bullens, Jeroen Blommaert, Charlotte Sleurs, Rebeca Alejandra Gavrila Laic, Jurgen Lemiere, Sandra Jacobs
Journal: Neuro-Oncology (2024)

Abstract Treatment for pediatric brain tumors has been associated with the risk of developing long-term neurocognitive impairment. However, it is not well understood which neurocognitive profiles exist within this population. We investigated neurocognitive functioning (NF) in survivors in early adulthood and aimed to assess the impact of radiotherapy dose (RTD) and time since treatment (TxT) on NF. Forty-six survivors of pediatric brain tumors (mean age 23.99±4.71, mean age at diagnosis 9.29±4.54) performed an extensive neurocognitive test battery resulting in intelligence (n=5), memory (n=2), and language (n=3) scores. NF in long-term survivors was compared to sex-, age-, and education-matched controls, and between the different treatment strategies (surgery-only n=19, chemotherapy n=8, radiotherapy n=11, or chemo-radiotherapy n=8). Furthermore, relation between max-RTD (range 40.28 – 61.61 Gy) as well as TxT and NF was assessed. Three ANCOVA models were tested, and false discovery rate (FDR) was applied. For all scales and domain scores, survivors scored lower compared to controls. Scores were significant lower on full scale intelligence (pfdr&amp;lt; 0.001), verbal comprehension (pfdr&amp;lt; 0.001), working memory (pfdr= 0.003), perceptual reasoning (pfdr&amp;lt; 0.001), processing speed (pfdr&amp;lt; 0.001), spoken word comprehension (pfdr= 0.001), and semantic word generation (pfdr= 0.036) compared to controls. NF was not significantly different between the different treatments, nor did the association with max-RTD reach significance. TxT was associated with verbal comprehension and spoken word comprehension; albeit significance was not retained after FDR correction. In this study, the overall survivor cohort scored lower on multiple cognitive outcomes. More detailed analysis of various risk factors might further elucidate the different neurocognitive profiles for this population. Furthermore, more detailed analysis of RTD distributions and affected brain structures may provide greater insight on the impact of radiotherapy on NF.
QOL-36. IMPACT OF RADIATION ON SYMPTOMS OF ANXIETY IN PEDIATRIC PATIENTS WITH BRAIN TUMORS
Authors: Bryony J Lucas, Heather H Stancel, Kimberly P Raghubar, Krystal K Christopher, Ana Sofia C Ibarrola, David R Grosshans, Arnold D Paulino, M Fatih Okcu, Murali M Chintagumpala, Austin L Brown, Michael E Scheurer, Lisa S Kahalley
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Children and adolescents with brain tumors are at increased risk for anxiety compared to unaffected peers, but the impact of treatment on anxiety are unknown. METHODS We identified patients diagnosed with a brain tumor at Texas Children’s Hospital (2012-2019), excluding high-grade glioma. Anxiety was evaluated using the BASC-2, with T-scores ≥60 considered positive. Baseline assessment occurred within six months of start of treatment and were repeated annually. Chi squared tests of independence were performed. RESULTS Of 156 patients included, 92 received proton radiation therapy (RT) and 64 did not receive any RT. 52% were male, and patients were diagnosed at a median age of 10.4 years (range: 6-20) with a median follow-up of 4.2 years (range: 0-11.4). 42% of patients (n=66/156) screened positive for anxiety at least once during the follow-up period. Among those treated with RT, 15% screened positive for anxiety at baseline and the proportion significantly increased at 1-year (29%) and 2-years (34%) follow-up (p=0.016). For patients spared radiation, there was no statistically significant change over time (p=0.56), although the proportion positive for anxiety trended lower over time with 30% positive at baseline, 26% positive at 1-year and 20% positive at 2-years of follow-up. In the non-RT cohort, patients reported more anxiety symptoms at baseline than patients who did receive RT (p=0.029), but no significant differences were observed at 1-year (p=0.80) or 2-year follow-up (p=0.13). CONCLUSIONS Nearly half of pediatric brain tumor patients report anxiety during or in the years following treatment. We identified differences in the trajectory of anxiety symptoms based on RT, with declining levels of anxiety observed in the population not receiving RT and an increasing proportion of patients reporting anxiety in the years following RT. These findings may help guide the delivery of supportive services to populations most at-risk of anxiety.
QOL-32. COGNITIVE AND PSYCHOLOGICAL LATE EFFECTS IN CHILDREN AND ADOLESCENTS WITH PINEAL REGION TUMORS: A 35-YEAR-LONG EXPERIENCE IN A TERTIARY REFERRAL HOSPITAL
Authors: Antonio Verrico, Angelica Pisati, Francesca Bagnasco, Sara De Giuseppe, Andrea Rossi, Gianluca Piccolo, Marta Molteni, Claudia Mercuri, Alessandro Consales, Salvina Barra, Flavio Giannelli, Camilla Satragno, Maria Luisa Garrè, Claudia Milanaccio, Sonia Di Profio
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND Pineal region tumors (PRT) account for 2.8% of all central nervous system tumors in children and adolescents up to 19 years of age. Modern therapies allow more than 2/3 of patients to overcome their disease, but late effects impair quality of life of survivors. This study aimed to define the prevalence of cognitive and psychological late effects in PRT-survivors. METHODS Demographic information, medical variables, cognitive and psychological age-appropriated assessments of childhood and adolescence PRT-survivors, followed-up at Gaslini Children’s Hospital between 1988 and 2023, were retrospectively collected. Neurocognitive assessment was performed using the Wechsler scale. Psychological assessment was obtained using the Child Behavior Checklist, Beck Depression Inventory, State-Trait Anxiety Inventory, Trauma Symptom Checklist for children and Impact of Event Scale–Revised. RESULTS Sixty patients were included (53 males, 88%); median age at diagnosis was 12.8 years (Interquartile range, IQR, 9.0–15.7 years). Main entities were: germinoma (17, 28%), non-germinomatous germ cell tumor (16, 27%), bifocal germinoma (13, 22%), pineoblastoma (6, 10%), teratoma (3, 5%). 20/60 patients (33%) had neuroaxis spread, 48/60 (80%) presented hydrocephalus, 41/60 (68%) underwent surgery, 16/60 (27%) needed ventricular-peritoneal shunt, 51/60 (86%) received chemotherapy and 56/60 (93%) required radiotherapy. Median follow-up was 8.9 years (IQR 4.1–15.2). Six patients died, 5/6 died for progressive disease. Intelligence quotient (IQ) score was available for 43/60 patients with a median value of 91 (IQR 85-107). Complete cognitive and neuropsychological assessment was available for 25/60 patients showing presence of: anxiety symptoms (16/25, 64%), depression symptoms (20/25, 80%) and post-traumatic symptoms (7/25, 28%). CONCLUSIONS In our cohort, PRT-survivors showed IQ scores within expected average and a high frequency of anxiety and depression symptoms. Deeper insights into the mechanisms underlying cognitive and psychological late effects are needed, focusing on the role of demographics, treatments and disease-specific variables as well as on tumor location.
MDB-21. MYC-DRIVEN RECURRENT MEDULLOBLASTOMA AND CD74: TARGETING THE NEXUS FOR EFFECTIVE TREATMENT
Authors: Benjamin Draper, Dean Thompson, Alaide Morcavallo, Louis Chesler, Steve Clifford, Lei F Huang, Laura K Donovan
Journal: Neuro-Oncology (2024)

Abstract BACKGROUND One of the most significant unmet clinical challenges in paediatric oncology is the development of novel therapeutic strategies for recurrent medulloblastoma (R-MB). MYC-driven MBs are defined as classically cold tumours with a low incidence of infiltrating immune cells, resulting in a therapeutic challenge. The identification of cell-cell communications, particularly ligand–receptor pairs, allows for the inference of significant intercellular communications based on the expression of corresponding genes. Consequently, we hypothesised that the most influential cell-cell interactions within the tumour immune microenvironment (TME) of MYC-driven MB could unveil prevalent immune-suppressive interactions and potential vulnerabilities for therapeutic exploration. METHODS/RESULTS Paired primary-recurrent bulk RNA-sequencing data, confirmed myeloid cells as the most infiltrating immune cell type in group3-MB and group4-MB. Comprehensive spatial phenotypic and cell-cell communication analyses corroborated this discovery, validating an increased incidence of macrophages in the matched-recurrent tumours. Subsequently, we used innovative algorithms for MB single-cell data to predict interactions between tumour-cell ligands and immune-cell receptors within the TME; macrophages emerged as the core immune-cells involved in interactions throughout the TMEs, with the most significant ligand-receptor interaction and inflammatory response between MIF and CD74. In-depth immunohistochemistry analyses of primary and recurrent group3 and group4 tumours, and exhaustive tissue microarrays demonstrated expression of both CD74 and MIF, with limited expression of CD74 within the brain. To investigate the therapeutic potential of CD74, we developed recurrent, immune competent MYC-driven medulloblastoma mouse models. Comprehensive deconvolution analysis confirmed the TME integrity of our models to mirror that of the human disease. Locoregional delivery and repeat dosing of a bioactive-CD74 peptide demonstrated complete tumour clearance in our immune-competent mouse models, demonstrating the significant therapeutic potential of targeting the CD74-MIF axis in MYC-driven primary and recurrent MB. CONCLUSIONS Essential cellular interactions and therapeutic vulnerabilities have been identified in the tumour-microenvironment of MYC-driven primary-recurrent MB.
Correction: Co-existing Neuroendocrine Tumors in the Ileum and Pancreas: A Clinico-Pathological Challenge
Authors: Alice Laffi, Alexia Francesca Bertuzzi, Silvia Carrara, Alessandro Zerbi, Andrea Lania, Elisabetta Lavezzi, Giuseppe Ferrillo, Jelena Jandric, Carlo Carnaghi, Roberta Elisa Rossi, Maria Susanna Grimaudo, Paola Spaggiari, Silvia Uccella
Journal: Endocrine Pathology (2024)
Flare Phenomenon After 177Lu-DOTA-IBA Therapy in Bone Metastases of Lung Cancer
Authors: Qingchu Hua, Wei Wang, Gengcuo Qu, Wenjie Pei, Yue Chen
Journal: Clinical Nuclear Medicine (2024)

Abstract The flare phenomenon is a transient increase in the number or intensity of lesions on bone scans after treatment, signifying curative effect. DOTA-ibandronic acid (DOTA-IBA) is a new prodrug that targets bone metastases and can be labeled with 177 Lu. Here, we report the case of a 58-year-old woman with bone metastasis, in whom the flare phenomenon was observed after 4 cycles of 177 Lu-DOTA-IBA treatment. No adverse effects were observed during the treatment and follow-up periods.
Erratum: Topical 188Re Ionizing Radiation Therapy Exerts High Efficacy in Curing Nonmelanoma Skin Cancer
Authors: Julia K Tietze, Martin Heuschkel, Maila I C Krönert, Jens Kurth, Gesine Bandow, Gregor Ojak, Pavel Grünwald, Johanna Isabelle Herold, Alexander Thiem, Miriam Dreßler, Bernd J Krause, Steffen Emmert, Sarah M Schwarzenböck
Journal: Clinical Nuclear Medicine (2024)
Macrophage ATG16L1: potential candidate for MASH treatment
Authors: Junjie Yu
Journal: Clinical and Molecular Hepatology (2024)

Non-alcoholic steatohepatitis (NASH), also known as metabolic dysfunction-associated steatohepatitis (MASH), is becoming prevalent around the world.It has been estimated that around 5% of population are affected by NASH, and 1-2% of NASH patients will further progress to cirrhosis, which is a key risk factor for hepatocellular carcinoma (HCC), threatening life (1-3).Recently, FDA approved the first drug, Rezdiffra, a thyroid hormone receptor-beta (THRβ) agonist, for NASH treatment, bringing hopes to
Nociceptive adenosine A2A receptor on trigeminal nerves orchestrates CGRP release to regulate the progression of oral squamous cell carcinoma
Authors: Lanxin Jiang, Ying Zhou, Shijie Tang, Dan Yang, Yixin Zhang, Jiuge Zhang, Fan Yang, Tong Zhou, Xiaoqiang Xia, Qianming Chen, Lu Jiang, Yuchen Jiang, Xiaodong Feng
Journal: International Journal of Oral Science (2024)

Abstract Oral squamous cell carcinoma (OSCC) associated pain commonly predicts adverse events among patients. This clinical feature indicates the engagement of nociceptors on sensory neurons during the development of malignancy. However, it is yet to be determined if targeting oncometabolite-associated nociception processes can hinder OSCC progression. In this study, we reported that nociceptive endings infiltrating both clinical samples and mouse tumor xenografts were associated with poorer clinical outcomes and drove tumor progression in vivo, as evidenced by clinical tissue microarray analysis and murine lingual denervation. We observed that the OSCC microenvironment was characteristic of excessive adenosine due to CD73 upregulation which negatively predicted clinical outcomes in the TCGA-HNSC patient cohort. Notably, such adenosine concentrative OSCC niche was associated with the stimulation of adenosine A 2A receptor (A 2A R) on trigeminal ganglia. Antagonism of trigeminal A 2A R with a selective A 2A R inhibitor SCH58261 resulted in impeded OSCC growth in vivo. We showed that trigeminal A 2A R overstimulation in OSCC xenograft did not entail any changes in the transcription level of CGRP in trigeminal ganglia but significantly triggered the release of CGRP, an effect counteracted by SCH58261. We further demonstrated the pro-tumor effect of CGRP by feeding mice with the clinically approved CGRP receptor antagonist rimegepant which inhibited the activation of ERK and YAP. Finally, we diminished the impact of CGRP on OSCC with istradefylline, a clinically available drug that targets neuronal A 2A R. Therefore, we established trigeminal A 2A R-mediated CGRP release as a promising druggable circuit in OSCC treatment.
Docetaxel and Carboplatin for the Treatment of Patients with Metastatic Castration-resistant Prostate Cancer and Biallelic Inactivation of Genes in the Homologous Recombination DNA Repair Pathway: The ABCD Trial
Authors: Ruben Raychaudhuri, Makayla DeJong, Matthew Rettig, Evan Y. Yu, Roman Gulati, Michael T. Schweizer, Peter S. Nelson, Colin C. Pritchard, Bruce Montgomery, Heather H. Cheng
Journal: European Urology (2024)
EBV promotes TCR-T-cell therapy resistance by inducing CD163+M2 macrophage polarization and MMP9 secretion
Authors: Yuanyuan Chen, Dijun Ouyang, Yan Wang, Qiuzhong Pan, Jingjing Zhao, Hao Chen, Xinyi Yang, Yan Tang, Qijing Wang, Yongqiang Li, Jia He, Jin-Qi You, Yingzi Li, Chi Xu, Yan Ren, Sisi Xie, Song Li, Jiamin Lian, Desheng Weng, Tong Xiang, Jian-Chuan Xia
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Epstein-Barr virus (EBV) is a double-stranded DNA oncogenic virus. Several types of solid tumors, such as nasopharyngeal carcinoma, EBV-associated gastric carcinoma, and lymphoepithelioma-like carcinoma of the lung, have been linked to EBV infection. Currently, several TCR-T-cell therapies for EBV-associated tumors are in clinical trials, but due to the suppressive immune microenvironment of solid tumors, the clinical application of TCR-T-cell therapy for EBV-associated solid tumors is limited. Figuring out the mechanism by which EBV participates in the formation of the tumor immunosuppressive microenvironment will help T cells or TCR-T cells break through the limitation and exert stronger antitumor potential. Methods Flow cytometry was used for analyzing macrophage differentiation phenotypes induced by EBV-infected and EBV-uninfected tumors, as well as the function of T cells co-cultured with these macrophages. Xenograft model in mice was used to explore the effects of M2 macrophages, TCR-T cells, and matrix metalloprotein 9 (MMP9) inhibitors on the growth of EBV-infected tumors. Results EBV-positive tumors exhibited an exhaustion profile of T cells, despite the presence of a large T-cell infiltration. EBV-infected tumors recruited a large number of mononuclear macrophages with CCL5 and induced CD163+M2 macrophages polarization through the secretion of CSF1 and the promotion of autocrine IL10 production by mononuclear macrophages. Massive secretion of MMP9 by this group of CD163+M2 macrophages induced by EBV infection was an important factor contributing to T-cell exhaustion and TCR-T-cell therapy resistance in EBV-positive tumors, and the use of MMP9 inhibitors improved the function of T cells cocultured with M2 macrophages. Finally, the combination of an MMP9 inhibitor with TCR-T cells targeting EBV-positive tumors significantly inhibited the growth of xenografts in mice. Conclusions MMP9 inhibitors improve TCR-T cell function suppressed by EBV-induced M2 macrophages. TCR-T-cell therapy combined with MMP9 inhibitors was an effective therapeutic strategy for EBV-positive solid tumors.
Hypothesis: AdAPT-001 and pseudoprogression – when seeing is not necessarily believing
Authors: Anthony Conley, Christopher Larson, Bryan Oronsky, Meaghan Stirn, Scott Caroen, Tony R Reid
Journal: Journal for ImmunoTherapy of Cancer (2024)

The purpose of this commentary is to highlight the high occurrence of clinical pseudoprogression and delayed responses that have been observed to date with the locally injected oncolytic adenovirus, AdAPT-001, currently in a Phase 1/2 clinical trial ( NCT04673942 ) for the treatment of treatment-refractory tumors. Not surprisingly, these have led to confusion about response assessment and whether to continue patients on treatment. AdAPT-001 carries a transforming growth factor (TGF)-beta trap (TGF-β), which sequesters TGF-β, a cytokine that potently regulates inflammation, fibrosis, and immunosuppression in cancer. Pseudoprogression (PsP) or progression prior to response or stabilization, has been widely recognized with radiotherapy for primary brain tumors and immune checkpoint inhibitors (ICIs). PsP has also been described and documented in the context of oncolytic virotherapy but perhaps to a lesser extent. However, repeated intratumoral injections with these immunostimulatory agents may induce a more intense immune response and release more antigenic epitopes than with ICIs, for example, which are strictly T-cell directed rather than also tumor-directed like AdAPT-001.
Wnt/β-catenin signaling pathway in carcinogenesis and cancer therapy
Authors: Pan Song, Zirui Gao, Yige Bao, Li Chen, Yuhe Huang, Yanyan Liu, Qiang Dong, Xiawei Wei
Journal: Journal of Hematology & Oncology (2024)

Abstract The Wnt/β-catenin signaling pathway plays a crucial role in various physiological processes, encompassing development, tissue homeostasis, and cell proliferation. Under normal physiological conditions, the Wnt/β-catenin signaling pathway is meticulously regulated. However, aberrant activation of this pathway and downstream target genes can occur due to mutations in key components of the Wnt/β-catenin pathway, epigenetic modifications, and crosstalk with other signaling pathways. Consequently, these dysregulations contribute significantly to tumor initiation and progression. Therapies targeting the Wnt/β-catenin signaling transduction have exhibited promising prospects and potential for tumor treatment. An increasing number of medications targeting this pathway are continuously being developed and validated. This comprehensive review aims to summarize the latest advances in our understanding of the role played by the Wnt/β-catenin signaling pathway in carcinogenesis and targeted therapy, providing valuable insights into acknowledging current opportunities and challenges associated with targeting this signaling pathway in cancer research and treatment.
Single-cell sequencing unveils extensive intratumoral heterogeneity of cancer/testis antigen expression in melanoma and lung cancer
Authors: Sofie Traynor, Mie K Jakobsen, Tina M Green, Hana Komic, Yaseelan Palarasah, Christina B Pedersen, Henrik J Ditzel, Fredrik B Thoren, Per Guldberg, Morten F Gjerstorff
Journal: Journal for ImmunoTherapy of Cancer (2024)

Cancer/testis antigens (CTAs) are widely expressed in melanoma and lung cancer, emerging as promising targets for vaccination strategies and T-cell-based therapies in these malignancies. Despite recognizing the essential impact of intratumoral heterogeneity on clinical responses to immunotherapy, our understanding of intratumoral heterogeneity in CTA expression has remained limited. We employed single-cell mRNA sequencing to delineate the CTA expression profiles of cancer cells in clinically derived melanoma and lung cancer samples. Our findings reveal a high degree of intratumoral transcriptional heterogeneity in CTA expression. In melanoma, every cell expressed at least one CTA. However, most individual CTAs, including the widely used therapeutic targets NY-ESO-1 and MAGE, were confined to subpopulations of cells and were uncoordinated in their expression, resulting in mosaics of cancer cells with diverse CTA profiles. Coordinated expression was observed, however, mainly among highly structurally and evolutionarily related CTA genes. Importantly, a minor subset of CTAs, including PRAME and several members of the GAGE and MAGE-A families, were homogenously expressed in melanomas, highlighting their potential as therapeutic targets. Extensive heterogeneity in CTA expression was also observed in lung cancer. However, the frequency of CTA-positive cancer cells was notably lower and homogenously expressed CTAs were only identified in one of five tumors in this cancer type. Our findings underscore the need for careful CTA target selection in immunotherapy development and clinical testing and offer a rational framework for identifying the most promising candidates.
Fate-mapping and functional dissection reveal perilous influence of type I interferon signaling in mouse brain aging
Authors: Ethan R. Roy, Sanming Li, Sepideh Saroukhani, Yanyu Wang, Wei Cao
Journal: Molecular Neurodegeneration (2024)

Abstract Background Aging significantly elevates the risk of developing neurodegenerative diseases. Neuroinflammation is a universal hallmark of neurodegeneration as well as normal brain aging. Which branches of age-related neuroinflammation, and how they precondition the brain toward pathological progression, remain ill-understood. The presence of elevated type I interferon (IFN-I) has been documented in the aged brain, but its role in promoting degenerative processes, such as the loss of neurons in vulnerable regions, has not been studied in depth. Methods To comprehend the scope of IFN-I activity in the aging brain, we surveyed IFN-I-responsive reporter mice at multiple ages. We also examined 5- and 24-month-old mice harboring selective ablation of Ifnar1 in microglia to observe the effects of manipulating this pathway during the aging process using bulk RNA sequencing and histological parameters. Results We detected age-dependent IFN-I signal escalation in multiple brain cell types from various regions, especially in microglia. Selective ablation of Ifnar1 from microglia in aged mice significantly reduced overall brain IFN-I signature, dampened microglial reactivity, lessened neuronal loss, restored expression of key neuronal genes and pathways, and diminished the accumulation of lipofuscin, a core hallmark of cellular aging in the brain. Conclusions Overall, our study demonstrates pervasive IFN-I activity during normal mouse brain aging and reveals a pathogenic, pro-degenerative role played by microglial IFN-I signaling in perpetuating neuroinflammation, neuronal dysfunction, and molecular aggregation. These findings extend the understanding of a principal axis of age-related inflammation in the brain, one likely shared with multiple neurological disorders, and provide a rationale to modulate aberrant immune activation to mitigate neurodegenerative process at all stages.