tbuckley/cabot-search huggingface dataset:
Comparison of 18F-DOPA Versus 68Ga-DOTATOC as Preferred PET Imaging Tracer in Well-Differentiated Neuroendocrine Neoplasms
Authors: Emile B. Veenstra, Derk Jan A. de Groot, Adrienne H. Brouwers, Annemiek M.E. Walenkamp, Walter Noordzij
Journal: Clinical Nuclear Medicine (2020)

The aim of this study was to retrospectively compare 18F-FDOPA versus 68Ga-DOTATOC PET in lesion detection rates and laboratory tumor markers in patients with neuroendocrine neoplasms (NENs).All patients with histologically proven NEN between May 2015 and February 2019 were included who underwent both 18F-DOPA and 68Ga-DOTATOC PET scans within 6 months from each other (mean, 75; median, 38; range, 2-168 days). All patients, except those with pancreatic NEN, received carbidopa before 18F-DOPA PET. Based on the number of lesions on both modalities, patients were divided into 3 categories: more lesions on 18F-DOPA (DOPA > DOTA), more lesions on 68Ga-DOTATOC (DOTA > DOPA), and equal number of lesions (DOPA = DOTA). Tumor markers chromogranin A, serotonin, and 5-hydroxyindoleacetic acid (5-HIAA) within a maximum of 3 months around either scan were retrieved from the patients' charts.18F-DOPA revealed significantly more lesions compared with 68Ga-DOTATOC (611 vs 385, P < 0.05). Twenty-four patients were included in the DOPA > DOTA group with 16 small intestinal (SI) NENs, 3 large intestinal, 4 pancreatic, and 1 tumor of unknown origin (TUO). For the 9 patients in the DOTA > DOPA group, 4 were SI, 2 pancreatic, 1 lung, and 2 TUOs. Twelve patients in the DOPA = DOTA group had 6 pancreatic tumors, 3 SI, 1 ovarian, and 2 TUOs. Only serotonin and 5-HIAA showed significant higher values for DOPA > DOTA compared with DOTA > DOPA (mean 24 vs 4, P < 0.05, and 320 vs 81, P < 0.05, respectively). Cutoff values of 20 nmol/109 for serotonin, 185 μg/L for chromogranin A, and 200 nmol/L for 5-HIAA were found to include almost exclusively DOPA > DOTA patients.There is an advantage of carbidopa pretreated 18F-DOPA over 68Ga-DOTATOC PET, especially for large intestinal NENs with high levels of biomarkers. There seems to be a relationship between increased biomarker value and improved lesion detection rates with the 18F-DOPA PET scan, which requires further prospective analysis.
TMOD-27. EFFICACY OF SOLUBLE PANOBINOSTAT (MTX110) IN PRECLINICAL MODELS OF ADULT GLIOBLASTOMA
Authors: David Ashley, Stephen T Keir, Martin A Roskoski, Rhian Davies, Ben Williams, Stephen J P Damment, Kelly Conlon
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Panobinostat is a histone deacetylase (HDAC) inhibitor with antineoplastic and anti-angiogenic effects in glioma. HDAC inhibitors have demonstrated therapeutic efficacy preclinically via multiple mechanisms, including the induction of cell-cycle arrest, differentiation, senescence, apoptosis, mitotic cell death, autophagy, generation of reactive oxygen species, inhibition of angiogenesis and metastasis, and improvement in tumor immunity. One of the biggest challenges in treating glioblastoma is achieving effective local drug concentrations, and trials using systemic administration of therapeutics have failed in GBM despite compelling pre clinical evidence. MTX110 (Midatech Pharma plc) is a water-soluble form of panobinostat currently in clinical development for DIPG and medulloblastoma using direct tumour delivery. We explored the therapeutic potential of MTX110 in GBM in our preclinical in vivo adult brain tumor models. METHODS Tumor-bearing mice were stratified to either the vehicle control or treatment group based on median tumor volume and were treated with Panobinostat/MTX110 at a dose of 15mg/kg IP, twice weekly for 5 consecutive weeks. The response to treatment was assessed by delay in tumor growth in days, expressed as a T (Treated) - C (Control) value. Statistical analysis was performed using SAS (a statistical analysis program) and the Wilcoxon rank order test. RESULTS MTX110 produced non-significant growth delays of 10.76 and 2.01 days (p Value ≥ 0.072 NS) in IDH wild type xenograft lines. However, in an IDH1 mutated line, MTX110 produced a significant growth delay of 23.35 days (p Value ≤ 0.018). Further work is ongoing to look at the therapeutic potential of MTX110 in combination with radiation in both IDH wild type and IDH mutated xenograft lines.
Immune Predictors of Response to Pembrolizumab Monotherapy As Consolidation in Multiple Myeloma Patients: Results of the GEM-Pembresid Clinical Trial
Authors: Enrique M. Ocio, Noemi Puig, Luis Corchete, José J Pérez, Julio Dávila, Teresa Paíno, Javier de la Rubia, Albert Oriol, Jesús Martín, Felipe De Arriba, Joan Bladé, M Jesús Blanchard, Ramón García-Sanz, Bruno Paiva, Juan-José Lahuerta, Jesus F. San Miguel, Maria-Victoria Mateos
Journal: Blood (2017)
INNV-27. BT-LIFE (BRAIN TUMOURS, LIFESTYLE INTERVENTIONS, AND FATIGUE EVALUATION): LESSONS LEARNED FROM RUNNING A NOVEL MULTI-SECTORAL RESEARCH TRIAL
Authors: Alasdair G Rooney, William Hewins, Amie Walker, Lisa Withington, Mairi Mackinnon, Sara Robson, Aimee Green, Garry Anderson, Helen Bulbeck, Claire Torrens, Julie Emerson, Jo Dunlop, Michelle Welsh, Tracy McEleney, Lisa Hopcroft, Mary Wells, Catherine McBain, Anthony Chalmers, Robin Grant
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND BT-LIFE is a multi-centre RCT of novel lifestyle coaching treatments for fatigued brain tumour patients. To our knowledge it is also the first example of ‘multi-sectoral research’ to combine healthcare, private, and charity sectors in this population. To maximise learning, the trial team devised a structured reflection opportunity to ask, “What went well and what would we do differently next time?” METHOD After trial closedown we convened a six-hour ‘focus group’ for management, principle investigators, research assistants, interventionists, qualitative researchers, trial statisticians, and the funder. Discussion was structured using a ‘timeline’ wall-chart which attendees freely populated with post-it notes summarising learning points from the trial. Minutes were taken in duplicate. RESULTS In total n=19 team members contributed. Many points were study-specific and will be used internally to plan a larger trial. Among points of wider interest, examples of success included: using regular teleconferences to co-ordinate a cohesive and highly collaborative team; obtaining secure nhs.net email addresses to facilitate multi-sectoral communication; and the clear value of employing one part-time research assistant per centre instead of relying on busy clinical staff to recruit. General future learning points included: speak to the prospective sponsor and ethical committees when writing the grant application to avoid pitfalls and facilitate faster opening if funding is secured; consider preceding emails with a phone call to ‘lay the ground’ in time-sensitive situations; identify staff training requirements as early as possible and cascade aggressively; and be sensitive to the fact that inter-sectoral attitudes and practices may vary widely and need actively monitored and managed. Therefore frequent and secure communication, pro-active problem-spotting, and inter-sectoral value alignment appear critical for success. CONCLUSION BT-LIFE provides many useful lessons for anyone interested in running multi-sectoral research.
BIOM-62 SENSITIVE DETECTION AND DISCRIMINATION OF INTRACRANIAL TUMORS BY BLOOD
Authors: Farshad Nassiri, Ankur Chakravarthy, Shengrui Feng, Roxana Shen, Romina Nejad, Jeffrey Zuccato, Mathew Voisin, Vikas Patil, Craig Horbinski, Kenneth Aldape, Gelareh Zadeh, Daniel de Carvalho
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND The diagnosis of intracranial tumors relies on tissue specimens obtained by invasive surgery. Non-invasive diagnostic approaches, particularly for patients with brain tumours, provide an opportunity to avoid surgery and mitigate unnecessary risk to patients. We reasoned that DNA methylation profiles of circulating tumor DNA in blood can be used as a clinically useful biomarker for patients with brain tumors, given the specificity of DNA methylation profiles for cell-of-origin. METHODS We generated methylation profiles on the plasma of 608 patients with cancer (219 intracranial, 388 extracranial) and 60 healthy controls using a cell-free methylated DNA immunoprecipitation combined with deep sequencing (cfMeDIP-seq) approach. Using machine-learning approaches we generated and evaluated models to distinguish brain tumors from extracranial cancers that may metastasize to the brain, as well as additional models to discriminate common brain tumors included in the differential diagnosis of solitary extra-axial and intra-axial tumors. RESULTS We observed high sensitivity and discriminative capacity for our models to distinguish gliomas from other cancerous and healthy patients (AUC=0.99, 95%CI 0.96–1), with similar performance in IDH mutant and wildtype gliomas as well as in lower- and high-grade gliomas. Excluding non-malignant contributors to plasma methylation did not change model performance (AUC=0.982, 95%CI 0.93–1). Models generated to discriminate intracranial tumors from each other also demonstrated high accuracy for common extra-axial tumors (AUCmeningioma=0.89, 95%CI 0.80–0.97; AUChemangiopericytoma=0.95, 95%CI 0.73–1) as well as intra-axial tumors ranging from low-grade indolent glial-neuronal tumors (AUC 0.93, 95%CI 0.80 – 1) to diffuse intra-axial gliomas with distinct molecular composition (AUCIDH-mutant glioma = 0.82, 95%CI 0.66 -0.98; AUCIDH-wildtype-glioma = 0.71, 95%CI 0.53 – 0.9). Plasma cfMeDIP-seq signals originated from corresponding tumor tissue DNA methylation signals (r=0.37, p&amp;lt; 2.2e-16). CONCLUSIONS These results demonstrate the potential for cfMeDIP-seq profiles to not only detect circulating tumor DNA, but to accurately discriminate common intracranial tumors that share cell-of-origin lineages.
LINC-19. CURRENT SITUATION OF PEDIATRIC TUMORS OF CENTRAL NERVOUS SYSTEM IN CHINA - THE FIRST CNOG NATIONAL WIDE REPORT
Authors: Jie Ma
Journal: Neuro-Oncology (2020)

Abstract Tumors of Central Nervous System (CNS) are most seen solid tumor in childhood. Accounting approximate 25–30% of pediatric neoplasms, treatments on these tumors are complicated as they occur in different age ranges, have various types according to classification system and contain different characteristic molecular profiles. There are huge gaps of medical services for children with CNS tumors in different regions in China, which is blamed to limited medical resources and lack of epidemiology data for Chinese population. After the establishment of CNOG (Children’s Neuro-Oncology Group) in China in 2017, national wide registry (CNOG-MC001) was conducted to collect data on the basic information about pediatric tumors of CNS. Results of 4059 cases from 37 centers providing medical services for pediatric CNS tumors in 25 provinces from 6 greater administrative areas in China showed distinct tumor ratio, compared to worldwide data by WHO classification. The mean of age was 8.01 ± 4.73, with a male vs. female ratio as 1.48 to 1. Embryonal tumor, astrocytic &amp; oligodendroglial tumors, and other astrocytic tumors were three most common tumor types in CNS of children. The lost follow-up rate was surprisingly high as 53.07%. In all, this is the first national wide registry for pediatric CNS tumor in China and the results attracted public and government’s attentions for further epidemic investigations.
A Critical Role for Fas-Mediated Off-Target Tumor Killing in T-cell Immunotherapy
Authors: Ranjan Upadhyay, Jonathan A. Boiarsky, Gvantsa Pantsulaia, Judit Svensson-Arvelund, Matthew J. Lin, Aleksandra Wroblewska, Sherry Bhalla, Nathalie Scholler, Adrian Bot, John M. Rossi, Norah Sadek, Samir Parekh, Alessandro Lagana, Alessia Baccarini, Miriam Merad, Brian D. Brown, Joshua D. Brody
Journal: Cancer Discovery (2021)

Abstract T cell–based therapies have induced cancer remissions, though most tumors ultimately progress, reflecting inherent or acquired resistance including antigen escape. Better understanding of how T cells eliminate tumors will help decipher resistance mechanisms. We used a CRISPR/Cas9 screen and identified a necessary role for Fas–FasL in antigen-specific T-cell killing. We also found that Fas–FasL mediated off-target “bystander” killing of antigen-negative tumor cells. This localized bystander cytotoxicity enhanced clearance of antigen-heterogeneous tumors in vivo, a finding that has not been shown previously. Fas-mediated on-target and bystander killing was reproduced in chimeric antigen receptor (CAR-T) and bispecific antibody T-cell models and was augmented by inhibiting regulators of Fas signaling. Tumoral FAS expression alone predicted survival of CAR-T–treated patients in a large clinical trial (NCT02348216). These data suggest strategies to prevent immune escape by targeting both the antigen expression of most tumor cells and the geography of antigen-loss variants. Significance: This study demonstrates the first report of in vivo Fas-dependent bystander killing of antigen-negative tumors by T cells, a phenomenon that may be contributing to the high response rates of antigen-directed immunotherapies despite tumoral heterogeneity. Small molecules that target the Fas pathway may potentiate this mechanism to prevent cancer relapse. This article is highlighted in the In This Issue feature, p. 521
Efficacy and Biomarker Analysis of Camrelizumab in Combination with Apatinib in Patients with Advanced Nonsquamous NSCLC Previously Treated with Chemotherapy
Authors: Caicun Zhou, Yina Wang, Jun Zhao, Gongyan Chen, Zhihua Liu, Kangsheng Gu, Meijuan Huang, Jianxing He, Jianhua Chen, Zhiyong Ma, Jifeng Feng, Jianhua Shi, Xinmin Yu, Ying Cheng, Yu Yao, Yuan Chen, Renhua Guo, Xiaoyan Lin, Zhehai Wang, Guanghui Gao, Quanren Wang, Weixia Li, Xinfeng Yang, Lihong Wu, Jun Zhang, Shengxiang Ren
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Our preclinical work suggests that appropriate angiogenesis inhibition could potentiate PD-1/PD-L1 blockade via alleviating hypoxia, increasing infiltration of CD8+ T cells and reducing recruitment of tumor-associated macrophages. We hereby conducted a clinical trial to evaluate this combination in pretreated patients with advanced non–small cell lung cancer (NSCLC). Patients and Methods: The study included phase Ib apatinib dose-escalation and phase II expansion cohorts. Patients received apatinib at doses of 250–500 mg orally once daily, in combination with camrelizumab 200 mg intravenously every 2 weeks. Results: From March 2017 to October 2018, 105 chemotherapy-pretreated patients with nonsquamous NSCLC were enrolled and received apatinib 250 mg (recommended phase II dose) and camrelizumab. Among them, one (1.0%) complete response, 28 (26.7%) partial responses, and 48 (45.7%) stable diseases were observed. In the efficacy-evaluable population (n = 94), objective response rate (ORR) was 30.9% [95% confidence interval (CI), 21.7–41.2]. The median progression-free survival was 5.7 months (95% CI, 4.5–8.8) and overall survival was 15.5 months (95% CI, 10.9–24.5). Efficacy of combination therapy was evident across all PD-L1 and tumor mutation burden subgroups, and appeared to be improved in patients with STK11/KEAP1 mutation (mutant vs. wild-type, ORR: 42.9% vs. 28.1%; 1-year survival rate: 85.1% vs. 53.1%). No unexpected adverse events were observed. Conclusions: Combined apatinib and camrelizumab showed encouraging antitumor activity and acceptable toxicity in chemotherapy-pretreated patients with advanced nonsquamous NSCLC. Patients with STK11/KEAP1 mutation might derive more benefits from this combination. We will validate these results in an ongoing phase III trial (NCT04203485).
Analysis of Radiation Facility Volume and Survival in Men With Lymph Node–Positive Prostate Cancer Treated With Radiation and Androgen Deprivation Therapy
Authors: Sagar A. Patel, Subir Goyal, Yuan Liu, Drew Moghanaki, Pretesh R. Patel, Sheela Hanasoge, Vishal R. Dhere, Jay W. Shelton, Karen D. Godette, Ashesh B. Jani, Bruce Hershatter, Benjamin W. Fischer-Valuck
Journal: JAMA Network Open (2020)

<h3>Importance</h3> Long-term control of node-positive (N1) prostate cancer, the incidence of which is increasing, is obtainable with aggressive treatment, and definitive external beam radiation therapy (EBRT) with long-term androgen deprivation therapy (ADT) is an increasingly preferred option. Caring for these patients is complex and may require resources more readily available at high-volume centers. <h3>Objective</h3> To evaluate the association between radiation facility case volume and overall survival (OS) in men with N1 prostate cancer. <h3>Design, Setting, and Participants</h3> This cohort study included 1899 men diagnosed with T1N1M0 to T4N1M0 prostate cancer treated with curative-intent EBRT and ADT between January 2004 and December 2016 at US facilities reporting to the National Cancer Database. Data analysis was performed from March to June 2020. <h3>Exposures</h3> Treatment at a center with high vs low average cumulative facility volume (ACFV), defined as the total number of prostate radiation cases at an individual patient’s treatment facility from 2004 until the year of that patient’s diagnosis. <h3>Main Outcomes and Measures</h3> OS was assessed between high- vs low-ACFV centers using the Kaplan-Meier method with and without propensity score–based weighted adjustment and multivariable Cox proportional hazards. The nonlinear association between continuous ACFV and OS was examined through a Martingale residual plot, and the optimal ACFV cutoff point that maximized the separation between high vs low ACFV was identified via a bias adjusted log rank test. <h3>Results</h3> A total of 1899 men met inclusion criteria. The median (interquartile range) age was 66 (60-72) years, 1491 (78.5%) were White individuals, and 1145 (60.3%) were treated at nonacademic centers. The optimal ACFV cutoff point was 66.4 patients treated per year. The median OS for patients treated at high-ACFV vs low-ACFV centers was 111.1 (95% CI, 101.5-127.9) months and 92.3 (95% CI, 87.7-103.9) months, respectively (<i>P</i> = .01). On multivariable analysis, treatment at a low-ACFV center was associated with increased risk of death (HR, 1.22; 95% CI, 1.02-1.46,<i>P</i> = .03) compared with treatment at a high-ACFV center. These results persisted after propensity score–based adjustment. <h3>Conclusions and Relevance</h3> This cohort study found a significant association of facility case volume with long-term outcomes in men with N1 prostate cancer undergoing EBRT with ADT. Specifically, treatment at a facility with high radiation case volume was independently associated with longer OS. Further studies should focus on identifying which factors unique to high-volume centers may be responsible for this benefit.
Abstract 19257: Spatiotemporal Gradients are Necessary for Initiation and Maintenance of Atrial Fibrillation in Mice
Authors: Uma Avula, Charlotte Buck, Meghana Noonavath, Hasan Garan, Steven Marx, Elaine Wan
Journal: Circulation (2017)

Introduction: Aberrant sodium influx in F1759A-NaV1.5 mice is sufficient to cause spontaneous atrial fibrillation (AF), as well as, similar electrophysiological and structural changes seen in human...
IMMU-06. DISCERNING THE DIFFERENT BONE MARROW IMMUNE LANDSCAPES
Authors: Michael Strong, Aqila Ahmed, Anda-Alexandra Calinescu, Xiaofeng Zhou, Tyler Robinson, Sabrina Rocco, Geoffrey Siegel, Gregory Clines, Bethany Moore, Evan Keller, Nicholas Szerlip
Journal: Neuro-Oncology (2020)

Abstract Roughly 400,000 people have bone metastases in the U.S. with the vast majority of these occurring in the spine. The etiology of bone metastasis still remains to be fully elucidated. This study explored the differences in immune landscape between long bone and spine that may contribute to higher rates of bone metastasis to the spine. Spines and femurs from male C57BL6/J mice (N=10) were processed for flow cytometry and immunophenotyping using Mass Cytometry by Time-Of-Flight (CyTOF). The cells were analyzed with CyTOF using a 33-surface protein marker mouse antibody panel. Spines (N=3) and femurs (N=2) from patients were analyzed with CyTOF using the Maxpar Complete Human T cell Immuno-Oncology Panel Set. There are global differences in the immune cell composition between the long bone and spine microenvironment. Flow cytometry revealed slight increases in the CD45+ and Cd11b+ cell populations in the bone marrow of murine spines compared to murine long bone, which are markers for myeloid-derived suppressor cells (MDSCs). Using CyTOF, significant differences in the immune cell landscape between long bone and spine were observed. In the murine long bone, an increase in monocytes/macrophages, myeloid progenitors, granulocytic MDSCs, granulocytes, and mast cells was observed compared to the spine. In the murine spine an elevation of CD8a+ DC cells, classical monocytes, MDSCs, pDCs, memory T helper cells, and NK T cells was seen. Evaluation of human long bone and spine revealed similar trends with a predominance of myeloid progenitor cells and monocytes in the human vertebra compared to the human long bone marrow. Significant differences in the immune microenvironment exist between the spine and long bone marrow in both murine and human samples. This is the first report of significant differences in immune cell populations between different skeletal locations. However, the functional significance of these differences has yet to be determined.
Targeted inhibition of cooperative mutation- and therapy-induced AKT activation in AML effectively enhances response to chemotherapy
Authors: Montserrat Estruch, Kristian Reckzeh, Camilla Vittori, Anders Centio, Mina Ali, Sophia Engelhard, Ling Zhao, Kyoung Jae Won, Paul Liu, Bo Torben Porse, Kim Theilgaard-Mönch
Journal: Leukemia (2020)