tbuckley/cabot-search huggingface dataset:
High Precision 3D Bio‐printing: Precision 3D‐Printed Cell Scaffolds Mimicking Native Tissue Composition and Mechanics (Adv. Healthcare Mater. 24/2020)
Authors: Amelie Erben, Marcel Hörning, Bastian Hartmann, Tanja Becke, Stephan A. Eisler, Alexander Southan, Séverine Cranz, Oliver Hayden, Nikolaus Kneidinger, Melanie Königshoff, Michael Lindner, Günter E. M. Tovar, Gerald Burgstaller, Hauke Clausen‐Schaumann, Stefanie Sudhop, Michael Heymann
Journal: Advanced Healthcare Materials (2020)
Phagocytic function of tumor-associated macrophages as a key determinant of tumor progression control: a review
Authors: Marc Lecoultre, Valérie Dutoit, Paul R Walker
Journal: Journal for ImmunoTherapy of Cancer (2020)

Tumor-associated macrophage (TAM) phagocytic activity is emerging as a new mechanism to harness for cancer treatment. Currently, many approaches are investigated at the preclinical level and some modalities have now reached clinical trials, including the targeting of the phagocytosis inhibitor CD47. The rationale for increasing TAM phagocytic activity is to improve innate anticancer immunity, and to promote T-cell mediated adaptive immune responses. In this context, a clear understanding of the impact of TAM phagocytosis on both innate and adaptive immunity is critical. Indeed, uncertainties persist regarding the capacity of TAM to present tumor antigens to CD8 T cells by cross-presentation. This process is critical for an optimal cytotoxic T-cell immune response and can be mediated by dendritic cells but also potentially by macrophages. In addition, the engulfment of cancer cells affects TAM functionality, as apoptotic cell uptake (a process termed efferocytosis) promotes macrophage anti-inflammatory functions. Because of the abundance of TAM in most solid tumors and the common use of apoptosis inducers such as radiotherapy to treat patients with cancer, efferocytosis potentially affects the overall immune balance within the tumor microenvironment (TME). In this review, we will discuss how cancer cell phagocytosis by TAM impacts antitumor immunity. First, we will focus on the potential of the phagocytic activity of TAM per se to control tumor progression. Second, we will examine the potential of TAM to act as antigen presenting cells for tumor specific CD8 T cells, considering the different characteristics of this process in the tumor tissue and at the molecular level. Finally, we will see how phagocytosis and efferocytosis affect TAM functionality and how these mechanisms impact on antitumor immunity. A better understanding of these aspects will enable us to better predict and interpret the consequences of cancer therapies on the immune status of the TME. Future cancer treatment regimens can thereby be designed to not only impact directly on cancer cells, but also to favorably modulate TAM phagocytic activity to benefit from the potential of this central immune player to achieve more potent therapeutic efficacy.
RADT-24. HIGH ABSORBED DOSES OF RHENIUM-186 NANOLIPOSOMES (RNL) IN RECURRENT GBM: A PHASE 1 STUDY
Authors: Andrew Brenner, John Floyd, Ande Bao, William Phillips, Vibhudutta Awasthi, Toral Patel, Jeffrey Weinberg
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION While external beam radiation therapy (EBRT) remains a central component of the management of primary brain tumors, it is limited by tolerance of the surrounding normal brain tissue. Nanoliposomal BMEDA-chelated-186Rhenium (RNL™) permits the delivery of beta-emitting radiation of high specific activity with excellent retention in the tumor. We report on the phase 1 results in recurrent glioma. METHODS A phase 1 dose-escalation study of RNL in recurrent glioma utilizing a standard 3 + 3 design was undertaken to determine the maximum tolerated dose of RNL following stereotactic biopsy. RNL is administered with the BrainLab Flexible Catheter by convection enhanced delivery (CED) with placement guided using iPlan Flow and the Varioguide system. Infusion is followed under whole body planar imaging and SPECT/CT. Repeat SPECT/CT imaging is performed immediately following, and at 1, 3, 5, and 8 days after RNL infustion to obtain dosimetry and distribution. RESULTS Thirteen patients have been treated to-date, 12 were recurrent glioblastoma, and 54% failed treatment with bevacizumab. The infused dose was progressively increased from 1.0 mCi to 13.4 mCi and the volume of infusate from 1.0 mL to 5.28 mL using 1 – 2 CED catheters. The mean absorbed dose to the distribution volume was 175 Gy (CI 97 – 254). The maximum absorbed dose to the tumor volume was 593 Gy. The mean retention of the administered dose at 24 hours was 61.4% (CI 45.4 – 77.5). The therapy has been well tolerated and no dose-limiting toxicity has been observed with no treatment related adverse effects despite markedly higher absorbed doses than EBRT in patients with prior treatment. The plan is to increase the dose to 22.3 mCi and the infusate volume to 8.8 mL. CONCLUSION Intratumoral RNL can deliver up to twenty times the absorbed dose of radiation administered by EBRT without significant toxicity.
CTNI-29. CODEL: PHASE III TRIAL OF RT ALONE, RT PLUS TMZ, OR TMZ ALONE FOR NEWLY-DIAGNOSED, 1p/19q CODELETED ANAPLASTIC OLIGODENDROGLIOMA. ANALYSIS FROM THE INITIAL STUDY DESIGN. (NCCTG N0577, ALLIANCE)
Authors: Kurt Jaeckle, Karla Ballman, Martin van den Bent, Caterina Giannini, Evanthia Galanis, Paul Brown, Robert Jenkins, Gregory Cairncross, Wolfgang Wick, Michael Weller, Kenneth Aldape, Jesse Dixon, S Keith Anderson, Jane Cerhan, Jeffrey S Wefel, Martin Klein, Stuart Grossman, David Schiff, Jeffrey Raizer, Frederick Dhermain, Donald Nordstrom, Patrick Flynn, Michael Vogelbaum
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND The original 3-arm CODEL design included a radiotherapy (RT)-alone control arm, an RT plus temozolomide (TMZ) arm, and an exploratory TMZ-alone arm. We report the analysis involving patients treated per the initial design. METHODS Adults (18+ years) with newly-diagnosed 1p/19q codeleted WHO grade III oligodendroglioma were randomized to RT (5940 cGy) alone (Arm A); RT with concomitant and adjuvant TMZ (Arm B); or TMZ alone (Arm C). Primary endpoint was OS, Arm A vs. B. Secondary comparisons were performed for OS and PFS, comparing pooled RT arms with the TMZ-alone arm. RESULTS 36 patients were randomized equally to the three arms. At median follow-up of 7.5 years, 83.3% (10/12) TMZ-alone patients had progressed, versus 37.5% (9/24) patients on the RT arms. PFS was shorter in TMZ-alone patients compared to RT-treated patients (HR=3.12; 95% CI: 1.26, 7.69; p=0.014). Death from disease progression occurred in 3/12 (25%) of TMZ-alone patients and 4/24 (16.7%) of RT-treated patients. OS did not statistically differ between arms, although this comparison was underpowered. After adjustment for IDH status (mutated vs. wildtype) in a Cox regression model, with IDH status and RT treatment status as co-variables (Arm C vs pooled A and B), PFS remained shorter for patients not receiving RT (HR= 3.33; 95% CI: 1.31, 8.45; p=0.011), and OS differences remained non-significant ((HR = 2.78; 95% CI 0.58, 13.22, p=0.20). Grade 3+ adverse events occurred in 25%, 42% and 33% patients (Arms A, B and C, respectively). Neurocognitive assessments, comparing baseline and 3 month timepoints, showed no significant differences between arms. CONCLUSIONS TMZ-alone treated patients experienced significantly shorter PFS than patients treated on the pooled RT arms, which remained significant when adjusting for IDH status. CODEL has been redesigned to compare the efficacy and toxicity of RT+PCV versus RT+TMZ. Clinicaltrials.gov Identifier: NCT00887146. Support: U10CA180821, U10CA180882, https://acknowledgments.alliancefound.org.
The deubiquitinase CYLD controls protective immunity against helminth infection by regulation of Treg cell plasticity
Authors: Jee H. Lee, Le Zou, Runqing Yang, Jihye Han, Qingqing Wan, Xian Zhang, Sarah El Baghdady, Andrea Roman, Chris Elly, Hyung-seung Jin, Yoon Park, Michael Croft, Yun-Cai Liu
Journal: Journal of Allergy and Clinical Immunology (2020)
EPCO-09. STEREOTACTIC IMAGE-GUIDED EPIGENOME PROFILING REVEALS DIVERSE EVOLUTIONARY GROWTH ROUTES IN DIFFUSE GLIOMAS
Authors: Floris Barthel, Niels Verburg, Kevin Anderson, Thomas Koopman, Kevin Johnson, Pieter Wesseling, Philip de Witt Hamer, Roel Verhaak
Journal: Neuro-Oncology (2020)

Abstract Intratumoral heterogeneity is a hallmark of diffuse gliomas and inhibits effective prediction of clinical outcome. To devise a three-dimensional reconstruction of tumor lineage, we used neuronavigation to acquire eight to twelve image-guided and spatially separated stereotactic biopsy samples from 16 adult patients with a diffuse glioma, which we characterized using DNA methylation arrays. A total of 133 samples were obtained from regions with and without imaging abnormalities. Methylation profiles were analyzed to construct phylogenetic trees and subsequently projected on image-derived tumor maps. Lineage analysis of these evolutionary trees indicated that the sampled gliomas largely evolved stochastically, suggesting that critical tumor drivers were acquired early in time. These results were further validated using 102 multi-region samples from 24 independent patients. Patristic (evolutionary) and cartesian (spatial) distances between pairs of tumor samples from the same patient demonstrated strong correlations, suggesting that this information could be used to determine trajectories of tumor evolution. Evolutionary and spatial distance metrics were combined with histologically obtained and computationally quantified cellularity and proliferation rates to infer vectors representing the direction and magnitude of tumor growth. Using the resulting vector field we determined the minimum and maximum rates of change in order infer the tumor’s evolutionary trajectory. Using this metric we identified three distinct growth patterns: (1) tumors with a trajectory oriented towards the tumor core, (2) outward growing tumors with a linear trajectory pointing outside tumor boundaries, and (3) outward growing tumors with a branching trajectory directed outside tumor boundaries. Association of evolutionary growth patterns with survival demonstrated distinct impacts on outcome, suggesting that growth patterns are an important determinant of tumor aggressiveness. Taken together, although our analyses indicated that the observed glioma heterogeneity is small and largely stochastic, when spatially mapped these changes can be used to track tumor lineage and identify clinically relevant growth patterns.
DIPG-19. TARGETING ATM MUTATION IN METASTATIC DIFFUSE MIDLINE GLIOMA – A CASE OF SUSTAINED RESPONSE USING PARP INHIBITOR
Authors: Karen Tsui, Andrew Law, Michael K Watson
Journal: Neuro-Oncology (2020)

Abstract Diffuse midline glioma (DMG) with H3.3K27M mutation is associated with an extremely poor prognosis, with a median survival of 10 to 12 months. Radiation remains the standard of care however there is no established curative therapy available. We describe a patient diagnosed with a diffuse intrinsic pontine glioma at 5 years of age by clinical and radiological criteria. He was treated with focal radiation 59Gy which resulted in reduction in size of the tumour, and partial improvement of T2 changes on MRI. At 18 months post diagnosis, the patient developed metastatic recurrence at the anterior fornix. This was biopsied and histopathology demonstrated a high grade glioma. Next generation sequencing revealed a H3F3A K27M mutation, and an ATM R3008H mutation. He received whole ventricular radiation 36Gy and boost to the lesion to 45Gy, followed by Olaparib 135mg/m2/day twice daily. He remains in radiological remission 20 months post metastatic relapse and has no organ toxicity to Olaparib. CONCLUSION: H3.3K27M and ATM co-segregating mutations are described in DMG. This is the first case report of targeting ATM mutation with a PARP inhibitor which resulted in prolonged remission of metastatic DMG. Olaparib was well tolerated.
Effect of Co-trimoxazole (Trimethoprim-Sulfamethoxazole) vs Placebo on Death, Lung Transplant, or Hospital Admission in Patients With Moderate and Severe Idiopathic Pulmonary Fibrosis
Authors: Andrew M. Wilson, Allan B. Clark, Tony Cahn, Edwin R. Chilvers, William Fraser, Matthew Hammond, David M. Livermore, Toby M. Maher, Helen Parfrey, Ann Marie Swart, Susan Stirling, David R. Thickett, Moira Whyte
Journal: JAMA (2020)

Idiopathic pulmonary fibrosis (IPF) has a poor prognosis and limited treatment options. Patients with IPF have altered lung microbiota, with bacterial burden within the lungs associated with mortality; previous studies have suggested benefit with co-trimoxazole (trimethoprim-sulfamethoxazole).To determine the efficacy of co-trimoxazole in patients with moderate and severe IPF.Double-blind, placebo-controlled, parallel randomized trial of 342 patients with IPF, breathlessness (Medical Research Council dyspnea scale score >1), and impaired lung function (forced vital capacity ≤75% predicted) conducted in 39 UK specialist interstitial lung disease centers between April 2015 (first patient visit) and April 2019 (last patient follow-up).Study participants were randomized to receive 960 mg of oral co-trimoxazole twice daily (n = 170) or matched placebo (n = 172) for between 12 and 42 months. All patients received 5 mg of folic acid orally once daily.The primary outcome was time to death (all causes), lung transplant, or first nonelective hospital admission. There were 15 secondary outcomes, including the individual components of the primary end point respiratory-related events, lung function (forced vital capacity and gas transfer), and patient-reported outcomes (Medical Research Council dyspnea scale, 5-level EuroQol 5-dimension questionnaire, cough severity, Leicester Cough Questionnaire, and King's Brief Interstitial Lung Disease questionnaire scores).Among 342 individuals who were randomized (mean age, 71.3 years; 46 [13%] women), 283 (83%) completed the trial. The median (interquartile range) duration of follow-up was 1.02 (0.35-1.73) years. Events per person-year of follow-up among participants randomized to the co-trimoxazole and placebo groups were 0.45 (84/186) and 0.38 (80/209), respectively, with a hazard ratio of 1.2 ([95% CI, 0.9-1.6]; P = .32). There were no statistically significant differences in other event outcomes, lung function, or patient-reported outcomes. Patients in the co-trimoxazole group had 696 adverse events (nausea [n = 89], diarrhea [n = 52], vomiting [n = 28], and rash [n = 31]) and patients in the placebo group had 640 adverse events (nausea [n = 67], diarrhea [n = 84], vomiting [n = 20], and rash [n = 20]).Among patients with moderate or severe IPF, treatment with oral co-trimoxazole did not reduce a composite outcome of time to death, transplant, or nonelective hospitalization compared with placebo.ISRCTN Identifier: ISRCTN17464641.
Abstract P470: Heterogeneity In Prevalence Of Cardiovascular Disease Risk Factors Among Hispanic Ethnic Groups: Evidence From The 2010-2018 National Health Interview Survey
Authors: Sabrina Elias, Ruth-alma N Turkson-ocran, Binu Koirala, Samuel Byiringiro, Hailey Miller, Diana Baptiste, Cheryl Dennison-Himmelfarb, Yvonne Commodore-mensah
Journal: Circulation (2020)

Introduction: Persons of Hispanic origin are a growing share of the U.S. population but include diverse ethnic groups with unique cultures, lifestyles, exposures, and countries of origin. Hispanics are disproportionately affected by cardiovascular disease (CVD) risk factors in comparison to non-Hispanics. However, few studies have examined the heterogeneity in their burden of CVD risk. Hypothesis: We hypothesized that there would be significant heterogeneity in the prevalence of CVD risk factors among ethnic subgroups of Hispanic adults. Methods: We used a cross-sectional design to examine the prevalence of CVD risk factors, defined per national guidelines, among Hispanic adults in the 2010-2018 National Health Interview Surveys. Generalized linear models using Poisson distribution were fitted to obtain adjusted predicted probabilities and risk of self-reported hypertension, overweight/obesity, diabetes, high cholesterol, physical inactivity, and current smoking by Hispanic ethnic subgroup. Results: We included 185,511 participants with mean(±sd) age 31(0.2) years and 50% male. Most were Mexican (65.1%) whereas, few were Dominican (3.0%). Prevalence of hypertension (28.4%), diabetes (12.9%), high cholesterol (25.0%), and current smoking (6.1%) was highest among Puerto Ricans. Prevalence of overweight/obesity was highest among Mexicans (74.5%) and physical inactivity was highest among Dominicans (62.3%). Compared to Mexicans, Central Americans were less likely to smoke and have hypertension, overweight/obesity, and diabetes (ps&lt;0.05). ( Table ) Conclusion: We observed striking heterogeneity in the prevalence of CVD risk factors across Hispanic ethnic subgroups, especially for diabetes, physical inactivity, and smoking. These results suggest that aggregating data on Hispanics may mask differences in CVD risk and hinder efforts to reduce health disparities in this population. Our findings provide actionable information on CVD risk factors for specific Hispanic ethnic subgroups.
LINC-33. MULTIMODALITY MANAGEMENT OF PAEDIATRIC PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA- UPDATED EXPERIENCE FROM A REGIONAL CANCER CENTRE IN NORTH INDIA
Authors: Ahitagni Biswas, Swarnaditya Roy, Yousra KN, Sameer Bakhshi, Vaishali Suri, Mehar Sharma, Pramod Julka
Journal: Neuro-Oncology (2020)

Abstract Paediatric primary central nervous system lymphoma(PCNSL) constitutes 1% of all PCNSLs. Data pertaining to paediatric PCNSL (2016–19) was abstracted by retrospective chart review. We identified 7 paediatric patients with PCNSL. None had congenital or acquired immunodeficiency. The median age at presentation was 13 years. The male to female ratio was 4:3. The median ECOG performance status was 2. On neuro-imaging, 3 patients had solitary and 4 patients had multiple lesions. CSF cytology showed atypical cells in 1 patient. None had ocular involvement. Systemic lymphoma work-up was negative in all. Biopsy and resection of tumour were done in 4 patients each. Histopathology revealed DLBCL in 6 and B-cell NHL in 1 patient. All patients underwent induction chemotherapy (median-5 cycles)- modified DeAngelis protocol (IV Methotrexate-2.5g/m2,IT Methotrexate-12 mg,Vincristine,Procarbazine and Rituximab-375mg/m2 every 2 weeks) in 6 and single agent Methotrexate -3.5g/m2 every 3 weeks in 1 patient. Severe haematological toxicities included grade 3 neutropenia, leucopenia and febrile neutropenia in 2,1 and 1 patient respectively. Radiotherapy(RT) was administered in all-whole brain RT(36-45Gy/20-25fractions/4-5weeks) in 6 patients and craniospinal RT(36Gy/18fractions/3.5weeks) followed by whole brain RT(9Gy/5fractions/1week) in 1 patient(with positive CSF cytology). Subsequently consolidation chemotherapy with 2 cycles of Cytarabine(3g/m2 IV D1-2 every 3 weeks) was administered in 5 patients. After a median follow-up of 14 months(mean-18.2 months), all patients are in complete radiological remission. Paediatric PCNSL is a rare tumour entity and multimodality management with high dose Methotrexate and Rituximab based chemo-immunotherapy and cranial radiotherapy leads to excellent early clinical outcome.
BIOM-33. LOW EXPRESSION OF DYNLT3 PREDICTS BETTER PROGNOSIS FOR FEMALE GLIOBLASTOMA PATIENTS
Authors: Yuanjun Hu, Jing Wang, Zhong-ping Chen
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Glioblastoma (GBM) is the most malignant tumor in the central nervous system. It has been confirmed that the prognosis of GBM has obvious gender predilection. As female patients have an advantage than males, it is increasingly accepted to take gender into account while treating GBM. Therefore, it is important to figure out molecular mechanisms related to gender predilection. METHODS We first analyzed the protein expression of GBM (Male=24, Female=16) based on the dataset from Clinical Proteomic Tumor Analysis Consortium (CPTAC) of the National Cancer Institute’s（NCI）and mainly focused on those differential expression proteins between males and females on X chromosome. Then the differentially expressed genes from CPTAC was further confirmed in TCGA data and their role in the overall survival of GBM patients were analyzed. RESULTS 18 proteins, differentially expressed between male and female were selected. 12 out of them expressed higher in female while the other 6 were higher in male (P&amp;lt; 0.05). We found one protein, DYNLT3 might be a predictor for GBM patients’ survival through analyzing the transcriptome profiling database of TCGA. The low expression of DYNLT3 was related to a longer survival of female group. The median survival was 556 days (95% CI, 446 to 665) with lower expression level of DYNLT3, compared with 375 days (95% CI, 291 to 459) in higher expression group (P=0.011 by log-rank test) in all cases including both male and female. For female group, the median survival was 653 days (95% CI, 464 to 842) with lower expression of DYNLT3, which was much better than 305 days (95% CI, 379 to 642) (P=0.008) with higher expression of DYNLT3. No significant predicting value of DYNLT3 expression was found in male group. CONCLUSIONS The expression of DYNLT3 might be a positive predictor for survival of GBM patients, especially for female cases.
GCT-27. CLINICAL FEATURES AND PROGNOSTIC FACTORS OF NONGERMINOMATOUS GERM CELL TUMORS IN 111 CONSECUTIVE PATIENTS IN A SINGLE INSTITUTION: IMPACT OF IRRADIATION AND CHEMOTHERAPY CYCLES ON SURVIVAL
Authors: Lei Wen, Juan Li, Qingjun Hu, Mingyao Lai, Cheng Zhou, Junjie Zhen, Changguo Shan, Weiping Hong, Rishun Luo, Yangqiong Zhang, Xing Zhang, Lichao Wang, Linbo Cai
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Limited data is available in intracranial nongerminomatous germ cell tumors (NGGCTs) in Chinese population. Here we aimed to retrospectively assess the clinical-pathological and prognostic factors of NGGCTs in a single large institution in China. METHODS From June 2003 to December 2018, 111 consecutive NGGCTs were treated in Guangdong Sanjiu Brain Hospital, China. RESULTS The median follow-up was 36.2 months (range, 1.2 to 131.2 months). Three-year EFS and OS for 111 NGGCTs patients were 78.5%±4.5% and 82.8%±4.0%, respectively. 98 patients received CSI plus boost yielded better survival than those who received reduced-volume radiotherapy or no radiotherapy (3y OS, 86.7% vs. 51.4%, p=0.007). Patients had at least four cycles of chemotherapy were strongly associated with improved 3-year OS, compared to those received less than 4 cycles (94.1% vs. 63.6%, p＜0.001). There was no significant difference in survival of patients stratified by age, surgery, hydrocephalus, as well as tumor diameter. Multivariate analysis identified chemotherapy cycles less than 4 was the only prognostic factor that conferring a worse OS (p=0.003). Patients both received CSI and at least 4 courses of chemotherapy were correlated with lower incidence of relapse (p=0.044). CONCLUSIONS Multimodal approach including CSI and enough courses of chemotherapy was effective and should be recommended for the treatment of newly diagnosed NGGCTs in Chinese population.