tbuckley/cabot-search huggingface dataset:
Targeting CD39 in Cancer Reveals an Extracellular ATP- and Inflammasome-Driven Tumor Immunity
Authors: Xian-Yang Li, Achim K. Moesta, Christos Xiao, Kyohei Nakamura, Mika Casey, Haiyan Zhang, Jason Madore, Ailin Lepletier, Amelia Roman Aguilera, Ashmitha Sundarrajan, Celia Jacoberger-Foissac, Clifford Wong, Tracy dela Cruz, Megan Welch, Alana G. Lerner, Bradley N. Spatola, Vanessa B. Soros, John Corbin, Ana C. Anderson, Maike Effern, Michael Hölzel, Simon C. Robson, Rebecca L. Johnston, Nicola Waddell, Corey Smith, Tobias Bald, Nishamol Geetha, Courtney Beers, Michele W. L. Teng, Mark J. Smyth
Journal: Cancer Discovery (2019)

We explored the mechanism of action of CD39 antibodies that inhibit ectoenzyme CD39 conversion of extracellular ATP (eATP) to AMP and thus potentially augment eATP-P2-mediated proinflammatory responses. Using syngeneic and humanized tumor models, we contrast the potency and mechanism of anti-CD39 mAbs with other agents targeting the adenosinergic pathway. We demonstrate the critical importance of an eATP-P2X7-ASC-NALP3-inflammasome-IL18 pathway in the antitumor activity mediated by CD39 enzyme blockade, rather than simply reducing adenosine as mechanism of action. Efficacy of anti-CD39 activity was underpinned by CD39 and P2X7 coexpression on intratumor myeloid subsets, an early signature of macrophage depletion, and active IL18 release that facilitated the significant expansion of intratumor effector T cells. More importantly, anti-CD39 facilitated infiltration into T cell-poor tumors and rescued anti-PD-1 resistance. Anti-human CD39 enhanced human T-cell proliferation and Th1 cytokine production and suppressed human B-cell lymphoma in the context of autologous Epstein-Barr virus-specific T-cell transfer. SIGNIFICANCE: Overall, these data describe a potent and novel mechanism of action of antibodies that block mouse or human CD39, triggering an eATP-P2X7-inflammasome-IL18 axis that reduces intratumor macrophage number, enhances intratumor T-cell effector function, overcomes anti-PD-1 resistance, and potentially enhances the efficacy of adoptive T-cell transfer.This article is highlighted in the In This Issue feature, p. 1631.
TMOD-16. MULTIFUNCTIONAL NANOPARTICLES USED FOR MAGNETIC RESONANCE/NIR FLUORESCENCE DUAL-MODAL IMAGING AND CHEMOTHERAPY OF GLIOMA
Authors: Shiguang Zhao
Journal: Neuro-Oncology (2019)

Abstract PURPOSE Glioma is the most common malignant brain tumor and infamous for its high invasiveness and lethality. Therefore, plenty of techniques like intraoperative MRI (iMRI) and fluorescence-guided surgery were performed to improve the surgical resection rate of glioma. In addition, the chemotherapy effect of glioma was severely restricted because of the low blood-brain barrier (BBB) permeability of traditional therapeutic drugs. Doxorubicin (DOX) is a widely used antineoplastic drug, but its application in glioma therapy is prevented by the BBB. Thus, it is urgent to develop novel diagnostic methods and drug delivery systems to improve glioma treatment effect. MATERIALS AND METHODS In this study, we constructed a multifunctional nanotheranostic agent which integrated MR imaging, fluorescence imaging and targeting chemotherapy for glioma by encapsulating iron oxide nanoparticles, DOX and indocyanine green (ICG) with PEGylated phospholipid. RESULTS The obtained multifunctional were proved with an average diameter of 22.9 nm. In vitro cell experiments demonstrated that the nanoparticle effectively enhanced cellular uptake of DOX compared with that of free DOX. In vivo MR and fluorescence imaging not only demonstrated that the nanotheranostic agent effectively crossed the BBB and selectively accumulated at the tumor area, but also easily monitored the real-time therapeutic outcome. Among all treatment groups, C6 glioma-bearing rats treated with nanoparticles exhibited the maximal degree of efficacy, including the longest survival times and smallest tumor volume. CONCLUSION All these results suggested that the multifunctional nanoparticles could be simultaneously used for iMRI and fluorescence-guided surgery to increase the resection rates, as well as delivering chemotheraputic drugs to tumor site to improve therapeutic effect. We believe that this multifunctional nanoparticle might serve as a potential theranostic treatment for glioma in the near future.
ACTR-50. PRESERVATION OF NEUROCOGNITIVE FUNCTION &amp; PATIENT-REPORTED SYMPTOMS WITH HIPPOCAMPAL AVOIDANCE (HA) DURING WHOLE-BRAIN RADIOTHERAPY (WBRT) FOR BRAIN METASTASES: LONG-TERM RESULTS OF NRG ONCOLOGY CC001
Authors: Terri Armstrong, Snehal Deshmukh, Paul Brown, Vinai Gondi, Tammy Benzinger, Mark Gilbert, Wolfgang Tome, Jeffrey Wefel, Deborah Bruner, David Roberge, Vijayananda Kundapur, Kiran Devisetty, Sunjay Shah, Kenneth Usuki, Andrew Baschnagel, Baldassarre Stea, Harold Yoon, Jing Li, Nadia Laack, Minesh Mehta, Lisa Kachnic
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND NRG-CC001 sought to evaluate the neuro-protective effects of avoiding the peri-hippocampal stem cell niche using intensity-modulated radiotherapy during WBRT. METHODS Patients with brain metastasis were stratified by RPA class and prior radiosurgery/surgery and randomized to WBRT+M or HA-WBRT+ Memantine (M) (30Gy in 10 fractions). Standardized NCF tests and the M.D. Anderson Symptom Inventory Brain Tumor (MDASI-BT) were obtained at baseline, 2, 4, 6, and 12 months (mos). The primary endpoint was NCF failure defined using the reliable change index. Pre-specified secondary endpoints included patient-reported symptoms using the MDASI-BT. Time to NCF was reported as cumulative incidence (with death without NCF failure as a competing risk); between-arms differences were tested using Gray’s test. Deterioration at discrete time-points were tested using chi-square tests. MDASI-BT symptom burden, interference, and cognitive and neurologic burden were analyzed using mixed effects models and t-tests within the model using Hochberg’s multiplicity adjustment. RESULTS A total of 518 patients were randomized from 7/2016 to 3/2018. Median follow-up for alive patients was 12.1 mos, with no difference between arms in terms of toxicity, overall survival or intracranial progression-free survival. HA-WBRT+M was associated with lower risk of NCF failure (adjusted HR=0.739, 95% CI: 0.577–0.945, p=0.0.016), with differences first noted at 4 mos in Trail Making Test Part-B (23.3% vs. 40.4% deteriorated, p=0.012). Age did not dilute treatment effect. HA-WBRT+M was associated with reduced cognitive symptom burden in an imputed model (estimate=-0.29, p=0.0425), and also reduced overall symptom burden (p&lt; 0.0001) and interference (p&lt; 0.0016) at 6 mos. CONCLUSIONS The addition of HA to WBRT+M preserved NCF and reduced patient reported cognitive symptom burden, overall symptom burden and symptom interference and should be considered standard of care for any patient fit enough to have WBRT. Supported by grants UG1CA189867 (NCORP), U10CA180868 (NRG Oncology Operations), DCP from the National Cancer Institute.
ASXL1/SRSF2 Co-Mutated Acute Myeloid Leukemia (AML): A Rare but Distinct Subpopulation with Dismal Outcomes
Authors: Daniel R. Richardson, David M Swoboda, Anastasia Ivanova, Steven M Johnson, Jonathan Galeotti, Sonia Esparza, Onyee Chan, Matthew C Foster, Catherine C. Coombs, Nathan D Montgomery, David A Sallman, Joshua F Zeidner
Journal: Blood (2019)
Non-invasive diagnosis of non-alcoholic steatohepatitis and fibrosis with the use of omics and supervised learning: A proof of concept study
Authors: Nikolaos Perakakis, Stergios A. Polyzos, Alireza Yazdani, Aleix Sala-Vila, Jannis Kountouras, Athanasios D. Anastasilakis, Christos S. Mantzoros
Journal: Metabolism (2019)
Moving forward to address key unanswered questions on targeting PD-1/PD-L1 in cancer: limitations in preclinical models and the need to incorporate human modifying factors
Authors: Catherine T. Le, William J. Murphy
Journal: Journal for ImmunoTherapy of Cancer (2019)

The tremendous clinical success of immune checkpoint inhibition (ICI), particularly targeting the programmed cell death protein 1 (PD-1)/programmed death-ligand 1/2 (PD-L1/2) pathway, has resulted in application to multiple cancers, as a monotherapy and as a companion to both conventional and novel agents. Despite this, the precise mechanisms underlying the anti-tumor effects of PD-1/PD-L1 blockade remain unclear. Emphasis has centered on its reversal of tumor-specific CD8+ T-cell exhaustion, although many cell types and processes are likely impacted. Due to the complex and pervasive roles of PD-1/PD-L1 on T-cell biology, including on initial T-cell priming, PD-1 blockade likely affects all aspects of T- cell responses, and these other effects may be even more critical for durable anti-tumor responses. Delineating these complex interactions necessitates in vivo modeling. By far, the healthy, young and inbred laboratory mouse, transplanted with an extensively cultured tumor cell line, has been the predominant preclinical model used to assess potential therapeutic efficacies. However, these mouse models often do not adequately reflect the tumor progression and cellular and genetic heterogeneity found within human cancers. Furthermore, laboratory mice also present with a vastly restricted immune profile compared to humans. This commentary discusses some of the critical questions that need to be addressed to optimize the use of ICI as well as caveats and limitations for consideration when extrapolating preclinical mouse data to the human cancer scenario.
NIH Consensus conference. Diagnosis and treatment of early melanoma
Journal: JAMA (1992)

THE INCIDENCE of melanoma of the skin appears to be rapidly rising. The increased incidence may be partially attributable to increased detection resulting from screening. In 1992, approximately 32000 newly diagnosed cases and 6700 deaths are expected in the United States. Melanoma tends to occur in adults in the prime of their family and professional lives. Detection and surgical treatment of the early stages of this malignancy are usually curative. In contrast, diagnosis and treatment in late stages often have dismal results. Traits associated with an increased risk of developing melanoma include multiple typical moles, atypical moles, freckling, history of severe sunburn, ease of burning, inability to tan, and light hair with blue eyes. Other factors include the presence of familial atypical mole and melanoma syndrome, disorders of DNA repair, and excessive sun exposure. Efforts to increase public awareness of melanoma and its treatment without causing unnecessary fear present a
TMOD-38. PRODUCTION OF D-2-HYDROXYGLUTARATE IN SACCHAROMYCES CEREVISIAE LEADS TO GROWTH IMPAIRMENT AND DECREASED SURVIVAL
Authors: Sophie Fiola, Eli Ganni, Rita Lo, Ka Yee Lok, Elena Kuzmin, Roberto Diaz
Journal: Neuro-Oncology (2019)

Abstract High levels of D-2-hydroxyglutarate (D2HG) are found in several types of cancers, most notably low grade gliomas (LGGs). The accumulation of D-2HG contributes to tumorigenesis through a variety of mechanisms including decreased utilization of oxidative phosphorylation and histone hypermethylation. The use of the budding yeast Saccharomyces cerevisiae as a model system to study cancer allows for faster, more efficient elucidation of various molecular mechanisms, including functional genomics via genomic array screening. S. cerevisiae encodes two homologs of the human D-2HG dehydrogenase: the mitochondrial Dld2 and cytosolic Dld3. We detected an increase in the production of D-2HG in the dld3∆ knockout strain by LC-MS. In addition, the dld3∆ knockout strain shows decreased survival and a growth impairment in glucose-containing liquid media. However, this strain did not show a significant growth impairment on glucose or glycerol-containing solid media. Using publicly available Synthetic Genomic Array (SGA) analysis data from TheCellMap.org, we investigated the top negative gene interactions for our dld3 knockout strain. GO analysis of these negative gene interactions showed enrichment of targets locating to the mitochondria, suggesting that the increase of 2-HG leads to mitochondrial impairment, consistent with previous observations in other models of LGGs. The top two targets of the SGA screen were mdm35, a mitochondrial interspace membrane protein involved in assembly of the mitochondrial respiratory chain complex and cdc8, a component of the de novo pyrimidine biosynthesis pathway. Taken together, these results suggest that the dld3∆ knockout strain is an appropriate model in which to study the D-2HG-driven changes that occur during tumorigenesis.
Bone Marrow Morphologic Findings in Patients Receiving IDH Inhibitor Therapy in Combination with Intensive Induction Chemotherapy: Challenges with Interpretation of the Day 14 Bone Marrow Biopsy
Authors: Emily F Mason, Olga Pozdnyakova, Mikhail Roshal, Amir T. Fathi, Eytan M. Stein, Aaron C. Shaver, Mark G. Frattini, Hongfang Wang, Lei Hua, Jimmy Mu, Caroline Almon, Michael Cooper, Richard M. Stone, Robert P. Hasserjian, Michael R. Savona
Journal: Blood (2019)
Different Clinical Implications of Kinase Domain BCR-ABL1 Variants Detected in Chronic Myeloid Leukemia and Acute Lymphoblastic Leukemia Patients
Authors: Ricardo Sanchez, Rosa Ayala, Gonzalo Carreño Gomez-Tarragona, Espino Maria Jose, Beatriz Cuevas, Vanegas Raul, Luis Felipe Casado Montero, Nuria Garcia-Ormeña, jose Angel Hernandez, Pilar Bravo, Cristina Seri, Eduardo Anguita, Eva Barragán, Francisca Ferrer Marin, maria Dolores Monteagudo, sanchez-Calero Jorge, Julian Sevilla, Elena Ruiz, Lucia Villalon, maria Del Mar Herraez, Rosalia Riaza, Elena Magro, Juan Luis Steegmann, Valentín García Gutiérrez, Joaquin Martinez-Lopez
Journal: Blood (2019)
ACTR-23. MAINTENANCE TREATMENT WITH IBRUTINIB FOLLOWING FIRST LINE METHOTREXATE-BASED IMMUNO-CHEMOTHERAPY IN ELDERLY PATIENTS WITH PRIMARY CNS LYMPHOMA (PCNSL). A PHASE 2 OPEN-LABEL STUDY
Authors: Osnat Bairey, Alexandra Benouaich-amiel, Shlomit Yust-Katz, Ronit Gurion, Tali Siegal
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Patients older than 60 years account for up to 70% of all PCNSL cases. Elderly PCNSL patients have median overall survival (OS) under 2 years and progression free survival (PFS) ranging between 6–16 months. Older patients have multiple comorbidities associated with low tolerability to high-dose (HD) chemotherapy. As maintenance treatment prolongs PFS and\or OS in several hematological malignancies we sought to investigate whether Ibrutinib maintenance may benefit elderly PCNSL patients. Ibrutinib was selected for maintenance since it has an impressive tolerability and activity in a range of systemic B-cell lymphomas. METHODS Single arm, open label, non-randomized study aiming to accrue 30 newly diagnosed PCNSL patients aged 60–85 years who received HD-methotrexate–based first line chemotherapy and have a documented response which is either partial (PR) or complete response (CR). The primary end-point is one and 2-year PFS and ibrutinib dose is 560mg/day. All patients undergo pre-maintenance neurocognitive evaluation which is repeated every 6 months. RESULTS Of the 16 patients screened for the study 2 were excluded due to relapse while on screening. 14 patients have been enrolled with a median age of 74 (61–80) years. The median interval between PCNSL diagnosis and start of ibrutinib maintenance is 7.6 (5.6–11.5) months. Currently, the median PFS is 22.5 (12–31.5) months. The adverse effects are largely grade 1/2 with rare grade 3/4 events. One patient discontinued treatment due to skin rash at 4.5 months. Two patients relapsed while on maintenance after 4 and 15 months of treatment. 3 patients with PR at enrolment improved to CR/CRu during maintenance. No invasive fungal infections have been observed. CONCLUSIONS Ibrutinib maintenance is feasible and well tolerated in newly diagnosed elderly PCNSL patients after first-line HD-MTX based treatment. The toxicity is mild to moderate. Enrollment is ongoing and updated outcomes will be presented at the meeting.
RARE-15. OUTCOMES OF TREATMENT OF GLIOMAS IN PATIENTS WITH NEUROFIBROMATOSIS TYPE I TREATED WITH RADIATION THERAPY
Authors: Jessica Son, Lindsey Sloan, Jaishri O Blakeley, Bronwyn Slobogean, Lawrence Kleinberg
Journal: Neuro-Oncology (2019)

Abstract INTRODUCTION Neurofibromatosis type 1 (NF1) is a rare tumor suppressor syndrome that predisposes to nervous system tumors. The optimal treatment of gliomas in adults with NF1 is uncertain. Specifically, little is known about the effectiveness or toxicity of radiation therapy (RT) in this population although it is standard of care for progressive low grade glioma (LGG) or high grade glioma (HGG) in general. We evaluated the tolerability of RT and time to progression (TTP) after completion of RT in people with NF1 diagnosed with glioma in adulthood. METHODS Charts were reviewed for patients with a confirmed NF1 syndrome, LGG or HGG, &gt; 18 years old, receiving RT and followed at Johns Hopkins University between 2009–2019. Secondary outcomes were overall survival (OS) from diagnosis and RT associated toxicity. Progression was defined radiographically; toxicity was graded by CTCAE. RESULTS Eight people (6 males) with median age of 36.5 years (range, 20–63) received RT at median of 56.7Gy either at the time of diagnosis (N=4) or at recurrence (N=4). Three patients (37.5%) had LGG; five (62.5%) had HGG. Tumor locations were brainstem (6) and temporal lobe (2). All patients received concurrent chemotherapy with RT; temozolomide (7) or bevacizumab (1). At median follow-up of 28.3 months (0.9–90.2) from RT completion, 5/8 patients had progression. Of those who progressed, median TTP was 12.7 months (2.5–26.6). The longest period of disease control was 28.9 months. One and two-year OS rates were 87% and 32%, respectively. RT associated toxicities were within the expected range. CONCLUSIONS Overall disease control after RT was variable, with some examples of extraordinary duration of disease control, and RT toxicities were within expected range. Collaborative efforts to examine a larger cohort of adults with NF1 associated gliomas are needed to define optimal care, but these observations suggest RT is a feasible modality.
Incidence of Delayed Seromas and Related Risk of Bia-ALCL in a Cohort of 3521 Breast Cancer Women with Textured Implants Prospectively Followed Long Term
Authors: Paola Ghione, Peter Cordeiro, Venkatraman Seshan, Natasha Galasso, Nivetha Ganesan, Qunying Hu, Ahmet Dogan, Steven M. Horwitz
Journal: Blood (2019)
Campaign against Tuberculosis
Authors: C GOMES
Journal: BMJ (1943)

Among the various phases of the public health movement in this country of the last decade or two, the effort toward the gradual eradication of tuberculosis stands out prominently in its comprehensive planning and organization. The field that, ten years ago, was almost barren of any organized machinery for the control of the disease, includes at present 1,200 local anti-tuberculosis organizations, 575 hospitals and sanatoriums, 450 special dispensaries, 1,000 dispensary physicians, 4,000 nurses and 400 open air schools. The total cost of creating and operating this machinery represents an outlay of over $100,000,000 of public and private funds. The results so far achieved are shown in (1) the steadily growing enlightenment of the people on the subject of tuberculosis, its cause, methods of prevention and treatment; (2) the gradually falling mortality from the disease (in the registration area<sup>1</sup>in 1902, the rate was 16.3 per 10,000; in 1911, 13.2),
Compassionate End-of-Life Care: Mixed-Methods Multisite Evaluation of the 3 Wishes Project
Authors: Meredith Vanstone, Thanh H. Neville, France J. Clarke, Marilyn Swinton, Marina Sadik, Alyson Takaoka, Orla Smith, Andrew J. Baker, Allana LeBlanc, Denise Foster, Vinay Dhingra, Peter Phung, Xueqing (Sherry) Xu, Yuhan Kao, Diane Heels-Ansdell, Benjamin Tam, Feli Toledo, Anne Boyle, Deborah J. Cook
Journal: Annals of Internal Medicine (2019)

Background: The 3 Wishes Project (3WP) is an end-of-life program that aims to honor the dignity of dying patients by creating meaningful patient- and family-centered memories while promoting humanistic interprofessional care. Objective: To determine whether this palliative intervention could be successfully implemented—defined as demonstrating value, transferability, affordability, and sustainability—beyond the intensive care unit in which it was created. Design: Mixed-methods formative program evaluation. (ClinicalTrials.gov: NCT04147169) Setting: 4 North American intensive care units. Participants: Dying patients, their families, clinicians, hospital managers, and administrators. Intervention: Wishes from dying patients, family members, and clinicians were elicited and implemented. Measurements: Patient characteristics and processes of care; the number, type, and cost of each wish; and semistructured interviews and focus groups with family members, clinicians, and managers. Results: A total of 730 patients were enrolled, and 3407 wishes were elicited. Qualitative data were gathered from 75 family members, 72 clinicians, and 20 managers or hospital administrators. Value included intentional comforting of families as they honored the lives and legacies of their loved ones while inspiring compassionate clinical care. Factors promoting transferability included family appreciation and a collaborative intensive care unit culture committed to dignity-conserving end-of-life care. Staff participation evolved from passive support to professional agency. Program initiation required minimal investment for reusable materials; thereafter, the mean cost was $5.19 (SD, $17.14) per wish. Sustainability was demonstrated by the continuation of 3WP at each site after study completion. Limitation: This descriptive formative evaluation describes tertiary care center–specific experiences rather than aiming for generalizability to all jurisdictions. Conclusion: The 3WP is a transferrable, affordable, and sustainable program that provides value to dying patients, their families, clinicians, and institutions. Primary Funding Source: Greenwall Foundation.
Inhibiting the Hippo Signaling Pathway Key Molecule YAP Suppresses Mantle Cell Lymphoma Proliferation By Regulating Multiple Pathogenrelated Signaling Pathways
Authors: Wenjie Xiong, Shuhua Yi, Yuting Yan, Zengjun Li, Wei Liu, Rui Lv, Zhen Yu, Dehui Zou, Lugui Qiu
Journal: Blood (2019)
GENE-05. THE LOSS OF SUCCINATE DEHYDROGENASE B EXPRESSION IS FREQUENTLY IDENTIFIED IN HEMANGIOBLASTOMA OF THE CENTRAL NERVOUS SYSTEM
Authors: Se-Hyuk Kim, Tae Hoon Roh, Hyunee Yim, Jin Roh, Kyi Beom Lee, Seon-Yong Jeong, Jang-Hee Kim, So Hyun Park
Journal: Neuro-Oncology (2019)

Abstract Succinate dehydrogenase (SDH) is a mitochondrial enzyme that plays an important role in both the Krebs cycle and the electron transport chain. SDH inactivation is associated with tumorigenesis in certain types of tumor. SDH consists of subunits A, B, C and D (SDHA, SDHB, SDHC, and SDHD, respectively). Immunohistochemistry for SDHB is a reliable method for detecting the inactivation of SDH by mutations in SDHA, SDHB, SDHC, SDHD and SDH complex assembly factor 2 (SDHAF2) genes with high sensitivity and specificity. SDHB immunohistochemistry has been used to examine the inactivation of SDH in various types of tumors. However, data on central nervous system (CNS) tumors are very limited. In the present study, we investigated the loss of SDHB immunoexpression in 90 cases of CNS tumors. Among the 90 cases of CNS tumors, only three cases of hemangioblastoma showed loss of SDHB immunoexpression. We further investigated SDHB immunoexpression in 35 cases of hemangioblastoma and found that 28 (80%) showed either negative or weak-diffuse pattern of SDHB immunoexpression, which suggests the inactivation of SDH. Our results suggest that SDH inactivation may represent an alternative pathway in the tumorigenesis of hemangioblastoma.
Whole Genome Bisulfite Sequencing of 63 Primary AML Samples Identifies a Unique DNA Hypermethylation Signature for Mutant IDH1/2 Cases That Is Different from That of TET2 Mutant AML
Authors: Ellie Wilson, Nichole Helton, Catrina Fronick, Robert Fulton, John S. Welch, Timothy J Ley, David H Spencer
Journal: Blood (2019)