tbuckley/cabot-search huggingface dataset:
COMP-04. MODELING PRECISION ONCOLOGY FOR GLIOBLASTOMA THROUGH INTEGRATION OF DESCRIPTIVE, FUNCTIONAL, AND NETWORK-BASED GENOMICS
Authors: Pia Hoellerbauer, Megan Kufeld, Sonali Arora, Emily Girard, James Olson, Matthew Biery, Nyasha Chambwe, Patrick Paddison
Journal: Neuro-Oncology (2019)

Abstract Precision oncology is largely based on the notion that identification and targeting of oncogenic drivers will lead to improved clinical outcomes. However, the promise of precision oncology awaits to be fulfilled for many cancers, including Glioblastoma (GBM), where identification of oncogenic drivers has yet to improve survival rates. Here, we have attempted to systematically identify GBM vulnerabilities by performing genome-wide CRISRP-Cas9 lethality screens in patient-derived GBM stem-like cells (GSCs). In validation studies, we comprehensively retested GSC-specific hits in multiple GSC isolates, which were also genomically profiled (e.g. RNA-seq, exome-seq, CNV), and further integrated these data with CRISPR-Cas9 lethality screens from over 500 human cell lines from the Broad Institute’s CRISPR Avana dataset. As a result, we have begun making GBM dependency predictions and functional associations for top scoring hits, including: tumor developmental subtype; loss of functional redundancy with other genes/proteins; cancer-specific subnetworks of genes involved in mitochondrial protein turnover and membrane trafficking; and genes of unknown function essential for subset of GBMs. A few examples of these categories include the following scenarios. We find ADAR (Adenosine Deaminase RNA Specific) gene dependency is associated with the mesenchymal GBM subtype. The EFR3Agene, which has roles in maintaining active pools of phosphatidylinositol 4-kinase, appears required when the expression of its paralog EFR3Bis low or absent in tumor cells. The F-box protein-encoding gene FBXO42appears non-essential to most human cells lines and neural stem cells, but when knocked out in sensitive GSCs causes mitotic arrest, mitotic catastrophe, and cell death. While still a work in progress, we hope to use these results as a foundation for exploring and illuminating patient-specific molecular vulnerabilities for brain tumors. The results also underscore the need for integration of functional genetic approaches, where gene activities are inhibited, into precision oncology paradigms.
SCIDOT-02. A PHASE I STUDY OF CONVECTION-ENHANCED DELIVERY OF LIPOSOMAL-IRINOTECAN (ONIVYDE) USING REAL-TIME IMAGING WITH GADOLINIUM IN PATIENTS WITH RECURRENT HIGH GRADE GLIOMAS: RESULTS THUS FAR
Authors: Karishma Kumar, Nicholas Butowski, Manish Aghi, Krystof Bankiewicz, John Bringas, Nancy Ann Oberheim Bush, Susan Chang, Jennifer Clarke, Jennie Taylor, Alastair Martin, Mitchell Berger
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Chemotherapy for high grade gliomas (HGG) is limited by the blood-brain-barrier (BBB). Convection enhanced delivery (CED) improves chemotherapy delivery by utilizing fluid convection obviating the challenges of crossing the BBB while minimizing systemic toxicity. CED of nanoliposomal-irinotecan (Onivyde) showed to be a superior delivery route for anti-tumor activity in animal models. An advance of this trial is the development and use of real time CED, which utilizes MRI to visualize the CED process with the aid of co-convected contrast agents, monitoring delivery into the brain and affording for corrective action. METHODS This is a 3 + 3 single dose escalation trial with 2 cohorts: 20mg/ml and 40mg/ml. Onivyde and GAD were co-infused via the same catheters in a one-time delivery. The total dose was personalized based on the patient’s tumor volume, and ranged from 20–680 mg of Onivyde, given via up to 4 catheters. Tumor diameters were allowed to be 1 – 4 cm, with injection volumes ranging from 2 – 17 mL of infusate. RESULTS 13 patients have been treated on this protocol, all in under 5 hours. There were 9 GBs, 1 gliosarcoma, 2 AAs, and 1 oligoastrocytoma. Utilizing imaging software, we correlated pre-infusion modeling of the drug distribution with post-infusion imaging. A number of technical challenges were overcome by real time monitoring; the total volume of distribution (Vd), and the Vd to volume infused (Vi) ratio for each infusion was ~2. Of all patients, the only notable AE was encephalopathy, which was resolved. CONCLUSIONS Image-guided distribution allows for safe real-time placement and adjustment of CED cannula of Onivyde into patient’s brains. Such methods allow for maximum tumor coverage and warrant further studies with repeat dosing.
Clonally Expanded T Cells Reveal Immunogenicity of Rhabdoid Tumors
Authors: Amaury Leruste, Jimena Tosello, Rodrigo Nalio Ramos, Arnault Tauziède-Espariat, Solène Brohard, Zhi-Yan Han, Kevin Beccaria, Mamy Andrianteranagna, Pamela Caudana, Jovan Nikolic, Céline Chauvin, Leticia Laura Niborski, Valeria Manriquez, Wilfrid Richer, Julien Masliah-Planchon, Sandrine Grossetête-Lalami, Mylene Bohec, Sonia Lameiras, Sylvain Baulande, Celio Pouponnot, Aurore Coulomb, Louise Galmiche, Didier Surdez, Nicolas Servant, Julie Helft, Christine Sedlik, Stéphanie Puget, Philippe Benaroch, Olivier Delattre, Joshua J. Waterfall, Eliane Piaggio, Franck Bourdeaut
Journal: Cancer Cell (2019)
Early Follicular Lymphoma Progression in Patients Treated with Frontline Immunochemotherapy with/without Rituximab Maintenance: Clinically Meaningful Even in Chemosensitive Individuals
Authors: Vit K Prochazka, David Belada, Andrea Janikova, Katerina Benesova, Heidi Mocikova, Juraj Duras, Robert Pytlik, Jan Pirnos, Alice Sýkorová, Vit Campr, Jozef Michalka, Kateřina Kopečková, Jitka Dlouha, Tomas Papajik, Marek Trneny
Journal: Blood (2019)
Prospective Assessment of Vesical Imaging Reporting and Data System (VI-RADS) and Its Clinical Impact on the Management of High-risk Non–muscle-invasive Bladder Cancer Patients Candidate for Repeated Transurethral Resection
Authors: Francesco Del Giudice, Giovanni Barchetti, Ettore De Berardinis, Martina Pecoraro, Vincenzo Salvo, Giuseppe Simone, Alessandro Sciarra, Costantino Leonardo, Michele Gallucci, Carlo Catalano, James W.F. Catto, Valeria Panebianco
Journal: European Urology (2019)
Outcomes of Patients with Suboptimal /Warning Response to Tyrosine Kinase Inhibitors: A Comparison of the 2009 and 2013 Guidelines of the European Leukemianet
Authors: Hycienth O Ahaneku, Hagop M. Kantarjian, Graciela M. Nogueras González, Gautam M. Borthakur, Srdan Verstovsek, Tapan M. Kadia, Naveen Pemmaraju, Guillermo Garcia-Manero, Marina Y Konopleva, Courtney D. DiNardo, Kiran Naqvi, Koji Sasaki, Ghayas C. Issa, Elias Jabbour, Jorge E. Cortes
Journal: Blood (2019)
Judith Mary Hockaday
Authors: Derek Hockaday
Journal: BMJ (2019)

Judith Mary Hockaday (nee Fitzsimons) was both of Irish stock and from a strongly medical family: her father was a consultant surgeon and her mother an industrial medical officer, while her maternal grandfather was a general practitioner in Cardiff. She did her preclinical training at Girton College, Cambridge, in 1947-50 and her clinical training at St Mary’s Hospital in Paddington (1950-53), where she was a house physician, senior house officer, and medical registrar. She then did an HP job at the Brompton Hospital, with the intention of a career in chest diseases, having already gained her membership of the Royal College of Physicians two years after qualifying. So in searching for the subject of a doctoral thesis, and probably via the “old girl” network and owing to the prevalence of chest tuberculosis, she was appointed registrar to Honour Smith at the tuberculous meningitis unit in Oxford in December 1957, without fully realising that this was a disease in rapid decline. Her MD thesis, on the results of treatment of tuberculous meningitis, was accepted in 1960, and was the basis of two papers in Tubercle . That year she married a member of George Pickering’s department at the Radcliffe Infirmary and therefore stayed in Oxford. Backed by all she’d learnt on the meningitis unit, was appointed registrar to Ritchie Russell and Charles Whitty in the department …
RBTT-02. RADIOSURGERY FOLLOWED BY TUMOR TREATING FIELDS FOR BRAIN METASTASES (1–10) FROM NSCLC IN THE PHASE 3 METIS TRIAL
Authors: Minesh Mehta, Vinai Gondi, Manmeet Ahluwalia, Paul Brown
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND: Tumor Treating Fields (TTFields) are non-invasive, loco-regional, anti-mitotic treatment modality comprising alternating electric fields. TTFields have demonstrated efficacy in preclinical non-small cell lung cancer (NSCLC) models. TTFields treatment to the brain was safe and extended overall survival in newly-diagnosed glioblastoma. The METIS study [NCT02831959] investigates the efficacy and safety of TTFields in NSCLC patients with brain metastases. Study Design: NSCLC patients (N=270) with 1–10 brain metastases are randomized 1:1 to stereotactic radio surgery (SRS) followed by continuous TTFields ((150 kHz, &gt; 18 hours/day) within 7 days of SRS or supportive care. The portable device delivers TTFields to the brain using 4 transducer arrays, while patients receive the best standard-of-care for systemic disease. Patients are followed every two months until second intracranial progression. Key inclusion criteria: KPS ≥70, new diagnosis of 1 inoperable or 2–10 supra- and/or infratentorial brain metastases from NSCLC amenable to SRS; and optimal therapy for extracranial disease. Prior WBRT or surgical resection of metastases, a single resectable lesion or recurrent brain metastases were exclusionary. Primary endpoint was time to 1st intracranial progression. Secondary endpoints included time to neurocognitive failure (HVLT, COWAT and TMT), overall survival, radiological response rate (RANO-BM and RECIST V1.1); quality-of-life; adverse events; time to first/second intracranial progression for patients with 1–4 and 5–10 brain metastases; bi-monthly intracranial progression rate from 2–12 months; and time to second intracranial and distant progression. The sample size (N=270) was calculated using a log-rank test (Lakatos 1988 and 2002) with 80% power at two sided alpha of 0.05 to detect a hazard ratio of 0.57. In August 2018, an independent Data Monitoring Committee (DMC) performed a review of the METIS trial data collected to that point. The DMC concluded that no unexpected safety issues had emerged and recommended continuation of the METIS study as planned.
ATIM-42. DOUBLE-BLINDED, PLACEBO CONTROLLED PHASE 2 STUDY OF ERC1671 IN RECURRENT GLIOBLASTOMA: OS CORRELATIONS WITH INITIAL AND MAXIMUM CD4+T LYMPHOCYTE COUNT IN THE PERIPHERAL BLOOD
Authors: Daniela Bota, Thomas Taylor, Kong Xiao-Tang, Beverly Fu, Mohamad Alsharif, Chrystel Pretto, Ankie Strik, Virgil Schijns, Apostolos Stathopoulos
Journal: Neuro-Oncology (2019)

Abstract Standard therapy for recurrent GBM is bevacizumab, a monoclonal VEGF inhibitor that targets tumor vascularization. The response to bevacizumab is transient and short-lived (4–6 months) after which patients typically develop progressive physical and mental debilitation culminating in death. ERC1671 is an allogeneic/autologous therapeutic vaccine – composed of whole, inactivated tumor cells mixed with tumor- cell lysates. The hypothesized action of ERC1671 is to potentiate the patients’ immune system against the tumor. Goals of this ongoing, phase 2 study are to to determine the safety and effectiveness (over-all survival) of ERC1671 in combination with GM-CSF and cyclophosphamide as an add-on treatment to bevacizumab at the time of GBM recurrence. To date 16 recurrent bevacizumab-naïve GBM patients have been randomized to ERC1671/GM-CSF/Cyclophosphamide + Bevacizumab or Placebo + Bevacizumab. Median age is 56.5 (39–74), 5 patients (31%) are female, and average KPS is 83 (70–100). Thirteen patients are deceased and were unblinded at the time of further progression: 5 received vaccine, 7 received placebo, and 1 is non-evaluable due to discontinuation before completing 1 cycle. Median overall survival of the deceased patients treated with ERC1671 + Bevacizumab was 328 days (10.9 months), compared to 245 days (8.2 months) for patients treated with Placebo + Bevacizumab. While sparse, the data to date suggest pre-treatment and maximal CD4+T lymphocyte count in the peripheral blood correlate with OS more strongly in the ERC1671 group than in the placebo group. First clinical results for toxicity show no difference in the distribution of AEs between the Vaccine and Placebo groups, with no Gr4/Gr5 AEs in either group. The phase 2 randomized, double-blinded study is ongoing with the addition of 2 subsites.
Pan-Tumor Pathologic Scoring of Response to PD-(L)1 Blockade
Authors: Julie E. Stein, Evan J. Lipson, Tricia R. Cottrell, Patrick M. Forde, Robert A. Anders, Ashley Cimino-Mathews, Elizabeth D. Thompson, Mohamad E. Allaf, Mark Yarchoan, Josephine Feliciano, Hao Wang, Elizabeth M. Jaffee, Drew M. Pardoll, Suzanne L. Topalian, Janis M. Taube
Journal: Clinical Cancer Research (2019)

Abstract Purpose: Pathologic response assessment of tumor specimens from patients receiving systemic treatment provides an early indication of therapeutic efficacy and predicts long-term survival. Grading systems for pathologic response were first developed for chemotherapy in select tumor types. Immunotherapeutic agents have a mechanism of action distinct from chemotherapy and are being used across a broad array of tumor types. A standardized, universal scoring system for pathologic response that encompasses features characteristic for immunotherapy and spans tumor types is needed. Experimental Design: Hematoxylin and eosin–stained slides from neoadjuvant surgical resections and on-treatment biopsies were assessed for features of immune-related pathologic response (irPR). A total of 258 specimens from patients with 11 tumor types as part of ongoing clinical trials for anti-PD-(L)1 were evaluated. An additional 98 specimens from patients receiving anti-PD-(L)1 in combination with other treatments were also reviewed, including those from three additional tumor types. Results: Common irPR features (immune activation, cell death, tissue repair, and regression bed) were present in all tumor types reviewed, including melanoma, non–small cell lung, head and neck squamous cell, Merkel cell, and renal cell carcinoma, among others. Features were consistent across primary tumors, lymph nodes, and distant metastases. Specimens from patients treated with anti-PD-(L)1 in combination with another agent also exhibited irPR features. Conclusions: irPR features are consistent across tumor types and treatment settings. Standardized, pan-tumor irPR criteria (irPRC) are defined and associated specimen-handling considerations are described. Future, prospective studies are merited to validate irPRC in larger datasets and to associate pathologic features with long-term patient outcomes.
Endogenous T cells prevent tumor immune escape following adoptive T cell therapy
Authors: Scott R. Walsh, Boris Simovic, Lan Chen, Donald Bastin, Andrew Nguyen, Kyle Stephenson, Talveer S. Mandur, Jonathan L. Bramson, Brian D. Lichty, Yonghong Wan
Journal: Journal of Clinical Investigation (2019)

While the outcome of adoptive T cell therapy (ACT) is typically correlated with the functionality of the inoculated T cells, the role of the endogenous T cells is unknown. The success of checkpoint blockade therapy has demonstrated the potentially curative value of preexisting tumor-primed T cells in cancer treatment. Given the results from checkpoint blockade therapy, we hypothesized that endogenous T cells contribute to long-term survival following ACT. Here, we describe a therapeutic approach combining ACT with an oncolytic vaccine that allows simultaneous analysis of antitumor immunity mediated by transferred and endogenous T cells. We found that, in addition to promoting the expansion and tumor infiltration of the transferred T cells, oncolytic vaccines boosted tumor-primed host T cells. We determined that transferred T cells contributed to rapid destruction of large tumor masses while endogenous T cells concurrently prevented the emergence of antigen-loss variants. Moreover, while transferred T cells disappeared shortly after tumor regression, endogenous T cells secured long-term memory with a broad repertoire of antigen specificity. Our findings suggest that this combination strategy may exploit the full potential of ACT and tumor-primed host T cells to eliminate the primary tumor, prevent immune escape, and provide long-term protective memory.
Mitapivat (AG-348), an Oral PK-R Activator, in Adults with Non-Transfusion Dependent Thalassemia: A Phase 2, Open-Label, Multicenter Study in Progress
Authors: Kevin H. M. Kuo, D. Mark Layton, Katrin Uhlig, Megan Lynch, Li Liu, Elliott P. Vichinsky
Journal: Blood (2019)
Exploring the Safety and Efficacy of Upfront Autologous Stem Cell Transplantation with LEED Preconditioning for Primary Central Nervous System Lymphoma
Authors: Hirofumi Yokota, Kotaro Miyao, Fumiya Ohara, Kenta Motegi, Hiroya Wakabayashi, Yuki Takeuchi, Shihomi Kuwano, Hitomi Sawa, Yuichiro Inagaki, Masashi Sawa
Journal: Blood (2019)
A New Valuable Technique in Diagnosis and Treatment Monitoring of Myeloproliferative Neoplasms
Authors: Yiqian Hu, Sanyun Wu, Yanan Liu, Mengxiao Zhang, Yingying Wang, Liang Shao, Bei Xiong, Xiaoyan Liu, Yicheng Zhang, Rui Lu, Yalan Yu, Ping Luo, Xuelan Zuo
Journal: Blood (2019)
A Novel Bioengineered miR-127 Prodrug Suppresses the Growth and Metastatic Potential of Triple-Negative Breast Cancer Cells
Authors: Maxine Umeh-Garcia, Catalina Simion, Pui-Yan Ho, Neelu Batra, Anastasia L. Berg, Kermit L. Carraway, Aiming Yu, Colleen Sweeney
Journal: Cancer Research (2019)

miR-127 is downregulated in breast cancer, where it has been shown to suppress the proliferation, migration, and invasion of breast cancer cells. In triple-negative breast cancer (TNBC), miR-127 downregulation correlates with decreased disease-free and overall patient survival. Tumor suppressor miRNAs may hold therapeutic promise but progress has been limited by several factors, including the lability and high cost of miRNA mimics. Here, we take a novel approach to produce a miR-127 prodrug (miR-127PD), which we demonstrate is processed to mature, functional miR-127-3p in TNBC tumor cells. miR-127PD decreased the viability and motility of TNBC cells, sensitized TNBC cells to chemotherapy, and restricted the TNBC stem cell population. Furthermore, systemic delivery of miR-127PD suppressed tumor growth of MDA-MB-231 and MDA-MB-468 TNBC cells and spontaneous metastasis of MDA-MB-231 cells. In addition, CERK, NANOS1, FOXO6, SOX11, SOX12, FASN, and SUSD2 were identified as novel, functionally important targets of miR-127. In conclusion, our study demonstrates that miR-127 functions as a tumor and metastasis suppressor in TNBC and that delivery of miR-127 may hold promise as a novel therapy. SIGNIFICANCE: Exogenous administration of miR-127, which is functionally activated in target cells, inhibits growth and spontaneous metastasis of triple-negative breast cancer.
Correcting Smad1/5/8, mTOR, and VEGFR2 treats pathology in hereditary hemorrhagic telangiectasia models
Authors: Santiago Ruiz, Haitian Zhao, Pallavi Chandakkar, Julien Papoin, Hyunwoo Choi, Aya Nomura-Kitabayashi, Radhika Patel, Matthew Gillen, Li Diao, Prodyot K. Chatterjee, Mingzhu He, Yousef Al-Abed, Ping Wang, Christine N. Metz, S. Paul Oh, Lionel Blanc, Fabien Campagne, Philippe Marambaud
Journal: Journal of Clinical Investigation (2019)

Hereditary hemorrhagic telangiectasia (HHT), a genetic bleeding disorder leading to systemic arteriovenous malformations (AVMs), is caused by loss-of-function mutations in the ALK1/ENG/Smad1/5/8 pathway. Evidence suggests that HHT pathogenesis strongly relies on overactivated PI3K/Akt/mTOR and VEGFR2 pathways in endothelial cells (ECs). In the BMP9/10-immunoblocked (BMP9/10ib) neonatal mouse model of HHT, we report here that the mTOR inhibitor, sirolimus, and the receptor tyrosine kinase inhibitor, nintedanib, could synergistically fully block, but also reversed, retinal AVMs to avert retinal bleeding and anemia. Sirolimus plus nintedanib prevented vascular pathology in the oral mucosa, lungs, and liver of the BMP9/10ib mice, as well as significantly reduced gastrointestinal bleeding and anemia in inducible ALK1-deficient adult mice. Mechanistically, in vivo in BMP9/10ib mouse ECs, sirolimus and nintedanib blocked the overactivation of mTOR and VEGFR2, respectively. Furthermore, we found that sirolimus activated ALK2-mediated Smad1/5/8 signaling in primary ECs — including in HHT patient blood outgrowth ECs — and partially rescued Smad1/5/8 activity in vivo in BMP9/10ib mouse ECs. These data demonstrate that the combined correction of endothelial Smad1/5/8, mTOR, and VEGFR2 pathways opposes HHT pathogenesis. Repurposing of sirolimus plus nintedanib might provide therapeutic benefit in patients with HHT.
SAT0247 A chinese version of the rheumatology attitudes index is a valid and reliable measure of learned helplessness in sle patients
Authors: KY Fong, J Thumboo, PH Feng, SP Chan, ML Boey, ST Thio
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> The Rheumatology Attitudes Index is a widely used measure of learned helplessness (LH), an acquired pattern of behaviour in which, as a result of adverse past experiences, individuals believe their efforts will be ineffective. LH is associated with poorer quality of life in a variety of rheumatic diseases, and with increased morbidity and mortality in patients with rheumatoid arthritis. Despite the importance of learned helplessness in rheumatic conditions, there are no validated measures of this construct in Chinese or other Asian languages. <h3>Objectives</h3> To assess the internal consistency, reliability and construct validity of a Chinese translation of the Rheumatology Attitudes Index (CRAI) and it's Helplessness (CHS) and Internality (CIS) subscales. <h3>Methods</h3> The source English RAI was translated into Chinese using standard techniques for cross-cultural adaptation. Chinese-speaking SLE patients completed identical, self-administered Chinese questionnaires containing the CRAI and assessing demographic and socio-economic variables twice within a 2 week period. SLE related activity, damage and quality of life were assessed using the BILAG, SLICC/ACR Damage Index and SF-36 Health Survey respectively. Scale psychometric properties were assessed through factor analysis, Cronbach's alpha, intra-class correlations and quantifying test-retest differences. Relationships between the CRAI, its subscales and external variables (known-groups construct validity) were studied using Spearman's rank correlation. <h3>Results</h3> Active disease and disease related damage were present in 52.2% and 49.3% of 69 Chinese speaking SLE patients with a median disease duration of 4.7 years. Internal consistency and reliability were acceptable, with Cronbach's a for the CHS, CIS and CRAI being 0.70, 0.69 and 0.74 respectively, mean differences in test-retest scores being 0.47, 0.55 and 0.93 points respectively (representing 1.6 to 2.4% of possible scale ranges) and intra class correlations ranging from 0.72 to 0.83. Factor analysis identified 2 major factors corresponding to the HS and IS subscales of the CRAI. Eight of 10 hypotheses relating the CRAI and CHS to demographic, disease and quality of life variables were confirmed, supporting the construct validity of these scales. <h3>Conclusion</h3> The CRAI and it's helplessness subscale are valid and reliable measures of learned helplessness in Chinese speaking SLE patients.