tbuckley/cabot-search huggingface dataset:
Guillain-Barre syndrome observed with adoptive transfer of lymphocytes genetically engineered with an NY-ESO-1 reactive T-cell receptor
Authors: Jocelyn Joseph, Michael J. Nathenson, Van Anh Trinh, Karan Malik, Erica Nowell, Kristen Carter, Shiao-Pei Weathers, George D. Demetri, Dejka Araujo, Anthony P. Conley
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> Adoptive transfer of autologous T-lymphocytes transduced with a high affinity NY-ESO-1-reactive T-cell receptor (NY-ESO-1<sup>c259</sup> T-cells) has emerged as a promising therapeutic strategy for patients with refractory synovial sarcoma. Secondary autoimmune T-cell mediated toxicities can occur long after initial adoptive T-cell transfer. We report on the first two cases of the development and management of Guillain-Barre syndrome in synovial sarcoma patients who received NY-ESO-1<sup>c259</sup> T-cells. <h3>Case presentation</h3> A 47 year-old woman and 39 year-old woman with refractory metastatic SS were treated with fludarabine-cyclophosphamide lymphodepletion followed by adoptive transfer of NY-ESO-1<sup>c259</sup> T-cells. On day 42 after adoptive T-cell therapy, patient one presented to the emergency room with a one-week history of numbness, paresthesia, and heaviness to both legs progressing to difficulty walking on the day of presentation. Although MRI brain and lumbar puncture were negative, electromyography (EMG) and nerve conduction studies (NCS) of the lower extremities and right arm performed revealed an abnormal study suggestive of a very mild, distal, motor, axonal polyneuropathy. Patient two presented on day 113 with bilateral foot numbness, left foot drop, unsteady gait, and pain in the left thigh, which progressed over two week to bilateral leg weakness, inability to walk, and numbness bilaterally in the hands, legs, and feet. Both patients received intravenous immunoglobulin (IVIG) 0.4 g/kg/day for 5 days for possible acute inflammatory demyelinating polyneuropathy (AIDP) likely related to NY-ESO-1 targeting T-cell therapy. After 3 and 5 doses, respectively, of IVIG, the patients reported improvement in symptoms and strength, and were later transferred to an inpatient rehabilitation facility to continue gaining strength. At patient one's neurology follow-up on day 95, she reported only mild left lower extremity (LLE) weakness and was gradually successfully regaining independence in motor function. At patient two's 9-month follow-up, the patient had regained normal function and independence. <h3>Conclusions</h3> Given the expanding applications of immunotherapy in cancer management, clinicians should stay vigilant against the potential development of unusual but life-threatening immune-mediated toxicities.
Pacifica: A Randomized, Controlled Phase 3 Study of Pacritinib Vs. Physician's Choice in Patients with Primary Myelofibrosis, Post Polycythemia Vera Myelofibrosis, or Post Essential Thrombocytopenia Myelofibrosis with Severe Thrombocytopenia (Platelet Count &lt;50,000/mL)
Authors: Claire N Harrison, Aaron T. Gerds, Jean-Jacques Kiladjian, Konstanze Döhner, Sarah A Buckley, Jennifer A. Smith, Adam R Craig, John Mascarenhas, Srdan Verstovsek
Journal: Blood (2019)
A phase I study (CA180021-Segment 2) of dasatinib in patients (pts) with advanced solid tumors
Authors: F. M. Johnson, A. Chiappori, H. Burris, L. Rosen, B. McCann, F. R. Luo, S. Mayfield, H. Palme, J. Platero, A. Blackwood-Chirchir
Journal: Journal of Clinical Oncology (2007)

14042 Background: SPRYCEL™ is a potent, orally active, multi-targeted kinase inhibitor, active against BCR-ABL and SRC family kinases. We report the results of a Phase I dose-escalation study evaluating safety, tolerability, pharmacokinetics, and biomarkers of dasatinib in pts with advanced solid tumors. Methods: Pts with adequate hematologic, renal, cardiac and liver function received oral dasatinib once daily for 7 days per week. Three doses and schedules were examined: 90 mg BID; 140 mg QD; and 180 mg QD. Pharmacokinetics and pharmacodynamic biomarkers were collected on Days 1 and 26 of Cycle 1. Tissue biomarkers were assessed at screening. CT was performed at least every 8 weeks, and FDG-PET at weeks 4, and 8. Results: 26 pts [M=15, F=11] ECOG PS ≤ 2 with epithelial tumors (n=14) or other solid tumors (n=12) have been treated in escalating dose levels. Toxicity was generally mild; most patients came off study for progressive disease. DLTs of pleural effusions were seen in 3/9 subjects on the 180 mg cohort, 2 of whom had pre-existing effusions. Patients with pleural effusion have been excluded from future enrollment. The maximum tolerated dose has not been identified. There have been no objective responses on CT. Six patients have had stable disease with continued study treatment for 2–10 months. Conclusions: Dasatinib can be safely administered at doses of 140 and 180 mg QD. Clinical efficacy, pharmacokinetics, and correlative studies of tumor biopsy material and early FDG-PET results will be reported. No significant financial relationships to disclose.
CSIG-10. ROLE OF c-Met/β1 INTEGRIN COMPLEX IN THE ESTABLISHMENT OF BRAIN METASTASES
Authors: Harsh Wadhwa, Darryl Lau, Ankush Chandra, Alan Nguyen, Sumedh Shah, Jordan Spatz, Michael Safaee, Sweta Sudhir, Akshar Patel, Justin Cheng, Manish Aghi
Journal: Neuro-Oncology (2019)

Abstract INTRODUCTION Metastases cause 90% of human cancer deaths. The metastatic cascade involves five steps: invasion, intravasation, extravasation, colonization, and proliferation. While individual mediators of these processes have been investigated, their interactions remain undefined. We previously demonstrated increased formation of a structural complex between receptor tyrosine kinase c-Met and β1 integrin in metastases compared to primary tumors. We used novel cell culture models and in vivo assays to define the role of this complex in individual steps of the metastatic cascade. METHODS The iDimerize heterodimer system was inserted into MDA-MB-231 breast adenocarcinoma cells, allowing c-Met/β1 heterodimerization induction via A/C heterodimerizer treatment. Scratch assays and novel transwell assay modifications were used to measure migration, invasion, intravasation, and extravasation. Proximity ligation assay was performed to measure c-Met/β1 complex. Nanostring panel was used to transcriptionally profile cells. RESULTS c-Met/β1 complex induction promotes breast cancer invasion (p&lt; 0.001), migration (p&lt; 0.05), intravasation (p&lt; 0.01), and adhesion to the vessel wall (p&lt; 0.01). However, it does not increase extravasation in culture or in vivo. These effects may be driven by the ability of c-Met/β1 to increase mesenchymal character (p&lt; 0.05) and stem cell population (p&lt; 0.001). Nanostring analysis revealed upregulated Wnt and hedgehog pathways after c-Met/β1 complex induction, particularly WNT7B (p&lt; 0.05). OS2966, an antibody preventing c-Met/β1 binding, decreased invasion (p&lt; 0.05), intravasation (p&lt; 0.05), and mesenchymal morphology (p&lt; 0.001) and gene expression (p&lt; 0.001). Brain- and bone-seeking breast cancer cells have higher c-Met/β1 complex than controls (p&lt; 0.05) and preferentially adhere to tissue-specific matrix (p&lt; 0.01). CONCLUSIONS The c-Met/β1 complex drives breast cancer cell intravasation. While extravasation is not affected by the complex, preferential affinity for tissue-specific matrix enables the c-Met/β1 complex to drive breast cancer metastases to brain and bone. Pharmacological targeting of the complex may prevent metastases, particularly to the brain and bone.
Overall Survival of Triple Class Refractory, Penta-Exposed Multiple Myeloma (MM) Patients Treated with Selinexor Plus Dexamethasone or Conventional Care: A Combined Analysis of the STORM and Mammoth Studies
Authors: Luciano J. Costa, Parameswaran Hari, Shaji K. Kumar, Shijie Tang, Ujjawal H Gandhi, Jatin J. Shah, Sundar Jagannath, Ajai Chari, Arjun Lakshman, Sharon Shacham, Xiwen Ma, David S. Siegel, Noa Biran, Sagar Lonial, Paul G. Richardson, Michael G. Kauffman, Ehsan Malek, Kelly N. Godby, Mark A. Fiala, Saurabh Chhabra, Saad Z. Usmani, Natalie Scott Callander, Yubin Kang, Amarendra K. Neppalli, Elvira Umyarova, Robert F. Cornell
Journal: Blood (2019)
Costimulatory Molecule DNAM-1 Is Essential for Optimal NK Education Post Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Qiannan Shang, Xingxing Yu, Xunhong Cao, Xuefei Liu, Zhengli Xu, Yingjun Chang, Xiaosu Zhao, Yu Wang, Xiaohui Zhang, Lanping Xu, Xiaojun Huang, Xiangyu Zhao
Journal: Blood (2019)
Internal double-J stent was associated with a lower incidence of ureteroileal anastomosis stricture than external ureteral catheter for patients undergoing radical cystectomy and orthotopic neobladder: A systematic review and meta-analysis
Authors: Yubo Yang, Yunjin Bai, Xiaoming Wang, Yin Tang, Ping Han, Xin Wei
Journal: International Journal of Surgery (2019)
Ancient DNA Reconstructs the Genetic Legacies of Precontact Puerto Rico Communities
Authors: Maria A Nieves-Colón, William J Pestle, Austin W Reynolds, Bastien Llamas, Constanza de la Fuente, Kathleen Fowler, Katherine M Skerry, Edwin Crespo-Torres, Carlos D Bustamante, Anne C Stone
Journal: Molecular Biology and Evolution (2019)

Abstract Indigenous peoples have occupied the island of Puerto Rico since at least 3000 BC. Due to the demographic shifts that occurred after European contact, the origin(s) of these ancient populations, and their genetic relationship to present-day islanders, are unclear. We use ancient DNA to characterize the population history and genetic legacies of precontact Indigenous communities from Puerto Rico. Bone, tooth, and dental calculus samples were collected from 124 individuals from three precontact archaeological sites: Tibes, Punta Candelero, and Paso del Indio. Despite poor DNA preservation, we used target enrichment and high-throughput sequencing to obtain complete mitochondrial genomes (mtDNA) from 45 individuals and autosomal genotypes from two individuals. We found a high proportion of Native American mtDNA haplogroups A2 and C1 in the precontact Puerto Rico sample (40% and 44%, respectively). This distribution, as well as the haplotypes represented, supports a primarily Amazonian South American origin for these populations and mirrors the Native American mtDNA diversity patterns found in present-day islanders. Three mtDNA haplotypes from precontact Puerto Rico persist among Puerto Ricans and other Caribbean islanders, indicating that present-day populations are reservoirs of precontact mtDNA diversity. Lastly, we find similarity in autosomal ancestry patterns between precontact individuals from Puerto Rico and the Bahamas, suggesting a shared component of Indigenous Caribbean ancestry with close affinity to South American populations. Our findings contribute to a more complete reconstruction of precontact Caribbean population history and explore the role of Indigenous peoples in shaping the biocultural diversity of present-day Puerto Ricans and other Caribbean islanders.
Acute Leukemia with Lineage Infidelity: Mixed Phenotype AML Exhibits a Distinct Immunophenotype with Clinical Features Overlapping Mixed Phenotype Acute Leukemia
Authors: Mindy P Kresch, Wenbin Xiao, Kamal Menghrajani, Christopher Famulare, Minal A Patel, Jeeyeon Baik, Mikhail Roshal, Ross L. Levine, Martin S. Tallman, Jacob L Glass
Journal: Blood (2019)
Enzyme responsiveness enhances the specificity and effectiveness of nanoparticles for the treatment of B16F10 melanoma
Authors: Yi Huang, Yanbin Shi, Qingjie Wang, Tongtong Qi, Xianglei Fu, Zili Gu, Yuhua Zhang, Guangxi Zhai, Xiaogang Zhao, Qifeng Sun, Guimei Lin
Journal: Journal of Controlled Release (2019)
TMOD-22. LOSS OF PTEN AND TRP53 IN OLIGODENDROCYTE PROGENITORS LEADS TO GLIOMA FORMATION
Authors: Ravinder Verma, Richard Lu
Journal: Neuro-Oncology (2019)

Abstract Tumor suppressors PTEN and TP53 are the most commonly mutated anti-oncogenes in human gliomas after TERT mutation. 38% and 17% of total 4023 samples of gliomas in TCGA show TP53 and PTEN mutations respectively. TP53 signaling pathway plays an important role in the suppression of tumor progression PTEN negatively regulates PI3 triphosphate levels and suppresses AKT/PKB pathways. In-frame and missense mutations in PTEN constitutively activates the proliferative pathway and give a survival advantage. Mice with conditional mutation of PTEN and TP53 in neural stem cells directed by hGFAP-Cre develop high-grade gliomas. Our recent study indicates that primitive oligodendrocyte-progenitor intermediates (Pri-OPC) are abundant and hyperproliferative cells and can be progressively reprogrammed towards a stem-like state susceptible to malignant transformation. We hypothesize that mutations in PTEN and TP53 in pri-OPC lineage cells can lead to glioma formation. OPCs distribute across the whole adult brain and exhibit a much higher number than NSCs that are restricted to very small niche areas. Olig1 and Olig2 mark pri-OPC and oligodendrocyte lineage cells. In this study, we inactivated the PTEN/TP53 gene in mouse pri-OPCs using Olig1-Cre or Olig2tva-Cre. The incidence of glioma formation was 100%. Both the tumor formed in these models display multifocal, high-grade, diffuse and infiltrating gliomas. Though tumors are derived from similar cell sources, they vary in the expression and extent of oncogenic pathways. Our transcriptomics profiling at different stages of tumorigenesis reveals that progressive activation of oncogenic signaling pathways establishes a tumorigenic state to promote malignant transformation, suggesting a dynamic process of tumorigenesis caused by the cooperative action of the PTEN and TP53 loss in the pri-OPC lineage.
Evaluation of the Functional Landscape of Systemic Immunity in Classical Hodgkin Using a Novel Single Cell Platform (Isolight)
Authors: Catherine Diefenbach, Linda Lam, Bruce G. Raphael, Kenneth B. Hymes, Michael L. Grossbard, Tibor Moskovits, Peter Martin, Jia Ruan, John P. Leonard, Pratip Chattopadhyay
Journal: Blood (2019)
Tories promise 6000 extra GPs by 2024
Authors: Gareth Iacobucci
Journal: BMJ (2019)

General practice hit the headlines this week when the Conservatives promised to deliver 6000 more GPs by 2024-25 as part of a pledge to provide 50 million more appointments in GP surgeries every year.1

The announcement was immediately dismissed as “empty promises” in some quarters,2 given that the government has failed to achieve a very similar pledge made in 2015 for 5000 extra GPs by 2020. The number of GPs has actually fallen,3 and workforce and workload pressures mean that the new target looks highly unachievable.

Labour’s Jonathan Ashworth was quick to pounce, arguing that the Conservatives “always make election promises which they fail to deliver on.” Labour has pledged to increase GP training places in England by around 43%—from 3500 to 5000 places—if elected.4

But the health and …
Prognostic Value of Disease Risk Score Versus Gait Speed in Older Adults with Lymphoma
Authors: Lee Mozessohn, Liying Zhang, Oreofe O. Odejide, Anna M. Tanasijevic, Richard Chen, Rena Buckstein, Robert J. Soiffer, Jorge J Castillo, Andrew Keezer, Jane Driver, Gregory A. Abel
Journal: Blood (2019)
Underdiagnosed Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome(VOD/SOS) As a Major Cause of Multi-Organ Failure in Acute Leukemia Transplant Patients: An Analysis from the EBMT Acute Leukemia Working Party
Authors: Abdul Hamid Bazarbachi, Rama Al Hamed, Myriam Labopin, Kazimierz Halaburda, Hélène Labussière-Wallet, Paolo Bernasconi, Wilfried Schroyens, Virginie Gandemer, Nicolaas Schaap, Pierre Simon Rohrlich, Pavel Jindra, John A Snowden, Depei Wu, Blandine Guffroy, Montserrat Rovira, Sylvain Chantepie, Xavier Poire, Dolores Caballero, Emmanouil Nikolousis, Mario Petrini, Fabio Ciceri, Frédéric Baron, Ali Bazarbachi, Selim Corbacioglu, Bipin N. Savani, Zinaida Peric, Arnon Nagler, Enric Carreras, Mohamad Mohty
Journal: Blood (2019)
Distal Enhancer Elements in ASXL1-Mutant Chronic Myelomonocytic Leukemia
Authors: Moritz Binder, Alexandre Gaspar Maia, Ryan M. Carr, Terra Lasho, Thomas E. Witzig, Christopher Pin, Kurt Berger, Bonnie Alver, Keith Robertson, David Marks, Martin Fernandez-Zapico, Mrinal M Patnaik
Journal: Blood (2019)
Transmembrane Receptors, Cytoskeleton and Cell Cycle Genes Were Progressively Deregulated in the Bone Marrow CD19+ and CD138+ Cells of Patientswwith Waldenstrom's Macroglolubinemia (WM) Vs. Subjects with IgM Monoclonal Gammopathy of Undetermined Significance Igmmgus Vs. Healthy Subjects
Authors: Alessandra Trojani, Alessandra Tedeschi, Annamaria Maria Frustaci, Marina Deodato, Luca Emanuele Bossi, Barbara Di Camillo, Marco Montillo, Enrica Morra, Roberto Cairoli
Journal: Blood (2019)
Vincristine-Induced Peripheral Neuropathy in Pediatric Oncology Patients Receiving Vincristine through Push Injections or One-Hour Infusions: Results of a Randomized Clinical Trial
Authors: Mirjam Esther Van De Velde, Gertjan Johannes Laurentius Kaspers, Floor Abbink, Marry M. van den Heuvel-Eibrink, Cor van den Bos, Inge M. van der Sluis, Heidi Segers, Leen Willems, Jutte Van Der Werff, Christophe Chantrain, Machteld Heleen van den Berg
Journal: Blood (2019)
Impact of Bridging Chemotherapy on Clinical Outcomes of CD19 CAR T Therapy in Relapse/Refractory Diffuse Large B- Cell Lymphoma in Real World Experience
Authors: Jérôme Paillassa, Laetitia Vercellino, Roberta Di Blasi, Sophie Bernard, Hannah Moatti, Côme Bommier, Matteo Guerra, Veronique Meignin, Sylvie Chevret, Catherine Thieblemont
Journal: Blood (2019)
Abstract 14551: Lower Omega-3 Fatty Acid Levels Could Predict Coronary Plaque Vulnerability in Patients With Coronary Artery Disease
Authors: Atsushi Sakamoto, Natsuko Hosoya, Toru Yoshizaki, Shigetaka Kageyama, Ryosuke Takeuchi, Koichiro Murata, Ryuzo Nawada, Tomoya Onodera, Akinori Takizawa, Masao Saotome, Hiroshi Satoh, Hideharu Hayashi
Journal: Circulation (2013)

Background: Accumulating evidences have revealed the robust relationship between aberrant serum lipid profiles and coronary artery disease (CAD). However, the question whether the altered serum lip...
RARE-39. COMBINATION OF TUMOR TREATING FIELDS (TTFIELDS) WITH LOMUSTINE (CCNU) AND TEMOZOLOMIDE (TMZ) IN NEWLY DIAGNOSED GLIOBLASTOMA (GBM) PATIENTS - A BI-CENTRIC ANALYSIS
Authors: Lazaros Lazaridis, Niklas Schäfer, Teresa Schmidt, Johannes Weller, Theophilos-Dimitrios Tzaridis, Björn Scheffler, Daniela Pierscianek, Christoph Kleinschnitz, Martin Stuschke, Ulrich Sure, Ulrich Herrlinger, Sied Kebir, Martin Glas
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND TTFields combined with TMZ chemotherapy demonstrated significantly improved PFS, OS and long-term survival in newly diagnosed glioblastoma (ndGBM) patients in the EF-14 trial; independent of MGMT-promoter methylation-status, age, grade of resection, and performance status. Recently, improved efficacy of lomustine/TMZ compared to TMZ monotherapy in ndGBM patients with MGMT-promotor methylation was reported in the CeTeG trial. As TTFields demonstrated a favorable safety profile as well as a high potential for being combined with other modalities and the encouraging results for methylated MGMT-promoter GBM patients in the CeTeG trial, there is a strong rationale for combining these treatment regimens. Here, we present a case series of patients receiving a combination of TTFields and lomustine/TMZ. METHODS Patients with ndGBM and MGMT-promoter methylation underwent combined therapy of TTFields plus lomustine/TMZ after surgery and radiochemotherapy. MGMT-promoter status was measured by pyrosequencing. Safety, feasibility, and first efficacy results are reported at data cut-off (April 26, 2019). RESULTS Sixteen patients with MGMT-promoter methylated ndGBM (median, range: age 50, 27–70; KPS 90, 60–100) have been treated with a combination of TTFields plus lomustine/TMZ. The analysis included patients with complete resection (n=7), partial resection (n=8), as well as biopsy (n=1). CTCAE grade 3 hematotoxicity was observed in seven patients (44%) but was unlikely related to the addition of TTFields to lomustine/TMZ. Medical device site reactions (low-grade skin reactions) were detected in six patients (38%). At data cut-off, the analyzed patient population demonstrated a median PFS of 20 months; the median OS was not yet reached. CONCLUSION The results of this analysis indicate that the combination of TTFields/lomustine/TMZ is safe and feasible. Moreover, the observed survival outcomes point to preliminary beneficial effects of the triple combination. Additional follow-up and increased sample size are required and planned for further safety and efficacy assessment of this treatment regimen.
Distinct and convergent consequences of splice factor mutations in myelodysplastic syndromes
Authors: Vikas Madan, Jia Li, Siqin Zhou, Weoi Woon Teoh, Lin Han, Manja Meggendorfer, Luca Malcovati, Mario Cazzola, Seishi Ogawa, Torsten Haferlach, Henry Yang, H. Phillip Koeffler
Journal: American Journal of Hematology (2019)

Myelodysplastic syndromes (MDS) are characterized by recurrent somatic alterations often affecting components of RNA splicing machinery. Mutations of splice factors SF3B1, SRSF2, ZRSR2 and U2AF1 occur in >50% of MDS. To assess the impact of spliceosome mutations on splicing and to identify common pathways/genes affected by distinct mutations, we performed RNA-sequencing of MDS bone marrow samples harboring spliceosome mutations (including hotspot alterations of SF3B1, SRSF2 and U2AF1; small deletions of SRSF2 and truncating mutations of ZRSR2), and devoid of other common co-occurring mutations. We uncover the landscape of splicing alterations in each splice factor mutant MDS and demonstrate that small deletions in SRSF2 cause highest number of splicing alterations compared with other spliceosome mutations. Although the mis-spliced events observed in different splice factor mutations were largely non-overlapping, a subset of genes, including EZH2, were aberrantly spliced in multiple mutant groups. We also verified aberrant splicing of key genes USP9X, USP24 (deubiquitinating enzymes), LUC7L2 (splice factor) and EED (PRC2 component) in MDS harboring small deletions of SRSF2. Pathway analysis revealed that mis-spliced genes in different mutant groups were enriched in RNA splicing and transport as well as several signaling cascades, suggesting converging biological consequences downstream of distinct spliceosome mutations. Our study reveals splicing signatures of each splice factor mutation and identifies shared and distinct sets of mis-spliced genes and affected biological processes in different spliceosome mutant MDS.