tbuckley/cabot-search huggingface dataset:
Investigating genes and pathways that play a role in immune responses mediated by anti-CTLA-4 therapy.
Authors: Jianjun Gao, Hong Chen, Derek Ng Tang, Padmanee Sharma
Journal: Journal of Clinical Oncology (2012)

2520^ Background: Blockade of the inhibitory T cell molecule CTLA-4 with a monoclonal antibody has led to enhanced anti-tumor immune responses and clinical benefit. Ipilimumab, an anti-CTLA-4 antibody (BMS), was recently FDA-approved for the treatment of metastatic melanoma. Only a subset of patients benefit from anti-CTLA-4. In order to identify genes and pathways that are induced by anti-CTLA-4, which may be used in future studies for potential correlation with clinical outcomes or provide additional targets for therapy, we purified and analyzed CD4 T cells from patients treated with anti-CTLA-4 for changes in gene expression profile. We also obtained tumor tissues from treated patients for similar studies. Methods: On an IRB-approved Phase Ia pre-surgical clinical trial, 6 patients with localized bladder cancer were treated with two doses of Ipilimumab at 10 mg/kg at weeks 1 and 4. Blood was collected pre-therapy and post-therapy (3 weeks after each dose). CD4 T cells were enriched from peripheral blood by using the CD4 T cell isolation kit from Miltenyi Biotec (Auburn, CA). Total RNA was isolated from purified CD4 T cells using Qiagen RNeasy kit for Affymetrix microarray analyses. Microarray data were then analyzed using Ingenuity iReport (Redwood City, CA). RT-PCR, RPPA and Western blot were used to confirm significant changes in genes or pathways identified in microarray analyses. Results: Ipilimumab treatment resulted in modulation of differentially expressed genes (DEGs). After dose #1, Ipilimumab only modulated 16 DEGs &gt;2-fold (p&lt;0.05) in CD4 T cells. After two doses of treatment, Ipilimumab significantly changed expression of a total of 100 DEGs. Further pathway analyses indicated that Ipilimumab induced a variety of pathways involved in cell cycle control, cell proliferation, apoptosis, and immune modulation. Specifically, these pathways include PI3K/AKT, MAP/ERK, IFN/JAK-STAT, granzyme, and protein ubiquination. Conclusions: Ipilimumab treatment results in modulation of multiple genes and pathways, which likely play important roles in anti-tumor immune responses and need to be considered for future optimization of anti-CTLA-4 therapy and design of combination immunotherapy strategies.
581P VHIO immune gene expression profiling (VIGex) panel, a tool to explore tumour immune microenvironment
Authors: F.M. Mancuso, Z. Ogbah, R. Fasani, D.G. Lo Giacco, L. Ramos, A. Oaknin, M. Alsina, E. Elez, T. Macarulla Mercade, C. Saura, J. Capdevila, M. Vieito, E. Felip, R. Dienstmann, A. Gros, J. Seoane, P.G. Nuciforo, J. Tabernero, E. Garralda, A. Vivancos
Journal: Annals of Oncology (2020)
Phase I study of intraventricular infusions of autologous ex vivo expanded NK cells in children with recurrent medulloblastoma and ependymoma
Authors: Soumen Khatua, Laurence J N Cooper, David I Sandberg, Leena Ketonen, Jason M Johnson, Michael E Rytting, Diane D Liu, Heather Meador, Prashant Trikha, Robin J Nakkula, Gregory K Behbehani, Dristhi Ragoonanan, Sumit Gupta, Aikaterini Kotrotsou, Tagwa Idris, Elizabeth J Shpall, Katy Rezvani, Rivka Colen, Wafik Zaky, Dean A Lee, Vidya Gopalakrishnan
Journal: Neuro-Oncology (2020)

Recurrent pediatric medulloblastoma and ependymoma have a grim prognosis. We report a first-in-human, phase I study of intraventricular infusions of ex vivo expanded autologous natural killer (NK) cells in these tumors, with correlative studies.Twelve patients were enrolled, 9 received protocol therapy up to 3 infusions weekly, in escalating doses from 3 × 106 to 3 × 108 NK cells/m2/infusion, for up to 3 cycles. Cerebrospinal fluid (CSF) was obtained for cellular profile, persistence, and phenotypic analysis of NK cells. Radiomic characterization on pretreatment MRI scans was performed in 7 patients, to develop a non-invasive imaging-based signature.Primary objectives of NK cell harvest, expansion, release, and safety of 112 intraventricular infusions of NK cells were achieved in all 9 patients. There were no dose-limiting toxicities. All patients showed progressive disease (PD), except 1 patient showed stable disease for one month at end of study follow-up. Another patient had transient radiographic response of the intraventricular tumor after 5 infusions of NK cell before progressing to PD. At higher dose levels, NK cells increased in the CSF during treatment with repetitive infusions (mean 11.6-fold). Frequent infusions of NK cells resulted in CSF pleocytosis. Radiomic signatures were profiled in 7 patients, evaluating ability to predict upfront radiographic changes, although they did not attain statistical significance.This study demonstrated feasibility of production and safety of intraventricular infusions of autologous NK cells. These findings support further investigation of locoregional NK cell infusions in children with brain malignancies.
Trastuzumab associated cardiotoxicity: Who is at risk?
Authors: Omalkhair A. M. Abulkhair, Ahmed Gasmelseed, Shabab Al Otaibi
Journal: Journal of Clinical Oncology (2013)

e11518 Background: Trastuzumab is an important agent in the treatment of both adjuvant and metastatic breast cancer with known cardio toxicity. Cardio toxicity is defined as reduction in left ventricular ejection fraction (LVEF) of &gt; 5% with signs and symptoms of heart failure (HF) or &gt; 10% without such symptoms. Methods: Retrospective review of all breast cancer patients treated in King Abdulaziz Medical City with trastuzumab for adjuvant and metastatic setting from 2003 to 2012. 150 cases were identified, patients with good quality echocardiogram and base line LVEF &gt; 55% were included (104). Patients had base line, then 3 monthly echocardiogram thereafter. Results: Studied patients showed that median age was 49 (43 - 58) years. There was a relevant decline in LVEF in 16 patients (15.38%), after mean exposure duration of 15 months. The study also revealed significant difference in EF decline between diabetic and non diabetic receiving herceptin (31.82% and 10.98% respectively, p-value 0.0213), and in 64.71% with hypercholesrolemia compared to 5.75% in those with normal cholesterol (p-value 0.0001). Conclusions: Given the limitations of this small retrospective review, we have shown that the prevalence of cardio toxicity in our patients is higher than published figures. Also, we have shown a significant correlation between diabetes, hyperlipidimia and cardio toxicity in trastuzumab treated patients. Such patients might need to be closely monitored for cardio toxicity.
Open-label extension study of the RNAi therapeutic ALN-VSP02 in cancer patients responding to therapy.
Authors: Maria Alsina, Josep Tabernero, Geoffrey Shapiro, Howard Burris, Jeffrey R. Infante, Glen J. Weiss, Andres Cervantes-Ruiperez, Mrinal M. Gounder, Luis Paz-Ares, Rick Falzone, Jamie Hill, Jeffrey Cehelsky, Akshay Vaishnaw, Jared Gollob, Patricia LoRusso
Journal: Journal of Clinical Oncology (2012)

3062 Background: ALN-VSP02 is an RNA interference (RNAi) therapeutic comprised of lipid nanoparticle-formulated small interfering RNAs targeting vascular endothelial growth factor (VEGF)-A and kinesin spindle protein (KSP). In a phase 1 trial, ALN-VSP02 administered as an iv infusion q2 wks was well-tolerated and showed evidence of anti-VEGF pharmacology and antitumor activity. Methods: Patients treated on the phase I trial with stable disease (SD) or better after 4 months (8 doses) were eligible to continue on an extension study until disease progression. Main objectives included continued evaluation of safety/tolerability and assessment of disease response. Results: Seven of 37 patients (18.9%) evaluable for response went onto the extension study, including 1 of 7 (14.2%) at 0.4 mg/kg, 2 of 5 (40%) at 0.7 mg/kg, and 4 of 11 (36.3%) at 1.0 mg/kg. All had progressed after one or more prior therapies. Tumor types included head and neck squamous cell carcinoma, angiosarcoma, endometrial cancer, renal cell carcinoma (RCC, N=2), and pancreatic neuroendocrine tumor (PNET, N=2). At the time of enrollment, 6 had SD and one (endometrial cancer with multiple liver metastases) had an unconfirmed partial response (PR). The average length of time on treatment (including phase I and extension studies) was 9.5 months (range 5-19). As of January 2012, 3 patients remain on study, including the endometrial cancer patient with an ongoing PR who has had &gt;80% tumor regression after 19 months of treatment at 0.7 mg/kg and two patients with RCC and PNET with continued SD after nearly 1 year of treatment at 1.0 mg/kg. The other patients with RCC and PNET at 1.0 mg/kg with SD came off after 8.5 and 5.5 months, respectively, for adverse events that included fatigue or elevated alkaline phosphatase. A decrease in spleen volume, likely an on-target effect and not associated with any adverse events, occurred to a greater degree on the extension study than on the phase I trial and was most pronounced in patients receiving ≥ 12 doses. Conclusions: ALN-VSP02 has preliminary activity against endometrial cancer, RCC and PNET and a favorable safety profile that permits chronic dosing. Phase II trials are warranted in these and other VEGF-overexpressing tumors.
20P Interim safety and efficacy results of a phase II clinical trial on trametinib and low-dose dabrafenib in patients with advanced BRAFV600 wild-type melanoma
Authors: G. Awada, J.K. Schwarze, E. Reijmen, C. Goyvaerts, G. Fasolino, S. Aspeslagh, B. Neyns
Journal: Annals of Oncology (2020)
Repeated Remote Ischemic Conditioning Reduces Doxorubicin-Induced Cardiotoxicity
Authors: Quan He, Fangfei Wang, Thomas D. Ryan, Meghana Chalasani, Andrew N. Redington
Journal: JACC CardioOncology (2020)

This study investigated the cardioprotective effect of repeated remote ischemic preconditioning (rRIC) on doxorubicin-induced cardiotoxicity in mice.Doxorubicin is an effective chemotherapeutic agent for a wide range of tumor types but its use and dosing are limited by acute and chronic cardiotoxicity. Remote ischemic conditioning (RIC) is cardioprotective in multiple cardiovascular injury models, but the effectiveness of rRIC in doxorubicin-induced cardiotoxicity has not been fully elucidated.rRIC was performed on mice before and after doxorubicin administration. Cardiac function was assessed by echocardiography and myocardial biology was tested by molecular approaches.Doxorubicin administration induced acute cardiotoxicity, as indicated by reduced cardiac function, reduced myocyte cross-section area and increased extracellular collagen deposition, increased circulating cardiac muscle damage markers, and decreased heart weight. Doxorubicin also adversely affected other organs, including the kidney, liver, and spleen, as evaluated by circulating markers or organ weight loss. rRIC not only abrogated doxorubicin-induced cardiotoxicity (left ventricular ejection fraction, doxorubicin 47.5 ± 1.1%, doxorubicin + rRIC 51.6 ± 0.7%, p = 0.017), but also was associated with multiorgan protection. Within the myocardium, rRIC attenuated doxorubicin-induced cardiomyocyte apoptosis, reduced inflammation, and increased autophagy signaling.rRIC may be a promising approach to reduce doxorubicin-induced cardiotoxicity.
Phase 2 study of <scp>hyper‐CMAD</scp> with liposomal vincristine for patients with newly diagnosed acute lymphoblastic leukemia
Authors: Koji Sasaki, Hagop Kantarjian, William Wierda, Farhad Ravandi‐Kashani, Jeffrey Jorgensen, Sa A. Wang, Joseph Khoury, Naval Daver, Jan Burger, Courtney D. Di Nardo, Nitin Jain, Nicholas J. Short, Zeev Estrov MD, Marina Konopleva MD, PhD, Maro Ohanian DO, Guillermo Garcia‐Manero, Tapan Kadia, Yesid Alvarado‐Valero, Musa Yilmaz, Sherry Pierce, Rebecca Garris, April Ingram, Jorge Cortes, Susan OʼBrien, Elias Jabbour
Journal: American Journal of Hematology (2020)

Liposomal vincristine is designed to reduce neurotoxicity and increase dose intensity delivery, and has been approved as salvage therapy in relapsed/refractory acute lymphoblastic leukemia (ALL). Our aim was to evaluate the response rate, toxicities, and outcome of adults with newly diagnosed ALL who received liposomal vincristine, rather than regular vincristine in combination with intensive chemotherapy (Hyper-CMAD). In a single-center, phase 2 study, patients ≥18 years with newly-diagnosed B-cell ALL were eligible to receive hyper-CMAD alternating with high-dose methotrexate and cytarabine. Rituximab was administered in CD20 positive ALL. Tyrosine kinase inhibitors (imatinib or dasatinib) were added in Philadelphia chromosome-positive (Ph-positive) ALL. Thirty-one patients were enrolled, median follow-up of 59 months (0.3-70). Thirteen patients (42%) had CD20 positive ALL, and 21 (68%) had Ph-positive ALL. Thirty (97%) achieved complete remission (CR). All 26 patients with abnormal karyotype achieved complete cytogenetic response (CCyR), and 27/30 (90%) achieved negative minimal residual disease status by multicolor flow cytometry. Of 20 evaluable Ph-positive ALL patients, major molecular response (MMR) was achieved in 19 patients (95%); complete molecular response (CMR) in 14 (70%). Grade 3/4 peripheral neuropathy was observed in five (16%) with all grade peripheral neuropathy in 21 (68%). With a median follow-up of 59 months, 21 (68%) patients are alive. The 5-year CR duration and survival rates were 73% and 61%, respectively. Ten (32%) patients died: one, sepsis on C1D10; four, unknown; one, post-transplant complications; four, relapse. Hyper-CMAD with liposomal vincristine is safe and demonstrated high response and survival rates in newly diagnosed ALL.
A SURPRISING CASE OF LATE-ONSET BACTERIAL ENDOCARDITIS ASSOCIATED WITH GORE HELEX SEPTAL OCCLUDER DEVICE SEVEN YEARS SINCE IMPLANTATION
Authors: Nazia Alvi, Samia Qadir, Seban Liu, Ankit Patel, Bharat Surani, Michael J. Anderson, Arshad Yousuf, Vikas Patel, Raju Z. Abraham
Journal: Journal of the American College of Cardiology (2020)
Cardiac iron concentration in relation to systemic iron status and disease severity in non‐ischaemic heart failure with reduced ejection fraction
Authors: Valentin G. Hirsch, Jörn Tongers, Julia Bode, Dominik Berliner, Julian D. Widder, Felicitas Escher, Vitalii Mutsenko, Bomee Chung, Fatemeh Rostami, Anja Guba‐Quint, Evangelos Giannitsis, Heinz‐Peter Schultheiss, Carla Vogt, Johann Bauersachs, Kai C. Wollert, Tibor Kempf
Journal: European Journal of Heart Failure (2020)

Abstract Aims Low cardiac iron levels promote heart failure in experimental models. While cardiac iron concentration (CI) is decreased in patients with advanced heart failure with reduced ejection fraction (HFrEF), CI has never been measured in non‐advanced HFrEF. We measured CI in left ventricular (LV) endomyocardial biopsies (EMB) from patients with non‐advanced HFrEF and explored CI association with systemic iron status and disease severity. Methods and results We enrolled 80 consecutive patients with non‐ischaemic HFrEF with New York Heart Association class II or III symptoms and a median (interquartile range) LV ejection fraction of 25 (18–33)%. CI was 304 (262–373) μg/g dry tissue. CI was not related to immunohistological findings or the presence of cardiotropic viral genomes in EMBs and was not related to biomarkers of systemic iron status or anaemia. Patients with CI in the lowest quartile (CI Q1 ) had lower body mass indices and more often presented with heart failure histories longer than 6 months than patients in the upper three quartiles (CI Q2–4 ). CI Q1 patients had higher serum N‐terminal pro‐B‐type natriuretic peptide levels than CI Q2–4 patients [3566 (1513–6412) vs. 1542 (526–2811) ng/L; P = 0.005]. CI Q1 patients also had greater LV end‐diastolic ( P = 0.001) and end‐systolic diameter indices ( P = 0.003) and higher LV end‐diastolic pressures ( P = 0.046) than CI Q2–4 patients. Conclusion Low CI is associated with greater disease severity in patients with non‐advanced non‐ischaemic HFrEF. CI is unrelated to systemic iron homeostasis. The prognostic and therapeutic implications of CI measurements in EMBs should be further explored.
CARDIOGENIC SHOCK DUE TO FULMINANT MYOCARDITIS AND FAVORABLE OUTCOME WITH VA-ECMO AND CONCOMITANT INTRA-AORTIC BALLOON PUMP
Authors: Juan Alan Fuentes Mendoza, Jose Ramon Benitez, Jahaziel Lopez, Carmen Alicia Sánchez Contreras, Estefanie Villanueva Rodriguez, Valery Johana Romero Ramirez, Juan Fuentes Jaime
Journal: Journal of the American College of Cardiology (2020)
QIM20-134: Genetic Testing for At-Risk Patients With Colorectal and/or Pancreatic Cancer at Our Institution, a Quality Improvement Project
Authors: Mina Shenouda, Vivek Yadala, Jennifer Dotson, Toni Pacioles
Journal: Journal of the National Comprehensive Cancer Network (2020)

"QIM20-134: Genetic Testing for At-Risk Patients With Colorectal and/or Pancreatic Cancer at Our Institution, a Quality Improvement Project" published on 20 Mar 2020 by National Comprehensive Cancer Network.
CONCURRENT IMPLANTATION OF A LEADLESS PACEMAKER FOLLOWED BY TAVR IS A NOVEL AND FEASIBLE PROCEDURE IN PATIENTS WITH SEVERE AORTIC STENOSIS AND SICK SINUS SYNDROME
Authors: Karan Rao, Ray Parkin, Suzanne Eshoo, Emily Granger, Kujan Nagaratnam, Ajita Kanthan, Peter Fahmy
Journal: Journal of the American College of Cardiology (2020)
Multidisciplinary care clinics: A model to deliver personalized survivorship care.
Authors: Fran Zandstra, Guadalupe R. Palos, Ludivine Russell, Jacklyn J Flores, Yvette DeJesus, Lewis E Foxhall, Maria Alma Rodriguez
Journal: Journal of Clinical Oncology (2012)

e19629 Background: Multidisciplinary care models provide a comprehensive approach to improve the care of long-term cancer survivors as recommended by the Institute of Medicine report.. Here we describe a Multidisciplinary Survivorship Care Model and the metrics used to evaluate the delivery of personalized care to long-term survivors. Methods: Critical components used to develop survivorship services included: 1) engaging clinical and administrative leadership; 2) conducting extensive reviews/syntheses of published literature including health promotion, prevention and risk reduction, late treatment effects, and rehabilitative services for each disease-site; 3) determining eligibility criteria to transition patients from active-disease care to survivorship care; 4) developing, implementing, and evaluating algorithms by involving a multidisciplinary team expert-consensus; 5) obtaining approval for integration of algorithms into practice by institutional credentialing and regulatory committees; 6) identifying appropriate survivorship clinics to pilot the feasibility of algorithms in routine clinical operations; 7) performing improvement checks of the clinic operations; and 8) revising operations and scheduling as needed. Metrics used to evaluate the progress of the clinical activity of each multidisciplinary survivorship care clinic (MSCC) included number of unique patients transitioned, number seen, number of arrived appointments, number of summary care plans issued, and survivors’ satisfaction. Results: The MSCCs included gynecology, thyroid, genitourinary, stem cell transplant, breast, head and neck, colorectal, lymphoma, and melanoma, with varied launch dates for each clinic. Between 09/01/2008 and 12/31/2011, there were a total of 7396 unique survivors, 12,741 arrived appointments, and 10,016 summary care plans completed within 30 days from appointment. Conclusions: Dedicated multidisciplinary survivorship care models are a comprehensive approach to deliver long-term survivorship care. Comparative effectiveness and other health outcomes research examining the feasibility, usability, acceptance, and effectiveness of the MSCC by providers and survivors is warranted.
Machine learning and artificial intelligence research for patient benefit: 20 critical questions on transparency, replicability, ethics, and effectiveness
Authors: Sebastian Vollmer, Bilal A Mateen, Gergo Bohner, Franz J Király, Rayid Ghani, Pall Jonsson, Sarah Cumbers, Adrian Jonas, Katherine S L McAllister, Puja Myles, David Grainger, Mark Birse, Richard Branson, Karel G M Moons, Gary S Collins, John P A Ioannidis, Chris Holmes, Harry Hemingway
Journal: BMJ (2020)

Machine learning, artificial intelligence, and other modern statistical methods are providing new opportunities to operationalise previously untapped and rapidly growing sources of data for patient benefit. Despite much promising research currently being undertaken, particularly in imaging, the literature as a whole lacks transparency, clear reporting to facilitate replicability, exploration for potential ethical concerns, and clear demonstrations of effectiveness. Among the many reasons why these problems exist, one of the most important (for which we provide a preliminary solution here) is the current lack of best practice guidance specific to machine learning and artificial intelligence. However, we believe that interdisciplinary groups pursuing research and impact projects involving machine learning and artificial intelligence for health would benefit from explicitly addressing a series of questions concerning transparency, reproducibility, ethics, and effectiveness (TREE). The 20 critical questions proposed here provide a framework for research groups to inform the design, conduct, and reporting; for editors and peer reviewers to evaluate contributions to the literature; and for patients, clinicians and policy makers to critically appraise where new findings may deliver patient benefit.
Ldb1 is required for Lmo2 oncogene–induced thymocyte self-renewal and T-cell acute lymphoblastic leukemia
Authors: LiQi Li, Apratim Mitra, Kairong Cui, Bin Zhao, Seeyoung Choi, Jan Y. Lee, Daniel B. Stamos, Dalal El-Khoury, Claude Warzecha, Karl Pfeifer, Joyce Hardwick, Keji Zhao, Bryan Venters, Utpal P. Davé, Paul E. Love
Journal: Blood (2020)
Immunogenetic characterization of clonal plasma cells in systemic light-chain amyloidosis
Authors: Isabel Cuenca, Daniel Alameda, Beatriz Sanchez-Vega, David Gomez-Sanchez, Diego Alignani, Marta Lasa, Esther Onecha, Ramon Lecumberri, Felipe Prosper, Enrique M. Ocio, Maria Esther González, Alfonso García de Coca, Javier De La Rubia, Mercedes Gironella, Luis Palomera, Albert Oriol, Maria Casanova, Valentin Cabañas, Francisco Taboada, Albert Pérez-Montaña, Felipe De Arriba, Noemi Puig, Gonzalo Carreño-Tarragona, Santiago Barrio, Jose Enrique de la Puerta, Angel Ramirez-Payer, Isabel Krsnik, Juan Jose Bargay, Juan Jose Lahuerta, Maria-Victoria Mateos, Jesus F. San-Miguel, Bruno Paiva, Joaquin Martinez-Lopez
Journal: Leukemia (2020)

Sequence-based analysis has come to play an integral role in many hematological malignancies [1], but disorders such as systemic light-chain (AL) amyloidosis remain poorly characterized due to its low incidence and small tumor size [2,3].Thus, greater knowledge about the immunogenetic landscape of AL amyloidosis is required since, for example, potential differences between the genomic profiles of AL amyloidosis and multiple myeloma (MM) could help identifying patients with monoclonal gammopathies at greater risk of developing AL amyloidosis and monitor presymptomatic organ damage [4,5].To gain further insight into the immunogenetic landscape of AL amyloidosis, we performed whole-exome sequencing (WES) on highly purified bone marrow clonal plasma cells (PCs) isolated by fluorescence activation cell sorting (FACS) based on patient-specific aberrant phenotypes.A total of 27 patients with confirmed new diagnosis of AL amyloidosis based on the presence of amyloid-related systemic syndrome, positive amyloid tissue staining with Congo red, restricted light-chain deposition by