tbuckley/cabot-search huggingface dataset:
Abstract 11363: Association of Dietary Protein, Animal and Vegetable Protein With the Incidence of Heart Failure Among Postmenopausal Women
Authors: Mohamad Firas Barbour, Farhan Ashraf, Mary B Roberts, Matthew Allison, Lisa Martin, Karen Johnson, Carolina Valdiviezo, Charles B Eaton
Journal: Circulation (2016)

Background: Heart failure (HF) is a highly prevalent disease especially in post-menopausal women. A better understanding of nutrition-related factors associated with HF is needed. Misclassification of diet due to self-reports can be partially ameliorated by use of biomarker calibration equations. Objectives: This study evaluated prospectively the association between biomarker calibrated dietary protein intake and the incidence of heart failure in a cohort of postmenopausal women. In addition, we studied the effect of energy adjusted animal and plant based dietary protein and the incidence of HF. Methods: Study participants are postmenopausal women (n=103,878) who are free of Heart Failure at baseline, evaluated from 1993-1998 in the Women health Initiative (WHI). We used self-reported intakes of total dietary protein, animal protein, and vegetable protein based upon a Food Frequency Questionnaire (FFQ) and calibration equations for protein derived from urinary nitrogen excretion and energy calibration based upon doubly labeled water. The association between dietary protein intake and the incidence Heart Failure was evaluated using cox proportional hazards models, and treating age as a continuous variable within age strata due to Simpson’s paradox. Results: Among 103,878 women in the study sample, 1711 women developed HF through 2005. Incremental biomarker calibrated dietary protein consumption was associated with an increase in the risk for Heart Failure. An inverse association was found between higher intakes of energy adjusted vegetable protein and HF although this association wasn’t statically significant if the association was adjusted to BMI and diet quality. Conclusion: Higher total dietary protein intake (calibrated), appears to be associated with substantially increased heart failure risk while the vegetable protein intake appears to be protective against developing Heart Failure. Further studies are needed to explore this association.
Pharmacokinetic Analysis of Continuous Intravenous Infusion of Lipo-Prostaglandin E1 As a Prophylaxis of Hepatic Veno-Occlusive Disease after Hematopoietic Stem Cell Transplantation
Authors: Che Ry Hong, Yewon Choi, Jaeseong Oh, Jung Sunwoo, Kyung Taek Hong, Jung Yoon Choi, Kyung-Sang Yu, Kyung Duk Park, Hee Young Shin, Hyoung Jin Kang
Journal: Blood (2016)
PERIPHERAL ANATOMIC DISTRIBUTION OF THROMBUS DOES NOT ADVERSELY AFFECT OUTCOMES IN PATIENTS UNDERGOING SURGICAL PULMONARY EMBOLECTOMY FOR SUBMASSIVE AND MASSIVE PULMONARY EMBOLISM
Authors: Chetan Pasrija, Isa Mohammed, Aakash Shah, Francis A. Brigante, Mehrdad Ghoreishi, James Gammie, Bartley Griffith, Zachary Kon
Journal: Journal of the American College of Cardiology (2017)
ACHILLES TENDON XANTHOMAS ARE INDEPENDENTLY ASSOCIATED WITH SEVERITY OF SUBCLINICAL CORONARY ATHEROSCLEROSIS IN FAMILIAL HYPERCHOLESTEROLEMIA
Authors: Leonardo Celeste Mangili, Marcio Miname, Otavio Mangili, Carlos Rochitte, Marcio Bittencourt, Raul Santos
Journal: Journal of the American College of Cardiology (2017)
Efficacy and Safety of Anti-Trop-2 Antibody Drug Conjugate Sacituzumab Govitecan (IMMU-132) in Heavily Pretreated Patients With Metastatic Triple-Negative Breast Cancer
Authors: Aditya Bardia, Ingrid A. Mayer, Jennifer R. Diamond, Rebecca L. Moroose, Steven J. Isakoff, Alexander N. Starodub, Nikita C. Shah, Joyce O’Shaughnessy, Kevin Kalinsky, Michael Guarino, Vandana Abramson, Dejan Juric, Sara M. Tolaney, Jordan Berlin, Wells A. Messersmith, Allyson J. Ocean, William A. Wegener, Pius Maliakal, Robert M. Sharkey, Serengulam V. Govindan, David M. Goldenberg, Linda T. Vahdat
Journal: Journal of Clinical Oncology (2017)

Purpose Trop-2, expressed in most triple-negative breast cancers (TNBCs), may be a potential target for antibody-drug conjugates. Sacituzumab govitecan, an antibody-drug conjugate, targets Trop-2 for the selective delivery of SN-38, the active metabolite of irinotecan. Patients and Methods We evaluated sacituzumab govitecan in a single-arm, multicenter trial in patients with relapsed/refractory metastatic TNBC who received a 10 mg/kg starting dose on days 1 and 8 of 21-day repeated cycles. The primary end points were safety and objective response rate; secondary end points were progression-free survival and overall survival. Results In 69 patients who received a median of five prior therapies (range, one to 12) since diagnosis, the confirmed objective response rate was 30% (partial response, n = 19; complete response, n = 2), the median response duration was 8.9 (95% CI, 6.1 to 11.3) months, and the clinical benefit rate (complete response + partial response + stable disease ≥ 6 months) was 46%. These responses occurred early, with a median onset of 1.9 months. Median progression-free survival was 6.0 (95% CI, 5.0 to 7.3) months, and median overall survival was 16.6 (95% CI, 11.1 to 20.6) months. Grade ≥ 3 adverse events included neutropenia (39%), leukopenia (16%), anemia (14%), and diarrhea (13%); the incidence of febrile neutropenia was 7%. The majority of archival tumor specimens (88%) were moderately to strongly positive for Trop-2 by immunohistochemistry. No neutralizing antibodies to the ADC or antibody were detected, despite repeated cycles developed. Conclusion Sacituzumab govitecan was well tolerated and induced early and durable responses in heavily pretreated patients with metastatic TNBC. As a therapeutic target and predictive biomarker, Trop-2 warrants further research.
Heterogeneity of epidermal growth factor receptor (EGFR) expression and variation in immunohistochemistry (IHC) testing may affect access to EGFR-targeted therapy in patients with advanced colorectal cancer (CRC)
Authors: M. W. Beer, C. Ung, S. S. Bacus, A. D. McCollum, A. Ervin-Haynes, R. Schinagl, H. Youssoufian, E. Rowinsky
Journal: Journal of Clinical Oncology (2006)

10104 Introduction: Cetuximab, an IgG1 MAb directed at the EGFR, has demonstrated benefit in pts with CRC and is currently indicated in EGFR expressing CRC. However, previous reports show heterogeneous EGFR expression between anatomic sites and suggest that results from IHC testing vary between labs. To assess this variability and the resultant impact on pt access to EGFR-targeted therapy, we compared EGFR results reported to clinicians by hospital and reference labs with those obtained at a single central lab. Methods: Formalin-fixed, paraffin-embeded CRC specimens submitted through the Targeted Diagnostics Advocacy Program (tdap) were assayed using the Dako EGFR pharmDx kit and scored using the FDA-approved package insert. If the initial specimen tested EGFR negative (−), additional specimens were requested for assay. Prior EGFR results, lab, and specimen ID were documented through review of anatomic pathology reports. Results: Of 332 evaluable CRC pts tested, 245 pts (74%) were previously reported as EGFR(−). After retesting, 167 (68%) pts were found to be EGFR The originally tested tumor block was retested in 82 pts and 41 pts (50%) were found to be EGFR (+). Retest results were similar for both hospital and reference labs. Of 66 pts with &gt;1 specimen from the same anatomic site tested, 21 (32%) were discordant (at least 1 (+) and one (−) result). Results from different anatomic sites were compared for 65 pts, 34 (52%) of which were discordant (+). Overall, 231 pts (70%) tested EGFR(+). Conclusion: This study shows marked heterogeneity in EGFR expression by IHC both within and across anatomic sites from the same pt as well as variability in both hospital and reference pathology labs. This variability undoubtedly has an adverse impact on pt access to EGFR-targeted therapy. The impact of EGFR heterogeneity may be reduced through the assay of multiple specimens. [Table: see text] [Table: see text]
PATHOLOGIC PLUMBING: UTILIZING MULTI-MODALITY IMAGING IN THE DIAGNOSIS OF A PATIENT WITH PULMONARY VEIN TO AZYGOS SYSTEM FISTULA AND DECOMPENSATED VALVULAR CARDIOMYOPATHY
Authors: Santosh Desai, Reza Arsanjani, Michael Gotway, Clinton Jokerst, Louis Lanza, Susan Wilansky, Fadi Shamoun
Journal: Journal of the American College of Cardiology (2017)
A Fully-Automated Screening Method for Anti-HLA Antibodies: Implications for Screening Plasma Donations To Prevent Transfusion-Related Acute Lung Injury (TRALI).
Authors: Elizabeth Culler, Sheilagh B. Barclay, Robert A. Bray, Howard M. Gebel, Christopher D. Hillyer, John D. Roback
Journal: Blood (2005)
THE INTERMOUNTAIN MAJOR ADVERSE CARDIOVASCULAR EVENTS RISK SCORES EFFECTIVELY AND EFFICIENTLY PREDICT 1- TO 3- YEAR POST-STENT MACE IN NON-MYOCARDIAL INFARCTION PATIENTS
Authors: Benjamin Davies Horne, J. Muhlestein, Durgesh Bhandary, Greta Hoetzer, Tami Bair, Naeem Khan, Donald Lappe
Journal: Journal of the American College of Cardiology (2017)
Predictive value of ribonucleotide reductase regulatory subunit M1 (RRM1) and excision cross-complementing-1 (ERCC1) in advanced urothelial carcinoma (UC) treated with first-line gemcitabine (G) and platinum (P)-based chemotherapy (CT).
Authors: Miso Kim, Ja Hyeon Ku, Cheol Kwak, Eunsik Lee, Hyeon Hoe Kim, Bhumsuk Keam, Tae Min Kim, Se-Hoon Lee, Kyung Chul Moon
Journal: Journal of Clinical Oncology (2013)

e15614 Background: Preclinical and clinical studies suggested that RRM1 and ERCC1 expression are associated with resistance to G and P, respectively. However, data which correlated RRM1 and ERCC1 status with tumor response to G + P in advanced US is lacking. We evaluated the significance of RRM1 and ERCC1 to predict tumor response to G + P and survival in advanced UC. Methods: We retrospectively collected tumor samples and reviewed clinical data of 55 patients (pts) with unresectable or metastatic UC, who were treated with 1st line G + P from Jan. 2006 to Dec. 2011. RRM1 and ERCC1 expression were measured by immunohistochemistry and scored using a semiquantitative H-score based on staining intensity and proportion. Results: The study population was predominantly male (80%) and had a median age of 66 years (range: 28-88). The primary sites of UC were bladder (61%), renal pelvis (27.3%) and ureter (10.9%). The RRM1 and ERCC1 expression were positive in 21.8% (12/55) and 25.4% (14/55), respectively. Thirty (69.8%) among 43 pts with low RRM1 expression achieved clinical responses (complete responses + partial responses), but three (25%) among 12 pts with high RRM1 expression achieved clinical responses after G + P (P=0.008). Twenty-three (56.1%) among 41 pts with low ERCC1 expression achieved clinical responses, but ten (71.4%) among 14 pts with high ERCC1 expression achieved clinical responses after G + P (P=0.361). In multivariate analysis, high RRM1 expression independently predicted for poorer tumor response to G + P (OR=10.04, 95% CI=1.74~57.93, P=0.010). High RRM1 expression were associated with shorter progression free survival (PFS) (P=0.005). Multivariate analysis confirmed that pts with high RRM1 expression had a significantly greater risk of progression than those with low RRM1 expression (OR=3.66, 95% CI=1.60~8.36, P=0.002). ERCC1 status was not statistically significant in terms of PFS. Conclusions: In advanced UC, RRM1 expression was predictive of clinical responses from 1st-line G + P. Large prospective validation trials of the clinical value of RRM1 are warranted.
BIVALIRUDIN VERSUS UNFRACTIONATED HEPARIN MONOTHERAPY IN PERCUTANEOUS CORONARY INTERVENTION: A COMPARISON OF ACUTE ADVERSE OUTCOMES
Authors: Perwaiz M. Meraj, Rajkumar Doshi, Amitkumar Patel, Bhavitha George, Lakhbir Kaur, Fatima Mozawalla, Tanzim Bhiuya, Rajiv Jauhar
Journal: Journal of the American College of Cardiology (2017)
HSP70-HSF1 Interplays Has a Role in the Pathogenesis of Chronic Lymphocytic Leukemia and Is a Druggable Target
Authors: Federica Frezzato, Flavia Raggi, Filippo Severin, Veronica Martini, Valentina Trimarco, Leonardo Martinello, Marco Pizzi, Andrea Visentin, Monica Facco, Francesco Piazza, Gianpietro Semenzato, Livio Trentin
Journal: Blood (2016)
MORTALITY AND MORBIDITY IN PATIENTS WITH HEART FAILURE AND REDUCED EJECTION FRACTION EXPOSED TO DIGOXIN: COMPREHENSIVE DATA ACCORDING TO ATRIAL FIBRILLATION IN 23,708 PATIENTS FROM THE SWEDISH HEART FAILURE REGISTRY
Authors: Gianluigi Savarese, Giuseppe Rosano, Camilla Hage, Ulf Dahlstrom, Paul Hauptman, Lars Lund, Lars H. Lund
Journal: Journal of the American College of Cardiology (2017)
Light scattering spectroscopy identifies the malignant potential of pancreatic cysts during endoscopy
Authors: Lei Zhang, Douglas K. Pleskow, Vladimir Turzhitsky, Eric U. Yee, Tyler M. Berzin, Mandeep Sawhney, Shweta Shinagare, Edward Vitkin, Yuri Zakharov, Umar Khan, Fen Wang, Jeffrey D. Goldsmith, Saveli Goldberg, Ram Chuttani, Irving Itzkan, Le Qiu, Lev T. Perelman
Journal: Nature Biomedical Engineering (2017)
LEFT ATRIAL APPENDAGE LIGATION WITH LARIAT DEVICE: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Mohit Turagam, Venkat Lakshmi Kishan Vuddanda, Valay Parikh, Poonam Velagapudi, Mohammad-Ali Jazayeri, Madhav Lavu, Donita Atkins, Sudharani Bommana, Andrea Natale, Luigi Di Biase, Madhu Reddy, Jie Cheng, Krzysztof Bartus, Randall Lee, Dhanunjaya Lakkireddy
Journal: Journal of the American College of Cardiology (2017)
CD31/PECAM-1 Is Overexpressed On Mantle-Cell Lymphoma (MCL) Primary Cells and Positively Regulates Engraftment and Growth of MCL Cell Lines in Immunodeficient Mice.
Authors: Jan Molinsky, Magdalena Klanova, Bokang Maswabi, Josef Karban, Martin Spacek, Marek Trneny, Emanuel Necas, Jan Zivny, Pavel Klener
Journal: Blood (2012)
Trusts must encourage junior doctors to report long working hours, GMC says
Authors: Abi Rimmer
Journal: BMJ (2017)

Junior doctors must be encouraged to raise concerns about their working hours and their training through exception reporting, the General Medical Council has said.

Exception reporting was introduced with the 2016 junior doctor contract in England. It allows junior doctors to report concerns about their working hours and their training.

In a statement issued on 9 March the GMC said that it strongly supported the new system. The regulator also said that it encouraged junior doctors to make use of exception reports to highlight any concerns and …
VISCERAL BUT NOT SUBCUTANEOUS ADIPOSE TISSUE ASSOCIATES WITH VASCULAR INFLAMMATION BY 18-FDG PET/CT IN PSORIASIS
Authors: Joshua P. Rivers, Amit Dey, Abhishek Chaturvedi, Jonathan Chung, Mohammad Tarek Kabbany, Mark Ahlman, Justin Rodante, Aditya Joshi, Charlotte Harrington, Martin Playford, Jianhua Yao, Tiffany Powell-Wiley, Nehal Mehta
Journal: Journal of the American College of Cardiology (2017)
Progressive Glomerular Damage in Sickle Cell Trait and Sickle Cell Anemia Mouse Models
Authors: Santosh L. Saraf, Justin R. Sysol, Alexandru Susma, Suman Setty, Xu Zhang, Krishnamurthy P. Gudehithlu, Jose A.L. Arruda, Ashok K. Singh, Roberto F. Machado, Victor R. Gordeuk
Journal: Blood (2016)
AORTIC VASCULAR INFLAMMATION BY 18-FDG PET/CT ASSOCIATES WITH HIGH-RISK CORONARY PLAQUES IN YOUNG PSORIASIS PATIENTS
Authors: Abhishek Chaturvedi, Joseph Lerman, Veit Sandfort, Jonathan Chung, Amit Dey, Joshua Rivers, Aditya Joshi, Anshuma Rana, Justin Rodante, Heather Teague, Joanna Silverman, Qimin Ng, Greg Sanda, Charlotte Harrington, Alexander Sorokin, Yvonne Baumer, Joel Gelfand, Martin Playford, Mark Ahlman, David Bluemke, Nehal Mehta
Journal: Journal of the American College of Cardiology (2017)
Radioimmunotherapy (90Y-Zevalin®) Combined with BEAM Conditioning Regimen and Autologous Stem Cell Transplantation for the Treatment of Non Hodgkin Lymphomas: Results of An Italian Multicenter Study.
Authors: Vincenzo Pavone, Anna Mele, Antonio Rana, Cosimo Del Casale, Anna Rita Messa, Giuseppina Greco, Silvia Sibilla, Rosa De Francesco, Vincenzo Frusciante, Antonio Varraso, Umberto Vitolo, Barbara Botto, Giusppe Milone, Salvatore Leotta, Pasquale Iacopino, Giuseppe Console, Attilio Olivieri, Michele Cimminiello, Vincenzo Mettivier, Luca Pezzullo, Donatella Baronciani, Emanuele Angelucci, Maurizio Musso, Renato Scalone, Nicola Cascavilla, Potito Rosario Scalzulli, Silvana Capalbo, Giacomo Loseto, Giovanni Quarta, Pellegrino Musto, Margherita Caputo, Angelo Ostuni
Journal: Blood (2008)
MORPHOLOGIC PATTERNS OF IN-STENT CHRONIC TOTAL OCCLUSIONS: AN INTRAVASCULAR ULTRASOUND STUDY
Authors: Dong Yin, Akiko Maehara, Gary Mintz, Raja Hatem, Lei Song, Kisaki Amemiya, Jeffrey Moses, Manish Parikh, Ajay Kirtane, Tamim Nazif, Khady Fall, Ming Liao, Tiffany Kim, Philip Green, Ziad Ali, Martin Leon, Masahiko Ochiai
Journal: Journal of the American College of Cardiology (2017)
Prospective assessment of chemotherapy-induced peripheral neuropathy (CIPN) in children with standard-risk acute lymphoblastic leukemia (SR ALL): Results of Children’s Oncology Group (COG) AALL0932.
Authors: Nina S. Kadan-Lottick, Xiaomin Lu, Marilyn Hockenberry, Moira K. Whitley, Stephen Hunger, Meenakshi Devidas, Naomi Joan Winick, Reuven J. Schore, Anne L. Angiolillo, Kirsten K. Ness
Journal: Journal of Clinical Oncology (2014)

7056 Background: Vincristine is associated with CIPN that can impair daily function. Methods: Patients 3.0-9.9 years without neurological disorders, enrolled on ALL0932 at 26 sites, were evaluated ~2 weeks post-induction (vincristine x 4 doses, dexamethasone x 28 days, and pegaspargase) by a physical/occupational therapist for peripheral neuropathy, proximal strength and fitness. Parents reported daily physical function with The Pediatric Outcomes Data Collection Instrument (PODCI). Percentages of measured impairments and limited daily function were calculated and analyzed by multivariable logistic regression. Results: The 149 (80% of eligible) subjects were 48% female, 56% white non-Hispanic (26% Hispanic, 18% other) and a mean of 5.1± 1.7 years. The table summarizes the substantial frequency of measured and reported impairments. Impaired peripheral motor function in the upper (OR=4.6; p=0.01) and lower extremities (OR=3.4; p=0.06) and younger age (OR=1.7; p=0.02) were associated with report of limited physical function. Conclusions: Our data suggest that induction therapy causes significant motor neuropathy predictive of daily physical function in young children with SR ALL. AALL0932 will assess how this neuropathy evolves throughout ALL therapy. Clinical trial information: NCT01190930. % Impaired Peripheral neuropathy Sensory Light touch Protective sensation Vibration Motor (extremity) Upper Lower 21* 11 57* 47* 27* Proximal strength Upper body Core 32* 45* Fitness 48* Upper extremity and physical function core scale (PODCI) 25* * P value from two-sided exact test < 0.001 compared to expected value of 7% for measured impairments and 13.6% for PODCI in healthy norms.
Migration Potential of Human Mesenchymal Stromal Cells Is Determined by Origin of Tissue Rather Than Their Developmental Stage
Authors: Marijke W. Maijenburg, Willy A. Noort, Marion Kleijer, Charlotte J.A. Kompier, Kees Weijer, Jaap D. van Buul, C. Ellen van der Schoot, Carlijn Voermans
Journal: Blood (2008)
Effect of Early Non-Hematologic Treatment Toxicity on Complete Remission (CR) and Time to CR in Acute Myeloid Leukemia Patients Undergoing Remission Induction Chemotherapy
Authors: Surbhi Sidana, Mayur Narkhede, Tomas Radivoyevitch, Moshe C. Ornstein, Cassandra Fincher, Amanda L. Maggiotto, Yogen Saunthararajah, Anjali S. Advani, Aaron T. Gerds, Hetty E. Carraway, Betty K. Hamilton, Matt E. Kalaycio, Jaroslaw P. Maciejewski, Mikkael A. Sekeres, Sudipto Mukherjee
Journal: Blood (2014)
IMPACT OF DIFFERENT CALCIUM LOCATIONS OF MITRAL ANNULUS AND AORTIC VALVE CUSPS ON RISK OF CONDUCTION DISTURBANCES AFTER TRANSCATHETER AORTIC VALVE IMPLANTATION
Authors: Yafim Brodov, Eli Konen, Mattia Di Segni, David Samooha, Ilya Novikov, Israel Barbash, Ehud Regev, Victor Guetta, Amit Segev, Paul Fefer, Johnathan Grossman, Fernando Chernomordik, Michael Glikson, Orly Goitein
Journal: Journal of the American College of Cardiology (2017)
DYNAMIC CHANGES OF MITRAL APPARATUS IN ACUTE MYOCARDIAL INFARCTION WITH ISCHEMIC MITRAL REGURGITATION: PROSPECTIVE 3D QUANTITATIVE ECHOCARDIOGRAPHIC STUDY
Authors: Toshiyuki Kimura, Nozomi Watanabe, Sergio Barros-Gomes, Veronique Roger, Maurice Enriquez-Sarano
Journal: Journal of the American College of Cardiology (2017)
THE LONG-TERM PROGNOSTIC VALUE OF HIGHLY SENSITIVE CARDIAC TROPONIN I IN PATIENTS WITH ACUTE PULMONARY EMBOLISM
Authors: Katherine T. Lee Chuy, Emad Hakemi, Tareq Alyousef, Geetanjali Dang, Rami Doukky, John H. Stroger
Journal: Journal of the American College of Cardiology (2017)
Prophylaxis In Congenital Factor VII Deficiency, Indications, Efficacy and Safety: Results of the STER
Authors: Mariasanta Napolitano, Muriel Giansily-Blaizot, Alberto Dolce, Jens Bierre Knudsen, Jean-Francois Schved, Guenter Auerswald, Jorgen Ingerslev, Tahir S Shamsi, Carmen Altisent, Pimlak Chararoenkwan, Lisa Michaels, Ampaiwan Chuansumrit, Giovanni di Minno, Umran Caliskan, Guglielmo Mariani
Journal: Blood (2010)
RADIOTRACER IMAGING OF ANGIOSOME FOOT PERFUSION CORRELATES WITH ANKLE-BRACHIAL INDEX AND DIFFERENTIATES CRITICAL LIMB ISCHEMIA PATIENTS FROM HEALTHY SUBJECTS
Authors: Jessica Buckley, Xenophon Papademetris, Carlos Mena-Hurtado, Peter A. Blume, Bauer Sumpio, Albert Sinusas, Mitchel Stacy
Journal: Journal of the American College of Cardiology (2017)
Effect of the anti-Warburg agent BPM 31510 on TAC therapy synergy and survival in a xenograft model of triple-negative breast cancer (TNBC).
Authors: Niven R. Narain, Anne R. Diers, Arleide Lee, Rakibou Ouro-Djobo, Michael Kiebish, Vivek Vishnudas, Joaquin Juan Jimenez, Rangaprasad Sarangarajan
Journal: Journal of Clinical Oncology (2015)

1096 Background: High glycolytic metabolism in breast cancer is known to support tumor progression and metastasis, and a unique glycolysis signature has been identified in ER- and triple-negative (TNBC) breast tumors. Here, the therapeutic effect of the anti-Warburg agent BPM 31510 (in clinical trials for solid tumors) was investigated alone and in combination with standard-of-care chemotherapy in a murine xenograft model of TNBC. Methods: Treatment cycles included TAC (5mg/kg docetaxel, 1 mg/kg doxorubicin, 35 mg/kg cyclophosphamide, 1x week) and/or BPM 31510 (75 mg/kg, IV 1x day) administered in cycles (3 weeks on, 1 week off) to MDA-MB231 tumor-bearing mice. Survival was assessed. A subset of tumors were analyzed histologically after 2 cycles of treatment. In vitro models were used to define mechanistic underpinnings. Results: BPM 31510 or chemotherapy alone improved survival; however, BPM 31510 monotherapy was associated with more than a 6 week increase in survival compared to TAC alone. BPM 31510 in combination with chemotherapy further attenuated tumor growth and enhanced survival compared to either treatment alone. Cleaved caspase 3 levels were higher in tumors from BPM 31510-treated mice, demonstrating activation of apoptosis in response to this treatment. A panel of primary, non-tumorigenic, and breast cancer cells was used to determine IC50 values for BPM 31510 in vitro. At doses comparable to circulating levels achieved in vivo, BPM 31510 exposure was selectively cytotoxic in cancer cells with the triple-negative MDA-MB231 cells demonstrating maximal sensitivity to cell death. Interestingly, although cellular proliferation rate was not predictive of anti-cancer responses to BPM 31510, a bioenergetic signature characterized by high glycolytic flux and low mitochondrial respiration was highly correlated with sensitivity to BPM 31510-induced cell death. Conclusions: These data demonstrate that BPM 31510 is effective as a single agent in breast cancer. When used in combination with chemotherapy, BPM 31510 augments survival, particularly in distinctly glycolytic TNBC, a sub-type for which prognosis is poor and few therapeutic options exist.