tbuckley/cabot-search huggingface dataset:
Abstract 542: Manipulation of Beta Adrenergic Receptor in Pressure-Overloaded Murine Hearts Mimics Adverse Cardiac Remodeling and Reverse Remodeling
Authors: Koichi Nishimura, Masanori Asakura, Yoshitaka Okuhara, Yoshiro Naito, Shinichi Hirotani, Masaharu Ishihara, Tohru Masuyama
Journal: Circulation Research (2018)

Background: Adverse cardiac remodeling (ACR) during pressure overload is a major concern in development of heart failure (HF). Cardiac reverse remodeling (CRR) normally occurs following induction of beta-receptor blockade and is linked to improved prognosis of HF. However, the detailed and regulatory mechanisms of both ACR and CRR remain to be fully elucidated. To solve these issues, a novel highly reproducible model that mimics these pathophysiological conditions is needed. Methods and results: We explored suitable experimental conditions for establishing a highly reproducible model that mimics adverse cardiac remodeling. To examine suitable durations of transverse aortic constriction (TAC) before one-week infusion of ISO (3mg/kg/day), mice were distributed into three groups according to TAC durations. Proportion of adverse cardiac remodeling was 44.4% (4 of 9) in one-week, 60.0% (6 of 10) in two-week, and 91.7% (11 of 12) in three-week TAC groups. Next we examined adequate dose of ISO infusion after three weeks of TAC. Proportion of adverse cardiac remodeling was 37.5% (3 of 8) in 1mg/kg/day, 83.3% (5 of 6) in 3mg/kg/day, and 100% (8 of 8) in 10mg/kg/day group. But infusion of 10mg/kg/day ISO caused an increase in systolic BP. Thus we identified 3-week TAC and subsequent one-week ISO (3mg/kg/day) infusion as a suitable model for ACR. To identify molecular signatures of failing hearts of our ACR model, we performed RNA-Seq analyses. We found the up-regulated genes were mainly related to fibrosis including Fbn1 , C1qtnf6 and Loxl2 and the down-regulated genes associated with mitochondrial functions including, Uqcrc1 , Ndufs3 , and Idh2 . Next, we followed the changes in cardiac function after ceasing ISO to investigate CRR. Decreased LVFS gradually recovered to baseline within 7 weeks after cessation of ISO and exhibited CRR. Gene expression signature of CRR hearts was almost identical to that of TAC hearts without ISO infusion. Conclusions: Our model exhibits a transition to adverse cardiac remodeling and subsequent reverse remodeling with high reproducibility. This novel mouse model might add new insights into these cardiac remodeling.
ISOLATED DIASTOLIC HYPERTENSION IN THE ATHEROSCLEROSIS RISK IN COMMUNITIES (ARIC) STUDY: CHANGING DEFINITIONS AND IMPLICATIONS FOR CARDIOVASCULAR HEALTH
Authors: John W. McEvoy, Natalie Daya, Faisal Rahman, Ron Hoogeveen, Roger Blumenthal, Amil Shah, Christie Ballantyne, Josef Coresh, Elizabeth Selvin
Journal: Journal of the American College of Cardiology (2019)
LEFT ATRIAL APPENDAGE CLOSURE IN PATIENTS WITH CONTRAINDICATIONS TO ORAL ANTICOAGULATION THERAPY: A SYSTEMATIC REVIEW AND POOLED META-ANALYSIS
Authors: Tawseef Dar, Fnu Sibghat Tul Llah, Bharath Yarlagadda, Shady Abohashem, Tarun Dahlia, Mohmad Tantary, Dhanunjaya Lakkireddy, Tariq Bhat
Journal: Journal of the American College of Cardiology (2019)
INCIDENCE, TIMING, AND PREDICTOR OF SUBCLINICAL MYOCARDIAL DAMAGE AFTER LOW-TO-MODERATE DOSE OF ANTHRACYCLINE CHEMOTHERAPY IN PATIENTS WITH BREAST CANCER
Authors: Kenji Nakatsuma, Neiko Ozasa, Mikiko Ohono, Hiroshi Ishiguro, Manabu Minami, Takafumi Yokomatsu, Eiichiro Nishi, Masakazu Toi, Takeshi Kimura
Journal: Journal of the American College of Cardiology (2019)
HEPATOKINE A1-MICROGLOBULIN SIGNALING ALTERS MACROPHAGE POLARIZATION, EXACERBATES ACUTE INFLAMMATION AND ADVERSE LEFT VENTRICULAR REMODELING IN MYOCARDIAL INFARCTION
Authors: Daihiko Hakuno, Masahiro Kimura, Yasuhiro Nakashima, Takahiro Horie, Yasuhide Kuwabara, Masataka Nishiga, Yuya Ide, Takeshi Kimura, Koh Ono
Journal: Journal of the American College of Cardiology (2019)
CHANGE IN MITRAL REGURGITATION AFTER HIS-BUNDLE PACING FOR CARDIAC RESYNCHRONIZATION
Authors: Jonathan Lattell, Davide Genovese, Parth V. Desai, Andrew Beaser, Zaid Aziz, Hemal M. Nayak, Roderick Tung, Roberto M. Lang, Gaurav A. Upadhyay
Journal: Journal of the American College of Cardiology (2019)
Erratum to: Single cell analysis of CD4+ T cell differentiation reveals three major cell states and progressive acceleration of proliferation
Authors: Valentina Proserpio, Andrea Piccolo, Liora Haim-Vilmovsky, Gozde Kar, Tapio Lönnberg, Valentine Svensson, Jhuma Pramanik, Kedar Nath Natarajan, Weichao Zhai, Xiuwei Zhang, Giacomo Donati, Melis Kayikci, Jurij Kotar, Andrew N. J. McKenzie, Ruddy Montandon, Kylie R. James, Daniel Fernandez-Ruiz, William R. Heath, Ashraful Haque, Oliver Billker, Steven Woodhouse, Pietro Cicuta, Mario Nicodemi, Sarah A. Teichmann
Journal: Genome biology (2016)
VALIDATION OF A NOVEL BIOMARKER-CLINICAL SCORE TO PREDICT THE PRESENCE OF OBSTRUCTIVE CORONARY DISEASE
Authors: Emmanuel Ekanem, Palak Shah, Federica Latta, Grady Barnes, Elizabeth Adams, Craig A. Magaret, Celine Peters, Rhonda F. Rhyne, Christopher DeFilippi
Journal: Journal of the American College of Cardiology (2019)
LONG-TERM OUTCOMES IN ASYMPTOMATIC PATIENTS UNDERGOING PERCUTANEOUS CORONARY INTERVENTIONS FOR STABLE CORONARY ARTERY DISEASE: ANALYSIS FROM A LARGE POOLED RANDOMIZED TRIAL DATASET
Authors: Eisuke Usui, Akiko Maehara, Zixuan Zhang, Pieter Smits, Clemens von Birgelen, Martin Leon, Patrick Serruys, Gary Mintz, Gregg Stone
Journal: Journal of the American College of Cardiology (2019)
TICAGRELOR IMPROVES BLOOD VISCOSITY-DEPENDENT MICROCIRCULATORY FLOW IN PATIENTS WITH LOWER EXTREMITY ARTERIAL DISEASE: PRIMARY RESULTS OF THE HEMA-KINESIS TRIAL
Authors: Robert S. Rosenson, Sherwin D. Najera, Qinzhong Chen, Prakash Krishnan, Martin L. Lee
Journal: Journal of the American College of Cardiology (2019)
VARIATION IN EMERGENCY DEPARTMENT PROVIDER ORDERING, TIME TO DISCHARGE, AND OUTCOMES IN ANATOMIC VERSUS FUNCTIONAL STRESS TESTING FOR RISK STRATIFICATION OF PATIENTS PRESENTING WITH CHEST DISCOMFORT
Authors: Ruth Tamrat, Senthil Selvaraj, Sheela Krishnan, Shan Davis, Ashwin Murthy, Dipika Gopal, Mahesh Vidula, Vivek Kulkarni, David Lambert, Paco Bravo, Daniel Kolansky, Dinesh Jagasia, Victor Ferrari, Frank Silvestry, Srinath Adusumalli
Journal: Journal of the American College of Cardiology (2019)
Impact of Epithelial–Stromal Interactions on Peritumoral Fibroblasts in Ductal Carcinoma in Situ
Authors: Carina Strell, Janna Paulsson, Shao-Bo Jin, Nicholas P Tobin, Artur Mezheyeuski, Pernilla Roswall, Ceren Mutgan, Nicholas Mitsios, Hemming Johansson, Sarah Marie Wickberg, Jessica Svedlund, Mats Nilsson, Per Hall, Jan Mulder, Derek C Radisky, Kristian Pietras, Jonas Bergh, Urban Lendahl, Fredrik Wärnberg, Arne Östman
Journal: JNCI Journal of the National Cancer Institute (2018)

Abstract Background A better definition of biomarkers and biological processes related to local recurrence and disease progression is highly warranted for ductal breast carcinoma in situ (DCIS). Stromal–epithelial interactions are likely of major importance for the biological, clinical, and pathological distinctions between high- and low-risk DCIS cases. Methods Stromal platelet derived growth factor receptor (PDGFR) was immunohistochemically assessed in two DCIS patient cohorts (n = 458 and n = 80). Cox proportional hazards models were used to calculate the hazard ratios of recurrence. The molecular mechanisms regulating stromal PDGFR expression were investigated in experimental in vitro co-culture systems of DCIS cells and fibroblasts and analyzed using immunoblot and quantitative real-time PCR. Knock-out of JAG1 in DCIS cells and NOTCH2 in fibroblasts was obtained through CRISPR/Cas9. Experimental data were validated by mammary fat pad injection of DCIS and DCIS-JAG1 knock-out cells (10 mice per group). All statistical tests were two-sided. Results PDGFRα(low)/PDGFRβ(high) fibroblasts were associated with increased risk for recurrence in DCIS (univariate hazard ratio = 1.59, 95% confidence interval [CI] = 1.02 to 2.46; P = .04 Wald test; multivariable hazard ratio = 1.78, 95% CI = 1.07 to 2.97; P = .03). Tissue culture and mouse model studies indicated that this fibroblast phenotype is induced by DCIS cells in a cell contact-dependent manner. Epithelial Jagged1 and fibroblast Notch2 were identified through loss-of-function studies as key juxtacrine signaling components driving the formation of the poor prognosis-associated fibroblast phenotype. Conclusions A PDGFRα(low)/PDGFRβ(high) fibroblast subset was identified as a marker for high-risk DCIS. The Jagged-1/Notch2/PDGFR stroma–epithelial pathway was described as a novel signaling mechanism regulating this poor prognosis-associated fibroblast subset. In general terms, the study highlights epithelial–stromal crosstalk in DCIS and contributes to ongoing efforts to define clinically relevant fibroblast subsets and their etiology.
Abstract 208: miR-34a Regulates the Secretome Production and Functional Potential of Human Cardiac Progenitor Cells by Heat Shock Factor
Authors: Rachana Mishra, Sudhish Sharma, Wen C Cheng, Progyaparamita Saha, Tami J Kingsbury, Curt I Civin, Sunjay Kaushal
Journal: Circulation Research (2018)

Background: We have identified that chronological aging affects the myocardial function and attenuation of LV remodeling potential of Human cardiac progenitor cells (CPCs). miR-34a expression is increased in adult hearts and promotes age-associated cell death. We studied the effect of miR-34a on the cellular properties and functional potential of cardiac progenitor cells (CPCs). Hypothesis: We hypothesize that modulation of miR-34a in CPCs can rejuvenate them and enhance their functional potential by controlling their secretome and exosome cargo through heat shock pathway. Methods: Human specimens were obtained during routine cardiac surgical procedures from right atrial appendage tissue discarded from neonates (&lt;1 month) and adults (&gt;40 years) patients and c-kit + Cardiac progenitor cells (CPCs) were generated. Results: Here we are reporting a novel finding that knock down (KD) of miR-34a in adult-derived CPCs (aCPCs) significantly increases their cell survival, cytokine secretion by directly binding to the PDGFB, HGF1, SCF, IGF1 and FGF and affect the exosome number and their cargo via heat shock factor. The transplantation of miR34a-KD-aCPCs in myocardial infarcted (MI) rodent model significantly improved left ventricle function as analyzed by echocardiography and reduced fibrosis in comparison to the transplantation of aCPCs. Previously, we have showed that heat shock factor 1 (HSF1) is the key chaperone pathway that affects CPC’s growth potential and functional activity. Here we are showing that up-regulation of miR-34a in CPCs are attributed towards down regulation of HSF1 and their exosome secretion. Conclusion: CPCs improve myocardial function by their secretome, which is directly and indirectly (HSF1) controlled by miR-34a during chronological aging .
A COMPARISON OF FEASIBILITY AND SAFETY USING TRANSRADIAL VERSUS DISTAL TRANSRADIAL APPROACH IN PATIENTS UNDERGOING CORONARY ANGIOGRAPHY AND PERCUTANEOUS CORONARY INTERVENTION
Authors: Shinsuke Mori, Yoshiaki Ito, Toshihiko Kishida, Tomoya Fukagawa, Shigemitsu Shirai, Kenji Makino, Yohsuke Honda, Masakazu Tsutsumi, Yasunari Sakamoto, Norihiro Kobayashi, Motoharu Araki, Masahiro Yamawaki, Keisuke Hirano
Journal: Journal of the American College of Cardiology (2019)
Abstract 539: MCUB Regulates the Macromolecular Composition of the Mitochondrial Calcium Uniporter Channel to Limit Mitochondrial Calcium Overload During Ischemic Cardiac Injury
Authors: Jonathan P Lambert, Timothy S Luongo, Pooja Jadiya, Erhe Gao, Anna M Lucchesee, Xueqian Zhang, Devin W Kolmetzky, Neil Shah, John W Elrod
Journal: Circulation Research (2018)

The mitochondrial calcium uniporter channel (mtCU) resides in the inner mitochondrial membrane and is a multi-subunit complex required for mitochondrial Ca 2+ ( m Ca 2+ ) uptake. RNA-seq and PCR analysis of mtCU component expression revealed that MCUB expression increases after myocardial infarction. To investigate how MCUB , a paralog of the MCU gene, contributes to mtCU regulation we created a MCUB -/- cell line (HeLa) using CRISPR-Cas9n. MCUB deletion increased histamine-mediated m [Ca 2+ ] transient amplitude by ~50% vs. WT controls (mito-R-GECO). Biophysical characterization found MCUB deletion increased mtCU capacitance and rate of m [Ca 2+ ] uptake. FPLC fractionation of mtCU revealed loss of MCUB increased MCU incorporation into the supercomplex, suggesting MCUB replacement of MCU and overall increase in functional mtCU supercomplexes. Next, we generated a cardiac-specific, tamoxifen-inducible MCUB overexpression mouse model (CAG-CAT-MCUB x MCM; MCUB-Tg) to examine how the MCUB/MCU ratio regulates mtCU function and cardiac physiology. MCUB-Tg mice were infected with AAV9-mitycam (mito genetic calcium reporter) and adult cardiomyocytes were isolated to record [ m Ca 2+ ] transients during pacing. Increasing the MCUB/MCU ratio decreased [ m Ca 2+ ] peak amplitude by ~30% and significantly reduced the [ m Ca 2+ ] uptake rate. FPLC assessment of the mtCU revealed MCUB was undetectable in the supercomplex fraction (~700kD) of Cre controls, but enriched in MCUB -Tg hearts. Examining the oxygen consumption rate of cardiomyocytes isolated from MCUB- Tg hearts found decreased maximal respiration and spare reserve capacity, which correlated with severe impairment in isoproterenol-induced contractile reserve. Mitochondria from MCUB -Tg mouse hearts were resistant to Ca 2+ induced mitochondrial swelling suggesting MCUB protects against permeability transition. MCUB -Tg mice subjected to myocardial ischemia reperfusion injury had a ~50% decrease in infarct size suggesting increased MCUB expression prevents m Ca 2+ overload and limits cell death. These data suggest that MCUB regulation of the mtCU is an endogenous compensatory mechanism to decrease m Ca 2+ overload during ischemic injury, but maladaptive in mitochondrial energetic responsiveness.
IS OBSTRUCTIVE SLEEP APNEA ASSOCIATED WITH SUB-CLINICAL CAROTID ATHEROSCLEROSIS IN THE ABSENCE OF TRADITIONAL RISK FACTORS? A META-ANALYSIS OF 2053 PATIENTS
Authors: Kleanthis Theodoropoulos, Yuri Malyshev, Umer Javed Suleman, Haroon Kamran, Ioannis Starakis, George Hahalis, George D. Dangas, Konstantinos Spiropoulos, Louis Salciccioli
Journal: Journal of the American College of Cardiology (2019)
OPTIMAL MEDICAL THERAPY USE AND LONG-TERM OUTCOMES IN CABG-ELIGIBLE HEART FAILURE PATIENTS: INSIGHTS FROM THE STICH TRIAL
Authors: Pedro Silvio Farsky, Jennifer White, Carla Sueta, Rafal Dabrowski, Ljubomir Djokovic, Mark Drazner, Haissam Haddad, Imtiaz Ali, Matyas Keltai, Ajay Naik, George Sopko, Krzysztof Golba, Bert Andersson, Peter Carson, Tomasz Kukulski, Hussein Al-Khalidi, Jean Rouleau, Eric Velazquez
Journal: Journal of the American College of Cardiology (2019)
Abstract 373: The Molecular Consequence of a Polymorphic 25bp Deletion in Intron 32 of <i>MYBPC3,</i> Specific to South Asians
Authors: Jennifer A Schwanekamp, Shiv K Viswanathan, Parth N Patel, Sangeetha Kandoi, Ratan Bhat, Rama S Verma, Christine E Seidman, Jonathan G Seidman, Winston Shim, Ralph Knöll, Sakthivel Sadayappan
Journal: Circulation Research (2018)

Background: MYBPC3 encodes cardiac myosin binding protein-C, which regulates sarcomeric stability and contractility. Previous work described a prevalent 25bp deletion in intron 32, MYBPC3 Δ 25bp , in the South Asian population. Occurring in an estimated 100 million carriers, this variant may be associated with cardiomyopathy and heart failure. MYBPC3 Δ25bp encompasses a splicing branch point that could affect splicing of exon 32 to exon 33, potentially resulting in an aberrantly spliced MYBPC3 transcript where exon 33 is skipped entirely. However, the mechanism by which MYBPC3 Δ 25bp associates with disease remains unclear. Methods: To determine the consequence of the 25bp deletion in vivo , mice were engineered that replaced the endogenous Mybpc3 intron 32 with either the normal human intron 32 or human intron 32 containing the 25bp deletion ( Mybpc3 Δ 25bp ) . We characterized Mybpc3 splicing in mice carrying human intron-32 and human iPSC derived cardiomyocytes (hiPSC-CM) from patients heterozygous and homozygous for MYBPC3 Δ 25bp by RT-PCR and using mini-gene assays (across 5 different mouse and human gene segments encompassing exon 32 through exon 34). Results: Echocardiography of mice 3 months of age revealed no changes in cardiac function by fractional shortening (WT: 32.8%, Het: 34.2%, Homo: 36.7%). However, homozygous Mybpc3 Δ 25bp mice had significantly smaller hearts compared to heterozygous and wildtype (3.4 vs 3.71 and 4.25 mg/g p=0.001). Mybpc3 Δ 25bp heterozygous and homozygous mice displayed minimal alternative splicing in exon 33 at baseline. Similarly, transcripts from hiPSC-CM from heterozygous and homozygous MYBPC3 Δ 25bp carriers also show minimal alternative splicing. Mini gene assays suggest that the 25bp deletion does reduce the proportion (77.5% v. 86.2%) of normally spliced transcripts. Conclusions: Taken together, these data suggest that under baseline conditions, MYBPC3 Δ 25bp results in minimal alternative splicing in both human iPSC-CMs and humanized mice harboring the 25bp deletion. While increase aberrant splicing may increase risk of hypertrophic cardiomyopathy in variant-carrying individuals, ongoing studies will determine whether other factors or gene mutations modulate the pathogenicity of the MYBPC3 Δ25bp variant.
MECHANICALLY EXPANDABLE VERSUS SELF EXPANDABLE VALVES IN TRANSCATHETER AORTIC VALVE REPLACEMENT: A META-ANALYSIS OF RANDOMIZED CONTROLLED AND PROPENSITY MATCHED STUDIES
Authors: Karan Wats, Robert Frankel, Adnan Sadiq, Jacob Shani, Moustafa Elsheshtawy
Journal: Journal of the American College of Cardiology (2019)
SCREENING ECHOCARDIOGRAPHY WITH REMOTE READING BY TELEMEDICINE AS A PRIORITIZATION TOOL IN PRIMARY CARE: DATA FROM THE PROVAR+ STUDY
Authors: Bruno Ramos Nascimento, Andrea Beaton, Maria do Carmo Nunes, Kaciane K.B. Oliveira, Lara C. Rabelo, Adriana Diamantino, Susana D.P. Reis, Breno D.F. Rezende, João Pedro P. Rios, Allison R. Tompsett, Waydder Antônio A. Costa, Mariana D.O. Mata, Augusto F.C. Pereira, Isabella M. Teixeira, Antonio Ribeiro, Craig Sable
Journal: Journal of the American College of Cardiology (2019)
RESOURCE UTILIZATION IN RISK STRATIFICATION OF PATIENTS PRESENTING TO THE EMERGENCY DEPARTMENT WITH CHEST DISCOMFORT
Authors: Ruth Tamrat, Sheela Krishnan, Senthil Selvaraj, Shan Davis, Ashwin Murthy, Dipika Gopal, Mahesh Vidula, Vivek Kulkarni, David Lambert, Paco Bravo, Daniel Kolansky, Dinesh Jagasia, Victor Ferrari, Frank Silvestry, Srinath Adusumalli
Journal: Journal of the American College of Cardiology (2019)
Abstract 19402: A Novel Mode of Mitochondrial Transplantation: Intracoronary Delivery of Autologous Mitochondria Provides Prolonged Increase in Coronary Blood Flow
Authors: Borami Shin, Mossab Saeed, Jesse Esch, Kamilla Moskowitzova, Giovanna Ramirez Barbieri, Douglas B Cowan, Jerusha K Thedsanamoorthy, Rouan Yao, Ingeborg Friehs, Alan Packard, James Inkster, Erin Snay, Leah Oberg, Pedro J del Nido, James D McCully
Journal: Circulation (2017)

Introduction: Autologous mitochondrial transplantation by direct injection has shown to be cardioprotective in ischemic injury. Herein, we investigate a novel mode of mitochondrial transplantation ...
INCREASING TRENDS OF CARDIOVASCULAR DISEASES IN PATIENTS LIVING WITH CHRONIC MALIGNANCIES: A 16 YEARS TREND ANALYSIS OF RATES OF CORONARY ARTERY DISEASE AND ARRHYTHMIAS IN PATIENTS WITH CHRONIC MYELOID LEUKEMIA
Authors: Odunayo Olorunfemi, Manasi Godbole, Saad Jamshed, Ayman Elbadawi, Ha Le Dung, Gbolahan Ogunbayo, Rebecca Ojo, Olatunde Ola, Atanda Adebayo, Oladimeji Akinboro, Carlos Alfonso, Jeffery Goldberger
Journal: Journal of the American College of Cardiology (2019)
SUSTAINED MEAN AORTIC PRESSURE GRADIENT REDUCTION THREE YEARS AFTER TRANSCATHETER AORTIC VALVE REPLACEMENTS: RESULTS FROM THE MARSHFIELD AORTIC VALVE EXPERIENCE PILOT SUBSTUDY
Authors: Peter Umukoro, Paul Yeung-Lai-Wah, Sunil Pathak, Sabri Elkhidir, Brooke Delgoffe, Richard Berg, Kelley Anderson, Romel Garcia-Montilla
Journal: Journal of the American College of Cardiology (2019)
NATIONAL TRENDS AND OUTCOMES OF PERIPHERAL VASCULAR INTERVENTION IN DIALYSIS PATIENTS WITH CRITICAL LIMB ISCHEMIA
Authors: Homam Moussa Pacha, Yasser Al-Khadra, Fahed Darmoch, Mohamad Soud, Amir Kaki, M. Chadi Alraies
Journal: Journal of the American College of Cardiology (2019)
HEMODYNAMIC AND CLINICAL CONSEQUENCES OF EARLY VERSUS DELAYED CLOSURE OF PATENT DUCTUS ARTERIOSUS IN EXTREMELY LOW BIRTH WEIGHT INFANTS
Authors: Ranjit Philip, Benjamin Waller, Ken-Michael Bayle, Nathan Stecchi, Kristen Washington, Brittany Graham, Shyam Sathanandam
Journal: Journal of the American College of Cardiology (2019)
Abstract PD4-12: Use of 64Cu-DOTA-trastuzumab positron emission tomography (PET) to predict response to ado-trastuzumab emtansine (TDM1)
Authors: JE Mortimer, JR Bading, P Frankel, L Tumyan, TT Tran, RC Rockne, JE Shively, N Gidwaney, J Park, DM Colcher
Journal: Cancer Research (2019)

Abstract Background: We have demonstrated that 64Cu-DOTA trastuzumab is an effective PET imaging agent for HER2 positive breast cancer and are now seeking to evaluate the methodology for prediction of response and benefit to ado-trastuzumab emtansine (TDM1) in women with metastatic disease. Methods: Patients with metastatic breast cancer were eligible if they had biopsy confirmed HER2 + disease, at least 1 site of metastasis 2.0 cm or larger outside the biopsy site, and were to receive TDM1 as therapy. Pretreatment staging included 18F-FDG/PET. Prior to injection of 64Cu-DOTA-trastuzumab, patients received 45 mg of cold trastuzumab to reduce liver uptake. PET-CT scans were obtained at 21-25 h and 47-48 h over fields of view chosen in reference to 18F-FDG scans. TDM1 was administered at a dose of 3.6 mg/kg every 3 weeks. Restaging 18F-FDG/PET was performed every 2 cycles, and response to therapy was determined by PERCIST criteria. The radiolabel uptake was measured in terms of maximum voxel standardized uptake value (SUVmax). Results: Ten women enrolled on study and are evaluable for response; three continue on TDM1 for 22-40 months and four patients remained on treatment for at least 1 year. The median age was 54.5 years (48-83 years); seven received prior trastuzumab-containing chemotherapy 3 wks to 55 months prior to study entry. HER2 was positive by IHC in 5 and by FISH in 5 (3 were 2+ by IHC; 1 was 1+ and 1 indeterminate). Complete or partial metabolic response was observed in 5 patients. Patients had their average SUVmax on 64Cu-DOTA trastuzumab PET (aSUVmax) assessed in addition to individual assessments on up to 8 lesions on both Day1 and Day2. The mean aSUVmax was (6.3, 8.8) for responding patients and (4.4, 5.2) for non-responder (day1, day2). The difference between responders and non-responders on Day1 aSUVmax was marginally significant (p=0.06), but significant on Day2 (p=0.04). The three highest aSUVmax on both day1 and day2 were three of the four patients with PFS&amp;gt;1 year. Data on the relationship of 64Cu-DOTA trastuzumab PET to IHC and FISH, and individual lesion SUVmax including evidence suggesting a potential threshold effect will be presented. Conclusions: In women with biopsy confirmed HER2 positive metastatic disease, 64Cu-DOTA-trastuzumab PET imaging is predictive for response to TDM1. Citation Format: Mortimer JE, Bading JR, Frankel P, Tumyan L, Tran TT, Rockne RC, Shively JE, Gidwaney N, Park J, Colcher DM. Use of 64Cu-DOTA-trastuzumab positron emission tomography (PET) to predict response to ado-trastuzumab emtansine (TDM1) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD4-12.