tbuckley/cabot-search huggingface dataset:
Abstract 12670: Variability in Radiation Dose and Image Quality: A Comparison Across Fluoroscopy-system Vendors and Generations of Equipment
Authors: Kevin D Hill, Michael P Carboni, Thomas P Doyle, Salim Idriss, Dana Janssen, George Nicholson, Shyam Sathanandam, Steve Mann, Gregory Fleming
Journal: Circulation (2016)

Increased recognition of the potentially harmful effects of ionizing radiation has spurred technological advances to reduce exposure during fluoroscopy. However there is currently little understanding of the dose-image quality (IQ) relationship between fluoroscopy vendors and across generations of equipment used for imaging during pediatric catheterization.We evaluated latest generation fluoroscopy systems from Phillips, Siemens, GE and Toshiba, and an older generation Phillips system (2004 release). Fluoroscopy and cineangiography were performed on a tissue simulation anthropomorphic phantom using a standardized imaging approach. Phantom surface exposures were used for Monte Carlo simulations to calculate radiation effective dose, accounting for differences in beam parameters. We also imaged a fluoroscopy IQ phantom to assess contrast-detail and line-per-inch visualization. IQ images were scored by 3 blinded reviewers with scores averaged to produce a composite rating (scale 0-18). To assess the impact of imaging approach we then simulated a neonatal cardiac catheterization incorporating "typical" imaging protocols provided by institutions using the various systems.Effective doses and IQ scores are summarized in the table. Effective doses varied by >400% with the older generation system consistently delivering markedly higher doses. The associated figure summarizes dose and IQ for a simulated neonatal cardiac catheterization which accounts for measured doses as well as the reported institutional imaging parameters summarized in the figure legend.These data demonstrate substantial technological improvements in fluoroscopy equipment and may be useful to justify institutional "upgrades". Comparing latest generation systems across vendors and institutions, we found variability in the dose-IQ relationship that reflects both equipment and imaging approach.
Abstract 90: Modulation of Cardiac Fibroblast to Myofibroblast Transition by Rho-associated Kinases ROCK1 and ROCK2
Authors: Svenja Hartmann, Aline Jatho, Malte Tiburcy, Wolfram H Zimmermann, Anne J Ridley, Susanne Lutz
Journal: Circulation Research (2016)

Background: Rho-associated kinases ROCK1 and ROCK2 play a critical role in the pathogenesis of myocardial fibrosis; however, their specific function in cardiac fibroblasts (CF) remains unclear. Remodelling processes in diseased hearts propels the transition of CF to a myofibroblast phenotype exemplified by increased proliferation, migration and synthesis of extracellular matrix (ECM) proteins. Therefore, we sought to investigate whether ROCK1/2 have an impact on CF characteristics in isolated cells and engineered cardiac tissue. Methods: Neonatal wild type (WT) rat CF and cardiomyocytes (CM) were isolated and lentivirally transduced/transfected resulting in downregulation of ROCK1 and ROCK2 by 75%. In addition, WT CF were treated with 10 μM Fasudil or 3 μM H1152P for non-specific ROCK1/2 inhibition. CF gene and protein expression, morphology, proliferation, and migration were assessed. Subsequently, CF and CM were mixed within a hydrogel to engineer heart constructs with assessments of contractile function/rigidity performed by isometric force and rheological measurements, respectively. Results: Knockdown of ROCK1 and ROCK2 and inhibition of ROCK1/2 activity altered CF morphology, disrupted cytoskeletal structures, and increased adhesion velocity. Moreover, decreased migration velocity and distance was detected, and the double knockdown and inhibition of ROCK1/2 attenuated proliferation of CF. In contraction measurements, engineered heart muscle (EHM) treated with ROCK inhibitors developed a significantly higher force of contraction per cross sectional area than control EHM. Destructive tensile strength measurement of engineered connective tissue (ECT) treated with ROCK inhibitors showed that rigidity was significantly reduced compared to control, suggesting that ROCK1/2 influence the regulation and turnover of the ECM and thus viscoelastic properties of engineered tissues. Indeed, RNA sequencing of ROCK inhibitor treated ECT showed that ROCK1/2 are involved in the regulation of ECM proteins, such as collagens, biglycan, decorin, elastin and its degrading enzyme MMP12. Conclusion: This study demonstrates that ROCK signalling controls myofibroblast characteristics of CF via remodelling of the cytoskeleton and the ECM.
Abstract 352: Dual Specificity Phosphatase 8 (dusp8) Regulates Cardiac Remodeling and Function by Affecting Erk1/2 Phosphorylation
Authors: Ruijie Liu, Jeffery Molkentin
Journal: Circulation Research (2015)

Rationale: Mitogen-activated protein kinases (MAPKs) are activated in the heart by various stress-inducing stimuli, where they participate in cardiac hypertrophy, contractility, and cell death. A family of dual-specificity phosphatases (DUSPs) directly inactivates each of the MAPK terminal effectors, thus providing a feedback mechanism to regulate the activity and recycling of MAPKs. How DUSPs regulate MAPK signaling to influence cardiac function is not well understood. Objective: To determine the role of DUSP8 in regulating MAPK signaling and the effect on cardiac disease. Methods and Results: We generated DUSP8 null (KO) and inducible cardiac specific DUSP8 transgenic mice to assess the effect on cardiac structure-function at baseline and with stress-responsiveness. Loss of DUSP8 did not alter cardiac structure-function or MAPK phosphorylation at baseline. However, with pressure overload or myocardial infarction injury, DUSP8 KO mice developed concentric hypertrophy with preserved cardiac function compared to wild type controls, suggesting a cardioprotective role for loss of DUSP8. DUSP8 transgenic mice developed cardiac hypertrophy at baseline as evidenced by elevated expression of hypertrophic marker genes as well as increased heart weights and cross sectional area of the myocytes. DUSP8 transgenic mice also had mild interstitial fibrosis and reduced fractional shortening. Biochemical analysis of MAPK phosphorylation demonstrated increased ERK phosphorylation in KO mice upon stress, suggesting a molecular mechanism underlying the increased concentric growth of DUSP8 KO cardiomyocytes. Conclusions: Taken together, these data demonstrate that DUSP8 modulates ERK phosphorylation to influence cardiomyocyte growth and consequent cardiac function with injury. Further analysis of MAPK phosphorylation in DUSP8 transgenic mice will provide more insight into DUSP8-ERK signaling in the heart.
The MITO8 phase III international multicenter randomized study testing the effect on survival of prolonging platinum-free interval (PFI) in patients with ovarian cancer (OC) recurring between 6 and 12 months after previous platinum-based chemotherapy: A collaboration of MITO, MANGO, AGO, BGOG, ENGOT, and GCIG.
Authors: Sandro Pignata, Giovanni Scambia, Francesco Raspagliesi, Viviana Murgia, Carmela Pisano, Vanda Salutari, Alessandra Bologna, Roberto Sorio, Gabriella Ferrandina, Cosimo Sacco, Ignace Vergote, Gennaro Cormio, Enrico Breda, Saverio Cinieri, Sabrina Chiara Cecere, Uwe A. G. Wagner, Gennaro Daniele, Ciro Gallo, Francesco Perrone, Maria Carmela Piccirillo
Journal: Journal of Clinical Oncology (2016)

5505 Background: A longer PFI is associated with better outcomes in patients with OC. It has long been hypothesized that artificially prolonging PFI by introducing a non-platinum based chemo (NPBC) might improve the sensitivity to following platinum. Methods: OC patients, ≤2 previous chemo, recurring/progressing 6-12 months after previous platinum-based chemo (PBC), ECOG PS ≤2, residual peripheral neuropathy ≤2, were randomized to receive experimental NPBC (pegylated liposomal doxorubicin or topotecan or gemcitabine, standard dose and timing) followed at progression by PBC (carboplatin/paclitaxel or carboplatin/gemcitabine if residual neurotoxicity, standard dose and timing) or the reverse standard treatment sequence. Primary endpoint: overall survival (OS). With 80% power in detecting a HR of 0.67, 0.05 two-tailed α, 193 events were required for primary analysis and 250 patients were planned. Analyses are based on intention to treat. Results: The trial was stopped prematurely due to slow recruitment with 215 patients randomized to the experimental (n=107) and standard arm (n=108). Final analysis was anticipated in agreement with the IDMC and was performed with 141 deaths and 177 events for progression free survival after second treatment from randomization (PFS2). Median age was 62; 94% of patients had received one previous line of chemotherapy; median platinum free interval before randomization was 8 months. Median follow-up was 38 months. In the experimental arm, median time from randomization to beginning of PBC was 7.8 months (IQ range: 3.7-13.3). In the experimental vs standard arm, median OS was 21.8 vs 24.5 months (HR 1.38, 95% CI: 0.99-1.94, p=0.06); median PFS2 was 12.8 vs 16.4 months (HR 1.41, 95% CI: 1.04-1.92, p=0.025). No toxic death or unexpected toxicity was reported. Conclusion: The MITO8 trial shows that prolonging PFI by introducing a NPBC does not improve and even worsens efficacy outcomes in patients with partially platinum sensitive recurrent OC. ClinicalTrials.gov NCT00657878.
Phase I/II study of pembrolizumab (pembro) plus ipilimumab (ipi) as second-line therapy for NSCLC: KEYNOTE-021 cohorts D and H.
Authors: Matthew A. Gubens, Lecia V. Sequist, James Stevenson, Steven Francis Powell, Liza Cosca Villaruz, Shirish M. Gadgeel, Corey J. Langer, Amita Patnaik, Hossein Borghaei, Shadia Ibrahim Jalal, Joseph Fiore, Joy Yang Ge, Harry Raftopoulos, Leena Gandhi
Journal: Journal of Clinical Oncology (2016)

9027 Background: The checkpoint inhibitor combination pembro (anti–PD-1) + ipi (anti–CTLA-4) yielded promising antitumor activity and manageable toxicity in previously treated NSCLC patients (pts) in a dose-finding cohort of KEYNOTE-021 (NCT02039674). We present data on additional pts enrolled in the pembro + ipi dose-finding (D) and expansion cohorts (H). Methods: Pts had advanced NSCLC and≥1 prior regimen. In cohort D, the first 6 pts received pembro + ipi at 1 of 3 doses every 3 wk (×4 cycles), followed by maintenance pembro. Based on emerging ipi toxicity data from other studies, ipi and pembro doses were reduced from 3 to 1 mg/kg and from 10 to 2 mg/kg, respectively. These lower doses were also used in cohort H. Response was assessed every 6 wk (RECIST v1.1, central imaging vendor review). AEs were graded by NCI CTCAE v4.0. Cohorts D and H were combined for efficacy analyses. Results: As of Dec 16, 2015, 45 pts received pembro 2 mg/kg + ipi 1 mg/kg; 6 additional pts in cohort D received the higher doses (presented previously). Median follow-up duration was 7 mo (range, 0.1-17). Treatment-related AEs were reported in 30 (67%) pts; 11 (24%) experienced gr 3-5 treatment-related AEs, most commonly diarrhea (2 pts). 4 (9%) pts discontinued treatment because of treatment-related AEs (all pembro + ipi). 1 treatment-related death (pancreatitis) was reported. ORR was 24% (2 CR, 9 PR); 18 (40%) pts had SD, and 8 (18%) had PD. 5 pts progressed prior to first radiologic response assessment. Median DOR was 14 mo. Median PFS/OS were 6 and 17 mo, respectively. There was no link between PD-L1 status and outcome (Table). Conclusions: With median follow-up of 7 mo, the combination of pembro + ipi in previously treated advanced NSCLC demonstrated a significant toxicity profile and an ORR similar to that of pembro alone. Longer follow-up may help define whether there are true differences in outcome between different PD-L1 subsets that merit further exploration. Clinical trial information: NCT02039674.Total N ORR (confirmed) Survival, median (95% CI), mo n (%) 95% CI PFS OS PD-L1 45 11 (24) 13-40 6 (1-17) 17 (6-17) TPS ≥50% 6 1 (17) 0.4-64 1 (0.2-6) 2 (0.3-NR) TPS ≥1%-49% 18 6 (33) 13-59 NR (1-NR) NR (3-NR) TPS <1% 21 4 (19) 5-42 6 (1-17) 17 (6-17) NR = not reached; TPS = tumor proportion score.
A phase Ib/II dose-escalation study evaluating triple combination therapy with a BRAF (encorafenib), MEK (binimetinib), and CDK 4/6 (ribociclib) inhibitor in patients (Pts) with <i>BRAF V600</i>-mutant solid tumors and melanoma.
Authors: Paolo Antonio Ascierto, Oliver Bechter, Pascal Wolter, Celeste Lebbe, Elena Elez, Wilson H. Miller, Georgina V. Long, Aurelius Gabriel Omlin, Salvatore Siena, Emiliano Calvo, Mike Pickard, Ashwin Gollerkeri, Lance Wollenberg, Caroline Germa, Reinhard Dummer
Journal: Journal of Clinical Oncology (2017)

9518 Background: The benefits of BRAF + MEK inhibition (dual combo) in pts with BRAF V600-mutant ( BRAF V600 ) melanoma are known. Preclinical data supports inhibiting CDK 4/6 and BRAF + MEK (triple combo) to improve antitumor activity. We report safety and preliminary efficacy from a phase 1b/2 study (NCT01543698) of encorafenib (ENCO; a selective BRAF kinase inhibitor), binimetinib (BINI; a MEK inhibitor), and ribociclib (RIBO; a CDK 4/6 inhibitor). Methods: Phase 1b of this open-label, multicenter study enrolled pts with confirmed BRAF V600 advanced solid tumors. Escalating doses of RIBO 100 mg-600 mg QD for 3 wk on/1 wk off were administered with ENCO 200 mg QD + BINI 45 mg BID in successive cohorts (6 pts each) until the maximum tolerated or recommended phase 2 dose (RP2D) was reached. Due to potential pharmacokinetic interactions with RIBO, the ENCO dose was lower than the dual combo RP2D (450 mg QD). Dose escalations followed an adaptive Bayesian model. In phase 2, the triple combo was tested in pts with BRAF V600 melanoma naïve to prior BRAF inhibitor treatment; the primary endpoint was objective response rate (ORR) per RECIST v1.1. Results: In phase 1b (n = 21), no dose-limiting toxicities were reported and the triple combo RP2D was ENCO 200 mg QD + BINI 45 mg BID + RIBO 600 mg QD. ENCO AUC was slightly lower than at the dual combo RP2D. In phase 2 (n = 42), 59.5% pts had an ECOG PS of 0 and 43% of pts had elevated lactate dehydrogenase. The most common (≥5%) grade 3/4 toxicities were neutropenia (26.2%), increased alanine transaminase (14.3%), diarrhea (7.1%), and anemia (7.1%). Ten pts (23.8%) discontinued treatment due to an AE, of which 4 were increased transaminases. The confirmed ORR was 52.4%, including 4 complete responses, 18 partial responses, and 15 pts with stable disease. Median duration of exposure in phase 2 was 9.1 mo (range, 0.0-21.6). Median progression-free survival was 9.0 mo (95% confidence interval, 7.0-11.1). Conclusions: Triple therapy with ENCO + BINI + RIBO in this small trial of pts with high disease burden was associated with responses in over half of pts and some evidence of increased toxicity. Clinical trial information: NCT01543698.
Dose Transition Pathways: The Missing Link Between Complex Dose-Finding Designs and Simple Decision-Making
Authors: Christina Yap, Lucinda J. Billingham, Ying Kuen Cheung, Charlie Craddock, John O'Quigley
Journal: Clinical Cancer Research (2017)

Abstract The ever-increasing pace of development of novel therapies mandates efficient methodologies for assessment of their tolerability and activity. Evidence increasingly support the merits of model-based dose-finding designs in identifying the recommended phase II dose compared with conventional rule-based designs such as the 3 + 3 but despite this, their use remains limited. Here, we propose a useful tool, dose transition pathways (DTP), which helps overcome several commonly faced practical and methodologic challenges in the implementation of model-based designs. DTP projects in advance the doses recommended by a model-based design for subsequent patients (stay, escalate, de-escalate, or stop early), using all the accumulated information. After specifying a model with favorable statistical properties, we utilize the DTP to fine-tune the model to tailor it to the trial's specific requirements that reflect important clinical judgments. In particular, it can help to determine how stringent the stopping rules should be if the investigated therapy is too toxic. Its use to design and implement a modified continual reassessment method is illustrated in an acute myeloid leukemia trial. DTP removes the fears of model-based designs as unknown, complex systems and can serve as a handbook, guiding decision-making for each dose update. In the illustrated trial, the seamless, clear transition for each dose recommendation aided the investigators' understanding of the design and facilitated decision-making to enable finer calibration of a tailored model. We advocate the use of the DTP as an integral procedure in the co-development and successful implementation of practical model-based designs by statisticians and investigators. Clin Cancer Res; 23(24); 7440–7. ©2017 AACR.
Phase I study evaluating high-dose treatment with ADXS11-001, a <i>Listeria monocytogenes</i>-listeriolysin O (<i>Lm</i>-LLO) immunotherapy, in women with cervical cancer.
Authors: Sharad A. Ghamande, Daniel Platt, Donna Wheatley, Bunja Jane Rungruang, John Edward Janik, Samir Khleif
Journal: Journal of Clinical Oncology (2016)

e14580 Background: Survival of patients (pts) with persistent, metastatic or recurrent cervical cancer is dismal. ADXS11-001 is an irreversibly attenuated Lm-LLO immunotherapy secreting a human papillomavirus-E7 tumor antigen as a truncated LLO-E7 fusion protein that induces antitumor T-cell immunity and reduces tumor immune tolerance. In pts with recurrent/refractory cervical cancer, ADXS11-001 was shown to be safe and effective. This study evaluates the safety/efficacy of a higher ADXS11-001 dose than that currently used in phase II trials. Methods: This phase I, dose-escalation, open-label study (NCT02164461) enrolled women ≥ 18 years with persistent, metastatic, or recurrent cervical squamous/adenocarcinoma not amenable to surgery/standard radiotherapy. Pts had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0–1 and measurable disease (RECIST v1.1) with documented progression on or intolerance to prior therapy. The primary endpoint was ADXS11-001 safety/tolerability; secondary endpoints included tumor response, progression-free survival, and correlative immunologic studies. Pts received ADXS11-001 every 3 weeks during a 12-week treatment cycle. A 3+3 design in 2 doses was used for dose escalation: 5 x 109 colony-forming units (CFU; Dose Level 1) and 1 x 1010 CFU (Dose Level 2). A reported dose-limiting toxicity rate < 33% was used to select the recommended phase II dose (RP2D). Results: Overall, 10 pts were enrolled; 9 were treated (Dose Level 1: 6 pts; Dose Level 2: 3 pts). Median age was 53 years; 78% had ECOG PS 0; 33% received ≥ 3 prior lines of systemic therapy; 28 doses of ADXS11-001 were administered at Dose Level 1 and 5 doses at Dose Level 2. All pts (9/9) experienced ≥ 1 adverse event (AE), of which 75% were treatment related (TRAEs, in 8/9 pts): 99% were grade 1–2, and the most common TRAEs occurring in ≥ 3 pts were chills, vomiting, hypotension, tachycardia, fever, and nausea. Only 1 grade 3 (hypotension) and no grade 4–5 TRAEs were reported. Conclusions: A higher ADXS11-001 dose was well tolerated, and the RP2D is 1 x 1010 CFU. Analysis of tumor response is ongoing to assess if treatment intensity impacts efficacy. Clinical trial information: NCT02164461.
Continuous Negative Abdominal Pressure Recruits Lungs at Lower Distending Pressures
Authors: Takeshi Yoshida, Doreen Engelberts, Gail Otulakowski, Bhushan Katira, Martin Post, Niall D. Ferguson, Laurent Brochard, Marcelo B. P. Amato, Brian P. Kavanagh
Journal: American Journal of Respiratory and Critical Care Medicine (2017)
Barriers to MACRA among a cohort of community oncologists.
Authors: Chadi Nabhan, Yolaine Smith, Frank R Ernst, Jennifer Fillman, Bruce A. Feinberg
Journal: Journal of Clinical Oncology (2017)

6613 Background: Value Based Care (VBC) initiatives specifically the Medicare and CHIP Reauthorization Act (MACRA), which includes Medicare Incentive Payment System (MIPS) and Alternative Payment Models (APMs), present challenges for community oncologists. Understanding barriers associated with implementation and compliance are essential for optimal execution. Methods: Using audience response technology, 52 community oncologists and 26 practice managers (PMs) of diverse geography, practice type and affiliations were surveyed in November 2016. Results: Of the attendees, 43% were participating in commercial payer VBC while 33% were participating in the Oncology Care Model (OCM), an APM. Reasons for non-participation: Cost of drugs 58%; data transparency 42%; human resources 33%; technology 29%. The majority of attendees stated limited awareness of MACRA reporting requirements. Once reporting was explained, the stated challenges to MACRA implementation included: inability to measure and track costs 76%; problematic quality improvement activities 56%; lack of patient engagement tools 52%; concern about interpreting CMS reports 52%; meeting meaningful use requirements 33%. In regard to preparation: 52% had survivorship or palliative care plans, 39% made infrastructure investments, and 23% were utilizing clinical pathways. Although 54% stated use of data analytics to maximize efficiency and profitability, half of these were not satisfied with ease of data extraction or output. One third opined that patient satisfaction was irrelevant to quality of care. In the end, nearly half stated reporting requirements could be managed; but 98% stated they were unwilling to assume downside financial risks for hospital and emergency room visits. Conclusions: Identifying and eliminating barriers to MACRA (MIPS/APMs) implementation may be critical to program success. The main reasons for OCM non-participation were costs of drugs and data transparency. There is significant dissatisfaction with available reporting and data extraction tools. Willingness to assume 2-sided risk for total cost of care was identified as the greatest risk to APM adoption.