Residual AR Research Articles

Abstract 7568: Molecular effects of neo-adjuvant hormone therapy for locally advanced prostate cancer: An ancillary study of the ARNEO phase 2 trial

Abstract Intensified hormone therapy in combination with radiotherapy improves outcome for very high-risk locally advanced prostate cancer. The impact of hormone therapy with surgery, however, is uncertain. In order to understand this better, we ran an ancillary translational study on ARNEO (NCT03080116), a Phase 2 clinical trial, which randomized 89 locally-advanced prostate cancer patients to 12 weeks LHRHa +/- apalutamide (APA) followed by prostatectomy. We performed clinical-grade transcriptome-wide expression array analysis (Veracyte, Inc. San Diego, CA) of FFPE diagnostic core biopsies (N=89) and tumors removed at prostatectomy (N=32 LHRHa, N=23 LHRHa + APA). We also performed RNASeq on fresh frozen biopsies of prostatectomy tumors (N=42 LHRHa, N=45 LHRHa + apalutamide) and LHRHa-naive control cases (N=61) matched for clinical and pathological risk factors. Pre-surgery serum PSA decreased by a median of 98% (IQR:90.2-99.3) after hormone treatment. This decrease was better associated with tumor AR signaling (r2=0.11) versus pre-treatment serum PSA (r2=0.0005), or between pre-treatment serum PSA with diagnostic biopsies (r2=0.008). We confirmed APA more potently suppressed AR signaling than LHRHa alone, with no detectable difference in direction of effect for differentially regulated genes/pathways. LHRHa + APA had less residual tumor (median Residual Cancer Burden, RCB=0.48cm3) than in LHRHa (median RCB=1.7cm3) but in cases with sufficient tumor, we observed residual active AR signaling pathways at prostatectomy in both treatment arms. To orthogonally confirm this, we selected 28 ERG positive cases (by IHC pre-treatment) and found retained ERG expression in 12/13 on LHRHa and 10/15 on LHRHa + APA. Using pathway analysis in the RNAseq data, we identified LHRHa +/- APA induced down-regulation of AR, metabolic pathways, as well as DNA repair, and up-regulation of hallmark NOTCH, Hedgehog, TGF-beta, WNT and immune signaling (adjusted p-value cutoff=0.001). Comparing differentially expressed genes on RNASeq between treatment-naïve versus LHRHa +/- APA treated tumors, we observed STING1 as significantly higher in LHRHa +/- APA vs control (Wilcoxon rank sum test p-value <0.001). We found that expression of STING1 was positively correlated with hallmark interferon alpha response (r=0.7, rs=0.6) that was correlated with apoptosis (r=0.5, rs=0.5). Whilst we show that adding APA to LHRHa increases suppression of AR activity and ERG expression, we find that 12 weeks is insufficient to abrogate AR signaling in most tumors, despite ~98% decrease in serum PSA. We identify novel processes modulated in humans by potent suppression of androgen activity, including upregulation of STING1-type 1 interferon response as a potential key modulator of treatment effect. Citation Format: Mazlina Ismail, Wout Devlies, Marina Parry, Gaetan Devos, Stefanie Friedrich, Charles Parker, Larissa Mendes, Elai Davicioni, Mark Linch, Frank Claessens, Steven Joniau, Gerhardt Attard. Molecular effects of neo-adjuvant hormone therapy for locally advanced prostate cancer: An ancillary study of the ARNEO phase 2 trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7568.

Comparative study between results of using synthetic versus pericardial patches for VSD closure in infants and children

Background: Generally ventricular septal defects (VSDs) are repaired with synthetic material: either Dacron (polyethylene terephthalate) or Goretex (expanded polytetrafluoroethylene) depending on surgeons preference. Aim of the work: To compare between the outcome of VSD closure by synthetic patches versus pericardial patches. Patients and methods: This study was conducted on 60 patients with surgical VSD closure. They were divided into 2 groups each included 30 patients. In group I synthetic patch (Dacron or Gortex) was used. In group II pericardial patch (fresh or treated or bovine) was used. The patients were evaluated at 3m and 6m after operation for: residual defects, endocarditis, heart block, AR, TR, LV dimensions and function and any other complications. Results: Ventilation time, was statistically significant shorter in group II (8.53 ± 6.37h) compared with Group I (30.60 ± 20.84h) p value 0.001*. Statistically significant shorter ICU time was found in group II (2.53 ± 0.90d) compared with group I (3.70 ± 1.62d). Twenty (66.7%) patients and 28(93.3%) patients in group I and II respectively had sinus rhythm. While 10 (33.3%) patients and 2 (6.7%) patients in group I and II respectively had temporary heart block.

Abstract 1594: Reversal of lineage plasticity in RB1/TP53-deleted prostate cancer through FGFR and Janus kinase inhibition

Abstract The inherent plasticity of tumor cells provides a mechanism of resistance to many molecularly targeted therapies, exemplified by adeno-to-neuroendocrine lineage transitions seen in prostate and lung cancer. Here we investigate the root cause of this lineage plasticity in a primary murine prostate organoid model that mirrors the lineage transition seen in patients. These cells lose luminal identity within weeks following deletion of Trp53 and Rb1, ultimately acquiring an Ar-negative, Syp+ phenotype after orthotopic in vivo transplantation. We performed single-cell transcriptomic analysis of a time-course experiment on the prostate organoid following Trp53 and Rb1 deletion. Critical to this study, we developed SEACells, a method that enumerates distinct, highly granular cell states, allowing for robust transcriptomic quantification. Leveraging the SEACell platform, we developed several graph-based computational approaches based on Markov absorption, diffusion maps, and attributed stochastic block models to quantify dynamic changes in plasticity. These quantitative models independently confirmed rapid collapse of cell-type fidelity in the form of a mixed luminal-basal phenotype following tumor suppressor gene deletion. These methods compute metrics for plasticity that we correlated to candidate driver gene programs. Among the strongest plasticity correlates, Jak-Stat and Fgfr signaling stood out as gene programs activated early in the time-course prior to any corresponding morphological changes. We further developed a regression-based approach to nominate ligand-receptor interactions that activate downstream Jak-Stat signaling, which identified Fgf-Fgfr interactions that were functionally validated with growth factor addition and pharmacological inhibition. Most strikingly, genetic or pharmacologic inhibition of Jak1/2 in combination with Fgfr blockade not only reversed the plastic state and restored organoids to their wild-type morphology, but also re-sensitized drug-resistant cells to antiandrogen therapy in models with residual AR expression. We additionally confirm early activation of Jak/Stat transcriptional programs in an Rb1/Trp53/Pten-deleted genetically engineered mouse model undergoing substantial cell-type diversification under plasticity in the context of the tumor microenvironment. Collectively, we show that lineage plasticity initiates quickly as a largely cell-autonomous process that is further increased in the in vivo setting, and through newly developed computational approaches, we identify a pharmacological strategy that restores lineage identity using clinical grade inhibitors. Citation Format: Joseph M. Chan, Wouter R. Karthaus, Manu Setty, Jillian R. Love, Samir Zaidi, Jimmy Zhao, Zi-ning Choo, Sitara Persad, Justin LaClair, Kayla E. Lawrence, Ojasvi Chaudhary, Ignas Masilionis, Linas Mazutis, Ronan Chaligne, Dana Pe'er, Charles Sawyers. Reversal of lineage plasticity in RB1/TP53-deleted prostate cancer through FGFR and Janus kinase inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1594.

Transcatheter aortic valve-in-valve implantation to treat aortic para-valvular regurgitation after TAVI

BackgroundPara-valvular regurgitation (PVR) after transcatheter aortic valve (TAV) implantation is associated with increased mortality. Redo-TAVI may be applied to treat PVR, yet with unknown efficacy. We thought to assess redo-TAVI efficacy in reducing PVR using the Redo-TAVI registry (45 centers; 600 TAV-in-TAV cases). MethodsPatients were excluded if redo-TAVI was done urgently (N = 253), for isolated TAV stenosis (N = 107) or if regurgitation location at presentation remained undetermined (N = 123). The study group of patients with PVR (N = 70) were compared against patients with intra-valvular regurgitation (IVR) (N = 41). Echocardiographic examinations of 67 (60%) patients were reassessed in a core-lab for data accuracy validation. ResultsCore-lab examination validated the jet location in 66 (98.5%) patients. At 30 days, the rate of residual AR ≥ moderate was 7 (10%) in the PVR cohort vs. 1 (2.4%) in the IVR cohort, p = 0.137. The rate of procedural success was 53 (75.7%) vs. 33 (80.5%), p = 0.561; procedural safety 51 (72.8%) vs. 31 (75.6%), p = 0.727; and mortality 2 (2.9%) vs. 1 (2.4%), p = 0.896 at 30 days and 7 (18.6%) vs. 2 (11.5%), p = 0.671 at 1 year, respectively. Of patients with residual PVR ≥ moderate at 30 days, 5/7 occurred after implanting balloon-expandable in self-expanding TAV and 2/7 after balloon-expandable in balloon-expandable TAV. ConclusionsThis study puts in perspective redo-TAVI efficacy and limitations to treat PVR after TAVI. Patient selection for this and other therapies for PVR needs further investigation.

Transcatheter aortic valve replacement for pure aortic valve regurgitation: "on-label" versus "off-label" use of TAVR devices.

Transcatheter aortic valve replacement (TAVR) has become the mainstay of treatment for aortic stenosis in patients with high surgical risk. Pure aortic regurgitation (PAR) is considered a relative contraindication for TAVR; however, TAVR is increasingly performed in PAR patients with unfavorable risk profile. Herein, we aim to summarize available data on TAVR for PAR with special emphasis on "on-label" versus "off-label" TAVR devices. Pubmed was searched for studies of patients undergoing TAVR for PAR. Primary outcome was 30day-mortality. Pooled estimated event rates were calculated. Twelve studies including a total of 640 patients were identified until December 2017. Among these, 208 (33%) patients were treated with devices with CE-mark approval for PAR ("on-label"; JenaValve and J valve). Overall, the procedural success rate was 89.9% (95% CI 81.1-96.1%; I2 80%). Major bleeding was reported in 6.4% (95% CI 2.9-10.8%; I2 48%). All-cause mortality at 30days was 10.4% (95% CI 7.1-14.2%; I2 20%). Stroke occurred in 2.2% (95% CI 0.9-3.9%; I2 0%). A permanent pacemaker was required in 10.7% (95% CI 7.3-14.6%; I2 23%). At 30days after TAVR, ≥ moderate AR post-interventional was observed in 11.5% (95% CI 2.9-23.6%; I2 90%). In the "on-label"-group, success rate was 93.0% (95% CI 85.9-98.1%; I2 52%). 30-day-mortality was 9.1% (95% CI 3.7-16.0%; I2 36%). More than trace AR was present in 2.8% (95% CI 0.1-7.6%; I2 0%). Compared to first-generation devices, second-generation devices were associated with significantly lower 30-day-mortality (r = - 0.10; p = 0.02), and significantly higher procedural success rates (r = 0.28; p < 0.001). Compared to other second-generation devices, the use of J valve or JenaValve was not associated with altered mortality (r = 0.04; p = 0.50), rates of > trace residual AR (r = - 0.05; p = 0.65) but with a significantly higher procedural success (r = 0.15; p = 0.042). Based on this summary of available observational data TAVR for PAR is feasible and safe in patients deemed inoperable. First-generation TAVR devices are associated with inferior outcome and should be avoided. The "on-label" use of PAR-certified TAVR devices is associated with a significantly higher procedural success rate and might be favorable compared to other second-generation devices.

Rupture of sinus of valsalva - A 15 years single institutional retrospective review: Preoperative heart failure has an impact on post operative outcome?

Background:We reviewed our experience with ruptured sinus of Valsalva aneurysms (RSOV) to determine a correlation with preexisting heart failure (HF) and coexisting cardiac lesions (aortic regurgitation [AR] and ventricular septal defect [VSD]) to postoperative left ventricular (LV) dysfunction and postoperative outcomes.Materials and Methods:Retrospective review of RSOV cases over 15 years showed that RSOV repair was done in 87 patients. We looked for patients who presented with HF and patients having AR and/or VSDs. Statistical analysis was done to see if the coexisting lesions and preoperative HF were associated with postoperative LV dysfunction. Chi-square test was used on contingency table for statistical analysis. Complications in the postoperative period and prolonged Intensive Care Unit stay were noted.Results:17% (15/87) presented with HF. Fifty-two patients had moderate to severe AR and 50 patients had VSD. Seventeen patients had postoperative LV dysfunction. The correlation of preoperative HF and coexisting lesions with postoperative LV dysfunction was not statistically significant. Two patients underwent redo surgery for residual RSOV and AR. Two patients had arrhythmias. One patient had cerebrovascular accident. No mortality was seen in the study.Conclusion:Preoperative HF and the presence of VSD and/or AR have no statistical significant correlation with postoperative LV dysfunction. As the outcome of RSOV repair is good, all patients need to undergo early repair to avoid complications.

Modifiability of the history dependence of force through chronic eccentric and concentric biased resistance training.

The increase and decrease in steady-state isometric force following active muscle lengthening and shortening are referred to as residual force enhancement (RFE) and force depression (FD), respectively. The RFE and FD states are associated with decreased (activation reduction; AR) and increased (activation increase; AI) neuromuscular activity, respectively. Although the mechanisms have been discussed over the last 60 years, no studies have systematically investigated the modifiability of RFE and FD with training. The purpose of the present study was to determine whether RFE and FD could be modulated through eccentric and concentric biased resistance training. Fifteen healthy young adult men (age: 24 ± 2 yr, weight: 77 ± 8 kg, height: 178 ± 5 cm) underwent 4 wk of isokinetic dorsiflexion training, in which one leg was trained eccentrically (-25°/s) and the other concentrically (+25°/s) over a 50° ankle excursion. Maximal and submaximal (40% maximum voluntary contraction) steady-state isometric torque and EMG values following active lengthening and shortening were compared to purely isometric values at the same joint angles and torque levels. Residual torque enhancement (rTE) decreased by ~36% after eccentric training ( P < 0.05) and increased by ~89% after concentric training ( P < 0.05), whereas residual torque depression (rTD), AR, AI, and optimal angles for torque production were not significantly altered by resistance training ( P ≥ 0.05). It appears that rTE, but not rTD, for the human ankle dorsiflexors is differentially modifiable through contraction type-dependent resistance training. NEW & NOTEWORTHY The history dependence of force production is a property of muscle unexplained by current cross bridge and sliding filament theories. Whether a muscle is actively lengthened (residual force enhancement; RFE) or shortened (force depression) to a given length, the isometric force should be equal to a purely isometric contraction-but it is not! In this study we show that eccentric training decreased RFE, whereas concentric training increased RFE and converted all nonresponders (i.e., not exhibiting RFE) into responders.

Quantitative Correlation between Electrical Resistivity and Microhardness of Cu-Ni-Mo Alloys via a Short-Range Order Cluster Model

Strength and electrical resistivity are coupled in metal alloys as both are based upon a similar microstructure mechanism, but the quantitative relationship between them is not known due to the complex microstructures involved. The present work analyzes the dependence of hardness and electrical resistivity on solute contents for ternary [Moy/(y+12)Ni12/(y+12)]xCu100−x alloys (at.%), where x = 0.3–15.0 is the total solute content and y = 0.5–6.0 the ratio between Mo and Ni. The alloys are designed following the cluster-plus-glue-atom model to reach three distinct structural states, i.e., cluster solution state (y = 1), where Mo is dissolved via a chemical short-range order characterized by Mo-centered and Ni-nearest-neighbored [Mo1-Ni12] cluster, cluster solution state plus extra Ni solution (y 1). The measured electrical resistivity and microhardness data are correlated with these three structural states to reveal the property dependencies on solute contents. The cluster solution enhances the strength, without causing much increase in the electrical resistivity, as the solutes are organized into cluster-type local atomic aggregates that decrease dislocation mobility more strongly than electron scattering. Analogous to residual resistivity ρR, which indicates the change of resistivity with reference to pure Cu, residual microhardness HR and residual lattice constant aR are also defined. For the ideal cluster solution state (y = 1, Mo/Ni = 1/12), the mentioned three parameters are correlated with the total solute content x by ρR = 1.08·x (10−8 Ω m), HR = 1.50·x (Kgf mm−2), and aR = − 1.08·x (10−4 nm). From these, ρR = 0.72HR = − aR. Such simple relationships indicate that resistivity and strength are dependent on the same cluster-type solution mechanism and can be a good reference for evaluating strength and resistivity performance of Cu alloys.

Five-year evolution of mild aortic regurgitation following transcatheter aortic valve implantation: early insights from a single-centre experience.

To assess the follow-up evolution and impact of mild aortic regurgitation (1 + AR) following transcatheter aortic valve implantation (TAVI). We evaluated the follow-up outcomes and AR evolution of 558 patients affected by native aortic stenosis who underwent TAVI with residual AR ≤ 1+. No residual AR was found in 294 (52.7%) patients, whereas 1 + AR was found in 264 (47.3%) patients. At 5.5 years, freedom from all-cause mortality (56.9% vs 53.5%), cardiac mortality (75.0% vs 74.3%) and heart failure (70.0% vs 63.9%) were similar between no-AR and 1 + AR groups, respectively (all P > 0.05). New York Heart Association Class I-II was found in 88.9% vs 82.4% of patients respectively ( P = 0.013). Freedom from AR ≥3+ at 5.5 years was 98.6% in the no-AR group vs 82.5% in the 1 + AR group (log-rank <0.001). Residual 1 + AR was found to be an independent predictor of increased follow-up AR ≥3+ ( P = 0.012). In 1 + AR group, higher left ventricle mass index independently predicted increased cardiac death [hazards ratio (HR) 1.01, confidence interval (CI) 1.00-1.02, P = 0.036] and heart failure rate (HR 1.01, CI 1.00-1.02, P = 0.002), while larger native aortic annulus perimeter predicted follow-up AR ≥ 3+ (HR 1.12, CI 1.02-1.22, P = 0.016). 5 years after TAVI, a higher progression of paravalvular AR to Grade ≥3+ together with worse symptoms were found in patients with residual 1 + AR compared with no-AR, although no marked difference in survival was observed. These findings raise further concerns about 1+ residual AR after TAVI, especially in the perspective of expanding indications to younger low-risk patients. Mechanisms that cause progression of paravalvular AR after TAVI remain to be clarified.

Dual source computed tomography based analysis of stent performance, its association with valvular calcification and residual aortic regurgitation after implantation of a balloon-expandable transcatheter heart valve.

The aim of this study was to investigate the mutual influence of valvular calcifications and transcatheter aortic valve stent geometry during and after implantation of a balloon-expandable SAPIEN ® /SAPIEN XT ® prostheses. Aortic valve calcification has been linked with adverse complications after transcatheter aortic valve implantation (TAVI). However, little is known about the fate of the calcifications after TAVI as well as its influence on transcatheter heart valve geometry. Thirty one patients underwent cardiac dual source computed tomography (DSCT) before and after a TAVI with the Edwards SAPIEN/SAPIEN XT ® prostheses. Detailed DSCT image analysis was performed with Mimics ® and 3Matic ® (both Materialise, Leuven, Belgium). Implanted stents reached an average degree of expansion of 84% and achieved good circularity despite the presence of fairly oval native annuli and a heterogeneous degree of valvular calcification. Both, the degree of stent expansion and the degree of stent eccentricity were inversely related to the degree of oversizing, but independent of the degree of valvular calcification and native annular ovality. Visualization of the position of calcific debris before and after TAVI showed that calcifications were shifted upwards and outwards as a consequence of the implantation procedure. The degree of stent eccentricity was related to residual aortic regurgitation grade ≥2. The SAPIEN ® /SAPIEN XT ® prostheses achieved good degrees of stent expansion and circularity regardless of the morphology of the landing zone. Increased stent ovality was associated with an elevated risk for aortic regurgitation. The total calcification volume, degree of annular ovality and stent expansion were not associated with residual AR.

Aortic valve decalcification for severe aortic valve stenosis in the elderly: medium-term results.

To present the results of a novel technique of aortic valve decalcification (AVD) in a consecutive population of elderly patients with severe aortic valve stenosis (AVS) and small aortic annulus. Between January 2008 and December 2012, a consecutive series of 34 patients (mean age 80 ± 13 years) with severe AVS were operated on using AVD. They were compared with a matched population of 68 patients (mean age 82 ± 7 years) submitted to aortic valve replacement (AVR) with bioprosthesis. The two groups were comparable for cardiac risk factors and admission symptoms. Preoperatively, all patients presented with severe AVS, small aortic annulus (19 mm) and preserved left ventricular function. Thirty-day mortality was 8.8 vs. 7.5% in the AVD and AVR groups, respectively (P = 0.88). Actuarial 2 and 5-year survival rates were 80 vs. 82% and 64 vs. 78% in the AVD and AVR groups, respectively (P = 0.27). Long-term valve-related events incidence was significantly higher in the AVD group (12%) compared with that in the AVR group (4%; P = 0.01). However, in the AVD group, patients with no or mild residual AR experienced 2 and 5 years of freedom from valve-related events, which is not significantly different from the patients submitted to the AVR group (P = 0.76). After AVD, a significant increase in the aortic valve area (from 0.8 to 1.9 cm) and a parallel reduction in the mean gradient (from 40 to 12 mmHg) was observed in all patients (P = 0.01). Postoperative aortic valve area (1.9 vs. 1.26 cm), as well as mean gradient (12 vs. 21 mmHg), were significantly better in the AVD group compared with that in the AVR group (P = 0.01). In this preliminary experience, AVD seems a good therapeutic option for elderly patients with severe AVS. Further studies with longer follow-up are needed in order to confirm these preliminary results and to ascertain the valve durability over time.

TCT-837 Effectiveness and possible complications of post dilatation in patients with residual significant aortic regurgitation following valve implantation using both Edwards and Corevalve systems: A single center study

Outcomes of postdilatation should be properly analysed in patients undergoing TAVI. Hereby, results and complications of postdilatation in patients with residual significant AR using both the Edwards and CoreValve systems are discussed thoroughly. From November 2007 to December 2011, 384 patients

The BDS statistic and residual test

The conventional nonparametric tests have been widely used in many fields for the residual analysis of a fitted model on observations. Also, in recent, a new technique called the BDS (Brock–Dechert–Scheinkman) statistic has been shown that it can be used as a powerful tool for the residual analysis, especially, of a nonlinear system. The purpose of this study is to compare the powers of the nonparametric tests and BDS statistic by residual analysis of the fitted models. This study evaluates stochastic models for four monthly rainfalls in Korea through the residual analysis by using the conventional nonparametric and BDS statistics. We use SARIMA and AR Error models for fitting each rainfall and perform the residual analysis by using the test techniques. As a result, we find that the BDS statistic is more reasonable than the conventional nonparametric tests for the residual analysis and AR Error model may be more appropriate than SARIMA model for modeling of monthly rainfalls.

Application of Neural Networks to a Predictive Extended Corresponding States Model for Pure Halocarbon Thermodynamics

The extended corresponding states (ECS) model has been extensively studied for representing the thermodynamic surface of pure fluids and mixtures in the aR(ρ, T) form, and the most advanced version is currently the one for hydrofluorocarbons, but the shape factors ϑ(ρ, T) and ϕ(ρ, T) have yet to be determined as analytical functions for the whole PρT surface of a pure fluid. For a sample of pure halocarbons, this work aims to solve the fundamental problem of determining the individual shape functions over the entire PρT domain through an innovative predictive procedure using a density model requiring only a single saturated liquid density input. An original algorithm using artificial neural networks enables the determination of the ϑ(ρ, T) and ϕ(ρ, T) functions from a priori knowledge of their functional forms. The proposed algorithm focuses on the determination of the residual Helmholtz energy aR(ρ, T) for each fluid, subsequently allowing any other thermodynamic residual function to be calculated through the first and second derivatives of temperature and density. For each fluid studied, the model has been validated for residual functions against the same functions coming from highly accurate dedicated equations of state. The prediction accuracies reach average absolute deviation values ranging from 0.3 to 7.8%, spanning from vapor and liquid regions to supercritical conditions, while the corresponding results of the conventional ECS method range from 0.54 to 20%.