Citations

Introduction: Aortic Stenosis (AS) is a common valve disease of the adult, caused by calcification of aortic cusps. The relationship between cusp calcification and severity of AS has been established mostly in men and it is unclear whether the calcification process and its relation to AS severity is similar in women Hypothesis: We hypothesized that the physiologic relation between aortic valve calcification (AVC) load and AS severity is different in men and women and that lower calcification loads may lead to severe AS in women Methods: We prospectively performed high resolution computed tomography (CT) without contrast in 679 patients with AS (Aortic valve area (AVA) <2cm 2 , Mean gradient ≥10 mmHg) at two academic centers (Rochester, MN; Paris, France) to measure AVC scores and compare these to the hemodynamic obstruction measured by Echo-Doppler. Results: Women vs. men were older (76±11 vs 74±11, p<0.0001) with slightly higher ejection fraction (62±12 vs 59±13, p=0.001) but AS severity was similar (AVA/body surface area 0.55±0.2 vs 0.56±0.2 cm 2 /m 2 ; Peak velocity 4±1 vs 3.9±1 m/s; Mean gradient 41±21 vs 38±18 mmHg, all p≥0.1). Yet, AVC load was lower in women vs men, score absolute or normalized for LVOT area (551±383 vs 626±399 all p<0.0001). For those with severe AS (Mean gradient >40 mmHg), AVC scores were 2433±1412 in women vs 3805±1587 in men. Multivariate analysis adjusting for age, BSA, LVOT area and mean gradient, confirmed that severe AS was achieved with lower AVC load in women (all p<0.0001). Conclusions: In this large multicenter AS population, women reached similar AS severity than males for lower calcium loads, even after adjustment for lower body and LVOT size. Hence the relation between valvular calcification process and severity of AS differs in women vs. men. Thus, future studies are needed to determine the differential mechanism of aortic calcification in men and women and diagnostic consideration must be given to gender in the interpretation of AS severity by AVC load.

Background: Several studies have evaluated preprocedural imaging predictors of left ventricular outflow tract obstruction (LVOTO) after transcatheter mitral valve replacement. The patient cohorts in these studies were heterogeneous and included patients with transcatheter mitral valve replacement in failed bioprostheses, annuloplasty rings, and severe mitral annular calcification (MAC). The goal of this study was to evaluate predictors of LVOTO specific to patients undergoing valve-in-MAC. Methods: This study included patients with severe MAC who underwent valve-in-MAC and had optimal quality preprocedural multidetector row computed tomography scans eligible for retrospective analysis. Baseline demographic, echocardiographic, and procedural data on these patients were collected. multidetector row computed tomography parameters were analyzed for association with LVOTO, defined as increase in mean LVOT gradient by ≥10 mm Hg with accompanying hemodynamic instability. Results: Seventy-one patients with optimal preprocedural computed tomography scans were included in this study (mean age, 72.5±13.5 years), 9 of which developed LVOTO (all female). Baseline mean LVOT area, neo-LVOT area (145.3 versus 270.9 mm 2 ; P =0.006), indexed neo-LVOT area (90.1 versus 157.4; P =0.05), and virtual transcatheter heart valve to septum distance (3.1 versus 6.9 mm; P =0.002) were lower in the LVOTO group. Expected % LVOT area reduction was higher in the latter group (58.3 versus 42.7%; P =0.008). In the univariable analysis, the baseline mean LVOT area, neo-LVOT area, indexed neo-LVOT area, and valve to septum distance were all significantly associated with LVOTO. Conclusions: The systolic mean LVOT area, neo-LVOT area, indexed neo-LVOT, expected percentage LVOT area reduction, and the valve to septum distance were associated with LVOTO after valve-in-MAC.

Background The indoleamine 2,3-dioxygenase (IDO) pathway is a key counter-regulatory mechanism that, in cancer, is exploited by tumors to evade antitumor immunity. Indoximod is a small-molecule IDO pathway inhibitor that reverses the immunosuppressive effects of low tryptophan (Trp) and high kynurenine (Kyn) that result from IDO activity. In this study, indoximod was used in combination with a checkpoint inhibitor (CPI) pembrolizumab for the treatment for advanced melanoma. Methods Patients with advanced melanoma were enrolled in a single-arm phase II clinical trial evaluating the addition of indoximod to standard of care CPI approved for melanoma. Investigators administered their choice of CPI including pembrolizumab (P), nivolumab (N), or ipilimumab (I). Indoximod was administered continuously (1200 mg orally two times per day), with concurrent CPI dosed per US Food and Drug Administration (FDA)-approved label. Results Between July 2014 and July 2017, 131 patients were enrolled. (P) was used more frequently (n=114, 87%) per investigator’s choice. The efficacy evaluable population consisted of 89 patients from the phase II cohort with non-ocular melanoma who received indoximod combined with (P). The objective response rate (ORR) for the evaluable population was 51% with confirmed complete response of 20% and disease control rate of 70%. Median progression-free survival was 12.4 months (95% CI 6.4 to 24.9). The ORR for Programmed Death-Ligand 1 (PD-L1)-positive patients was 70% compared with 46% for PD-L1-negative patients. The combination was well tolerated, and side effects were similar to what was expected from single agent (P). Conclusion In this study, the combination of indoximod and (P) was well tolerated and showed antitumor efficacy that is worth further evaluation in selected patients with advanced melanoma.

Objectives Unbiased information regarding the surgical management of patients with mitral regurgitation (MR) at the nationwide level are scarce and mainly US-based. The Programme de Médicalisation des Systèmes d’Information, a mandatory national database, offers the unique opportunity to assess the presentation and outcomes of all consecutive mitral valve (MV) surgeries performed in France in the contemporary era. Methods We collected all MV surgeries performed for MR in France in 2014–2016. MR aetiology was classified as degenerative (DMR), secondary (SMR) or Other (rheumatic or congenital disease and infective endocarditis). Results During the 3-year period, 18 167 MV surgeries were performed in France (55% repair and 45% replacement; 52% isolated). Age was 66±12 years and 59% were male. Aetiology was DMR in 42%, SMR in 16% and other in 42% including 19% with uncertain aetiologies. Overall, in-hospital mortality was 6.5% and increased with age, female gender, Charlson Comorbidity Index, type of surgery (replacement vs repair), associated surgery (combined vs isolated) and MR aetiology (all p<0.01). In-hospital mortality and rate of death/readmission for heart failure (HF) at 1 year were 3.4% and 13%, respectively for DMR (2.4% and 11% for isolated DMR) and 7.8% and 27%, respectively for SMR (5.5% and 23% for isolated SMR). Repair rate was 55% overall, 68% in DMR and 72% for isolated DMR surgery (70% of all DMR). Repair rates decreased with age, Charlson Comorbidity Index and female sex (all p<0.0001). Conclusion In this cross-sectional contemporary prospective nationwide database, in-hospital mortality and 1 year rate of death and HF readmission were considerable overall and in all subsets. Repair rates were suboptimal overall especially in the elderly and women subsets. These results underline the need to develop strategies to improve management and outcomes of patients with both DMR and SMR.

Background Although US recent data suggest that mitral regurgitation (MR) is severely undertreated and carries a poor outcome, population‐based views on outcome and management are limited. We aimed to define the current treatment standards, clinical outcomes, and costs related to MR at the nationwide level. Methods and Results In total, 107 412 patients with MR were admitted in France in 2014 to 2015. Within 1 year, 8% were operated and 92% were conservatively managed and constituted our study population (68% primary MR and 32% secondary MR). The mean age was 77±15 years; most patients presented with comorbidities. In‐hospital and 1‐year mortality rates were 4.1% and 14.3%, respectively. Readmissions were common (63% at least once and 37% readmitted ≥2 times). Rates of 1‐year mortality or all‐cause readmission and 1‐year mortality or heart failure readmission were 67% and 34%, respectively, and increased with age, Charlson index, heart failure at admission, and secondary MR etiology; however, the event rate remained notably high in the primary MR subset (64% and 28%, respectively). The mean costs of hospital admissions and of readmissions were 5345±6432 and 10 080±10 847 euros, respectively. Conclusions At the nationwide level, MR was a common reason for admission and affected an elderly population with frequent comorbidities. Less than 10% of patients underwent a valve intervention. All subsets of patients who were conservatively managed incurred high mortality and readmissions rates, and MR represented a major societal burden with an extrapolated annual cost of 350 to 550 million euros (390–615 million US dollars). New strategies to improve the management and outcomes of patients with both primary and secondary MR are critical and warranted.

Abstract Background Mitral regurgitation (MR) is the most common heart valve disorder worldwide. The contrast between the large burden of MR and the overall low number of performed mitral valve surgery suggest a marked undertreatment of MR patients. Large and comprehensive contemporary data assessing the management and outcome of patients with MR as well as the societal burden of the disease at the Nationwide level are currently lacking. Methods Based on a French mandatory administrative hospital-discharge database, we collected all admissions in France both in public and private hospitals in 2014 and 2015 with MR as primary or secondary code. Patients with infective endocarditis, congenital or rheumatic disease were excluded. Cost were calculated for patients admitted in public hospitals. Results In 2014–2015, 107,412 patients with MR were admitted in France in 1238 public and private hospitals; 74,098 patients (69%) presented with primary MR (PMR) and 33,314 patients (31%) with secondary MR (SMR). Overall 8,676 patients (8%) were operated on (81% PMR) within 1 year and 98,736 (92%) were conservatively managed and constituted our study population. Mean age was 77±15 years (50% were ≥80 years and 12% ≥90 years) and 53% were female. Most of the patients presented with comorbidities and Charlson Index was ≥2 in 53% of the population. In-hospital and one-year mortality were 4.1% and 14.3% respectively. Readmission were very common and one-year mortality/readmission all cause, and one-year mortality / CHF readmission rates were 67% and 34% respectively and increased with age, Charlson Index, CHF at presentation and SMR etiology but events rate remained notably high in the PMR subset (64% and 28% respectively). The total annual cost in public hospitals (initial hospitalisation and readmissions) was 325,716,311 euros. When only readmissions for heart failure were considered (43% of all readmissions), total annual cost was 202,904,869 euros. Conclusion In this large administrative contemporary nationwide database, 1) MR was a common reason for admission and affected an elderly population with frequent comorbidities, 2) less than 10% of patients were offered any intervention, 3) MR was associated with high mortality and readmissions rates in all subsets; 4) MR represented a major societal burden with an extrapolated annual cost between 250 and 400 million euros. These finding highlight the critical need to develop strategies to improve the overall management and outcomes of patients with both primary and secondary MR. Acknowledgement/Funding Edwards Lifesciences

Abstract Background Contemporary and unbiased information regarding the surgical management of patients with mitral regurgitation (MR) at the Nationwide level are scarce. The PMSI, a mandatory administrative database, offers the unique opportunity to assess the presentation and outcomes of all consecutive mitral valve (MV) surgeries performed in France in the contemporary era. Methods We collected all (isolated or combined) MV surgeries performed for MR in France both in public and private hospitals between 2014 and 2016. Based on an algorithm we developed, MR etiology was classified as degenerative (DMR), secondary (SMR) or OTHER (rheumatic, congenital, infective endocarditis or unknown). Results Between January 2014 and December 2016, 18,167 mitral valve surgeries were performed in France (55% repair and 45% replacement; 52% isolated MV surgery). Mean age was 66±12 years and 59% were male. Etiology was DMR in 42%, SMR in 16% and OTHER in 42%. Among DMR, repair rate was 68% overall and 72% in the subset who underwent an isolated MV surgery (70% of all DMR). Repair rates decreased with age, Charlson index and sex (female) (all P<0.0001). Among SMR, a repair was performed in 39% and a combined surgery in 51%. In-hospital mortality and rate of death / readmission for CHF at one year were 3.4% and 13% respectively for DMR (2.4% and 5.5% respectively for isolated DMR) and 7.8% and 17.8% respectively for SMR (5.5% and 12.4% respectively for isolated SMR). Center volume was associated with a lower in-hospital mortality (p=0.002) but not with higher DMR repair rate (P=0.85). Conclusion In this large administrative contemporary nationwide database, 1) DMR surgery was twice as frequent as SMR and more frequently performed isolated; 2) Repair rates in DMR were suboptimal overall but more critically in the elderly and women subsets. 3) Operative mortality and one-year rate of death and readmission were approximately twice as high in SMR than in DMR and overall considerable even for isolated DMR surgery; and 4) In DMR, center volume had no impact on repair rate but an independent impact on outcome. These results underline the need to develop strategies to improve management and outcomes of patients with both degenerative and secondary MR.

Abstract Background: The indoleamine 2,3-dioxygenase (IDO) pathway is a key counter-regulatory mechanism that normally inhibits immune responses when appropriate. In the setting of cancer, IDO pathway-mediated immune suppression is exploited by tumors in order to prevent and defeat anti-tumor immunity. Small-molecule inhibitors of the IDO pathway, such as indoximod, are an increasingly validated class of potential cancer therapeutics. Additionally, pre-clinical tumor models have shown complementary effects with indoximod / anti-PD1 checkpoint inhibitor treatment combinations. A clinical trial was developed based upon these data. Methods: Upon successful completion of a Phase 1b dose escalation cohort, metastatic melanoma patients were enrolled in a single arm Phase 2 trial evaluating the addition of indoximod to standard of care checkpoint inhibitors approved for melanoma. Treating physicians were allowed to administer their choice of approved checkpoint inhibitor. The large majority of patients received indoximod with pembrolizumab and this interim report is limited to those patients. Indoximod was administered continuously in 21 days cycles (1200mg po twice daily) concurrently with pembrolizumab (3mg/kg q21 days). Study endpoint is best overall response (objective response rate (ORR) = complete response rate (CR) + partial response rate (PR)) per site reported RECIST criteria. Results: At time of data cut-off, 60 patients had received indoximod /pembrolizumab and were evaluable for response, defined as having at least one follow-up imaging study performed. The ORR was 52% (31/60) with a CRR of 8% (5/60). The combination was well tolerated. The most frequently reported adverse events (regardless of attribution), occurring in ≥ 20% of subjects, were fatigue, diarrhea, nausea, arthralgia, headache, cough, rash, pruritus, and hypertension. The most frequently reported laboratory abnormalities (regardless of attribution), were anemia (17%) and hyperglycemia (17%). Conclusions: The interim analysis of the combination of indoximod and pembrolizumab demonstrates an ORR of 52% which compares favorably with the established ORR for pembrolizumab alone. Updated data to be presented. NCT02073123. Citation Format: Yousef Zakharia, Robert McWilliams, Monaster Shaheen, Kenneth Grossman, Joseph Drabick, Mohammed Milhem, Olivier Rixie, Samir Khleif, Ryan Lott, Eugene Kennedy, David Munn, Nicholas Vahanian, Charles Link. Interim analysis of the Phase 2 clinical trial of the IDO pathway inhibitor indoximod in combination with pembrolizumab for patients with advanced melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT117. doi:10.1158/1538-7445.AM2017-CT117