Transcatheter Aortic Valve Implantation in Low-Risk Tricuspid or Bicuspid Aortic Stenosis: The NOTION-2 Trial.

BACKGROUND AND AIMS: Transcatheter aortic valve implantation (TAVI) has become the first choice to treat older patients with severe symptomatic aortic stenosis (AS). This study aimed to compare TAVI with surgery in low-risk patients ≤ 75 years of age, including both tricuspid and bicuspid AS. METHODS: The NOTION-2 trial enrolled and 1:1 randomized low-risk patients aged ≤ 75 years with severe symptomatic AS to TAVI or surgery. The primary endpoint was a composite of all-cause mortality, stroke or rehospitalization (related to the procedure, valve or heart failure) at 12 months. RESULTS: A total of 370 patients were enrolled with a mean age of 71.1 years and a median Society of Thoracic Surgeons risk score of 1.1%. A total of 100 patients had bicuspid AS. The 1-year incidence of the primary endpoint was 10.2% in the TAVI group and 7.1% in the surgery group (absolute risk difference 3.1%; 95% confidence interval [CI], -2.7% to 8.8%; hazard ratio (HR) 1.4, 95% CI: 0.7 to 2.9; p=0.3). Patients with TAVI, when compared to surgery, had lower risk of major bleeding and new-onset atrial fibrillation and higher risk of non-disabling stroke, permanent pacemaker implantation and moderate-or-greater paravalvular regurgitation. The risk of the primary composite endpoint was 8.7% and 8.3% in patients with tricuspid AS (HR 1.0, 95% CI: 0.5 to 2.3) and 14.3% and 3.9% in patients with bicuspid AS (HR 3.8, 95% CI: 0.8 to 18.5) treated with TAVI or surgery, respectively (P for interaction=0.1). CONCLUSIONS: Among low-risk patients aged ≤ 75 years with severe symptomatic AS, the rate of the composite of death, stroke, or rehospitalization at one year was similar between TAVI and surgery. TAVI outcomes in young bicuspid AS patients warrant caution and should be further investigated. (NOTION-2, ClinicalTrials.gov, NCT02825134).

Outcomes and predictors of left ventricle recovery in patients with severe left ventricular dysfunction undergoing transcatheter aortic valve implantation.

BACKGROUND: Data on the likelihood of left ventricle (LV) recovery in patients with severe LV dysfunction and severe aortic stenosis undergoing transcatheter aortic valve implantation (TAVI) and its prognostic value are limited. AIMS: We aimed to assess the likelihood of LV recovery following TAVI, examine its association with midterm mortality, and identify independent predictors of LV function. METHODS: In our multicentre registry of 17 TAVI centres in Western Europe and Israel, patients were stratified by baseline LV function (ejection fraction [EF] >/≤30%) and LV response: no LV recovery, LV recovery (EF increase ≥10%), and LV normalisation (EF ≥50% post-TAVI). RESULTS: Our analysis included 10,872 patients; baseline EF was ≤30% in 914 (8.4%) patients and >30% in 9,958 (91.6%) patients. The LV recovered in 544 (59.5%) patients, including 244 (26.7%) patients whose LV function normalised completely (EF >50%). Three-year mortality for patients without severe LV dysfunction at baseline was 29.4%. Compared to this, no LV recovery was associated with a significant increase in mortality (adjusted hazard ratio 1.32; p<0.001). Patients with similar LV function post-TAVI had similar rates of 3-year mortality, regardless of their baseline LV function. Three variables were associated with a higher likelihood of LV recovery following TAVI: no previous myocardial infarction (MI), estimated glomerular filtration rate >60 mL/min, and mean aortic valve gradient (mAVG) (expressed either as a continuous variable or as a binary variable using the standard low-flow, low-gradient aortic stenosis [AS] definition). CONCLUSIONS: LV recovery following TAVI and the extent of this recovery are major determinants of midterm mortality in patients with severe AS and severe LV dysfunction undergoing TAVI. Patients with no previous MI and those with an mAVG >40 mmHg show the best results following TAVI, which are at least equivalent to those for patients without severe LV dysfunction. (ClinicalTrials.gov: NCT04031274).

Orbital atherectomy to facilitate transfemoral transcatheter aortic valve implantation in patients with calcified iliofemoral arteries: a case series.

Background: The transfemoral (TF) approach drives most of the advantages of transcatheter aortic valve implantation (TAVI) over surgical aortic valve replacement. Alternative accesses for TAVI are associated with higher complication rates, but are still considered in ∼5% of cases due to peripheral arterial disease (PAD). Percutaneous transluminal angioplasty can still allow TF-TAVI in selected cases with severe calcific PAD; however, ancillary techniques for calcium management are often needed. Case Summary: Orbital atherectomy was selected to facilitate TF-TAVI in two patients with different degrees and aspects of calcific PAD. Pre-procedural computed tomography analysis was key to choose the most appropriate technique for calcium management. We describe our experience with a step-by-step procedural approach to orbital atherectomy-assisted TF-TAVI. Discussion: PAD is not uncommon in patients affected by severe symptomatic aortic valve stenosis. Orbital atherectomy can still allow TF-TAVI in selected cases with severe calcific PAD. A meticulous patient selection and a standardized, step-wise procedural execution are mandatory to optimize outcomes.

Transcatheter aortic valve durability: a contemporary clinical review.

Encouraged by randomized controlled trials demonstrating non-inferiority of transfemoral transcatheter aortic valve implantation (TAVI) compared to surgical aortic valve replacement (SAVR) across all surgical risk categories, there has been a dramatic increase in the use of TAVI in a younger patient cohort with severe aortic stenosis, endorsed by both European and American Cardiac Societies. However, the standard use of TAVI in younger, less co-morbid patients with a longer life expectancy can only be supported if there is sound data demonstrating long-term durability of transcatheter aortic valves (TAVs). In this article, we have reviewed available randomized and observational registry clinical data pertaining to TAV long-term durability, placing emphasis on trials and registries using the new standardized definitions of bioprosthetic valve dysfunction (BVD) and bioprosthetic valve failure (BVF). Despite inherent difficulties in interpreting the available data, the determination reached is that the risk of structural valve deterioration (SVD) is potentially lower after TAVI than SAVR at 5 to 10 years, and that the two treatment modalities have a similar risk of BVF. This supports the adoption of TAVI in younger patients evident in current practice. However, the routine use of TAVI in younger patients with bicuspid aortic valve stenosis should be cautioned due to insufficient long-term TAV durability data in this particular patient population. Finally, we highlight the importance of future research into the unique potential mechanisms that can potentially contribute to TAV degeneration.

Commissural Alignment and Coronary Access after Transcatheter Aortic Valve Replacement.

Transcatheter aortic valve implantation (TAVR) is the first therapeutic option for elderly patients with severe symptomatic aortic stenosis, and indications are steadily expanding to younger patients and subjects with lower surgical risk and longer life expectancy. Commissural alignment between native and transcatheter valves facilitates coronary access after TAVR and is thus considered a procedural goal, allowing long-term management of coronary artery disease. Moreover, commissural alignment may potentially have a positive impact on transvalvular hemodynamic and valve durability. This review focus on technical hints to achieve commissural alignment and current evidence for different transcatheter aortic valves.

In vitro expansion of Wilms' tumor protein 1 epitope-specific primary T cells from healthy human peripheral blood mononuclear cells.

Wilms' tumor protein 1 (WT1) is a tumor-associated antigen overexpressed in various cancers. As a self-antigen, negative selection reduces the number of WT1-specific T cell receptors (TCRs). Here, we provide a protocol to generate WT137-45-specific TCRs using healthy human peripheral blood mononuclear cells. We describe the expansion of WT1-specific T cell clones by two consecutive in vitro stimulations with autologous WT137-45-pulsed dendritic cells and peripheral blood lymphocytes. We then detail the detection with human leukocyte antigen/WT137-45 tetramers.

Feasibility, safety and predictors of a successful "blind wiring" antegrade approach in the percutaneous treatment of chronic coronary total occlusions.

BACKGROUND: Antegrade wiring using only antegrade guiding catheter without contralateral injection (defined as "blind antegrade wiring") may represent a valid initial treatment strategy for selected chronic coronary total occlusions (CTOs) due to the potentially lower risk of vascular complications. A careful selection of lesions eligible for this strategy as well as an accurate balance between the likelihood of success and failure is paramount. The aim of the study is to determine the rate of successful revascularization, the potential predictors of failure and the incidence of major complications, when using a "blind antegrade wiring" technique. METHODS: In this multicentric study, consecutive patients with CTO undergoing percutaneous coronary intervention (PCI) were retrospectively screened. All cases approached using "blind antegrade wiring" technique were included. RESULTS: Out of 155 consecutive CTO-PCIs, 94 involved initial "blind antegrade wiring" strategy. Successful revascularization by means of "blind antegrade wiring" technique was achieved in 73 (78%) patients. Final successful revascularization was obtained in 19 of the remaining 21 procedures with "blind antegrade wiring" failure using other techniques (by adding a second contralateral guiding catheter; 98% total successful revascularization). Logistic regression analysis identified higher J-CTO Score as the only predictor of "blind antegrade wiring" failure. One complication occurred (wire-based coronary perforation). CONCLUSIONS: "Blind antegrade wiring" may be considered as initial strategy for selected CTO-PCI, mainly for CTOs with low J-CTO Score. This strategy would allow in a substantial number of cases to avoid a priori dual injection, keeping it as secondary strategy in case of "blind antegrade wiring" failure.

Trends and outcomes in transcatheter aortic valve implantation in Belgium: a 13-year single centre experience.

BACKGROUND: Transcatheter aortic valve implantation (TAVI) has been adopted as an alternative to surgery in severe aortic stenosis treatment, even in low-intermediate risk. The aim of this study is to retrospectively report our single-centre 13-year TAVI experience with emphasis on learning curve, referral indication and trends in outcomes over time. METHODS: We included 361 consecutive patients who underwent TAVI from January 2008 to December 2020, grouped according to similar per-year volume of procedures: G1 (2008-2014), G2 (2015-2017) and G3 (2018-2020). RESULTS: The number of procedures increased (group size: 59 vs. 106 vs. 196). No major differences were observed in STS-PROM and EuroSCORE-II between groups, despite TAVI in patients with prior surgical revascularisation was mainly performed in G1. Trans-femoral approach raised from 80.8 to 93.4%, while the most common alternative access was trans-subclavian. The pre-dilation rate was higher in G1 with lower prosthesis post-dilation rate. The length of hospital stay decreased in time by 30%. At 30 days a reduction in all-cause mortality, vascular complications, bleedings and para-valvular leak combined with higher rate of permanent pacing were observed over the groups. At 1-year there was no difference in all-cause mortality but over 30% reduction in cardiovascular death (8.5 vs. 7.5 vs. 5.6%). CONCLUSIONS: Favourable trends were observed across the groups, with an improvement in periprocedural outcomes and cardiovascular mortality at 1-year. These improvements could depend on increased expertise because mortality reduction was noted only after reaching a significant procedure volume. A trend towards lower risk patients selection was present in our cohort, as previously described worldwide.

Comparison of Different Stenting Techniques in Left Main Bifurcation Disease: Evidence From a Network Meta-Analysis.

OBJECTIVES: We aimed to assess which bifurcation technique performs best in unprotected left-main (LM) percutaneous coronary intervention (PCI). BACKGROUND: Provisional stenting was considered the preferred technique for LM bifurcation PCI due to the supposed lower risks of thrombosis and restenosis. However, recent studies showed potential advantages of double kissing (DK)-crush technique over the other strategies. METHODS: We performed a frequentist network meta-analysis comparing different stenting techniques in the setting of LM bifurcation. PubMed, Embase, the Cochrane Central Register of Controlled Trials, and Clinicaltrials.gov were searched. Both randomized clinical trials and non-randomized clinical trials were considered eligible for inclusion. Incidence rate ratios (IRRs) were computed using a random-effects model for death, cardiac death, myocardial infarction, target-vessel revascularization, target-lesion revascularization, and stent thrombosis, including 95% confidence intervals (CIs). RESULTS: A total of 10 studies (2364 patients) were included. Compared with provisional stenting, DK-crush was associated with fewer cardiac deaths (IRR, 0.34; 95% CI, 0.17-0.70; P<.01), myocardial infarctions (IRR, 0.19; 95% CI, 0.08-0.44; P<.001), stent thromboses (IRR, 0.31; 95% CI, 0.14-0.69; P<.01), target-vessel revascularizations (IRR, 0.25; 95% CI, 0.14-0.46; P<.001), and target-lesion revascularizations (IRR, 0.25; 95% CI, 0.14-0.46; P<.001). DK-crush was also associated with a lower risk of myocardial infarction (IRR, 0.19; 95% CI, 0.05-0.76; P=.02) when compared with standard crush and lower risk of target-lesion revascularization when compared with culotte (IRR, 0.32; 95% CI, 0.12-0.83; P=.02) and crush (IRR, 0.07; 95% CI, 0.02-0.28; P<.001). CONCLUSIONS: DK-crush is the best technique for unprotected LM bifurcation PCI.

Ribonucleic Acid Engineering of Dendritic Cells for Therapeutic Vaccination: Ready 'N Able to Improve Clinical Outcome?

Targeting and exploiting the immune system has become a valid alternative to conventional options for treating cancer and infectious disease. Dendritic cells (DCs) take a central place given their role as key orchestrators of immunity. Therapeutic vaccination with autologous DCs aims to stimulate the patient's own immune system to specifically target his/her disease and has proven to be an effective form of immunotherapy with very little toxicity. A great amount of research in this field has concentrated on engineering these DCs through ribonucleic acid (RNA) to improve vaccine efficacy and thereby the historically low response rates. We reviewed in depth the 52 clinical trials that have been published on RNA-engineered DC vaccination, spanning from 2001 to date and reporting on 696 different vaccinated patients. While ambiguity prevents reliable quantification of effects, these trials do provide evidence that RNA-modified DC vaccination can induce objective clinical responses and survival benefit in cancer patients through stimulation of anti-cancer immunity, without significant toxicity. Succinct background knowledge of RNA engineering strategies and concise conclusions from available clinical and recent preclinical evidence will help guide future research in the larger domain of DC immunotherapy.

Poly(I:C) primes primary human glioblastoma cells for an immune response invigorated by PD-L1 blockade.

Prognosis of glioblastoma remains dismal, underscoring the need for novel therapies. Immunotherapy is generating promising results, but requires combination strategies to unlock its full potential. We investigated the immunomodulatory capacities of poly(I:C) on primary human glioblastoma cells and its combinatorial potential with programmed death ligand (PD-L) blockade. In our experiments, poly(I:C) stimulated expression of both PD-L1 and PD-L2 on glioblastoma cells, and a pro-inflammatory secretome, including type I interferons (IFN) and chemokines CXCL9, CXCL10, CCL4 and CCL5. IFN-ß was partially responsible for the elevated PD-1 ligand expression on these cells. Moreover, real-time PCR and chloroquine-mediated blocking experiments indicated that poly(I:C) triggered Toll-like receptor 3 to elicit its effect. Cocultures of poly(I:C)-treated glioblastoma cells with peripheral blood mononuclear cells enhanced lymphocytic activation (CD69, IFN-γ) and cytotoxic capacity (CD107a, granzyme B). Additional PD-L1 blockade further propagated immune activation. Besides activating immunity, poly(I:C)-treated glioblastoma cells also doubled the attraction of CD8+ T cells, and to a lesser extent CD4+ T cells, via a mechanism which included CXCR3 and CCR5 ligands. Our results indicate that by triggering glioblastoma cells, poly(I:C) primes the tumor microenvironment for an immune response. Secreted cytokines allow for immune activation while chemokines attract CD8+ T cells to the front, which are postulated as a prerequisite for effective PD-1/PD-L1 blockade. Accordingly, additional blockade of the concurrently elevated tumoral PD-L1 further reinforces the immune activation. In conclusion, our data proposes poly(I:C) treatment combined with PD-L1 blockade to invigorate the immune checkpoint inhibition response in glioblastoma.

Desirable cytolytic immune effector cell recruitment by interleukin-15 dendritic cells.

Success of dendritic cell (DC) therapy in treating malignancies is depending on the DC capacity to attract immune effector cells, considering their reciprocal crosstalk is partially regulated by cell-contact-dependent mechanisms. Although critical for therapeutic efficacy, immune cell recruitment is a largely overlooked aspect regarding optimization of DC vaccination. In this paper we have made a head-to-head comparison of interleukin (IL)-15-cultured DCs and conventional IL-4-cultured DCs with regard to their proficiency in the recruitment of (innate) immune effector cells. Here, we demonstrate that IL-4 DCs are suboptimal in attracting effector lymphocytes, while IL15 DCs provide a favorable chemokine milieu for recruiting CD8+ T cells, natural killer (NK) cells and gamma delta (γδ) T cells. Gene expression analysis revealed that IL-15 DCs exhibit a high expression of chemokines involved in antitumor immune effector cell attraction, while IL-4 DCs display a more immunoregulatory profile characterized by the expression of Th2 and regulatory T cell-attracting chemokines. This is confirmed by functional data indicating an enhanced recruitment of granzyme B+ effector lymphocytes by IL-15 DCs, as compared to IL-4 DCs, and subsequent superior killing of tumor cells by the migrated lymphocytes. Elevated CCL4 gene expression in IL-15 DCs and lowered CCR5 expression on both migrated γδ T cells and NK cells, led to validation of increased CCL4 secretion by IL15 DCs. Moreover, neutralization of CCR5 prior to migration resulted in an important inhibition of γδ T cell and NK cell recruitment by IL-15 DCs. These findings further underscore the strong immunotherapeutic potential of IL-15 DCs.

Interleukin-15 enhances the proliferation, stimulatory phenotype, and antitumor effector functions of human gamma delta T cells.

BACKGROUND: Adoptive immunotherapy is gaining momentum to fight malignancies, whereby γδ T cells have received recent attention as an alternative cell source as to natural killer cells and αß T cells. The advent of γδ T cells is largely due to their ability to recognize and target tumor cells using both innate characteristic and T cell receptor (TCR)-mediated mechanisms, their capacity to enhance the generation of antigen-specific T cell responses, and their potential to be used in an autologous or allogeneic setting. METHODS: In this study, we explored the beneficial effect of the immunostimulatory cytokine interleukin (IL)-15 on purified γδ T cells and its use as a stimulatory signal in the ex vivo expansion of γδ T cells for adoptive transfer. The expansion protocol was validated both with immune cells of healthy individuals and acute myeloid leukemia patients. RESULTS: We report that the addition of IL-15 to γδ T cell cultures results in a more activated phenotype, a higher proliferative capacity, a more pronounced T helper 1 polarization, and an increased cytotoxic capacity of γδ T cells. Moreover γδ T cell expansion starting with peripheral blood mononuclear cells from healthy individuals and acute myeloid leukemia patients is boosted in the presence of IL-15, whereby the antitumor properties of the γδ T cells are strengthened as well. CONCLUSIONS: Our results support the rationale to explore the use of IL-15 in clinical adoptive therapy protocols exploiting γδ T cells.

The tumor-associated antigen RHAMM (HMMR/CD168) is expressed by monocyte-derived dendritic cells and presented to T cells.

We formerly demonstrated that vaccination with Wilms' tumor 1 (WT1)-loaded autologous monocyte-derived dendritic cells (mo-DCs) can be a well-tolerated effective treatment in acute myeloid leukemia (AML) patients. Here, we investigated whether we could introduce the receptor for hyaluronic acid-mediated motility (RHAMM/HMMR/CD168), another clinically relevant tumor-associated antigen, into these mo-DCs through mRNA electroporation and elicit RHAMM-specific immune responses. While RHAMM mRNA electroporation significantly increased RHAMM protein expression by mo-DCs, our data indicate that classical mo-DCs already express and present RHAMM at sufficient levels to activate RHAMM-specific T cells, regardless of electroporation. Moreover, we found that RHAMM-specific T cells are present at vaccination sites in AML patients. Our findings implicate that we and others who are using classical mo-DCs for cancer immunotherapy are already vaccinating against RHAMM.

Generation and Cryopreservation of Clinical Grade Wilms' Tumor 1 mRNA-Loaded Dendritic Cell Vaccines for Cancer Immunotherapy.

First described in the 1970s, dendritic cells (DC) are currently subjects of intense investigation to exploit their unique antigen-presenting and immunoregulatory capacities. In cancer, DC show promise to elicit or amplify immune responses directed against cancer cells by activating natural killer (NK) cells and tumor antigen-specific T cells. Wilms' tumor 1 (WT1) protein is a tumor-associated antigen that is expressed in a majority of cancer types and has been designated as an antigen of major interest to be targeted in clinical cancer immunotherapy trials. In this chapter, we describe the generation, cryopreservation, and thawing of clinical grade autologous monocyte-derived DC vaccines that are loaded with WT1 by messenger RNA (mRNA) electroporation. This in-house-developed transfection method gives rise to presentation of multiple antigen epitopes and can be used for all patients without restriction of human leukocyte antigen (HLA) type.

Bisphosphonates for cancer treatment: Mechanisms of action and lessons from clinical trials.

A growing body of evidence points toward an important anti-cancer effect of bisphosphonates, a group of inexpensive, safe, potent, and long-term stable pharmacologicals that are widely used as osteoporosis drugs. To date, they are already used in the prevention of complications of bone metastases. Because the bisphosphonates can also reduce mortality in among other multiple myeloma, breast, and prostate cancer patients, they are now thoroughly studied in oncology. In particular, the more potent nitrogen-containing bisphosphonates have the potential to improve prognosis. The first part of this review will elaborate on the direct and indirect anti-tumoral effects of bisphosphonates, including induction of tumor cell apoptosis, inhibition of tumor cell adhesion and invasion, anti-angiogenesis, synergism with anti-neoplastic drugs, and enhancement of immune surveillance (e.g., through activation of γδ T cells and targeting macrophages). In the second part, we shed light on the current clinical position of bisphosphonates in the treatment of hematological and solid malignancies, as well as on ongoing and completed clinical trials investigating the therapeutic effect of bisphosphonates in cancer. Based on these recent data, the role of bisphosphonates is expected to further expand in the near future outside the field of osteoporosis and to open up new avenues in the treatment of malignancies.