Clinical characteristics and outcomes of alcohol septal ablation in the era of transcatheter valve interventions.

BACKGROUND: The clinical efficacy and safety of alcohol septal ablation (ASA) for obstructive hypertrophic cardiomyopathy (HCM) have been well-established; however, less is known about outcomes in patients undergoing preemptive ASA before transcatheter mitral valve replacement (TMVR). AIMS: The goal of this study is to characterize the procedural characteristics and examine the clinical outcomes of ASA in both HCM and pre-TMVR. METHODS: This retrospective study compared procedural characteristics and outcomes in patient who underwent ASA for HCM and TMVR. RESULTS: In total, 137 patients were included, 86 in the HCM group and 51 in the TMVR group. The intraventricular septal thickness (mean 1.8 vs. 1.2 cm; p < 0.0001) and the pre-ASA LVOT gradient (73.6 vs. 33.8 mmHg; p ≤ 0.001) were higher in the HCM group vs the TMVR group. The mean volume of ethanol injected was higher (mean 2.4 vs. 1.7 cc; p < 0.0001). The average neo-left ventricular outflow tract area increased significantly after ASA in the patients undergoing TMVR (99.2 ± 83.37 mm2 vs. 196.5 ± 114.55 mm2; p = <0.0001). The HCM group had a greater reduction in the LVOT gradient after ASA vs the TMVR group (49.3 vs. 18 mmHg; p = 0.0040). The primary composite endpoint was higher in the TMVR group versus the HCM group (50.9% vs. 25.6%; p = 0.0404) and had a higher incidence of new permanent pacemaker (PPM) (25.5% vs. 18.6%; p = 0.3402). The TMVR group had a higher rate of all-cause mortality (9.8% vs. 1.2%; p = 0.0268). CONCLUSIONS: Preemptive ASA before TMVR was performed in patients with higher degree of clinical comorbidities, and correspondingly is associated with worse short-term clinical outcomes in comparison to ASA for HCM patients. ASA before TMVR enabled percutaneous mitral interventions in a small but significant minority of patients that would have otherwise been excluded. The degree of LVOT and neoLVOT area increase is significant and predictable.

Feasibility and technicality of aortic valve lithotripsy-facilitate balloon valvuloplasty in patients with severe aortic stenosis unsuitable for immediate valvular replacement.

BACKGROUND: Aortic valve lithotripsy can fragment aortic valve calcium deposits and potentially restore leaflet pliability in animal model and ex-vivo, but clinical data is limited. Transcatheter aortic valve implantation (TAVR) might not be feasible as an urgent procedure in critically ill patients. Balloon valvuloplasty has the major limitation of valve recoil and inducing aortic regurgitation. AIMS: To determine the clinical feasibility of aortic valve lithotripsy-facilitated balloon valvuloplasty in patients with severe aortic stenosis unsuitable for valvular replacement. METHODS: We performed lithotripsy as adjunctive therapy to balloon aortic valvuloplasty in ten consecutive patients, most of whom were deemed unfit for TAVR. Lithotripsy of the aortic valve was performed with simultaneous inflation of one to three peripheral lithotripsy balloons to deliver ultrasound pulses. Rapid pacing was not used during lithotripsy. Aortic valve velocity, gradient, and valve area were measured before and after the procedure by echocardiogram. Transvalvular pressure gradient was recorded intra-procedurally. Periprocedural and ninety-day clinical outcomes were followed. RESULTS: Procedure was technically successful in 9 out of 10 patients and aborted in one patient due to cardiogenic shock. One patient had femoral closure device related complication. There was a statistically significant decrease in valvular gradient and increase in aortic valve area. 9 out of 10 patients recovered from acute episode and were discharged. 6 patients had improvement in NYHA class. 4 patients were subsequently able to receive TAVR. 90-day mortality occurred in 3 patients. There was no stroke or bradyarrhythmia peri-procedurally and no heart failure hospitalization at 90 days. CONCLUSION: Aortic valve lithotripsy-facilitated balloon valvuloplasty has reasonable feasibility, safety and technical reproducibility and acute clinical result. Hemodynamic effect is similar to that of balloon valvuloplasty reported in the literature. Subsequent Prognosis is not altered in critically ill patients.

Phallus preservation and reconstruction: 5-year outcomes of national penile cancer centralisation in the Republic of Ireland.

INTRODUCTION: Penile cancer is a rare urological malignancy with an age-standardised incidence of 0.8 per 100,000 person-years [1]. Given this low incidence it has been suggested that centralised care may improve patient outcomes in relation to phallus sparing surgery and nodal assessment [2]. We aim to assess the outcomes after 5-years of national centralisation of penile cancer care. METHODS: A retrospective analysis of prospectively collected data was performed. All patients undergoing penile cancer surgery from January 2018 to December 2022 following centralisation of care were included. The primary outcome was proportion of phallus sparing procedures performed. Secondary outcomes were patient characteristics, histologic outcomes and procedures performed. RESULTS: 124 patients underwent surgery in the study period. Mean age was 64.49 (±13.87). Overall, 82.3% of patients underwent phallus sparing surgery. This remained stable over the 5-year period from 2018 to 2022 â€‹at 92%, 85%, 76%, 79% and 78% respectively (p â€‹= â€‹0.534). 62.7% had reconstruction performed, including split-thickness skin graft neoglans formation, (57.8% [n â€‹= â€‹37]), preputial flap (32.8% [n â€‹= â€‹21]), glans resurfacing (4.7% [n â€‹= â€‹3]), shaft advancement flap (1.6% [n â€‹= â€‹1]), penile shaft skin graft (1.6% [n â€‹= â€‹1]), and partial penectomy with urethral centralisation (1.6% [n â€‹= â€‹1]). Phallus preservation was not affected by positive nodal status (OR 0.75 [95% CI 0.249-2.266], p â€‹= â€‹0.564) or T-stage ≥1b (OR 0.51 [95% CI 0.153-1.711], p â€‹= â€‹0.276). There has been a significant reduction in Nx nodal status from 64% in 2017 to 15% in 2021 (p â€‹= â€‹0.009). CONCLUSION: Centralisation of treatment for rare malignancies such as penile cancer may improve oncologic outcomes and rates of phallus preservation. This study has shown centralisation to has a high rate of phallus preservation. Further long-term analysis of outcomes in Ireland is required.

GABA co-released from striatal dopamine axons dampens phasic dopamine release through autoregulatory GABAA receptors.

Striatal dopamine axons co-release dopamine and gamma-aminobutyric acid (GABA), using GABA provided by uptake via GABA transporter-1 (GAT1). Functions of GABA co-release are poorly understood. We asked whether co-released GABA autoinhibits dopamine release via axonal GABA type A receptors (GABAARs), complementing established inhibition by dopamine acting at axonal D2 autoreceptors. We show that dopamine axons express α3-GABAAR subunits in mouse striatum. Enhanced dopamine release evoked by single-pulse optical stimulation in striatal slices with GABAAR antagonism confirms that an endogenous GABA tone limits dopamine release. Strikingly, an additional inhibitory component is seen when multiple pulses are used to mimic phasic axonal activity, revealing the role of GABAAR-mediated autoinhibition of dopamine release. This autoregulation is lost in conditional GAT1-knockout mice lacking GABA co-release. Given the faster kinetics of ionotropic GABAARs than G-protein-coupled D2 autoreceptors, our data reveal a mechanism whereby co-released GABA acts as a first responder to dampen phasic-to-tonic dopamine signaling.

Contemporary experience of percutaneous management of complex aortic and ventricular pseudoaneurysms associated to perivalvular leak: A case series and review of literature.

BACKGROUND: Percutaneous closure of aortic and ventricular pseudoaneurysms (PSA) has only been reported on a case report and series basis. In previous case reports, percutaneous closure has been performed successfully in patients of prohibitive surgical risk. This case series aims to show feasibility of percutaneous closure of aortic and ventricular pseudoaneurysm secondary to perivalvular leak (PVL) in a small patient population and the utility of multimodality imaging as an integral tool in procedural planning. This is the largest complex case series to date describing the feasibility and success rate of complex PSA closure, with a follow-up period of up to 4 years. MATERIAL AND METHODS: We performed institutional review and systemic literature review to identify all paravalvular leak cases with associated pseudoaneurysm formation for which a closure procedure was performed. Ten patients were identified. Pooled analysis for cases from institutional review (n = 10) and systemic literature review (n = 39) was performed. The success rate was 100 %. At 30-days, the mortality was 0 %. CONCLUSION: In paravalvular leak patients with subsequent pseudoaneurysm formation, exhaustive imaging evaluation is required for closure. However, it can be achievable with favorable rates of success.

The role of total neoadjuvant therapy in locally advanced rectal cancer: a survey of specialists attending the All-Ireland Colorectal Cancer Conference 2022 including lead investigators of OPRA, PRODIGE-23 and RAPIDO.

BACKGROUND: The treatment of locally advanced rectal cancer (LARC) has evolved following recent landmark trials of total neoadjuvant therapy (TNT)-the delivery of preoperative chemotherapy sequenced with radiation. AIM: To assess the preferences of colorectal surgery (CRS), radiation oncology (RO) and medical oncology (MO) specialists attending the All-Ireland Colorectal Cancer Conference (AICCC) 2022 regarding the neoadjuvant management of LARC. METHODS: A live electronic survey explored the preferred treatment approach and TNT regimen for early-, intermediate-, bad-, and advanced-risk categories of rectal cancer according to the European Society of Medical Oncology (ESMO) guidelines. The survey was preceded by an update from lead investigators of TNT trials (OPRA, PRODIGE-23 and RAPIDO), who then participated in a multidisciplinary panel discussion. RESULTS: Ten CRS, 7 RO and 15 MO (32 of 45 specialists) participated fully in the survey resulting in a response rate of 71%. Ninety-four percent, 76% and 53% of specialists preferred a TNT approach for patients with advanced, bad, and intermediate-risk rectal cancer, respectively. A consolidation TNT regimen of long-course chemoradiotherapy followed by chemotherapy was the most preferred regimen. Upfront surgery was preferred by 77% for early-risk disease. CONCLUSION: This survey illustrated the general acceptance of TNT by rectal cancer specialists attending the AICCC as a valuable treatment strategy for higher-risk category LARC. Whilst the treatment of LARC changes, it remains best practice to individualize care, incorporating the selective use of TNT as discussed by an MDT and in keeping with the patient's goals of care.

3D print and multi-modality imaging guided transcatheter closure of multiple left ventricular pseudoaneurysms.

Left ventricular pseudoaneurysm (PSA) after surgical aortic valve replacement (AVR) is a known but uncommon complication. It is associated with risks such as thromboembolism and life-threatening rupture. Surgical repair has traditionally been utilized in low-risk patients but transcatheter closure has become a promising therapeutic option. This case report describes the utility of multimodality imaging in pre-, intra-, and post-procedural evaluation of transcatheter PSA closure and is among the first to demonstrate the utility of 3D print model.

Trimodality therapy versus perioperative chemotherapy in the management of locally advanced adenocarcinoma of the oesophagus and oesophagogastric junction (Neo-AEGIS): an open-label, randomised, phase 3 trial.

BACKGROUND: The optimum curative approach to adenocarcinoma of the oesophagus and oesophagogastric junction is unknown. We aimed to compare trimodality therapy (preoperative radiotherapy with carboplatin plus paclitaxel [CROSS regimen]) with optimum contemporaneous perioperative chemotherapy regimens (epirubicin plus cisplatin or oxaliplatin plus fluorouracil or capecitabine [a modified MAGIC regimen] before 2018 and fluorouracil, leucovorin, oxaliplatin, and docetaxel [FLOT] subsequently). METHODS: Neo-AEGIS (CTRIAL-IE 10-14) was an open-label, randomised, phase 3 trial done at 24 centres in Europe. Patients aged 18 years or older with clinical tumour stage T2-3, nodal stage N0-3, and M0 adenocarcinoma of the oesophagus and oesophagogastric junction were randomly assigned to perioperative chemotherapy (three preoperative and three postoperative 3-week cycles of intravenous 50 mg/m2 epirubicin on day 1 plus intravenous 60 mg/m2 cisplatin or intravenous 130 mg/m2 oxaliplatin on day 1 plus continuous infusion of 200 mg/m2 fluorouracil daily or oral 625 mg/m2 capecitabine twice daily up to 2018, with four preoperative and four postoperative 2-week cycles of 2600 mg/m2 fluorouracil, 85 mg/m2 oxaliplatin, 200 mg/m2 leucovorin, and 50 mg/m2 docetaxel intravenously on day 1 as an option from 2018) or trimodality therapy (41·4 Gy in 23 fractions on days 1-5, 8-12, 15-19, 22-26, and 29-31 with intravenous area under the curve 2 mg/mL per min carboplatin plus intravenous 50 mg/m2 paclitaxel on days 1, 8, 15, 22, and 29). The primary endpoint was overall survival, assessed in all randomly assigned patients who received at least one dose of study drug, regardless of which study drug they received, by intention to treat. Secondary endpoints were disease-free survival, site of treatment failure, operative complications, toxicity, pathological response (complete [ypT0N0] and major [tumour regression grade 1 and 2]), margin-free resection (R0), and health-related quality of life. Toxicity and safety data were analysed in the safety population, defined as patients who took at least one dose of study drug, according to treatment actually received. The initial power calculation was based on superiority of trimodality therapy (n=366 patients); it was adjusted after FLOT became an option to a non-inferiority design with a margin of 5% for perioperative chemotherapy (n=540). This study is registered with ClinicalTrials.gov, NCT01726452. FINDINGS: Between Jan 24, 2013, and Dec 23, 2020, 377 patients were randomly assigned, of whom 362 were included in the intention-to treat population (327 [90%] male and 360 [99%] White): 184 in the perioperative chemotherapy group and 178 in the trimodality therapy group. The trial closed prematurely in December, 2020, after the second interim futility analysis (143 deaths), on the basis of similar survival metrics and the impact of the COVID-19 pandemic. At a median follow-up of 38·8 months (IQR 16·3-55·1), median overall survival was 48·0 months (95% CI 33·6-64·8) in the perioperative chemotherapy group and 49·2 months (34·8-74·4) in the trimodality therapy group (3-year overall survival 55% [95% CI 47-62] vs 57% [49-64]; hazard ratio 1·03 [95% CI 0·77-1·38]; log-rank p=0·82). Median disease-free survival was 32·4 months (95% CI 22·8-64·8) in the perioperative chemotherapy group and 24·0 months (18·0-40·8) in the trimodality therapy group [hazard ratio 0·89 [95% CI 0·68-1·17]; log-rank p=0·41). The pattern of recurrence, locoregional or systemic, was not significantly different (odds ratio 1·35 [95% CI 0·63-2·91], p=0·44). Pathological complete response (odds ratio 0·33 [95% CI 0·14-0·81], p=0·012), major pathological response (0·21 [0·12-0·38], p<0·0001), and R0 rates (0·21 [0·08-0·53], p=0·0003) favoured trimodality therapy. The most common grade 3-4 adverse event was neutropenia (49 [27%] of 183 patients in the perioperative chemotherapy group vs 11 [6%] of 178 patients in the trimodality therapy group), followed by diarrhoea (20 [11%] vs none), and pulmonary embolism (ten [5%] vs nine [5%]). One (1%) patient in the perioperative chemotherapy group and three (2%) patients in the trimodality therapy group died from serious adverse events, two (one in each group) of which were possibly related to treatment. No differences were seen in operative mortality (five [3%] deaths in the perioperative chemotherapy group vs four [2%] in the trimodality therapy group), major morbidity, or in global health status at 1 and 3 years. INTERPRETATION: Although underpowered and incomplete, Neo-AEGIS provides the largest comprehensive randomised dataset for patients with adenocarcinoma of the oesophagus and oesophagogastric junction treated with perioperative chemotherapy (predominantly the modified MAGIC regimen), and CROSS trimodality therapy, and reports similar 3-year survival and no major differences in operative and health-related quality of life outcomes. We suggest that these data support continued clinical equipoise. FUNDING: Health Research Board, Cancer Research UK, Irish Cancer Society, Oesophageal Cancer Fund, and French National Cancer Institute.

Permutations in pacer wire implantation in patients evaluated for transcatheter tricuspid valve interventions.

Pacer wire induced tricuspid regurgitation is not well-understood. The mechanisms behind pacer wired induced tricuspid regurgitation have not been clearly defined. This clinical vignette sets to identify different technical mechanisms behind cardiac lead induced tricuspid regurgitation to help optimize cardiac lead implantation strategies for future device implantation.

Preclinical evaluation of the CDK4/6 inhibitor palbociclib in combination with a PI3K or MEK inhibitor in colorectal cancer.

BACKGROUND: Studies have demonstrated the efficacy of Palbociclib (CDK 4/6 inhibitor), Gedatolisib (PI3K/mTOR dual inhibitor) and PD0325901 (MEK1/2 inhibitor) in colorectal cancer (CRC), however single agent therapeutics are often limited by the development of resistance. METHODS: We compared the anti-proliferative effects of the combination of Gedatolisib and Palbociclib and Gedatolisib and PD0325901 in five CRC cell lines with varying mutational background and tested their combinations on total and phosphoprotein levels of signaling pathway proteins. RESULTS: The combination of Palbociclib and Gedatolisib was superior to the combination of Palbociclib and PD0325901. The combination of Palbociclib and Gedatolisib had synergistic anti-proliferative effects in all cell lines tested [CI range: 0.11-0.69] and resulted in the suppression of S6rp (S240/244), without AKT reactivation. The combination of Palbociclib and Gedatolisib increased BAX and Bcl-2 levels in PIK3CA mutated cell lines. The combination of Palbociclib and Gedatolisib caused MAPK/ERK reactivation, as seen by an increase in expression of total EGFR, regardless of the mutational status of the cells. CONCLUSION: This study shows that the combination of Palbociclib and Gedatolisib has synergistic anti-proliferative effects in both wild-type and mutated CRC cell lines. Separately, the phosphorylation of S6rp may be a promising biomarker of responsiveness to this combination.

Application of Impella Mechanical Circulatory Support Devices in Transcatheter Aortic Valve Replacement and Balloon Aortic Valvuloplasty: A Single-Center Experience.

BACKGROUND/PURPOSE: Percutaneous valve interventions for aortic stenosis (AS) include transcatheter aortic valve replacement (TAVR) and balloon aortic valvuloplasty (BAV). Intraprocedural mechanical circulatory support (MCS) with Impella devices (Abiomed, Danvers, MA) is used in select high-risk patients, although data regarding its efficacy is limited. This study sought to evaluate the clinical outcomes of Impella use in patients with AS who underwent TAVR and BAV at a quaternary-care center. METHODS/MATERIALS: All patients with severe AS who underwent TAVR and BAV with Impella between 2013 and 2020 were included. Patient demographics, outcomes, complications, and 30-day mortality data was analyzed. RESULTS: Over the study period 2680 procedures were performed, 1965 TAVR and 715 BAV. 120 utilized Impella support, 26 TAVR and 94 BAV. Among TAVR Impella cases, justifications for MCS included cardiogenic shock (53.9 %), cardiac arrest (19.2 %), and coronary occlusion (15.4 %). Among BAV Impella cases, justifications for MCS included cardiogenic shock (55.3 %) and protected percutaneous coronary intervention (43.6 %). The 30-day mortality rate in TAVR Impella was 34.6 % and in BAV Impella was 28 %. BAV Impella cases involving cardiogenic shock had a higher rate of 45 %. Impella remained in-use past 24 h from the procedure in 32.2 % cases. Vascular access-related complications occurred in 4.8 % cases and bleeding complications occurred in 1.5 % cases. Conversion to open-heart surgery occurred in 0.7 % cases. CONCLUSIONS: MCS is an option for high-risk patients with severe AS who require TAVR and BAV. Despite hemodynamic support, the 30-day mortality rate remained high especially in cases where support was employed for cardiogenic shock.

Utilization of TandemHeart in cardiogenic shock: Insights from the THEME registry.

BACKGROUND: TandemHeart has been demonstrated to improve hemodynamic and metabolic complications in cardiogenic shock (CS). Contemporary outcomes have not been reported. OBJECTIVES: To evaluate the outcomes of the TandemHeart (LivaNova) in contemporary real-world use. METHODS: We analyzed baseline characteristics, hemodynamic changes, and outcomes of all patients treated with TandemHeart who were enrolled in the THEME registry, a multicenter, prospective, observational study. RESULTS: Between May 2015 and June 2019, 50 patients underwent implantation of the TandemHeart device. 22% of patients had TandemHeart implanted within 12 h, 32% within 24 h, and 52% within 48 h of CS diagnosis. Cardiac index (CI) was significantly improved 24 h after implantation (median change 1.0, interquartile range (IQR) (0.5-1.4 L/min/m2 ). In survivors, there was a significant improvement in CI (1.0, IQR (0.5-2.25 L/min/m2 ) and lactate clearance -2.3 (-5.0 to -0.7 mmol/L). The 30-day and 180-day survival were 74% (95% confidence interval: 60%-85%) and 66% (95% confidence interval: 51%-79%), respectively. Survival was similarly high in those in whom TandemHeart has been used as a bridge to surgery (85% 180-day survival). CONCLUSION: In a contemporary cohort of patients presenting in CS, the use of TandemHeart is associated with a 74% 30-day survival and a 66% 180-day survival.

FOXO1 represses PPARα-Mediated induction of FGF21 gene expression.

Fibroblast growth factor 21 (FGF21) has emerged as a metabolic regulator that exerts potent anti-diabetic and lipid-lowering effects in animal models of obesity and type 2 diabetes, showing a protective role in fatty liver disease and hepatocellular carcinoma progression. Hepatic expression of FGF21 is regulated by PPARα and is induced by fasting. Ablation of FoxO1 in liver has been shown to increase FGF21 expression in hyperglycemia. To better understand the role of FOXO1 in the regulation of FGF21 expression we have modified HepG2 human hepatoma cells to overexpress FoxO1 and PPARα. Here we show that FoxO1 represses PPARα-mediated FGF21 induction, and that the repression acts on the FGF21 gene promoter without affecting other PPARα target genes. Additionally, we demonstrate that FoxO1 physically interacts with PPARα and that FoxO1/3/4 depletion in skeletal muscle contributes to increased Fgf21 tissue levels. Taken together, these data indicate that FOXO1 is a PPARα-interacting protein that antagonizes PPARα activity on the FGF21 promoter. Because other PPARα target genes remained unaffected, these results suggest a highly specific mechanism implicated in FGF21 regulation. We conclude that FGF21 can be specifically modulated by FOXO1 in a PPARα-dependent manner.