Exploiting in silico modelling to enhance translation of liver cell therapies from bench to bedside.

Cell therapies are emerging as promising treatments for a range of liver diseases but translational bottlenecks still remain including: securing and assessing the safe and effective delivery of cells to the disease site; ensuring successful cell engraftment and function; and preventing immunogenic responses. Here we highlight three therapies, each utilising a different cell type, at different stages in their clinical translation journey: transplantation of multipotent mesenchymal stromal/signalling cells, hepatocytes and macrophages. To overcome bottlenecks impeding clinical progression, we advocate for wider use of mechanistic in silico modelling approaches. We discuss how in silico approaches, alongside complementary experimental approaches, can enhance our understanding of the mechanisms underlying successful cell delivery and engraftment. Furthermore, such combined theoretical-experimental approaches can be exploited to develop novel therapies, address safety and efficacy challenges, bridge the gap between in vitro and in vivo model systems, and compensate for the inherent differences between animal model systems and humans. We also highlight how in silico model development can result in fewer and more targeted in vivo experiments, thereby reducing preclinical costs and experimental animal numbers and potentially accelerating translation to the clinic. The development of biologically-accurate in silico models that capture the mechanisms underpinning the behaviour of these complex systems must be reinforced by quantitative methods to assess cell survival post-transplant, and we argue that non-invasive in vivo imaging strategies should be routinely integrated into transplant studies.

The impact of preoperative micronutrient supplementation in lung surgery. A prospective randomized trial of oral supplementation of combined alpha-ketoglutaric acid and 5-hydroxymethylfurfural.

OBJECTIVE: Preoperative micronutrient supplementation in fast-track surgery programs have shown to reduce complications, shorten recovery, and thereby lower costs. In a prospective randomized study, the metabolic effects of a combination of alpha-ketoglutaric acid (alpha-KG) and 5-hydroxymethylfurfural (5-HMF) were evaluated concerning their impact on improvement of exercise capacity and reduction of oxidative stress in lung surgery. METHODS: Thirty-two consecutive patients admitted for lung resection due to NSCLC were randomized to the study protocol. All patients received preoperative nutritional guidelines according to general recommendations. In 16 (study group), a supplementation of 7.2g alpha-KG and 720 mg 5-HMF/day (SANOPAL) was administered from days 1 to 10. Spiroergometric evaluation was carried out at baseline and day 10 after micronutrient supplementation. Blood samples for the determination of oxidative stress, i.e. carbonyl proteins (CPs) and isoprostanes (IPs) were taken on at baseline, in the operating room just before resection treatment, and 25 min after single lung ventilation (SLV). RESULTS: Spiroergometric re-evaluation showed a significant increase of VO2max (p=0.0108) and Watt's (p=0.011) in favor of the study group. Determination of oxidative stress showed a significant reduction of CPs before (p=0.048) and after SLV (p=0.0001) for the study group compared to the control group. The same is true for IPs before (p=0.003) and after SLV (p=0.02). Hospitalization and intensive care unit (ICU) of the study group showed a significant reduction compared to the control group (p=0.03 and p=0.02, respectively). CONCLUSIONS: Simple oral supplementation using a combination of alpha-KG and 5-HMF of preoperative micronutrition may therefore be one further step in a multimodality approach of fast-track surgery programs also in lung surgery.

Comparison of intracardiac echocardiography versus transesophageal echocardiography guidance for percutaneous transcatheter closure of atrial septal defect.

Transcatheter closure of interatrial septal defects is guided by transesophageal echocardiography (TEE), which requires general anesthesia in most cases. Using a new intracardiac echocardiographic (ICE) catheter may avoid endotracheal and esophageal intubation while using only local anesthesia. Forty-two patients underwent transcatheter interatrial septal defect closure; half of them underwent TEE guidance with general anesthesia and the other half underwent ICE guidance with local anesthesia. Device deployment success rate, adequate 2-dimensional and Doppler visualization of the defect and deployment steps, interatrial communication closure at 24 hours, and at 3 and 6 months, procedure time length, complications, fluoroscopic time, and length of hospitalization were compared between both methods. All interventions were completed successfully with no complications, except for 1 patient in the TEE group who had a minor oral trauma. Echocardiographic visualization of the septal defect and deployment was adequate by both methods. Catheterization laboratory time (92 +/- 18 vs 50 +/- 12 minutes, p <0.001) and interventional procedure length (47 +/- 8 vs 35 +/- 6 minutes, p <0.001) were shortened using ICE. There was no difference in the rate of closure after 6-month follow-up by either method. ICE guidance offers equivalent echocardiographic views compared with TEE and similar rates of closure. ICE is associated with decreased procedure length while eliminating the risks of endotracheal or esophageal intubation and general anesthesia.

Difficult retrieval of the EPI Filterwire with a 5 French FR4 coronary catheter following carotid stenting.

Carotid angioplasty and stenting with an embolic protection device is emerging as a reasonable alternative to carotid endarterectomy in high-risk patients. The deployment and retrieval of these devices, however, can be problematic. We describe a case where a 5 Fr FR4 coronary catheter was used to retrieve an EPI Filterwire device following carotid stenting.

Approaches to correct device malposition in percutaneous PFO closure: anatomical and technical implications.

We describe three patients with initial failure of transcatheter patent foramen ovale closure. Two patients had residual defects successfully closed during the initial session, and one patient had a persistent shunt, which was corrected at a later time. Anatomical and technical considerations and the role of intracardiac ultrasound are discussed.

Risk of bleeding complications is not increased in patients undergoing rescue versus primary percutaneous coronary intervention for acute myocardial infarction.

BACKGROUND: Concern for major bleeding complications (MBC) may lead to withholding of anticoagulation and fibrinolytic therapy in preparation for primary percutaneous coronary intervention (PCI), potentially resulting in unacceptable delays in achieving reperfusion. OBJECTIVES: The primary objective of this study was to evaluate MBC associated with primary and rescue PCI and how timing to revascularization affects this variable. METHODS: We evaluated 659 consecutive patients presenting within 24 hours of an acute ST elevation myocardial infarctions (MI). One hundred and eighty-three patients presented for rescue PCI and 476 for primary PCI. Eighty-seven rescue PCI patients were treated within 6 hours of their first dose of fibrinolytic. Demographics, procedural variables, outcomes, and major adverse cardiovascular events (MACE) were compared between the primary and rescue PCI groups and between early and late presenters in the rescue PCI group. RESULTS: We observed that the incidence of MBC was 8% in patients undergoing rescue PCI and 6% in primary PCI (P=0.35). There were no significant differences in bleeding associated with GP IIb/IIIa receptor antagonist use, procedural success, or MACE. Similarly, in patients presenting for early or late rescue PCI there was no significant difference in MBC, procedural success, or MACE. CONCLUSIONS: We concluded that early or late rescue PCI and primary PCI have similar rates of MBC and overall in-hospital outcomes for patients presenting within 24 hours of acute MI. Delaying the timing of a rapid reperfusion strategy in an effort to decrease the incidence of MBC complications is generally not justified.

Superiority of endovascular grafts compared to bare metal stents with transstent coil embolization for endovascular abdominal aortic aneurysm repair in patients at high risk for surgery.

We sought to determine the effectiveness of uncovered stents with aneurysm transstent coil embolization compared with endografts for percutaneous abdominal aortic aneurysm (AAA) repair. Thirty-six patients with AAA considered inoperable underwent endovascular repair using the Ancure bifurcated endograft or overlapping uncovered stents with transstent coil embolization. Procedural success, outcomes, serial aneurysm size, aneurysm blood flow, and growth ratios were compared between groups. One patient in each group died due to the procedure and two patients in the endograft cohort required acute surgical repair. After 2.0 +/- 0.8 years of follow-up, three patients required endograft placement, four surgical repair, three had AAA rupture, with two AAA-related deaths in the uncovered stent group. No late deaths or surgical conversion occurred in the endograft group. The primary AAA flow exclusion and aneurysm expansion rate and growth were superior in the endograft group and during follow-up. In high-risk patients with AAA, the use of endografts was superior compared to uncovered stents with transstent coil embolization for endovascular repair.

The use of brachytherapy to treat renal artery in-stent restenosis.

The percutaneous treatment of renal artery stenosis has become the accepted revascularization strategy by most physicians treating this disorder. Unfortunately, as renal artery angioplasty and stent implantation become increasingly prevalent the Achilles heel of angioplasty, in-stent restenosis, also rises. There are currently no data suggestive of the optimal treatment strategy for renal artery in-stent restenosis. However, given the similarities in the pathophysiology between renal artery and coronary artery in-stent restenosis, brachytherapy is considered a reasonable option. This is the strategy that has been suggested and used by a number of operators. This case report describes two examples of renal artery in-stent restenosis treated with angioplasty and brachytherapy.

Wireless laser-assisted angioplasty of the superficial femoral artery in patients with critical limb ischemia who have failed conventional percutaneous revascularization.

Percutaneous revascularization has become an effective treatment for patients suffering from chronic critical limb ischemia (CLI) due to chronic atherosclerotic obstructions, including total occlusions. Unlike other vascular beds, total chronic occlusions of the femoropopliteal arteries are frequently found in patients with severe claudication or CLI. As a consequence, patients with long chronic total occlusions of the femoropopliteal arteries are generally not considered optimal candidates for percutaneous revascularization and are frequently referred for surgical revascularization. In the present study, we sought to evaluate the feasibility, safety, and outcome of a modified wireless laser ablation technique to recanalize total occlusions in patients with CLI who had failed conventional percutaneous techniques for limb salvage. Procedural success, complications, actuarial freedom of limb loss, and surgical revascularization were evaluated in 25 patients after a mean follow-up of 13 +/- 8 months. Procedural success was achieved in 21 patients (84%). Actuarial freedom from surgical revascularization or limb loss was 72%. There was one vascular perforation. No deaths or distal embolization occurred. Three patients (12%) required limb amputation during follow-up, whereas four patients (16%) had surgical revascularization in the presence of feasible vascular targets. Limb salvage was achieved in 88% of patients when laser recanalization was combined with surgical revascularization. These results suggest that the use of laser ablation is safe and facilitates angioplasty and stenting in patients with CLI that failed conventional endovascular revascularization. This technique might prevent limb loss in patients with CLI due to femoropopliteal total occlusions, particularly in patients with unsuitable anatomy for surgical revascularization.

Interatrial defect sizing by intracardiac and transesophageal echocardiography compared with fluoroscopic measurements in patients undergoing percutaneous transcatheter closure.

The purpose of this study was to evaluate prospectively the feasibility and accuracy of using echocardiographic measurements by transesophageal and intracardiac echocardiography (TEE and ICE, respectively) for interatrial septal defect sizing during percutaneous transcatheter closure. Forty-two patients underwent balloon sizing of interatrial septal defects using TEE in 21 of them and ICE in the other half. These measurements were correlated with quantitative fluoroscopic analysis and evaluated for bias and agreement between methods using a Bland-Altman analysis. Echocardiographic measurements were obtained by ICE and TEE in all patients. An excellent correlation was found between TEE and quantitative fluoroscopy (r = 0.898; P < 0.001) and between ICE and quantitative fluoroscopy (r = 0.876; P < 0.001), with a significant agreement (P < 0.001) and minimal positive bias toward the echocardiographic measurements. Both TEE and ICE are excellent methods of interatrial defect sizing when compared with quantitative fluoroscopic measurements.