Calprotectin as a new inflammatory marker of abdominal aortic aneurysm: A pilot study.

INTRODUCTION: Abdominal aortic aneurysm (AAA) is a relevant clinical problem due to the risk of rupture of progressively dilated infrarenal aorta. It is characterized by degradation of elastic fibers, extracellular matrix, and inflammation of the arterial wall. Though neutrophil infiltration is a known feature of AAA, markers of neutrophil activation are scarcely analyzed; hence, the main objective of this study. METHODS: Plasma levels of main neutrophil activation markers were quantified in patients with AAA and a double control group (CTL) formed by healthy volunteers (HV) and patients with severe atherosclerosis submitted for carotid endarterectomy (CE). Calprotectin, a cytoplasmic neutrophil protein, was quantified, by Western blot, in arterial tissue samples from patients with AAA and organ donors. Colocalization of calprotectin and neutrophil elastase was assessed by immunofluorescence. RESULTS: Plasma calprotectin and IL-6 were both elevated in patients with AAA compared with CTL (p ⩽ 0.0001) and a strong correlation was found between both molecules (p < 0.001). This difference was maintained when comparing with HV and CE for calprotectin but only with HV for IL-6. Calprotectin was also elevated in arterial tissue samples from patients with AAA compared with organ donors (p < 0.0001), and colocalized with neutrophils in the arterial wall. CONCLUSIONS: Circulating calprotectin could be a specific AAA marker and a potential therapeutical target. Calprotectin is related to inflammation and neutrophil activation in arterial wall and independent of other atherosclerotic events.

Cell Therapy of Vascular and Neuropathic Complications of Diabetes: Can We Avoid Limb Amputation?

Globally, a leg is amputated approximately every 30 seconds, with an estimated 85 percent of these amputations being attributed to complications arising from diabetic foot ulcers (DFU), as stated by the American Diabetes Association. Peripheral arterial disease (PAD) is a risk factor resulting in DFU and can, either independently or in conjunction with diabetes, lead to recurring, slow-healing ulcers and amputations. According to guidelines amputation is the recommended treatment for patients with no-option critical ischemia of the limb (CTLI). In this article we propose cell therapy as an alternative strategy for those patients. We also suggest the optimal time-frame for an effective therapy, such as implanting autologous mononuclear cells (MNCs), autologous and allogeneic mesenchymal stromal cells (MSC) as these treatments induce neuropathy relief, regeneration of the blood vessels and tissues, with accelerated ulcer healing, with no serious side effects, proving that advanced therapy medicinal product (ATMPs) application is safe and effective and, hence, can significantly prevent limb amputation.

"In Vitro" Evaluation of Energy-Based Sealing of Graft Side Branches in Bypass Surgery.

INTRODUCTION: Our objective was to compare the in vitro efficacy of electrothermal bipolar [EB] vessel sealing and ultrasonic harmonic scalpel [HS] versus mechanical interruption, with conventional ties or surgical clips (SC), in sealing saphenous vein (SV) collaterals, during its eventual preparation for bypass surgery. METHODS: Experimental in vitro study on 30 segments of SV. Each fragment included two collaterals at least 2 mm in diameter. One of them was sealed by ligation with 3/0 silk ties (control) and the other one with EB (n = 10), HS (n = 10) or medium-6 mm SC (n = 10). After incorporation in a closed circuit with pulsatile flow, the pressure was progressively increased until causing rupture. Collateral diameter, burst pressure, leak point, and histological study were recorded. RESULTS: Burst pressure was higher for SC (1320.20 ± 373.847 mmHg) as compared with EB (942.2 ± 344.9 mmHg, p = 0.065), and especially with HS (637.00 ± 320.61 mmHg, p = 0.0001). No statistically significant difference between EB and HS was found, and bursting always happened at supraphysiological pressures. The leak point for HS was always detected in the sealing zone (10/10), while for EB and SC, it occurred in the sealing zone only in 6/10(60%) and 4/10(40%), respectively (p = 0.015). CONCLUSIONS: Energy delivery devices showed similar efficacy and safety in sealing of SV side branches. Although bursting pressure was lower than with tie ligature or SC, non-inferiority efficacy was shown at the range of physiological pressures in both, EB and HS. Due to their speed and easy handling, they may be useful in the preparation of the venous graft during revascularization surgery. However, remaining questions about healing process, potential spread of tissue damage and sealing durability, will require further analysis.

Update on the Use of Infrared Thermography in the Early Detection of Diabetic Foot Complications: A Bibliographic Review.

Foot lesions are among the most frequent causes of morbidity and disability in the diabetic population. Thus, the exploration of preventive control measures is vital for detecting early signs and symptoms of this disease. Infrared thermography is one of the complementary diagnostic tools available that has proven to be effective in the control of diabetic foot. The last review on this topic was published in 2015 and so, we conducted a bibliographic review of the main databases (PubMed, the Web of Science, Cochrane library, and Scopus) during the third quarter of 2023. We aimed to identify the effectiveness of infrared thermography as a diagnostic element in pre-ulcerous states in diabetic patients and to detect diabetic foot ulcer complications. We obtained a total of 1199 articles, 26 of which were finally included in the present review and published after 2013. After analyzing the use of infrared thermography in diabetic patients both with and without ulcers, as well as in healthy individuals, we concluded that is an effective tool for detecting early-stage ulcers in diabetic foot patients.

Comparison of Three Workstations For Abdominal Aortic Aneurysm Sizing: Impact in Decision Making and Graft Selection.

PURPOSE: The aim of this study was to assess the agreement of multiplanar reconstruction (MPR) and semiautomated central lumen line (CLL) analysis of abdominal aortic aneurysms (AAA), with 3 different software workstations (WS1, WS2, WS3) and 2 experienced practitioners as well as to analyze its eventual impact in graft selection. MATERIALS AND METHODS: Twenty computed tomography (CT) angiography data sets were randomly chosen from a series of 100 consecutive studies. Measurements were performed twice by each reader, in random order, and included 8 parameters (5 diameters and 3 lengths). Each observer performed a complete set of 60 studies. Intra-observer and interobserver variability for every WS was assessed. Measurements were evaluated using Bland-Altman analysis, correlation coefficients (r), and concordance correlation coefficients (CCC [95% confidence interval (CI)]). RESULTS: A high overall agreement between repeated measurements for both observers was obtained (r=0.989; CCC=0.988 [0.982-0.992] and r=0.998; CCC=0.996 [0.994-0.997], for observers 1 and 2, respectively). However, reproducibility for individual parameters was excellent for observer 2 and only moderate for observer 1. A high overall agreement was obtained for interobserver concordance (r=0.987; CCC=0.986 [0.982-0.989]). When analyzing for individual parameters, greatest interobserver differences were found at CLL measurement of the diameter of aortic neck (WS2) and bifurcation (WS1 and WS2) as well as iliac diameter in all 3 WS for both CLL and MPR. Similar differences were observed in paired comparison between WS when involving these parameters. Careful inspection of Bland-Altman charts revealed some cases of disagreement between WS and observers that would affect decision making on graft selection, changing the neck diameter to a different size, in 2 cases when measuring with WS1, and iliac diameter in 4 cases (2 of them with WS1 and 2 with WS2). Greatest discordance was observed regarding ipsilateral iliac length affecting 7 measurements that would lead to change the length of the selected limb graft (2 with WS1, 3 with WS2, and 2 with WS3). CONCLUSIONS: Although a high agreement between different observers using different WS for AAA measurements is to be expected, small differences may lead to the selection of a different graft size. The use of a single software by experienced users, and double check by a different one, may be advisable. CLINICAL IMPACT: Influence of inter and intraobserver variability in CT measurements during planning of endovascular aneurysm repair (EVAR) has been extensively reviewed. However, its impact in graft selection (final choose of diameter and lengths) has been scarcely analyzed. The results of this study suggest that, although a high agreement between different observers using different workstations for AAA measurements is to be expected, small differences may lead to the selection of a different graft size. The use of a single software by experienced users, and double check by a different one, may be advisable.

Extended methane mitigation capacity of a mid-season drainage beyond the rice growing season: a case in Spain.

Rice cultivation is a major source of methane (CH4) emissions. Intermittent irrigation systems in rice cultivation, such as the mid-season drainage (MSD), are effective strategies to mitigate CH4 emissions during the growing season, though the reduction rates are variable and dependent on the crop context. Aeration periods induce alteration of soil CH4 dynamics that can be prolonged after flooding recovery. However, whether these changes persist beyond the growing season remains underexplored. A field experiment was conducted in Spain to study the effect of MSD implemented during the rice growing season on greenhouse gas (GHG) emissions in relation to the standard permanently flooded water management (PFL). Specifically, the study aimed at (1) assessing the CH4 mitigation capacity of MSD in the studied area and (2) testing the hypothesis that the mitigating effect of MSD can be extended into the following winter flooded fallow season. Year-round GHG sampling was conducted, seasonal and annual cumulative emissions of CH4 and N2O as well as the global warming potential were calculated, and grain yield was measured. MSD reduced growing season CH4 emissions by ca. 80% without yield penalties. During the flooded fallow season, MSD reduced CH4 emissions by ca. 60%, despite both fields being permanently flooded. The novelty of our observations lies in the amplified mitigation capacity of MSD by extending the CH4 mitigation effect to the following flooded winter fallow season. This finding becomes especially relevant in rice systems with flooded winter fallow season given the large contribution of this season to the annual CH4 emissions.

Intraplaque calcium and its relation with the progression of carotid atheromatous disease.

BACKGROUND: Calcification and progression of atheromatous disease (AD) both have been independently related with the risk of stroke. However, the link between the two phenomena is still unclear. The main objective of this study was to analyze the temporal evolution of Ca content of carotid atheromatous plaques and its relation with the progression of carotid AD using quantitative CT Angiography (CTA). METHODS: Forty-three asymptomatic patients with stenosis of the internal carotid artery (ICA)>50% completed the study. Contrast mold volume and calcium (Ca) content by quantitative CTA and Modified Agatston Score (Ca volume × radiological density) were assessed at baseline and after 12±2 months. Biochemical parameters, including main markers of Ca/Phosphorus (P) metabolism, were determined. RESULTS: CTA measurement showed an increase of volumetric stenosis (volume decrease of the contrast mold), compared to baseline (475.45 [155.6] mm3 × U.H vs. 501.3 [171.9] mm3 × U.H; P=0.04) as well as an increase of intraplaque Ca (64.58 [57.8] mm3 × U.H. vs. 56.8 [52.3] P=0.002). An inverse correlation between baseline Ca content and volumetric stenosis progression (r=-0.481; P<0.001), as well as between the increase of carotid Ca and plasma levels of vitamin D (r=0.4; P=0.025) were also found. Multiple regression analysis found a model with baseline intraplaque Ca, adjusted by Body Mass Index (BMI) as most predictive of carotid AD progression. CONCLUSIONS: These results suggest that a higher content of Ca confers greater stability against the progression of carotid AD and, eventually, its ability to generate symptomatology.

Thrombospondins in human aortic aneurysms.

Thrombospondins are a family of matricellular proteins with a multimeric structure that is known to be involved in several biological and pathological processes. Their relationship with vascular disorders has raised special interest recently. Aortic aneurysms are related to the impairment of vascular remodeling, in which extracellular matrix proteins seem to play an important role. Thus, research in thrombospondins, and their potential role in aneurysm development is progressively gaining importance. Nevertheless, studies showing thrombospondin dysregulation in human samples are still scarce. Although studies performed in vitro and in vivo models are essential to understand the molecular mechanisms and pathways underlying the disorder, descriptive studies in human samples are also necessary to ascertain their real value as biomarkers and/or novel therapeutic targets. The present article reviews the latest findings regarding the role of thrombospondins in aortic aneurysm development, paying particular attention to the studies performed in human samples.

Usefulness of red cell distribution width to predict mortality in patients undergoing endovascular repair of abdominal aortic aneurysms.

BACKGROUND: Red cell distribution width (RDW) reflecting impaired erythropoyesis, has been associated with poor prognosis and mortality in several conditions. The aim of this study was to determine the relationship between RDW and the 5-year survival after the endovascular repair of abdominal aortic aneurysms (EVAR) and its ability to improve the discriminative power of a survival predictive score. METHODS: Retrospective analysis of 284 patients undergoing EVAR at a single centre. The pattern of relationship between RDW and survival was assessed with penalized smoothing splines. Categorized RDW values were added to a predictive score based in standard preoperative variables, whose improvement in discriminative power was calculated on the basis of changes in the C-statistics and the continuous Net Reclassification Index (c-NRI). RESULTS: The survival rate at 5 years was 66.2% and was independently associated with hemoglobin (HR=0.85, P<0.004), statin intake (HR=0.54, P<0.004), heart failure (HR=2.53, P<0.018), atrial fibrillation (HR=2.53, P<0.000) and the non-revascularized coronary artery disease (HR=2.15, P<0.005). The relationship between RDW values and 5-year survival was linear. RDW-CV and RDW-SD were categorized to cut-off values of ≥15% (N.=83, 29.2%) and ≥50 fL (N.=82, 28.9%) that were independently associated with poorer 5-year survival rates (HR=2.03, CI 95%=1.29-3.19, P=0.002 and HR=1.89, CI 95%=1.21-2.95, P=0.005, respectively). The addition of the RDW CV or the RDW-SD to the baseline predictive score significantly improved the c-NRI (0.437, P<0.001 and 0.442, P<0.001, respectively). CONCLUSIONS: High preoperative RDW levels were linear and adversely related to 5-year survival after EVAR, improved the discriminative power of a predictive score based in standard preoperative variables and may help in decision-making at the time of surgical planning.

Efficacy and safety of intramuscular administration of allogeneic adipose tissue derived and expanded mesenchymal stromal cells in diabetic patients with critical limb ischemia with no possibility of revascularization: study protocol for a randomized controlled double-blind phase II clinical trial (The NOMA Trial).

BACKGROUND: Chronic lower limb ischemia develops earlier and more frequently in patients with type 2 diabetes mellitus. Diabetes remains the main cause of lower-extremity non-traumatic amputations. Current medical treatment, based on antiplatelet therapy and statins, has demonstrated deficient improvement of the disease. In recent years, research has shown that it is possible to improve tissue perfusion through therapeutic angiogenesis. Both in animal models and humans, it has been shown that cell therapy can induce therapeutic angiogenesis, making mesenchymal stromal cell-based therapy one of the most promising therapeutic alternatives. The aim of this study is to evaluate the feasibility, safety, and efficacy of cell therapy based on mesenchymal stromal cells derived from adipose tissue intramuscular administration to patients with type 2 diabetes mellitus with critical limb ischemia and without possibility of revascularization. METHODS: A multicenter, randomized double-blind, placebo-controlled trial has been designed. Ninety eligible patients will be randomly assigned at a ratio 1:1:1 to one of the following: control group (n = 30), low-cell dose treatment group (n = 30), and high-cell dose treatment group (n = 30). Treatment will be administered in a single-dose way and patients will be followed for 12 months. Primary outcome (safety) will be evaluated by measuring the rate of adverse events within the study period. Secondary outcomes (efficacy) will be measured by assessing clinical, analytical, and imaging-test parameters. Tertiary outcome (quality of life) will be evaluated with SF-12 and VascuQol-6 scales. DISCUSSION: Chronic lower limb ischemia has limited therapeutic options and constitutes a public health problem in both developed and underdeveloped countries. Given that the current treatment is not established in daily clinical practice, it is essential to provide evidence-based data that allow taking a step forward in its clinical development. Also, the multidisciplinary coordination exercise needed to develop this clinical trial protocol will undoubtfully be useful to conduct academic clinical trials in the field of cell therapy in the near future. TRIAL REGISTRATION: ClinicalTrials.gov NCT04466007 . Registered on January 07, 2020. All items from the World Health Organization Trial Registration Data Set are included within the body of the protocol.

In Silico Hemodynamics and Filtering Evaluation of a Commercial Embolic Protection Device.

During the last years, several kinds of Embolic Protection Devices (EPD) have been developed, with the aim of minimizing complication caused by thrombi generated during Carotid Artery Stenting (CAS). These devices are capable of capturing small particles generated during the intervention, avoiding cerebral stroke and improving the outcomes of the surgery. However, they have associated complications, like the increase on flow resistance associated by their use or the lack of knowledge on their actual filtration efficiency for thrombi of low size. Current work proposes a validated computational methodology in order to predict the hemodynamic features and filtering efficiency of a commercial EPD. It will be observed how Computational Fluid Dynamics predicts pressure drop with fair agreement with the experimental measurements. Finally, this work analyzes the filtration efficiency and the influence of the distribution of injected particles on this parameter. The capabilities of the filter for retaining particles of diameter below the pore size is, additionally, discussed.

[Sarcopenia index in hospitalized patients with chronic obstructive pulmonary disease exacerbation]. / Índice de sarcopenia en pacientes hospitalizados por agudización de la enfermedad pulmonar obstructiva crónica.

Sarcopenia (loss of muscle mass and function) implies a worse prognosis. However, its diagnosis is complex and is not made in routine clinical care. A biomarker has been proposed as a surrogate estimator of skeletal muscle mass, the so-called sarcopenia index ([serum creatinine/cystatine C] x100) which is associated with prognostic features in various diseases including patients with stable chronic obstructive pulmonary disease (COPD). The aim of our study was to prospectively evaluate the potential clinical and prognostic information of this biomarker in COPD exacerbation. This is a one-year prospective study of consecutive patients admitted for COPD exacerbation. A total of 89 patients, 70 men (79%) and 19 women (21%) were included. Those with lower values of the sarcopenia index had a higher level of dyspnoea and a longer hospitalization. In the correlation analysis, the index had statistically significant values with FEV1 (r = 0.23), PaCO2 (r = -0.30), bicarbonate (r = -0.31), dyspnoea (r = -0.25) and length of admission (r = -0.30). In patients admitted for COPD exacerbation, the sarcopenia index was related to prognostic characteristics, so that lower values were associated with longer duration of hospital admission, more dyspnoea and greater functional impairment. As this is an index associated with muscle mass, its determination may identify patients who could be the subject of a differentiated therapeutic plan.

La presencia de sarcopenia (pérdida de masa y función muscular) implica peor pronóstico. Sin embargo, su diagnóstico es complejo y no se realiza en la atención clínica habitual. Se ha propuesto un biomarcador como estimador subrogado de la masa muscular esquelética, el denominado índice de sarcopenia ([creatinina sérica/cistatina C] x100) que se asocia a características pronósticas en diversas enfermedades incluyendo pacientes con enfermedad pulmonar obstructiva crónica (EPOC) estable. El objetivo de nuestro estudio ha sido evaluar de forma prospectiva la potencial información clínica y pronóstica de este biomarcador en agudización de la EPOC. Se trata de un estudio prospectivo, durante un año, de los pacientes consecutivos que ingresan por agudización de su EPOC. Se incluyeron 89 pacientes, 70 varones (79%) y 19 mujeres (21%). Aquellos con valores disminuidos del índice de sarcopenia tenían más disnea y requerían una internación más prolongada. En el análisis de correlación se obtuvo valores con significación estadística del índice con FEV1 (r = 0.23), PaCO2 (r = -0.30) y bicarbonato (r = -0.31), y con la disnea (r = -0.25) y la duración del ingreso (r =- 0.30). En los ingresados por agudización de la EPOC el índice de sarcopenia se relacionó con características pronósticas, de modo que los valores inferiores se asociaron a mayor duración de la internación, más disnea y mayor afectación funcional. Al tratarse de un índice asociado a la masa muscular, su determinación podría identificar a pacientes a incluir en un plan terapéutico diferenciado.

Appropriateness of surgery performed for abdominal aortic aneurysm at tertiary hospitals in Spain.

BACKGROUND: The aim of this study was to analyze the appropriateness of the type of repair (open or endovascular) performed for abdominal aortic aneurysm (AAA) in five university hospitals in Spain, according to evidence-based recommendations. METHODS: A multicenter, retrospective cross-sectional study of patients with AAA who underwent elective open surgical repair (OSR) or endovascular aneurysm repair (EVAR). Data were collected on demographic and clinical variables and type of surgical repair. A pair of vascular surgeons from each participating hospital performed a blinded assessment based on GRADE recommendations. The concordance between the two evaluators and the agreement between their evidence-based recommendation and the procedure performed were assessed. RESULTS: A total of 186 patients were selected; 179 were included. Mean age was 72.5 years (standard deviation [SD], 8.4), mean Charlson Comorbidity Index (CCI) was 2.04 (SD, 1.9). OSR was performed in 53.2% (N.=99) and EVAR in 46.8% (N.=87) of cases. Overall, 65.9% (118/179) of interventions performed were considered appropriate: 50% (47/94) of OSRs and 83.5% (71/85) of EVARs. The patient characteristics were similar for all the hospitals, but the chosen surgical technique did show significant differences among these centers. There were no significant differences among the hospitals in the proportion of cases judged as appropriate, either overall (P=0.346) or for each type of procedure (P=0.531 and P=0.538 for OSR and EVAR, respectively). CONCLUSIONS: In this study, most of the AAA repairs performed were appropriate according to GRADE recommendations. A higher proportion of EVARs were considered appropriate than OSRs. Choice of AAA repair should be standardized using evidence-based clinical practice guidelines, while incorporating patient preferences, to reduce the existing variability and ensure appropriate selection of AAA repair technique.

Índice de sarcopenia en pacientes hospitalizados por agudización de la enfermedad pulmonar obstructiva crónica / Sarcopenia index in hospitalized patients with chronic obstructive pulmonary disease exacerbation

Resumen La presencia de sarcopenia (pérdida de masa y función muscular) implica peor pronóstico. Sin embargo, su diagnóstico es complejo y no se realiza en la atención clínica habitual. Se ha propuesto un biomarcador como estimador subrogado de la masa muscular esquelética, el denominado índice de sarcopenia ([creatinina sérica/cistatina C] x100) que se asocia a características pronósticas en diversas enfermedades incluyendo pacientes con enfermedad pulmonar obstructiva crónica (EPOC) estable. El objetivo de nuestro estudio ha sido evaluar de forma prospectiva la potencial información clínica y pronóstica de este biomarcador en agudización de la EPOC. Se trata de un estudio prospectivo, durante un año, de los pacientes consecutivos que ingresan por agudización de su EPOC. Se incluyeron 89 pacientes, 70 varones (79%) y 19 mujeres (21%). Aquellos con valores disminuidos del índice de sarcopenia tenían más disnea y requerían una internación más prolongada. En el análisis de correlación se obtuvo valores con significación estadística del índice con FEV1 (r = 0.23), PaCO (r = -0.30) y bicarbonato (r = -0.31), y con la disnea (r = -0.25) y la duración del ingreso (r =0.30). En los ingresados por agudización de la EPOC el índice de sarcopenia se relacionó con características pronósticas, de modo que los valores inferiores se asociaron a mayor duración de la internación, más disnea y mayor afectación funcional. Al tratarse de un índice asociado a la masa muscular, su determinación podría identificar a pacientes a incluir en un plan terapéutico diferenciado.

Abstract Sarcopenia (loss of muscle mass and function) implies a worse prognosis. However, its diagnosis is complex and is not made in routine clinical care. A biomarker has been proposed as a surrogate estimator of skeletal muscle mass, the so-called sarcopenia index ([serum creatinine/cystatine C] x100) which is associated with prognostic features in various diseases including patients with stable chronic obstructive pulmonary disease (COPD). The aim of our study was to prospectively evaluate the potential clinical and prognostic information of this biomarker in COPD exacerbation. This is a one-year prospective study of consecutive patients admitted for COPD exacerbation. A total of 89 patients, 70 men (79%) and 19 women (21%) were included. Those with lower values of the sarcopenia index had a higher level of dyspnoea and a longer hospitalization. In the correlation analysis, the index had statistically significant values with FEV1 (r = 0.23), PaCO (r = -0.30), bicarbonate (r = -0.31), dyspnoea (r = -0.25) and length of admission (r = -0.30). In patients admitted for COPD exacerbation, the sarcopenia index was related to prognostic characteristics, so that lower values were associated with longer duration of hospital admission, more dyspnoea and greater functional impairment. As this is an index associated with muscle mass, its determination may identify patients who could be the subject of a differentiated therapeutic plan.

Phase I Study of MEDI3726: A Prostate-Specific Membrane Antigen-Targeted Antibody-Drug Conjugate, in Patients with mCRPC after Failure of Abiraterone or Enzalutamide.

PURPOSE: MEDI3726 is an antibody-drug conjugate targeting the prostate-specific membrane antigen and carrying a pyrrolobenzodiazepine warhead. This phase I study evaluated MEDI3726 monotherapy in patients with metastatic castration-resistant prostate cancer after disease progression on abiraterone and/or enzalutamide and taxane-based chemotherapy. PATIENTS AND METHODS: MEDI3726 was administered at 0.015-0.3 mg/kg intravenously every 3 weeks until disease progression/unacceptable toxicity. The primary objective was to assess safety, dose-limiting toxicities (DLT), and MTD/maximum administered dose (MAD). Secondary objectives included assessment of antitumor activity, pharmacokinetics, and immunogenicity. The main efficacy endpoint was composite response, defined as confirmed response by RECIST v1.1, and/or PSA decrease of ≥50% after ≥12 weeks, and/or decrease from ≥5 to <5 circulating tumor cells/7.5 mL blood. RESULTS: Between February 1, 2017 and November 13, 2019, 33 patients received MEDI3726. By the data cutoff (January 17, 2020), treatment-related adverse events (TRAE) occurred in 30 patients (90.9%), primarily skin toxicities and effusions. Grade 3/4 TRAEs occurred in 15 patients (45.5%). Eleven patients (33.3%) discontinued because of TRAEs. There were no treatment-related deaths. One patient receiving 0.3 mg/kg had a DLT of grade 3 thrombocytopenia. The MTD was not identified; the MAD was 0.3 mg/kg. The composite response rate was 4/33 (12.1%). MEDI3726 had nonlinear pharmacokinetics with a short half-life (0.3-1.8 days). The prevalence of antidrug antibodies was 3/32 (9.4%), and the incidence was 13/32 (40.6%). CONCLUSIONS: Following dose escalation, no MTD was identified. Clinical responses occurred at higher doses, but were not durable as patients had to discontinue treatment due to TRAEs.

Applications of liquid biopsy in the Pharmacological Audit Trail for anticancer drug development.

Anticancer drug development is a costly and protracted activity, and failure at late phases of clinical testing is common. We have previously proposed the Pharmacological Audit Trail (PhAT) intended to improve the efficiency of drug development, with a focus on the use of tumour tissue-based biomarkers. Blood-based 'liquid biopsy' approaches, such as targeted or whole-genome sequencing studies of plasma circulating cell-free tumour DNA (ctDNA) and circulating tumour cells (CTCs), are of increasing relevance to this drug development paradigm. Liquid biopsy assays can provide quantitative and qualitative data on prognostic, predictive, pharmacodynamic and clinical response biomarkers, and can also enable the characterization of disease evolution and resistance mechanisms. In this Perspective, we examine the promise of integrating liquid biopsy analyses into the PhAT, focusing on the current evidence, advances, limitations and challenges. We emphasize the continued importance of analytical validation and clinical qualification of circulating tumour biomarkers through prospective clinical trials.

Preimplantation genetic testing for carriers of BRCA1/2 pathogenic variants.

The detection of germline BRCA1/2 pathogenic variant has relevant implications for the patients and their family members. Family planning, prophylactic surgery and the possibility of preimplantation genetic testing for monogenic disorders (PGT-M) to avoid transmittance of pathogenic variants to the offspring are relevant topics in this setting. PGT-M is valuable option for BRCA carriers, but it remains a controversial and underdiscussed topic. Although the advances in PGT technologies have improved pregnancy rate, there are still several important challenges associated with its use. The purpose of this review is to report the current evidence on PGT-M for BRCA1/2 carriers, ethical concerns and controversy associated with its use, reproductive implications of BRCA pathogenic variants, underlying areas in which an educational effort would be beneficial as well as possibilities for future research efforts in the field.

Trans-popliteal hybrid retrograde technique for revascularization of chronic total occlusions of the superficial femoral artery.

OBJECTIVES: We present the technical description and preliminary results of a hybrid approach for the treatment of chronic total occlusions of superficial femoral artery in the setting of critical limb-threatening ischemia (CLTI). METHODS: A retrospective analysis of selected case series was performed. A trans-popliteal hybrid technique was carried out in seven limbs (six patients). Open exposure of above-the-knee popliteal artery was performed over its maximum calcification zone. After retrograde recanalization and graft-stenting of the entire superficial femoral artery, endarterectomy of the popliteal artery was performed for debulking and widening of the distal landing zone of the endoprosthesis. The latter is included in the bovine patch suture to avoid leaving a segment untreated. RESULTS: Technical success, haemodynamic and clinical improvement were achieved in all procedures. Median length of treated occlusion was 19.8 cm. After a mean follow-up of 12 months (range 6-26 months), the primary patency was 85.7% (only one asymptomatic occlusion occurred). There were no major cardiovascular or limb adverse events. No re-interventions were required. CONCLUSION: This less-invasive, one-incision technique is safe and effective for the restoration of in-line flow from groin to ankle, currently recommended in CLTI revascularization. It could be especially useful in highly calcified popliteal artery lesions, hostile groins or those at high risk of infection and in cases of vein absence for bypass surgery.

Genotype FBN1/phenotype relationship in a cohort of patients with Marfan syndrome.

Marfan syndrome (MFS) is a systemic connective tissue disorder caused by mutations in the fibrillin-1 (FBN1) gene, and cardiovascular involvement is the leading cause of mortality. We sought to examine the genotype/phenotype realtionship in 61 consecutive patients with a phenotype and genotype compatible with MFS. The FBN1 gene was analyzed by massive sequencing using a hybridization capture-based target enrichment custom panel. Forty-three different variants of FBN1 were identified, of which 17 have not been previously reported. The causal variants of MFS were grouped into mutations resulting in haploinsufficiency (HI group; 23 patients) and mutations producing a dominant-negative effect (DN group; 38 patients). Patient information was collected from electronic medical records and clinical evaluation. While no significant differences were found between the two groups, the HI group included more cases with aortic dissection and occurring at a younger age that the DN group (34.7% vs. 15.8%; p = 0.160). Irrespective of the mutation group, males presented with a higher probability of aortic involvement (4-fold higher risk than females) and aortic dissections events occurred at younger ages. Patients with DN variants carrying a cysteine substitution had a higher incidence of ectopia lentis.