Biodegradable multi-walled carbon nanotubes trigger anti-tumoral effects

Carbon nanotubes are of huge biotechnological interest because they can penetrate most biological barriers and, inside cells, can biomimetically interact with the cytoskeletal filaments, triggering anti-proliferative and cytotoxic effects in highly dividing cells. Unfortunately, their intrinsic properties and bio-persistence represent a putative hazard that relapses their application as therapies against cancer. Here we investigate mild oxidation treatments to improve the intracellular enzymatic digestion of MWCNTs, but preserving their morphology, responsible for their intrinsic cytotoxic properties. Cell imaging techniques and confocal Raman spectroscopic signature analysis revealed that cultured macrophages can degrade bundles of oxidized MWCNTs (o-MWCNTs) in a few days. The isolation of nanotubes from these phagocytes 96 hours after exposure confirmed a significant reduction of approximately 30% in the total length of these filaments compared to the control o-MWCNTs extracted from the cell culture medium, or the intracellular pristine MWCNTs. More interestingly, in vivo single intratumoral injections of o-MWCNTs triggered ca. 30% solid melanoma tumour growth-inhibitory effects while displaying significant signs of biodegradation at the tumoral/peri-tumoral tissues a week after the therapy has had the effect. These results support the potential use of o-MWCNTs as antitumoral agents and reveal interesting clues of how to enhance the efficient clearance of in vivo carbon nanotubes.This work has been supported by the Spanish MINECO and European Union FEDER under Projects ref. PI13/01074, PI16/000496, MAT2015-69508-P, the NanoBioApp Network Ref. MINECO-17-MAT2016-81955-REDT, IDIVAL Projects ref. INNVAL15/16, INNVAL 17/11, PREVAL 16/03, and the Raman4clinics BMBS COST Action BM1401

Efficient Exchange in a Bioinspired Dynamic Covalent Polymer Network via a Cyclic Phosphate Triester Intermediate

Bond exchange via neighboring group-assisted reactions in dynamic covalent networks results in efficient mechanical relaxation. In Nature, the high reactivity of RNA toward nucleophilic substitution is largely attributed to the formation of a cyclic phosphate ester intermediate via neighboring group participation. We took inspiration from RNA to develop a dynamic covalent network based on β-hydroxyl-mediated transesterifications of hydroxyethyl phosphate triesters. A simple one-step synthetic strategy provided a network containing phosphate triesters with a pendant hydroxyethyl group. 31P solid-state NMR demonstrated that a cyclic phosphate triester is an intermediate in transesterification, leading to dissociative network rearrangement. Significant viscous flow at 60-100 °C makes the material suitable for fast processing via extrusion and compression molding

Current Challenges and Opportunities of Photodynamic Therapy against Cancer

BACKGROUND: Photodynamic therapy (PDT) is an established, minimally invasive treatment for specific types of cancer. During PDT, reactive oxygen species (ROS) are generated that ultimately induce cell death and disruption of the tumor area. Moreover, PDT can result in damage to the tumor vasculature and induce the release and/or exposure of damage-associated molecular patterns (DAMPs) that may initiate an antitumor immune response. However, there are currently several challenges of PDT that limit its widespread application for certain indications in the clinic. METHODS: A literature study was conducted to comprehensively discuss these challenges and to identify opportunities for improvement. RESULTS: The most notable challenges of PDT and opportunities to improve them have been identified and discussed. CONCLUSIONS: The recent efforts to improve the current challenges of PDT are promising, most notably those that focus on enhancing immune responses initiated by the treatment. The application of these improvements has the potential to enhance the antitumor efficacy of PDT, thereby broadening its potential application in the clinic

The Relation between Obesity and Mortality in Postcardiotomy Veno-arterial Membrane Oxygenation

Background: Obesity is an important health problem in cardiac surgery and among patients requiring postcardiotomy venoarterial extracorporeal membrane oxygenation (V-A ECMO). Still, whether these patients are at risk for unfavorable outcomes after postcardiotomy V-A ECMO remains unclear. The current study evaluated the association between body mass index (BMI) and in-hospital outcomes in this setting. Methods: The Post-cardiotomy Extracorporeal Life Support (PELS-1) study is an international, multicenter study. Patients requiring postcardiotomy V-A ECMO in 36 centers from 16 countries between 2000 and 2020 were included. Patients were divided in 6 BMI categories (underweight, normal weight, overweight, class I, class II, and class III obesity) according to international recommendations. Primary outcome was in-hospital mortality, and secondary outcomes included major adverse events. Mixed logistic regression models were applied to evaluate associations between BMI and mortality. Results: The study cohort included 2046 patients (median age, 65 years; 838 women [41.0%]). In-hospital mortality was 60.3%, without statistically significant differences among BMI classes for in-hospital mortality (P = .225) or major adverse events (P = .126). The crude association between BMI and in-hospital mortality was not statistically significant after adjustment for comorbidities and intraoperative variables (class I: odds ratio [OR], 1.21; 95% CI, 0.88-1.65; class II: OR, 1.45; 95% CI, 0.86-2.45; class III: OR, 1.43; 95% CI, 0.62-3.33), which was confirmed in multiple sensitivity analyses. Conclusions: BMI is not associated to in-hospital outcomes after adjustment for confounders in patients undergoing postcardiotomy V-A ECMO. Therefore, BMI itself should not be incorporated in the risk stratification for postcardiotomy V-A ECMO.</p

Patient and Management Variables Associated With Survival After Postcardiotomy Extracorporeal Membrane Oxygenation in Adults: The PELS‐1 Multicenter Cohort Study

Background Extracorporeal membrane oxygenation (ECMO) has been increasingly used for postcardiotomy cardiogenic shock, but without a concomitant reduction in observed in‐hospital mortality. Long‐term outcomes are unknown. This study describes patients’ characteristics, in‐hospital outcome, and 10‐year survival after postcardiotomy ECMO. Variables associated with in‐hospital and postdischarge mortality are investigated and reported. Methods and Results The retrospective international multicenter observational PELS‐1 (Postcardiotomy Extracorporeal Life Support) study includes data on adults requiring ECMO for postcardiotomy cardiogenic shock between 2000 and 2020 from 34 centers. Variables associated with mortality were estimated preoperatively, intraoperatively, during ECMO, and after the occurrence of any complications, and then analyzed at different time points during a patient's clinical course, through mixed Cox proportional hazards models containing fixed and random effects. Follow‐up was established by institutional chart review or contacting patients. This analysis included 2058 patients (59% were men; median [interquartile range] age, 65.0 [55.0–72.0] years). In‐hospital mortality was 60.5%. Independent variables associated with in‐hospital mortality were age (hazard ratio [HR], 1.02 [95% CI, 1.01–1.02]) and preoperative cardiac arrest (HR, 1.41 [95% CI, 1.15–1.73]). In the subgroup of hospital survivors, the overall 1‐, 2‐, 5‐, and 10‐year survival rates were 89.5% (95% CI, 87.0%–92.0%), 85.4% (95% CI, 82.5%–88.3%), 76.4% (95% CI, 72.5%–80.5%), and 65.9% (95% CI, 60.3%–72.0%), respectively. Variables associated with postdischarge mortality included older age, atrial fibrillation, emergency surgery, type of surgery, postoperative acute kidney injury, and postoperative septic shock. Conclusions In adults, in‐hospital mortality after postcardiotomy ECMO remains high; however, two‐thirds of those who are discharged from hospital survive up to 10 years. Patient selection, intraoperative decisions, and ECMO management remain key variables associated with survival in this cohort. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03857217

Heterogeneity in Clinical Practices for Post-Cardiotomy Extracorporeal Life Support: a Pilot Survey from the PELS-1 Multicenter Study

Background: High-quality evidence for post-cardiotomy extracorporeal life support (PC-ECLS) management is lacking. This study investigated the real-world PC-ECLS clinical practices. Methods: This cross-sectional, multi-institutional, international pilot survey explored center organization, anticoagulation management, left ventricular unloading, distal limb perfusion, PC-ECLS monitoring and transfusions practices. Twenty-nine questions were distributed among 34 hospitals participating in the Post-cardiotomy Extra-Corporeal Life Support Study. Results: Of the 32 centers [16 low-volume (50%); 16 high-volume (50%)] that responded, 16 (50%) had dedicated ECLS specialists. Twenty-six centers (81.3%) reported using additional mechanical circulatory supports. Anticoagulation practices were highly heterogeneous: 24 hospitals (75%) reported using patient's bleeding status as a guide, without a specific threshold in 54.2% of cases. Transfusion targets ranged 7-10 g/dL. Most centers used cardiac venting on a case-by-case basis (78.1%) and regular distal limb perfusion (84.4%). Nineteen (54.9%) centers reported dedicated monitoring protocols including daily echocardiography (87.5%), Swan-Ganz catheterization (40.6%), cerebral near-infrared spectroscopy (53.1%) and multimodal assessment of limb ischemia. Inspection of the circuit (71.9%), oxygenator pressure drop (68.8%), plasma free hemoglobin (75%), d-dimer (59.4%), lactate dehydrogenase (56.3%) and fibrinogen (46.9%) are used to diagnose hemolysis and thrombosis. Conclusions: This study shows remarkable heterogeneity in clinical practices for PC-ECLS management. More standardized protocols and better implementation of available evidence are recommended

On-Support and Post-Weaning Mortality in Post-Cardiotomy Extracorporeal Membrane Oxygenation

Background: Post-cardiotomy veno-arterial extracorporeal membrane oxygenation (V-A ECMO) is characterized by discrepancies between weaning and survival-to-discharge rates. This study analyzes the differences between post-cardiotomy V-A ECMO patients who survived, died on ECMO, or died after ECMO weaning. Causes of death and variables associated with mortality at different time points are investigated. Methods: The retrospective, multicenter, observational Post-cardiotomy Extracorporeal Life Support Study includes adults requiring post-cardiotomy V-A ECMO between 2000 and 2020. Variables associated with on-ECMO mortality and post-weaning mortality were modeled using mixed-Cox proportional hazards including random effects for center. Results: In 2058 patients [males:59%; median age:65 (IQR:55-72 years)], weaning rate was 62.7%, while survival-to-discharge was 39.6%. Deceased patients (n=1244) included 754 on-ECMO deaths [(36.6%; median support time:79 (IQR:24-192 hours)], and 476 post-weaning deaths [(23.1%; median support time:146 (IQR:96-235.5 hours)]. Multi-organ (n=431/1158, 37.2%) and persistent heart failure (n=423/1158, 36.5%) were the main causes of death, followed by bleeding (n=56/754, 7.4%) for on-ECMO mortality and sepsis (n=61/401, 15.4%) for post-weaning mortality. On-ECMO death was associated with emergency surgery, preoperative cardiac arrest, cardiogenic shock, right ventricular failure, cardiopulmonary bypass time, ECMO implantation timing. Diabetes, post-operative bleeding, cardiac arrest, bowel ischemia, acute kidney injury, and septic shock were associated with post-weaning mortality. Conclusions: A discrepancy exists between weaning and discharge rate in post-cardiotomy ECMO. Deaths occurred during ECMO support in 36.6% of patients, mostly associated with unstable pre-operative hemodynamics. Another 23.1% of patients died after weaning in association with severe complications. This underscores the importance of post-weaning care for post-cardiotomy V-A ECMO patients

The importance of timing in postcardiotomy venoarterial extracorporeal membrane oxygenation: A descriptive multicenter observational study

Objectives: Postcardiotomy extracorporeal membrane oxygenation (ECMO) can be initiated intraoperatively or postoperatively based on indications, settings, patient profile, and conditions. The topic of implantation timing only recently gained attention from the clinical community. We compare patient characteristics as well as in-hospital and long-term survival between intraoperative and postoperative ECMO. Methods: The retrospective, multicenter, observational Postcardiotomy Extracorporeal Life Support (PELS-1) study includes adults who required ECMO due to postcardiotomy shock between 2000 and 2020. We compared patients who received ECMO in the operating theater (intraoperative) with those in the intensive care unit (postoperative) on in-hospital and postdischarge outcomes. Results: We studied 2003 patients (women: 41.1%; median age: 65 years; interquartile range [IQR], 55.0-72.0). Intraoperative ECMO patients (n = 1287) compared with postoperative ECMO patients (n = 716) had worse preoperative risk profiles. Cardiogenic shock (45.3%), right ventricular failure (15.9%), and cardiac arrest (14.3%) were the main indications for postoperative ECMO initiation, with cannulation occurring after (median) 1 day (IQR, 1-3 days). Compared with intraoperative application, patients who received postoperative ECMO showed more complications, cardiac reoperations (intraoperative: 19.7%; postoperative: 24.8%, P = .011), percutaneous coronary interventions (intraoperative: 1.8%; postoperative: 3.6%, P = .026), and had greater in-hospital mortality (intraoperative: 57.5%; postoperative: 64.5%, P = .002). Among hospital survivors, ECMO duration was shorter after intraoperative ECMO (median, 104; IQR, 67.8-164.2 hours) compared with postoperative ECMO (median, 139.7; IQR, 95.8-192 hours, P < .001), whereas postdischarge long-term survival was similar between the 2 groups (P = .86). Conclusions: Intraoperative and postoperative ECMO implantations are associated with different patient characteristics and outcomes, with greater complications and in-hospital mortality after postoperative ECMO. Strategies to identify the optimal location and timing of postcardiotomy ECMO in relation to specific patient characteristics are warranted to optimize in-hospital outcomes