Triggering Endogenous Cardiac Repair and Regeneration via Extracellular Vesicle-Mediated Communication

A variety of paracrine signals create networks within the myocardium and mediate intercellular communications. Indeed, paracrine stimulation of the endogenous regenerative program of the heart, mainly based on resident cardiac progenitor cell (CPC) activation together with cardiomyocyte proliferation, has become increasingly relevant for future cardiac medicine. In the last years, it has been shown that extracellular vesicles (EV), including exosomes (Ex), are powerful conveyors of relevant biological effects. EV have been proposed not only as promising therapeutic tool for triggering cardiac regeneration and improving repair, but also as means of better understanding the physiological and pathological relationships between specific cardiac components, including cardiomyocytes and fibroblasts. Actually, EV from different kinds of exogenous stem cells have been shown to mediate beneficial effects on the injured myocardium. Moreover, endogenous cells, like CPC can instruct cardiovascular cell types, including cardiomyocytes, while cardiac stromal cells, especially fibroblasts, secrete EV that modulate relevant aspects of cardiomyocyte biology, such as hypertrophy and electrophysiological properties. Finally, cardiomyocytes too may release EV influencing the function of other cardiac cell types. Therefore, EV-based crosstalk is thought to be important in both physiology and pathology, being involved in the responses of the heart to noxious stimuli. In this review we will discuss the role of EV in both regulating cardiac homeostasis and driving heart regeneration. In particular, we will address their role in: (i) providing cardio-protection and enhancing cardiac repair mechanisms; (ii) CPC biology; and (iii) influencing adult cardiomyocyte behavior

Robot-Assisted Total Mesorectal Excision Versus Laparoscopic Total Mesorectal Excision:A Retrospective Propensity Score-Matched Cohort Analysis in Experienced Centers

BACKGROUND: The superiority of robot-assisted over laparoscopic total mesorectal excision has not been proven. Most studies do not consider the learning curve while comparing the surgical technique. OBJECTIVE: This study aims to compare laparoscopic with robot-assisted total mesorectal excision performed by surgeons who completed the learning curve of the technique. DESIGN: This is a multicenter retrospective propensity score-matched analysis. SETTINGS: The study was performed in 2 large, dedicated robot-assisted hospitals and 5 large, dedicated laparoscopic hospitals. PATIENTS: Patients were included if they underwent a robot-assisted or laparoscopic total mesorectal excision for rectal cancer with curative intent at a dedicated center for the minimally invasive technique between January 1, 2015, and December 31, 2017. INTERVENTIONS: We compared robot-assisted with laparoscopic total mesorectal excision. MAIN OUTCOME MEASURES: The main outcome was conversion to laparotomy during surgery. Secondary outcomes were postoperative morbidity and positive circumferential resection margin. RESULTS: A total of 884 patients were included and, after matching, 315 patients per treatment group remained. Conversion was similar between laparoscopic and robot-assisted total mesorectal excision (4.4% vs 2.5% (p = 0.20)). Positive circumferential resection margin was equal (3.2% vs 4.4% (p = 0.41)). Overall morbidity was comparable as well, although a lower rate of wound infections was observed in the robot-assisted group (5.7% vs 1.9% (p = 0.01)). More primary anastomoses were constructed in the robot-assisted group (50.8% vs 68.3% (p < 0.001)). Finally, more open procedures were performed in dedicated laparoscopic centers, with an overrepresentation of cT4N+ tumors in this group. LIMITATIONS: This is a retrospective multicenter cohort; however, propensity score matching was applied to control for confounding by indication. CONCLUSIONS: Robot-assisted and laparoscopic total mesorectal excision are equally safe in terms of short-term outcomes. However, with the robot-assisted approach, more primary anastomoses were constructed, and a lower wound infection rate was observed. See Video Abstract at http://links.lww.com/DCR/B677

The QT_c-Bazett Interval in Former Very Preterm Infants in Adolescence and Young Adulthood is Not Different from Term-Born Controls

Introduction: Although relevant for precision pharmacovigilance, there are conflicting data on whether former preterm birth is associated with QTc-Bazett prolongation in later life. Methods: To explore QTc-Bazett interval differences between former preterm and/or extremely low birth weight (ELBW) cases and term-born controls in adolescence and young adulthood, we analyzed pooled individual data after a structured search on published cohorts. To test the absence of a QTc-Bazett difference, a non-inferiority approach was applied (one-sided, upper limit of the 95% confidence interval [CI] mean QTc-Bazett difference, 5 and 10 ms). We also investigated the impact of characteristics, either perinatal or at assessment, on QTc-Bazett in the full dataset (cases and controls). Data were reported as median and range. Results: The pooled dataset contained 164 former preterm and/or ELBW (cases) and 140 controls born full-term from three studies. The median QTc-Bazett intervals were 409 (335–490) and 410 (318–480) ms in cases and controls. The mean QTc-Bazett difference was 1 ms, with an upper 95% CI of 6 ms (p &gt; 0.05 and p &lt; 0.01 for 5 and 10 ms, respectively). In the full dataset, females had a significantly longer QTc-Bazett than males (415 vs. 401 ms; p &lt; 0.0001). Conclusions: QTc-Bazett intervals are not significantly different between former preterm and/or ELBW cases and term-born controls, and we rejected a potential prolongation &gt; 10 ms in cases. When prescribing QTc-prolonging drugs, pharmacovigilance practices in this subpopulation should be similar to the general public (NCT05243537).</p

Increased long-term mortality after open colorectal cancer surgery:A multicentre population-based study

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Comparison of three-year oncological results after restorative low anterior resection, non-restorative low anterior resection and abdominoperineal resection for rectal cancer

Introduction: Oncological outcome might be influenced by the type of resection in total mesorectal excision (TME) for rectal cancer. The aim was to see if non-restorative LAR would have worse oncological outcome. A comparison was made between non-restorative low anterior resection (NRLAR), restorative low anterior resection (RLAR) and abdominoperineal resection (APR). Materials and methods: This retrospective cohort included data from patients undergoing TME for rectal cancer between 2015 and 2017 in eleven Dutch hospitals. A comparison was made for each different type of procedure (APR, NRLAR or RLAR). Primary outcome was 3-year overall survival (OS). Secondary outcomes included 3-year disease-free survival (DFS) and 3-year local recurrence (LR) rate. Results: Of 998 patients 363 underwent APR, 132 NRLAR and 503 RLAR. Three-year OS was worse after NRLAR (78.2%) compared to APR (86.3%) and RLAR (92.2%, p < 0.001). This was confirmed in a multivariable Cox regression analysis (HR 1.85 (1.07, 3.19), p = 0.03). The 3-year DFS was also worse after NRLAR (60.3%), compared to APR (70.5%) and RLAR (80.1%, p < 0.001), HR 2.05 (1.42, 2.97), p < 0.001. The LR rate was 14.6% after NRLAR, 5.2% after APR and 4.8% after RLAR (p = 0.005), HR 3.22 (1.61, 6.47), p < 0.001. Conclusion: NRLAR might be associated with worse 3-year OS, DFS and LR rate compared to RLAR and APR

Nationwide standardization of minimally invasive right hemicolectomy for colon cancer and development and validation of a video-based competency assessment tool (the Right study)

BACKGROUND: Substantial variation exists when performing a minimally invasive right hemicolectomy (MIRH) due to disparities in training, expertise and differences in implementation of innovations. This study aimed to achieve national consensus on an optimal and standardized MIRH technique for colon cancer and to develop and validate a video-based competency assessment tool (CAT) for MIRH. METHOD: Statements covering all elements of MIRH were formulated. Subsequently, the Delphi technique was used to reach consensus on a standardized MIRH among 76 colorectal surgeons from 43 different centres. A CAT was developed based on the Delphi results. Nine surgeons assessed the same 12 unedited full-length videos using the CAT, allowing evaluation of the intraclass correlation coefficient (ICC). RESULTS: After three Delphi rounds, consensus (≥80% agreement) was achieved on 23 of the 24 statements. Consensus statements included the use of low intra-abdominal pressure, detailed anatomical outline how to perform complete mesocolic excision with central vascular ligation, the creation of an intracorporeal anastomosis, and specimen extraction through a Pfannenstiel incision using a wound protector. The CAT included seven consecutive steps to measure competency of the MIRH and showed high consistency among surgeons with an overall ICC of 0.923. CONCLUSION: Nationwide consensus on a standardized and optimized technique of MIRH was reached. The CAT developed showed excellent interrater reliability. These achievements are crucial steps to an ongoing nationwide quality improvement project (the Right study).</p

Nationwide standardization of minimally invasive right hemicolectomy for colon cancer and development and validation of a video-based competency assessment tool (the Right study)

BACKGROUND: Substantial variation exists when performing a minimally invasive right hemicolectomy (MIRH) due to disparities in training, expertise and differences in implementation of innovations. This study aimed to achieve national consensus on an optimal and standardized MIRH technique for colon cancer and to develop and validate a video-based competency assessment tool (CAT) for MIRH. METHOD: Statements covering all elements of MIRH were formulated. Subsequently, the Delphi technique was used to reach consensus on a standardized MIRH among 76 colorectal surgeons from 43 different centres. A CAT was developed based on the Delphi results. Nine surgeons assessed the same 12 unedited full-length videos using the CAT, allowing evaluation of the intraclass correlation coefficient (ICC). RESULTS: After three Delphi rounds, consensus (≥80% agreement) was achieved on 23 of the 24 statements. Consensus statements included the use of low intra-abdominal pressure, detailed anatomical outline how to perform complete mesocolic excision with central vascular ligation, the creation of an intracorporeal anastomosis, and specimen extraction through a Pfannenstiel incision using a wound protector. The CAT included seven consecutive steps to measure competency of the MIRH and showed high consistency among surgeons with an overall ICC of 0.923. CONCLUSION: Nationwide consensus on a standardized and optimized technique of MIRH was reached. The CAT developed showed excellent interrater reliability. These achievements are crucial steps to an ongoing nationwide quality improvement project (the Right study).</p

Prevention of severe infectious complications after colorectal surgery using oral non-absorbable antimicrobial prophylaxis:results of a multicenter randomized placebo-controlled clinical trial

BACKGROUND: Surgical site infections (SSIs) are common complications after colorectal surgery. Oral non-absorbable antibiotic prophylaxis (OAP) can be administered preoperatively to reduce the risk of SSIs. Its efficacy without simultaneous mechanical cleaning is unknown. METHODS: The Precaution trial was a double-blind, placebo-controlled randomized clinical trial conducted in six Dutch hospitals. Adult patients who underwent elective colorectal surgery were randomized to receive either a three-day course of preoperative OAP with tobramycin and colistin or placebo. The primary composite endpoint was the incidence of deep SSI or mortality within 30 days after surgery. Secondary endpoints included both infectious and non-infectious complications at 30 days and six months after surgery. RESULTS: The study was prematurely ended due to the loss of clinical equipoise. At that time, 39 patients had been randomized to active OAP and 39 to placebo, which reflected 8.1% of the initially pursued sample size. Nine (11.5%) patients developed the primary outcome, of whom four had been randomized to OAP (4/39; 10.3%) and five to placebo (5/39; 12.8%). This corresponds to a risk ratio in the intention-to-treat analysis of 0.80 (95% confidence interval (CI) 0.23-2.78). In the per-protocol analysis, the relative risk was 0.64 (95% CI 0.12-3.46). CONCLUSIONS: Observational data emerging during the study provided new evidence for the effectiveness of OAP that changed both the clinical and medical ethical landscape for infection prevention in colorectal surgery. We therefore consider it unethical to continue randomizing patients to placebo. We recommend the implementation of OAP in clinical practice and continuing monitoring of infection rates and antibiotic susceptibilities. TRIAL REGISTRATION: The PreCaution trial is registered in the Netherlands Trial Register under NL5932 (previously: NTR6113) as well as in the EudraCT register under 2015-005736-17