Prrx1b restricts fibrosis and promotes Nrg1-dependent cardiomyocyte proliferation during zebrafish heart regeneration.

Fibroblasts are activated to repair the heart following injury. Fibroblast activation in the mammalian heart leads to a permanent fibrotic scar that impairs cardiac function. In other organisms, such as zebrafish, cardiac injury is followed by transient fibrosis and scar-free regeneration. The mechanisms that drive scarring versus scar-free regeneration are not well understood. Here, we show that the homeobox-containing transcription factor Prrx1b is required for scar-free regeneration of the zebrafish heart as the loss of Prrx1b results in excessive fibrosis and impaired cardiomyocyte proliferation. Through lineage tracing and single-cell RNA sequencing, we find that Prrx1b is activated in epicardial-derived cells where it restricts TGFß ligand expression and collagen production. Furthermore, through combined in vitro experiments in human fetal epicardial-derived cells and in vivo rescue experiments in zebrafish, we conclude that Prrx1 stimulates Nrg1 expression and promotes cardiomyocyte proliferation. Collectively, these results indicate that Prrx1 is a key transcription factor that balances fibrosis and regeneration in the injured zebrafish heart. This article has an associated 'The people behind the papers' interview.

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).

A new surgical technique: robotic intracorporeal Kono-S anastomosis in Crohn's - a safety and feasibility case series on short-term outcomes.

AIM: The Kono-S anastomosis was introduced as a possible solution to the high surgical recurrence rates in Crohn's disease. However, this technique is known to be challenging, which is why it was originally performed in an extracorporeal setting. The aim of this case series was to assess safety, in terms of intra-/postoperative complications, and feasibility, in terms of successful performance of anastomosis, of a robot-assisted intracorporeal Kono-S anastomosis. METHOD: This is a prospective single-centre consecutive case series. Patients were considered eligible if they were diagnosed with refractory Crohn's disease with significant bowel stenosis of the terminal ileum. All patients underwent robot-assisted intracorporeal Kono-S anastomosis. Perioperative care was provided according to the Enhanced Recovery After Surgery® protocol. Follow-up for postoperative complications was 30 days. RESULTS: Twenty patients were included, of whom 11 (55%) were men. The median age was 30 years [interquartile range (IQR) 22-51 years] and the median BMI was 25 kg/m2 (IQR 19-28 kg/m2). Intracorporeal Kono-S anastomosis was successfully performed in all cases. The median operating time was 155 min (IQR 144-176 min) and the median length of stay was 3 days (IQR 1-5 days). No conversions or 30-day mortality were observed. One patient experienced anastomotic leakage, which was treated with radiologically guided drainage. A total of three patients experienced postoperative complications in the first 30 days. CONCLUSION: Performance of intracorporeal robot-assisted Kono-S anastomosis seems safe and feasible in this case series for Crohn's disease. Since this is a first case series, further research is required to confirm results in a larger population-based cohort.

Better stoma care using the Stoma App: does it help? A first randomized double-blind clinical trial on the effect of mobile healthcare on quality of life in stoma patients.

BACKGROUND: Receiving a stoma significantly impacts patients' quality of life. Coping with this new situation can be difficult, which may result in a variety of physical and psychosocial problems. It is essential to provide adequate guidance to help patients cope with their stoma, as this positively influences self-efficacy in return. Higher self-efficacy reduces psychosocial problems increasing patient's quality of life. This study investigates whether a new mobile application, the Stoma App, improves quality of life. And if personalized guidance, timed support, and peer contact offered as an in-app surplus makes a difference. METHODS: A double-blind, randomized controlled trial was conducted between March 2021 and April 2023. Patients aged > 18 years undergoing ileostomy or colostomy surgery, in possession of a compatible smartphone were included. The intervention group received the full version of the app containing personalized and time guidance, peer support, and generic (non-personalized) stoma-related information. The control group received a restricted version with only generic information. Primary outcome was stoma quality of life. Secondary outcomes included psychological adaption, complications, re-admittance, reoperations, and length of hospital stay. RESULTS: The intervention version of the app was used by 96 patients and the control version by 112 patients. After correction for confounding, the intervention group reported a significant 3.1-point improvement in stoma-related quality of life one month postoperatively (p = 0.038). On secondary outcomes, no significant improvements could be retrieved of the intervention group. CONCLUSION: The Stoma App improves the quality of life of stoma patients. Peer support and personalized guidance are of significant importance in building self-efficacy. It is to be recommended to implement Stoma app-freely available software qualifying as a medical device-in standard stoma care pathways for the benefits of both patients and healthcare providers.

Abnormal preoperative haematological parameters in Endometrial cancer; reflecting tumour aggressiveness or reduced response to radiotherapy?

BACKGROUND: In endometrial cancer (EC), preoperative anaemia, thrombocytosis and leucocytosis appear to be associated with worse prognosis. It remains unclear whether these parameters solely reflect tumour aggressiveness, or also impact response to adjuvant treatment. Therefore, our primary aim is to evaluate the prognostic relevance of anaemia, thrombocytosis and leucocytosis on survival in EC. Secondary, to explore their predictive relevance in response to radiotherapy in EC. METHODS: A retrospective multicentre cohort study was performed within 10 hospitals. Preoperative haematological parameters were defined as: Anaemia - haemoglobin <7.45 mmol/L (<12 g/Dl), thrombocytosis - platelets >400 × 109 platelets/L, leucocytosis - leukocytes >10 × 109/L. The relationship of haematological parameters with clinicopathological characteristics, ESGO/ESTRO/ESP risk groups and survival were evaluated. Furthermore, the predictive value of haematological parameters was determined on the overall response to adjuvant radiotherapy and for the ESGO/ESTRO/ESP intermediate-risk group solely receiving radiotherapy. RESULTS: A total of 894 patients were included with a median follow-up of 4.5 years. Anaemia was present in 103 (11.5%), thrombocytosis in 79 (8.8%) and leucocytosis in 114 (12.7%) patients. The presence of anaemia or thrombocytosis was significantly associated with ESGO/ESTRO/ESP high-risk (respectively, P = 0.002 and P = 0.041). In the entire cohort, anaemia remained independently associated with decreased disease-specific survival (HR 2.31, 95% CI (1.19-4.50), P = 0.013) after adjusting for age, the abnormal haematological parameters and ESGO/ESTRO/ESP risk groups. In patients that were treated with adjuvant radiotherapy (n = 239), anaemia was associated with significant reduced 5-year disease-specific and recurrence-free survival (P = 0.005 and P = 0.025, respectively). In ESGO/ESTRO/ESP intermediate risk patients that received solely vaginal brachytherapy (n = 74), anaemia was associated with reduced disease-specific survival (P = 0.041). CONCLUSIONS: Current data demonstrate the importance of preoperative anaemia as independent prognostic factor in patients with EC. Moreover, anaemia seems to be associated with reduced response to radiotherapy. Prospective validation in a larger study cohort is needed to verify anaemia as predictive biomarker for radiotherapy.What is already known on this subject? In endometrial cancer, preoperative abnormal haematological parameters like, anaemia, thrombocytosis and leucocytosis appears to be associated with FIGO advanced-stage and unfavourable outcome.What do the results of this study add? It remains unclear whether anaemia, thrombocytosis or leucocytosis solely reflecting worse prognosis by advanced tumour stage, or also impact response to adjuvant treatment. Current data demonstrate that anaemia is independent associated with decreased disease-specific survival and anaemia seems related with reduced response to radiotherapy and in specific to vaginal brachytherapy in ESGO/ESTRO/ESP intermediate risk patients.What are the implications of these findings for clinical practice and/or further research? Specific applied adjuvant treatment is needed if patients with anaemia have a reduced response to radiotherapy in EC. Prospective validation in a larger study cohort is required to verify anaemia as predictive biomarker for radiotherapy and to further evaluate the prognostic/predictive impact of anaemia in addition to the molecular subgroups.

In this study we focused on three specific blood values before surgery to predict survival outcomes in endometrial cancer patients: low haemoglobin (anaemia), high platelet count (thrombocytosis) and high white blood cell count (leucocytosis). We studied 894 patients with endometrial cancer over about 4.5 years, in which 11.5% had anaemia, 8.8% thrombocytosis and 12.7% leucocytosis. Anaemia was linked to a lower chance of surviving endometrial cancer, even after we considering patients' age, thrombocytosis, leucocytosis and the endometrial cancer risk classification groups. In patients who received radiotherapy after surgery (293 patients), anaemia was linked to a lower change of surviving and cancer coming back within 5 years. In patients within the intermediate endometrial cancer risk classification group who only received specific radiotherapy (74 patients), anaemia was even linked with lower chance of survival. In conclusion, anaemia is an important factor in predicting endometrial cancer outcomes, and it might also make radiotherapy less effective for some patients.

Can MRI Be Used as a Sole Diagnostic Modality in Determining Clinical Stage in Cervical Cancer?

OBJECTIVE: The objective of this study was to compare staging by MRI to clinical staging in patients with cervical cancer and to determine the histological accuracy of staging by MRI and examination under anesthesia (EUA) in early stage disease. METHODS: This was a retrospective cohort study of patients diagnosed with cervical cancer between 2010 and 2020 at the Radboud University Medical Centre, the Netherlands. Pretreatment stage (FIGO 2009) by MRI was compared with staging by EUA. Diagnostic accuracy in terms of sensitivity, specificity, positive, and negative predictive value was calculated for MRI and EUA in patients undergoing surgery (early stage disease) with histological results as a reference standard. RESULTS: A total of 358 patients were included in the study and MRI-based stage differed from EUA stage in 30.7%. In 12.3% this meant a discrepancy in treatment assignment between MRI and EUA. Diagnostic accuracy of MRI in terms of sensitivity and specificity for detecting early stage disease was comparable to EUA in surgical patients. Further analyses showed that premenopausal status, early stage disease and a tumor diameter of <2 cm were associated with improved comparability of MRI and EUA (98%). CONCLUSION: There is still a large discrepancy between MRI and EUA. In patients with suspected early stage disease, diagnostic accuracy of MRI is similar to EUA, especially for premenopausal women with early stage disease and a tumor diameter of <2 cm.

Evaluation of National Surgical Practice for Lateral Lymph Nodes in Rectal Cancer in an Untrained Setting.

BACKGROUND: Involved lateral lymph nodes (LLNs) have been associated with increased local recurrence (LR) and ipsi-lateral LR (LLR) rates. However, consensus regarding the indication and type of surgical treatment for suspicious LLNs is lacking. This study evaluated the surgical treatment of LLNs in an untrained setting at a national level. METHODS: Patients who underwent additional LLN surgery were selected from a national cross-sectional cohort study regarding patients undergoing rectal cancer surgery in 69 Dutch hospitals in 2016. LLN surgery consisted of either 'node-picking' (the removal of an individual LLN) or 'partial regional node dissection' (PRND; an incomplete resection of the LLN area). For all patients with primarily enlarged (≥7 mm) LLNs, those undergoing rectal surgery with an additional LLN procedure were compared to those  undergoing only rectal resection. RESULTS: Out of 3057 patients, 64 underwent additional LLN surgery, with 4-year LR and LLR rates of 26% and 15%, respectively. Forty-eight patients (75%) had enlarged LLNs, with corresponding recurrence rates of 26% and 19%, respectively. Node-picking (n = 40) resulted in a 20% 4-year LLR, and a 14% LLR after PRND (n = 8; p = 0.677). Multivariable analysis of 158 patients with enlarged LLNs undergoing additional LLN surgery (n = 48) or rectal resection alone (n = 110) showed no significant association of LLN surgery with 4-year LR or LLR, but suggested higher recurrence risks after LLN surgery (LR: hazard ratio [HR] 1.5, 95% confidence interval [CI] 0.7-3.2, p = 0.264; LLR: HR 1.9, 95% CI 0.2-2.5, p = 0.874). CONCLUSION: Evaluation of Dutch practice in 2016 revealed that approximately one-third of patients with primarily enlarged LLNs underwent surgical treatment, mostly consisting of node-picking. Recurrence rates were not significantly affected by LLN surgery, but did suggest worse outcomes. Outcomes of LLN surgery after adequate training requires further research.

Finding the sentinel lymph node in early cervical cancer: When is unusual not uncommon?

OBJECTIVE: To report our institutional experience with sentinel lymph node (SLN) detection using indocyanine green for cervical cancer, in terms of detection rates, detection of SLN at unusual locations, and factors associated with unusual SLN locations. In addition, we performed a systematic review of the literature to identify factors associated with unusual SLN localizations. METHODS: This is a retrospective cohort study of women with early-stage cervical cancer undergoing sentinel lymph node mapping between 2015 and 2019. Outcome measures were SLN detection rates, detection rates of unusual locations for SLN and risk factors for aberrant lymphatic drainage pathways. In addition, studies evaluating factors associated with unusual SLN locations in cervical cancer were assessed in a systematic review. RESULTS: A total of 100 patients were included. The unilateral SLN detection rate was 88%, whereas the bilateral detection rate was 75%. In 37% of all patients, SLN were found in unusual locations, and in 10% of patients SLN were solely found in unusual locations. Body mass index (BMI) was associated with finding SLN in unusual locations, with unusual nodes detected in 52% of patients with BMI <25 kg/m2 and in 28% of patients with BMI ≥25 kg/m2. The systematic review identified three studies, identifying lower BMI, nulliparity and tumor size of >20 mm as factors associated with finding SLN at unusual locations. CONCLUSION: Aberrant drainage sites represent a significant proportion of SLN detected in cervical cancer. Factors associated with increased rates of unusual nodal locations are a lower BMI, with a possible association with nulliparity and tumor size of >20 mm.

Patient- and physician-reported radiation-induced toxicity of short-course radiotherapy with a prolonged interval to surgery for rectal cancer.

AIM: A prolonged interval (>4 weeks) between short-course radiotherapy (25 Gy in five fractions) (SCRT-delay) and total mesorectal excision for rectal cancer has been associated with a decreased postoperative complication rate and offers the possibility of organ preservation in the case of a complete tumour response. This prospective cohort study systematically evaluated patient-reported bowel dysfunction and physician-reported radiation-induced toxicity for 8 weeks following SCRT-delay. METHOD: Patients who were referred for SCRT-delay for intermediate risk, oligometastatic or locally advanced rectal cancer were included. Repeated measurements were done for patient-reported bowel dysfunction (measured by the low anterior resection syndrome [LARS] questionnaire and categorized as no, minor or major LARS) and physician-reported radiation-induced toxicity (according to Common Terminology Criteria for Adverse Events version 4.0) before start of treatment (baseline), at completion of SCRT and 1, 2, 3, 4, 6 and 8 weeks thereafter. RESULTS: Fifty-one patients were included; 31 (61%) were men and the median age was 67 years (range 44-91). Patient-reported bowel dysfunction and physician-reported radiation-induced toxicity peaked at weeks 1-2 after completion of SCRT and gradually declined thereafter. Major LARS was reported by 44 patients (92%) at some time during SCRT-delay. Grade 3 radiation-induced toxicity was reported in 17 patients (33%) and concerned predominantly diarrhoea. No Grade 4-5 radiation-induced toxicity occurred. CONCLUSION: During SCRT-delay, almost every patient experiences temporary mild-moderate radiation-induced toxicity and major LARS, but life-threatening toxicity is rare. SCRT-delay is a safe alternative to SCRT-direct surgery that should be proposed when counselling rectal cancer patients on neoadjuvant strategies.

Impact of a diverting ileostomy in total mesorectal excision with primary anastomosis for rectal cancer.

BACKGROUND: The role of diverting ileostomy in total mesorectal excision (TME) for rectal cancer with primary anastomosis is debated. The aim of this study is to gain insight in the clinical consequences of a diverting ileostomy, with respect to stoma rate at one year and stoma-related morbidity. METHODS: Patients undergoing TME with primary anastomosis for rectal cancer between 2015 and 2017 in eleven participating hospitals were included. Retrospectively, two groups were compared: patients with or without diverting ileostomy construction during primary surgery. Primary endpoint was stoma rate at one year. Secondary endpoints were severity and rate of anastomotic leakage, overall morbidity rate within thirty days and stoma (reversal) related morbidity. RESULTS: In 353 out of 595 patients (59.3%) a diverting ileostomy was constructed during primary surgery. Stoma rate at one year was 9.9% in the non-ileostomy group and 18.7% in the ileostomy group (p = 0.003). After correction for confounders, multivariate analysis showed that the construction of a diverting ileostomy during primary surgery was an independent risk factor for stoma at one year (OR 2.563 (95%CI 1.424-4.611), p = 0.002). Anastomotic leakage rate was 17.8% in the non-ileostomy group and 17.2% in the ileostomy group (p = 0.913). Overall 30-days morbidity rate was 37.6% in the non-ileostomy group and 56.1% in the ileostomy group (p < 0.001). Stoma reversal related morbidity rate was 17.9%. CONCLUSIONS: The stoma rate at one year was higher in patients with ileostomy construction during primary surgery. The incidence and severity of anastomotic leakage were not reduced by construction of an ileostomy. The morbidity related to the presence and reversal of a diverting ileostomy was substantial.

The Intervention Selection Toolbox to improve patient-relevant outcomes: an implementation and qualitative evaluation study in colorectal cancer surgery.

BACKGROUND: The concept of value-based healthcare is being used worldwide to improve healthcare. The Intervention Selection Toolbox was developed to bridge the gap of value-based healthcare, between insights in outcomes and actual quality improvement initiatives. In this study we aimed to evaluate the use of the Intervention Selection Toolbox in daily practice of a quality improvement team in a hospital setting. METHODS: A methodological triangulation design was used. The Intervention Selection Toolbox was used by a multidisciplinary quality improvement team for colorectal cancer care in a large teaching hospital. In-depth semi-structured interviews, focusing on the key elements of process evaluation, were conducted after implementation with representatives of the quality improvement team to evaluate the use of the Intervention Selection Toolbox. Quantitative data regarding improvement initiatives and degree of implementation was also collected. RESULTS: The use of the Intervention Selection Toolbox initially resulted in 80 potential quality improvement initiatives. Eventually, two high potential improvement initiatives were selected. Some components of the toolbox were successfully implemented in daily practice, although 'standard monitoring' and 'causal chain analysis' proved more difficult to implement. Qualitative analysis was performed with ten members of the multidisciplinary team before thematic saturation occurred. Interviewed members had a wide range in characteristics: age 28-61 years, clinical experience 6-38 years and educational attainment from vocational program to academic doctorate. The Interviews showed added value in the use of the toolbox, but identified time and organizational management as restricting factors. CONCLUSIONS: The Intervention Selection Toolbox is useful to systematically identify improvement initiatives with impact on health outcomes that matter to patients. However, before implementation organizational structure should be optimized to maximize success and efficiency on integration of the Intervention Selection Toolbox.

Uncoupling DNA damage from chromatin damage to detoxify doxorubicin.

The anthracycline doxorubicin (Doxo) and its analogs daunorubicin (Daun), epirubicin (Epi), and idarubicin (Ida) have been cornerstones of anticancer therapy for nearly five decades. However, their clinical application is limited by severe side effects, especially dose-dependent irreversible cardiotoxicity. Other detrimental side effects of anthracyclines include therapy-related malignancies and infertility. It is unclear whether these side effects are coupled to the chemotherapeutic efficacy. Doxo, Daun, Epi, and Ida execute two cellular activities: DNA damage, causing double-strand breaks (DSBs) following poisoning of topoisomerase II (Topo II), and chromatin damage, mediated through histone eviction at selected sites in the genome. Here we report that anthracycline-induced cardiotoxicity requires the combination of both cellular activities. Topo II poisons with either one of the activities fail to induce cardiotoxicity in mice and human cardiac microtissues, as observed for aclarubicin (Acla) and etoposide (Etop). Further, we show that Doxo can be detoxified by chemically separating these two activities. Anthracycline variants that induce chromatin damage without causing DSBs maintain similar anticancer potency in cell lines, mice, and human acute myeloid leukemia patients, implying that chromatin damage constitutes a major cytotoxic mechanism of anthracyclines. With these anthracyclines abstained from cardiotoxicity and therapy-related tumors, we thus uncoupled the side effects from anticancer efficacy. These results suggest that anthracycline variants acting primarily via chromatin damage may allow prolonged treatment of cancer patients and will improve the quality of life of cancer survivors.

SPONGE-assisted versus Trendelenburg position surgery in laparoscopic sigmoid and rectal cancer surgery (SPONGE trial): randomized clinical trial.

BACKGROUND: In minimally invasive surgery of the sigmoid colon and rectum a retractor sponge has been introduced as an alternative to the Trendelenburg position. This randomized clinical trial (RCT) compared postoperative duration of hospital stay and perioperative outcomes in patients with sigmoid or rectal cancer undergoing sponge-assisted versus Trendelenburg position surgery. METHODS: The SPONGE trial is a single-centre RCT nested within the Dutch nationwide prospective observational cohort of patients with colorectal cancer, and follows the Trials within Cohorts (TwiCs) design. Patients with sigmoid or rectal cancer undergoing elective laparoscopic or robotic surgery were randomized to either sponge-assisted or Trendelenburg surgery on a 1:1 basis using block randomization. Duration of postoperative hospital stay was the primary outcome and was compared using the Mann-Whitney U test. Secondary endpoints included the proportion of complications, readmissions, or mortality versus the χ2 test in intention-to-treat and per-protocol analyses. This trial was not blinded for patients in the intervention arm or physicians. RESULTS: Between November 2015 and June 2021, 82 patients were randomized to sponge-assisted surgery and 81 to Trendelenburg surgery. After post-randomization exclusion, 150 patients remained for analyses (75 patients per arm). There was no statistically significant difference in median duration of hospital stay (5 days versus 4 days, respectively; P = 0.06), 30-day postoperative complications (30 per cent versus 31 per cent; P = 1.00), readmission rate (8 per cent versus 15 per cent; P = 0.30), or mortality (0 per cent versus 1 per cent, P = 1.00). The per-protocol analysis showed similar results. No adverse device events were seen. CONCLUSION: Sponge-assisted laparoscopic/robotic surgery does not reduce the duration of hospital stay, or perioperative morbidity or mortality. TRIAL REGISTRATION: NCT02574013 (http://www.clinicaltrials.gov).

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.ESCISIÓN MESORRECTAL TOTAL ASISTIDA POR ROBOT VERSUS ESCISIÓN MESORRECTAL TOTAL LAPAROSCÓPICA: UNA PUNTUACIÓN DE PROPENSIÓN RETROSPECTIVA ANÁLISIS DE COHORTES EMPAREJADAS EN CENTROS EXPERIMENTADOS. ANTECEDENTES: No se ha demostrado la superioridad de la escisión mesorrectal total asistida por robot sobre la laparoscópica. La mayoría de los estudios no tienen en cuenta la curva de aprendizaje al comparar la técnica quirúrgica. OBJETIVO: Este estudio tiene como objetivo comparar la escisión mesorrectal total laparoscópica con la asistida por robot realizada por cirujanos que completaron la curva de aprendizaje de la técnica. DISEO: Este es un análisis multicéntrico retrospectivo emparejado por puntuación de propensión. AJUSTES: El estudio se realizó en dos grandes hospitales dedicados asistidos por robots y cinco grandes hospitales laparoscópicos dedicados. PACIENTES: Se incluyeron pacientes que se sometieron a escisión mesorrectal total asistida por robot o laparoscópica para cáncer de recto con intención curativa, en un centro dedicado a la técnica mínimamente invasiva entre el 1 de enero de 2015 y el 31 de diciembre de 2017. INTERVENCIONES: Comparamos la escisión mesorrectal total asistida por robot con la laparoscópica. PRINCIPALES MEDIDAS DE RESULTADO: El principal resultado fue la conversión a laparotomía durante la cirugía. Los resultados secundarios fueron la morbilidad posoperatoria y el margen circunferencial positivo. RESULTADOS: Se incluyó a un total de 884 pacientes y, después de emparejar, quedaron 315 pacientes por grupo de tratamiento. La conversión fue similar entre la escisión mesorrectal total laparoscópica y asistida por robot (4,4% frente a 2,5% [p = 0,20]). El margen de resección circunferencial positivo fue igual (3,2% vs 4,4% [p = 0,41]). La morbilidad general también fue comparable, aunque se observó una menor tasa de infecciones de heridas en el grupo asistido por robot (5,7% frente a 1,9% [p = 0,01]). Se construyeron más anastomosis primarias en el grupo asistido por robot (50,8% frente a 68,3% [p < 0,001]). Finalmente, se realizaron procedimientos más abiertos en centros laparoscópicos dedicados, con una sobrerrepresentación de tumores cT4N + en este grupo. LIMITACIONES: Ésta es una cohorte multicéntrica retrospectiva; sin embargo, se aplicó el emparejamiento por puntuación de propensión para controlar los factores de confusión por indicación. CONCLUSIONES: La escisión mesorrectal total asistida por robot y laparoscópica son igualmente seguras en términos de resultados a corto plazo. Sin embargo, con el abordaje asistido por robot, se construyeron más anastomosis primarias y se observó una menor tasa de infección de la herida. Consulte Video Resumen en http://links.lww.com/DCR/B677. (Traducción-Dr. Gonzalo Hagerman).

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

AIM: Unlike meta-analyses of randomized controlled trials, population-based studies in colorectal cancer (CRC) patients have shown a significant association between open surgery and increased 30- and 90-day mortality compared with laparoscopic surgery. Long-term mortality, however, is scarcely reported. This retrospective population-based study aimed to compare long-term mortality after open and laparoscopic surgery for CRC. METHOD: The Dutch Colorectal Audit and the Dutch Cancer Centre registry were used to identify patients from three large nonacademic teaching hospitals who underwent curative resection for CRC between 2009 and 2018. Patients with relative contraindications for laparoscopic surgery (cT4 or pT4 tumours, distant metastasis requiring additional resection and emergency surgery) were excluded. Multivariable regression was used to assess the effect of laparoscopic surgery on long-term mortality with adjustment for gender, age, American Society of Anesthesiologists score, TNM stage, chemoradiation therapy and other confounders. RESULTS: We included 4531 patients, of whom 1298 (29%) underwent open surgery. The median follow-up was 43 months (interquartile range 23-71 months). Open surgery was associated with an increased risk of long-term mortality (adjusted hazard ratio 1.26, 95% confidence interval 1.10-1.45, p = 0.001). Mixed-effects Cox regression with year of surgery as a random effect also showed an increased risk after open surgery (adjusted hazard ratio 1.33, 95% confidence interval 1.11-1.52, p = 0.004). CONCLUSION: Open surgery seems to be associated with increased long-term mortality in the elective setting for CRC patients. A minimally invasive approach might improve long-term outcomes.

Endoglin/CD105-Based Imaging of Cancer and Cardiovascular Diseases: A Systematic Review.

Molecular imaging of pathologic lesions can improve efficient detection of cancer and cardiovascular diseases. A shared pathophysiological feature is angiogenesis, the formation of new blood vessels. Endoglin (CD105) is a coreceptor for ligands of the Transforming Growth Factor-ß (TGF-ß) family and is highly expressed on angiogenic endothelial cells. Therefore, endoglin-based imaging has been explored to visualize lesions of the aforementioned diseases. This systematic review highlights the progress in endoglin-based imaging of cancer, atherosclerosis, myocardial infarction, and aortic aneurysm, focusing on positron emission tomography (PET), single-photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), near-infrared fluorescence (NIRF) imaging, and ultrasound imaging. PubMed was searched combining the following subjects and their respective synonyms or relevant subterms: "Endoglin", "Imaging/Image-guided surgery". In total, 59 papers were found eligible to be included: 58 reporting about preclinical animal or in vitro models and one ex vivo study in human organs. In addition to exact data extraction of imaging modality type, tumor or cardiovascular disease model, and tracer (class), outcomes were described via a narrative synthesis. Collectively, the data identify endoglin as a suitable target for intraoperative and diagnostic imaging of the neovasculature in tumors, whereas for cardiovascular diseases, the evidence remains scarce but promising.

BMP Receptor Inhibition Enhances Tissue Repair in Endoglin Heterozygous Mice.

Hereditary hemorrhagic telangiectasia type 1 (HHT1) is a severe vascular disorder caused by mutations in the TGFß/BMP co-receptor endoglin. Endoglin haploinsufficiency results in vascular malformations and impaired neoangiogenesis. Furthermore, HHT1 patients display an impaired immune response. To date it is not fully understood how endoglin haploinsufficient immune cells contribute to HHT1 pathology. Therefore, we investigated the immune response during tissue repair in Eng+/- mice, a model for HHT1. Eng+/- mice exhibited prolonged infiltration of macrophages after experimentally induced myocardial infarction. Moreover, there was an increased number of inflammatory M1-like macrophages (Ly6Chigh/CD206-) at the expense of reparative M2-like macrophages (Ly6Clow/CD206+). Interestingly, HHT1 patients also showed an increased number of inflammatory macrophages. In vitro analysis revealed that TGFß-induced differentiation of Eng+/- monocytes into M2-like macrophages was blunted. Inhibiting BMP signaling by treating monocytes with LDN-193189 normalized their differentiation. Finally, LDN treatment improved heart function after MI and enhanced vascularization in both wild type and Eng+/- mice. The beneficial effect of LDN was also observed in the hind limb ischemia model. While blood flow recovery was hampered in vehicle-treated animals, LDN treatment improved tissue perfusion recovery in Eng+/- mice. In conclusion, BMPR kinase inhibition restored HHT1 macrophage imbalance in vitro and improved tissue repair after ischemic injury in Eng+/- mice.

Human epicardium-derived cells reinforce cardiac sympathetic innervation.

RATIONALE: After cardiac damage, excessive neurite outgrowth (sympathetic hyperinnervation) can occur, which is related to ventricular arrhythmias/sudden cardiac death. Post-damage reactivation of epicardium causes epicardium-derived cells (EPDCs) to acquire a mesenchymal character, contributing to cardiac regeneration. Whether EPDCs also contribute to cardiac re/hyperinnervation, is unknown. AIM: To investigate whether mesenchymal EPDCs influence cardiac sympathetic innervation. METHODS AND RESULTS: Sympathetic ganglia were co-cultured with mesenchymal EPDCs and/or myocardium, and neurite outgrowth and sprouting density were assessed. Results showed a significant increase in neurite density and directional (i.e. towards myocardium) outgrowth when ganglia were co-cultured with a combination of EPDCs and myocardium, as compared to cultures with EPDCs or myocardium alone. In absence of myocardium, this outgrowth was not directional. Neurite differentiation of PC12 cells in conditioned medium confirmed these results via a paracrine effect, in accordance with expression of neurotrophic factors in myocardial explants co-cultured with EPDCs. Of interest, EPDCs increased the expression of nerve growth factor (NGF) in cultured, but not in fresh myocardium, possibly due to an "ischemic state" of cultured myocardium, supported by TUNEL and Hif1α expression. Cardiac tissues after myocardial infarction showed robust NGF expression in the infarcted, but not remote area. CONCLUSION: Neurite outgrowth and density increases significantly in the presence of EPDCs by a paracrine effect, indicating a new role for EPDCs in the occurrence of sympathetic re/hyperinnervation after cardiac damage.

Body mass index and sexual function in women with gynaecological cancer.

OBJECTIVES: To investigate the association between body mass index (BMI) and sexual functioning in gynaecologic cancer patients. To determine the association between socio-economic deprivation and sexual functioning. METHODS: This is a prospective cohort study on women undergoing surgery for suspected or proven gynaecological cancer between September 2014 and February 2016 in the Royal Cornwall Hospital Trust. Patients were invited to participate by completing the Female Sexual Function Index (FSFI) at three time points: preoperative, 3 months postoperative, and 1 year postoperative. A semiparametric model of the FSFI score was used to establish the association between BMI and sexual functioning. RESULTS: A total of 257 patients were approached of which 166 patients were included. Fifty-two patients (33.8%) were overweight (BMI, 25-29.9 kg/m2 ), 44 (28.6%) were obese (BMI, 30-39.9 kg/m2 ), and a further 20 (13.0%) morbidly obese (BMI ≥ 40 kg/m2 ). Overweight and obese women reported improved sexual functioning compared with normal-weight women in endometrial, ovarian, and vulvar cancers. Among cervical cancer, worse sexual functioning was seen in women with an increased BMI; however, this was not significant. Younger age was associated with improved sexual function, and sexual functioning was better postoperatively for all patients compared with preoperatively. There was no evidence of relationship between deprivation and sexual functioning in gynaecological cancer patients. CONCLUSION: Higher BMI is associated with improved sexual functioning in endometrial, ovarian, and vulvar cancer; however, this was not seen in cervical cancer patients. There is no evidence of correlation between deprivation and sexual functioning.

Health-related quality of life in rectal cancer patients undergoing neoadjuvant chemoradiation with delayed surgery versus short-course radiotherapy with immediate surgery: a propensity score-matched cohort study.

BACKGROUND: Neoadjuvant chemoradiation with delayed surgery (CRT-DS) and short-course radiotherapy with immediate surgery (SCRT-IS) are two commonly used treatment strategies for rectal cancer. However, the optimal treatment strategy for patients with intermediate-risk rectal cancer remains a discussion. This study compares quality of life (QOL) between SCRT-IS and CRT-DS from diagnosis until 24 months after treatment. METHODS: In a prospective colorectal cancer cohort, rectal cancer patients with clinical stage T2-3N0-2M0 undergoing SCRT-IS or CRT-DS between 2013 and 2017 were identified. QOL was assessed using EORTC-C30 and EORTC-CR29 questionnaires before the start of neoadjuvant treatment (baseline) and at 3, 6, 12, 18 and 24 months after. Patients were 1:1 matched using propensity sore matching. Between- and within-group differences in QOL domains were analyzed with linear mixed-effects models. Symptoms and sexual interest at 12 and 24 months were compared using logistic regression models. RESULTS: 156 of 225 patients (69%) remained after matching. The CRT-DS group reported poorer emotional functioning at 3, 6, 12, 18 and 24 months (mean difference with SCRT-IS: -9.4, -12.1, -7.3, -8.0 and -7.9 respectively), and poorer global health, physical-, role-, social- and cognitive functioning at 6 months (mean difference with SCRT-IS: -9.1, -9.8, -14.0, -9.2 and -12.6, respectively). Besides emotional functioning, all QOL domains were comparable at 12, 18 and 24 months. Within-group changes showed a significant improvement of emotional functioning after baseline in the SCRT-IS group, whereas only a minor improvement was observed in the CRT-DS group. Symptoms and sexual interest in male patients at 12 and 24 months were comparable between the groups. CONCLUSIONS: In rectal cancer patients, CRT-DS may induce a stronger decline in short-term QOL than SCRT-IS. From 12 months onwards, QOL domains, symptoms and sexual interest in male patients were comparable between the groups. However, emotional functioning remained higher after SCRT-IS than after CRT-DS.