Delivery of Mesenchymal Stem Cells during Hypothermic Machine Perfusion in a Translational Kidney Perfusion Study.

In transplantation, hypothermic machine perfusion (HMP) has been shown to be superior to static cold storage (SCS) in terms of functional outcomes. Ex vivo machine perfusion offers the possibility to deliver drugs or other active substances, such as Mesenchymal Stem Cells (MSCs), directly into an organ without affecting the recipient. MSCs are multipotent, self-renewing cells with tissue-repair capacities, and their application to ameliorate ischemia- reperfusion injury (IRI) is being investigated in several preclinical and clinical studies. The aim of this study was to introduce MSCs into a translational model of hypothermic machine perfusion and to test the efficiency and feasibility of this method. Methods: three rodent kidneys, six porcine kidneys and three human kidneys underwent HMP with 1-5 × 106 labelled MSCs within respective perfusates. Only porcine kidneys were compared to a control group of 6 kidneys undergoing HMP without MSCs, followed by mimicked reperfusion with whole blood at 37 °C for 2 h for all 12 kidneys. Reperfusion perfusate samples were analyzed for levels of NGAL and IL-ß by ELISA. Functional parameters, including urinary output, oxygen consumption and creatinine clearance, were compared and found to be similar between the MSC treatment group and the control group in the porcine model. IL-1ß levels were higher in perfusate and urine samples in the MSC group, with a median of 285.3 ng/mL (IQR 224.3-407.8 ng/mL) vs. 209.2 ng/mL (IQR 174.9-220.1), p = 0.51 and 105.3 ng/mL (IQR 71.03-164.7 ng/mL) vs. 307.7 ng/mL (IQR 190.9-349.6 ng/mL), p = 0.16, respectively. MSCs could be traced within the kidneys in all models using widefield microscopy after HMP. The application of Mesenchymal Stem Cells in an ex vivo hypothermic machine perfusion setting is feasible, and MSCs can be delivered into the kidney grafts during HMP. Functional parameters during mimicked reperfusion were not altered in treated kidney grafts. Changes in levels of IL-1ß suggest that MSCs might have an effect on the kidney grafts, and whether this leads to a positive or a negative outcome on IRI in transplantation needs to be determined in further experiments.

Pulmonary metastasectomy and repeat metastasectomy for colorectal pulmonary metastases: outcomes from the Dutch Lung Cancer Audit for Surgery.

BACKGROUND: Surgical resection of recurrent pulmonary metastases in patients with colorectal cancer is an established treatment option; however, the evidence for repeat resection is limited. The aim of this study was to analyse long-term outcomes from the Dutch Lung Cancer Audit for Surgery. METHODS: Data from the mandatory Dutch Lung Cancer Audit for Surgery were used to analyse all patients after metastasectomy or repeat metastasectomy for colorectal pulmonary metastases from January 2012 to December 2019 in the Netherlands. Kaplan-Meier survival analysis was performed to determine the difference in survival. Multivariable Cox regression analyses were performed to identify predictors of survival. RESULTS: A total of 1237 patients met the inclusion criteria, of which 127 patients underwent repeat metastasectomy. Five-year overall survival was 53 per cent after pulmonary metastasectomy for colorectal pulmonary metastases and 52 per cent after repeat metastasectomy (P = 0.852). The median follow-up was 42 (range 0-285) months. More patients experienced postoperative complications after repeat metastasectomy compared with the first metastasectomy (18.1 per cent versus 11.6 per cent respectively; P = 0.033). Eastern Cooperative Oncology Group performance status greater than or equal to 1 (HR 1.33, 95 per cent c.i. 1.08 to 1.65; P = 0.008), multiple metastases (HR 1.30, 95 per cent c.i. 1.01 to 1.67; P = 0.038), and bilateral metastases (HR 1.50, 95 per cent c.i. 1.01 to 2.22; P = 0.045) were prognostic factors on multivariable analysis for pulmonary metastasectomy. Diffusing capacity of the lungs for carbon monoxide less than 80 per cent (HR 1.04, 95 per cent c.i. 1.01 to 1.06; P = 0.004) was the only prognostic factor on multivariable analysis for repeat metastasectomy. CONCLUSION: This study demonstrates that patients with colorectal pulmonary metastases have comparable median and 5-year overall survival rates after primary or recurrent pulmonary metastasectomy. However, repeat metastasectomy has a higher risk of postoperative complications.

Impact of the COVID-19 pandemic on surgical care in the Netherlands.

BACKGROUND: The COVID-19 pandemic caused disruption of regular healthcare leading to reduced hospital attendances, repurposing of surgical facilities, and cancellation of cancer screening programmes. This study aimed to determine the impact of COVID-19 on surgical care in the Netherlands. METHODS: A nationwide study was conducted in collaboration with the Dutch Institute for Clinical Auditing. Eight surgical audits were expanded with items regarding alterations in scheduling and treatment plans. Data on procedures performed in 2020 were compared with those from a historical cohort (2018-2019). Endpoints included total numbers of procedures performed and altered treatment plans. Secondary endpoints included complication, readmission, and mortality rates. RESULTS: Some 12 154 procedures were performed in participating hospitals in 2020, representing a decrease of 13.6 per cent compared with 2018-2019. The largest reduction (29.2 per cent) was for non-cancer procedures during the first COVID-19 wave. Surgical treatment was postponed for 9.6 per cent of patients. Alterations in surgical treatment plans were observed in 1.7 per cent. Time from diagnosis to surgery decreased (to 28 days in 2020, from 34 days in 2019 and 36 days in 2018; P < 0.001). For cancer-related procedures, duration of hospital stay decreased (5 versus 6 days; P < 0.001). Audit-specific complications, readmission, and mortality rates were unchanged, but ICU admissions decreased (16.5 versus 16.8 per cent; P < 0.001). CONCLUSION: The reduction in the number of surgical operations was greatest for those without cancer. Where surgery was undertaken, it appeared to be delivered safely, with similar complication and mortality rates, fewer admissions to ICU, and a shorter hospital stay.

COVID-19 has had a significant impact on healthcare worldwide. Hospital visits were reduced, operating facilities were used for COVID-19 care, and cancer screening programmes were cancelled. This study describes the impact of the COVID-19 pandemic on Dutch surgical healthcare in 2020. Patterns of care in terms of changed or delayed treatment are described for patients who had surgery in 2020, compared with those who had surgery in 2018­2019. The study found that mainly non-cancer surgical treatments were cancelled during months with high COVID-19 rates. Outcomes for patients undergoing surgery were similar but with fewer ICU admissions and shorter hospital stay. These data provide no insight into the burden endured by patients who had postponed or cancelled operations.

A Comparison of Pulsatile Hypothermic and Normothermic Ex Vivo Machine Perfusion in a Porcine Kidney Model.

BACKGROUND: Hypothermic machine perfusion (HMP) is a well-established method for deceased donor kidney preservation. Normothermic machine perfusion (NMP) might offer similar or greater advantages. We compared the 2 methods in an ex vivo perfusion model using 34 porcine kidneys. METHODS: Thirty kidneys were stored on ice for 24 h before undergoing 4 h of HMP (n = 15) or NMP (n = 15) followed by 2 h of normothermic ex vivo reperfusion with whole blood. Four kidneys underwent 28 h of cold static storage followed by 2 h of normothermic ex vivo reperfusion. During the 2 h of normothermic ex vivo reperfusion, perfusate flow rates, urinary output, and oxygen consumption rates were compared between all groups. RESULTS: Porcine kidneys after HMP showed significantly higher urinary output (5.31 ± 2.06 versus 2.44 ± 1.19 mL/min; P = 0.002), oxygen consumption (22.71 ± 6.27 versus 11.83 ± 1.29 mL/min; P = 0.0016), and perfusate flow rates (46.24 ± 12.49 versus 26.16 ± 4.57 mL/min; P = 0.0051) than kidneys after NMP. TUNEL staining of tissue sections showed significantly higher rates of apoptosis in kidneys after NMP (P = 0.027). CONCLUSIONS: In our study, the direct comparison of HMP and NMP kidney perfusion in a translational model demonstrated superiority of HMP; however, further in vivo studies would be needed to validate those results.

Non-sustained ventricular tachycardia in patients with congenital heart disease: An important sign?

BACKGROUND: Sustained ventricular tachycardia (susVT) and ventricular fibrillation (VF) are observed in adult patients with congenital heart disease (CHD). These dysrhythmias may be preceded by non-sustained ventricular tachycardia (NSVT). The aims of this study are to examine the 1] time course of ventricular tachyarrhythmia (VTA) in a large cohort of patients with various CHDs and 2] the development of susVT/VF after NSVT. METHODS: In this retrospective study, patients with VTA on ECG, 24-hour Holter or ICD-printout or an out-of-hospital-cardiac arrest due to VF were included. In patients with an ICD, the number of shocks was studied. RESULTS: Patients (N=145 patients, 59% male) initially presented with NSVT (N=103), susVT (N=25) or VF (N=17) at a mean age of 40 ± 14 years. Prior to VTA, 58 patients had intraventricular conduction delay, 14 an impaired ventricular dysfunction and 3 had coronary artery disease. susVT/VF rarely occurred in patients with NSVT (N=5). Fifty-two (36%) patients received an ICD; appropriate and inappropriate shocks, mainly due to supraventricular tachycardia (SVT), occurred in respectively 15 (29%) (NSVT: N=1, susVT: N=9, VF: N=5) and 12 (23%) (NSVT: N=4, susVT: N=5, VF: N=3) patients. CONCLUSIONS: VTA in patients with CHD appear on average at the age of 40 years. susVT/VF rarely developed in patients with only NSVT, whereas recurrent episodes of susVT/VF frequently developed in patients initially presenting with susVT/VF. Hence, a wait-and-see treatment strategy in patients with NSVT and aggressive therapy of both episodes of VTA and SVT in patients with susVT/VF seems justified.