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Evidence should define and guide modern clinical care, yet many relevant questions in surgical practice remain unconfirmed by substantial data. Evidence-based medicine requires both the implementation of its principles in day-to-day work and the acquisition of new evidence preferably by randomized controlled trials and systematic reviews. Meaningful clinical research, however, is challenging to conduct, and its overall infrastructure in Germany was, until recently, considered poor compared to other leading countries. Although this has been significantly improved after the establishment of the Study Center of the German Surgical Society (SDGC) and the surgical clinical trial network CHIR-Net, limited focus has been put on the training, teaching, and recruitment of medical students to become competent clinical researchers and clinician scientists. To ensure continuing comprehensive clinical research in surgery, CHIR-Net aims to establish a student-driven multicenter research network in Germany, which is embedded in both the national CHIR-Net and the pan-European and international frameworks. Student-Initiated German Medical Audits (SIGMA) is a product of the strong collaboration between clinical scientists and medical trainees, enabling students to contribute to high-quality clinical trials. Additionally, participants are offered extensive training to support the next generation of research-active clinicians. Starting on 2018, SIGMA will perform its first multicenter observational study in Germany.

Abstract Background Incisional hernia is a frequent complication in abdominal surgery. This article describes the development of a prospective randomized clinical trial designed to determine whether watchful waiting is an acceptable alternative to surgical repair for patients with oligosymptomatic incisional hernia. Methods/Design This clinical multicenter trial has been designed to compare watchful waiting and surgical repair for patients with oligosymptomatic incisional hernia. Participants are randomized to watchful waiting or surgery and followed up for two years. The primary efficacy endpoint is pain/discomfort during normal activities as a result of the hernia or hernia repair two years after enrolment, as measured by the hernia-specific Surgical Pain Scales (SPS). The target sample size of six hundred thirty-six patients was calculated to detect non-inferiority of the experimental intervention (watchful waiting) in the primary endpoint. Sixteen surgical centers will take part in the study and have submitted their declaration of commitment giving the estimated number of participating patients per year. A three-person data safety monitoring board will meet annually to monitor and supervise the trial. Discussion To date, we could find no published data on the natural course of incisional hernias. To our knowledge, watchful waiting has never been compared to standard surgical repair as a treatment option for incisional hernias. A trial to compare the outcome of the two approaches in patients with oligosymptomatic incisional hernias is urgently needed to provide data that can facilitate the choice between treatment options. If watchful waiting was equal to surgical repair, the high costs of surgical repair could be saved. The design for such a trial is described here. This multicenter trial will be funded by the German Research Foundation (DFG). The ethics committee of the Charité has approved the study protocol. Approval has been obtained from ten study sites at time of this submission. The electronic Case Report Forms have been created. The first patient was to be randomized November 14th, 2011. An initiation meeting took place in Berlin January 9th, 2012. Trial Registration ClinicalTrials.gov: NCT01349400

Abstract Background Wound infection affects a considerable portion of patients after abdominal operations, increasing health care costs and postoperative morbidity and affecting quality of life. Antibacterial coating has been suggested as an effective measure to decrease postoperative wound infections after laparotomies. The INLINE metaanalysis has recently shown the superiority of a slowly absorbable continuous suture for abdominal closure; with PDS plus® such a suture has now been made available with triclosan antibacterial coating. Methods/Design The PROUD trial is designed as a randomised, controlled, observer, surgeon and patient blinded multicenter superiority trial with two parallel groups and a primary endpoint of wound infection during 30 days after surgery. The intervention group will receive triclosan coated polydioxanone sutures, whereas the control group will receive the standard polydioxanone sutures; abdominal closure will otherwise be standardized in both groups. Statistical analysis is based on intention-to-treat population via binary logistic regression analysis, the total sample size of n = 750 is sufficient to ensure alpha = 5% and power = 80%, an interim analysis will be carried out after data of 375 patients are available. Discussion The PROUD trial will yield robust data to determine the effectiveness of antibacterial coating in one of the standard sutures for abdominal closure and potentially lead to amendment of current guidelines. The exploration of clinically objective parameters as well as quality of life holds immediate relevance for clinical management and the pragmatic trial design ensures high external validity. Trial Registration The trial protocol has been registered with the German Clinical Trials Register (DRKS00000390).

Background and Objective: The development of early screening for lung cancer has led to improved overall survival in patients with non-small cell lung cancer (NSCLC). However, the management of NSCLC patients with resectable and potentially resectable chest wall invasion (CWI) requires attention. The purpose of this review is to summarize the role of surgery (chest wall resections) in NSCLC patients with CWI., Methods: A literature search and review from three databases (PubMed, Embase, and ScienceDirect) comprised the last 39 years. This review was focused on the treatment of NSCLC patients with CWI, mainly including the preoperative evaluation, principles of treatment and strategic decision-making, surgical complications, and prognostic factors., Key Content and Findings: Through the collection of relevant literature on NSCLC that invades the chest wall, this narrative review describes the actual role in clinical practice and future developments of chest wall resections. Preoperative treatment requires the multidisciplinary team (MDT) team to conduct accurate clinical staging of the patient and pay attention to the patient's lymph node status and rib invasion status. The successful implementation of chest wall resection and possible chest wall reconstruction requires refined individualized treatment based on the patient's clinical characteristics, supplemented by possible postoperative systemic treatment., Conclusions: Surgery plays an important role in treating NSCLC patients with CWI, and a collaborative, experienced MDT is an essential component of the successful treatment of CWI with lung cancer. In the future, more high-quality clinical research is needed to focus on CWI patients so that patients can receive more effective treatment options and better clinical prognosis., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-774/coif). The special series “Chest Wall Resections and Reconstructions” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare., (2024 Journal of Thoracic Disease. All rights reserved.)

Purpose: Minimal-invasive liver surgery (MILS) reduces surgical trauma and is associated with fewer postoperative complications. To amplify these benefits, perioperative multimodal concepts like Enhanced Recovery after Surgery (ERAS), can play a crucial role. We aimed to evaluate the cost-effectiveness for MILS in an ERAS program, considering the necessary additional workforce and associated expenses., Methods: A prospective observational study comparing surgical approach in patients within an ERAS program compared to standard care from 2018-2022 at the Charité - Universitätsmedizin Berlin. Cost data were provided by the medical controlling office. ERAS items were applied according to the ERAS society recommendations., Results: 537 patients underwent liver surgery (46% laparoscopic, 26% robotic assisted, 28% open surgery) and 487 were managed by the ERAS protocol. Implementation of ERAS reduced overall postoperative complications in the MILS group (18% vs. 32%, p = 0.048). Complications greater than Clavien-Dindo grade II incurred the highest costs (€ 31,093) compared to minor (€ 17,510) and no complications (€13,893; p < 0.001). In the event of major complications, profit margins were reduced by a median of € 6,640., Conclusions: Embracing the ERAS society recommendations in liver surgery leads to a significant reduction of complications. This outcome justifies the higher cost associated with a well-structured ERAS protocol, as it effectively offsets the expenses of complications., (© 2024. The Author(s).)

Background: Adherence to enhanced recovery after surgery (ERAS) protocols is crucial for successful liver surgery. The aim of this study was to assess the impact of minimally invasive liver surgery complexity on adherence after implementing an ERAS protocol., Methods: Between July 2018 and August 2021, a prospective observational study involving minimally invasive liver surgery patients was conducted. Perioperative treatment followed ERAS guidelines and was recorded in the ERAS interactive audit system. Kruskal-Wallis and ANOVA tests were used for analysis, and pairwise comparisons utilized Wilcoxon rank sum and Welch's t-tests, adjusted using Bonferroni correction., Results: A total of 243 patients were enrolled and categorized into four groups based on the Iwate criteria: low (n = 17), intermediate (n = 81), advanced (n = 74) and expert difficulty (n = 71). Complexity correlated with increased overall and major morbidity rate, as well as longer length of stay (all P < 0.001; standardized mean difference = 0.036, 0.451, 0.543 respectively). Adherence to ERAS measures decreased with higher complexity (P < 0.001). Overall adherence was 65.4%. Medical staff-centred adherence was 79.9%, while patient-centred adherence was 38.9% (P < 0.001). Complexity significantly affected patient-centred adherence (P < 0.001; standardized mean difference (SMD) = 0.420), but not medical staff-centred adherence (P = 0.098; SMD = 0.315). Postoperative phase adherence showed major differences among complexity groups (P < 0.001, SMD = 0.376), with mobilization measures adhered to less in higher complexity cases., Conclusion: The complexity of minimally invasive liver surgery procedures impacts ERAS protocol adherence for each patient. This can be addressed using complexity-adjusted cut-offs and 'gradual adherence' based on the relative proportion of cut-off values achieved., (© The Author(s) 2024. Published by Oxford University Press on behalf of BJS Foundation Ltd.)

Objectives: Skip-N2 metastasis (N0N2), thus N2 metastasis in the absence of N1 metastasis, occurs in ∼20-30% of non-small-cell lung cancer patients. N0N2 patients have a better prognosis than continuous-N2 metastasis (N1N2) patients following surgery. However, this effect remains controversial. Therefore, we conducted a multicentre study to compare the long-term survival and disease-free interval (DFI) of N1N2- and N0N2 patients., Methods: One- and 3-year survival rates were measured. Kaplan-Meier curves and a Cox proportional hazards model assessed survival and were used to identify prognostic factors for overall survival. In addition, we performed propensity score matching (PSM) to rule out confounding factors. All patients received adjuvant chemoradiation therapy according to European guidelines., Results: Between January 2010 and December 2020, 218 stage IIIA/B N2 patients were included in our analysis. The Cox regression analysis revealed that N1N2 significantly influenced the overall survival rate. Before PSM, N1N2 patients showed significantly more metastatic lymph nodes (P < 0.001) and significantly larger tumours (P = 0.05). After PSM, baseline characteristics did not differ between groups. Before and after PSM, N0N2 patients showed significantly better 1- (P = 0.01; P = 0.009) and 3-year (P < 0.001) survival rates than N1N2 patients. Furthermore, N0N2 patients showed significantly longer DFI than N1N2 patients before and after PSM (P < 000.1)., Conclusions: Prior and after PSM analysis, N0N2 patients were confirmed to have better survival and DFI than N1N2 patients. Our results demonstrate that stage IIIA/B N2 patients are heterogeneous and would benefit from a more precise subdivision and differential treatment., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: Twenty-three recommendations were summarized by the Enhanced Recovery After Surgery (ERAS) society for liver surgery. The aim was to validate the protocol especially with regard to adherence and the impact on morbidity., Methods: Using the ERAS Interactive Audit System (EIAS), ERAS items were evaluated in patients undergoing liver resection. Over a period of 26 months, 304 patients were prospectively enrolled in an observational study (DRKS00017229). Of those, 51 patients (non-ERAS) were enrolled before and 253 patients (ERAS) after the implementation of the ERAS protocol. Perioperative adherence and complications were compared between the two groups., Results: Overall adherence increased from 45.2% in the non-ERAS group to 62.7% in the ERAS group (P<0.001). This was associated with significant improvements in the preoperative and postoperative phase (P<0.001), rather than in the outpatient and intraoperative phase (both P>0.05). Overall complications decreased from 41.2% (n=21) in the non-ERAS group to 26.5% (n=67) in the ERAS group (P=0.0423), which was mainly due to the reduction of grade 1-2 complications from 17.6% (n=9) to 7.6% (n=19) (P=0.0322). As for patients undergoing open surgery, implementation of ERAS lead to a reduction of overall complications in patients scheduled for minimally invasive liver surgery (MILS) (P=0.036)., Conclusions: Implementation of the ERAS protocol for liver surgery according to the ERAS guidelines of the ERAS Society reduced Clavien-Dindo grade 1-2 complications particularly in patients who underwent MILS. The ERAS guidelines are beneficial for the outcome, while adherence to the various items has not yet been satisfactorily defined., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-21-294/coif). The authors have no conflicts of interest to declare., (2023 Hepatobiliary Surgery and Nutrition. All rights reserved.)

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) utilises the angiotensin-converting enzyme 2 (ACE2) transmembrane peptidase as cellular entry receptor. However, whether SARS-CoV-2 in the alveolar compartment is strictly ACE2-dependent and to what extent virus-induced tissue damage and/or direct immune activation determines early pathogenesis is still elusive., Methods: Spectral microscopy, single-cell/-nucleus RNA sequencing or ACE2 "gain-of-function" experiments were applied to infected human lung explants and adult stem cell derived human lung organoids to correlate ACE2 and related host factors with SARS-CoV-2 tropism, propagation, virulence and immune activation compared to SARS-CoV, influenza and Middle East respiratory syndrome coronavirus (MERS-CoV). Coronavirus disease 2019 (COVID-19) autopsy material was used to validate ex vivo results., Results: We provide evidence that alveolar ACE2 expression must be considered scarce, thereby limiting SARS-CoV-2 propagation and virus-induced tissue damage in the human alveolus. Instead, ex vivo infected human lungs and COVID-19 autopsy samples showed that alveolar macrophages were frequently positive for SARS-CoV-2. Single-cell/-nucleus transcriptomics further revealed nonproductive virus uptake and a related inflammatory and anti-viral activation, especially in "inflammatory alveolar macrophages", comparable to those induced by SARS-CoV and MERS-CoV, but different from NL63 or influenza virus infection., Conclusions: Collectively, our findings indicate that severe lung injury in COVID-19 probably results from a macrophage-triggered immune activation rather than direct viral damage of the alveolar compartment., Competing Interests: Conflict of interest: J-C. Rückert and H. Radbruch report support from DFG RA 2491/1-1, BMBF (Defeat Pandemics). A.E. Hauser reports support from Charité – Universitätsmedizin Berlin and Deutsches Rheuma-Forschungszentrum Berlin, and grants from Deutsche Forschungsgemeinschaft (HA5354/10-1, TRR130,P17 and C01, HA5354/8-1). T. Wolff reports support from Federal Ministry of Education and Research (BMBF) grant 01K12006F. M. Kessler reports grants from BMBF Organo-Strat, Einstein 3R. M. Dohmen reports contracts with Max-Delbrück Center, Berlin; grants from Gender Equality Fund, Berlin Institute of Health. F. Klauschen reports consulting fees, lecture honoraria, travel support and participation on advisory boards with BMS, Novartis, Roche and Lilly, and is a co-founder of AI-BIH/Charité-Spinoff Aignostics GmbH. F. Heppner reports consulting fees, lecture honoraria, payment for expert testimony and leadership roles at Novartis, AstraZeneca and ThinkHealth Hygiene Solutions. V.M. Corman reports the following patents: 20210190797 (Methods and reagents for diagnosis of SARS-CoV-2 infection); 9841834 (Human recombinant monoclonal antibody against SARS-CoV-2 spike glycoprotein); 9909654 (A pharmaceutical combination comprising an anti-viral protonophore and a serine protease inhibitor). D. Niemeyer reports that Technische Universität Berlin, Freie Universität Berlin and Charité – Universitätsmedizin have filed a patent application for siRNAs inhibiting SARS-CoV-2 replication with D. Niemeyer as coauthor. M.A. Müller reports the following patents: 20210190797 (Methods and reagents for diagnosis of SARS-CoV-2 infection); 9841834 (Human recombinant monoclonal antibody against SARS-CoV-2 spike glycoprotein); 9909654 (A pharmaceutical combination comprising an anti-viral protonophore and a serine protease inhibitor); and has participated on an advisory board for ECDC/WHO. S. Ludwig reports consulting fees from Atriva Therapeutics GmbH, Biontec SE; and has patent PCT/EP2021/063485 pending. M. Witzenrath reports grants from Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, Deutsche Gesellschaft für Pneumologie, European Respiratory Society, Marie Curie Foundation, Else Kröner Fresenius Stiftung, Capnetz Stiftung, International Max Planck Research School, Quark Pharma, Takeda Pharma, Noxxon, Pantherna, Silence Therapeutics, Vaxxilon, Actelion, Bayer Health Care, Biotest and Boehringer Ingelheim; consulting fees from Noxxon, Pantherna, Silence Therapeutics, Vaxxilon, Aptarion, GlaxoSmithKline, Sinoxa and Biotest; lecture honoraria from AstraZeneca, Berlin Chemie, Chiesi, Novartis, Teva, Actelion, Boehringer Ingelheim, GlaxoSmithKline, Biotest, Bayer Health Care; and has the following patents issued: EPO 12181535.1 (IL-27 for modulation of immune response in acute lung injury), WO/2010/094491 (Means for inhibiting the expression of Ang-2), DE 102020116249.9 (Camostat/Niclosamide cotreatment in SARS-CoV-2 infected human lung cells). All other authors have nothing to disclose., (Copyright ©The authors 2022.)

Influenza A virus (IAV) causes pandemics and annual epidemics of severe respiratory infections. A better understanding of the molecular regulation in tissue and cells upon IAV infection is needed to thoroughly understand pathogenesis. We analyzed IAV replication and gene expression induced by IAV strain H3N2 Panama in isolated primary human alveolar epithelial type II cells (AECIIs), the permanent A549 adenocarcinoma cell line, alveolar macrophages (AMs) and explanted human lung tissue by bulk RNA sequencing. Primary AECII exhibit in comparison to AM a broad set of strongly induced genes related to RIG-I and interferon (IFN) signaling. The response of AECII was partly mirrored in A549 cells. In human lung tissue, we observed induction of genes unlike in isolated cells. Viral RNA was used to correlate host cell gene expression changes with viral burden. While relative induction of key genes was similar, gene abundance was highest in AECII cells and AM, while weaker in the human lung (due to less IAV replication) and A549 cells (pointing to their limited suitability as a model). Correlation of host gene induction with viral burden allows a better understanding of the cell-type specific induction of pathways and a possible role of cellular crosstalk requiring intact tissue., (© 2022. The Author(s).)

Mechanisms of epithelial renewal in the alveolar compartment remain incompletely understood. To this end, we aimed to characterize alveolar progenitors. Single-cell RNA-sequencing (scRNA-seq) analysis of the HTII-280 + /EpCAM + population from adult human lung revealed subclusters enriched for adult stem cell signature (ASCS) genes. We found that alveolar progenitors in organoid culture in vitro show phenotypic lineage plasticity as they can yield alveolar or bronchial cell-type progeny. The direction of the differentiation is dependent on the presence of the GSK-3β inhibitor, CHIR99021. By RNA-seq profiling of GSK-3β knockdown organoids we identified additional candidate target genes of the inhibitor, among others FOXM1 and EGF. This gives evidence of Wnt pathway independent regulatory mechanisms of alveolar specification. Following influenza A virus (IAV) infection organoids showed a similar response as lung tissue explants which confirms their suitability for studies of sequelae of pathogen-host interaction., (© 2022. The Author(s).)

(1) Background: Liver transplantation (LT) is an established treatment for selected patients with end-stage liver disease resulting in a subsequent need for long-term immunosuppressive therapy. With cumulative exposure to immunosuppression (IS), the risk for the development of de novo lung carcinoma increases. Due to limited therapy options and prognosis after diagnosis of lung cancer, the question of the mode and extent of IS in this particular situation is raised. (2) Methods: All patients diagnosed with de novo lung cancer in the follow-up after LT were identified from the institution's register of liver allograft recipients (Charité-Universitätsmedizin Berlin, Germany) transplanted between 1988 and 2021. Survival analysis was performed based on the IS therapy following diagnosis of lung cancer and the oncological treatment approach. (3) Results: Among 3207 adult LTs performed in 2644 patients at our institution, 62 patients (2.3%) developed de novo lung carcinoma following LT. Lung cancer was diagnosed at a median interval of 9.7 years after LT (range 0.7-27.0 years). Median survival after diagnosis of lung carcinoma was 13.2 months (range 0-196 months). Surgical approach with curative intent significantly prolonged survival rates compared to palliative treatment (median 67.4 months vs. 6.4 months). Reduction of IS facilitated a significant improvement in survival (median 38.6 months vs. 6.7 months). In six patients (9.7%) complete IS weaning was achieved with unimpaired liver allograft function. (4) Conclusion: Reduction of IS therapy after the diagnosis of de novo lung cancer in LT patients is associated with prolonged survival. The risk of acute rejection does not appear to be increased with restrictive IS management. Therefore, strict reduction of IS should be an early intervention following diagnosis. In addition, surgical resection should be attempted, if technically feasible and oncologically meaningful.

Respiratory infections caused by multidrug-resistant Acinetobacter baumannii are difficult to treat and associated with high mortality among critically ill hospitalized patients. Bacteriophages (phages) eliminate pathogens with high host specificity and efficacy. However, the lack of appropriate preclinical experimental models hampers the progress of clinical development of phages as therapeutic agents. Therefore, we tested the efficacy of a purified lytic phage, vB&#95;AbaM&#95;Acibel004, against multidrug-resistant A. baumannii clinical isolate RUH 2037 infection in immunocompetent mice and a human lung tissue model. Sham- and A. baumannii -infected mice received a single-dose of phage or buffer via intratracheal aerosolization. Group-specific differences in bacterial burden, immune and clinical responses were compared. Phage-treated mice not only recovered faster from infection-associated hypothermia but also had lower pulmonary bacterial burden, lower lung permeability, and cytokine release. Histopathological examination revealed less inflammation with unaffected inflammatory cellular recruitment. No phage-specific adverse events were noted. Additionally, the bactericidal effect of the purified phage on A. baumannii was confirmed after single-dose treatment in an ex vivo human lung infection model. Taken together, our data suggest that the investigated phage has significant potential to treat multidrug-resistant A. baumannii infections and further support the development of appropriate methods for preclinical evaluation of antibacterial efficacy of phages.

The COVID-19 pandemic challenges international and national healthcare systems. In the field of thoracic surgery, procedures may be deferred due to mandatory constraints of the access to diagnostics, staff and follow-up facilities. There is a lack of prospective data on the management of benign and malignant thoracic conditions in the pandemic. Therefore, we derived recommendations from 14 thoracic societies to address key questions on the topic of COVID-19 in the field of thoracic surgery. Respective recommendations were extracted and the degree of consensus among different organizations was calculated. A high degree of consensus was found to temporarily suspend non-critical elective procedures or procedures for benign conditions and to prioritize patients with symptomatic or advanced cancer. Prior to hospitalization, patients should be screened for respiratory symptoms indicating possible COVID-19 infection and most societies recommended to screen all patients for COVID-19 prior to admission. There was a weak consensus on the usage of serology tests and CT scans for COVID-19 diagnostics. Nearly all societies suggested to postpone elective procedures in patients with suspected or confirmed COVID-19 and recommended constant reevaluation of these patients. Additionally, we summarized recommendations focusing on precautions in the theater and the management of chest drains. This study provides a novel approach to informed guidance for thoracic surgeons during the COVID-19 pandemic in the absence of scientific evidence-based data.