Search

Summary: Background: Open partial pancreatoduodenectomy (OPD) represents the current gold standard of surgical treatment of a wide range of diseases of the pancreatic head but is associated with morbidity in around 40% of cases. Robotic partial pancreatoduodenectomy (RPD) is being used increasingly, yet, no randomised controlled trials (RCTs) of RPD versus OPD have been published, leaving a low level of evidence to support this practice. Methods: This investigator-initiated, exploratory RCT with two parallel study arms was conducted at a high-volume pancreatic centre in line with IDEAL recommendations (stage 2b). Patients scheduled for elective partial pancreatoduodenectomy (PD) for any indication were randomised (1:1) to RPD or OPD with a centralised web-based tool. The primary endpoint was postoperative cumulative morbidity within 90 days, assessed via the Comprehensive Complication Index (CCI). Biometricians were blinded to the intervention, but patients and surgeons were not. The trial was registered prospectively (DRKS00020407). Findings: Between June 3, 2020 and February 14, 2022, 81 patients were randomly assigned to RPD (n = 41) or OPD (n = 40), of whom 62 patients (RPD: n = 29, OPD: n = 33) were analysed in the modified intention to treat analysis. Four patients in the OPD group were randomised, but did not undergo surgery in our department and one patient was excluded in the RPD group due to other reason. Nine patients in the RPD group and 3 patients in the OPD were excluded from the primary analysis because they did not undergo PD, but rather underwent other types of surgery. The CCI after 90 days was comparable between groups (RPD: 34.02 ± 23.48 versus OPD: 36.45 ± 27.65, difference in means [95% CI]: −2.42 [−15.55; 10.71], p = 0.713). The RPD group had a higher incidence of grade B/C pancreas-specific complications compared to the OPD group (17 (58.6%) versus 11 (33.3%); difference in rates [95% CI]: 25.3% [1.2%; 49.4%], p = 0.046). The only complication that occurred significantly more often in the RPD than in the OPD group was clinically relevant delayed gastric emptying. Procedure-related and overall hospital costs were significantly higher and duration of surgery was longer in the RPD group. Blood loss did not differ significantly between groups. The intraoperative conversion rate of RPD was 23%. Overall 90-day mortality was 4.8% without significant differences between RPD and OPD. Interpretation: In the setting of a very high-volume centre, both RPD and OPD can be considered safe techniques. Further confirmatory multicentre RCTs are warranted to uncover potential advantages of RPD in terms of perioperative and long-term outcomes. Funding: Federal Ministry of Education and Research (BMBF: 01KG2010).

Abstract Background In Germany and Western Europe, gastroesophageal junction cancer (AEG) and proximal gastric cancer are currently treated with (transhiatal-extended) total gastrectomy (TG) according to the latest treatment guidelines. TG leads to a severe and long-lasting impairment of postoperative health-related quality of life (HRQoL) of the treated patients. Recent studies have suggested that HRQoL of these patients could be improved by proximal gastrectomy with double-tract reconstruction (PG-DTR) without compromising oncologic safety. Our aim is therefore to conduct a randomized controlled non-inferiority trial comparing PG-DTR with TG in AEG II/III and gastric cancer patients with overall survival as primary endpoint and HRQoL as key secondary endpoint. Methods This protocol is written with reference to the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P 2015) statement. We will conduct searches in the electronic databases MEDLINE, Web of Science Core Collection, ScienceDirect, and Cochrane Library. We will also check references of relevant studies and perform a cited reference research. Titles and abstracts of the records identified by the searches will be screened, and full texts of all potentially relevant articles will be obtained. We will consider randomized trials and non-randomized studies. The selection of studies, data extraction, and assessment of risk of bias of the included studies will be conducted independently by two reviewers. Meta-analysis will be performed using RevMan 5.4 (Review Manager (RevMan) Version 5.4, The Cochrane Collaboration). Discussion This systematic review will identify the current study pool concerning the comparison of TG and PG-DTR and help to finally refine the research questions and to allow an evidence-based trial design of the planned multicenter randomized-controlled trial. Ethics and dissemination Ethical approval is not required for this systematic review. Study findings will be shared by publication in a peer-reviewed journal. Systematic review registration PROSPERO CRD42021291500.

Abstract Background Pancreatic ductal carcinoma (PDAC) is the fourth most frequent cause of cancer-related death in the Western world, and its incidence is rising. In patients that undergo curative resection, local recurrence (LR) is frequent. A recently described surgical technique of extended pancreatoduodenectomy (PD) termed the TRIANGLE operation has been proposed as a promising approach to reduce LR and improve disease-free survival in PDAC patients. Methods The TRIANGLE trial is a multicentre confirmatory randomised controlled superiority trial with two parallel study groups. A total of 270 patients with suspected or histologically confirmed pancreatic head cancer scheduled for PD will be included in the trial and randomly assigned to the intervention group (extended PD defined as Inoue level 3 dissection along the superior mesenteric and celiac artery as well as removal of all soft tissue in the so-called triangle between the celiac artery, the SMA and the mesenterico-portal axis) or the control group (conventional PD with lymphadenectomy and removal of soft tissue according to current guidelines). The primary endpoint of the trial will be the disease-free survival of patients. Other perioperative outcomes as well as oncological parameters and patient-reported outcomes will be analysed as secondary outcomes. Discussion Despite multimodal treatment, LR remains high and disease-free survival is limited following PD for PDAC. The TRIANGLE operation could address these shortcomings of conventional PD as indicated in several retrospective studies. However, this technique could be associated with more adverse events for patients including intractable diarrhoea. The TRIANGLE trial will close the evidence gap as well as offer a risk-benefit assessment of this more radical approach to PD. Trial registration German Clinical Trials Register DRKS00030576 (UTN U1111-1243-4412) 19th December 2022.

Abstract Background Oesophageal cancer (EC) is the sixth leading cause of cancer death worldwide. Oesophageal resection is the only curative treatment option for EC which is frequently performed via an abdominal and right thoracic approach (Ivor-Lewis operation). This 2-cavity operation is associated with a high risk of major complications. To reduce postoperative morbidity, several minimally invasive techniques have been developed that can be broadly classified into either hybrid oesophagectomy (HYBRID-E) via laparoscopic/robotic abdominal and open thoracic surgery or total minimally invasive oesophagectomy (MIN-E). Both, HYBIRD-E and MIN-E, compare favourable to open oesophagectomy. However, there is still an evidence gap comparing HYBRID-E with MIN-E with regard to postoperative morbidity. Methods The MICkey trial is a multicentre randomized controlled superiority trial with two parallel study groups. A total of 152 patients with oesophageal cancer scheduled for elective oesophagectomy will be randomly assigned 1:1 to the control group (HYBRID-E) or to the intervention group (MIN-E). The primary endpoint will be overall postoperative morbidity assessed via the comprehensive complication index (CCI) within 30 days after surgery. Specific perioperative parameters, as well as patient-reported and oncological outcomes, will be analysed as secondary outcomes. Discussion The MICkey trial will address the yet unanswered question whether the total minimally invasive oesophagectomy (MIN-E) is superior to the HYBRID-E procedure regarding overall postoperative morbidity. Trial registration DRKS00027927 U1111-1277-0214. Registered on 4th July 2022

Abstract The use of digital technology is increasing rapidly across surgical specialities, yet there is no consensus for the term ‘digital surgery’. This is critical as digital health technologies present technical, governance, and legal challenges which are unique to the surgeon and surgical patient. We aim to define the term digital surgery and the ethical issues surrounding its clinical application, and to identify barriers and research goals for future practice. 38 international experts, across the fields of surgery, AI, industry, law, ethics and policy, participated in a four-round Delphi exercise. Issues were generated by an expert panel and public panel through a scoping questionnaire around key themes identified from the literature and voted upon in two subsequent questionnaire rounds. Consensus was defined if >70% of the panel deemed the statement important and

Abstract Background Malnutrition is associated with poor survival in pancreatic cancer patients. Nutritional scores show great heterogeneity diagnosing malnutrition. The aim of this study was to find the score best suitable to identify patients with malnutrition related to worse survival after surgery for pancreatic ductal adenocarcinoma (PDAC). This study represents a follow‐up study to the prospective NURIMAS Pancreas trial that evaluated short term impact of nutritional score results after surgery. Methods Risk of malnutrition was evaluated preoperatively using 12 nutritional assessment scores. Patients were followed‐up prospectively for at least 3 years. Patients at risk for malnutrition were compared with those not at risk according to each score using Kaplan–Meier survival statistics. Results A total of 116 patients receiving a PDAC resection in curative intent were included. Malnutrition according to the Subjective Global Assessment score (SGA), the Short Nutritional Assessment Questionnaire (SNAQ), and the INSYST2 score was associated with worse overall survival (SGA: at‐risk: 392 days; not at‐risk: 942 days; P = 0.001; SNAQ: at‐risk: 508 days; not at‐risk: 971 days; P = 0.027; INSYST2: at‐risk: 538 days; not at risk: 1068; P = 0.049). In the multivariate analysis, SGA (hazard ratio of death 2.16, 95% confidence interval 1.34–3.47, P = 0.002) was associated with worse overall survival. Conclusions Malnutrition as defined by the Subjective Global Assessment is independently associated with worse survival in resected PDAC patients. The SGA should be used to stratify PDAC patients in clinical studies. Severely malnourished patients according to the SGA profit from intensified nutritional therapy should be evaluated in a randomized controlled trial.

Abstract Surgical resection of the liver is the standard treatment for colorectal liver metastases, but 70% of patients still experience recurrence, resulting in limited survival. Molecular biomarkers promise guidance within the selection process of individualized treatment and provide better prognostic forecasting of recurrence and response to treatment. Presently, most investigated biomarkers include mutations of KRAS, BRAF, TP53, PIK3CA, APC, expression of Ki‐67, and microsatellite instability. As some colorectal cancer tumors exhibit more than one molecular target, in line with a rising number of potential biomarkers, the complexity of their clinical implementation is rising steadily. Therefore, it is important to approach new insights into molecular biomarkers with explicit caution to their clinical applicability and significance, as there are contradictory results arising from multiple available studies and meta‐analyses. This review helps to shed light on the complexity of promising biomarkers in both the prognosis and diagnosis of colorectal liver metastases.

Abstract The COVID-19 pandemic has worldwide individual and socioeconomic consequences. Chest computed tomography has been found to support diagnostics and disease monitoring. A standardized approach to generate, collect, analyze, and share clinical and imaging information in the highest quality possible is urgently needed. We developed systematic, computer-assisted and context-guided electronic data capture on the FDA-approved mint LesionTM software platform to enable cloud-based data collection and real-time analysis. The acquisition and annotation include radiological findings and radiomics performed directly on primary imaging data together with information from the patient history and clinical data. As proof of concept, anonymized data of 283 patients with either suspected or confirmed SARS-CoV-2 infection from eight European medical centers were aggregated in data analysis dashboards. Aggregated data were compared to key findings of landmark research literature. This concept has been chosen for use in the national COVID-19 response of the radiological departments of all university hospitals in Germany.

Abstract Background Anastomotic leakage (AL) in the upper gastrointestinal (GI) tract is associated with high morbidity and mortality rates. Especially intrathoracic anastomotic leakage leads to life-threatening complications. Endoscopic vacuum therapy (EVT) for anastomotic leakage after transthoracic esophageal resection represents a novel concept. However, sound clinical data are still scarce. This retrospective, single-center study aimed to evaluate the feasibility, effectiveness, and safety of EVT for intrathoracic anastomotic leakage following abdomino-thoracic esophageal resection. Methods From March 2014 to September 2019 259 consecutive patients underwent elective transthoracic esophageal resection. 72 patients (27.8%) suffered from AL. The overall collective in-hospital mortality rate was 3.9% (n = 10). Data from those who underwent treatment with EVT were included. Results Fifty-five patients were treated with EVT. Successful closure was achieved in 89.1% (n = 49) by EVT only. The EVT-associated complication rate was 5.4% (n = 3): bleeding occurred in one patient, while minor sedation-related complications were observed in two patients. The median number of EVT procedures per patient was 3. The procedures were performed at intervals of 3–5 days, with a 14-day median duration of therapy. The mortality rate of patients with AL was 7.2% (n = 4). Despite successfully terminated EVT, three patients died because of multiple organ failure, acute respiratory distress syndrome, and urosepsis (5.4%). One patient (1.8%) died during EVT due to cardiac arrest. Conclusions EVT is a safe and effective approach for intrathoracic anastomotic leakages following abdomino-thoracic esophageal resections. It offers a high leakage-closure rate and the potential to lower leakage-related mortalities. Trial registration: This trial was registered and approved by the Institutional Ethics Committee of the University of Heidelberg on 16.04.2014 (Registration Number: S-635/2013).

Abstract Background The only curative treatment for most esophageal cancers is radical esophagectomy. Minimally invasive esophagectomy (MIE) aims to reduce postoperative morbidity, but is not yet widely established. Linear stapled anastomosis is a promising technique for MIE because it is quite feasible even without robotic assistance. The aim of the present study is to compare total MIE with linear stapled anastomosis to open esophagectomy (OE) with circular stapled anastomosis with special regard to postoperative morbidity in an expertise-based randomized controlled trial (RCT). Methods/design This superiority RCT compares MIE with linear stapled anastomosis (intervention) to OE with circular stapled anastomosis (control) for Ivor-Lewis esophagectomy. It was initiated in February 2019, and recruitment is expected to last for 3 years. For inclusion, patients must be 18 years of age or more with a resectable primary malignancy in the distal esophagus. Participants with tumor localizations above the azygos vein, metastasis, or infiltration into adjacent tissue will be excluded. In an expertise-based approach, the allocated treatment will only be carried out by the single most experienced surgeon of the surgical center for each respective technique. The sample size was calculated with 20 participants per group for the primary endpoint postoperative morbidity according to comprehensive complication index (CCI) within 30 postoperative days. Secondary endpoints include anastomotic insufficiency, pulmonary complications, other intra- and postoperative outcome parameters such as estimated blood loss, operative time, length of stay, short-term oncologic endpoints, adherence to a standardized fast-track protocol, postoperative pain, and postoperative recovery (QoR-15). Quality of life (SF-36, CAT EORTC QLQ-C30, CAT EORTC QLQ-OES18) and oncological outcomes are evaluated with 60 months follow-up. Discussion MIVATE is the first RCT to compare OE with circular stapled anastomosis to total MIE with linear stapled anastomosis exclusively for intrathoracic anastomosis. The expertise-based approach limits bias due to heterogeneity of surgical expertise. The use of a dedicated fast-track protocol in both OE and MIE will shed light on the role of the access strategy alone in this setting. The findings of this study will serve to define which approach has the best perioperative outcome for patients requiring esophagectomy. Trial registration German Clinical Trials Register DRKS00016773 . Registered on 18 February 2019.

Abstract Background Partial pancreatoduodenectomy (PD) is the indicated surgical procedure for a wide range of benign and malignant diseases of the pancreatic head and distal bile duct and offers the only potential cure for pancreatic head cancer. The current gold standard, open PD (OPD) performed via laparotomy, is associated with morbidity in around 40% of cases, even at specialised centres. Robotic PD (RPD) might offer a viable alternative to OPD and has been shown to be feasible. Encouraging perioperative results have been reported for RPD in a number of small, non-randomised studies. However, since those studies showed a considerable risk of bias, a thorough comparison of RPD with OPD is warranted. Methods The EUROPA (EvalUation of RObotic partial PAncreatoduodenectomy) trial is designed as a randomised controlled unblinded exploratory surgical trial with two parallel study groups. A total of 80 patients scheduled for elective PD will be randomised after giving written informed consent. Patients with borderline or non-resectable carcinoma of the pancreatic head as defined by the National Comprehensive Cancer Network guidelines, distant metastases or an American Society of Anaesthesiologists (ASA) score > III will be excluded. The experimental intervention, RPD, will be compared with the control intervention, OPD. An intraoperative dropout of approximately eight patients per group is expected because they may receive another type of surgical procedure than planned. Overall, 64 patients need to be analysed. The primary endpoint of the trial is overall postoperative morbidity within 90 days after index operation, measured using the Comprehensive Complication Index (CCI). The secondary endpoints include the feasibility of recruitment and assessment of clinical, oncological and safety parameters and quality of life and cost-effectiveness. Discussion The EUROPA trial is the first randomised controlled trial comparing RPD with OPD. Differences in postoperative morbidity will be evaluated to design a future multicentre confirmatory efficacy trial. Trial registration German Clinical Trial Register DRKS00020407 . Registered on 9 March 2020

Abstract Background Early diagnosis of anastomotic leakage (AL) after esophageal resection is crucial for the successful management of this complication. Inflammatory serological markers are indicators of complications during the postoperative course. The aim of the present study was to evaluate the prognostic value of routine inflammatory markers to predict anastomotic leakage after transthoracic esophageal resection. Methods Data from all consecutive patients undergoing transthoracic esophageal resection between January 2010 and December 2016 were analyzed from a prospective database. Besides clinicodemographic parameters, C-reactive protein, white blood cell count and albumin were analyzed and the Noble/Underwood (NUn) score was calculated to evaluate their predictive value for postoperative anastomotic leakage. Diagnostic accuracy was measured by sensitivity, specificity, and negative and positive predictive values using area under the receiver operator characteristics curve. Results Overall, 233 patients with transthoracic esophageal resection were analyzed, 30-day mortality in this group was 3.4%. 57 patients (24.5%) suffered from AL, 176 patients were in the AL negative group. We found significant differences in WBCC, CRP and NUn scores between patients with and without AL, but the analyzed markers did not show an independent relevant prognostic value. For CRP levels below 155 mg/dl from POD3 to POD 7 the negative predictive value for absence of AI was > 80%. Highest diagnostic accuracy was detected for CRP levels on 4th POD with a cut-off value of 145 mg/l reaching negative predictive value of 87%. Conclusions In contrast to their prognostic value in other surgical procedures, CRP, WBCC and NUn score cannot be recommended as independent markers for the prediction of anastomotic leakage after transthoracic esophageal resection. CRP is an accurate negative predictive marker and discrimination of AL and no-AL may be helpful for postoperative clinical management. Trial registration The study was approved by the local ethical committee (S635-2013).

Introduction Partial pancreatoduodenectomy (PD) is the treatment of choice for many malignant and benign diseases of the pancreatic head. Postoperative complication rates of up to 40% are regularly reported. One of the most common and potentially life-threatening complication is the postoperative pancreatic fistula (POPF). Parenchymal risk factors like main pancreatic duct diameter or texture of the pancreatic gland have already been identified in retrospective studies. The aim of this study is to evaluate the diagnostic value of parenchymal risk factors on POPF in a prospective manner.Methods and analysis All patients scheduled for elective PD at the Department of General, Visceral and Transplantation Surgery of the University of Heidelberg will be screened for eligibility. As diagnostic factors, diameter and texture of the pancreatic gland as well as radiological and histopathological features will be recorded. Furthermore, the new four class risk classification system by the International Study Group of Pancreatic Surgery (ISGPS) will be recorded. The postoperative course will be monitored prospectively. The primary endpoint will be the association of the main pancreatic duct size and the texture of the pancreatic gland on POPF according to the updated ISGPS definition. The diagnostic value of the above-mentioned factors for POPF will be evaluated in a univariable and multivariable analysis.Ethics and dissemination PARIS is a monocentric, prospective, diagnostic study to evaluate the association of parenchymal risk factors and the development of POPF approved by the Ethics Committee of the medical faculty of Heidelberg University (S-344/2019). Results will be available in 2022 and will be published at national and international meetings. With this knowledge, the intraoperative and perioperative decision-making process could be eased and improve the individual outcome of patient.Trial registration number DRKS00017184.

Although 21 pancreatic cancer susceptibility loci have been identified in individuals of European ancestry through genome-wide association studies (GWASs), much of the heritability of pancreatic cancer risk remains unidentified. A recessive genetic model could be a powerful tool for identifying additional risk variants. To discover recessively inherited pancreatic cancer risk loci, we performed a re-analysis of the largest pancreatic cancer GWAS, the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4), including 8,769 cases and 7,055 controls of European ancestry. Six single nucleotide polymorphisms (SNPs) showed associations with pancreatic cancer risk according to a recessive model of inheritance. We replicated these variants in 3,212 cases and 3,470 controls collected from the PANcreatic Disease ReseArch (PANDoRA) consortium. The results of the meta-analyses confirmed that rs4626538 (7q32.2), rs7008921 (8p23.2) and rs147904962 (17q21.31) showed specific recessive effects (p10−3), although none of the six SNPs reached the conventional threshold for genome-wide significance (p < 5×10−8). Additional bioinformatic analysis explored the functional annotations of the SNPs and indicated a possible relationship between rs36018702 and expression of the BCL2L11 and BUB1 genes, which are known to be involved in pancreatic biology. Our findings, while not conclusive, indicate the importance of considering non-additive genetic models when performing GWAS analysis. The SNPs associated with pancreatic cancer in this study could be used for further meta-analysis for recessive association of SNPs and pancreatic cancer risk and might be a useful addiction to improve the performance of polygenic risk scores.

Abstract Background Incisional hernias are among the most frequent complications following abdominal surgery and cause substantial morbidity, impaired health-related quality of life and costs. Despite improvements in abdominal wall closure techniques, the risk for developing an incisional hernia is reported to be between 10 and 30% following midline laparotomies. There have been two recent innovations with promising results to reduce hernia risks, namely the small stitches technique and the placement of a prophylactic mesh. So far, these two techniques have not been evaluated in combination. Methods The HULC trial is a multicentre, randomized controlled, observer- and patient-blinded surgical effectiveness trial with two parallel study groups. A total of 812 patients scheduled for elective abdominal surgery via a midline laparotomy will be randomized in 12 centres after informed consent. Patients will be randomly assigned to the control group receiving closure of the midline incision with a slowly absorbable monofilament suture in the small stitches technique or to the intervention group, who will receive a small stitches closure followed by augmentation with a light-weight polypropylene mesh in the onlay technique. The primary endpoint will be the occurrence of incisional hernias, as defined by the European Hernia Society, within 24 months after surgery. Further perioperative parameters, as well as patient-reported outcomes, will be analysed as secondary outcomes. Discussion The HULC trial will address the yet unanswered question of whether a combination of small stitched fascial closure and onlay mesh augmentation after elective midline laparotomies reduces the risk of incisional hernias. The HULC trial marks the logical and innovative next step in the development of a safe abdominal closure technique. Trial registration German Clinical Trials Register, DRKS00017517. Registered on 24th June 2019.

Abstract Background The placement of prophylactic intra-abdominal drains has been common practice in abdominal operations including pancreatic surgery. The PANDRA trial showed that the omission of drains following pancreatic head resection was non-inferior to intra-abdominal drainage in terms of postoperative reinterventions and superior in terms of clinically relevant pancreatic fistula rate and fistula-associated complications. The aim of the present PANDRA II trial is to evaluate the clinical outcome with versus without prophylactic drain placement after distal pancreatectomy. Methods The PANDRA II trial is a mono-center, randomized controlled, non-inferiority trial with two parallel study groups. In the control group at least one passive intra-abdominal drain is placed at the pancreatic resection margin. In the experimental group no drains are placed. The primary endpoint of this trial will be the Comprehensive Complication Index (CCI) measuring all postoperative complications within 90 days. Secondary endpoints are in-hospital mortality and morbidity, including the rates of postoperative pancreatic fistula, chyle leak, postpancreatectomy hemorrhage, delayed gastric emptying, reinterventions and reoperations, surgical site infection, and abdominal fascia dehiscence. Moreover, length of hospital stay, duration of intensive care unit stay, and the rate of readmission after discharge from hospital (up to day 90 after surgery) are assessed. We will need to analyze 252 patients to test the hypothesis that no drainage is non-inferior to drain placement in terms of the CCI (δ 7.5 points) in a one-sided t test with a one-sided level of significance of 2.5% and a power of 80%. Discussion The results of the PANDRA II trial will help to evaluate the effect of an omission of prophylactic intraperitoneal drainage on the rate of complications after open or minimally invasive distal pancreatectomy. Trial registration German Clinical Trials Register (DRKS), DRKS00013763. Registered on 6 March 2018.

Abstract Background Extended liver resections still bear the risk of severe haemorrhage. Moreover, the amount of blood loss during liver resection determines the need for perioperative blood transfusions and is of prognostic relevance in oncologic surgery. Even though there is an ongoing debate about its effectiveness and tolerable duration, the Pringle Maneuver (PM) as an occlusion of the hepatic inflow is routinely applied to reduce blood loss during parenchymal dissection. In combination with the stapler resection technique, PM is expected to minimize blood loss during major liver resection safely due to the short parenchymal dissection duration. Methods In a single center prospective, randomized, controlled, parallel, confirmatory trial the combination of PM and stapler resection technique in patients undergoing right and left hepatectomies will be tested against the control group that applies stapler resection without the use of PM. The primary endpoint of the study is the total intraoperative blood loss. The measurement of the intraoperative blood loss is conducted with respect to all handled rinse fluids during surgery and by weighing used swabs to generate accurate and comparable data. Secondary endpoints include intra- and postoperative blood transfusion requirements, liver function parameters and the 90-day mortality rate. A sample size of fifty-three patients in either group was calculated to detect a clinically significant difference in blood loss of at least 450 ml with an α of 5% at 80% power. The individual follow-up will be 90 days. Discussion This is the first clinical trial to test the combination of PM and stapler resection technique as a means to reduce intraoperative blood loss in hepatic left or right resection. Given the short parenchymal dissection duration in stapler resection, PM is expected to be applied shortly without compromising liver function postoperatively. Trial registration The PriMaL StHep trial has been prospectively registered to the German Clinical Trial Registry (WHO ID: DRKS00010427) on April 21st. 2016.

Introduction In recent years, minimally invasive distal pancreatectomy (MIDP) has been used with increasing frequency to accelerate patient recovery. Distal pancreatectomy has an overall morbidity rate of 30%–40%. The known advantages of minimally invasive techniques must be rigorously compared with those of open surgery before they can be completely implemented into clinical practice.Methods and analysis DISPACT-2 is a multicentre randomised controlled trial comparing minimally invasive (conventional laparoscopic or robotic assisted) with open distal pancreatic resection in patients undergoing elective surgery for benign as well as malign diseases of the pancreatic body and tail. After screening for eligibility and obtaining informed consent, a total of 294 adult patients will be preoperatively randomised in a 1:1 ratio. The primary hypothesis is that MIDP is non-inferior to open distal pancreatectomy in terms of postoperative mortality and morbidity expressed as the Comprehensive Complication Index (CCI) within 3 months after index operation, with a non-inferiority margin of 7.5 CCI points. Secondary endpoints include pancreas-specific complications, oncological safety and patient reported outcomes. Follow-up for each individual patient will be 2 years.Ethics and dissemination The DISPACT-2 trial has been approved by the Ethics Committee of the medical faculty of Heidelberg University (S-693/2017). Results of the primary endpoint will be available in 2024 and will be published at national and international meetings. Full results will be made available in an open access, peer-reviewed journal. The website www.dispact.de contains up-to-date information regarding the trial.Trial registration number DRKS00014011

Introduction Peritoneal fenestration is an effective preventive method for reducing the rate of lymphatic complications in kidney transplantation (KTx). The size of the fenestration plays an important role in its effectiveness. A large peritoneal window is no longer indicated, due to herniation and difficulties in performing biopsies. Small preventive fenestration is effective but will be closed too early. The aim of this study is to evaluate whether metal clips around the edges of a small fenestration result in optimal effects with minimum fenestration size.Methods and analysis This trial has been initiated in July 2019 and is expected to last for 2 and a half years. All patients older than 18 years, who receive kidneys from deceased donors, will be included. The kidney recipients will be randomly allocated to either a control arm (small fenestration alone) or an intervention arm (small fenestration with clipping). All fenestrations will be round, maximum 2 cm, and close to the kidney hilum. Clipping will be performed with eight metal clips around the peritoneal window (360°) in every 45° in an oblique position. The primary endpoint is the incidence of symptomatic post-KTx lymphatic complications, which require interventional treatment within 6 months after KTx. Secondary endpoints are intraoperative and postoperative outcomes, including blood loss, operation time, severity grade of lymphocele/lymphorrhea and relative symptoms.Ethics and dissemination This protocol study received approval from the Ethics Committee of the University of Heidelberg (Registration Number S-318/2017). A Standard Protocol Items: Recommendations for Interventional Trials checklist is available for this protocol. The results will be disseminated through peer-reviewed journals and conference presentations.Trial registration number ClinicalTrials.gov Registry (NCT03682627).

Introduction Anastomotic leakage is the most important complication in colorectal surgery occurring in up to 20% after low anterior rectal resection. Therefore, a diverting ileostomy is usually created during low anterior resection to protect the anastomosis or rather to diminish the consequences in case of anastomotic leakage. The so-called virtual or ghost ileostomy is a pre-stage ostomy that can be easily exteriorised, if anastomotic leakage is suspected, in order to avoid the severe consequences of anastomotic leakage. On the other hand, an actual ileostomy can be avoided in patients, who do not develop anastomotic leakage.Methods and analysis The GHOST trial is a randomised controlled pilot trial comparing ghost ileostomy with conventional loop ileostomy in patients undergoing low anterior resection with total mesorectal excision for rectal cancer. After screening for eligibility and obtaining informed consent, a total of 60 adult patients are included in the trial. Patients are intraoperatively randomised to the trial groups in a 1:1 ratio after assuring that none of the intraoperative exclusion criteria are present. The main outcome parameter is the comprehensive complication index as a measure of safety. Further outcomes include specific complications, stoma-related complications, complications of ileostomy closure, frequency of transformation of ghost ileostomy into conventional ileostomy, frequency of terminal ostomy creation, proportion of patients with an ostomy at 6 months after index surgery, anorectal function (Wexner score) and quality of life assessed by the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and CR29 questionnaires. Follow-up for each individual patient will be 6 months.Ethics and dissemination The GHOST trial has been approved by the Medical Ethics Committee of Heidelberg University (reference number S-694/2017). If the intervention proves to be safe, loop ileostomy could be spared in a large proportion of patients, thus also avoiding stoma-related complications and a second operation (ileostomy closure) with its inherent complications in these patients.Trial registration number German Clinical Trials Registry (DRKS00013997); Universal Trial Number: U1111-1208-9742.

Introduction Postoperative pancreatic fistula (POPF) is still the most frequently occurring and clinically relevant complication after distal pancreatectomy (DP). Preoperative endoscopic injection of botulinum toxin (BTX) into the sphincter of Oddi represents an innovative approach to prevent POPF. The aim of this project (PREBOTPilot) is to generate the first randomised controlled trial data on the safety, feasibility and efficacy of preoperative endoscopic BTX injection into the sphincter of Oddi to prevent clinically relevant POPF following DP.Methods and analysis PREBOTPilot is an investigator-initiated, single-centre, randomised, controlled, open-label, phase II clinical trial with two parallel study groups and an exploratory study design. 60 patients scheduled for DP will be randomised to intervention and control group. In the intervention group, patients will undergo preoperative endoscopic injection of BTX into the sphincter of Oddi, whereas in the control group no preoperative endoscopy will be performed. The combined primary endpoint is the occurrence of clinically relevant POPF and/or death within 30 days after DP. The secondary endpoints comprise further postoperative outcome parameters and quality of life up to 3 months after DP as well as safety and feasibility of the procedure. Statistical analysis is based on the modified intention-to-treat population, excluding patients without status post DP. For safety analysis, rates of adverse events (AEs) and serious AEs will be calculated with 95% CIs for group comparisons.Ethics, funding and dissemination PREBOTPilot has been approved by the German Federal Institute for Drugs and Medical Devices (reference number 4043654) and the Ethics Committee of Heidelberg University (reference number AFmo-523/2019). This trial is supported by the German Federal Ministry of Education and Research (BMBF). The results of the trial will be presented at national and international conferences and published in a peer-reviewed journal.Trial registration number DRKS00020401.

Introduction Pancreatic cancer is the fourth-leading cause of cancer-related death in developed countries. Despite advances in systemic chemotherapy, the mainstay of curative therapy for non-metastatic disease is surgical resection. However, the perioperative period is characterised by stress and inflammatory reactions that can contribute to metastatic spread and disease recurrence. Catecholamines and prostaglandins play a crucial role in these reactions. Therefore, a drug repurposing of betablockers and cyclooxygenase inhibitors seems reasonable to attenuate tumour-associated inflammation by inhibiting psychological, surgical and inflammatory stress responses. This may cause a relevant antitumourigenic and antimetastatic effect during the perioperative period, a window for cancer-directed therapy that is currently largely unexploited.Methods and analysis This is a prospective, single-centre, two-arm randomised, patient and observer blinded, placebo-controlled, phase-II trial evaluating safety and feasibility of combined perioperative treatment with propranolol and etodolac in adult patients with non-metastatic cancer of the pancreatic head undergoing elective pancreatoduodenectomy. 100 patients fulfilling the eligibility criteria will be randomised to perioperative treatment for 25 days perioperatively with a combination of propranolol and etodolac or placebo. Primary outcome of interest will be safety in terms of serious adverse events and reactions within 3 months. Furthermore, adherence to trial medication will be assessed as feasibility outcomes. Preliminary efficacy data will be evaluated for the purpose of power calculation for a potential subsequent phase-III trial. The clinical trial is accompanied by a translational study investigating the mechanisms of action of the combined therapy on a molecular basis.Ethics and dissemination The PROSPER-trial has been approved by the German Federal Institute for Drugs and Medical Devices (reference number 4042875) and the Ethics Committee of the Medical Faculty of the University of Heidelberg (reference number AFmo-385/2018). The final trial results will be published in a peer-reviewed journal and will be presented at appropriate national and international conferences.Trial registration numbers DRKS00014054; EudraCT number: 2018-000415-25.

Abstract Background The surgical technique used in liver transplantation has undergone constant evolution in an effort to develop a safe, highly standardized procedure. Despite this, the initial step of recipient hepatectomy has not been the focus of clinical research thus far. Due to advanced coagulopathy in liver transplant recipients, this part of the operation still carries the risk of severe hemorrhage. This trial is designed to compare an electrothermal bipolar vessel sealing device (LigaSure™) and an ultrasound dissector (HARMONIC ACE®+7) with standard surgical techniques during the recipients’ hepatectomy in liver transplantation. Methods/design In a single-center, prospective, randomized, controlled, parallel, three-armed, confirmatory, open trial, LigaSure™ and HARMONIC ACE®+7 will be compared with standard surgical techniques that use titanium clips and conventional knot-tying ligations during recipient hepatectomy in liver transplantation. Intraoperative total blood loss is the primary endpoint of the trial. Secondary endpoints include blood loss during hepatectomy, the duration of both the hepatectomy and the entire surgical procedure, and blood transfusion requirements of the procedure. To generate reliable data, intraoperative blood loss will be recorded with respect to all rinse fluids during surgery, ascites, and by weighing used swabs. At 80% power and an alpha of 0.025 for both of the experimental groups, 23 subjects will be analyzed per protocol in each study arm in order to detect clinically relevant reduction of intraoperative blood loss. The intention-to-treat analysis will include 69 patients. The follow-up period for each patient will be 90 days for safety reasons, whereas all clinical outcomes will be measured within the first 10 postoperative days. Discussion To our knowledge, this is the first prospective, randomized trial comparing two innovative technical methods of vessel sealing and dissection with standard techniques for recipient hepatectomy. This will be done to detect relevant reduction of intraoperative blood loss during liver transplant. The results of the trial are expected to improve patient outcome and safety after liver transplant and to increase the general safety of this procedure. Trial registration ClinicalTrials.gov, NCT 03323242. Registered on October 26, 2017.

Abstract Background The prevention of postoperative complications is of prime importance after complex elective abdominal operations. Preoperative patient education may prevent postoperative complications and improve patients’ wellbeing, but evidence for its efficacy is poor. The aims of the PEDUCAT trial were (a) to assess the impact of preoperative patient education on postoperative complications and patient-reported outcomes in patients scheduled for elective complex visceral surgery and (b) to evaluate the feasibility of cluster randomization in this setting. Methods Adult patients (age ≥ 18 years) scheduled for elective major visceral surgery were randomly assigned in clusters to attend a preoperative education seminar or to the control group receiving the department’s standard care. Outcome measures were the postoperative complications pneumonia, deep vein thrombosis (DVT), pulmonary embolism, burst abdomen, and in-hospital fall, together with patient-reported outcomes (postoperative pain, anxiety and depression, patient satisfaction, quality of life), length of hospital stay (LOS), and postoperative mortality within 30 days after the index operation. Statistical analysis was primarily by intention to treat. Results In total 244 patients (60 clusters) were finally included (intervention group 138 patients; control group 106 patients). Allocation of hospital wards instead of individual patients facilitated study conduct and reduced confusion about group assignment. In the intervention and control groups respectively, pneumonia occurred in 7.4% versus 8.3% (p = 0.807), pulmonary embolism in 1.6% versus 1.0% (p = 0.707), burst abdomen in 4.2% versus 1.0% (p = 0.165), and in-hospital falls in 0.0% versus 4.2% of patients (p = 0.024). DVT did not occur in any of the patients. Mortality rates (1.4% versus 1.9%, p = 0.790) and LOS (14.2 (+/− 12.0) days versus 16.1 (+/− 15.0) days, p = 0.285) were also similar in the intervention and control groups. Conclusions Cluster randomization was feasible in the setting of preoperative patient education and reduced the risk of contamination effects. The results of this trial indicate good postoperative outcomes in patients undergoing major visceral surgery without superiority of preoperative patient education compared to standard patient care at a high-volume center. However, preoperative patient education is a helpful instrument not only for teaching patients but also for training the nursing staff. Trial registration German Clinical Trials Registry, DRKS00004226. Registered on 23 October 2012. Registered 8 days after the first enrollment.

Abstract Background Neoadjuvant (chemo-)radiation has proven to improve local control compared to surgery alone, but this improvement did not translate into better overall or disease-specific survival. The addition of oxaliplatin to fluoropyrimidine-based neoadjuvant chemoradiotherapy holds the potential of positively affecting survival in this context since it has been proven effective in the palliative and adjuvant setting of colorectal cancer. Thus, the objective of this systematic review is to assess the efficacy, safety, and quality of life resulting from adding a platinum derivative to neoadjuvant single-agent fluoropyrimidine-based chemoradiotherapy in patients with Union for International Cancer Control stage II and III rectal cancer. Methods MEDLINE, Web of Science, and Cochrane Central Register of Controlled Trials will be systematically searched to identify all randomized controlled trials comparing single-agent fluoropyrimidine-based chemoradiotherapy to combined neoadjuvant therapy including a platinum derivative. Predefined data on trial design, quality, patient characteristics, and endpoints will be extracted. Quality of included trials will be assessed according to the Cochrane Risk of Bias Tool, and the GRADE recommendations will be applied to judge the quality of the resulting evidence. The main outcome parameter will be survival, but also treatment toxicity, perioperative morbidity, and quality of life will be assessed. Discussion The findings of this systematic review and meta-analysis will provide novel insights into the efficacy and safety of combined neoadjuvant chemoradiotherapy including a platinum derivative and may form a basis for future clinical decision-making, guideline evaluation, and research prioritization. Systematic review registration PROSPERO CRD42017073064

OBJECTIVES:To test the feasibility of a randomized controlled study design comparing epidural analgesia (EDA) with continuous wound infiltration (CWI) in respect to postoperative complications and mobility to design a future multicentre randomized controlled trial. DESIGN, SETTING, PARTICIPANTS:CWI has been developed to address drawbacks of EDA. Previous studies have established the equivalent analgesic potential of CWI compared to EDA. This is a single centre, non-blinded pilot randomized controlled trial at a tertiary surgical centre. Patients undergoing elective non-colorectal surgery via a midline laparotomy were randomized to EDA or CWI. Endpoints included recruitment, feasibility of assessing postoperative mobility with a pedometer and morbidity. No primary endpoint was defined and all analyses were explorative. INTERVENTIONS:CWI with local anaesthetics (experimental group) vs. thoracic EDA (control). RESULTS:Of 846 patients screened within 14 months, 71 were randomized and 62 (31 per group) included in the intention-to-treat analysis. Mobility was assessed in 44 of 62 patients and revealed no differences within the first 3 postoperative days. Overall morbidity did not differ between the two groups (measured via the comprehensive complication index). Median pain scores at rest were comparable between the two groups, while EDA was superior in pain treatment during movement on the first, but not on the second and third postoperative day. Duration of preoperative induction of anaesthesia was shorter with CWI than with EDA. Of 17 serious adverse events, 3 were potentially related to EDA, while none was related to CWI. CONCLUSION:This trial confirmed the feasibility of a randomized trial design to compare CWI and EDA regarding morbidity. Improvements in the education and training of team members are necessary to improve recruitment. TRIAL REGISTRATION:DRKS00008023.

A bioartificial endocrine pancreas is proposed as a future alternative to current treatment options. Patients with insulin-secretion deficiency might benefit. This is the first systematic review that provides an overview of scaffold materials and techniques for insulin-secreting cells or cells to be differentiated into insulin-secreting cells. An electronic literature survey was conducted in PubMed/MEDLINE and Web of Science, limited to the past 10 years. A total of 197 articles investigating 60 different materials met the inclusion criteria. The extracted data on materials, cell types, study design, and transplantation sites were plotted into two evidence gap maps. Integral parts of the tissue engineering network such as fabrication technique, extracellular matrix, vascularization, immunoprotection, suitable transplantation sites, and the use of stem cells are highlighted. This systematic review provides an evidence-based structure for future studies. Accumulating evidence shows that scaffold-based tissue engineering can enhance the viability and function or differentiation of insulin-secreting cells both in vitro and in vivo.

Introduction Pancreatic surgery is a large and complex field of research. Several evidence gaps exist for specific diseases or surgical procedures. An overview on existing knowledge is needed to plan and prioritise future research. The aim of this project is to create a systematic and living evidence map of pancreatic surgery.Methods and analysis A systematic literature search in MEDLINE (via PubMed), Web of Science and Cochrane Central Register of Controlled Trials will be performed searching for all randomised controlled trials (RCT) and systematic reviews (SR) on pancreatic surgery. RCT and SR will be grouped in research topics. Baseline and outcome data from RCT will be extracted, presented and effect sizes meta-analysed. Data from SR will be used to identify evidence gaps. A freely accessible web-based evidence map in the format of a mind map will be created. The evidence map and meta-analyses will be updated periodically.Dissemination After completion of the project, a permanently updated evidence map of pancreatic surgery will be available to patients, physicians, researchers and funding bodies via www.evidencemap.surgery. Its use will allow clinical decision-making based on primary data and prioritisation of future research endeavours.PROSPERO registration number CRD42019133444.

Introduction Pancreatic cancer is a devastating disease with an exceptionally poor prognosis. Complete resection of the primary tumour followed by adjuvant chemotherapy is the current standard treatment for patients with resectable disease and the only curative treatment option. However, long-term survival remains rare. Tumour cell dissemination due to manipulation during surgery may increase the rate of future metastases and local recurrence, and perioperative chemotherapy might diminish local, distant and circulating minimal residual disease. Yet, safety and feasibility of systemic chemotherapeutic treatments during pancreatic cancer resection have to be evaluated in a first instance.Methods and analysis This is a prospective, single-centre phase I/II feasibility study to investigate the safety and tolerability of a combination of intraoperative chemotherapy and surgical resection in pancreatic cancer. Forty patients with locally confined or borderline resectable pancreatic cancer, meeting all proposed criteria will be included. Participants will receive 400 mg/m2 calcium folinate over 2 hours and 2000 mg/m2 5-fluorouracil over 48 hours, started on the day before pancreatic surgery and thus continuing during surgery. Participants will be followed until 60 days after surgery. The primary endpoint is the 30-day overall complication rate according to the Clavien-Dindo classification. Secondary endpoints comprise toxicity and treatment associated complications. Patients receiving perioperative chemotherapy will be compared with a propensity score matched contemporary control group of 70 patients with pancreatic cancer receiving the standard treatment. This trial also contains an ancillary translational study to analyse disseminated tumour cells and effects of pharmacological interventions in pancreatic cancer.Ethics and dissemination CombiCaRe has been approved by the German Federal Institute for Drugs and Medical Devices (reference number 4042787) and the Medical Ethics Committee of Heidelberg University (reference number AFmo-269/2018). The results of this trial will be presented at national and international conferences and published in peer-reviewed journals.Trial registration number German Clinical Trials Register (DRKS00015766).

BACKGROUND:Postoperative pancreatic fistula (POPF) remains a frequent problem especially after distal pancreatectomy. The application of 2-octyl cyanoacrylate showed promising results in the reduction of POPF after pancreatoduodenectomy prompting an expansion of this technique to distal pancreatectomy. Thus, the objective of the current study was to assess safety, feasibility and preliminary efficacy of an intraoperative 2-octyl cyanoacrylate application after distal pancreatectomy. METHODS:Between April 2015 and June 2016 adult patients scheduled for elective distal pancreatectomy were considered eligible for the study. It was planned to include a total of 35 patients. After distal pancreatectomy with hand-sewn closure of the pancreatic remnant, a 2-octyl cyanoacrylate surgical glue was applied to the cut surface of the pancreas. Patients were followed up for three months with main focus on safety in terms of (serious) adverse events. Further endpoints included POPF, other pancreas-specific and surgical complications. RESULTS:15 patients were included in the study because the manufacturer stopped production and distribution of the investigational device thereafter. There was a total of ten serious adverse events but no device-related events and no mortality. The serious adverse events depicted a typical safety profile after distal pancreatectomy. POPF occurred in five cases (33.3%), delayed gastric emptying and post-pancreatectomy haemorrhage in two cases respectively (13.3%). CONCLUSIONS:Application of 2-octyl cyanoacrylate to the pancreatic remnant after distal pancreatectomy seems feasible and safe. The planned evaluation of preliminary efficacy was not possible due to the inadvertent early termination and subsequent small sample size of the study. Novel techniques for prevention and therapy of POPF should be evaluated in future trials.

[This corrects the article DOI: 10.1371/journal.pone.0139547.].

BACKGROUND:Parastomal hernia (PH) is the most common complication after ostomy formation. Prophylactic mesh placement may be effective in reducing the rate of PH at the stoma site. The aims of this systematic review were to summarize the evidence with regard to the safety and effectiveness in comparison with the standard procedure without mesh placement and to identify important risk constellations. METHOD:A systematic literature search was performed in PubMed, EMBASE and the Cochrane library with no language or date restrictions. Randomized (RCTs) and non-randomized controlled trials (nRCTs) were included. The main outcomes of interest were PH (primary outcome) rate and stoma-related complications (secondary outcomes) such as stenosis or fistula. Statistical analysis included meta-analyses of pooled data and subgroup analyses. RESULTS:Eleven trials (eight RCTs; three nRCTs) with a total of 755 patients were included. PH rate varied from 0% to 59% in the intervention and from 20% to 94% in the control group. RCTs showed a significant reduction of PH rate in the mesh group (OR 0.24; 95% CI 0.10 to 0.58, p = 0.034), whereas included nRCTs did not. No significant differences were observed in postoperative complication rates. Subgroup analyses showed superiority of non-absorbable meshes and sublay mesh positioning in open surgery. CONCLUSION:Prophylactic mesh placement is safe and reduces PH rate. A recommendation for prophylactic non-absorbable meshes in a sublay position can be made for patients undergoing open colorectal operations with end-ostomies. Further research endeavors should focus on patient-oriented outcomes, not only PH rate, with respect to tailored treatment in specific patient populations.