Evaluation of robotic versus open partial pancreatoduodenectomy-study protocol for a randomised controlled pilot trial (EUROPA, DRKS00020407).

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.

Minimally Invasive Versus open AbdominoThoracic Esophagectomy for esophageal carcinoma (MIVATE) - study protocol for a randomized controlled trial DRKS00016773.

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.

Prospective study to evaluate the prognostic value of different nutritional assessment scores in liver surgery: NURIMAS Liver (DRKS00006340).

BACKGROUND: Malnutrition is recognised as a preoperative risk factor for patients undergoing hepatic resection. It is important to identify malnourished patients and take preventive therapeutic action before surgery. However, there is no evidence regarding which existing nutritional assessment score (NAS) is best suited to predict outcomes of liver surgery. METHODS: All patients scheduled for elective liver resection at the surgical department of the University Hospital of Heidelberg and the Municipal Hospital of Karlsruhe were screened for eligibility. Twelve NASs were calculated before operation, and patients were categorised according to each score as being either at risk or not at risk for malnutrition. The association of malnutrition according to each score and occurrence of at least one major complication was the primary endpoint, which was achieved using a multivariate logistic regression analysis including established risk factors in liver surgery as covariates. RESULTS: The population consisted of 182 patients. The percentage of patients deemed malnourished by the NAS varied among the different scores, with the lowest being 2.20% (Mini Nutritional Assessment) and the highest 52.20% (Nutritional Risk Classification). Forty patients (22.0%) had a major complication. None of the scores were significantly associated with major complications. CONCLUSIONS: None of the twelve investigated NAS defined a state of malnutrition that was independently associated with postoperative complications. Other means of measuring malnutrition in liver surgery should be investigated prospectively.

Hand-Assisted laparoscopic donor nephrectomy PERiumbilical versus Pfannenstiel incision and return to normal physical ACTivity (HAPERPACT): study protocol for a randomized controlled trial.

BACKGROUND: Hand-assisted laparoscopic living donor nephrectomy (HALDN) using a periumbilical or Pfannenstiel incision was developed to improve donor outcome after a kidney transplant. The aim of this study was to investigate two methods of hand assistance and kidney removal during HALDN and their effect on the time it takes for the donor to return to normal physical activity. METHODS/DESIGN: This study was initiated in November 2017 and is expected to last for 2 years. To be eligible for the study, donors must be more than 20 years of age and must not be receiving permanent pain therapy. Only donors with a single artery and vein in the graft are being enrolled in this trial. Donors with infections or scars in the periumbilical or hypogastric area, bleeding disorders, chronic use of immunosuppressive agents, or active infection will be excluded. Donors will be randomly allocated to either a control arm (periumbilical incision) or an intervention arm (Pfannenstiel incision). The sample size was calculated as 26 organ donors in each group. The primary endpoint is the number of days it takes the donor to return to normal physical activity (up to 4 weeks after the operation). Secondary endpoints are intraoperative outcomes, including estimated blood loss, warm ischemia time, and duration of the operation. Postoperative pain will be assessed using the visual analog scale, rescue analgesic use, and peak expiratory flow rate. Length of hospital stay, physical activity score, time to return to work, donor satisfaction, cosmetic score, postoperative complications, and all-cause mortality in living donors will also be reported. Delayed graft function, primary non-function, serum creatinine levels, and glomerular filtration rate will also be assessed in the recipients after transplantation. DISCUSSION: This is the first randomized controlled trial to compare the time it takes the living donor to return to normal physical activity after HALDN using two different types of incision. The comprehensive findings of this study will help decide which nephrectomy procedure is best for living donors with regard to patient comfort and satisfaction as well as graft function in the recipient after transplantation. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03317184 . Registered on 23 October 2017.

Nutritional risk in major abdominal surgery: NURIMAS Liver (DRKS00010923) - protocol of a prospective observational trial to evaluate the prognostic value of different nutritional scores in hepatic surgery.

BACKGROUND: Malnutrition is commonly known as a risk factor in surgical procedures. The nutritional status seems particularly relevant to the clinical outcome of patients undergoing hepatic resection. Thus, identifying affected individuals and taking preventive therapeutic actions before surgery is an important task. However, there are only very few studies, that investigate which existing nutritional assessment score (NAS) is suited best to predict the postoperative outcome in liver surgery. OBJECTIVE: Nutritional Risk in Major Abdominal Surgery (NURIMAS) Liver is a prospective observational trial that analyses the predictive value of 12 different NAS for postoperative morbidity and mortality after liver resection. METHODS: After admission to the surgical department of the University Hospital in Heidelberg or the municipal hospital of Karlsruhe, all patients scheduled for elective liver resection will be screened for eligibility. Participants will fill in a questionnaire and undergo a physical examination in order to evaluate nutritional status according to Nutritional Risk Index, Nutritional Risk Screening Score, Subjective Global Assessment, Malnutrition Universal Screening Tool, Mini Nutritional Assessment, Short Nutritional Assessment Questionnaire, Imperial Nutritional Screening System, Imperial Nutritional Screening System II, Nutritional Risk Classification and the ESPEN malnutrition criteria. Postoperative morbidity and mortality will be tracked prospectively throughout the postoperative course. The association of malnutrition according to each score and occurrence of at least one major complication will be analysed using both chi-squared tests and a multivariable logistic regression analysis. Already established risk factors in liver surgery will be added as covariates. DISCUSSION: NURIMAS Liver is a bicentric, prospective observational trial. The aim of this study is to investigate the predictive value of clinical nutritional assessment scores on postoperative morbidity and mortality after hepatic resection. This is necessary, as only a validated identification of malnourished patients at high risk for postoperative complications, enables targeted preventive action.

Anti-angiogenic activity of VXM01, an oral T-cell vaccine against VEGF receptor 2, in patients with advanced pancreatic cancer: A randomized, placebo-controlled, phase 1 trial.

VEGFR-2 is expressed on tumor vasculature and a target for anti-angiogenic intervention. VXM01 is a first in kind orally applied tumor vaccine based on live, attenuated Salmonella bacteria carrying an expression plasmid, encoding VEGFR-2. We here studied the safety, tolerability, T effector (Teff), T regulatory (Treg) and humoral responses to VEGFR2 and anti-angiogenic effects in advanced pancreatic cancer patients in a randomized, dose escalation phase I clinical trial. Results of the first 3 mo observation period are reported. Locally advanced or metastatic, pancreatic cancer patients were enrolled. In five escalating dose groups, 30 patients received VXM01 and 15 placebo on days 1, 3, 5, and 7. Treatment was well tolerated at all dose levels. No dose-limiting toxicities were observed. Salmonella excretion and salmonella-specific humoral immune responses occurred in the two highest dose groups. VEGFR2 specific Teff, but not Treg responses were overall increased in vaccinated patients. We furthermore observed a significant reduction of tumor perfusion after 38 d in vaccinated patients together with increased levels of serum biomarkers indicative of anti-angiogenic activity, VEGF-A, and collagen IV. Vaccine specific Teff responses significantly correlated with reductions of tumor perfusion and high levels of preexisting VEGFR2-specific Teff while those showing no antiangiogenic activity had low levels of preexisting VEGFR2 specific Teff, showed a transient early increase of VEGFR2-specific Treg and reduced levels of VEGFR2-specific Teff at later time points - pointing to the possibility that early anti-angiogenic activity might be based at least in part on specific reactivation of preexisting memory T cells.

Complications after end-to-end vs. side-to-side anastomosis in ileocecal Crohn's disease--early postoperative results from a randomized controlled multi-center trial (ISRCTN-45665492).

BACKGROUND: Recurrent Crohn's disease activity at the site of anastomosis after ileocecal resection is of great surgical importance. This prospective randomized multi-center trial with an estimated case number of 224 patients was initially planned to investigate whether stapled side-to-side anastomosis, compared to hand-sewn end-to-end anastomosis, results in a decreased recurrence of Crohn's disease following ileocolic resection (primary endpoint). The secondary endpoint was to focus on the early postoperative results comparing both surgical methods. The study was terminated early due to insufficient patient recruitment and because another large study investigated the same question, while our trial was ongoing. METHODS AND STUDY DESIGN: Patients with stenosing ileitis terminalis in Crohn's disease who underwent an ileocolic resection were randomized to side-to-side or end-to-end anastomosis. Due to its early discontinuation, our study only investigated the secondary endpoints, the early postoperative results (complications: bleeding, wound infection, anastomotic leakage, first postoperative stool, duration of hospital stay). RESULTS: From February 2006 until June 2010, 67 patients were enrolled in nine participating centers. The two treatment groups were comparable to their demographic and pre-operative data. BMI and Crohn's Disease Activity Index were 22.2 (± 4.47) and 200.5 (± 73.66), respectively, in the side-to-side group compared with 23.3 (± 4.99) and 219.6 (± 89.03) in the end-to-end group. The duration of surgery was 126.7 (± 42.8) min in the side-to-side anastomosis group and 137.4 (± 51.9) min in the end-to-end anastomosis group. Two patients in the end-to-end anastomosis group developed an anastomotic leakage (6.5%). Impaired wound healing was found in 13.9% of the side-to-side anastomosis group, while 6.5% of the end-to-end anastomosis group developed this complication. The duration of hospital stay was comparable in both groups with 9.9 (± 3.93) and 10.4 (± 3.26) days, respectively. CONCLUSIONS: Because of the early discontinuation of the study, it is not possible to provide a statement about the perianastomotic recurrence rates regarding the primary endpoint. With regard to the early postoperative outcome, we observed no difference between the two types of anastomosis.

Double-blind, placebo-controlled first in human study to investigate an oral vaccine aimed to elicit an immune reaction against the VEGF-Receptor 2 in patients with stage IV and locally advanced pancreatic cancer.

BACKGROUND: The investigational oral DNA vaccine VXM01 targets the vascular endothelial growth factor receptor 2 (VEGFR-2) and uses Salmonella typhi Ty21a as a vector. The immune reaction elicited by VXM01 is expected to disrupt the tumor neovasculature and, consequently, inhibit tumor growth. VXM01 potentially combines the advantages of anti-angiogenic therapy and active immunotherapy. METHODS/DESIGN: This phase I trial examines the safety, tolerability, and immunological and clinical responses to VXM01. The randomized, placebo-controlled, double blind dose-escalation study includes up to 45 patients with locally advanced and stage IV pancreatic cancer. The patients will receive four doses of VXM01 or placebo in addition to gemcitabine as standard of care. Doses from 106 cfu up to 1010 cfu of VXM01 will be evaluated in the study. An independent data safety monitoring board (DSMB) will be involved in the dose-escalation decisions. In addition to safety as primary endpoint, the VXM01-specific immune reaction, as well as clinical response parameters will be evaluated. DISCUSSION: The results of this study shall provide the first data regarding the safety and immunogenicity of the oral anti-VEGFR-2 vaccine VXM01 in cancer patients. They will also define the recommended dose for phase II and provide the basis for further clinical evaluation, which may also include additional cancer indications. TRIAL REGISTRATION: EudraCT No.: 2011-000222-29, NCT01486329, ISRCTN68809279.