Publications by authors named "André L Mihaljevic"

70 Publications

Description and analysis of representative COVID-19 cases-A retrospective cohort study.

PLoS One 2021 30;16(7):e0255513. Epub 2021 Jul 30.

Heidelberg Institute of Global Health, Heidelberg University Hospital, Heidelberg, Germany.

Background: Most data on COVID-19 was collected in hospitalized cases. Much less is known about the spectrum of disease in entire populations. In this study, we examine a representative cohort of primarily symptomatic cases in an administrative district in Southern Germany.

Methods: We contacted all confirmed SARS-CoV-2 cases in the administrative district. Consenting participants answered a retrospective survey either via a telephone, electronically or via mail. Clinical and sociodemographic features were compared between hospitalized and non-hospitalized patients. Additionally, we assessed potential risk factors for hospitalization and time to hospitalization in a series of regression models.

Results: We included 897 participants in our study, 69% out of 1,305 total cases in the district with a mean age of 47 years (range 2-97), 51% of which were female and 47% had a pre-existing illness. The percentage of asymptomatic, mild, moderate (leading to hospital admission) and critical illness (requiring mechanical ventilation) was 54 patients (6%), 713 (79%), 97 (11%) and 16 (2%), respectively. Seventeen patients (2%) died. The most prevalent symptoms were fatigue (65%), cough (62%) and dysgeusia (60%). The risk factors for hospitalization included older age (OR 1.05 per year increase; 95% CI 1.04-1.07) preexisting lung conditions (OR 3.09; 95% CI 1.62-5.88). Female sex was a protective factor (OR 0.51; 95% CI 0.33-0.77).

Conclusion: This representative analysis of primarily symptomatic COVID-19 cases confirms age, male sex and preexisting lung conditions but not cardiovascular disease as risk factors for severe illness. Almost 80% of infection take a mild course, whereas 13% of patients suffer moderate to severe illness.

Trial Registration: German Clinical Trials Register, DRKS00022926. URL: https://www.drks.de/drks_web/setLocale_EN.do.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0255513PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323911PMC
August 2021

The TRIANGLE operation for pancreatic head and body cancers: early postoperative outcomes.

HPB (Oxford) 2021 Jul 6. Epub 2021 Jul 6.

Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 420, 69120 Heidelberg, Germany. Electronic address:

Background: Surgical resection is the mainstay of potential cure for patients with pancreatic cancer, however, local recurrence is frequent. Previously, we have described an extended resection technique for pancreatoduodenectomy aiming at a radical resection of the nerve and lymphatic tissue between celiac artery, superior mesenteric artery and mesenteric-portal axis (TRIANGLE operation). Until now, data on postoperative outcome have not been reported, yet.

Methods: Patients who underwent either partial (PD) or total pancreatoduodenectomy (TP) applying the TRIANGLE procedure were identified. These cohorts were compared to matched historic cohorts with standard resections.

Results: Overall, 330 patients were analysed (PD and PD each n = 108; TP and TP each n = 57). More lymph nodes were harvested in TRIANGLE compared to standard resection (PD: 27.5 (21-35) versus 31.5 (24-40); P = 0.0187, TP: 33 (28-49) versus 44 (29-53); P = 0.3174) and the rate of tumour positive resections margins, R1(direct), dropped. Duration of operation was significantly longer and blood loss higher. Postoperative mortality and complications did not differ significantly.

Conclusion: Pancreatoduodenectomy according to the TRIANGLE protocol can be performed without increased morbidity and mortality at a high-volume centre. Long-term survival and quality of life need to be investigated in prospective clinical trials with adequate sample size.
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http://dx.doi.org/10.1016/j.hpb.2021.06.432DOI Listing
July 2021

Health-related quality of life in primary hepatic cancer: a systematic review assessing the methodological properties of instruments and a meta-analysis comparing treatment strategies.

Qual Life Res 2021 Sep 20;30(9):2429-2466. Epub 2021 Jul 20.

Department of General, Visceral and Transplant Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.

Purpose: Patient-reported outcomes including health-related quality of life (HRQoL) are important oncological outcome measures. The validation of HRQoL instruments for patients with hepatocellular and cholangiocellular carcinoma is lacking. Furthermore, studies comparing different treatment options in respect to HRQoL are sparse. The objective of the systematic review and meta-analysis was, therefore, to identify all available HRQoL tools regarding primary liver cancer, to assess the methodological quality of these HRQoL instruments and to compare surgical, interventional and medical treatments with regard to HRQoL.

Methods: A systematic literature search was conducted in MEDLINE, the Cochrane library, PsycINFO, CINAHL and EMBASE. The methodological quality of all identified HRQoL instruments was performed according to the COnsensus-based Standards for the selection of health status Measurements INstruments (COSMIN) standard. Consequently, the quality of reporting of HRQoL data was assessed. Finally, wherever possible HRQoL data were extracted and quantitative analyses were performed.

Results: A total of 124 studies using 29 different HRQoL instruments were identified. After the methodological assessment, only 10 instruments fulfilled the psychometric criteria and could be included in subsequent analyses. However, quality of reporting of HRQoL data was insufficient, precluding meta-analyses for 9 instruments.

Conclusion: Using a standardized methodological assessment, specific HRQoL instruments are recommended for use in patients with hepatocellular and cholangiocellular carcinoma. HRQoL data of patients undergoing treatment of primary liver cancers are sparse and reporting falls short of published standards. Meaningful comparison of established treatment options with regard to HRQoL was impossible indicating the need for future research.
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http://dx.doi.org/10.1007/s11136-021-02810-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8405513PMC
September 2021

Risk of the Watch-and-Wait Concept in Surgical Treatment of Intraductal Papillary Mucinous Neoplasm.

JAMA Surg 2021 Sep;156(9):818-825

Department of General, Visceral, and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany.

Importance: The natural history of intraductal papillary mucinous neoplasms (IPMNs) remains uncertain. The inconsistencies among published guidelines preclude accurate decision-making. The outcomes and potential risks of a conservative watch-and-wait approach vs a surgical approach must be compared.

Objective: To provide an overview of the surgical management of IPMNs, focusing on the time of resection.

Design, Setting, And Participants: This cohort study was conducted in a single referral center; all patients with pathologically proven IPMN who received a pancreatic resection at the institution between October 2001 and December 2019 were analyzed. Preoperatively obtained images and the medical history were scrutinized for signs of progression and/or malignant features. The timeliness of resection was stratified into too early (adenoma and low-grade dysplasia), timely (intermediate-grade dysplasia and in situ carcinoma), and too late (invasive cancer). The perioperative characteristics and outcomes were compared between these groups.

Exposures: Timeliness of resection according to the final pathological findings.

Main Outcomes And Measures: The risk of malignant transformation at the final pathology.

Results: Of 1439 patients, 438 (30.4%) were assigned to the too early group, 504 (35.1%) to the timely group, and 497 (34.5%) to the too late group. Radiological criteria for malignant conditions were detected in 53 of 382 patients (13.9%), 149 of 432 patients (34.5%), and 341 of 385 patients (88.6%) in the too early, timely, and too late groups, respectively (P < .001). Patients in the too early group underwent more parenchyma-sparing resections (too early group, 123 of 438 [28.1%]; timely group, 40 of 504 [7.9%]; too late group, 5 of 497 [1.0%]; P < .001), while morbidity (too early group, 112 of 438 [25.6%]; timely group, 117 of 504 [23.2%]; too late group, 158 of 497 [31.8%]; P = .002) and mortality (too early group, 4 patients [0.9%]; timely, 4 [0.8%]; too late, 13 [2.6%]; P = .03) were highest in the too late group. Of the 497 patients in the too late group, 124 (24.9%) had a previous history of watch-and-wait care.

Conclusions And Relevance: Until the biology and progression patterns of IPMN are clarified and accurate guidelines established, a watch-and-wait policy should be applied with caution, especially in IPMN bearing a main-duct component. One-third of IPMNs reach the cancer stage before resection. At specialized referral centers, the risks of surgical morbidity and mortality are justifiable.
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http://dx.doi.org/10.1001/jamasurg.2021.0950DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8135052PMC
September 2021

A Simple Classification Of Pancreatic Duct Size and Texture Predicts Postoperative Pancreatic Fistula: A classification of the International Study Group of Pancreatic Surgery (ISGPS).

Ann Surg 2021 Mar 12. Epub 2021 Mar 12.

*Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 420, 69120 Heidelberg, Germany †The Study Center of the German Surgical Society (SDGC), University of Heidelberg, Im Neuenheimer Feld 420, 69120 Heidelberg, Germany ‡Department of Surgery, The University of Pennsylvania, Philadelphia, PA §Department of Surgery, Clinic Beau-Site, Bern, Switzerland ¶Department of General and Pancreatic Surgery, The Pancreas Institute, University of Verona Hospital Trust, Verona, Italy ||Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands **Department of General, Visceral and Thoracic-Surgery, University Hospital Hamburg-Eppendorf, Hamburg, Germany ††Pancreatic Surgery Unit, Pancreas Translational & Clinical Research Center, San Raffaele Scientific Institute, "Vita-Salute" University, Milan, Italy ‡‡Massachusetts General Hospital, Harvard Medical School, Boston, USA §§Department of Digestive & HPB Surgery, Hospital Edouard Herriot, HCL, UCBL1, Lyon, France ¶¶Department of Surgery, Klinikum rechts der Isar, School of Medicine, Technische Universität München, Munich, Germany ||||Department of General, Visceral, and Transplantation Surgery, Ludwig Maximilians-University, Munich, Germany ***Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Dresden, Germany †††Clinic for Digestive Surgery, Clinical Center of Serbia and School of Medicine, University of Belgrade, Belgrade, Serbia ‡‡‡Department of Surgery, University of Pécs, Medical School, Pécs, Hungary §§§Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, USA ¶¶¶Pancreas Center, The First Affiliated Hospital with Nanjing Medical University, Nanjing, P.R. China ||||||Department of GI and HPB Surgical Oncology, Tata Memorial Hospital, Mumbai, India ****Department of Surgery, Massachusetts General Hospital and the Harvard Medical School, Boston, MA. ††††Medical School, University of Cyprus, Nicosia, Cyprus.

Objective: The aim of this study was to develop a classification system for pancreas-associated risk factors in pancreatoduodenectomy (PD).

Summary Background Data: Postoperative pancreatic fistula (POPF) is the most relevant PD-associated complication. A simple standardized surgical reporting system based on pancreas- associated risk factors is lacking.

Methods: A systematic literature search was conducted to identify studies investigating clinically relevant POPF (CR-POPF) and pancreas-associated risk factors after PD. A meta-analysis of CR-POPF rate for texture of the pancreas (soft vs. not-soft) and main pancreatic duct (MPD) diameter was performed using the Mantel-Haenszel method. Based on the results, the ISGPS proposes the following classification: A, not-soft (hard) texture and MPD >3 mm; B, not-soft (hard) texture and MPD ≤3 mm; C, soft texture and MPD >3 mm; D, soft texture and MPD ≤3 mm. The classification was evaluated in a multi-institutional, international cohort.

Results: Of the 2,917 articles identified, 108 studies were included in the analyses. Soft pancreatic texture was significantly associated with the development of CR-POPF (odds ratio 4.24, 95%CI 3.67 to 4.89, p < 0.01) following PD. Similarly, MPD diameter ≤3 mm significantly increased CR-POPF risk compared with >3 mm diameter MPDs (odds ratio 3.66, 95%CI 2.62 to 5.12, p < 0.01). The proposed four-stage system was confirmed in an independent cohort of 5,533 patients with CR-POPF rates of 3.5%, 6.2%, 16.6%, and 23.2% for type A-D, respectively (p < 0.001).

Conclusion: For future pancreatic surgical outcomes studies the ISGPS recommends reporting these risk factors according to the proposed classification system for better comparability of results.
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http://dx.doi.org/10.1097/SLA.0000000000004855DOI Listing
March 2021

Gastric Venous Congestion After Total Pancreatectomy Is Frequent and Dangerous.

Ann Surg 2021 Mar 4. Epub 2021 Mar 4.

*Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany †Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany ‡Department of Radiology, Heidelberg University Hospital, Heidelberg, Germany §Institute of Medical Biometry and Informatics, Heidelberg University, Heidelberg, Germany ||Department of Anesthesiology, Heidelberg University Hospital, Heidelberg, Germany.

Objective: The aim of this study was to determine the role of gastric venous congestion (GVC) in mortality after total pancreatectomy (TP).

Background: Data from a nationwide administrative database revealed that TP is associated with a 23% mortality rate in Germany.

Methods: A total of 585 consecutive patients who had undergone TP (n = 514) or elective completion pancreatectomy (n = 71) between January 2015 and December 2019 were analyzed. Univariable and multivariable analyses were performed to identify risk factors for GVC and 90-day mortality.

Results: GVC was observed in 163 patients (27.9%) requiring partial or total gastrectomy. Splenectomy (OR 2.14, 95% CI 1.25-3.80, p = 0.007) and coronary vein resection (OR 5.49, 95% CI 3.19-9.64, p < 0.001) were independently associated with GVC. The overall 90-day mortality after TP was 4.1% (24 of 585 patients), 7.4% in patients with GVC and 2.8% in those without GVC (p = 0.014). Of the 24 patients who died after TP, 12 (50%) had GVC.

Conclusion: GVC is a frequent albeit not well-known finding after TP, especially when splenectomy and resection of the coronary vein are performed. Adequate decision making for partial gastrectomy during TP is crucial. Insufficient gastric venous drainage after TP is life-threatening.
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http://dx.doi.org/10.1097/SLA.0000000000004847DOI Listing
March 2021

Development, testing and generalizability of a standardized evaluation form for the assessment of patient-directed reports in the new final medical licensing examination in Germany.

GMS J Med Educ 2021 15;38(3):Doc71. Epub 2021 Mar 15.

Institut für medizinische und pharmazeutische Prüfungsfragen (IMPP), Mainz, Germany.

As doctors often fail to explain diagnoses and therapies to patients in an understandable and appropriate way, the improvement of doctor-patient communication is essential. The current medical training and examinations are focused on verbal rather than on written communication. Following the premise of "assessment drives learning", the final medical licensing examination in Germany has been further developed by the German National Institute for state examinations in Medicine, Pharmacy and Psychotherapy (IMPP). As part of the discharge management the candidates have to prepare a report for the patient that is understandable and provides them with all important information about their stay in hospital. A standardized evaluation form for formative and summative feedback has been developed and tested with regard to applicability and the assurance of test quality criteria, especially the reliability to assess the written communication skills of the students. In an expert consensus procedure, a draft for a standardized evaluation form was developed. This form was revised after an initial trial run on patient-directed reports written by students in their last year of medical studies. Afterwards twenty-one patient-directed reports were evaluated by fourteen different examiners. The reliability was tested by calculating the generalizability-coefficient and by analysing the inter-rater reliability. The first test on the evaluation of the patient-directed reports indicated the practicability of the application and the usefulness of the evaluation form as an instrument for assessing the written communication skills of students. The analyses of the inter-rater reliability showed that the degree of agreement in the evaluations was partly different between two groups of examiners. The calculated G-coefficient indicates a high reliability. The content validity of the evaluation form was given through the comprehensive medical expertise in the development process. Assessing written patient-directed communication is a benefit of the newly developed last part of the medical licensing examination in Germany. Continuous formative assessment and feedback based on the evaluation form is intended to improve the written communication skills of future doctors. Furthermore, a better understanding of their diagnosis and treatment as well as a trusting relationship with their doctor may empower patients in the medical decision process and lead to fewer dismissal errors in the future. For consistent use of the evaluation form a standardized training of examiners should be implemented.
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http://dx.doi.org/10.3205/zma001467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994883PMC
March 2021

Multicenter Prospective Cohort Study of the Patient-Reported Outcome Measures PRO-CTCAE and CAT EORTC QLQ-C30 in Major Abdominal Cancer Surgery (PATRONUS): A Student-Initiated German Medical Audit (SIGMA) Study.

Ann Surg Oncol 2021 Jun 8;28(6):3075-3089. Epub 2021 Mar 8.

Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany.

Background: The patient-reported outcomes (PRO) version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) and the computerized adaptive testing (CAT) version of the EORTC quality-of-life questionnaire QLQ-C30 have been proposed as new PRO measures in oncology; however, their implementation in patients undergoing cancer surgery has not yet been evaluated.

Methods: Patients undergoing elective abdominal cancer surgery were enrolled in a prospective multicenter study, and postoperative complications were recorded according to the Dindo-Clavien classification. Patients reported PRO data using the CAT EORTC QLQ-C30 and the PRO-CTCAE to measure 12 core cancer symptoms. Patients were followed-up for 6 months postoperatively. The study was carried out by medical students of the CHIR-Net SIGMA study network.

Results: Data of 303 patients were obtained and analyzed across 15 sites. PRO-CTCAE symptoms 'poor appetite', 'fatigue', 'exhaustion' and 'sleeping problems' increased after surgery and climaxed 10-30 days postoperatively. At 3-6 months postoperatively, no PRO-CTCAE symptom differed significantly to baseline. Patients reported higher 'social functioning' (p = 0.021) and overall quality-of-life scores (p < 0.05) 6 months after cancer surgery compared with the baseline level. There was a lack of correlation between postoperative complications or death and any of the PRO items evaluated. Feasibility endpoints for student-led research were met.

Conclusion: The two novel PRO questionnaires were successfully applied in surgical oncology. Postoperative complications do not affect health-reported quality-of-life or common cancer symptoms following major cancer surgery. The feasibility of student-led multicenter clinical research was demonstrated, but might be enhanced by improved student training.
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http://dx.doi.org/10.1245/s10434-021-09646-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8119276PMC
June 2021

Postoperative acute pancreatitis is a serious but rare complication after distal pancreatectomy.

HPB (Oxford) 2021 Jan 13. Epub 2021 Jan 13.

Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany. Electronic address:

Background: The clinical relevance of hyperamylasemia after distal pancreatectomy (DP) remains unclear and no internationally accepted definition of postoperative acute pancreatitis (POAP) exists. The aim of this study was to characterize POAP after DP and to assess the role of serum amylase (SA) in POAP.

Methods: Outcomes of 641 patients who had undergone DP between 2015 and 2019 were analyzed. Postoperative SA was determined in all patients. POAP was defined based on contrast-enhanced computed tomography (CT) or intraoperative findings during relaparotomy.

Results: An elevation of SA on postoperative day 1 (hyperamylasemia) was found in 398 patients (62.1%). Twelve patients (1.87%) were identified with POAP. Ten patients demonstrated radiologic criteria for POAP and in two patients POAP was diagnosed during relaparotomy. Outcome of POAP patients was worse than that of patients with hyperamylasemia alone and that with normal SA without POAP evidence (postoperative pancreatic fistula 50% vs 30.6% vs 18.5%; length of hospital stay 26 days vs 12 vs 11, respectively). The overall 90-day mortality of all 641 patients was 0.6%.

Conclusion: POAP is a serious but rare complication after DP. Hyperamylasemia is of prognostic relevance after DP, but it seems not sufficient as a single parameter to diagnose POAP.
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http://dx.doi.org/10.1016/j.hpb.2021.01.004DOI Listing
January 2021

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

Trials 2021 Jan 8;22(1):40. Epub 2021 Jan 8.

Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.

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.
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http://dx.doi.org/10.1186/s13063-020-04933-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796523PMC
January 2021

Not all Whipple procedures are equal: Proposal for a classification of pancreatoduodenectomies.

Surgery 2021 06 30;169(6):1456-1462. Epub 2020 Dec 30.

Department of General, Visceral, and Transplantation Surgery, Heidelberg University Hospital, Germany. Electronic address:

Background: Pancreatoduodenectomy is the standard treatment for pathologies of the pancreatic head and is performed routinely worldwide. The aim of the study was to analyze this procedure in terms of extent of surgery, technical difficulty, and clinical outcomes and thereby provide a standardized surgical categorization of pancreatoduodenectomies for future reference.

Methods: For this cohort study, all patients who underwent pancreatoduodenectomy at a single center within an 18-year period (October 2001 to December 2019) were identified in a prospectively maintained database. Based on technical difficulty and extent of surgery, 4 pancreatoduodenectomy types were proposed: (1) standard pancreatoduodenectomy; (2) pancreatoduodenectomy with portal vein/superior mesenteric vein resection; (3) pancreatoduodenectomy with multivisceral resection; and (4) pancreatoduodenectomy with arterial resection. Patient characteristics, surgical parameters, and perioperative morbidity and mortality were analyzed. The 4 types were compared with regard to their surgical outcomes.

Results: A total of 3,953 pancreatoduodenectomies were performed in the study period. Standard pancreatoduodenectomy (type 1) was the most frequent procedure (n = 2,931, 74.1%), followed by pancreatoduodenectomy with portal vein/superior mesenteric vein resection (type 2: n = 568, 14.4%), pancreatoduodenectomy with multivisceral resection (type 3: n = 415, 10.5%), and pancreatoduodenectomy with arterial resection (type 4: n = 39, 1.0%). Demographic baseline characteristics were clinically comparable among pancreatoduodenectomy types. Mortality within 90-days correlated with the type of pancreatoduodenectomy (type 1: 2.9%; type 2: 4.2%; type 3: 6.3%; type 4: 10.3%; P = .0007). Overall surgical morbidity was 41.7% (type 1), 40.8% (type 2), 52.5% (type 3), and 59.0% (type 4) (P < .0001), including postoperative pancreatic fistula type B/C (type 1: 11.9%; type 2: 7.7%; type 3: 14.7%; type 4: 15.4; P = .0031) and delayed gastric emptying (type 1: 19.4%; type 2: 22.5%; type 3: 22.0%; type 4: 25.6%; P = .187) as the most frequent complications. Relaparotomies were more frequent in type 4 (20.5%) and type 3 (20.6%) than in type 2 (12.0%) or type 1 (10.4%) pancreatoduodenectomy (P < .0001). Intensive care unit stay ≥2 days was more frequent in type 4 (48.7%) compared with type 3 (25.7%) or type 2 (27.1%) and type 1 (18.6%) (P < .0001).

Conclusion: The results show different clinical outcomes for the 4 types of pancreatoduodenectomy. Morbidity and mortality correlate with pancreatoduodenectomy type. The proposed pancreatoduodenectomy classification is useful for reporting pancreatoduodenectomy procedures, enhances the comparability of future studies, may be used for training purposes, and may guide intra and postoperative decision-making.
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http://dx.doi.org/10.1016/j.surg.2020.11.030DOI Listing
June 2021

Enucleation for benign or borderline tumors of the pancreas: comparing open and minimally invasive surgery.

HPB (Oxford) 2021 Jun 18;23(6):921-926. Epub 2020 Oct 18.

Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany. Electronic address:

Background: The feasibility and safety of minimally invasive enucleation (ME) for benign or borderline pancreatic tumors is still unclear. The aim of this study was to compare outcomes between ME and open enucleation (OE).

Methods: All patients undergoing pancreatic enucleation between October 2001 and January 2020 were analyzed from a prospective database. Consecutive patients undergoing ME were compared with patients undergoing OE in a matched-pair analysis (1:2).

Results: Of 358 patients, undergoing enucleation, 120 matched patients (ME n = 40, OE n = 80) were included. Patients undergoing ME had less blood loss (median 50 vs. 100 ml, P = 0.025) and had a higher proportion of patients discharged by 7 days, than patients undergoing OE (38% vs. 18%, P = 0.016). The rates of clinically relevant postoperative pancreatic fistula (POPF) and major complications (Clavien grade ≥ 3) were similar between both groups. Risk factor analysis for POPF B/C showed no significant parameters associated with POPF, including tumor size and proximity to the main pancreatic duct.

Conclusion: Compared with conventional OE, ME reduces the amount of bleeding and allows earlier postoperative discharge, without increasing the incidence of major complications. Thus, minimally invasive enucleation should be considered for benign tumors of the pancreas when technically and oncologically feasible.
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http://dx.doi.org/10.1016/j.hpb.2020.10.001DOI Listing
June 2021

Arterial Resection in Pancreatic Cancer Surgery: Effective After a Learning Curve.

Ann Surg 2020 Jun 12. Epub 2020 Jun 12.

*Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany †Institute for Medical Biometry and Informatics, Heidelberg University, Heidelberg, Germany.

Objective: To investigate the perioperative and oncologic long-term outcomes of patients with LAPC after surgical resection at a high-volume center for pancreatic surgery.

Background: The role of surgery in LAPC with arterial involvement is controversial.

Methods: We analyzed 385 consecutive patients undergoing PAR (n = 195) or PAD (n = 190) of the encased artery for LAPC between January 1, 2003 and April 30, 2019.

Results: There were 183 total pancreatectomies, 113 partial pancreatoduodenectomies, 79 distal pancreatectomies, and 10 resections for tumor recurrences, including 121 multivisceral resections and 171 venous resections. Forty-three patients (11.4%) had resectable oligometastatic disease. All of the 190 patients undergoing PAD (100%) and 95 of the 195 patients undergoing PAR (48.7%) received neoadjuvant chemotherapy. The R0 (circumferential resection margin negative) resection rate was 28%. The median hospital stay was 15 days (range: 3-236). The median survival after surgery for LAPC was 20.1 months and the overall 5-year survival rate 12.5%. In-hospital mortality was 8.8% for the entire patient cohort (n = 385). With increasing case load and growing expertise, there was a significant reduction of in-hospital mortality to 4.8% (n = 186) after 2013 (P = 0.005). The learning curve of experienced pancreatic surgeons for PAR was 15 such procedures.

Conclusion: Our data demonstrate that an arterial surgical approach is effective in LAPC with promising long-term survival. PAD after neoadjuvant treatment is safe. PAR is a technically demanding procedure and requires a high level of expertise.
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http://dx.doi.org/10.1097/SLA.0000000000004054DOI Listing
June 2020

PREventive effect of FENestration with and without clipping on post-kidney transplantation lymphatic complications (PREFEN): study protocol for a randomised controlled trial.

BMJ Open 2020 10 13;10(10):e032286. Epub 2020 Oct 13.

Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Baden-Württemberg, Germany

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).
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http://dx.doi.org/10.1136/bmjopen-2019-032286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554503PMC
October 2020

Periarterial divestment in pancreatic cancer surgery.

Surgery 2021 05 5;169(5):1019-1025. Epub 2020 Oct 5.

Department of General, Visceral, and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany. Electronic address:

Background: Modern pancreatic cancer surgery changed with the introduction of effective neoadjuvant therapies. Complete tumor resection is the mainstay for long-term, disease-free, and overall survival and has been a prerequisite for decreasing local recurrence. The medial resection margin in the area of the superior mesenteric vessels limits the radicalness of the resection, especially in borderline and locally advanced cases. Therefore, the periarterial soft tissue around the peripancreatic visceral arteries must be completely cleared. This procedure, namely periarterial divestment, is technically demanding but often represents an alternative to arterial resection.

Objective: Here we describe the technique and our initial experience with periarterial divestment along the peripancreatic visceral arteries during pancreatic surgery. This technique, in combination with previously published resection strategies, such as artery first maneuver and mesenterico-portal venous bypass first, enables tumor resection in locally advanced pancreatic cancer.

Conclusion: Periarterial divestment can prevent the need for arterial resection in borderline and locally advanced pancreatic cancer, especially after neoadjuvant therapy. The feasibility, improved safety, and oncologic equivalence of arterial divestment versus arterial resection for pancreatic cancer surgery must be evaluated by clinical trials.
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http://dx.doi.org/10.1016/j.surg.2020.08.030DOI Listing
May 2021

Pancreatic resection with perioperative drug repurposing of propranolol and etodolac: trial protocol of the phase-II randomised placebo controlled PROSPER trial.

BMJ Open 2020 09 30;10(9):e040406. Epub 2020 Sep 30.

Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.

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.
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http://dx.doi.org/10.1136/bmjopen-2020-040406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7528424PMC
September 2020

Cavernous transformation of the portal vein in pancreatic cancer surgery-venous bypass graft first.

Langenbecks Arch Surg 2020 Nov 11;405(7):1045-1050. Epub 2020 Sep 11.

Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.

Background: In recent years, several techniques have been introduced to allow safe oncologic resections of cancers of the pancreatic head. While resections of the mesenterico-portal axis became now a part of the routine treatment, patients with a cavernous transformation of the portal vein still pose a surgical challenge and are regularly deemed unresectable.

Objective: Here, we describe a technique of initial venous bypass graft placement between the superior mesenteric vein or its tributaries and the portal vein before the resection of the pancreatic head. This approach avoids uncontrollable bleeding as well as venous congestion of the intestine with a continuous hepatic perfusion and facilitates oncologic resection of pancreatic head cancers. This technique, in combination with previously published resection strategies, enables tumor resection in locally advanced pancreatic head cancers.

Conclusions: Venous bypass graft first operations facilitate and enable the resection of the pancreatic head cancers in patients with a cavernous transformation of the portal vein thus rendering these patients resectable.
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http://dx.doi.org/10.1007/s00423-020-01974-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541372PMC
November 2020

Fifty Years of Surgery for Pancreatic Cancer.

Pancreas 2020 09;49(8):1005-1013

From the Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.

The surgical treatment of pancreatic cancer (PDAC) has seen sweeping changes during the past 5 decades. Up to the middle of the 20th century resection rates were below 5%, but the numbers of curative resections for PDAC are now continuously increasing due to improved neoadjuvant treatment concepts as well as progress in surgical techniques and perioperative management. During the same period, mortality rates after pancreatic surgery have decreased considerably and are now less than 5%. One of the most important cornerstones of reduced mortality has been the concentration of PDAC surgery in specialized centers. In addition, the management of postoperative complications has improved greatly as a result of optimized interdisciplinary teamwork. Adjuvant chemotherapy has become the reference treatment in resected PDAC, achieving significantly prolonged survival. Moreover, the concept of borderline resectable PDAC has emerged to characterize tumors with increased risk for tumor-positive resection margins or worse outcome. The best treatment strategy for borderline resectable PDAC is currently under debate, whereas neoadjuvant therapy has become established as a beneficial treatment option for patients with locally advanced PDAC, enabling conversion surgery in up to 60% of cases. This review article summarizes the principal changes in PDAC surgery during the past 50 years.
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http://dx.doi.org/10.1097/MPA.0000000000001634DOI Listing
September 2020

Systematic Review and Metaanalysis of Lymph Node Metastases of Resected Pancreatic Neuroendocrine Tumors.

Ann Surg Oncol 2021 Mar 27;28(3):1614-1624. Epub 2020 Jul 27.

Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.

Background: The optimal surgical strategy for pancreatic neuroendocrine tumors (PNETs) is unknown. However, current guidelines recommend a watch-and-wait strategy for small nonfunctional PNETs (NF-PNETs). The aim of this study is to investigate the risk stratification and prognostic significance of lymph node metastasis (LNM) of PNETs to guide decision-making for lymphadenectomy.

Patients And Methods: The MEDLINE and Web of Science databases were systematically searched for studies reporting either risk factors of LNM in resected PNETs or survival of patients with LNM. The weighted average incidence of LNM was calculated according to tumor characteristics. Random-effects metaanalyses were performed, and pooled hazard ratios (HR) and their 95% confidence intervals (CI) were calculated to determine the impact of LNM on overall survival (OS). In subgroup analyses, NF-PNETs were assessed.

Results: From a total of 5883 articles, 98 retrospective studies with 13,374 patients undergoing resection for PNET were included. In all PNETs, the weighted median rates of LNM were 11.5% for small (≤ 2 cm) PNETs and 15.8% for G1 PNETs. In NF-PNETs, the rates were 11.2% for small PNETs and 10.3% for G1 PNETs. LNM of all PNETs (HR 3.87, 95% CI 3.00-4.99, P < 0.001) and NF-PNETs (HR 4.98, 95% CI 2.81-8.83, P < 0.001) was associated with worse OS.

Conclusions: LNM is potentially prevalent even in small and well-differentiated PNETs and is associated with worse prognosis. A watch-and-wait strategy for small NF-PNETs should be reappraised, and oncologic resection with lymphadenectomy can be considered. Prospective and controlled studies are needed in the future.
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http://dx.doi.org/10.1245/s10434-020-08850-7DOI Listing
March 2021

Randomised-controlled feasibility trial on abdominal wall closure techniques in patients undergoing relaparotomy (ReLap study; DRKS00013001).

Langenbecks Arch Surg 2020 Jun 6;405(4):427-434. Epub 2020 Jun 6.

Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.

Background: Patients undergoing relaparotomy are generally underrepresented in clinical trials, despite how common the procedure is in clinical practice. Specifically, techniques for re-do abdominal wall closure have never been evaluated in a randomised-controlled trial. The aim of this trial was to identify the optimal abdominal wall closure technique in patients undergoing relaparotomy.

Methods: In this monocentric, randomised feasibility trial, patients scheduled for elective relaparotomy were randomised to abdominal wall closure with either the small stitches technique, using Monomax® 2-0, or the large stitches technique, using PDS II® 1 loop. Patients' postoperative courses were followed for 1 year after the index operation. Effectiveness and safety outcomes were compared at a level of significance of 5% between the two techniques.

Results: A total of 100 out of 131 patients (76.3%) were evenly randomised to the small stitches and large stitches groups. The time for abdominal wall closure did not differ between the two techniques (small stitches 27.5 ± 9.5 min versus large stitches 25.3 ± 12.4 min; p = 0.334). The overall comprehensive complication index was 14.4 ± 15.5 in the small stitches group and 19.9 ± 23.4 in the large stitches group (p = 0.168). Specifically, rates of surgical site infection (small stitches 30.0% versus large stitches 36.0%; p = 0.524) and burst abdomen (small stitches 4.0% versus large stitches 0.0%; p = 0.495) did not differ. After 1 year, incisional hernia rate was 7.5% in the small stitches group and 10.0% in the large stitches group (p > 0.999).

Discussion: Both abdominal wall closure techniques investigated in this trial were feasible in relaparotomy patients. This exploratory trial revealed no noticeable difference in the effectiveness or safety of the small stitches technique with Monomax® 2-0 versus the large stitches technique with PDS II® 1 loop. Therefore, surgeons should stay with their preferred suture technique in relaparotomy patients.

Trial Registration: Deutsches Register Klinischer Studien ( www.germanctr.de ): DRKS00013001.
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http://dx.doi.org/10.1007/s00423-020-01903-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359135PMC
June 2020

Top ten research priorities for pancreatic cancer therapy.

Lancet Oncol 2020 06;21(6):e295-e296

Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg 69120, Germany; The Study Centre of the German Surgical Society, Heidelberg University Hospital, Heidelberg 69120, Germany. Electronic address:

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http://dx.doi.org/10.1016/S1470-2045(20)30179-0DOI Listing
June 2020

What and how are students taught about communicating risks to patients? Analysis of a medical curriculum.

PLoS One 2020 29;15(5):e0233682. Epub 2020 May 29.

Department of General, Internal and Psychosomatic Medicine, Center for Psychosocial Medicine, Heidelberg University Hospital, Heidelberg, Germany.

Background: Communication is a core competence in medical care. Failure of physicians to properly communicate inherent risks of medical interventions has been linked with inadequate training at school. This study analyses a medical curriculum for assessing the content and quality of teaching risk communication to students.

Methods: A checklist based on the national guidelines of core competencies on risk communication required of physicians was developed. Participant observers surveyed all teaching sessions at a medical school during a semester to record the frequency, characteristics and clinical context used by lectures during classes. Data were analyzed using statistical and descriptive methods to determine the prevalence and quality of teaching content.

Results: 231 teaching sessions were surveyed. The inter-rater reliability was 81%. Lecturers mentioned topics of risk communication in 61.5% of teaching sessions (83.7% in surgery, 43.3% in internal medicine) but core biostatistics concepts were not discussed in more than 80% of these sessions. Important topics such as patient safety and preventable diseases were underrepresented. Risk communication was mainly taught in large-group, theoretical sessions and rarely with supplementary teaching material (7.4%). Students asked questions in 15.2% of courses, more often in surgery classes than in internal medicine.

Conclusion: Statistical and clinical topics relevant for teaching risk communication to medical students are not only underrepresented but also minimally explained by lecturers. Supplementary material on risk communication is rarely provided to students during classes. High-resource demanding, small-group teaching formats are not necessarily interactive as students ask few questions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0233682PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7259606PMC
August 2020

Postoperative complications and mobilisation following major abdominal surgery with vs. without fitness tracker-based feedback (EXPELLIARMUS): study protocol for a student-led multicentre randomised controlled trial (CHIR-Net SIGMA study group).

Trials 2020 Mar 23;21(1):293. Epub 2020 Mar 23.

Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.

Background: Postoperative complications following major abdominal surgery are frequent despite progress in surgical technique and perioperative care. Early and enhanced postoperative mobilisation has been advocated to reduce postoperative complications, but it is still unknown whether it can independently improve outcomes after major surgery. Fitness trackers (FTs) are a promising tool to improve postoperative mobilisation, but their effect on postoperative complications and recovery has not been investigated in clinical trials.

Methods: This is a multicentre randomised controlled trial with two parallel study groups evaluating the efficacy of an enhanced and early mobilisation protocol in combination with FT-based feedback in patients undergoing elective major abdominal surgery. Participants are randomly assigned (1:1) to either the experimental group, which receives daily step goals and a FT giving feedback about daily steps, or the control group, which is mobilised according to hospital standards. The control group also receives a FT, however with a blackened screen; thus no FT-based feedback is possible. Randomisation will be stratified by type of surgery (laparoscopic vs. open). The primary endpoint of the study is postoperative morbidity within 30 days measured via the Comprehensive Complication Index. Secondary endpoints include number of steps as well as a set of functional, morbidity and safety parameters. A total of 348 patients will be recruited in 15 German centres. The study will be conducted and organised by the student-led German Clinical Trial Network SIGMA.

Discussion: Our study aims at investigating whether the implementation of a simple mobilisation protocol in combination with FT-based feedback can reduce postoperative morbidity in patients undergoing major abdominal surgery. If so, FTs would offer a cost-effective intervention to enhance postoperative mobilisation and improve patient outcomes.

Trial Registration: Deutsches Register Klinischer Studien (DRKS, German Clinical Trials Register): DRKS00016755, UTN U1111-1228-3320. Registered on 06.03.2019.
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http://dx.doi.org/10.1186/s13063-020-4220-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7092422PMC
March 2020

Continuous wound infiltration versus epidural analgesia for midline abdominal incisions - a randomized-controlled pilot trial (Painless-Pilot trial; DRKS Number: DRKS00008023).

PLoS One 2020 6;15(3):e0229898. Epub 2020 Mar 6.

Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0229898PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7059935PMC
June 2020

Hernia reduction following laparotomy using small stitch abdominal wall closure with and without mesh augmentation (the HULC trial): study protocol for a randomized controlled trial.

Trials 2019 Dec 16;20(1):738. Epub 2019 Dec 16.

Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.

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.
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http://dx.doi.org/10.1186/s13063-019-3921-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6915967PMC
December 2019

Primary Open Versus Closed Implantation Strategy for Totally Implantable Venous Access Ports: The Multicentre Randomized Controlled PORTAS-3 Trial (DRKS 00004900).

Ann Surg 2020 12;272(6):950-960

Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.

Objectives: PORTAS-3 was designed to compare the frequency of pneumothorax or haemothorax in a primary open versus closed strategy for port implantation.

Background Data: The implantation strategy for totally implantable venous access ports with the optimal benefit/risk ratio remains unclear.

Methods: PORTAS-3 was a multicentre, randomized, controlled, parallel-group superiority trial. Adult patients with oncological disease scheduled for elective port implantation were randomized to a primary open or closed strategy. Primary endpoint was the rate of pneumothorax or haemothorax. Assuming a difference of 2.5% between the 2 groups, a sample size of 1154 patients was needed to prove superiority of the open group. A logistic regression model after the intention-to-treat principle was applied for analysis of the primary endpoint.

Results: Between November 9, 2014 and September 5, 2016, 1205 patients were randomized. Of these, 1159 (open n = 583; closed n = 576) were finally analyzed. The rate of pneumothorax or haemothorax was significantly reduced with the open strategy [odds ratio 0.27, 95% confidence interval (CI) 0.09-0.88; P = 0.029]. Operation time was shorter for the closed strategy. Primary success rates, tolerability, morbidity, dose rate of radiation, and 30-day mortality did not differ significantly between the groups.

Conclusion: A primary open strategy by cut-down of the cephalic vein, if necessary enhanced by a modified Seldinger technique, reduces the frequency of pneumothorax or haemothorax after central venous port implantation significantly compared with a closed strategy by primary puncture of the subclavian vein without routine sonographic guidance. Therefore, open surgical cut-down should be the reference standard for port implantation in comparable cohorts.

Trial Registration: German Clinical Trials Register DRKS 00004900.
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http://dx.doi.org/10.1097/SLA.0000000000003705DOI Listing
December 2020

[Design and Evaluation of a Clinical Investigator Training for Student-lead Prospective Multicentre Clinical Trials: a CHIR-Net SIGMA Research-based Learning Project].

Zentralbl Chir 2020 Dec 28;145(6):521-530. Epub 2019 Oct 28.

Klinik für Allgemein-, Viszeral und Transplantationschirurgie, Universitätsklinikum Heidelberg, Deutschland.

Background: Scientific skills are not sufficiently taught during medical training, neither in medical school nor during postgraduate education. This results in a lack of clinician scientists. In order to counter this problem, the surgical study network (CHIR) founded SIGMA (Student-initiated German Medical Audit). This paper describes the development, performance and evaluation of a Clinical Investigator Training (CIT) aiming to qualify students to autonomously conduct clinical trials.

Material And Methods: Based on the Kern cycle, a curriculum was developed, composed of three parts: online tutorials, a workshop and a follow-up period. The educational objectives were defined according to Bloom's taxonomy of knowledge. The learning objectives were based on the requirements of the "Network of Coordinating Centers for Clinical Trials" and the German Medical Association as well as content relevant to clinical studies. A wide range of educational instruments and assessments were used. By including all relevant professional groups involved in clinical trials, an interconnected working environment for students was generated. The increase in knowledge was assessed by a multiple-choice pre/post exam. The satisfaction of participants was analysed by a 5-point Likert scale, on which 5 indicated full approval.

Results: The first SIGMA CIT was realised in 2018; the workshop took place in Heidelberg in February. Thirty-two medical students from thirteen different centres participated. On average, 53.8 ± 8.3% of questions were answered correctly in the pre-test, compared with 71.2 ± 7.2% in the post-test (p < 0.0001). The maximal individual improvement was 30%; the lowest difference compared to the pre-test was 5%. Subjective evaluation results were positive with an average result of 4.63 ± 0.34 on a 5-point Likert scale.

Conclusion: It is feasible to teach medical students the fundamentals of clinical trials. A compact Clinical Investigator Training using modern principles of teaching is able to prepare students for an autonomous performance of clinical trials.
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http://dx.doi.org/10.1055/a-1007-1995DOI Listing
December 2020

Evidence map of pancreatic surgery: protocol for a living systematic review and meta-analysis.

BMJ Open 2019 09 30;9(9):e032353. Epub 2019 Sep 30.

Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.

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.
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http://dx.doi.org/10.1136/bmjopen-2019-032353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6773280PMC
September 2019

Escherichia coli Bacterobilia Is Associated with Severe Postoperative Pancreatic Fistula After Pancreaticoduodenectomy.

J Gastrointest Surg 2020 08 19;24(8):1802-1808. Epub 2019 Jul 19.

Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.

Background: The benefit of preoperative biliary stenting in the treatment of pancreatic ductal adenocarcinoma is controversially debated. Data from recent meta-analyses favor primary surgery for the majority of resectable pancreatic cancers. Regardless of this evidence, preoperative biliary stenting via endoscopy (EBS) is commonly performed, often before involvement of a surgeon. The goal of this study was to elucidate the association of bile duct stenting, microbiological dislocation of gut flora to the biliary compartment, and major postoperative complications.

Methods: Patient data was derived from a prospectively maintained database including all pancreatic resections between January 2006 and December 2014. Patients receiving pancreaticoduodenectomy for malignant disease in the head of the pancreas with prior EBS were included. Microbiological data were obtained through conventional culture from intraoperative bile duct swabs.

Results: Two hundred ninety-eight patients were enrolled in this study. Severe postoperative complications were associated with stent colonization: Postoperative pancreatic fistula type C occurred more frequently in E. coli-colonized patients (sample estimated odds ratio (OR) = 4.07), and the rate of lymphatic fistula was elevated in Enterococcus-colonized patients (OR = 3.25). Longer stenting duration (> 16 days) was associated with the prevalence of these bacteria.

Conclusion: Major surgical complications following pancreaticoduodenectomy, including severe pancreatic fistula, are associated with bacterobilia after EBS. The indication for bile duct stenting should be evaluated in a multidisciplinary setting.
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http://dx.doi.org/10.1007/s11605-019-04325-7DOI Listing
August 2020
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