Oncological outcomes of standard versus prolonged time to surgery after neoadjuvant chemoradiotherapy for oesophageal cancer in the multicentre, randomised, controlled NeoRes II trial.

BACKGROUND: The optimal time to surgery (TTS) after neoadjuvant chemoradiotherapy (nCRT) for oesophageal cancer is unknown and has traditionally been 4-6 weeks in clinical practice. Observational studies have suggested better outcomes, especially in terms of histological response, after prolonged delay of up to 3 months after nCRT. The NeoRes II trial is the first randomised trial to compare standard to prolonged TTS after nCRT for oesophageal cancer. PATIENTS AND METHODS: Patients with resectable, locally advanced oesophageal cancer were randomly assigned to standard delay of surgery of 4-6 weeks or prolonged delay of 10-12 weeks after nCRT. The primary endpoint was complete histological response of the primary tumour in patients with adenocarcinoma (AC). Secondary endpoints included histological tumour response, resection margins, overall and progression-free survival in all patients and stratified by histologic type. RESULTS: Between February 2015 and March 2019, 249 patients from 10 participating centres in Sweden, Norway and Germany were randomised: 125 to standard and 124 to prolonged TTS. There was no significant difference in complete histological response between AC patients allocated to standard (21%) compared to prolonged (26%) TTS (P = 0.429). Tumour regression, resection margins and number of resected lymph nodes, total and metastatic, did not differ between the allocated interventions. The first quartile overall survival in patients allocated to standard TTS was 26.5 months compared to 14.2 months after prolonged TTS (P = 0.003) and the overall risk of death during follow-up was 35% higher after prolonged delay (hazard ratio 1.35, 95% confidence interval 0.94-1.95, P = 0.107). CONCLUSION: Prolonged TTS did not improve histological complete response or other pathological endpoints, while there was a strong trend towards worse survival, suggesting caution in routinely delaying surgery for >6 weeks after nCRT.

The ISCON-trial protocol: laparoscopic ischemic conditioning prior to esophagectomy in patients with esophageal cancer and arterial calcifications.

BACKGROUND: Anastomotic leakage is the most important surgical complication following esophagectomy. A major cause of leakage is ischemia of the gastric tube that is used for reconstruction of the gastrointestinal tract. Generalized cardiovascular disease, expressed by calcifications of the aorta and celiac axis stenosis on a pre-operative CT scan, is associated with an increased risk of anastomotic leakage. Laparoscopic ischemic conditioning (ISCON) aims to redistribute blood flow and increase perfusion at the anastomotic site by occluding the left gastric, left gastroepiploic and short gastric arteries prior to esophagectomy. This study aims to assess the safety and feasibility of laparoscopic ISCON in selected patients with esophageal cancer and concomitant arterial calcifications. METHODS: In this prospective single-arm safety and feasibility trial based upon the IDEAL recommendations for surgical innovation, a total of 20 patients will be included recruited in 2 European high-volume centers for esophageal cancer surgery. Patients with resectable esophageal carcinoma (cT1-4a, N0-3, M0) with "major calcifications" of the thoracic aorta accordingly to the Uniform Calcification Score (UCS) or a stenosis of the celiac axis accordingly to the modified North American Symptomatic Carotid Endarterectomy Trial (NASCET) score on preoperative CT scan, who are planned to undergo esophagectomy are eligible for inclusion. The primary outcome variables are complications grade 2 and higher (Clavien-Dindo classification) occurring during or after laparoscopic ISCON and before esophagectomy. Secondary outcomes include intra- and postoperative complications of esophagectomy and the induction of angiogenesis by biomarkers of microcirculation and redistribution of blood flow by measurement of indocyanine green (ICG) fluorescence angiography. DISCUSSION: We hypothesize that in selected patients with impaired vascularization of the gastric tube, laparoscopic ISCON is feasible and can be safely performed 12-18 days prior to esophagectomy. Depending on the results, a randomized controlled trial will be needed to investigate whether ISCON leads to a lower percentage and less severe course of anastomotic leakage in selected patients. TRIAL REGISTRATION: Clinicaltrials.gov, NCT03896399 . Registered 4 January 2019.

Two-stage hybrid Ivor-Lewis esophagectomy as surgical strategy to reduce postoperative morbidity for high-risk patients.

BACKGROUND: Ivor-Lewis esophagectomy (ILE) is the standard surgical care for esophageal cancer patients but postoperative morbidity impairs quality of life and reduces long-term oncological outcome. Two-stage ILE separating the abdominal and thoracic phase into two distinct surgical procedures has proven to enhance microcirculation of the gastric conduit and therefore most likely reduces complications. However, two-stage ILE has not been evaluated systematically in selected groups of patients scheduled for this procedure. This investigation aims to demonstrate the feasibility of two-stage ILE in high-risk patients. PATIENTS AND METHODS: In this retrospective analysis of data obtained from a prospective database, a consecutive series of 275 hybrid ILE (hILE) were included. Patients were divided into two groups based on one- or two-stage hILE. Postoperative complications were assessed according to ECCG (Esophageal Complication Consensus Group) criteria and compared using the Clavien-Dindo score. Indication for two-stage esophagectomy was classified as pre- or intraoperative decision. RESULTS: 34 out of 275 patients (12.7%) underwent two-stage hILE. Patients of the two-stage group were significantly older. In 21 of 34 patients (61.8%) the decision for a two-stage procedure was made prior to esophagectomy, in 13 (38.2%) patients intraoperatively after completion of the laparoscopic gastric mobilization. The most frequent preoperative reason to select the two-stage procedure was a stenosis of the coeliac trunc and superior mesenteric artery (n = 10). The predominant cause for an intraoperative change of strategy was a laparoscopically diagnosed hepatic fibrosis/cirrhosis (n = 5).Overall morbidity and major' complications (CD > IIIa) were comparable for both groups (11.7% in both groups). The overall anastomotic leak rate was 12.4% and was non-significant lower for the two-stage procedure. CONCLUSION: Two-stage hILE is a feasible concept to individualize the surgical treatment of patients with well-defined clinical risk factors for postoperative morbidity. It can also be applied after completion of the abdominal phase of IL esophagectomy without compromising the patient safety.

Fit-for-Discharge Criteria after Esophagectomy: An International Expert Delphi Consensus.

There are no internationally recognized criteria available to determine preparedness for hospital discharge after esophagectomy. This study aims to achieve international consensus using Delphi methodology. The expert panel consisted of 40 esophageal surgeons spanning 16 countries and 4 continents. During a 3-round, web-based Delphi process, experts voted for discharge criteria using 5-point Likert scales. Data were analyzed using descriptive statistics. Consensus was reached if agreement was ≥75% in round 3. Consensus was achieved for the following basic criteria: nutritional requirements are met by oral intake of at least liquids with optional supplementary nutrition via jejunal feeding tube. The patient should have passed flatus and does not require oxygen during mobilization or at rest. Central venous catheters should be removed. Adequate analgesia at rest and during mobilization is achieved using both oral opioid and non-opioid analgesics. All vital signs should be normal unless abnormal preoperatively. Inflammatory parameters should be trending down and close to normal (leucocyte count ≤12G/l and C-reactive protein ≤80 mg/dl). This multinational Delphi survey represents the first expert-led process for consensus criteria to determine 'fit-for-discharge' status after esophagectomy. Results of this Delphi survey may be applied to clinical outcomes research as an objective measure of short-term recovery. Furthermore, standardized endpoints identified through this process may be used in clinical practice to guide decisions regarding patient discharge and may help to reduce the risk of premature discharge or prolonged admission.

Diagnostic criteria and symptom grading for delayed gastric conduit emptying after esophagectomy for cancer: international expert consensus based on a modified Delphi process.

Delayed gastric conduit emptying (DGCE) after esophagectomy for cancer is associated with adverse outcomes and troubling symptoms. Widely accepted diagnostic criteria and a symptom grading tool for DGCE are missing. This hampers the interpretation and comparison of studies. A modified Delphi process, using repeated web-based questionnaires, combined with live interim group discussions was conducted by 33 experts within the field, from Europe, North America, and Asia. DGCE was divided into early DGCE if present within 14 days of surgery and late if present later than 14 days after surgery. The final criteria for early DGCE, accepted by 25 of 27 (93%) experts, were as follows: >500 mL diurnal nasogastric tube output measured on the morning of postoperative day 5 or later or >100% increased gastric tube width on frontal chest x-ray projection together with the presence of an air-fluid level. The final criteria for late DGCE accepted by 89% of the experts were as follows: the patient should have 'quite a bit' or 'very much' of at least two of the following symptoms; early satiety/fullness, vomiting, nausea, regurgitation or inability to meet caloric need by oral intake and delayed contrast passage on upper gastrointestinal water-soluble contrast radiogram or on timed barium swallow. A symptom grading tool for late DGCE was constructed grading each symptom as: 'not at all', 'a little', 'quite a bit', or 'very much', generating 0, 1, 2, or 3 points, respectively. For the five symptoms retained in the diagnostic criteria for late DGCE, the minimum score would be 0, and the maximum score would be 15. The final symptom grading tool for late DGCE was accepted by 27 of 31 (87%) experts. For the first time, diagnostic criteria for early and late DGCE and a symptom grading tool for late DGCE are available, based on an international expert consensus process.

Endoscopic and histopathologic reflux-associated mucosal damage in the remnant esophagus following transthoracic esophagectomy for cancer-5-year long-term follow-up.

Gastroesophageal reflux is a common problem following esophagectomy and reconstruction with gastric interposition. Despite a routine prescription of proton pump inhibitors, reflux-associated mucosal damage in the remnant esophagus is frequently observed. Purpose of this study is to evaluate mucosal damage in the esophageal remnant during long-term follow-up and to compare the prevalence of this damage between the subgroups of esophageal squamous cell and adenocarcinoma. All patients undergoing transthoracic Ivor-Lewis esophagectomy were prospectively entered in our IRB approved database. All patients underwent a routine check-up program with yearly surveillance endoscopies following esophagectomy. Only patients with a complete follow-up were included into this study. Endoscopic and histopathologic mucosal changes of the remnant esophagus were analyzed in close intervals. A total of 50 patients met the inclusion criteria, consisting of 31 adenocarcinomas (AC) and 19 squamous cell carcinomas (SCC). Mucosal damage was already seen 1 year after surgery in 20 patients macroscopically (43%) and in 21 patients microscopically (45%). At 5-year follow-up the prevalence for macroscopic and microscopic damage was 55% and 60%, respectively. The prevalence of mucosal damage was higher in AC patients than in SCC patients (1y-FU: 51% [AC] vs. 28% [SCC]; 5y-FU: 68% [AC] vs. 35% [SCC], P < 0.05). Newly acquired Barrett's esophagus was seen in 10 patients (20%) with two of those patients (20%) showing histopathologic proof of neoplasia. This study shows a high prevalence of reflux-associated mucosal damage in the remnant esophagus one year out of surgery and only a moderate increase in prevalence in the following years. Mucosal damage was more frequently seen in AC patients and the occurrence of de-novo Barrett's esophagus and de-novo neoplasia was high. Endoscopic surveillance with targeted biopsies seems to be an indispensable tool to follow patients after esophagectomy appropriately.

Simultaneous laryngopharyngeal pH monitoring (Restech) and conventional esophageal pH monitoring-correlation using a large patient cohort of more than 100 patients with suspected gastroesophageal reflux disease.

24-hour esophageal pH-metry is not designed to detect laryngopharyngeal reflux (LPR). The new laryngopharyngeal pH-monitoring system (Restech) may detect LPR better. There is no established correlation between these two techniques as only small case series exist. The aim of this study is to examine the correlation between the two techniques with a large patient cohort. All patients received a complete diagnostic workup for gastroesophageal reflux including symptom evaluation, endoscopy, 24-hour pH-metry, high resolution manometry, and Restech. Consecutive patients with suspected gastroesophageal reflux and disease-related extra-esophageal symptoms were evaluated using 24-hour laryngopharyngeal and concomitant esophageal pH-monitoring. Subsequently, the relationship between the two techniques was evaluated subdividing the different reflux scenarios into four groups. A total of 101 patients from December 2013 to February 2017 were included. All patients presented extra-esophageal symptoms such as cough, hoarseness, asthma symptoms, and globus sensation. Classical reflux symptoms such as heartburn (71%), regurgitation (60%), retrosternal pain (54%), and dysphagia (32%) were also present. Esophageal 24-hour pH-metry was positive in 66 patients (65%) with a mean DeMeester Score of 66.7 [15-292]. Four different reflux scenarios were detected (group A-D): in 39% of patients with abnormal esophageal pH-metry, Restech evaluation was normal (group A, n = 26, mean DeMeester-score = 57.9 [15-255], mean Ryan score = 2.6 [2-8]). In 23% of patients with normal pH-metry (n = 8, group B), Restech evaluation was abnormal (mean DeMeester-score 10.5 [5-13], mean Ryan score 63.5 [27-84]). The remaining groups C and D showed corresponding results. Restech evaluation was positive in 48% of cases in this highly selective patient cohort. As demonstrated by four reflux scenarios, esophageal pH-metry and Restech do not necessarily need to correspond. Especially in patients with borderline abnormal 24-hour pH-metry, Restech may help to support the decision for or against laparoscopic anti-reflux surgery.

A structured training program for minimally invasive esophagectomy for esophageal cancer- a Delphi consensus study in Europe.

Evidence suggests that structured training programs for laparoscopic procedures can ensure a safe standard of skill acquisition prior to independent practice. Although minimally invasive esophagectomy (MIO) is technically demanding, no consensus on requirements for training for the MIO procedure exists. The aim of this study is to determine essential steps required for a structured training program in MIO using the Delphi consensus methodology. Eighteen MIO experts from 13 European hospitals were asked to participate in this study. The consensus process consisted of two structured meetings with the expert panel, and two Delphi questionnaire rounds. A list of items required for training MIO were constructed for three key domains of MIO, including (1) requisite criteria for units wishing to be trained and (2) to proctor MIO, and (3) a framework of a MIO training program. Items were rated by the experts on a scale 1-5, where 1 signified 'not important' and 5 represented 'very important.' Consensus for each domain was defined as achieving Cronbach alpha ≥0.70. Items were considered as fundamental when ≥75% of experts rated it important (4) or very important (5). Both Delphi rounds were completed by 16 (89%) of the 18 invited experts, with a median experience of 18 years with minimally invasive surgery. Consensus was achieved for all three key domains. Following two rounds of a 107-item questionnaire, 50 items were rated as essential for training MIO. A consensus among European MIO experts on essential items required for training MIO is presented. The identified items can serve as directive principles and core standards for creating a comprehensive training program for MIO.

Colonization with third-generation cephalosporin-resistant Enterobacteriaceae on hospital admission: prevalence and risk factors.

OBJECTIVES: The objectives of this study were to prospectively assess the rectal carriage rate of third-generation cephalosporin-resistant Enterobacteriaceae (3GCREB) in non-ICU patients on hospital admission and to investigate resistance mechanisms and risk factors for carriage. METHODS: Adult patients were screened for 3GCREB carriage at six German tertiary care hospitals in 2014 using rectal swabs or stool samples. 3GCREB isolates were characterized by phenotypic and molecular methods. Each patient answered a questionnaire about potential risk factors for colonization with MDR organisms (MDROs). Univariable and multivariable risk factor analyses were performed to identify factors associated with 3GCREB carriage. RESULTS: Of 4376 patients, 416 (9.5%) were 3GCREB carriers. Escherichia coli was the predominant species (79.1%). ESBLs of the CTX-M-1 group (67.3%) and the CTX-M-9 group (16.8%) were the most frequent ß-lactamases. Five patients (0.11%) were colonized with carbapenemase-producing Enterobacteriaceae. The following risk factors were significantly associated with 3GCREB colonization in the multivariable analysis (P < 0.05): centre; previous MDRO colonization (OR = 2.12); antibiotic use within the previous 6 months (OR = 2.09); travel outside Europe (OR = 2.24); stay in a long-term care facility (OR = 1.33); and treatment of gastroesophageal reflux disease (GERD) (OR = 1.22). CONCLUSIONS: To our knowledge, this is the largest admission prevalence study of 3GCREB in Europe. The observed prevalence of 9.5% 3GCREB carriage was higher than previously reported and differed significantly among centres. In addition to previously identified risk factors, the treatment of GERD proved to be an independent risk factor for 3GCREB colonization.

Management of Tracheo- or Bronchoesophageal Fistula After Ivor-Lewis Esophagectomy.

BACKGROUND: The development of tracheo- or bronchoesophageal fistula (TBF) after Ivor-Lewis esophagectomy remains to be a rare complication associated with a high mortality rate. METHODS: In this retrospective study, the charts of patients with TBF after esophagectomy were analyzed in terms of individual patient characteristics, esophagotracheal complications, respiratory function, management, and outcome. RESULTS: Between January 2000 and December 2014, 1204 patients underwent Ivor-Lewis esophagectomy for esophageal cancer; 13 patients (1.1 %) developed a TBF. In all 13 patients, a concomitant leakage of the intrathoracic esophagogastrostomy was evident, either prior to diagnosis of TBF (metachronous TBF) or simultaneously (synchronous TBF). TBF was predominantly located in the left main bronchus (n = 6, 46.1 %) or trachea (n = 5, 38.5 %). Management of TBF included re-thoracotomy (n = 7), interventional endoscopic (n = 10) or bronchoscopic therapy (n = 4). In the majority of patients (n = 8), management consisted of two subsequent treatment modalities. In 3 out of four patients, TBF was successfully treated by endoscopic stenting only. Five patients (38.5 %) died following a septic course with multiple organ failure. CONCLUSIONS: The development of TBF after Ivor-Lewis esophagectomy is always combined with anastomotic leakage of the esophagogastrostomy. Treatment options primarily depend on the vascularization of the gastric conduit, the severity of the concomitant aspiration pneumonia, and the volume of the air leakage.

[Perioperative management of transthoracic oesophagectomies : Fundamentals of interdisciplinary care and new approaches to accelerated recovery after surgery]. / Perioperatives Management der transthorakalen Ösophagektomie : Grundlagen der interdisziplinären Patientenversorgung und neue Konzepte zur beschleunigten postoperativen Erholung.

Locally advanced carcinomas of the oesophagus require multimodal treatment. The core element of curative therapy is transthoracic en bloc oesophagectomy, which is the standard procedure carried out in most specialized centres. Reconstruction of intestinal continuity is usually achieved with a gastric sleeve, which is anastomosed either intrathoracically or cervically to the remaining oesophagus. This thoraco-abdominal operation is associated with significant postoperative morbidity, not least because of a vast array of pre-existing illnesses in the surgical patient. For an optimal outcome, the careful interdisciplinary selection of patients, preoperative risk evaluation and conditioning are essential. The caseload of the centres correlates inversely with the complication rate. The leading surgical complication is anastomotic leakage, which is diagnosed endoscopically and usually treated with the aid of endoscopic procedures. Pulmonary infections are the most frequent non-surgical complication. Thoracic epidural anaesthesia and perfusion-orientated fluid management can reduce the rate of pulmonary complications. Patients are ventilated protecting the lungs and are extubated as early as possible. Oesophagectomies should only be performed in high-volume centres with the close cooperation of surgeons and anaesthesia/intensive care specialists. Programmes of enhanced recovery after surgery (ERAS) hold further potential for the patient's quicker postoperative recovery. In this review article the fundamental aspects of the interdisciplinary perioperative management of transthoracic oesophagectomy are described.

Preoperative airway colonization prior to transthoracic esophagectomy predicts postoperative pulmonary complications.

PURPOSE: Respiratory complications are responsible to a high degree for postoperative morbidity and mortality after Ivor-Lewis esophagectomy. The etiology of respiratory failure is known to be multifactorial with preoperative impaired lung function being the most important one. The aim of this study was to investigate the correlation between preoperative airway colonization (PAC) and postoperative respiratory complications. METHODS: In this observational study, 64 patients with esophageal cancer were included. All patients underwent Ivor-Lewis esophagectomy with laparoscopic or open gastric mobilization. After induction of anesthesia and intubation with a double-lumen tube, bronchial exudate was collected by random endoluminal suction for further microbiological work-up. Length of postoperative mechanical ventilation (<24 h, 24-72 h, >72 h), re-intubation, and tracheostomy were recorded as primary and secondary study endpoints. RESULTS: In 13 of 64 study patients (20.3 %), pathological colonization of the bronchial airways could be proved prior to esophagectomy. Haemophilus species was the most frequently identified pathogen. PAC was associated with a longer history of smoking (p = 0.025), a lower preoperative forced expiratory volume (FEV1, p = 0.009) or vital capacity (VC, p = 0.038), a prolonged postoperative mechanical ventilation (p < 0.001), and a higher frequency of re-intubation (p < 0.001) and tracheostomy (p = 0.017). In the multivariate analysis, PAC was identified as an independent predictor of respiratory failure (hazard ratio 11.4, 95 % confidence interval 2.6-54, p = 0.002). Mortality in the PAC group was 30.8 % compared to 0 % in patients without PAC (p < 0.0001). CONCLUSION: PAC is a significant risk factor for postoperative respiratory failure. A routine bronchoscopy and bronchoalveolar lavage as part of preoperative management prior to esophagectomy need to be discussed.

Management of upper intestinal leaks using an endoscopic vacuum-assisted closure system (E-VAC).

BACKGROUND: Esophageal perforations and postoperative leakage of esophagogastrostomy are considered to be life-threatening conditions due to the development of mediastinitis and consecutive sepsis. Vacuum-assisted closure (VAC), a well-established treatment method for superficial infected wounds, is based on a negative pressure applied to the wound via a vacuum-sealed sponge. Endoluminal VAC (E-VAC) therapy is a novel method, and experience with its esophageal application is limited. METHODS: This retrospective study summarizes the experience of a center with a high volume of upper gastrointestinal surgery using E-VAC therapy for patients with leakages of the esophagus. The study investigated 14 patients who had esophageal defects treated with E-VAC. Three patients had a spontaneous defect; two patients had an iatrogenic defect; and nine patients had a postoperative esophageal defect. RESULTS: The average duration of application was 12.1 days, and an average of 3.9 E-VAC systems were used. For 6 of the 14 patients, E-VAC therapy was combined with the placement of self-expanding metal stents. Complete restoration of the esophageal defect was achieved in 12 (86 %) of the 14 patients. Two patients died due to prolonged sepsis. CONCLUSION: This report demonstrates that E-VAC therapy adds an additional treatment option for partial esophageal wall defects. The combination of E-VAC treatment and endoscopic stenting is a successful novel procedure for achieving a high closure rate.

MicroRNA profiling in locally advanced esophageal cancer indicates a high potential of miR-192 in prediction of multimodality therapy response.

To identify possible predictive markers, our study aimed to characterize microRNA (miRNA) profiles of responder and nonresponder in the multimodality therapy of locally advanced esophageal cancer. Initially, a microarray-based approach was performed including eight patients with esophageal cancer. Patients received neoadjuvant chemoradiation followed by surgical resection. Major histopathological response was defined if resected specimens contained less than 10% vital tumor cells (major/minor response: 4/4 patients). Intratumoral RNA was isolated from both, pretherapeutic tissue biopsies in addition to corresponding surgical specimens. The profile of 768 miRNAs was analyzed in 16 specimens (preneoadjuvant and postneoadjuvant therapy). Selected miRNAs were than analyzed on pretherapeutic and post-therapeutic biopsies of 80 patients with esophageal cancer, who underwent multimodality therapy (major/minor response: 30/50 patients). Comprehensive miRNA profiling identified miRNAs in pretherapeutic biopsies that were significantly different between major/minor responders. Based on the microarray results, miR-192, miR-194 and miR-622 were selected and the dysregulated miRNAs were studied on an extended series of esophageal cancer patients. The expression of miR-192, miR-194 and miR-622 was significantly reduced after neoadjuvant therapy confirming the array profiling data. Importantly, the pretherapeutic intratumoral expression of miR-192 and miR-194 was significantly associated with the histopathologic response of esophageal squamous cell carcinoma to multimodal therapeutic treatment. Therefore, in patients with locally advanced esophageal cancer undergoing neoadjuvant chemoradiation followed by esophagectomy, miR-192 and miR-194 in pretherapeutic biopsies are considered as indicators of major histopathologic regression.

Vascular endothelial growth factor expression following ischemic conditioning of the gastric conduit.

The partial devascularization of the stomach, necessary for esophageal reconstruction with a gastric conduit, impairs microcirculation in the anastomotic region of the gastric fundus. Ischemic conditioning of the gastric tube is considered as a possible approach to improve microcirculation in the gastric mucosa. The aim of this study was to investigate whether ischemic conditioning induces neo-angiogenesis in the gastric fundus by expression of vascular endothelial growth factor (VEGF). Twenty patients with an esophageal carcinoma scheduled for esophagectomy and gastric reconstruction were included. To compare VEGF expression before and after ischemic conditioning, preoperative endoscopic biopsies were taken from the gastric fundus. The surgical procedure consisted of two separate steps, the complete gastric mobilization including partial devascularization of the stomach and after a delay of 4-5 days high transthoracic esophagectomy with intrathoracic gastric reconstruction (Ivor-Lewis procedure). The second tissue sample was obtained from the donut of the stapled esophagogastrostomy. For further work-up, preoperative biopsies and the gastric donuts were fixed in liquid nitrogen. Preoperative and intraoperative VEGF expression was measured by quantitative real-time reverse transcription-polymerase chain reaction (VEGF×100/ß-actin) and results were compared using Wilcoxon test for paired samples. In all 40 specimens, a distinct expression of VEGF could be detected. Comparing the level of VEGF expression of the preoperative biopsies and postoperative tissue sample, no significant difference could be demonstrated following ischemic conditioning. In this model of ischemic conditioning with delayed reconstruction of 4-5 days, no induction of neo-angiogenesis could be demonstrated by measurement of VEGF expression.

[How safe is sedation in gastrointestinal endoscopy? A multicentre analysis of 388,404 endoscopies and analysis of data from prospective registries of complications managed by members of the Working Group of Leading Hospital Gastroenterologists (ALGK)]. / Wie sicher ist die Sedierung in der gastrointestinalen Endoskopie? Eine multizentrische Auswertung von 388 404 Endoskopien und Auswertung der Daten aus prospektiv geführten Komplikationsregistern von Mitgliedern der Arbeitsgemeinschaft leitender Gastroenterologen im Krankenhaus (ALGK).

BACKGROUND: Gastrointestinal endoscopies are increasingly being carried out with sedation. All of the drugs used for sedation are associated with a certain risk of complications. Data currently available on sedation-associated morbidity and mortality rates are limited and in most cases have substantial methodological limitations. The aim of this study was to record severe sedation-associated complications in a large number of gastrointestinal endoscopies. METHODS: Data on severe sedation-associated complications were collected on a multicentre basis from prospectively recorded registries of complications in the participating hospitals (median documentation period 27 months, range 9 - 129 months). RESULTS: Data for 388,404 endoscopies from 15 departments were included in the study. Severe sedation-associated complications occurred in 57 patients (0.01 %). Forty-one percent of the complications and 50 % of all complications with a fatal outcome (10/20 patients) occurred during emergency endoscopies. In addition, it was found that 95 % of the complications and 100 % of all fatal complications affected patients in ASA class ≥ 3. CONCLUSIONS: Including nearly 400,000 endoscopies, this study represents the largest prospective, multicenter record of the complications of sedation worldwide. The analysis shows that sedation is carried out safely in gastrointestinal endoscopy. The morbidity and mortality rates are much lower than previously reported in the literature in similar groups of patients. Risk factors for the occurrence of serious complications include emergency examinations and patients in ASA class ≥ 3.

Laparoscopic ischemic conditioning of the stomach prior to esophagectomy induces gastric neo-angiogenesis.

BACKGROUND: The risk of an anastomotic leakage (AL) following Ivor-Lewis esophagectomy is increased in patients with calcifications of the aorta or a stenosis of the celiac trunc. Ischemic conditioning (ISCON) of the gastric conduit prior to esophagectomy is supposed to improve gastric vascularization at the anastomotic site. The prospective ISCON trial was conducted to proof the safety and feasibility of this strategy with partial gastric devascularization 14 days before esophagectomy in esophageal cancer patients with a compromised vascular status. This work reports the results from a translational project of the ISCON trial aimed to investigate variables of neo-angiogenesis. METHODS: Twenty esophageal cancer patients scheduled for esophagectomy were included in the ISCON trial. Serum samples (n = 11) were collected for measurement of biomarkers and biopsies (n = 12) of the gastric fundus were taken before and after ISCON of the gastric conduit. Serum samples were analyzed including 62 different cytokines. Vascularization of the gastric mucosa was assessed on paraffin-embedded sections stained against CD34 to detect the degree of microvascular density and vessel size. RESULTS: Between November 2019 and January 2022 patients were included in the ISCON Trial. While serum samples showed no differences regarding cytokine levels before and after ISCON biopsies of the gastric mucosa demonstrated a significant increase in microvascular density after ISCON as compared to the corresponding gastric sample before the intervention. CONCLUSION: The data prove that ISCON of the gastric conduit as esophageal substitute induces significant neo-angiogenesis in the gastric fundus which is considered as surrogate of an improved vascularization at the anastomotic site.

Evaluation of histological regression grading systems in the neoadjuvant therapy of rectal cancer: do they have prognostic impact?

PURPOSE: Neoadjuvant treatment options have been developed to improve survival of patients with locally advanced rectal cancer. As only patients with a major histopatholocial response benefit from this preoperative therapy, several tumor regression grading systems have been developed. However, currently no accepted comprehensive grading system for clinical use is available. Therefore, we studied the impact of four histological regression grading systems in the neoadjuvant therapy of rectal cancer. METHODS: In this retrospective study, 85 patients with locally advanced rectal cancer were included. All patients received a neoadjuvant radiochemotherapy followed by surgical resection. The histological regression grading was evaluated using four classification systems: (1) grading system by the Japanese society of colorectal cancer, (2) grading system by Junker-Müller, (3) grading system by Dworak, (4) Cologne grading system. The four classification systems were analyzed for their prognostic impact. RESULTS: The following significant correlations were detected between the four classification systems and the ypTNM categories: (1) patients with a ypT3/4 category had significantly more often a worse histopathologic response in all four grading systems (p = 0.001); (2) a ypN0 category was significantly correlated with good histopathologic response only in the Cologne grading system; (3) in the Junker-Müller and Dworak grading systems, a ypM0 category was significantly correlated with a good histopathologic response (p = 0.046; p = 0.03). However, none of the used classification systems had a prognostic impact on survival. CONCLUSIONS: Currently, none of the analyzed histological regression grading systems is effective for clinical use.

A genome-wide association study for quantitative trait loci of show-jumping in Hanoverian warmblood horses.

Show-jumping is an economically important breeding goal in Hanoverian warmblood horses. The aim of this study was a genome-wide association study (GWAS) for quantitative trait loci (QTL) for show-jumping in Hanoverian warmblood horses, employing the Illumina equine SNP50 Beadchip. For our analyses, we genotyped 115 stallions of the National State stud of Lower Saxony. The show-jumping talent of a horse includes style and ability in free-jumping. To control spurious associations based on population stratification, two different mixed linear animal model (MLM) approaches were employed, besides linear models with fixed effects only and adaptive permutations for correcting multiple testing. Population stratification was explained best in the MLM considering Hanoverian, Thoroughbred, Trakehner and Holsteiner genes and the marker identity-by-state relationship matrix. We identified six QTL for show-jumping on horse chromosomes (ECA) 1, 8, 9 and 26 (-log(10) P-value >5) and further putative QTL with -log(10) P-values of 3-5 on ECA1, 3, 11, 17 and 21. Within six QTL regions, we identified human performance-related genes including PAPSS2 on ECA1, MYL2 on ECA8, TRHR on ECA9 and GABPA on ECA26 and within the putative QTL regions NRAP on ECA1, and TBX4 on ECA11. The results of our GWAS suggest that genes involved in muscle structure, development and metabolism are crucial for elite show-jumping performance. Further studies are required to validate these QTL in larger data sets and further horse populations.

[Surgical education has its price]. / Die chirurgische Weiterbildung hat ihren Preis.

The radical economisation of the German health-care system has caused an increasing cost awareness. Following this trend, medical education has been identified as a possible expense factor. The theoretical and practical training of young doctors needs time and costs money. However, a detailed cost analysis is still not available, since the complex daily work schedule of young professionals only allows the calculation of single cost factors. Investigations in the USA estimate the costs of surgical training at US$ 80 000 per year and per resident. At present in Germany, surgical training is indirectly financed by the DRG flat rates of the health insurance companies. Possible alternatives include the implementation of a "training fond" which is financed by a percentage fee of the DRG's as well as an on-top funding by the federal government. This "training fond" would support only those surgical units that offer a structured and certified training to surgical residents. However, a systematic cost analysis of such a structured curriculum is necessary for any further discussion.