An international Delphi consensus for surgical quality assessment of lymphadenectomy and anastomosis in minimally invasive total gastrectomy for gastric cancer.

BACKGROUND: Minimally invasive total gastrectomy (MITG) is a mainstay for curative treatment of patients with gastric cancer. To define and standardize optimal surgical techniques and further improve clinical outcomes through the enhanced MITG surgical quality, there must be consensus on the key technical steps of lymphadenectomy and anastomosis creation, which is currently lacking. This study aimed to determine an expert consensus from an international panel regarding the technical aspects of the performance of MITG for oncological indications using the Delphi method. METHODS: A 100-point scoping survey was created based on the deconstruction of MITG into its key technical steps through local and international expert opinion and literature evidence. An international expert panel comprising upper gastrointestinal and general surgeons participated in multiple rounds of a Delphi consensus. The panelists voted on the issues concerning importance, difficulty, or agreement using an online questionnaire. A priori consensus standard was set at > 80% for agreement to a statement. Internal consistency and reliability were evaluated using Cronbach's α. RESULTS: Thirty expert upper gastrointestinal and general surgeons participated in three online Delphi rounds, generating a final consensus of 41 statements regarding MITG for gastric cancer. The consensus was gained from 22, 12, and 7 questions from Delphi rounds 1, 2, and 3, which were rephrased into the 41 statetments respectively. For lymphadenectomy and aspects of anastomosis creation, Cronbach's α for round 1 was 0.896 and 0.886, and for round 2 was 0.848 and 0.779, regarding difficulty or importance. CONCLUSIONS: The Delphi consensus defined 41 steps as crucial for performing a high-quality MITG for oncological indications based on the standards of an international panel. The results of this consensus provide a platform for creating and validating surgical quality assessment tools designed to improve clinical outcomes and standardize surgical quality in MITG.

Combining Solid and Liquid Biopsy for Therapy Monitoring in Esophageal Cancer.

Esophageal cancer (EC) has one of the highest mortality rates among cancers, making it imperative that therapies are optimized and dynamically adapted to individuals. In this regard, liquid biopsy is an increasingly important method for residual disease monitoring. However, conflicting detection rates (14% versus 60%) and varying cell-free circulating tumor DNA (ctDNA) levels (0.07% versus 0.5%) have been observed in previous studies. Here, we aim to resolve this discrepancy. For 19 EC patients, a complete set of cell-free DNA (cfDNA), formalin-fixed paraffin-embedded tumor tissue (TT) DNA and leukocyte DNA was sequenced (139 libraries). cfDNA was examined in biological duplicates and/or longitudinally, and TT DNA was examined in technical duplicates. In baseline cfDNA, mutations were detected in 12 out of 19 patients (63%); the median ctDNA level was 0.4%. Longitudinal ctDNA changes were consistent with clinical presentation. Considerable mutational diversity was observed in TT, with fewer mutations in cfDNA. The most recurrently mutated genes in TT were TP53, SMAD4, TSHZ3, and SETBP1, with SETBP1 being reported for the first time. ctDNA in blood can be used for therapy monitoring of EC patients. However, a combination of solid and liquid samples should be used to help guide individualized EC therapy.

[Video-assisted Double-lumen Tubes in Robot-assisted Oesophageal Surgery]. / Videogestützte Doppellumentuben in der roboterassistierten Ösophaguschirurgie.

Robot-assisted esophagectomies are still considered high-risk procedures requiring complex surgical and anesthesiological planning and coordination. The operative space during the thoracic operative part is created by one-lung ventilation. Due to special patient positioning and intraoperative repositioning maneuvers, however, access to patient airway or double-lumen tube manipulation, if necessary, is only possible to a certain extent. In this work, we present our experiences establishing a video-guided double-lumen tube for esophageal surgery. From our point of view, the use of video-guided double-lumen tubes is very suitable increasing patient safety and coordination in the operational team during esophagectomy.

Hybrid laparoscopic versus fully robot-assisted minimally invasive esophagectomy: an international propensity-score matched analysis of perioperative outcome.

BACKGROUND: Currently, little is known regarding the optimal technique for the abdominal phase of RAMIE. The aim of this study was to investigate the outcome of robot-assisted minimally invasive esophagectomy (RAMIE) in both the abdominal and thoracic phase (full RAMIE) compared to laparoscopy during the abdominal phase (hybrid laparoscopic RAMIE). METHODS: This retrospective propensity-score matched analysis of the International Upper Gastrointestinal International Robotic Association (UGIRA) database included 807 RAMIE procedures with intrathoracic anastomosis between 2017 and 2021 from 23 centers. RESULTS: After propensity-score matching, 296 hybrid laparoscopic RAMIE patients were compared to 296 full RAMIE patients. Both groups were equal regarding intraoperative blood loss (median 200 ml versus 197 ml, p = 0.6967), operational time (mean 430.3 min versus 417.7 min, p = 0.1032), conversion rate during abdominal phase (2.4% versus 1.7%, p = 0.560), radical resection (R0) rate (95.6% versus 96.3%, p = 0.8526) and total lymph node yield (mean 30.4 versus 29.5, p = 0.3834). The hybrid laparoscopic RAMIE group showed higher rates of anastomotic leakage (28.0% versus 16.6%, p = 0.001) and Clavien Dindo grade 3a or higher (45.3% versus 26.0%, p < 0.001). The length of stay on intensive care unit (median 3 days versus 2 days, p = 0.0005) and in-hospital (median 15 days versus 12 days, p < 0.0001) were longer for the hybrid laparoscopic RAMIE group. CONCLUSIONS: Hybrid laparoscopic RAMIE and full RAMIE were oncologically equivalent with a potential decrease of postoperative complications and shorter (intensive care) stay after full RAMIE.

[Robots in visceral and thoracic surgery-Quo vadis?] / Roboter in der Viszeral- und Thoraxchirurgie ­ quo vadis?

Robotic surgical systems are now an inherent part of the German hospital landscape. In recent years, there has been an enormous increase in installed systems and operations performed, especially in abdominal surgery. Even though there is a lack of studies with the highest grade of evidence, the advantages of the technique are obvious-particularly technically demanding operations can now be performed safely and less invasively for patients. Robotics are now being implemented in many non-university institutions. At the Israelite Hospital (Israelitisches Krankenhaus) Hamburg it could be demonstrated that with systematic and modular training, i.e. execution of certain surgical steps, it is possible to significantly flatten the learning curve while maintaining excellent oncological quality, postoperative morbidity and mortality. The costs to have a system up and running are the main limitations for the implementation of robotic surgery. The acquisition, material and maintenance costs are substantial so that the type of intervention and the training of prospective surgeons are limited by the costs. The robotic approach will fully unroll its disruptive character compared to laparoscopy once it is competitive not only qualitatively in the field of medical contents but also economically. In the future the ROBIN working group of the German Society for General and Visceral Surgery (DGAV) wants to create the basic prerequisites for valid studies by working with registers and could act as an independent central intermediary between hospitals and the industry to promote practical innovations and systematic training for surgeons.

C-Reactive Protein as Predictor for Infectious Complications after Robotic and Open Esophagectomies.

INTRODUCTION: The value of C-reactive protein (CRP) as a predictor of anastomotic leakage (AL) after esophagectomy has been addressed by numerous studies. Despite its increasing application, robotic esophagectomy (RAMIE) has not been considered separately yet in this context. We, therefore, aimed to evaluate the predictive value of CRP in RAMIE. MATERIAL AND METHODS: Patients undergoing RAMIE or completely open esophagectomy (OE) at our University Center were included. Clinical data, CRP- and Procalcitonin (PCT)-values were retrieved from a prospectively maintained database and evaluated for their predictive value for subsequent postoperative infectious complications (PIC) (AL, gastric conduit leakage or necrosis, pneumonia, empyema). RESULTS: Three hundred and five patients (RAMIE: 160, OE: 145) were analyzed. PIC were noted in 91 patients on postoperative day (POD) 10 and 123 patients on POD 30, respectively. Median POD of diagnosis of PIC was POD 8. Post-operative CRP-values in the robotic-group peaked one and two days later, respectively, and converged from POD 5 onward compared to the open-group. In the group with PIC, CRP-levels in the robotic-group were initially lower and started to differ significantly from POD 3 onward. In the open-group, increases were already noticed from POD 3 on. Procalcitonin levels did not differ. Best Receiver operating curve (ROC)-results were on POD 4, highest negative predictive values at POD 5 (RAMIE) and POD 4 (OE) with cut-off values of 70 mg/L and 88.3 mg/L, respectively. CONCLUSION: Post-operative CRP is a good negative predictor for PIC, after both RAMIE and OE. After RAMIE, CRP peaks later with a lower cut-off value.

The Role of ICG in Robot-Assisted Liver Resections.

Introduction: Robotic-assisted liver surgery (RALS) with its known limitations is gaining more importance. The fluorescent dye, indocyanine green (ICG), is a way to overcome some of these limitations. It accumulates in or around hepatic masses. The integrated near-infrared cameras help to visualize this accumulation. We aimed to compare the influence of ICG staining on the surgical and oncological outcomes in patients undergoing RALS. Material and Methods: Patients who underwent RALS between 2014 and 2021 at the Department of General Surgery at the University Hospital Schleswig-Holstein, Campus Kiel, were included. In 2019, ICG-supported RALS was introduced. Results: Fifty-four patients were included, with twenty-eight patients (50.9%) receiving preoperative ICG. Hepatocellular carcinoma (32.1%) was the main entity resected, followed by the metastasis of colorectal cancers (17%) and focal nodular hyperplasia (15.1%). ICG staining worked for different tumor entities, but diffuse staining was noted in patients with liver cirrhosis. However, ICG-supported RALS lasted shorter (142.7 ± 61.8 min vs. 246.4 ± 98.6 min, p < 0.001), tumors resected in the ICG cohort were significantly smaller (27.1 ± 25.0 mm vs. 47.6 ± 35.2 mm, p = 0.021) and more R0 resections were achieved by ICG-supported RALS (96.3% vs. 80.8%, p = 0.075). Conclusions: ICG-supported RALS achieve surgically and oncologically safe results, while overcoming the limitations of RALS.

Robotic-assisted minimally invasive Ivor Lewis esophagectomy within the prospective multicenter German da Vinci Xi registry trial.

PURPOSE: Robotic-assisted minimally invasive esophagectomy (RAMIE) has become one standard approach for the operative treatment of esophageal tumors at specialized centers. Here, we report the results of a prospective multicenter registry for standardized RAMIE. METHODS: The German da Vinci Xi registry trial included all consecutive patients who underwent RAMIE at five tertiary university centers between Oct 17, 2017, and Jun 5, 2020. RAMIE was performed according to a standard technique using an intrathoracic circular stapled esophagogastrostomy. RESULTS: A total of 220 patients were included. The median age was 64 years. Total minimally invasive RAMIE was accomplished in 85.9%; hybrid resection with robotic-assisted thoracic approach was accomplished in an additional 11.4%. A circular stapler size of ≥28 mm was used in 84%, and the median blood loss and operative time were 200 (IQR: 80-400) ml and 425 (IQR: 335-527) min, respectively. The rate of anastomotic leakage was 13.2% (n=29), whereas the two centers with >70 cases each had rates of 7.0% and 12.0%. Pneumonia occurred in 19.5% of patients, and the 90-day mortality was 3.6%. Cumulative sum analysis of the operative time indicated the end of the learning curve after 22 cases. CONCLUSIONS: High-quality multicenter registry data confirm that RAMIE is a safe procedure and can be reproduced with acceptable leak rates in a multicenter setting. The learning curve is comparably low for experienced robotic surgeons.

Eso-Sponge® for anastomotic leakage after oesophageal resection or perforation: outcomes from a national, prospective multicentre registry.

BACKGROUND: Anastomotic leakage (AL) after oesophagectomy and oesophageal perforations are associated with significant morbidity and mortality. Minimally invasive endoscopy is often used as first-line treatment, particularly endoluminal vacuum therapy (EVT). The aim was to assess the performance of the first commercially available endoluminal vacuum device (Eso-Sponge®) in the management of AL and perforation of the upper gastrointestinal tract (GIT). METHODS: The Eso-Sponge® registry was designed in 2014 as a prospective, observational, national, multicentre registry. Patients were recruited with either AL or perforation within the upper GIT. Data were collected with a standardized form and transferred into a web-based platform. Twenty hospitals were enrolled at the beginning of the study (registration number NCT02662777; http://www.clinicaltrials.gov). The primary endpoint was successful closure of the oesophageal defect. RESULTS: Eleven out of 20 centres recruited patients. A total of 102 patients were included in this interim analysis; 69 patients with AL and 33 with a perforation were treated by EVT. In the AL group, a closure of 91 per cent was observed and 76 per cent was observed in the perforation group. The occurrence of mediastinitis (P = 0.002) and the location of the defect (P = 0.008) were identified as significant predictors of defect closure. CONCLUSIONS: The Eso-Sponge® registry offers the opportunity to collate data on EVT with a uniform, commercially available product to improve standardization. Our data show that EVT with the Eso-Sponge® is an option for the management of AL and perforation within the upper GIT.

Detection of Circulating and Disseminated Tumor Cells and Their Prognostic Value under the Influence of Neoadjuvant Therapy in Esophageal Cancer Patients.

Detection of circulating (CTC) or disseminated tumor cells (DTC) are correlated with negative prognosis in esophageal cancer (EC) patients. In this study, DTC- and CTC-associated markers CK20 and DEFA5 were determined by RT-PCR in EC patients and correlated with clinical parameters to determine their prognostic impact. The blood and bone marrow (BM) of 216 EC patients after tumor resection with or without neoadjuvant therapy and as control blood samples from 38 healthy donors and BM from 24 patients with non-malignant diseases were analyzed. Both markers were detected in blood and BM of EC patients and the control cohort. A cut-off value was determined to define marker positivity for correlation with clinical data. CK20 expression was detected in 47/206 blood samples and in 49/147 BM samples of EC patients. DEFA5 positivity was determined in 96/206 blood samples and 98/147 BM samples, not correlating with overall survival (OS). However, CK20 positivity in BM and DEFA5 negativity in blood were associated with reduced OS in EC patients without neoadjuvant therapy, while in patients with neoadjuvant therapy DEFA5 positivity in BM was associated with improved OS. Overall, our study suggests DEFA5 as a prognostic biomarker in liquid biopsies of EC patients which requires further validation.

Robotic infant surgery with 3 mm instruments: a study in piglets of less than 10 kg body weight.

No data exist concerning the appication of a new robotic system with 3 mm instruments (Senhance®, Transenterix) in infants and small children. Therefore, the aim of this study was to test the system for its feasibility, performance and safety of robotic pediatric abdominal and thoracic surgery in piglets simulating infants with a body weight lower than 10 kg. 34 procedures (from explorative laparoscopy to thoracoscopic esophageal repair) were performed in 12 piglets with a median age of 23 (interquartile range: 12-28) days and a median body weight of 6.9 (6.1-7.3) kg. The Senhance® robotic system was used with 3 mm instruments, a 10 mm 3D 0° or 30° videoscope and advanced energy devices, the setup consisted of the master console and three separate arms. The amount, size, and position of the applied ports, their distance as well as the distance between the three operator arms of the robot, external and internal collisions, and complications of the procedures were recorded and analyzed. We were able to perform all planned surgical procedures with 3 mm robotic instruments in piglets with a median body weight of less than 7 kg. We encountered two non-robot associated complications (bleeding from the inferior caval and hepatic vein) which led to termination of the live procedures. Technical limitations were the reaction time and speed of robotic camera movement with eye tracking, the excessive bending of the 3 mm instruments and intermittent need of re-calibration of the fulcrum point. Robotic newborn and infant surgery appears technically feasible with the Senhance® system. Software adjustments for camera movement and sensitivity of the fulcrum point calibration algorithm to adjust for the increased compliance of the abdominal wall of infants, therefore reducing the bending of the instruments, need to be implemented by the manufacturer as a result of our study. To further evaluate the Senhance® system, prospective trials comparing it to open, laparoscopic and other robotic systems are needed.

Robotic-assisted minimally invasive esophagectomy (RAMIE) for esophageal cancer training curriculum-a worldwide Delphi consensus study.

BACKGROUND: Structured training protocols can safely improve skills prior initiating complex surgical procedures such as robotic-assisted minimally invasive esophagectomy (RAMIE). As no consensus on a training curriculum for RAMIE has been established so far it is our aim to define a protocol for RAMIE with the Delphi consensus methodology. METHODS: Fourteen worldwide RAMIE experts were defined and were enrolled in this Delphi consensus project. An expert panel was created and three Delphi rounds were performed starting December 2019. Items required for RAMIE included, but were not limited to, virtual reality simulation, wet-lab training, proctoring, and continued monitoring and education. After rating performed by the experts, consensus was defined when a Cronbach alpha of ≥0.80 was reached. If ≥80% of the committee reached a consensus an item was seen as fundamental. RESULTS: All Delphi rounds were completed by 12-14 (86-100%) participants. After three rounds analyzing our 49-item questionnaire, 40 items reached consensus for a training curriculum of RAMIE. CONCLUSION: The core principles for RAMIE training were defined. This curriculum may lead to a wider adoption of RAMIE and a reduction in time to reach proficiency.

Worldwide Techniques and Outcomes in Robot-assisted Minimally Invasive Esophagectomy (RAMIE): Results From the Multicenter International Registry.

OBJECTIVE: This international multicenter study by the Upper GI International Robotic Association aimed to gain insight in current techniques and outcomes of RAMIE worldwide. BACKGROUND: Current evidence for RAMIE originates from single-center studies, which may not be generalizable to the international multicenter experience. METHODS: Twenty centers from Europe, Asia, North-America, and South-America participated from 2016 to 2019. Main endpoints included the surgical techniques, clinical outcomes, and early oncological results of ramie. RESULTS: A total of 856 patients undergoing transthoracic RAMIE were included. Robotic surgery was applied for both the thoracic and abdominal phase (45%), only the thoracic phase (49%), or only the abdominal phase (6%). In most cases, the mediastinal lymphadenectomy included the low paraesophageal nodes (n=815, 95%), subcarinal nodes (n = 774, 90%), and paratracheal nodes (n = 537, 63%). When paratracheal lymphadenectomy was performed during an Ivor Lewis or a McKeown RAMIE procedure, recurrent laryngeal nerve injury occurred in 3% and 11% of patients, respectively. Circular stapled (52%), hand-sewn (30%), and linear stapled (18%) anastomotic techniques were used. In Ivor Lewis RAMIE, robot-assisted hand-sewing showed the highest anastomotic leakage rate (33%), while lower rates were observed with circular stapling (17%) and linear stapling (15%). In McKeown RAMIE, a hand-sewn anastomotic technique showed the highest leakage rate (27%), followed by linear stapling (18%) and circular stapling (6%). CONCLUSION: This study is the first to provide an overview of the current techniques and outcomes of transthoracic RAMIE worldwide. Although these results indicate high quality of the procedure, the optimal approach should be further defined.

Inhibition of ADAM17 impairs endothelial cell necroptosis and blocks metastasis.

Metastasis is the major cause of death in cancer patients. Circulating tumor cells need to migrate through the endothelial layer of blood vessels to escape the hostile circulation and establish metastases at distant organ sites. Here, we identified the membrane-bound metalloprotease ADAM17 on endothelial cells as a key driver of metastasis. We show that TNFR1-dependent tumor cell-induced endothelial cell death, tumor cell extravasation, and subsequent metastatic seeding is dependent on the activity of endothelial ADAM17. Moreover, we reveal that ADAM17-mediated TNFR1 ectodomain shedding and subsequent processing by the γ-secretase complex is required for the induction of TNF-induced necroptosis. Consequently, genetic ablation of ADAM17 in endothelial cells as well as short-term pharmacological inhibition of ADAM17 prevents long-term metastases formation in the lung. Thus, our data identified ADAM17 as a novel essential regulator of necroptosis and as a new promising target for antimetastatic and advanced-stage cancer therapies.

CD95L Inhibition Impacts Gemcitabine-Mediated Effects and Non-Apoptotic Signaling of TNF-α and TRAIL in Pancreatic Tumor Cells.

Despite the potential apoptotic functions, the CD95/CD95L system can stimulate survival as well as pro-inflammatory signaling, particularly through the activation of NFκB. This holds true for the TNF/TNFR and the TRAIL/TRAILR systems. Thus, signaling pathways of these three death ligands converge, yet the specific impact of the CD95/CD95L system in this crosstalk has not been well studied. In this study, we show that gemcitabine stimulates the expression of pro-inflammatory cytokines, such as IL6 and IL8, under the influence of the CD95/CD95L system and the pharmacological inhibitor, sCD95Fc, substantially reduced the expression in two PDAC cell lines, PancTuI-luc and A818-4. The stem cell phenotype was reduced when induced upon gemcitabine as well by sCD95Fc. Moreover, TNF-α as well as TRAIL up-regulate the expression of CD95 and CD95L in both cell lines. Conversely, we detected a significant inhibitory effect of sCD95Fc on the expression of both IL8 and IL6 induced upon TNF-α and TRAIL stimulation. In vivo, CD95L inhibition reduced xeno-transplanted recurrent PDAC growth. Thus, our findings indicate that inhibition of CD95 signaling altered the chemotherapeutic effects of gemcitabine, not only by suppressing the pro-inflammatory responses that arose from the CD95L-positive tumor cells but also from the TNF-α and TRAIL signaling in a bi-lateral crosstalk manner.

Multiscale heterogeneity in gastric adenocarcinoma evolution is an obstacle to precision medicine.

BACKGROUND: Cancer is a somatic evolutionary disease and adenocarcinomas of the stomach and gastroesophageal junction (GC) may serve as a two-dimensional model of cancer expansion, in which tumor subclones are not evenly mixed during tumor progression but rather spatially separated and diversified. We hypothesize that precision medicine efforts are compromised when clinical decisions are based on a single-sample analysis, which ignores the mechanisms of cancer evolution and resulting intratumoral heterogeneity. Using multiregional whole-exome sequencing, we investigated the effect of somatic evolution on intratumoral heterogeneity aiming to shed light on the evolutionary biology of GC. METHODS: The study comprised a prospective discovery cohort of 9 and a validation cohort of 463 GCs. Multiregional whole-exome sequencing was performed using samples form 45 primary tumors and 3 lymph node metastases (range 3-10 tumor samples/patient) of the discovery cohort. RESULTS: In total, the discovery cohort harbored 16,537 non-synonymous mutations. Intratumoral heterogeneity of somatic mutations and copy number variants were present in all tumors of the discovery cohort. Of the non-synonymous mutations, 53-91% were not present in each patient's sample; 399 genes harbored 2-4 different non-synonymous mutations in the same patient; 175 genes showed copy number variations, the majority being heterogeneous, including CD274 (PD-L1). Multi-sample tree-based analyses provided evidence for branched evolution being most complex in a microsatellite instable GC. The analysis of the mode of evolution showed a high degree of heterogeneity in deviation from neutrality within each tumor. We found evidence of parallel evolution and evolutionary trajectories: different mutations of SMAD4 aligned with different subclones and were found only in TP53 mutant GCs. CONCLUSIONS: Neutral and non-neutral somatic evolution shape the mutational landscape in GC along its lateral expansions. It leads to complex spatial intratumoral heterogeneity, where lymph node metastases may stem from different areas of the primary tumor, synchronously. Our findings may have profound effects on future patient management. They illustrate the risk of mis-interpreting tumor genetics based on single-sample analysis and open new avenues for an evolutionary classification of GC, i.e., the discovery of distinct evolutionary trajectories which can be utilized for precision medicine.

Defining benchmarks for robotic-assisted low anterior rectum resection in low-morbid patients: a multicenter analysis.

PURPOSE: To define the best possible outcomes for robotic-assisted low anterior rectum resection (RLAR) using total mesorectal excision (TME) in low-morbid patients, performed by expert robotic surgeons in German robotic centers. The benchmark values were derived from these results. METHODS: The data was retrospectively collected from five German expert centers. After patient exclusion (prior surgery, extended surgery, no prior anastomosis, hand-sewn anastomosis), the benchmark cohort was defined (n = 226). The median with interquartile range was first calculated for the individual centers. The 75th percentile of the median results was defined as the benchmark cutoff and represents the "perfect" achievable outcome. This applied to all benchmark values apart from lymph node yield, where the cutoff was defined as the 25th percentile (more lymph nodes are better). RESULTS: The benchmark values for conversion and intraoperative complication rates were ≤ 4.0% and ≤ 1.4%, respectively. For postoperative complications, the benchmark was ≤ 28% for "any" and ≤ 18.0% for major complications. The R0 and complete TME rate benchmarks were both 100%, with a lymph node yield of > 18. The benchmark for rate of anastomotic insufficiency was < 12.5% and 90-day mortality was 0%. Readmission rates should not exceed 4%. CONCLUSION: This outcome analysis of patients with low comorbidity undergoing RLAR may serve as a reference to evaluate surgical performance in robotic rectum resection.

Multicenter Experience in Robot-Assisted Minimally Invasive Esophagectomy - a Comparison of Hybrid and Totally Robot-Assisted Techniques.

BACKGROUND: Oncological esophageal surgery has evolved significantly in the last decades. From open esophagectomy over (hybrid) minimally invasive surgery, nowadays, robot-assisted minimally invasive esophagectomy (RAMIE) approaches are applied. Current techniques require an analysis of possible advantages and disadvantages indicating the direction towards a novel gold standard. METHODS: Robot-assisted Ivor Lewis esophagectomies, performed in the period from April 2017 to June 2019 in five German centers (Berlin, Cologne, Hamburg, Kiel, Mainz), were included in this study. Pre-, intra-, and postoperative parameters were assessed. Cases were grouped for hybrid (H-RAMIE) versus totally robot-assisted (T-RAMIE) approaches. Postoperative parameters and complications were compared using risk ratios. RESULTS: A total of 175 operations were performed as T-RAMIE and 67 as H-RAMIE. Patient age (median age 62 years) and sex (83.1% male) were similarly distributed in both groups. Median duration of esophagectomy was significantly lower in the T-RAMIE group (385 versus 427 min, p < 0.001). The risks of "overall morbidity" (32.0 versus 47.8%; risk ratio [RR], 95% confidence interval (CI): 1.5, 1.1-2.1; p = 0.026), "anastomotic leak" (10.3 versus 22.4%; RR, CI: 2.2, 1.2-4.1; p = 0.020), and "respiratory failure" (1.1 versus 7.5%; RR, CI: 6.5, 1.3-32.9; p = 0.019) were significantly higher in case of H-RAMIE. CONCLUSIONS: In the five participating German centers, T-RAMIE was the preferred procedure (72.3% of operations). In comparison to H-RAMIE, T-RAMIE was associated with a significantly reduced risk of postoperative morbidity, anastomotic leak, and respiratory failure as well as a significantly reduced time necessary for esophagectomy.

Topology impacts TRAIL therapy: Differences in primary cancer growth and liver metastasis between orthotopic and subcutaneous xenotransplants of pancreatic ductal adenocarcinoma cells.

BACKGROUND: To study novel treatment modalities for pancreatic ductal adenocarcinoma (PDAC), we need to transfer the knowledge from in vitro to in vivo. It is important to mirror the clinical characteristics of the typically local invasive growth of pancreatic cancer and the distant spread resulting in liver metastasis. Notably, for xenotransplant studies using human specimen, two models, i.e. subcutaneous (s.c.) and orthotopic (o.t.) transplantation are widely used. METHODS: The subcutaneously and orthotopically inoculated Colo357 Bcl-xL cell-derived tumors were directly compared with and without TNF-related apoptosis inducing ligand (TRAIL) treatment. The size of primary tumors, number of liver metastasis and the histologic markers Ki67, M30, TNF-α and CD31 were assessed. RESULTS: Upon TRAIL treatment, the primary tumors did not change their size, neither in the s.c. nor in the o.t. approaches. But when s.c. was compared to o.t., the size of the s.c. tumors was more than two-fold bigger than that of the o.t. tumors (P < 0.01). However, mice with orthotopically inoculated PDAC cells developed liver metastasis upon TRAIL treatment much more frequently (n = 13/17) than mice with subcutaneously inoculated PDAC cells (n = 1/11) (P < 0.01). As a likely driving force for this increased metastasis, a higher TNF-α staining intensity in the o.t. tumors was observed by immunohistochemistry. CONCLUSIONS: These data from a direct side-by-side comparison underline the importance of the proper inoculation site of the PDAC cells. Local invasion and liver metastases are a hallmark of PDAC in the clinic; the o.t. model is clearly superior in reflecting this setting. Moreover, a serious side-effect of a possible new therapeutic compound became obvious only in the o.t.