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.

Combined regression score predicts outcome after neoadjuvant treatment of oesophageal cancer.

BACKGROUND: Histopathologic regression following neoadjuvant treatment (NT) of oesophageal cancer is a prognostic factor of survival, but the nodal status is not considered. Here, a score combining both to improve prediction of survival after neoadjuvant therapy is developed. METHODS: Seven hundred and fifteen patients with oesophageal squamous cell (SCC) or adenocarcinoma (AC) undergoing NT and esophagectomy were analysed. Histopathologic response was classified according to percentage of vital residual tumour cells (VRTC): complete response (CR) without VRTC, major response with <10% VRTC, minor response with >10% VRTC. Nodal stage was classified as ypN0 and ypN+. Kaplan-Meier and Cox regression were used for survival analysis. RESULTS: Survival analysis identified three groups with significantly different mortality risks: (1) low-risk group for CR (ypT0N0) with 72% 5-year overall survival (5y-OS), (2) intermediate-risk group for minor/major responders and ypN0 with 59% 5y-OS, and (3) high-risk group for minor/major responders and ypN+ with 20% 5y-OS (p < 0.001). Median survival in AC and SCC cohorts were comparable (3.8 (CI 95%: 3.1, 5.3) vs. 4.6 years (CI 95%: 3.3, not reached), p = 0.3). CONCLUSIONS: Histopathologic regression and nodal status should be combined for estimating AC and SCC prognosis. Poor survival in the high-risk group highlights need for adjuvant therapy.

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.

[Evidence in minimally invasive oncological surgery of the esophagus]. / Evidenz in der minimal-invasiven onkologischen Chirurgie des Ösophagus.

BACKGROUND: Thoracoabdominal esophagectomy still plays a major role in the oncological treatment for esophageal cancer. Minimally invasive procedures were developed to reduce the high rate of postoperative morbidity and mortality without negatively affecting the oncological outcome. OBJECTIVE: What evidence supports minimally invasive oncological surgery of the esophagus? Do patients benefit from minimally invasive esophagectomy compared to an open approach? Is the reduction of surgical access trauma specifically advantageous? MATERIAL AND METHODS: Review, evaluation and critical analysis of the international literature. RESULTS: A reduction in postoperative morbidity by decreasing surgical trauma was confirmed by three prospective randomized clinical trials, while showing at least similar oncological outcomes. Diverse retrospective analyses and meta-analyses also came to the same result. CONCLUSION: A minimization of surgical access trauma during thoracoabdominal esophagectomy reduces postoperative morbidity compared to conventional open surgery. Recent evidence suggests that oncological outcomes are not altered depending on the surgical approach.

[Perioperative enhanced recovery after surgery program for Ivor Lewis esophagectomy : First experiences of a high-volume center]. / Perioperatives "Enhanced-recovery-after-surgery"-Programm der Ivor-Lewis-Ösophagektomie : Erste Erfahrungen eines High-volume-Zentrums.

BACKGROUND AND OBJECTIVE: Transthoracic esophagectomy is generally accepted as the standard of surgical care for patients with esophageal cancer. Despite improvements in the perioperative management this surgical procedure is associated with a clinically relevant morbidity. Fast-track protocols (synonym: enhanced recovery after surgery, ERAS) are conceived to perioperatively maintain the physiological homoeostasis and thereby to accelerate postoperative rehabilitation and reduce morbidity. In this prospective observational study the initial experiences of a high-volume center with the implementation of an ERAS protocol after transthoracic esophagectomy were analyzed. MATERIAL AND METHODS: A total of 26 patients with esophageal cancer and a low index of comorbidities prior to hybrid Ivor Lewis esophagectomy were included in this study. According to an ERAS protocol all patients underwent a standardized perioperative treatment pathway aiming to discharge the patients from the inpatient treatment on postoperative day 10. The primary outcome parameter was the rate of major complications (Clavien-Dindo IIIb/IV), which was compared to a cohort of 52 non-ERAS patients. RESULTS AND CONCLUSION: The ERAS programs with the various core elements can be implemented in patients scheduled for transthoracic esophagectomy, although the organizational and personnel expenditure of this fast-track protocol is high. The length of hospital stay appears to be reduced without compromising patient safety. The limiting variable of the ERAS protocol remains the early and adequate enteral feeding load of the gastric conduit before discharge on postoperative day 10.

Mitochondrial respiration controls neoangiogenesis during wound healing and tumour growth.

The vasculature represents a highly plastic compartment, capable of switching from a quiescent to an active proliferative state during angiogenesis. Metabolic reprogramming in endothelial cells (ECs) thereby is crucial to cover the increasing cellular energy demand under growth conditions. Here we assess the impact of mitochondrial bioenergetics on neovascularisation, by deleting cox10 gene encoding an assembly factor of cytochrome c oxidase (COX) specifically in mouse ECs, providing a model for vasculature-restricted respiratory deficiency. We show that EC-specific cox10 ablation results in deficient vascular development causing embryonic lethality. In adult mice induction of EC-specific cox10 gene deletion produces no overt phenotype. However, the angiogenic capacity of COX-deficient ECs is severely compromised under energetically demanding conditions, as revealed by significantly delayed wound-healing and impaired tumour growth. We provide genetic evidence for a requirement of mitochondrial respiration in vascular endothelial cells for neoangiogenesis during development, tissue repair and cancer.

A combination of low-dose bevacizumab and imatinib enhances vascular normalisation without inducing extracellular matrix deposition.

BACKGROUND: Vascular endothelial growth factor (VEGF)-targeting drugs normalise the tumour vasculature and improve access for chemotherapy. However, excessive VEGF inhibition fails to improve clinical outcome, and successive treatment cycles lead to incremental extracellular matrix (ECM) deposition, which limits perfusion and drug delivery. We show here, that low-dose VEGF inhibition augmented with PDGF-R inhibition leads to superior vascular normalisation without incremental ECM deposition thus maintaining access for therapy. METHODS: Collagen IV expression was analysed in response to VEGF inhibition in liver metastasis of colorectal cancer (CRC) patients, in syngeneic (Panc02) and xenograft tumours of human colorectal cancer cells (LS174T). The xenograft tumours were treated with low (0.5 mg kg-1 body weight) or high (5 mg kg-1 body weight) doses of the anti-VEGF antibody bevacizumab with or without the tyrosine kinase inhibitor imatinib. Changes in tumour growth, and vascular parameters, including microvessel density, pericyte coverage, leakiness, hypoxia, perfusion, fraction of vessels with an open lumen, and type IV collagen deposition were compared. RESULTS: ECM deposition was increased after standard VEGF inhibition in patients and tumour models. In contrast, treatment with low-dose bevacizumab and imatinib produced similar growth inhibition without inducing detrimental collagen IV deposition, leading to superior vascular normalisation, reduced leakiness, improved oxygenation, more open vessels that permit perfusion and access for therapy. CONCLUSIONS: Low-dose bevacizumab augmented by imatinib selects a mature, highly normalised and well perfused tumour vasculature without inducing incremental ECM deposition that normally limits the effectiveness of VEGF targeting drugs.

[Resection of advanced esophagogastric adenocarcinoma : Extended indications]. / Resektion beim fortgeschrittenen Adenokarzinom des Magens und des Ösophagus : Erweiterung der Indikation.

In the current German S3 guidelines surgical treatment is not recommended for metastatic gastric cancer or metastatic adenocarcinoma of the esophagogastric junction; however, in routine practice the indications can be extended so that there may be occasions in which radical surgical intervention for specific individuals may be appropriate as part of a multimodal therapy with curative intent. This article presents the scientific rationale of such an approach based on the available literature considering modern, multimodal therapy concepts including criteria to be met for radical surgery. Currently only retrospective trials and limited current meta-analysis data are available for justifying surgical treatment for metastatic adenocarcinoma. The recently published initial results of the FLOT-3 study identified a patient subgroup that benefits from a resection even though metastasis has occurred. Whether surgical therapy will become an integral part of the treatment of limited metastatic adenocarcinoma of the stomach and esophagus in the future, has to be demonstrated by large prospective randomized studies, such as the RENAISSANCE/FLOT-5 study.

Dual targeting of Angiopoetin-2 and VEGF potentiates effective vascular normalisation without inducing empty basement membrane sleeves in xenograft tumours.

BACKGROUND: Effective vascular normalisation following vascular endothelial growth factor (VEGF) inhibition is associated with endothelial cell regression leaving empty basement membrane sleeves (BMS). These long-lived BMS permit the rapid regrowth of tumour vasculature upon treatment cessation and promote resistance to VEGF-targeting drugs. Previous attempts at removing BMS have failed. Angiopoietin-2 (Ang2) is a vascular destabilizing factor that antagonises normalisation. We hypothesised that Ang2 inhibition could permit vascular normalisation at significantly reduced doses of VEGF inhibition, avoiding excessive vessel regression and the formation of empty BMS. METHODS: Mice xenografted with human colorectal cancer cells (LS174T) were treated with low (0.5 mg kg(-1)) or high (5 mg kg(-1)) doses of the VEGF-targeting antibody bevacizumab with or without an Ang2 blocking peptibody L1-10. Tumour growth, BMS formation and normalisation parameters were examined including vessel density, pericyte coverage, adherence junctions, leakiness, perfusion, hypoxia and proliferation. RESULTS: Dual targeting of VEGF and Ang2 achieved effective normalisation at only one-tenth of the dose required with bevacizumab alone. Pericyte coverage, vascular integrity, adherence junctions and perfusion as prerequisites for improved access of chemotherapy were improved without inducing empty BMS that facilitate rapid vascular regrowth. CONCLUSIONS: Dual targeting of VEGF and Ang2 can potentiate the effectiveness of VEGF inhibitors and avoid the formation of empty BMS.