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The outbreak of the coronavirus disease 2019 (COVID-19) pandemic imposed limitations for elective surgery, impacting the associated hospital standards worldwide. As certain treatment windows must be adhered to in oncological surgery, the limited intensive care unit (ICU) capacity had to be critically distributed in order to do justice to both acutely ill and oncology patients. This manuscript summarizes the impact of COVID-19 on the management of oncological surgery of the upper gastrointestinal tract and particularly esophageal surgery in German medical centers.A survey of German centers for esophageal surgery was performed on the impact of COVID-19 on operative management for esophageal surgery during the first lockdown. After inspection, assessment, critical analysis and interpretation, the results were compared to the international literature.Initial recommendations of international societies warned for caution and restraint regarding interventions of the upper gastrointestinal tract that were not absolutely necessary. Oncological surgery should be performed under strict restrictions, especially only after negative testing for COVID-19 and only with sufficiently available personal protective equipment for the personnel. Furthermore, minimally invasive procedures were preferably not recommended. In diseases with alternative treatment options, such as definitive chemoradiotherapy of esophageal squamous cell carcinoma, these should be given priority when possible. In the further development of the pandemic, it was shown that due to a high standardization of preoperative management, postoperative results comparable to pre-pandemic times could be achieved particularly with respect to the diagnostics of infections.HINTERGRUND: Mit Ausbruch der COVID-19(„coronavirus disease 2019“)-Pandemie kam es zu Einschränkungen in der elektiven Chirurgie und den damit verbundenen Standards der jeweiligen Krankenhäuser. Da in der onkologischen Chirurgie bestimmte therapeutische Zeitfenster einzuhalten sind, mussten die begrenzten Intensivkapazitäten kritisch verteilt werden, um sowohl akut als auch onkologisch erkrankten Patienten gerecht zu werden. Diese Arbeit fasst die Auswirkungen von COVID-19 auf das Management der onkologischen Chirurgie des oberen Gastrointestinaltraktes sowie im Speziellen der Ösophaguschirurgie in deutschen Zentren zusammen.Es erfolgte eine Befragung deutscher Zentren für Ösophaguschirurgie zu Auswirkungen auf ihr operatives Management während des ersten Lockdowns. Diese Ergebnisse wurden nach Sichtung, Auswertung sowie kritischer Analyse und Interpretation mit der internationalen Literatur verglichen.Erste Empfehlungen internationaler Fachgesellschaften mahnten insgesamt zur Zurückhaltung bei nicht zwingend notwendigen Eingriffen am oberen Gastrointestinaltrakt. Onkologische Eingriffe sollten unter strengen Auflagen, insbesondere nur nach negativer Testung auf COVID-19 und nur bei ausreichend vorhandener persönlicher Schutzausrichtung für das Personal durchgeführt werden. Des Weiteren wurde ein minimal-invasives Vorgehen eher nicht empfohlen. Bei alternativen Behandlungsmöglichkeiten, z. B. der definitiven Radiochemotherapie des Plattenepithelkarzinoms des Ösophagus, sollte diese, wenn möglich bevorzugt werden. Im weiteren Pandemieverlauf zeigte sich, dass durch eine hohe Standardisierung der präoperativen Vorbereitung, auch insbesondere im Hinblick auf die Infektionsdiagnostik, vergleichbare Ergebnisse zur präpandemischen Zeit erzielt werden konnten.

Background Patients with locally advanced esophageal or gastroesophageal adenocarcinoma benefit from multimodal therapy concepts including neoadjuvant chemoradiation (nCRT), respectively, perioperative chemotherapy (pCT). However, it remains unclear which treatment is superior concerning postoperative morbidity. Methods In this study, we compared the postsurgical survival (30-day/90-day/1-year mortality) (primary endpoint), treatment response, and surgical complications (secondary endpoints) of patients who either received nCRT (CROSS protocol) or pCT (FLOT protocol) due to esophageal/gastroesophageal adenocarcinoma. Between January 2013 and December 2017, 873 patients underwent Ivor Lewis esophagectomy in our high-volume center. 339 patients received nCRT and 97 underwent pCT. After 1:1 propensity score matching (matching criteria: sex, age, BMI, ASA score, and Charlson score), 97 patients per subgroup were included for analysis. Results After matching, tumor response (ypT/ypN) did not differ significantly between nCRT and pCT (p = 0.118, respectively, p = 0.174). Residual nodal metastasis occurred more often after pCT (p = 0.001). Postsurgical mortality was comparable within both groups. No patient died within 30 or 90 days after surgery while the 1-year survival rate was 72.2% for nCRT and 68.0% for pCT (p = 0.47). Only grade 3a complications according to Clavien–Dindo were increased after pCT (p = 0.04). There was a trend towards a higher rate of pylorospasm within the pCT group (nCRT: 23.7% versus pCT: 37.1%) (p = 0.061). Multivariate analysis identified pCT, younger age, and Charlson score as independent variables for pylorospasm. Conclusion Both nCRT and pCT are safe and efficient within the multimodal treatment of esophageal/gastroesophageal adenocarcinoma. We did not observe differences in postoperative morbidity. However, functional aspects such as gastric emptying might be more frequent after pCT.

Die thorakoabdominale Osophagektomie spielt bei der Therapie des Osophaguskarzinoms weiterhin die tragende Rolle. Minimal-invasive Verfahren wurden entwickelt, um die hohe Rate an postoperativer Morbiditat und Mortalitat zu reduzieren, ohne das onkologische Ergebnis dabei zu gefahrden. Welche Evidenz besteht in der minimal-invasiven onkologischen Chirurgie des Osophagus? Profitieren Patienten von einer minimal-invasiven Osophagektomie im Vergleich zur offenen Technik? Ist eine Reduktion des chirurgischen Zugangstraumas im Einzelnen von Vorteil? Die internationale Literatur wurde gesichtet, ausgewertet und kritisch analysiert. Drei prospektiv randomisierte Studien bestatigen eine Reduktion der postoperativen Morbiditat durch die Reduktion des chirurgischen Zugangstraumas bei mindestens gleichwertigem onkologischem Ergebnis. Zu diesem Ergebnis kommen auch diverse retrospektive Analysen sowie Metaanalysen. Eine Minimierung des chirurgischen Zugangstraumas bei der thorakoabdominalen Osophagektomie fuhrt zu einer Reduktion der postoperativen Morbiditat im Vergleich zur offenen Chirurgie. Das onkologische Ergebnis bleibt davon nach aktueller Datenlage unbeeintrachtigt.

Robotische Systeme wurden vor uber 20 Jahren zum ersten Mal in die Viszeralchirurgie eingefuhrt, kurz darauf fuhrte Horgan in Chicago 2003 die erste roboterassistierte Osophagusresektion durch. Ziel dieser Arbeit ist die Darstellung neuer Techniken und Trainingsmethoden fur die roboterassistierte Chirurgie mit Kosten-Nutzen-Bewertung am Beispiel der Ivor-Lewis-Osophagektomie Es erfolgte eine systematische Literaturrecherche zu neuen Technologien im Bereich der roboterassistierten Chirurgie und Kostenanalyse der intraoperativen Verbrauchsmaterialien fur die Hybrid-Ivor-Lewis-Osophagektomie sowie die roboterassistierte Ivor-Lewis-Osophagektomie. Roboterassistierte Osophaguschirurgie ist komplex und erfordert eine aufwendige Lernphase. Diese kann durch moderne Trainingsmethoden deutlich verkurzt werden. Neue Robotersysteme zielen auf den Einsatz bildgestutzter Chirurgie und kunstliche Intelligenz. Roboterassistierte Eingriffe in der Osophagustumorchirurgie sind signifikant teurer als vergleichbare Eingriffe ohne diese Technologie. Onkologische Kurz- und Langzeitvorteile fur den Patienten nach roboterassistierten Eingriffen am oberen Gastrointestinaltrakt mussen weiter evaluiert werden, um den Einsatz robotischer Technologie zu rechtfertigen.

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., During angiogenesis the vasculature switches from a quiescent to a proliferative state. Here the authors show that mitochondrial respiration in endothelial cells controls angiogenesis during development, tumour growth and tissue repair.

Simple Summary Pancreatic cancer has the lowest survival rate of all malignancies. Understanding the interplay between tumor and stroma could lead to the development of new therapies. The metabolic role of interleukin 17B/interleukin 17B receptor (IL-17B/RB) has not been adequately studied in pancreatic cancer and is poorly understood. Here, we investigate the IL-17B/RB-mediated interactions between the tumor and the stroma. We analyze murine as well as human stromal and tumor cells, animal experiments with immunocompromised mice, and human cell lines with overexpression and knockdown of IL-17RB. We report that aberrant expression of IL-17B/RB in stromal pancreatic stellate cells (PSCs) accelerates tumor cell growth. IL-17B/RB-signaling supplies energy by increased oxidative phosphorylation (OXPHOS). Blocking IL-17B/RB to inhibit the tumor to stroma crosstalk could be a potential targeted therapy for pancreatic cancer. Abstract In pancreatic ductal adenocarcinoma (PDAC), the tumor stroma constitutes most of the cell mass and contributes to therapy resistance and progression. Here we show a hitherto unknown metabolic cooperation between pancreatic stellate cells (PSCs) and tumor cells through Interleukin 17B/Interleukin 17B receptor (IL-17B/IL-17RB) signaling. Tumor-derived IL-17B carrying extracellular vesicles (EVs) activated stromal PSCs and induced the expression of IL-17RB. PSCs increased oxidative phosphorylation while reducing mitochondrial turnover. PSCs activated tumor cells in a feedback loop. Tumor cells subsequently increased oxidative phosphorylation and decreased glycolysis partially via IL-6. In vivo, IL-17RB overexpression in PSCs accelerated tumor growth in a co-injection xenograft mouse model. Our results demonstrate a tumor-to-stroma feedback loop increasing tumor metabolism to accelerate tumor growth under optimal nutritional conditions.

Background Molecular markers predicting survival in esophageal adenocarcinoma (EAC) are rare. Specifically, in favorable oncologic situations, e.g. nodal negativity or major neoadjuvant therapy response, there is a lack of additional risk factors that serve to predict patients’ outcome more precisely. This study evaluated X-linked inhibitor of apoptosis protein (XIAP) as a potential marker improving outcome prediction. Methods Tissue microarrays from 362 patients that were diagnosed with resectable EAC were included in the study. XIAP was stained by immunohistochemistry and correlated to clinical outcome, molecular markers and markers of the cellular tumor microenvironment. Results XIAP did not impact on overall survival (OS) in the whole study collective. Subgroup analyses stratifying for common genetic markers (TP53, ERBB2, ARID1A/SWI/SNF) did not disclose any impact of XIAP expression on survival. Detailed subgroup analyses of [1] nodal negative patients, [2] highly T-cell infiltrated tumors and [3] therapy responders to neoadjuvant treatment revealed a significant inverse role of high XIAP expression in these specific oncologic situations; elevated XIAP expression detrimentally affected patients’ outcome in these subgroups. [1]: OS XIAP low: 202 months (m) vs. XIAP high: 38 m; [2]: OS 116 m vs. 28.2 m; [3]: OS 31 m vs. 4 m). Conclusions Our data suggest XIAP expression in EAC as a worthy tool to improve outcome prediction in specific oncologic settings that might directly impact on clinical diagnosis and treatment of EAC in the future. Electronic supplementary material The online version of this article (10.1186/s12885-019-5722-1) contains supplementary material, which is available to authorized users.

Robotic surgery was introduced into general surgery more than 20 years ago. Shortly afterwards, Horgan performed the first robotic-assisted esophagectomy in 2003 in Chicago. The aim of this manuscript is to elucidate new developments and training methods in robotic surgery with a cost-benefit analysis for robotic-assisted Ivor Lewis esophagectomy.Systematic literature search regarding new technology and training methods for robotic surgery and cost analysis of intraoperative materials for hybrid and robotic-assisted Ivor Lewis esophagectomy.Robotic-assisted esophageal surgery is complex and involves an extensive learning curve, which can be shortened with modern teaching methods. New robotic systems aim at the use of image-guided surgery and artificial intelligence. Robotic-assisted surgery of esophageal cancer is significantly more expensive that surgery without this technology.Oncological short-term and long-term benefits need to be further evaluated to support the higher cost of robotic esophageal cancer surgery.EINLEITUNG: Robotische Systeme wurden vor über 20 Jahren zum ersten Mal in die Viszeralchirurgie eingeführt, kurz darauf führte Horgan in Chicago 2003 die erste roboterassistierte Ösophagusresektion durch. Ziel dieser Arbeit ist die Darstellung neuer Techniken und Trainingsmethoden für die roboterassistierte Chirurgie mit Kosten-Nutzen-Bewertung am Beispiel der Ivor-Lewis-Ösophagektomie METHODEN: Es erfolgte eine systematische Literaturrecherche zu neuen Technologien im Bereich der roboterassistierten Chirurgie und Kostenanalyse der intraoperativen Verbrauchsmaterialien für die Hybrid-Ivor-Lewis-Ösophagektomie sowie die roboterassistierte Ivor-Lewis-Ösophagektomie.Roboterassistierte Ösophaguschirurgie ist komplex und erfordert eine aufwendige Lernphase. Diese kann durch moderne Trainingsmethoden deutlich verkürzt werden. Neue Robotersysteme zielen auf den Einsatz bildgestützter Chirurgie und künstliche Intelligenz. Roboterassistierte Eingriffe in der Ösophagustumorchirurgie sind signifikant teurer als vergleichbare Eingriffe ohne diese Technologie.Onkologische Kurz- und Langzeitvorteile für den Patienten nach roboterassistierten Eingriffen am oberen Gastrointestinaltrakt müssen weiter evaluiert werden, um den Einsatz robotischer Technologie zu rechtfertigen.

Simple Summary One of the most severe postoperative complications after a transthoracic esophagectomy for esophageal cancer is a leakage of the anastomosis created between the remnant esophagus and the stomach. There is substantial debate on which surgical technique and which stapler are the best. The aim of this study was to retrospectively analyze whether the stapler diameter had an impact on postoperative anastomotic leak rates during a 4-year time frame from 2016 to 2020. A total of 632 patients (open, hybrid, and totally minimally invasive esophagectomy) met the inclusion criteria. A total of 214 patients underwent an anastomosis with a 25 mm stapler vs. 418 patients with a 28 mm stapler. Anastomotic leak rates were 15.4% vs. 10.8%, respectively. Stapler size should be chosen according to the individual anatomical situation of the patient and may be of higher relevance in patients undergoing totally minimally invasive reconstruction. Abstract Anastomotic leak is one of the most severe postoperative complications and is therefore considered a benchmark for the quality of surgery for esophageal cancer. There is substantial debate on which anastomotic technique is the best for patients undergoing Ivor Lewis esophagectomy. Our standardized technique is a circular stapled anastomosis with either a 25 or 28 mm anvil. The aim of this study was to retrospectively analyze whether the stapler diameter had an impact on postoperative anastomotic leak rates during a 4-year time frame from 2016 to 2020. A total of 632 patients (open, hybrid, and totally minimally invasive esophagectomy) met the inclusion criteria. A total of 214 patients underwent an anastomosis with a 25 mm stapler vs. 418 patients with a 28 mm stapler. Anastomotic leak rates were 15.4% vs. 10.8%, respectively (p = 0.0925). Stapler size should be chosen according to the individual anatomical situation of the patient. Stapler size may be of higher relevance in patients undergoing totally minimally invasive reconstruction.

Simple Summary Esophageal cancer is one of the top ten most deadly cancers. Even when diagnosed in a curable stage, patients prognosis poor. One of the parameters that is very relevant for long-term survival is response to radio(chemo)therapy prior surgery. Complete response rates are between 24 and 50 percent. This puts more than a half of every esophageal cancer patient that is diagnosed in a non-metastasized stage at high risk of recurrence. To improve response rates of treatment regimens prior curative surgery is, therefore, a major challenge in treating esophageal cancer. Not only the response of the cancer cell itself to cancer therapy is determining patients’ fate. Cells around the tumor cells called the tumor microenvironment that together with the cancer cell constitute a malignant tumor are also involved in tumor progression and therapy response. This review depicts the most important parts of the esophageal cancer microenvironment, evaluates chances and challenges of current already established therapeutic concepts that target this microenvironment. It furthermore elucidates specific pathways that are potential valuable targets in the future. Abstract Esophageal cancer is among the top ten most deadly cancers worldwide with adenocarcinomas of the esophagus showing increasing incidences over the last years. The prognosis is determined by tumor stage at diagnosis and in locally advanced stages by response to (radio-)chemotherapy followed by radical surgery. Less than a third of patients with esophageal adenocarcinomas completely respond to neoadjuvant therapies which urgently asks for further strategies to improve these rates. Aiming at the tumor microenvironment with novel targeted therapies can be one strategy to achieve this goal. This review connects experimental, translational, and clinical findings on each component of the esophageal cancer tumor microenvironment involving tumor angiogenesis, tumor-infiltrating immune cells, such as macrophages, T-cells, myeloid-derived suppressor cells, and cancer-associated fibroblasts. The review evaluates the current state of already approved concepts and depicts novel potentially targetable pathways related to esophageal cancer tumor microenvironment.

Minimally invasive single-port surgery is often associated with large incisions up to 2–3 cm, complicated handling due to the lack of triangulation, and instrument crossing. Aim of this prospective study was to perform true single-port surgery (cholecystectomy) without the use of assisting trocars using a new surgical platform that allows for triangulation incorporating robotic features, and to measure the perioperative outcome and cosmetic results. As the first European site after FDA and CE-mark approval, the new device has been introduced to our academic center. In patients with cholecystitis and cholecystolithiasis, the operation was performed through only one 15-mm trocar. For patients safety, intraoperative cholangiography using intravenous ICG and a standard Stryker 1588 system was routinely performed. Symphonx was used in n = 12 patients for abdominal surgery (6 females, mean age 42.5 [30–77], mean BMI 26.2 [19.3–38.9]. A total of 8 patients underwent surgery using no additional ports besides the 15-mm trocar; in the remaining patients, one assisting instrument (3–5 mm) was used. Mean OR time was 107 [72–221] minutes. The postoperative course was uneventful in 11 patients; in one patient, a seroma at the surgical site required interventional drainage 1 month postoperatively. No intraoperative complications occurred. This is the first human case series using the commercially available symphonX platform for abdominal laparoscopic surgery and the first series using the system without assisting instruments. Laparoscopic cholecystectomy in patients with cholecystitis and cholecystolithiasis using the symphonX platform through only one 15-mm trocar is feasible, safe, and more cost-efficient compared to robotic platforms.

Background: In the phase III AVAGAST trial, the addition of bevacizumab to chemotherapy improved progression-free survival (PFS) but not overall survival (OS) in patients with advanced gastric cancer. We studied the role of Angiopoietin-2 (Ang-2), a key driver of tumour angiogenesis, metastasis and resistance to antiangiogenic treatment, as a biomarker. Methods: Previously untreated, advanced gastric cancer patients were randomly assigned to receive bevacizumab (n = 387) or placebo (n = 387) in combination with chemotherapy. Plasma collected at baseline and at progression was analysed by ELISA. The role of Ang-2 as a prognostic and a predictive biomarker of bevacizumab efficacy was studied using a Cox proportional hazards model. Logistic regression analysis was applied for correlations with metastasis. Results: Median baseline plasma Ang-2 levels were lower in Asian (2143 pg ml\(^-\)\(^1\)) vs non-Asian patients (3193 pg ml\(^-\)\(^1\)), P

Dickkopf-2 (DKK2) has been described as Wnt/beta-catenin pathway antagonist and its expression is mediated by micro RNA-221 (miRNA-221). So far, there is only limited data characterizing the role of DKK2 expression in esophageal cancer. A tissue micro array of 192 patients with esophageal adenocarcinoma was analyzed immunohistochemically for DKK2, miRNA-221 expression by RNA scope, and GATA6 amplification by fluorescence in-situ hybridization. The data was correlated with clinical, pathological and molecular data (TP53, HER2, c-myc, GATA6, PIK3CA, and KRAS amplifications). DKK2 expression was detectable in 21.7% and miRNA-221 expression in 33.5% of the patients. We observed no correlation between DKK2 or miRNA-221 expression and clinico-pathological data DKK2 expression was correlated with TP53 mutations and amplification of GATA6. We did not detect a survival difference in dependence of DKK2 for the total cohort, however, in patients without neoadjuvant treatment DKK2 expression correlated with a prolonged survival (median overall-survival 202 vs. 55 months, p = 0.012) which turned opposite in patients that underwent neoadjuvant treatment. High amounts of miRNA-221 were in trend associated with a prolonged overall-survival (p = 0.070). DKK2 as a Wnt antagonist is associated with prolonged survival in patients without neoadjuvant treatment and changes its prognostic value to the contrary in patients after neoadjuvant therapy. The modulatory effects of neoadjuvant treatment in connection with DKK2 expression are not fully understood, but when considering DKK2 as a tumor marker, it is necessary to see it in the context of neoadjuvant therapy.

Squamous cell carcinoma of the vulva (SQCV) is the fifth most common cancer in women and accounts for about 5% of all genital cancers in women. The PD-L1 signaling pathway is activated in many malignant neoplasms and its blockade enhances anti-cancer immunity. The aim of our study was to examine the protein expression of PD-L1 and PD-1 in squamous cell cancer of the vulva, its correlations with clinicopathologic features and prognostic value. Patients with SQCV treated in one institution were used for the analyses. PD-L1 immunohistochemistry was performed on 4 µm-thick section of the respective FFPE tissue blocks using the 28-8 antibody. PD-L1 scoring was performed separately for tumour cells (TC) and tumour associated immune cells. DNA was extracted to determine HPV status. Kaplan–Meier estimates for disease-free-survival and overall-survival were calculated and compared by log-rank test. PD-L1 expression in tumour cells could be observed in 32.9% of the patients. The expression of PD-L1 in peritumoural immune cells was confirmed in 91.4% of the patients. A significant correlation between PD-L1 expression in tumour cells and tumour stage was detected (p = 0.007). PD-L1 expression was independent from HPV status. Using the log-rank test we could not prove any significant differences in disease-free survival (p = 0.434) and overall survival (p = 0.858). Regression analysis showed that nodal status is a predictive factor of survival (p

The cytosolic appearance and propagation of bacteria cause overwhelming cellular stress responses that induce apoptosis under normal conditions. Therefore, successful bacterial colonization depends on the ability of intracellular pathogens to block apoptosis and to safeguard bacterial replicative niches. Here, we show that the cytosolic Gram-negative bacterium Shigella flexneri stalls apoptosis by inhibiting effector caspase activity. Our data identified lipopolysaccharide (LPS) as a bona fide effector caspase inhibitor that directly binds caspases by involving its O-antigen (O Ag) moiety. Bacterial strains that lacked the O Ag or failed to replicate within the cytosol were incapable of blocking apoptosis and exhibited reduced virulence in a murine model of bacterial infection. Our findings demonstrate how Shigella inhibits pro-apoptotic caspase activity, effectively delays coordinated host-cell demise and supports its intracellular propagation. Next to the recently discovered pro-inflammatory role of cytosolic LPS, our data reveal a distinct mode of LPS action that, through the disruption of the early coordinated non-lytic cell death response, ultimately supports the inflammatory breakdown of infected cells at later time points. The lipopolysaccharide of the intracellular pathogen Shigella, in particular its O antigen, interacts with caspases and blocks their activation to prevent apoptosis.

Background Immune infiltration is implicated in the development of acquired resistance to anti-angiogenic cancer therapy. We therefore investigated the correlation between neutrophil infiltration in metastasis of colorectal cancer (CRC) patients and survival after treatment with bevacizumab. Our study identifies CD177+ tumour neutrophil infiltration as an adverse prognostic factor for bevacizumab treatment. We further demonstrate that a novel anti-VEGF/anti-Ang2 compound (BI-880) can overcome resistance to VEGF inhibition in experimental tumour models. Methods A total of 85 metastatic CRC patients were stratified into cohorts that had either received chemotherapy alone (n = 39) or combined with bevacizumab (n = 46). Tumour CD177+ neutrophil infiltration was correlated to clinical outcome. The impact of neutrophil infiltration on anti-VEGF or anti-VEGF/anti-Ang2 therapy was studied in both xenograft and syngeneic tumour models by immunohistochemistry. Results The survival of bevacizumab-treated CRC patients in the presence of CD177+ infiltrates was significantly reduced compared to patients harbouring CD177− metastases. BI-880 treatment reduced the development of hypoxia associated with bevacizumab treatment and improved vascular normalisation in xenografts. Furthermore, neutrophil depletion or BI-880 treatment restored treatment sensitivity in a syngeneic tumour model of anti-VEGF resistance. Conclusions Our findings implicate CD177 as a biomarker for bevacizumab and suggest VEGF/Ang2 inhibition as a strategy to overcome neutrophil associated resistance to anti-angiogenic treatment.

In the normal quiescent vasculature, only 0.01% of endothelial cells (ECs) are proliferating. However, this proportion increases dramatically following the angiogenic switch during tumor growth or wound healing. Recent evidence suggests that this angiogenic switch is accompanied by a metabolic switch. Here, we show that proliferating ECs increasingly depend on mitochondrial oxidative phosphorylation (OxPhos) for their increased energy demand. Under growth conditions, ECs consume three times more oxygen than quiescent ECs and work close to their respiratory limit. The increased utilization of the proton motif force leads to a reduced mitochondrial membrane potential in proliferating ECs and sensitizes to mitochondrial uncoupling. The benzoquinone embelin is a weak mitochondrial uncoupler that prevents neoangiogenesis during tumor growth and wound healing by exhausting the low respiratory reserve of proliferating ECs without adversely affecting quiescent ECs. We demonstrate that this can be exploited therapeutically by attenuating tumor growth in syngenic and xenograft mouse models. This novel metabolic targeting approach might be clinically valuable in controlling pathological neoangiogenesis while sparing normal vasculature and complementing cytostatic drugs in cancer treatment.

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.

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.

Der vorliegende Beitrag untersucht anhand einer systematischen Literaturrecherche den Einfluss der sozialen Ungleichheit auf die medizinische und gesundheitsbezogene Versorgung in Deutschland. Das Thema „Soziale Ungleichheit, medizinische und gesundheitsbezogene Versorgung in Deutschland“ ist auserst komplex, da im allgemeinen verschiedenste Komponenten der sozialen Ungleichheit in der Versorgung darunter verstanden werden. So konnen unter sozialer Ungleichheit horizontale Ungleichheiten wie Alter und Geschlecht wie auch vertikale Ungleichheiten wie Beruf, Bildung und Einkommen, also der soziale Status bzw. die soziale Schicht, untersucht werden. Der vorliegende Beitrag konzentriert sich auf diese - auch soziookonomischen Merkmale genannten - Aspekte der sozialen Ungleichheit, d.h. auf die Unterschiede in Bildung, Beruf und Einkommen (Jockel 1998, Mielck 2000). Zur Analyse der horizontalen Ungleichheit sei an dieser Stelle exemplarisch auf jungste umfassende Arbeiten zu diesem Thema bzw. Beitrage im vorliegenden Band verwiesen (Babitsch 2005, Knesebeck 2005, Richter 2005, siehe auch die Beitrage der Autoren in diesem Band).