Andrea Tal

Angiopoietin 2 stimulates TIE2-expressing monocytes to suppress T cell activation and to promote regulatory T cell expansion

Angiopoietin 2 (ANGPT2) is a proangiogenic cytokine whose expression is often upregulated by endothelial cells in tumors. Expression of its receptor, TIE2, defines a highly proangiogenic subpopulation of myeloid cells in circulation and tumors called TIE2-expressing monocytes/macrophages (TEMs). Genetic depletion of TEMs markedly reduces tumor angiogenesis in various tumor models, emphasizing their essential role in driving tumor progression. Previously, we demonstrated that ANGPT2 augments the expression of various proangiogenic genes, the potent immunosuppressive cytokine, IL-10, and a chemokine for regulatory T cells (Tregs), CCL17 by TEMs in vitro. We now show that TEMs also express higher levels of IL-10 than TIE2− macrophages in tumors and that ANGPT2-stimulated release of IL-10 by TEMs suppresses T cell proliferation, increases the ratio of CD4+ T cells to CD8+ T cells, and promotes the expansion of CD4+CD25highFOXP3+ Tregs. Furthermore, syngeneic murine tumors expressing high levels of ANGPT2 contained not only high numbers of TEMs but also increased numbers of Tregs, whereas genetic depletion of tumor TEMs resulted in a marked reduction in the frequency of Tregs in tumors. Taken together, our data suggest that ANGPT2-stimulated TEMs represent a novel, potent immunosuppressive force in tumors.

Intraductal endoscopic radiofrequency ablation for the treatment of hilar non-resectable malignant bile duct obstruction

AIM To evaluate the safety and technical success of endoscopic radiofrequency ablation (RFA) for palliative treatment of malignant hilar bile duct obstruction. METHODS In this study, a recently CE and FDA-approved endoscopic RFA catheter was first tested in an ex vivo pig liver model to study the effect of electrosurgical variables on the extent of the area of induced necrosis. Subsequently, a retrospective analysis was conducted of all patients treated with endoscopic RFA for malignant biliary obstruction at our center between February 2012 and April 2013. All patients received an additional plastic stent implantation into the biliary tree following RFA. RESULTS In the pig model, ablation time of 60-90 seconds using the bipolar soft coagulation mode at 8-10 watts with an effect of 8 was found to be the most feasible setting. Twelve patients (5 females, 7 males; mean age, 70 years) underwent 19 endoscopic RFA (range, 1-5) sessions. Deployment of RFA was successful in all patients. Systemic chemotherapy was administered in four patients. We observed biliary bleeding 4-6 wk after the intervention in three cases and two of these patients died: in one patient, spontaneous hemobilia occurred, whereas bleeding started during stent extraction in the other. In the third patient, bleeding was stopped by insertion of a non-covered self-expanding metal stent. Another three patients developed cholangitis during follow-up. Seven patients died during follow-up and median survival was 6.4 mo (95%CI: 0.05-12.7) from the time of the first RFA. CONCLUSION Endoscopic RFA is an easy to perform and technically highly successful procedure. However, hemobilia possibly associated with RFA occurred in three of our patients. Therefore, larger prospective studies are needed to further evaluate the safety and efficacy of this promising new method.

Switching of vascular phenotypes within a murine breast cancer model induced by angiopoietin-2

Sustained growth of solid tumours can rely on both the formation of new and the co‐option of existing blood vessels. Current models suggest that binding of angiopoietin‐2 (Ang‐2) to its endothelial Tie2 receptor prevents receptor phosphorylation, destabilizes blood vessels, and promotes vascular permeability. In contrast, binding of angiopoietin‐1 (Ang‐1) induces Tie2 receptor activation and supports the formation of mature blood vessels covered by pericytes. Despite the intense research to decipher the role of angiopoietins during physiological neovascularization and tumour angiogenesis, a mechanistic understanding of angiopoietin function on vascular integrity and remodelling is still incomplete. We therefore assessed the vascular morphology of two mouse mammary carcinoma xenotransplants (M6378 and M6363) which differ in their natural angiopoietin expression. M6378 displayed Ang‐1 in tumour cells but no Ang‐2 in tumour endothelial cells in vivo. In contrast, M6363 tumours expressed Ang‐2 in the tumour vasculature, whereas no Ang‐1 expression was present in tumour cells. We stably transfected M6378 mouse mammary carcinoma cells with human Ang‐1 or Ang‐2 and investigated the consequences on the host vasculature, including ultrastructural morphology. Interestingly, M6378/Ang‐2 and M6363 tumours displayed a similar vascular morphology, with intratumoural haemorrhage and non‐functional and abnormal blood vessels. Pericyte loss was prominent in these tumours and was accompanied by increased endothelial cell apoptosis. Thus, overexpression of Ang‐2 converted the vascular phenotype of M6378 tumours into a phenotype similar to M6363 tumours. Our results support the hypothesis that Ang‐1/Tie2 signalling is essential for vessel stabilization and endothelial cell/pericyte interaction, and suggest that Ang‐2 is able to induce a switch of vascular phenotypes within tumours. Copyright

ERCP in elderly patients: increased risk of sedation adverse events but low frequency of post-ERCP pancreatitis

BACKGROUND AND AIMS The continually increasing life expectancy in man comes along with an increasing number of endoscopic interventions performed in patients with advanced or even very advanced age. Data on the feasibility and safety of ERCP in elderly patients are relatively scarce. METHODS By a systematic query of the University Hospital Frankfurt clinical database, patients undergoing their first ERCP procedure at our center were retrospectively identified. Patients were grouped according to age at the day of the intervention (>80 years, 61-80 years, 40-60 years, and <40 years). Demographic data, indication, outcome, and risk factors were compared among the indicated groups. RESULTS A total of 758 patients who underwent ERCP procedures at our center were identified and included in the study. Main indications for ERCP were intraductal gallstones in 345 patients (45%) and tumor obstruction of the bile ducts (distal common bile duct: n = 126 [16.5%], hilar cholangiocarcinoma: n = 89 [11.7%], tumor of papilla of Vater: n = 16 [2.1%]). Gallstones were the most common cause for ERCP in patients aged >80 years (53.8%), and normal findings indicating exclusion of relevant disease were more frequent in patients <80 years (13.4%) compared with older patients (4.3%) (P < .01). Sedation adverse events were significantly more common in individuals aged >80 years compared with younger patients (3.4% vs 0.5%; P < .01). However, post-ERCP pancreatitis was significantly less frequent in the older patients (>80 years) (0.9% vs 5.3%; P < .05). Other adverse events were equally distributed in all age groups. The ERCP success rate (>80%) was not different among age groups. CONCLUSIONS ERCP is safe and efficient in patients aged 80 years or older. However, conscious sedation must be carefully monitored in older patients because risk of sedation adverse events is increased. The incidence of post-ERCP pancreatitis is lower in older patients compared with younger ones.

Colon capsule endoscopy: Current status and future directions

Colon capsule endoscopy (CCE; PillCam Colon; Given Imaging; Yoqneam, Israel) is a minimally invasive wireless technique for the visualization of the colon. With the recent introduction of the second generation colon capsule the diagnostic accuracy of CCE for polyp detection has significantly improved and preliminary data suggest it may be useful to monitor mucosal inflammation in patients with inflammatory bowel disease. Limitations include the inability to take biopsies and the procedural costs. However, given the potentially higher acceptance within an average risk colorectal cancer (CRC) screening population, its usefulness as a screening tool with regard to CRC prevention should be further evaluated.

The capsule endoscopy “suspected blood indicator” (SBI) for detection of active small bowel bleeding: no active bleeding in case of negative SBI

Abstract Objective. Capsule endoscopy (CE) is the gold standard to diagnose small bowel bleeding. The “suspected blood indicator” (SBI) offers an automated detection of active small bowel bleeding but validity of this technique is unknown. The objective was to analyze specificity and sensitivity of the SBI using the second small bowel capsule generation for the detection of active bleeding. Methods. This is a retrospective analysis of all patients (199) who attended our clinic for CE from June 2008 through March 2013. The second-generation PillCam SB 2 capsule was used for detection of (1) luminal blood content and (2) potentially responsible small bowel lesions. The findings of an independent investigator were correlated to SBI findings and a number of SBI markings were analyzed by a receiver operating characteristic (ROC). Results. In 157/199 cases, no sign of active bleeding or altered blood was detected. One hundred and thirty-seven of these 157 cases provided at least one SBI marking and a mean of 18.4 positive SBI markings per record were found. In 20 cases, neither SBI nor the human investigator detected abnormalities. Thirteen patients showed investigator-detected minor bleeding with mean SBI findings of 36 positive screenshots per record. When major bleeding was diagnosed by the investigator (n = 29), SBI detected a mean of 46.6 SBI-positive markings. SBI turned positive in 179 patients, whereas the investigator detected active bleeding in 42 cases. All patients with active bleeding were detected by SBI (sensitivity 100%, specificity 13%). ROC analysis revealed 51.0 SBI markings being the optimal cutoff for active versus no bleeding (sensitivity 79.1%, specificity 90.4%, misclassification of 15.3%). Conclusion. The new SBI software is a reliable tool to exclude active bleeding and/or major lesions but analysis of the CE video by a trained investigator is still important for the detection of lesions responsible for past bleeding.

Self-expandable metal stent for malignant colonic obstruction: outcome in proximal vs. left sided tumor localization.

INTRODUCTION The aim of this study was to evaluate the outcome of through-the-scope (TTS) implanted self-expanding metal stent (SEMS) comparing left-sided vs. proximal placement with regard to complications and outcome in palliation of malignant colorectal obstruction. MATERIAL AND METHODS All patients were consecutively retrospectively enrolled to this study between January 2009 and February 2012 due to impending or prevalent complete malignant colorectal obstruction. TTS applicable uncovered nitinol SEMS with unique flexible properties were used (Taewoong Medical, South Korea). Left-sided obstruction (aboral from the left flexure) was compared to proximal (from the ileo-cecal valve to the left flexure) localization. All patients have been discussed in the interdisciplinary tumor conference and the recommendation to treat by endoscopic stent placement was given in consensus. RESULTS A total of 15 patients was enrolled to this study (10 male and 5 female; mean age 68.3 ± 15.4 years, range 48 - 94), five patients with obstructions located in the proximal hemicolon whereas ten patients had a left-sided malignancy. Technical success was achieved in all cases and there was no early complication noticed. Three late complications included tumor overgrowth (n = 1), stent occlusion (1), and dislocation (1). Stent-in-stent insertion achieved, again, clinical success. The site of SEMS implantation (proximal vs. left colon) had no impact on patient outcome or complication rate. SEMS patency duration was 269.8 ± 175.2 days (range 30 - 570) and mean survival of the patients was 305.1 ± 279.3 days (range 16 - 990). CONCLUSION TTS application of flexible, non-covered SEMS seems to be safe and effective for palliation of malignant colorectal obstruction independent of localization of the tumor in the colon.

Multispecies blow fly myiasis combined with hypothermia in a man assumed to be dead

We describe the case of a man who was found with severe hypothermia and advanced myiasis involving five species of blow flies, which eventually led to a transtibial amputation of the man’s right leg. A case of such a heavy and species-rich infestation with fly larvae in an urban environment is extraordinary and has, to our knowledge, never been described so far. Best practice in cases such as this one demands accurate species identification not only to ensure appropriate treatment and pest management but also, from a forensic point of view, to explore the possibility of third-party responsibility. The cooperation between physicians and forensic entomologists is highlighted.

Circulating hypoxia marker carbonic anhydrase IX (CA9) in patients with hepatocellular carcinoma and patients with cirrhosis

Background and aims Expression of carbonic anhydrase IX (CA9), an enzyme expressed in response to hypoxia, acidosis and oncogenic alterations, is reported to be a prognostic factor in HCC patients. Here we evaluated serum CA9 levels in HCC and cirrhosis patients. Methods HCC and cirrhosis patients were prospectively recruited and CA9 levels were determined. CA9 levels were compared to stages of cirrhosis and HCC stages. The association of the CA9 levels and overall survival (OS) was assessed. Furthermore, immunohistochemical CA9 expression in HCC and cirrhosis was evaluated. Results 215 patients with HCC were included. The median serum CA9 concentration in patients with HCC was 370 pg/ml and significantly higher than in a healthy cohort. Patients with advanced cancer stages (BCLC and ALBI score) had hid significant higher levels of CA9 in the serum. HCC patients with high serum CA9 concentrations (>400 pg/ml) had an increased mortality risk (hazard ratio (HR) 1.690, 95% confidence interval (CI) 1.017–2.809, P = 0.043). Serum CA9 concentration in cirrhotic patients did not differ significantly from HCC patients. Higher CA9 levels in cirrhotic patients correlated with portal hypertension and esophageal varices. Patients with ethanol induced cirrhosis had the highest CA9 levels in both cohorts. Levels of CA9 did not correlate with immunohistochemical expression. Conclusions We conclude that a high CA9 level is a possible prognostic indicator for a poor outcome in HCC patients. The high CA9 levels are probably mainly associated with portal hypertension. Ductular reactions might be a possible source of serum CA9.

Predictive Value of Computed Tomography Scans and Clinical Findings for the Need of Endoscopic Necrosectomy in Walled-off Necrosis From Pancreatitis

Objectives Choosing the best treatment option at the optimal point of time for patients with walled-off necrosis (WON) is crucial. We aimed to identify imaging parameters and clinical findings predicting the need of necrosectomy in patients with WON. Methods All patients with endoscopically diagnosed WON and pseudocyst were retrospectively identified. Post hoc analysis of pre-interventional contrast-enhanced computed tomography was performed for factors predicting the need of necrosectomy. Results Sixty-five patients were included in this study. Forty patients (61.5%) were diagnosed with pseudocyst and 25 patients (38.5%) with WON. Patients with WON mostly had acute pancreatitis with biliary cause compared with more chronic pancreatitis and toxic cause in pseudocyst group (P = 0.002 and P = 0.004, respectively). Logistic regression revealed diabetes as a risk factor for WON. Computed tomography scans revealed 4.62% (n = 3) patients as false positive and 24.6% (n = 16) as false negative findings for WON. Reduced perfusion and detection of solid findings were independent risk factors for WON. Conclusions Computed tomography scans are of low diagnostic yield when needed to predict treatment of patients with pancreatic cysts. Reduced pancreatic perfusion and solid findings seem to be a risk factor for WON, whereas patients with diabetes seem to be at higher risk of developing WON.