Statement

StatementGeert Müller-Gerbes: Einschaltquotentrotz Programmqualitä

Metabolic implication of tigecycline as an efficacious second-line treatment for sorafenib-resistant hepatocellular carcinoma

Sorafenib represents the current standard of care for patients with advanced-stage hepatocellular carcinoma (HCC). However, acquired drug resistance occurs frequently during therapy and is accompanied by rapid tumor regrowth after sorafenib therapy termination. To identify the mechanism of this therapy-limiting growth resumption, we established robust sorafenib resistance HCC cell models that exhibited mitochondrial dysfunction and chemotherapeutic crossresistance. We found a rapid relapse of tumor cell proliferation after sorafenib withdrawal, which was caused by renewal of mitochondrial structures alongside a metabolic switch toward high electron transport system (ETS) activity. The translation-inhibiting antibiotic tigecycline impaired the biogenesis of mitochondrial DNA-encoded ETS subunits and limited the electron acceptor turnover required for glutamine oxidation. Thereby, tigecycline prevented the tumor relapse in vitro and in murine xenografts in vivo. These results offer a promising second-line therapeutic approach for advanced-stage HCC patients with progressive disease undergoing sorafenib therapy or treatment interruption due to severe adverse events

Multicenter cohort study of patients with buried bumper syndrome treated endoscopically with a novel, dedicated device.

BACKGROUND AND AIMS Buried bumper syndrome (BBS) is a rare adverse event of percutaneous endoscopic gastrostomy (PEG) placement in which the internal bumper migrates through the stomal tract to become embedded within the gastric wall. Excessive tension between the internal and external bumpers, causing ischemic necrosis of the gastric wall, is thought to be the main etiological factor. Several techniques for endoscopic management of BBS have been described using off-label devices. The Flamingo-Set is a novel, sphincterotome-like device, specifically designed for BBS management. We aimed to evaluate the effectiveness of the Flamingo device in a large, homogeneous cohort of patients with BBS. METHODS A guidewire is inserted through the external access of the PEG tube into the gastric lumen. The Flamingo device is then introduced into the stomach over the guidewire. This dedicated tool can be flexed by 180°, exposing a sphincterotome-like, cutting wire, which is used to incise the overgrown tissue until the PEG bumper is exposed. A retrospective, international multicenter cohort study was conducted on 54 patients between December 2016 and February 2019. RESULTS The buried bumper was successfully removed in 53 out of 55 procedures (96.4%). The median time for the endoscopic removal of the buried bumper was 22 minutes (range 5-60). Periprocedural endoscopic adverse events occurred in 7 procedures (12.7 %) and were successfully managed endoscopically. A median follow-up of 150 days (range 33-593) was performed in 29 patients (52.7%), during which no significant adverse events occurred. CONCLUSION Through our experience, we find that this dedicated novel device is safe, quick, and effective for minimally invasive, endoscopic management of BBS

Metabolic implication of tigecycline as an efficacious second-line treatment for sorafenib-resistant hepatocellular carcinoma.

Sorafenib represents the current standard of care for patients with advanced-stage hepatocellular carcinoma (HCC). However, acquired drug resistance occurs frequently during therapy and is accompanied by rapid tumor regrowth after sorafenib therapy termination. To identify the mechanism of this therapy-limiting growth resumption, we established robust sorafenib resistance HCC cell models that exhibited mitochondrial dysfunction and chemotherapeutic crossresistance. We found a rapid relapse of tumor cell proliferation after sorafenib withdrawal, which was caused by renewal of mitochondrial structures alongside a metabolic switch toward high electron transport system (ETS) activity. The translation-inhibiting antibiotic tigecycline impaired the biogenesis of mitochondrial DNA-encoded ETS subunits and limited the electron acceptor turnover required for glutamine oxidation. Thereby, tigecycline prevented the tumor relapse in vitro and in murine xenografts in vivo. These results offer a promising second-line therapeutic approach for advanced-stage HCC patients with progressive disease undergoing sorafenib therapy or treatment interruption due to severe adverse events