The composition of immune infiltrates strongly affects the prognosis of patients with colorectal cancer (CRC). Interleukin (IL)-33 and regulatory T cells (Tregs) in the tumor microenvironment have been separately implicated in CRC; however their contribution to intestinal carcinogenesis is still controversial. Here, we reveal that IL-33 signaling promotes CRC by changing the phenotype of Tregs. In mice with CRC, tumor-infiltrating Tregs preferentially upregulate IL-33 receptor (ST2), and IL-33/ST2 signaling positively correlates with tumor number and size. Transcriptomic and flow cytometry analyses demonstrate that ST2 expression induces a more activated and migratory phenotype in FOXP3 + Tregs, which favors their accumulation in the tumor environment. Consequently, genetic ablation of St2 reduces Treg infiltration and concomitantly enhances the frequencies of effector CD8 + T cells, thereby restraining CRC. Mechanistically, IL-33 curtails IL-17 production by FOXP3 + Tregs and inhibits Th17 differentiation. In humans, numbers of activated ST2-expressing Tregs are increased in blood and tumor lesions of CRC patients, suggesting a similar mode of regulation. Together, these data indicate a central role of IL-33/ST2 signaling in shaping an immunosuppressive environment during intestinal tumorigenesis. Blockade of this pathway may provide a strategy to modulate the composition of CRC immune infiltrates.

Laparoscopic adjustable gastric banding (LAGB) has been considered by many as the treatment of choice for morbid obesity because of its simplicity and encouraging early results. The aim of this prospective study was to critically assess the effects, complications, and outcome after LAGB in the long-term, based on a 12-year experience. Between June 1998 and June 2009, all patients with implantation of a LAGB have been enrolled in a prospective clinical trial. Results were recorded and classified, with special regard to long-term complications, re-operation rate, and graft survival. LAGB was performed in 167 patients (120 female, 47 male) with a mean age of 40.1±5.2 years. Operative mortality was 0%, overall 1.2% (not band-related). Overall patient follow-up was 94.0%. Mean excess weight loss (EWL) after 1, 2, 5, 8, and 10 years was 31.1±7.5% (p<0.005), 44.2±6.5% (p< 0.001), 50.3±6.9% (p<0.001), 51.7±6.3% (p<0.001), and 48.8±6.0% (p<0.001), respectively. The non-responder rate (EWL<30%) after 2, 5, 8, and 10 years was 24.5%, 18.3%, 12.5%, and 16.6%, respectively. The early complication rate (<30 days) was 7.8% (13/167), with 10 minor and three major complications. Late complications (>30 days) occurred in 40.1% (67/167), of whom seven were minor and 60 were major complications (three band infections, two band migrations, 11 band leakages, two slippings/pouch dilatations, two band intolerances, and 40 esophageal dilatations). The overall re-operation rate was 20.4% (34/167). The graft survival of the implanted band after 2, 5, 8, 10, and 12 years was 98.8%, 94.0%, 86.8%, 85.0%, and 85.0%, respectively. The failure rate of the procedure after 2, 5, 8, and 10 years was 25.7%, 24.3%, 25.7%, and 31.6%, respectively. In the present long-term highparticipation follow-up study, LAGB is a safe and effective surgical treatment for morbid obesity. However, the high complication, re-operation, and long-term failure rates lead to the conclusion that LAGB should be performed in selected cases only, until reliable criteria for patients at low risk for long-term complications are developed.

The Molecular Adsorbent Recirculating System (MARS) represents an attractive artificial liver support system for the treatment of liver insufficiency. However, neither indications for MARS treatment (i.e., after extended liver resection) nor criteria for discontinuation of therapy have been evaluated. Therefore, we analyzed the clinical data of all our surgical patients who received MARS treatment for acute liver failure (n = 7). The aim of the study was to identify prognostic indicators for survival. Four of 174 patients resected for hepatic malignancy at our institution received a total of 13 MARS treatments. Two additional patients were successfully bridged to orthotopic liver transplantation with seven MARS treatments and one patient was MARS supported after liver transplantation of a steatotic graft with three MARS treatments. Five of the seven patients survived and were dismissed an average of 31 days, ranging from 17 to 47 days, after the final MARS treatment. No technical complications or adverse effects were observed during the MARS treatments. Important prognostic factors for hepatic recovery and survival were indocyanin green plasma disappearance rates greater than 5%/min and an increase in clotting factor V levels after each MARS treatment. We conclude that MARS therapy can be an effective treatment of postoperative liver insufficiency in the surgical hepatobiliary unit.

Colorectal cancer (CRC) is one of the most frequent malignancies worldwide. Despite considerable progress in early detection and treatment, there is still an unmet need for novel antitumor therapies, particularly in advanced CRC. Regulatory T cells (Tregs) are increased in the peripheral blood and tumor tissue of CRC patients. Recently, transient ablation of tumorassociated Tregs was shown to foster CD8+ T cell-mediated anti-tumoral immunity in murine CRC models. However, before considering therapies, targeting Tregs in cancer patients and detailed knowledge of the phenotype and features of tumor-associated Tregs is indispensable.Here we demonstrate in a murine model of inflammation-induced CRC that tumor-associated Tregs are mainly of thymic origin and equipped with a specific set of molecules strongly associated with enhanced migratory properties. Particularly, a dense infiltration of Tregs in mouse and human CRC lesions correlated with increased expression of the orphan chemoattractant receptor GPR15 on these cells. Comprehensive gene expression analysis revealed that tumor-associated GPR15+ Tregs have a Th17-like phenotype, thereby producing IL-17 and TNF-α. Gpr15 deficiency repressed Treg infiltration in CRC, which paved the way for enhanced anti-tumoral CD8+ T cell immunity and reduced tumorigenesis. In conclusion, GPR15 represents a promising novel target for modifying T cell-mediated anti-tumoral immunity in CRC.