Simple Summary Netrin-1 (NTN-1) regulates obesity-associated low-grade inflammation, being also involved in the control of cell migration and proliferation. We aim to study whether excess visceral adipose tissue in patients with obesity and colon cancer is associated with increased NTN1 and the expression levels of its main receptors, promoting an inflammatory microenvironment that favours colon cancer development. Increased expression levels of NTN1 and its receptor NEO1 in the visceral adipose tissue from patients with obesity and colon cancer together with elevated DCC and UNC5B mRNA levels in patients with colon cancer were found. Moreover, the treatment of colorectal cancer cells with NTN-1 and with the adipocyte-derived secretome obtained from patients with obesity increased the migration of colorectal cancer cells. These results suggest that NTN-1 plays an important role in obesity-associated colon cancer development. Netrin (NTN)-1, an extracellular matrix protein with a crucial role in inflammation, is dysregulated during obesity (OB) and influences colon cancer (CC) progression. To decipher the mechanisms underlying CC development during obesity, we examined the expression of NTN1 and its receptors in the visceral adipose tissue (VAT) of 74 (25 normal weight (NW)) (16 with CC) and 49 patients with OB (12 with CC). We also evaluated the effect of caloric restriction (CR) on the gene expression levels of Ntn1 and its receptors in the colon from a rat model fed a normal diet. The impact of adipocyte-conditioned media (ACM) from patients with OB and NTN-1 was assessed on the expression levels of neogenin 1(NEO1), deleted in colorectal carcinomas (DCC) and uncoordinated-5 homolog B (UNC5B) in Caco-2 and HT-29 human colorectal cell lines, as well as on Caco-2 cell migration. Increased NTN1 and NEO1 mRNA levels in VAT were due to OB (p < 0.05) and CC (p < 0.001). In addition, an upregulation in the expression levels of DCC and UNC5B in patients with CC (p < 0.01 and p < 0.05, respectively) was observed. Decreased (p < 0.01) Ntn1 levels in the colon from rats submitted to CR were found. In vitro experiments showed that ACM increased DCC (p < 0.05) and NEO1 (p < 0.01) mRNA levels in HT-29 and Caco-2 cell lines, respectively, while UNC5B decreased (p < 0.01) in HT-29. The treatment with NTN-1 increased (p < 0.05) NEO1 mRNA levels in HT-29 cells and DCC (p < 0.05) in both cell lines. Finally, we revealed a potent migratory effect of ACM and NTN-1 on Caco-2 cells. Collectively, these findings point to increased NTN-1 during OB and CC fuelling cancer progression and exerting a strong migratory effect on colon cancer cells.

Background: Laparoscopic resection is the treatment of choice for colorectal cancer. Rates of conversion to open surgery range between 7% and 30% and controversy exists as to the effect of this on oncologic outcomes. The objective of this study was to analyze what factors are predictive of conversion and what effect they have on oncologic outcomes. Methods: From a prospective database of patients undergoing laparoscopic surgery between 2000 and 2018 a univariate and multivariate analyses were made of demographic, pathologic, and surgical variables together with complementary treatments comparing purely laparoscopic resection with conversions to open surgery. Overall and disease-free survival were compared using the Kaplan-Meier method. Results: Of a total of 829 patients, 43 (5.18%) converted to open surgery. In the univariate analysis, 12 variables were significantly associated with conversion, of which left-sided resection [odds ratio (OR): 2.908; P=0.02], resection of the rectum (OR: 4.749, P=0.014), and local invasion of the tumor (OR: 6.905, P<0.01) were independently predictive factors in the multiple logistic regression. Female sex was associated with fewer conversions (OR: 0.375, P=0.012). The incidence and pattern of relapses were similar in both groups and there were no significant differences between overall and disease-free survival. Conclusions: Left-sided resections, resections of the rectum and tumor invasion of neighboring structures are associated with higher rates of conversion. Female sex is associated with fewer conversions. Conversion to open surgery does not compromise oncologic outcomes at 5 and 10 years.

Dysfunctional adipose tissue (AT) in the context of obesity leads to chronic inflammation together with an altered extracellular matrix (ECM) remodelling, favouring cancer development and progression. Recently, the influence of dermatopontin (DPT) in AT remodelling and inflammation has been proposed. We aimed to evaluate the role of DPT in the development of obesity-associated colon cancer (CC). Samples obtained from 73 subjects [26 lean (LN) and 47 with obesity (OB)] were used in a case-control study. Enrolled subjects were further subclassified according to the established diagnostic protocol for CC (42 without CC and 31 with CC). In vitro studies in the adenocarcinoma HT-29 cell line were performed to analyse the impact of pro- and anti-inflammatory mediators on the transcript levels of DPT as well as the effect of DPT on ECM remodelling and inflammation. Although obesity increased (p < 0.05) the circulating levels of DPT, its concentrations were significantly decreased (p < 0.05) in patients with CC. Gene expression levels of DPT in the colon from patients with CC were downregulated and, oppositely, a tendency towards increased mRNA levels in visceral AT was found. We further showed that DPT expression levels in HT-29 cells were enhanced (p < 0.05) by inflammatory factors (LPS, TNF-alpha and TGF-beta), whereas the anti-inflammatory IL-4 decreased (p < 0.05) its expression levels. We also demonstrated that DPT upregulated (p < 0.05) the mRNA of key molecules involved in ECM remodelling (COL1A1, COL5A3, TNC and VEGFA) whereas decorin (DCN) expression was downregulated (p < 0.05) in HT-29 cells. Finally, we revealed that the adipocyte-conditioned medium obtained from volunteers with OB enhanced (p < 0.01) the expression of DPT in HT-29 and Caco-2 cells. The decreased circulating and expression levels of DPT in the colon together with the tendency towards increased levels in visceral AT in patients with CC and its influence on the expression of ECM proteins suggest a possible role of DPT in the OB-associated CC.

Background: Excess adiposity leads to a dysfunctional adipose tissue that contributes to the development of obesity-associated comorbidities such as type 2 diabetes (T2D). Interleukin-1 receptor antagonist (IL-1RA) is a naturally occurring antagonist of the IL-1 receptor with anti-inflammatory properties. The aim of the present study was to compare the circulating concentrations of IL-1RA and its mRNA expression in visceral adipose tissue (VAT) in subjects with normal weight (NW), obesity with normoglycemia (OB-NG), or obesity with impaired glucose tolerance or T2D (OB-IGT&T2D) and to analyze the effect of changes in body fat percentage (BF%) on IL-1RA levels. Methods: Serum concentrations of IL-1RA were measured in 156 volunteers. Expression of IL1RN mRNA in VAT obtained from 36 individuals was determined. In addition, the concentrations of IL-1RA were measured before and after weight gain as well as weight loss following a dietetic program or Roux-en-Y gastric bypass (RYGB). Results: Serum levels of IL-1RA were significantly increased in individuals with obesity, being further increased in the OBIGT&T2D group (NW 440 +/- 316, OB-NG 899 +/- 562, OB-IGT&T2D 1265 +/- 739 pg/mL; P<0.001) and associated with markers of inflammation and fatty liver. IL1RN mRNA expression in VAT was significantly increased in the OB-IGT&T2D group and correlated in the global cohort with the mRNA expression of SPP1, CCL2, CD68, and MMP9. Levels of IL-1RA were not modified after modest changes in BF%, but RYGB-induced weight loss significantly decreased IL-1RA concentrations from 1233 +/- 1009 to 660 +/- 538 pg/ mL (P<0.001). Conclusion: Serum IL-1RA concentrations are increased in patients with obesity being further elevated in obesity-associated IGT and T2D in association with markers of adipose tissue dysfunction. The mRNA expression of IL1RN is markedly increased in VAT of subjects with obesity and T2D in relation with genes involved in macrophage recruitment, inflammation and matrix remodeling. Serum IL-1RA concentrations are reduced when a notable amount of BF% is loss. Measurement of IL-1RA is an excellent biomarker of adipose tissue dysfunction in obesity-associated metabolic alterations.

Objective: The protein microfibril-associated glycoprotein (MAGP)-1 constitutes a crucial extracellular matrix protein. We aimed to determine its impact on visceral adipose tissue (VAT) remodelling during obesity-associated colon cancer (CC). Methods: Samples obtained from 79 subjects (29 normoponderal (NP) (17 with CC) and 50 patients with obesity (OB) (19 with CC)) were used in the study. Circulating concentrations of MAGP-1 and its gene expression levels (MFAP2) in VAT were analysed. The impact of inflammation-related factors and adipocyte-conditioned media (ACM) on MFAP2 mRNA levels in colon adenocarcinoma HT-29 cells were further analysed. The effects of MAGP-1 in the expression of genes involved in the extracellular matrix (ECM) remodelling and tumorigenesis in HT-29 cells was also explored. Results: Obesity (p < 0.01) and CC (p < 0.001) significantly decreased MFAP2 gene expression levels in VAT whereas an opposite trend in TGFB1 mRNA levels was observed. Increased mRNA levels of MFAP2 after the stimulation of HT-29 cells with lipopolysaccharide (LPS) (p < 0.01) and interleukin (IL)-4 (p < 0.01) together with a downregulation (p < 0.05) after hypoxia mimicked by CoCl2 treatment was observed. MAGP-1 treatment significantly enhanced the mRNA levels of the ECM-remodelling genes collagen type 6 alpha 3 chain (COL6A3) (p < 0.05), decorin (DCN) (p < 0.01), osteopontin (SPP1) (p < 0.05) and TGFB1 (p < 0.05). Furthermore, MAGP-1 significantly reduced (p < 0.05) the gene expression levels of prostaglandin-endoperoxide synthase 2 (COX2/PTGS2), a key gene controlling cell proliferation, growth and adhesion in CC. Interestingly, a significant decrease (p < 0.01) in the mRNA levels of MFAP2 in HT-29 cells preincubated with ACM from volunteers with obesity compared with control media was observed. Conclusion: The decreased levels of MAGP-1 in patients with obesity and CC together with its capacity to modulate key genes involved in ECM remodelling and tumorigenesis suggest MAGP-1 as a link between AT excess and obesity-associated CC development.

EUS-guided anastomoses with LAMS have emerged as a therapeutic option for patients with obstruction of the digestive tract. However, the long-term permeability of these anastomoses remains unknown. Most of the published cases involve the gastric wall and experience in distal obstruction is limited to few case reports. We review our series of patients treated with LAMS for gastrointestinal obstruction and describe the technical success according to the anastomotic site and the long-term follow-up in those cases in which the stent migrated spontaneously or was removed. Out of 30 cases treated with LAMS, EUS-guided anastomosis did not involve the gastric wall in 6 patients. These procedures were technically more challenging as two failures were recorded (2/6, 33%) while technical success was achieved in 100% of the cases in which the stent was placed through the gastric wall. In two of the patients, one with entero-enteric and another with recto-colic anastomosis, stent removal after spontaneous displacement was followed by long term permeability of the EUS-guided anastomosis (172 and 234 days respectively). In a EUS-guided gastroenterostomy the stent was removed at 118 days, but closure of the fistula was confirmed 26 days later. Our experience suggests that LAMS placement between bowel loops is feasible and might allow the creation of an anastomosis with long-term patency. As compared to LAMS placement between bowel loops, when LAMS are placed through the gastric wall, removal of the LAMS seems to lead to closure of the fistula.

Background: Laparoscopic resection is the ideal treatment of colon cancer. The aim of the study was to analyze the predictive factors for postoperative complications and their impact on oncologic outcomes in laparoscopic resections in colon cancer. Materials and Methods: In all patients undergoing elective laparoscopic surgery the number and degree of severity of postoperative complications were recorded and classified according to Clavien-Dindo. A univariate analysis was made of the demographic, surgical, and oncologic variables of patients with and without complications. The statistically significant variables were then entered into a multivariate model. In both groups overall and disease-free survival were analyzed using Kaplan-Meier estimates. Results: Of 524 patients, 138 (26.3%) experienced some type of complication, 110 less severe (79.7%) and 28 (20.4%) severe. Twenty-nine conversions to open surgery occurred (5.5%) and hospital mortality was 0.2%. In the multivariate analysis, use of corticosteroids [odds ratio (OR): 3.619], oral anticoagulants (OR: 3.49), blood transfusions (OR: 4.30), and conversion to open surgery (OR: 3.93) were significantly associated with the development of complications. However, sigmoid resections were associated with fewer complications (OR: 0.45). Overall 5-year and 10-year survival in both groups, was 83.3%, 74.1%, 76.0%, and 67.1%, respectively (P = 0.18). Disease-free survival at 5 and 10 years, excluding stage IV tumors, was 88.6% and 90.4%, respectively (P = 0.881). Conclusions: The use of corticosteroids, oral anticoagulants, blood transfusions, and conversion to open surgery are all independent predictive factors of postoperative complications. Sigmoid resections are associated with fewer complications. In laparoscopic resections of the colon, complications do not negatively affect long-term oncologic outcomes.