Increased expression of IL-1ß in adipose tissue in obesity influences the development of colon cancer by promoting inflammation.

Excess adiposity contributes to the development of colon carcinoma (CC). Interleukin (IL)-1ß is a pro-inflammatory cytokine relevant in obesity-associated chronic inflammation and tumorigenic processes. We herein aimed to study how obesity and CC affects the expression of IL1B, and to determine the impact of IL-1ß on the regulation of metabolic inflammation and gut barrier function in the context of obesity and CC. Samples from 71 volunteers were used in a case-control study and a rat model of diet-induced obesity (DIO). Furthermore, bariatric surgery was used to determine the effect of weight loss on the intestinal gene expression levels of Il1b. To evaluate the effect of IL-1ß and obesity in CC, we treated the adenocarcinoma cell line HT-29 with IL-1ß and the adipocyte-conditioned medium (ACM) from patients with obesity. We showed that obesity (P < 0.05) and CC (P < 0.01) upregulated the transcript levels of IL1B in visceral adipose tissue as well as in the colon from patients with CC (P < 0.01). The increased expression of Il1b in the ileum and colon in DIO rats decreased after weight loss achieved by either sleeve gastrectomy or caloric restriction (both P < 0.05). ACM treatment on HT-29 cells upregulated (P < 0.05) the transcripts of IL1B and CCL2, while reducing (P < 0.05) the expression of the anti-inflammatory ADIPOQ and MUC2 genes. Additionally, IL-1ß upregulated (P < 0.01) the expression of CCL2 and TNF whilst downregulating (P < 0.01) the transcript levels of IL4, ADIPOQ and TJP1 in HT-29 cells. We provide evidence of the important role of IL-1ß in obesity-associated CC by directly promoting inflammation.

Liver transplantation in colorectal metastases. Is there an indication for this procedure?

Almost 25 % of patients with colorectal cancer present metastases at the time of diagnosis and 50 % go on to develop metastases in the course of the disease. Surgical resection is the only curative treatment although only between 20 % and 30 % of patients present resectable lesions. Although liver transplantation is contraindicated in unresectable metastases of colorectal cancer, ever since the publication of the results of a pilot study there has been renewed interest in transplantation in these patients. In two consecutive trials overall and recurrence-free 5-year survival rates of 83 % and 35 % respectively, have been reported, Currently several trials are ongoing which are expected to allow the patient selection criteria for the indication of liver transplantation to be refined.

Single anastomosis duodeno-ileal bypass with sleeve gastrectomy generates sustained improvement of glycemic control compared with sleeve gastrectomy in the diet-induced obese rat model.

Bariatric surgery has become a recognized and effective procedure for treating obesity and type 2 diabetes (T2D). Our objective was to directly compare the caloric intake-independent effects of sleeve gastrectomy (SG) and single anastomosis duodenoileal bypass with SG (SADI-S) on glucose tolerance in rats with diet-induced obesity (DIO) and to elucidate the differences between bariatric surgery and caloric restriction.A total of 120 adult male Wistar rats with DIO and insulin resistance were randomly assigned to surgical (sham operation, SG, and SADI-S) and dietary (pair-feeding the amount of food eaten by animals undergoing the SG or SADI-S surgeries) interventions. Body weight and food intake were weekly monitored, and 6 weeks after interventions, fasting plasma glucose, oral glucose and insulin tolerance tests, plasma insulin, adiponectin, GIP, GLP-1, and ghrelin levels were determined.The body weight of SADI-S rats was significantly (p < 0.001) lower as compared to the sham-operated, SG, and pair-fed groups. Furthermore, SADI-S rats exhibited decreased whole body fat mass (p < 0.001), lower food efficiency rates (p < 0.001), and increased insulin sensitivity, as well as improved glucose and lipid metabolism compared to that of the SG and pair-fed rats.SADI-S was more effective than SG, or caloric restriction, in improving glycemic control and metabolic profile, with a higher remission of insulin resistance as well as long-term weight loss.

Effect of guanylin peptides on pancreas steatosis and function in experimental diet-induced obesity and after bariatric surgery.

Introduction: Obesity contributes to ectopic fat deposition in non-adipose organs, including the pancreas. Pancreas steatosis associates with inflammation and ß-cell dysfunction, contributing to the onset of insulin resistance and type 2 diabetes. An improvement of pancreatic steatosis and indices of insulin resistance is observed following bariatric surgery, but the underlying mechanisms remain unknown. We sought to analyze whether guanylin (GUCA2A) and uroguanylin (GUCA2B), two gut hormones involved in the regulation of satiety, food preference and adiposity, are involved in the amelioration of pancreas fat accumulation after bariatric surgery. Methods: Pancreas steatosis, inflammation, islet number and area were measured in male Wistar rats with diet-induced obesity (n=125) subjected to surgical (sham operation and sleeve gastrectomy) or dietary (pair-fed to the amount of food eaten by gastrectomized animals) interventions. The tissue distribution of guanylate cyclase C (GUCY2C) and the expression of the guanylin system were evaluated in rat pancreata by real-time PCR, Western-blot and immunohistochemistry. The effect of guanylin and uroguanylin on factors involved in insulin secretion and lipogenesis was determined in vitro in RIN-m5F ß-cells exposed to lipotoxic conditions. Results: Sleeve gastrectomy reduced pancreas steatosis and inflammation and improved insulin sensitivity and synthesis. An upregulation of GUCA2A and GUCY2C, but not GUCA2B, was observed in pancreata from rats with diet-induced obesity one month after sleeve gastrectomy. Interestingly, both guanylin and uroguanylin diminished the lipotoxicity in palmitate-treated RIN-m5F ß-cells, evidenced by lower steatosis and downregulated lipogenic factors Srebf1, Mogat2 and Dgat1. Both guanylin peptides reduced insulin synthesis (Ins1 and Ins2) and release from RIN-m5F ß-cells, but only guanylin upregulated Wnt4, a factor that controls ß-cell proliferation and function. Discussion: Together, sleeve gastrectomy reduced pancreatic steatosis and improved ß-cell function. Several mechanisms, including the modulation of inflammation and lipogenesis as well as the upregulation of GUCA2A in the pancreas, might explain this beneficial effect of bariatric surgery.

Increased Aquaporin-7 Expression Is Associated with Changes in Rat Brown Adipose Tissue Whitening in Obesity: Impact of Cold Exposure and Bariatric Surgery.

Glycerol is a key metabolite for lipid accumulation in insulin-sensitive tissues. We examined the role of aquaporin-7 (AQP7), the main glycerol channel in adipocytes, in the improvement of brown adipose tissue (BAT) whitening, a process whereby brown adipocytes differentiate into white-like unilocular cells, after cold exposure or bariatric surgery in male Wistar rats with diet-induced obesity (DIO) (n = 229). DIO promoted BAT whitening, evidenced by increased BAT hypertrophy, steatosis and upregulation of the lipogenic factors Pparg2, Mogat2 and Dgat1. AQP7 was detected in BAT capillary endothelial cells and brown adipocytes, and its expression was upregulated by DIO. Interestingly, AQP7 gene and protein expressions were downregulated after cold exposure (4 °C) for 1 week or one month after sleeve gastrectomy in parallel to the improvement of BAT whitening. Moreover, Aqp7 mRNA expression was positively associated with transcripts of the lipogenic factors Pparg2, Mogat2 and Dgat1 and regulated by lipogenic (ghrelin) and lipolytic (isoproterenol and leptin) signals. Together, the upregulation of AQP7 in DIO might contribute to glycerol influx used for triacylglycerol synthesis in brown adipocytes, and hence, BAT whitening. This process is reversible by cold exposure and bariatric surgery, thereby suggesting the potential of targeting BAT AQP7 as an anti-obesity therapy.

Delays to surgery following chemoradiotherapy lead to poorer oncologic outcomes in patients with localized pancreatic adenocarcinoma.

BACKGROUND: although neoadjuvant chemoradiotherapy (NCRT) and surgery are accepted as treatments for pancreatic ductal adenocarcinoma (PDAC), some authors have highlighted the risks of delaying surgery. The objective of this study was to analyze the impact of prolonging the time interval between NCRT and surgery (NCRT-TTS) in PDAC. METHODS: patients treated with NCRT and pancreatoduodenectomy (PD) were identified. Clinical, histopathological variables were analyzed about whether NCRT-TTS was greater or less than 50 days. Five- and ten-year overall survival (OS) and disease-free survival (DFS) were analyzed depending on whether the delay was greater than 50 days or not. RESULTS: one hundred (8.3 %) of 120 eligible patients underwent PD (61 male, median age of 63.7 years). In 71 (71 %) patients, the median NCRT-TTS was 39 (24-50) days and in 29 (29 %) 61 days. There were no differences between the two groups except for carbohydrate antigen 19-9 (CA 19-9) levels, the incidence of cholangitis, American Society of Anesthesiologists (ASA) score, intraoperative blood transfusions and degree of histopathologic response (all p < 0.001). Median DFS when the NCRT-TTS was less than 50 days was higher than when the interval exceeded 50 days (51.0 months [95 % CI: 20.3-81.6] vs 17.0 months [95 %: CI 10.9-23.0]; HR [95 % CI 1.08-3.46], p = 0.026). Five-year DFS was higher in the subgroup with NCRT-TTS of less than 50 days compared to the group with an interval of more than 50 days (43.5 % vs 23.65 % [HR 1.812, 95 % CI: 1.001-3.280], p = 0.050). CONCLUSIONS: an increase in the NCRT-TTS > 50 days is associated with poorer OS and DFS in patients with localized PDAC treated with NCRT and PD.

Predictors of postoperative complications and readmissions in laparoscopic pancreas resection: Results of a cohort 105 consecutive cases. A retrospective study.

INTRODUCTION: Laparoscopic resection of the pancreas (LRP) has been implemented to a varying degree because it is technically demanding and requires a long learning curve. In the present study we analyze the risk factors for complications and hospital readmissions in a single center study of 105 consecutive LRPs. METHODS: We conducted a retrospective study using a prospective database. Data were collected on age, gender, BMI, ASA score, type of surgery, histologic type, operative time, hospital stay, postoperative complications, degree of severity and hospital readmission. RESULTS: The cohort included 105 patients, 63 females and 42 males with a median age and BMI of 58 (53-70) and 25.5 (22,2-27.9) respectively. Eighteen (17%) central pancreatectomies, 5 (4.8%) enucleations, 81 (77.6%) distal pancreatectomies and one total pancreatectomy were performed. Fifty-six patients (53.3%) experienced some type of complication, of which 13 (12.3%) were severe (Clavien-Dindo > IIIb) and 11 (10.5%) patients were readmitted in the first 30 days after surgery. In the univariate analysis, age, male gender, ASA score, central pancreatectomy and operative time were significantly associated with the development of complications (P <0.05). In the multivariate analysis, male gender (OR 7.97; 95% CI 1.08-58.88)), severe complications (OR 59.40; 95% CI, 7.69-458.99), and the development of intrabdominal collections (OR 8.97; 95% CI, 1.28-63.02)) were associated with hospital readmission. CONCLUSIONS: Age, male gender, ASA score, operative time and central pancreatectomy are associated with a higher incidence of complications. Male gender, severe complications and intraabdominal collections are associated with more hospital readmissions.

Netrin-1 Promotes Visceral Adipose Tissue Inflammation in Obesity and Is Associated with Insulin Resistance.

Netrin (NTN)-1 exhibits pro- and anti-inflammatory roles in different settings, playing important roles in the obesity-associated low-grade chronic inflammation. We aimed to determine the impact of NTN-1 on obesity and obesity-associated type 2 diabetes, as well as its role in visceral adipose tissue (VAT) inflammation. A total of 91 subjects were enrolled in this case-control study. Circulating levels of NTN-1 and its receptor neogenin (NEO)-1 were determined before and after weight loss achieved by caloric restriction and bariatric surgery. mRNA levels of NTN1 and NEO1 were assessed in human VAT, liver, and peripheral blood mononuclear cells. In vitro studies in human visceral adipocytes and human monocytic leukemia cells (THP-1)-derived macrophages were performed to analyze the impact of inflammation-related mediators on the gene expression levels of NTN1 and its receptor NEO1 as well as the effect of NTN-1 on inflammation. Increased (p < 0.001) circulating concentrations of NTN-1 in obesity decreased (p < 0.05) after diet-induced weight loss being also associated with a reduction in glucose (p < 0.01) and insulin levels (p < 0.05). Gene expression levels of NTN1 and NEO1 were upregulated (p < 0.05) in the VAT from patients with obesity with the highest expression in the stromovascular fraction cells compared with mature adipocytes (p < 0.01). NTN1 expression levels were enhanced (p < 0.01) under hypoxia and by inflammatory factors in both adipocytes and macrophages. Adipocyte-conditioned media strongly upregulated (p < 0.001) the mRNA levels of NTN1 in macrophages. The treatment of adipocytes with NTN-1 promoted the upregulation (p < 0.05) of pro-inflammatory and chemotactic molecules as well as its receptor NEO1. Collectively, these findings suggest that NTN-1 regulates VAT chronic inflammation and insulin resistance in obesity.

Improved Adipose Tissue Function after Single Anastomosis Duodeno-Ileal Bypass with Sleeve-Gastrectomy (SADI-S) in Diet-Induced Obesity.

Bariatric surgery has been recognized as the safest and most effective procedure for controlling type 2 diabetes (T2D) and obesity in carefully selected patients. The aim of the present study was to compare the effects of Sleeve Gastrectomy (SG) and Single Anastomosis Duodenoileal Bypass with SG (SADI-S) on the metabolic profile of diet-induced obese rats. A total of 35 four-week-old male Wistar rats were submitted to surgical interventions (sham operation, SG and SADI-S) after 4 months of being fed a high-fat diet. Body weight, metabolic profile and the expression of molecules involved in the control of subcutaneous white (SCWAT), brown (BAT) and beige (BeAT) adipose tissue function were analyzed. SADI-S surgery was associated with significantly decreased amounts of total fat pads (p < 0.001) as well as better control of lipid and glucose metabolism compared to the SG counterparts. An improved expression of molecules involved in fat browning in SCWAT and in the control of BAT and BeAT differentiation and function was observed following SADI-S. Together, our findings provide evidence that the enhanced metabolic improvement and their continued durability after SADI-S compared to SG rely, at least in part, on the improvement of the BeAT phenotype and function.

Neoadjuvant treatment in localized and resectable cancer of the pancreas: a new therapeutic paradigm.

Ductal carcinoma of the pancreas (DCP) is one of the most devastating tumors and ranks fourth among the causes of death from cancer. It is estimated that by 2030 it will be among the top three "cancer killers", along with lung cancer and hepatocarcinoma. Overall survival at five years from diagnosis is 5-10% in centers with experience. At the time of diagnosis, only 10-15% of patients present tumors localized to the pancreas and which are susceptible to curative resection (R0) (resectable tumors). Fifty percent present with systemic disease (stage IV) and 30-35% present borderline or locally advanced tumors which are generally not resectable due to vascular invasion.

Acute pancreatitis: an opportunity for gastroenterology hospitalists?

Acute pancreatitis (AP) is the third most frequent cause of hospital admissions for digestive disorders in the US and Europe after digestive bleeding and cholelithiasis/cholecystitis. The incidence of AP ranges from 15 to 100 cases per 100,000 inhabitants per year, and has been steadily increasing in recent years. In Spain, the reported incidence is 72 patients per 100,000 inhabitants per year. The most frequent cause is biliary lithiasis (50 %-60 % of cases); fortunately, 80 % of patients have only mild symptoms-as defined by the revised Atlanta Classification-and progress favorably, although mortality rate is 4.2 %. Clinical guidelines explicitly indicate that laparoscopic cholecystectomy should be performed during the first 48-72 hours or at the time of hospital admission in mild cases of biliary origin.

Small pancreatic neuroendocrine tumors: observing and monitoring or prompt surgical resection.

Over recent decades there has been a significant increase in the annual incidence of neuroendocrine tumors of the pancreas (PanNETs), from 0.4 to 0.8 per 100,000 inhabitants, due to a more widespread use of more sensitive imaging techniques (cross-sectional and functional imaging).

Comparison of phenotypes and outcomes following resection of incidental versus symptomatic pancreatic neuroendocrine tumors.

BACKGROUND AND AIM: fifty to 70 percent of pancreatic neuroendocrine tumors are diagnosed incidentally. The objective of this study was to compare the phenotype and oncological outcomes of incidental versus symptomatic pancreatic neuroendocrine tumors. METHODS: a retrospective study was performed, identifying all incidental and symptomatic tumors resected between 2000 and 2019. Baseline characteristics, symptoms, operative variables and pathological stage were all recorded. Patterns of recurrence and overall and disease-free survival were analyzed in both groups. RESULTS: fifty-one incidental and 45 symptomatic pancreatic tumor resections were performed. Symptomatic tumors were more frequent in females (29 vs 17; p = 0.005) and younger patients (median years; 50 vs 58; p = 0.012) and were detected at a more advanced stage (p = 0.027). There were no differences in location and most resections (n = 49; 51 %) were performed laparoscopically. There were no operative mortalities and 17 (17.7 %) severe complications (≥ IIIb on the Clavien-Dindo classification) were recorded with no differences between the two groups. With a median follow-up of 64.4 months (range 13.5-90), overall survival at five and ten years was 89.7 % and 72.8 % for the non-incidental tumors and 80.9 % and 54.6 % for the incidental tumors (p = ns), respectively. Disease-free survival in both groups (excluding M1a) was 71.2 % and 47.5 %, and 93.7 % and 78.1 %, respectively (p = ns). CONCLUSIONS: symptomatic tumors are more frequent in females and present at more advanced pathological stages. There were no significant differences in overall and disease-free survival between the two groups. Resection of incidental tumors ≥ 1.5-2 cm seems advisable, although each case should be assessed on an individual basis.

Critical stenosis of the celiac trunk by the arcuate ligament, successfully treated by a laparoscopic approach.

A 56-year-old female was referred to our department with a five-month history of progressive abdominal pain related to physical exertion and copious meals. The pain was located in the mesogastric region and the right flank and remitted when the patient lay in the recumbent position with the knees bent. The patient reported nausea and a weight loss of 12 kg over the previous ten years. She had been diagnosed 18 years previously with hereditary leiomyomatosis and renal cancer and had undergone a hysterectomy and partial nephrectomy.

The Differential Expression of the Inflammasomes in Adipose Tissue and Colon Influences the Development of Colon Cancer in a Context of Obesity by Regulating Intestinal Inflammation.

BACKGROUND: Inflammasomes maintain tissue homeostasis and their altered regulation in the colon, and the adipose tissue (AT) leads to chronic activation of inflammatory pathways promoting colon cancer (CC) development. We aimed to analyze the potential involvement of inflammasomes in obesity-associated CC. METHODS: Ninety-nine volunteers [61 with obesity (OB) and 38 normoponderal (NP)] further subclassified according to the approved protocol for the diagnosis of CC (58 without CC and 41 with CC) were included in the case-control study. RESULTS: CC (P<0.01) and obesity (P<0.01) were accompanied by increased mRNA levels of NLRP3, NLRP6, ASC, IL1B and NOD2 in VAT. Contrarily, patients with CC exhibited a downregulation of NLRP6 and IL18 in their colon. Additionally, we revealed that the decreased Nlrp1 (P<0.05), Nlrp3 (P<0.01) and Nlrp6 (P<0.01) mRNA levels in the colon from obese rats significantly increase (P<0.05) after caloric restriction. Adipocyte-conditioned media obtained from subjects with obesity reduced (P<0.01) the mRNA of NLRP3 as well as molecules involved in maintaining the intestinal integrity (MUC2, CLDN1 and TJP1) and the anti-inflammatory factors FGF21, KLF4, and IL33 and in HT-29 cells. We also found that the knockdown of NLRP6 in HT-29 cells significantly upregulated (P<0.05) the mRNA of NLRP1 and NLRP3 and inhibited (P<0.05) the expression levels of MUC2. Finally, we showed that the incubation of HT-29 with Akkermansia muciniphila influence (P<0.05) the inflammasome expression profile as well as intestinal integrity-related genes and aberrant inflammation. CONCLUSIONS: These findings provide evidence that the downregulated levels of NLRP6 and IL18 in the colon from patients with CC may be responsible for a reduced intestinal-barrier integrity, triggering local inflammation, which in turn acts on the dysfunctional AT in obesity, increasing the expression of different inflammasome components and flaring up a vicious cycle of uncontrollable inflammatory cascades that favours a pro-tumorigenic microenvironment.

Conversion to Open Surgery in Laparoscopic Colorectal Cancer Resection: Predictive Factors and its Impact on Long-Term Outcomes. A Case Series Study.

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.