Predictive factors of recurrence for laparoscopic repair of primary and incisional ventral hernias with single mesh from a multicenter study.

Laparoscopic ventral hernia repair (LVHR) is a widely practiced treatment for primary (PH) and incisional (IH) hernias, with acceptable outcomes. Prevention of recurrence is crucial and still highly debated. Purpose of this study was to evaluate predictive factors of recurrence following LVHR with intraperitoneal onlay mesh with a single type of mesh for both PH and IH. A retrospective, multicentre study of data collected from patients who underwent LVHR for PH and IH with an intraperitoneal monofilament polypropylene mesh from January 2014 to December 2018 at 8 referral centers was conducted, and statistical analysis for risk factors of recurrence and post-operative outcomes was performed. A total of 1018 patients were collected, with 665 cases of IH (65.3%) and 353 of PH (34.7%). IH patients were older (p < 0.001), less frequently obese (p = 0.031), at higher ASA class (p < 0.001) and presented more frequently with large, swiss cheese type and border site defects (p < 0.001), compared to PH patients. Operative time and hospital stay were longer for IH (p < 0.001), but intraoperative and early post-operative complications and reinterventions were comparable. IH group presented at major risk of recurrence than PH (6.7% vs 0.9%, p < 0.001) and application of absorbable tacks resulted a significative predictive factor for recurrence increasing the risk by 2.94 (95% CI 1.18-7.31). LVHR with a light-weight polypropylene mesh has low intra- and post-operative complications and is appropriate for both IH and PH. Non absorbable tacks and mixed fixation system seem to be preferable to absorbable tacks alone.

Screening for Squamous Cell Anal Cancer in HIV Positive Patients: A Five-Year Experience.

AIM: Potential screening modalities for early diagnosis of squamous cell anal cancer (SCC) in HIV patients include digital anorectal examination (DARE), anal Papanicolaou testing (Pap test), human papilloma virus (HPV) co-testing, and high-resolution anoscopy. The aim of this study was to demonstrate the results of a five-year screening program for SCC in HIV patients. MATERIALS AND METHODS: We conducted a retrospective study on 204 HIV patients who underwent a screening program for SCC from October 2010 to January 2015. All patients were screened by DARE, anal Pap test, including HPV test and cytology, and high-resolution video-proctoscopy (HR-VPS) with and without acetic acid 3%. Depending on macroscopic appearance and biopsies, patients underwent observation or treatment. Median follow-up was 36 months. RESULTS: Cytologic abnormalities (Cyt+) for high-risk HPV genotypes were recorded in 34% of patients. HR-VPS was positive in 59 patients (29%), of whom 13 patients (22%) were positive for warts; the rest have typical features of anal intraepithelial neoplasia (AIN). Sixteen (8%) patients had AIN (AIN I-III) and underwent wide local excision, ablation, or imiquimod. Absence of progression was recorded. Fourteen patients (7%) had SCC: eight (57%) with no evidence of recurrence, two (14%) had recurrence, and four (29%) died from metastatic disease. CONCLUSIONS: Our data demonstrated a successful screening program in preventing SCC in HIV patients. We demonstrate the advantages of progression towards SCC. Moreover, we used a new screening tool, the HR-VPS, a low-cost and manageable instrument to collect patients' long-term data.

BAR502, a dual FXR and GPBAR1 agonist, promotes browning of white adipose tissue and reverses liver steatosis and fibrosis.

Non-alcoholic steatohepatitis (NASH) is a highly prevalent chronic liver disease. Here, we have investigated whether BAR502, a non-bile acid, steroidal dual ligand for FXR and GPBAR1, reverses steato-hepatitis in mice fed a high fat diet (HFD) and fructose. After 9 week, mice on HFD gained ≈30% of b.w (P < 0.01 versus naïve) and were insulin resistant. These overweighting and insulin resistant mice were randomized to receive HFD or HFD in combination with BAR502. After 18 weeks, HFD mice developed NASH like features with severe steato-hepatitis and fibrosis, increased hepatic content of triacylglycerol and cholesterol and expression of SREPB1c, FAS, ApoC2, PPARα and γ, α-SMA, α1 collagen and MCP1 mRNAs. Treatment with BAR502 caused a ≈10% reduction of b.w., increased insulin sensitivity and circulating levels of HDL, while reduced steatosis, inflammatory and fibrosis scores and liver expression of SREPB1c, FAS, PPARγ, CD36 and CYP7A1 mRNA. BAR502 increased the expression of SHP and ABCG5 in the liver and SHP, FGF15 and GLP1 in intestine. BAR502 promoted the browning of epWAT and reduced liver fibrosis induced by CCl4. In summary, BAR502, a dual FXR and GPBAR1 agonist, protects against liver damage caused by HFD by promoting the browning of adipose tissue.

Dissociation of intestinal and hepatic activities of FXR and LXRα supports metabolic effects of terminal ileum interposition in rodents.

The farnesoid X receptor (FXR) and the liver x receptors (LXRs) are bile acid-activated receptors that are highly expressed in the enterohepatic tissues. The mechanisms that support the beneficial effects of bariatric surgery are only partially defined. We have investigated the effects of ileal interposition (IT), a surgical relocation of the distal ileum into the proximal jejunum, on FXR and LXRs in rats. Seven months after surgery, blood concentrations of total bile acids, taurocholic acid, an FXR ligand, and taurohyocholic acid, an LXRα ligand, were significantly increased by IT (P < 0.05). In contrast, liver and intestinal concentrations of conjugated and nonconjugated bile acids were decreased (P < 0.05). These changes were associated with a robust induction of FXR and FXR-regulated genes in the intestine, including Fgf15, a negative regulator of bile acid synthesis. IT repressed the liver expression of glucose-6-phosphatase (G6PC) and phosphoenolpyruvate carboxykinase (Pepck), two gluconeogenetic genes, along with the expression of LXRα and its target genes sterol regulatory element-binding protein (Srebp) 1c and fatty acid synthase (Fas) in the liver. Treating IT rats with chenodeoxycholic acid ameliorated insulin signaling in the liver. Whether confirmed in human settings, these results support the association of pharmacological therapies with bariatric surgeries to exploit the selective activation of intestinal nuclear receptors.

Epigenetic modulation by methionine deficiency attenuates the potential for gastric cancer cell dissemination.

INTRODUCTION: Methionine dependency occurs frequently in tumor cells. Here we have investigated the effect of methionine deficiency on metastatic potential of gastric cancer cells in vitro and in vivo. MATERIALS AND METHODS: Model of peritoneal carcinomatosis and xenograft was generated by intraperitoneal or subcutaneous implantation of gastric cancer cells in NOD-SCID mice. In comparison to control medium, 3-day culture of MKN45, MKN74, and KATOIII cells in a methionine-deficient medium inhibited cell proliferation, increased the rate of cell apoptosis, and reduced cell adhesion and migration. In the xenograft model induced by implantation of MNK45 and MNK74 cells, two cycles of methionine-deficient diet reduced the tumor growth. Further on, a 10-day cycle of methionine-deficient diet reduced the number of peritoneal nodules in the model of peritoneal carcinomatosis induced by MKN45 cells injection. Finally, a microarray analysis of the methylation of promoter CpG islets demonstrated that methionine deficiency reduced the promoter methylation of E-cadherin whose expression was markedly increased in vivo and in vitro. RESULTS: In summary, we have provided evidence that a methionine-deficient diet modulates the growth of gastric tumor cells and in vitro deficiency of methionine increased apoptosis and decreased cellular adhesion and migration associated to epigenetic change of E-cadherin gene, in vivo and in vitro.

Gene expression changes induced by HIPEC in a murine model of gastric cancer.

BACKGROUND: Peritoneal carcinogenesis (PC) is the most frequent pattern of metastasis in patients with locally advanced gastric cancer. Despite this, there is a consensus on the use of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) for the treatment of PC from gastric cancer. The molecular mechanisms involved in beneficial effects of HIPEC remain unexplored. MATERIALS AND METHODS: Human gastric cancer MKN45 cells were injected into the peritoneal cavity of immune-deficient NOD-SCID mice. After induction of PC, the animals were randomized into five groups: HIPEC with mitomycin and cisplatin; normothermic intraperitoneal chemotherapy (NIPEC); normothermic intraperitoneal saline; hyperthermic intraperitoneal saline alone; no treatment. After 10 days of treatment, the mice were sacrificed and the extent of PC was assessed. RESULTS: Compared with the other groups of treatment, HIPEC reduced the extent and severity of peritoneal dissemination as measured by assessing the total number of peritoneal and mesenteric nodules (p<0,05) and the HIPEC procedure increased median survival significantly. By gene array analysis, HIPEC was found to effectively modulate the expression of a subset of genes involved in formation of peritoneal metastasis, including adenomatous polyposis coli; beta (3) subunit of the integrin gene; chemokine stromal cell-derived factor-1 receptor; spleen tyrosine kinase; vascular endothelial growth factor receptor 3; collagen, type IV, alpha 2 and Carbossi-terminal binding proteins 1. CONCLUSION: In the present study we have provided evidence that HIPEC protects against peritoneal dissemination in a mouse model of peritoneal gastric carcinogenesis and brings about specific changes in gene expression wich may be related to this protection.

Mechanistic role of p38 MAPK in gastric cancer dissemination in a rodent model peritoneal metastasis.

Peritoneal dissemination is a highly frequent complication of poorly differentiated gastric cancers for which no effective therapies are available. Constitutive activation of mitogen-activated protein kinases (MAPKs) signaling cascades is recognized as a causative factor in the malignant transformation of several carcinoma cell types. In the present study we provide evidence that p38 MAPK inhibition protects against gastric cancer cells dissemination in a mouse model of peritoneal carcinomatosis. Administering mice with ML3403 and SB203580, potent and selective p38 MAPK inhibitors, attenuate the formation of neoplastic foci induced by intraperitoneal inoculation of gastric cancer cells. By gene array analysis we found that such a protective effect correlates with a robust downregulation in the expression of CXC chemokine receptor-4, Fms-related tyrosine kinase 4 (FLT4), the non-receptor spleen tyrosine kinase (SYK) and the collagen α2(IV) (COL4A2) in neoplasic foci. Inhibition of p38 MAPK in vivo increased the sensitivity of tumor cells to cisplatin and associated with a robust downregulation in the expression of the multidrug resistance (MDR)-1, a well defined marker of resistance to chemotherapy. In summary, p38 MAPK inhibition by a small molecule is beneficial in preventing the peritoneal dissemination of poorly differentiated gastric cancer cells by acting at multiple check-points in the process of attachment and diffusion of tumor cells in the peritoneum.