FGFR3 mutation increases bladder tumourigenesis by suppressing acute inflammation.

Recent studies of muscle-invasive bladder cancer show that FGFR3 mutations are generally found in a luminal papillary tumour subtype that is characterised by better survival than other molecular subtypes. To better understand the role of FGFR3 in invasive bladder cancer, we examined the process of tumour development induced by the tobacco carcinogen OH-BBN in genetically engineered models that express mutationally activated FGFR3 S249C or FGFR3 K644E in the urothelium. Both occurrence and progression of OH-BBN-driven tumours were increased in the presence of an S249C mutation compared to wild-type control mice. Interestingly, at an early tumour initiation stage, the acute inflammatory response in OH-BBN-treated bladders was suppressed in the presence of an S249C mutation. However, at later stages of tumour progression, increased inflammation was observed in S249C tumours, long after the carcinogen administration had ceased. Early-phase neutrophil depletion using an anti-Ly6G monoclonal antibody resulted in an increased neutrophil-to-lymphocyte ratio at later stages of pathogenesis, indicative of enhanced tumour pathogenesis, which supports the hypothesis that suppression of acute inflammation could play a causative role. Statistical analyses of correlation showed that while initial bladder phenotypes in morphology and inflammation were FGFR3-dependent, increased levels of inflammation were associated with tumour progression at the later stage. This study provides a novel insight into the tumour-promoting effect of FGFR3 mutations via regulation of inflammation at the pre-tumour stage in the bladder. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

[Features of cytokines profile in various forms of systemic inflammatory response syndrome in patients with acute calculous cholecystitis]. / Osobennosti tsitokinemii pri razlichnykh variantakh sindroma sistemnoi vospalitel'noi reaktsii u bol'nykh s ostrym kal'kuleznym kholetsistitom.

AIM: Comparative evaluation of systemic concentration of some cytokines in various forms of SIR in patients with acute calculous cholecystitis. MATERIAL AND METHODS: The study included 32 patients with acute calculous cholecystitis and SIR. According to ASSR/SCCM criteria SIR 2 was in 11, SIR 3 - in 8, SIR 4 - in 7 patients, 6 patients had sepsis. Serum TNF-α, IL-6, IL-4 and IL-10 were determined prior to surgery, in 3 and 7 days postoperatively by using of ELISA. RESULTS: There was a cytokine imbalance whose severity depended on SIR severity and presence of sepsis. CONCLUSION: Surgical intervention on background of basis therapy does not correct cytokine imbalance. So adequate pharmacological correction is required.

Deficiencies of Circulating Mucosal-associated Invariant T Cells and Natural Killer T Cells in Patients with Acute Cholecystitis.

Mucosal-associated invariant T (MAIT) cells and natural killer T (NKT) cells are known to play crucial roles in a variety of diseases, including autoimmunity, infectious diseases, and cancers. However, little is known about the roles of these invariant T cells in acute cholecystitis. The purposes of this study were to examine the levels of MAIT cells and NKT cells in patients with acute cholecystitis and to investigate potential relationships between clinical parameters and these cell levels. Thirty patients with pathologically proven acute cholecystitis and 47 age- and sex-matched healthy controls were enrolled. Disease grades were classified according to the revised Tokyo guidelines (TG13) for the severity assessment for acute cholecystitis. Levels of MAIT and NKT cells in peripheral blood were measured by flow cytometry. Circulating MAIT and NKT cell numbers were significantly lower in acute cholecystitis patients than in healthy controls, and these deficiencies in MAIT cells and NKT cell numbers were associated with aging in acute cholecystitis patients. Notably, a reduction in NKT cell numbers was found to be associated with severe TG13 grade, death, and high blood urea nitrogen levels. The study shows numerical deficiencies of circulating MAIT and NKT cells and age-related decline of these invariant T cells. In addition, NKT cell deficiency was associated with acute cholecystitis severity and outcome. These findings provide an information regarding the monitoring of these changes in circulating MAIT and NKT cell numbers during the course of acute cholecystitis and predicting prognosis.

Laparoscopic cholecystectomy in elderly patients: an evaluation of immunity.

OBJECTIVE: We sought to investigate the impact of laparoscopic cholecystectomy (LC) on the inflammatory response and immunological function of elderly patients compared with that on the younger ones. METHODS: Between June 2012 and June 2013, this prospective study investigated a total of 112 patients having the surgery of LC due to symptomatic cholelithiasis or polyps, among whom 52 were elderly patients with the age beyond 65 years old and the remaining 60 were younger than the age. Peripheral venous blood samples were taken from these patients prior to surgery and on post-operative days 1, 3 and 7, respectively. The perioperative clinical outcomes and immunological function results were analyzed and compared between the two groups divided by age. RESULTS: The demographics of the two groups did not differ except for the age. Surgical trauma seemed more serious for elderly patients as illustrated by the longer operating time, hospital stay and more quantity of patients got complication. Both groups indicated changes in inflammatory and immune aspects. Compared with the younger ones, elderly patients showed less quantity of preoperative basic immune cells, delayed immune responses after the surgical trauma of LC and hyporeactivity of inflammatory response when accepting LC. CONCLUSIONS: An examination of the inflammatory reaction and immune response after LC demonstrated that there are significant differences observed in two groups divided by age. Further studies with more samples are required to determine the exact relationship of perioperative immune change and higher adverse outcome rate of aged people.

[The cytokine profile in the patients with acute calculous cholecystitis and correction of its disorders].

The results of application of systemic cytokinotherapy and splenopid in patients, operated on for an acute calculous cholecystitis, are presented. While in patients of a control group the conventional basic therapy was conducted, to the patients of the main group the systemic cytokinotherapy and splenopid were conducted preoperatively and postoperatively on background of basic therapy during 3-10 days at average. In both groups preoperatively the reduction of interleukin-2 (IL-2) and gamma-interferon (IFNgamma) content were observed, as well as raising of the blood level of the tumor necrosis factor-alpha (TNF-alpha), IL-6 and IL-10. In the patients of a control group a tendency towards the studied indices normalisation was noted postoperatively, and in the patients of the main group the elimination of the organism cytokine state dysbalance was achieved. While doing comparative analysis of ratio of TNF-alpha/IL-10 and IL-2/IL-10 in the blood serum in the main group there was established, that up to the observation period end the both indices were close to the norm.

[Optimization of an acute destructive cholecystitis treatment using application of mini-laparotomy access, laser irradiation and regional lymphotropic therapy].

Comparative analysis of the treatment results in 120 patients, suffering destructive form of biliary calculous disease (DFBCD) was performed. Depending on operative access and postoperative conservative therapy applied the patients were divided into two groups. In the main group in 58 patients, suffering DFBCD, a minilaparotomy access was applied, using "mini-assistant" apparatus named after M. I. Prudkov and postoperatively--low-intensive laser irradiation and regional lymphotropic therapy. In a comparison group in 62 patients various laparotomic accesses were used, and a standard postoperative therapy was performed. Normalization of clinical, laboratory and immune indices in the main group were observed in twice earlier than in a control one, and economical together with moral-psychological effect was measured in reduction of the medicines quantity used as well as the patients stationary stay.

Systemic immune response after open versus laparoscopic cholecystectomy in acute cholecystitis: a prospective randomized study.

OBJECTIVE: Laparoscopic surgery is thought to reduce the postoperative immunologic effects of surgical trauma. The aim of this study is to evaluate the influence of surgical trauma on systemic inflammation and the immune response in acute cholecystitis. MATERIAL AND METHODS: Thirty-three patients with acute calculous cholecystitis were assigned to laparoscopic cholecystectomy (LC, n=18) or open cholecystectomy (OC, n=15). Blood samples were obtained preoperatively and on postoperative day 1 (24 h after surgery) and day 3 (72 h after surgery), and blood concentration of C-reactive protein (CRP), leukocyte subpopulations, as well as levels of tumor necrosis factor-alpha (TNF-alpha) ex vivo secretion by peripheral blood mononuclear cells (PBMCs) were measured in both groups. RESULTS: Hospitalization was significantly shorter in the LC group than in the OC group (LC group: 3.7+/-1.2 days versus OC group: 6.3+/-2.7 days, p=0.010). There was no postoperative morbidity in the LC group, but two patients in the OC group had postoperative complications. Postoperative TNF-alpha ex vivo secretion by PBMCs and PBMC counts in the OC group were significantly lower than those in the LC group (p=0.002). The CRP level declined by postoperative day 3, but was significantly less in the OC group than in the LC group (p<0.001). Postoperative monocyte counts significantly decreased in the OC group compared with those in the LC group (p=0.001). CONCLUSIONS: A laparoscopic approach appears to cause less surgical trauma and immunosuppression than open surgery in patients with acute cholecystitis.

Bile duct ligation induced acute inflammation up-regulates cyclooxygenase-2 content and PGE2 release in guinea pig gallbladder smooth muscle cell cultures.

INTRODUCTION: This study examines hypotheses that BDL induces increased guinea pig gallbladder smooth muscle PGE2 release by up-regulation of COX-2. METHODS: BDL, Sham and Control Hartley guinea pig gallbladders were placed in cell culture, grown to confluence and underwent Western Blot analysis for smooth muscle cell content of COX-1, COX-2, Prostacylin Synthase, actin, caldesmon, vinculin, meta-vinculin and tropomyosin and were assayed for basal release of 6-keto-PGF(1alpha), PGE2 and TxB2 by EIA. RESULTS: BDL did not alter content of smooth muscle cytoskeletal proteins. BDL for 48 h increased smooth muscle cell release of PGE2 and 6-keto-PGF(1alpha) by 3-fold or more when compared to the Control and Sham groups. Western Blot analysis showed increased content of COX-2 in the BDL group. CONCLUSIONS: BDL for 48 h markedly increased endogenous guinea pig smooth muscle cell PG release, which was due to increased COX-2 synthesis.