Safety of robotic cholecystectomy as index training procedure: the UK experience.

AIMS: To evaluate the safety profile of robotic cholecystectomy performed within the United Kingdom (UK) Robotic Hepatopancreatobiliary (HPB) training programme. METHODS: A retrospective evaluation of prospectively collected data from eleven centres participating in the UK Robotic HPB training programme was conducted. All adult patients undergoing robotic cholecystectomy for symptomatic gallstone disease or gallbladder polyp were considered. Bile duct injury, conversion to open procedure, conversion to subtotal cholecystectomy, length of hospital stay, 30-day re-admission, and post-operative complications were the evaluated outcome parameters. RESULTS: A total of 600 patients were included. The median age was 53 (IQR 65-41) years and the majority (72.7%; 436/600) were female. The main indications for robotic cholecystectomy were biliary colic (55.5%, 333/600), cholecystitis (18.8%, 113/600), gallbladder polyps (7.7%, 46/600), and pancreatitis (6.2%, 37/600). The median length of stay was 0 (IQR 0-1) days. Of the included patients, 88.5% (531/600) were discharged on the day of procedure with 30-day re-admission rate of 5.5% (33/600). There were no bile duct injuries and the rate of conversion to open was 0.8% (5/600) with subtotal cholecystectomy rate of 0.8% (5/600). CONCLUSION: The current study confirms that robotic cholecystectomy can be safely implemented to routine practice with a low risk of bile duct injury, low bile leak rate, low conversion to open surgery, and low need for subtotal cholecystectomy.

IL-17A - A regulator in acute inflammation: Insights from in vitro, in vivo and in silico studies.

Acute inflammation following sterile injury is both inevitable and necessary to restore homeostasis and promote tissue repair. However, when excessive, inflammation can jeopardize the viability of organs and cause detrimental systemic effects. Identifying key-regulators of the immune cascade induced by surgery is vital to attenuating excessive inflammation and its subsequent effects. In this review, we describe the emerging role of IL-17A as a key-regulator in acute inflammation. The role of IL-17A in chronic disease states, such as rheumatoid arthritis, psoriasis and cancer has been well documented, but its significance in acute inflammation following surgery, sepsis, or traumatic injury has not been well studied. We aim to highlight the role of IL-17A in acute inflammation caused by trauma, liver ischemia, and organ transplantation, as well as in post-operative surgical infections. Further investigation of the roles of this cytokine in acute inflammation may stimulate novel therapies or diagnostic modalities.

Computational Analysis Supports IL-17A as a Central Driver of Neutrophil Extracellular Trap-Mediated Injury in Liver Ischemia Reperfusion.

Hepatic ischemia reperfusion (I/R) is a clinically relevant model of acute sterile inflammation leading to a reverberating, self-sustaining inflammatory response with resultant necrosis. We hypothesized that computerized dynamic network analysis (DyNA) of 20 inflammatory mediators could help dissect the sequence of post-I/R mediator interactions that induce injury. Although the majority of measured inflammatory mediators become elevated in the first 24 h, we predicted that only a few would be secreted early in the process and serve as organizational centers of downstream intermediator complexity. In support of this hypothesis, DyNA inferred a central organizing role for IL-17A during the first 3 h of reperfusion. After that, DyNA revealed connections among almost all the inflammatory mediators, representing an ongoing cytokine storm. Blocking IL-17A immediately after reperfusion disassembled the inflammatory networks and protected the liver from injury. Disassembly of the networks was not achieved if IL-17A blockage was delayed two or more hours postreperfusion. Network disassembly was accompanied by decrease in neutrophil infiltration and neutrophil extracellular trap (NET) formation. By contrast, administration of recombinant IL-17A increased neutrophil infiltration, NET formation, and liver necrosis. The administration of DNase, a NET inhibitor, significantly reduced hepatic damage despite prior administration of IL-17A, and DNase also disassembled the inflammatory networks. In vitro, IL-17A was a potent promoter of NET formation. Therefore, computational analysis identified IL-17A's early, central organizing role in the rapid evolution of a network of inflammatory mediators that induce neutrophil infiltration and NET formation responsible for hepatic damage after liver I/R.

Neutrophil extracellular traps promote inflammation and development of hepatocellular carcinoma in nonalcoholic steatohepatitis.

Nonalcoholic steatohepatitis (NASH) is a progressive, inflammatory form of fatty liver disease. It is the most rapidly rising risk factor for the development of hepatocellular carcinoma (HCC), which can arise in NASH with or without cirrhosis. The inflammatory signals promoting the progression of NASH to HCC remain largely unknown. The propensity of neutrophils to expel decondensed chromatin embedded with inflammatory proteins, known as neutrophil extracellular traps (NETs), has been shown to be important in chronic inflammatory conditions and in cancer progression. In this study, we asked whether NET formation occurs in NASH and contributes to the progression of HCC. We found elevated levels of a NET marker in serum of patients with NASH. In livers from STAM mice (NASH induced by neonatal streptozotocin and high-fat diet), early neutrophil infiltration and NET formation were seen, followed by an influx of monocyte-derived macrophages, production of inflammatory cytokines, and progression of HCC. Inhibiting NET formation, through treatment with deoxyribonuclease (DNase) or using mice knocked out for peptidyl arginine deaminase type IV (PAD4-/- ), did not affect the development of a fatty liver but altered the consequent pattern of liver inflammation, which ultimately resulted in decreased tumor growth. Mechanistically, we found that commonly elevated free fatty acids stimulate NET formation in vitro. CONCLUSION: Our findings implicate NETs in the protumorigenic inflammatory environment in NASH, suggesting that their elimination may reduce the progression of liver cancer in NASH. (Hepatology 2018).

The Effects of Physical Exercise on Fatty Liver Disease.

The increasing prevalence of obesity has made nonalcoholic fatty liver disease (NAFLD) the most common chronic liver disease. As a consequence, NAFLD and especially its inflammatory form nonalcoholic steatohepatitis (NASH) are the fastest increasing etiology of end-stage liver disease and hepatocellular carcinoma. Physical inactivity is related to the severity of fatty liver disease irrespective of body weight, supporting the hypothesis that increasing physical activity through exercise can improve fatty liver disease. This review summarizes the evidence for the effects of physical exercise on NAFLD and NASH. Several clinical trials have shown that both aerobic and resistance exercise reduce the hepatic fat content. From clinical and basic scientific studies, it is evident that exercise affects fatty liver disease through various pathways. Improved peripheral insulin resistance reduces the excess delivery of free fatty acids and glucose for free fatty acid synthesis to the liver. In the liver, exercise increases fatty acid oxidation, decreases fatty acid synthesis, and prevents mitochondrial and hepatocellular damage through a reduction of the release of damage-associated molecular patterns. In conclusion, physical exercise is a proven therapeutic strategy to improve fatty liver disease.

Drag reducing polymers decrease hepatic injury and metastases after liver ischemia-reperfusion.

INTRODUCTION: Surgery, a crucial therapeutic modality in the treatment of solid tumors, can induce sterile inflammatory processes which can result in metastatic progression. Liver ischemia and reperfusion (I/R) injury, an inevitable consequence of hepatic resection of metastases, has been shown to foster hepatic capture of circulating cancer cells and accelerate metastatic growth. Efforts to reduce these negative consequences have not been thoroughly investigated. Drag reducing polymers (DRPs) are blood-soluble macromolecules that can, in nanomolar concentrations, increase tissue perfusion, decrease vascular resistance and decrease near-wall microvascular concentration of neutrophils and platelets thereby possibly reducing the inflammatory microenvironment. We hypothesize that DRP can potentially be used to ameliorate metastatic capture of tumor cells and tumor growth within the I/R liver. METHODS: Experiments were performed utilizing a segmental ischemia model of mice livers. Five days prior or immediately prior to ischemia, murine colon adenocarcinoma cells (MC38) were injected into the spleen. DRP (polyethylene oxide) or a control of low-molecular-weight polyethylene glycol without drag reducing properties were administered intraperitoneally at the onset of reperfusion. RESULTS: After three weeks from I/R, we observed that liver I/R resulted in an increased ability to capture and foster growth of circulating tumor cells; in addition, the growth of pre-existing micrometastases was accelerated three weeks later. These effects were significantly curtailed when mice were treated with DRPs at the time of I/R. Mechanistic investigations in vivo indicated that DRPs protected the livers from I/R injury as evidenced by significant decreases in hepatocellular damage, neutrophil recruitment into the liver, formation of neutrophil extracellular traps, deposition of platelets, formation of microthrombi within the liver sinusoids and release of inflammatory cytokines. CONCLUSIONS: DRPs significantly attenuated metastatic tumor development and growth. DRPs warrant further investigation as a potential treatment for liver I/R injury in the clinical setting to improve cancer-specific outcomes.

IL-33 exacerbates liver sterile inflammation by amplifying neutrophil extracellular trap formation.

BACKGROUND & AIMS: Neutrophils and liver sinusoidal endothelial cells (LSECs) both contribute to sterile inflammatory injury during ischemia/reperfusion (I/R), a well-known liver surgical stress. Interleukin-33 (IL-33) has been shown to drive neutrophil infiltration during inflammatory responses through its receptor ST2. We recently reported that infiltrating neutrophils form neutrophil extracellular traps (NETs), which exacerbate sterile inflammatory injury in liver I/R. Here, we sought to determine the role of IL-33 in NET formation during liver sterile inflammation. METHODS: Evaluation of IL-33 forming NETs was investigated using a partial liver I/R model to generate sterile injury in healthy WT, IL-33 and ST2 knockouts. Serum levels of IL-33 and myeloperoxidase (MPO)-DNA complex were measured in both humans and mice after the first surgery. Liver damage was assessed. Mouse neutrophil depletion was performed by intraperitoneal injection of anti-Ly6G antibody before I/R. RESULTS: Patients undergoing liver resection showed a significant increase in serum IL-33 compared to healthy volunteers. This coincided with higher serum MPO-DNA complexes. NET formation was decreased in IL-33 and ST2 knockout mice compared with control mice, after liver I/R. IL-33 or ST2 deficiency protected livers from I/R injury, whereas rIL-33 administration during I/R exacerbated hepatotoxicity and systemic inflammation. In vitro, IL-33 is released from LSECs to promote NET formation. IL-33 deficient LSECs failed to induce NETs. ST2 deficient neutrophils limited their capacity to form NETs in vitro and adoptive transfer of ST2 knockout neutrophils to neutrophil-depleted WT mice significantly decreased NET formation. CONCLUSIONS: Data establish that IL-33, mainly released from LSECs, causes excessive sterile inflammation after hepatic I/R by inducing NET formation. Therapeutic targeting of IL-33/ST2 might extend novel strategies to minimize organ damage in various clinical settings associated with sterile inflammation. LAY SUMMARY: Liver ischemia and reperfusion injury results in the formation of neutrophil extracellular traps, which contribute to organ damage in liver surgeries. Herein, we show that IL-33 is released from liver sinusoidal endothelial cells to promote NET formation during liver I/R, which exacerbates inflammatory cascades and sterile inflammation.

Thorn-induced pseudotumour of the fibula.

Foreign body granulomas are common in the hand and foot. Diagnosis of the same is often delayed or missed, especially in unusual locations and in the paediatric age group. Radiographs usually reveal an osteolytic lesion with absence of periosteal reaction and non-metallic foreign bodies are not visualised in plain radiographs. An ultrasound and MRI can delineate the foreign body. Clinical and radiological presentation mimics that of a tumour and hence is rightly called pseudotumour. We present a case of thorn-induced pseudotumour of the fibula in a 5-year-old boy.

Routine neonatal circumcision for the prevention of urinary tract infections in infancy.

BACKGROUND: Neonatal circumcision is a fairly common surgical procedure that may be carried out for medical reasons, one of them being prevention of urinary tract infections (UTI) in male infants. Circumcision could help in reducing the incidence of UTI by reducing periurethral bacterial colonization, which is accepted as a potential risk factor in UTI. Evidence is needed to inform the benefits or harm for the routine use of this intervention. OBJECTIVES: To assess the effectiveness and safety of routine neonatal circumcision for the prevention of UTIs in infancy. SEARCH METHODS: We searched the Cochrane Neonatal Review Group Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. We completed this search 30 June 2011. SELECTION CRITERIA: Randomised controlled trials and quasi-randomised controlled trials. DATA COLLECTION AND ANALYSIS: Two review authors had planned to independently screen studies, extract data and assess risk of bias using standard Cochrane Collaboration methodologies. We did not identify any studies for inclusion in this review. MAIN RESULTS: We did not identify any relevant studies after a comprehensive search of the literature. AUTHORS' CONCLUSIONS: We were unable to identify any randomised controlled trials on the use of routine neonatal circumcision for prevention of UTI in male infants. Until further evidence becomes available, clinicians should continue to base their decisions on position statements and recommendations and in conjunction with the opinions of the children's parents.