E. Andrews

Exploitation of the Toll-like receptor system in cancer: a doubled- edged sword?

The toll-like receptor (TLR) system constitutes a pylogenetically ancient, evolutionary conserved, archetypal pattern recognition system, which underpins pathogen recognition by and activation of the immune system. Toll-like receptor agonists have long been used as immunoadjuvants in anti cancer immunotherapy. However, TLRs are increasingly implicated in human disease pathogenesis and an expanding body of both clinical and experimental evidence suggests that the neoplastic process may subvert TLR signalling pathways to advance cancer progression. Recent discoveries in the TLR system open a multitude of potential therapeutic avenues. Extrapolation of such TLR system manipulations to a clinical oncological setting demands care to prevent potentially deleterious activation of TLR-mediated survival pathways. Thus, the TLR system is a double-edge sword, which needs to be carefully wielded in the setting of neoplastic disease.

Bacterial endotoxin enhances colorectal cancer cell adhesion and invasion through TLR-4 and NF-κB-dependent activation of the urokinase plasminogen activator system

Perioperative exposure to lipopolysaccharide (LPS) is associated with accelerated metastatic colorectal tumour growth. LPS directly affects cells through Toll-like receptor 4 (TLR-4) and the transcription factor NF-κB. The urokinase plasminogen activator (u-PA) system is intimately implicated in tumour cell extracellular matrix (ECM) interactions fundamental to tumour progression. Thus we sought to determine if LPS directly induces accelerated tumour cell ECM adhesion and invasion through activation of the u-PA system and to elucidate the cellular pathways involved. Human colorectal tumour cell lines were stimulated with LPS. u-PA concentration, u-PA activity, active u-PA, surface urokinase plasminogen activator receptor (u-PAR) and TLR-4 expression were assessed by ELISA, colorimetric assay, western blot analysis and flow cytometry respectively. In vitro tumour cell vitronectin adhesion and ECM invasion were analysed by vitronectin adhesion assay and ECM invasion chambers. u-PA and u-PAR function was inhibited with anti u-PA antibodies or the selective u-PA inhibitors amiloride or WXC-340, TLR-4 by TLR-4-blocking antibodies and NF-κB by the selective NF-κB inhibitor SN-50. LPS upregulates u-PA and u-PAR in a dose-dependent manner, enhancing in vitro tumour cell vitronectin adhesion and ECM invasion by >40% (P<0.01). These effects were ameliorated by u-PA and u-PAR inhibition. LPS activates NF-κB through TLR-4. TLR-4 and NF-κB inhibition ameliorated LPS-enhanced u-PA and u-PAR expression, tumour cell vitronectin adhesion and ECM invasion. LPS promotes tumour cell ECM adhesion and invasion through activation of the u-PA system in a TLR-4- and NF-κB-dependent manner.

A review of clinical guidelines.

Clinical guidelines are increasingly used in patient management but few clinicians are familiar with their origin or appropriate application.

Transanal endoscopic microsurgery repair of rectourethral fistula after high-intensity focused ultrasound ablation of prostate cancer

A 68-year-old man presented, 3 years after diagnosis of a T1cN0M0 Gleason 6 prostate cancer, to a consultant urologist who had an interest in high-intensity focused ultrasound (HIFU) treatment of prostate cancer. Initial treatment with hormone therapy was effective but had to be stopped because the patient developed intolerable side effects. As a result of stopping hormone therapy, the prostatic specific antigen (PSA) level rose. The patient had a significant cardiac history, including recent coronary artery stenting and ventricular tachyarrhythmias that necessitated insertion of an indwelling dual-chamber automatic implantable cardioverter defibrillator (AICD) system, and therefore radical surgery was not recommended. After consideration of seed implant brachytherapy, the patient decided in favour of HIFU, which was performed using a Sonablate 500 (Focus Surgery Inc., Indianapolis, IN, USA) at standard settings. Unfortunately, 2 weeks after the procedure, the patient described urine leakage from the rectum. Flexible sigmoidoscopy demonstrated a 5-mm fistula, 7–8 cm from the anal verge in the anterior midline position, consistent with a rectourethral fistula (Fig. 1). Despite urinary and faecal diversion, the fistula failed to close. After discussion, a transanal endoscopic microsurgical (TEM) repair of the fistula was planned. The edges of the fistula were excised and a full-thickness flap of the rectal wall was mobilized. The urethral opening was closed with a single Z suture using 4 ⁄ 0 Vicryl (polyglactin 910) (Ethicon Inc, Somerville, NJ, USA). The full-thickness rectal wound was closed using a continuous 3 ⁄ 0 PDS (polydioxanone) suture with silver clips in lieu of knots. Postoperative recovery was uncomplicated. An interval voiding urethrogram showed no evidence of fistulation, and a water-soluble enema confirmed no leakage from the rectum to the urethra. Urodynamic studies showed normal flow and continence of urine. The colostomy was reversed without incident and the patient’s bowel function remains normal. Colonoscopy 1 year after repair showed a well-healed scar at the site of the previous fistula. The patient’s PSA remains low without hormonal therapy, demonstrating no compromise of his oncological outcome.

Successful laparoscopic management of an incarcerated obturator hernia

Obturator hernia is a rare pelvic hernia that occurs primarily in multiparous, elderly (>70 years of age), thin females. This case highlights the successful laparoscopic mesh repair of an incarcerated obturator hernia in an octogenarian. The authors report a case of an incarcerated obturator hernia in an elderly female with subsequent high-grade small bowel and its successful laparoscopic operative management. A review of the relevant literature was also performed following a search on the online literature databases such as PUBMED and EMBASE. Laparoscopic mesh repair of the incarcerated obturator hernia and an ipsilateral femoral hernia found incidentally was successfully performed. A review of the literature showed a significant burden of morbidity and mortality associated with obturator hernias. Laparoscopic mesh repair has been previously shown to be a safe therapeutic modality. Small bowel obstruction and leg pain in a thin elderly lady should arouse suspicion for an incarcerated obturator hernia. Laparoscopic management of an incarcerated obturator hernia is a feasible and safe therapeutic option.

Inhibition of urokinase plasminogen activator with a novel enzyme inhibitor, wxc-340, ameliorates endotoxin and surgery-accelerated growth of murine metastases

The urokinase plasminogen activator (u-PA) is intimately associated with tumour invasion and metastases. Surgery facilitates accelerated metastatic tumour growth in murine models, a phenomenon related to elevated perioperative bacterial lipopolysaccaride (LPS) and inflammatory cytokine levels. The objectives of the study were to examine the role of u-PA in cytokine-enhanced tumour cell invasion in vitro and surgery-induced accelerated metastatic tumour growth in vivo and to assess the potential benefit of a novel selective u-PA inhibitor WXC-340 in this setting. CT-26 murine colorectal carcinoma cells were stimulated with LPS, tumour necrosis factor α (TNF-α) and interleukin 6 (IL-6). Cell supernatant u-PA expression and activity were determined using a colorimetric assay and Western blot analysis, respectively. Baseline and cytokine-stimulated in vitro invasion were assessed using ECmatrix invasion chambers. Two established murine models of accelerated metastatic tumour growth were used to investigate the consequences of u-PA inhibition on postoperative metastatic tumour burden. The effect of u-PA inhibition in vitro and in vivo was examined using the novel selective u-PA inhibitor, WXC-340. Proinflammatory cytokine stimulation significantly enhanced in vitro u-PA expression, activity and extracellular matrix invasion by approximately 50% compared to controls (P<0.05). This was abrogated by WXC-340. In vivo WXC-340 almost completely ameliorated both LPS- and surgery-induced, metastatic tumour growth compared to controls (P>0.05). In conclusion, u-PA cascade is actively involved in cytokine-mediated enhanced tumour cell invasion and LPS and surgery-induced metastatic tumour growth. Perioperative u-PA inhibition with WXC-340 may represent a novel therapeutic paradigm.

Changes in Outcome and Management of Perforated Diverticulitis over a 10 Year Period

Abstract Introduction : Aggressive non-operative intervention and evolving surgical strategies have altered the treatment of perforated diverticulitis in the acute setting. These strategies have predominantly been implemented over the last decade. The aim of this study was to assess the impact of this on patient outcome during their index admission and subsequently. Methods : Consecutive patients admitted with acute diverticulitis between 1999 and 2010 were identified. Patient demographics, treatment strategies and outcomes were collected and analysed. Patients who had an episode of perforated diverticulitis during their index admission were followed. Results : 739 patients were admitted with acute diverticulitis. Of these, 115 (15.7%) had perforated diverticulitis. 53 (47.8%) underwent an intervention. There was a reduction in the mean age of patients admitted with acute diverticulitis of 8.9% over the study period (p = 0.002). There was a significant increase in the use of CT scanning pre-operatively (p < 0.001). ‘Non-resectional’ interventions have emerged in the form of laparoscopic lavage (n = 5) and percutaneous abscess drainage (n = 14). There was associated improved length of stay (p < 0.001). Conclusion : Outcomes for patients with perforated diverticulitis have improved, contributed to in part by an increased use of non-resectional management strategies.

An evaluation of the relationship between Enterobius vermicularis infestation and acute appendicitis in a paediatric population – A retrospective cohort study

BACKGROUND Enterobius vermicularis is an often unexpected finding in appendectomy specimen, most commonly seen in paediatric cases. Predicting the presence of E. vermicularis in the setting of appendectomy is important to avoid unnecessary appendectomy and associated morbidity. We sought to identify the incidence of E. vermicularis in a paediatric population undergoing appendectomy for clinically suspected acute appendicitis and identify predictive factors for E. vermicularis. METHODS This study was performed in an 800-bed University Teaching Hospital, in the Republic of Ireland. We identified all paediatric appendectomies performed at our institute from January to December 2012 using prospectively maintained operating theatre logbooks. In-hospital Histopathology database, medical notes and operative findings were reviewed for each patient and relevant data recorded. Statistical analysis was performed using IBM SPSS, version 21. RESULTS In total 182 paediatric appendectomies were performed during the year 2012 for clinically suspected acute appendicitis. Demographics included: Mean age 11.14 years (3-16), gender 1M: 1F. 58.8% of procedures were completed laparoscopically, 39% open and 2.2% were converted. The negative appendectomy rate was 22.5%. The annual incidence of E. vermicularis in acute appendicitis specimen from a paediatric cohort at our institute was 7% (1 in 14). In specimen containing E. vermicularis, 69% had no evidence of appendicitis and of those that had, no gangrene or perforation was seen. The presence of E. vermicularis in paediatric patients with RIF pain may be predicted by Eosinophilia (p = 0.016), normal WCC (p = 0.034) and normal Neutrophil count (p = 0.014). CONCLUSIONS E. vermicularis is responsible for 7% of acute appendicitis. It is responsible for a significantly higher negative appendectomy rate which if predicted may avoid unnecessary appendectomy and associated morbidity.

Enhanced recovery after elective colorectal surgery: now the standard of care

Enhanced recovery programmes have been studied in randomised trials with evidence of quicker recovery of gut function, reduced morbidity, mortality and hospital stay and improved physiological and nutritional outcomes. They aim to reduce the physiological and psychological stress of surgery and consequently the uncontrolled stress response. The key elements, reduced pre-operative fasting, intravenous fluid restriction and early feeding after surgery, are in conflict with traditional management plans but are supported by strong clinical evidence. Given the strength of the current data enhanced recovery should now be the standard of care.

A new specifically designed forceps for chest drain insertion

Insertion of a chest drain can be associated with serious complications. It is recommended that the drain is inserted with blunt dissection through the chest wall but there is no specific instrument to aid this task. We describe a new reusable forceps that has been designed specifically to facilitate the insertion of chest drains.A feasibility study of its use in patients who required a chest drain as part of elective cardiothoracic operations was undertaken. The primary end-point was successful and accurate placement of the drain. The operators also completed a questionnaire rating defined aspects of the procedure. The new instrument was used to insert the chest drain in 30 patients (19 male, 11 female; median age 61.5 years (range 16-81 years)). The drain was inserted successfully without the trocar in all cases and there were no complications. Use of the instrument rated as significantly easier relative to experience of previous techniques in all specified aspects. The new device can be used to insert intercostal chest drains safely and efficiently without using the trocar or any other instrument.