S D Killeen

Provider volume and outcomes for oncological procedures.

Oncological procedures may have better outcomes if performed by high‐volume providers.

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.

Mycotic aneurysm of the popliteal artery secondary to Streptococus pneumoniae: a case report and review of the literature.

IntroductionCases of true mycotic popliteal artery aneurysm are rare. Presentation is variable but invasive and non-invasive investigations collectively facilitate diagnosis and guide operative procedures. Definitive treatment generally utilizes surgical intervention with excision and reconstruction using autologous vein graft. Prolonged targeted antibiotic therapy is an important adjuvant.Case presentationWe describe the clinical presentation, radiological investigations and strategies on the management of a 47-year-old Caucasian Irish man who presented with a mycotic aneurysm of the popliteal artery due to thromboembolisation from Streptococus pneumoniae endocarditis.ConclusionCases of true mycotic popliteal artery aneurysms are rare. To the best of our knowledge this is the first documented case of a popliteal artery mycotic aneurysm developing secondary to Streptococus pneumoniae highlighting the changing profile of causative microorganisms.

Daily Diurnal Variation in Admissions for Ruptured Abdominal Aortic Aneurysms

BackgroundMany vascular events, such as myocardial infarction and cerebrovascular accident, demonstrate a circadian pattern of presentation. Blood pressure is intimately related to these pathologies and is the one physiological variable consistently associated with abdominal aortic aneurysm rupture. It also demonstrates a diurnal variation. The purpose of this study was to determine if rupture of an abdominal aortic aneurysm (RAAA) exhibits a diurnal variation.MethodsA retrospective cohort-based study was performed to determine the timing of presentation of RAAA to the vascular unit of Cork University Hospital over a 15-year period. Time of admission, symptom onset, and co-morbidities such as hypertension were noted. Fournier’s analysis and chi-squared analysis were performed. To ameliorate possible confounding factors, patients admitted with perforated peptic ulcers were examined in the same manner.ResultsA total of 148 cases of RAAA were identified, with a male preponderance (71.7% [124] male versus 29.3% [44] female patients) and a mean age of 74.4 ± 7.2 years at presentation. 70.9% (105) were known to have hypertension, 52.2% (77) were current smokers, and 46.8% (69) were being treated for chronic obstructive airway disease (COAD). Time of symptom onset was recorded in 88.5% (131) of patients. There was a marked early morning peak in RAAA admissions, with the highest number of RAAA being admitted between 08.00 and 09.59. A second, smaller peak was observed at 14.00-15.59. These findings were suggestive of diurnal variation. [χ2 =16.75, p < 0.003]. Some 40% (59) of patients were admitted between 00.00 and 06.00, an incidence significantly higher than for other time periods (06.00-12.00, 12.00-18.00, and 18.00-24.00) [χ2 = 18.72; df = 3; p < 0.0003]. A significantly higher number of patients admitted between 00.00 and 06.00 were known hypertensives (χ2 = 7.94; p < 0.05).ConclusionsThe findings of this study suggest a distinct circadian pattern of presentation for RAAA. Systolic blood pressure has a circadian rhythm that mirrors this pattern of presentation. Our results further support the association between RAAA and hypertension, and they may also indicate that chronotropic blood pressure control combating the early-morning peak in systolic blood pressure may assist in the management of abdominal aortic aneurysms.

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.