Leicester Royal Infirmary

About: Leicester Royal Infirmary is a healthcare organization based out in Leicester, United Kingdom. It is known for research contribution in the topics: Population & Carotid endarterectomy. The organization has 5300 authors who have published 6204 publications receiving 208464 citations.

Measurements using the alkaline comet assay predict bladder cancer cell radiosensitivity.

Abstract: In the UK, bladder cancer is a common urological malignancy, affecting more than 12 500 individuals each year and causing nearly 5000 deaths per annum (CRC, 2001). In all, 90% of bladder cancers are transitional cell carcinomas (TCCs) and ∼30% of bladder tumours are muscle invasive at presentation, a feature that is associated with significant risk of metastasis (30–60%). Patients with organ-confined, muscle-invasive tumours, (T2/3/4a) who are deemed fit, are considered for potentially curative treatment in the form of radical surgery (cystectomy) or radiotherapy. Radical cystectomy (removal of the bladder and urinary diversion) is associated with significant morbidity and a mortality rate of ∼2% (Skinner et al, 1988; Studer et al, 1995). Furthermore, the necessary creation of an abdominal wall stoma (ileal conduit) may impact on quality of life, and erectile dysfunction is virtually universal. The outcome following radical cystectomy varies with tumour stage, with an overall 5-year survival of ∼40%. Radical radiotherapy (RT) is the mainstay of bladder-sparing treatment regimens. It avoids the trauma of major surgery and is considered a primary treatment for patients deemed unfit for surgery. However, RT is itself associated with dose-related complications arising from bowel and bladder being included in the radiation field. Furthermore, while for ∼50% of patients radical RT results in effective local tumour control and acceptable bladder function (Quilty et al, 1986; Jenkins et al, 1989), the remaining patients suffer local recurrence. For this latter group, the decision to treat with RT is disadvantageous, as these patients have been unnecessarily exposed to additional risks of ionising radiation. In addition, the time taken to recognise treatment failure (3–6 months) may provide further opportunity for metastatic spread, before secondary treatment (salvage cystectomy) is undertaken. Also, the morbidity in patients undergoing salvage cystectomy has been found to be significantly higher than in patients undergoing primary cystectomy (Rosario et al, 2000). Consequently, if a patient's bladder tumour RT response could be predicted in advance, RT could be promoted in patients with tumours that are predicted to respond. Conversely, patients with nonresponsive tumours could be identified and offered surgery at an earlier stage. In this way, the overall local control rates could be improved. While much work has been undertaken to develop assays capable of predicting tumour response to RT, none has been successfully applied to clinical practice. However, ex vivo measures of the surviving fraction of tumour cells at 2 Gy (SF2) suggest that intrinsic radiosensitivity (IRS) is a significant factor in determining tumour radiocurability (West, 1995; West et al, 1997). However, the SF2 assay fails to provide information on a time scale appropriate for treatment planning and also suffers from limited success rates; in an unpublished study, <10% of bladder tumours gave rise to colonies on soft agar (McKeown, McKelvey-Martin and Ho, personal communication). In addition, the relationship between clonogenic survival and clinical response is far from proven. The limitations of SF2 have stimulated research into methods to provide a more rapid and complete measure of IRS. DNA is the most important cellular target for the lethal effects of ionising radiation, with double-strand breaks (DSBs) proposed to be the principal lesions responsible for radiogenic cell killing (Ward, 1988; Iliakis, 1991). Unfortunately, the relative yield of radiogenic DSBs is low, and high radiation doses tend to be required to produce measurable levels; doses that are far greater than those used clinically. Indeed, while a recent study using the neutral comet assay to measure DSBs reports an association between DSB manifestation and survival (Price et al, 2000), the correlations were not definite, with one cell line yielding a false impression of radiosensitivity at the high doses (30 Gy) required for the assay. This highlights a benefit of conducting predictive tests of radiosensitivity at clinically relevant doses. In contrast with DSBs, the yield of radiation-induced single-strand breaks (SSBs) is far greater (Ward, 1988), and can be readily measured at low clinically relevant doses of radiation. Furthermore, the mechanisms that are proposed to vary the yield of radiation-induced DSBs formation are also expected to vary the yield of radiation-induced SSBs (Ward, 1990). Consequently, the extent of radiation-induced SSB formation can be considered a valid surrogate marker of radiogenic DSB formation. The alkaline comet assay (ACA) is a highly sensitive method for the assessment of SSBs and alkali labile sites (ALSs), and can readily detect levels of damage induced by clinically relevant doses of radiation (Singh et al, 1994; Singh, 1996). In a previous study of just three bladder cancer cell lines, an inverse correlation was obtained between clonogenic survival and mean tail moment (TM) for comet formation, suggesting that ACA could potentially be used to predict the radio response of the single cell lines (McKelvey-Martin et al, 1998). In the present study, we report our evaluation of ACA as a measure of bladder cancer cell radiosensitivity in vitro using a panel of six bladder cancer cell lines, and demonstrate that the extent of comet formation best reflects bladder cancer cell radiosensitivity; these results are supported by two independent, parallel studies using colorectal tumour cells (Dunne et al, 2003) and bladder tumour cells (McKeown et al, 2003). We also report on a preliminary study to determine the differing ACA radio response of epithelial cells isolated from human bladder tumour biopsies.

A systematic review of the prognostic value of lymph node ratio, number of positive nodes and total nodes examined in pancreatic ductal adenocarcinoma.

Abstract: BACKGROUND Pancreatic ductal adenocarcinoma is the most common pancreatic cancer. Five-year overall survival is currently 3.3-6.0%. The aim of this review was to evaluate the prognostic value of lymph node ratio, number of positive nodes and total nodes examined on overall survival rate following pancreatic resection. MATERIALS AND METHODS A literature search was conducted of MEDLINE, EMBASE, the Cochrane Library and Central Register of Controlled Trials and the Cochrane Database of Systematic Review databases, from January 1996 to January 2016. RESULTS Overall, 19 studies including 4,883 patients examined the relationship between lymph node ratio and overall survival. A high lymph node ratio was associated with decreased overall survival in 17 studies. A total of 12 studies examined the relationship between the number of positive nodes and overall survival, and 11 studies revealed that an increase in the number of positive nodes was associated with decreased overall survival. In 15 studies examining the relationship between the total nodes examined and overall survival, there was no association with overall survival in 12 studies. CONCLUSIONS Lymph node ratio and number of positive nodes are factors associated with overall survival in pancreatic ductal adenocarcinoma, but not total nodes examined.

Advanced Glycation End Products Stimulate an Enhanced Neutrophil Respiratory Burst Mediated Through the Activation of Cytosolic Phospholipase A2 and Generation of Arachidonic Acid

Abstract: Background— Advanced glycation end products (AGEs) enhance NADPH oxidase, and hence respiratory burst activity, of stimulated neutrophils. They are thus potentially vasculopathic, especially in diabetes, uremia, and aging, in which AGEs classically accumulate. We investigated the underlying mechanisms. Methods and Results— Neutrophils prelabeled with [3H]arachidonic acid display increased [3H]arachidonate release on exposure to AGE-albumin over exposure to albumin alone (by 151±16%, P<0.01). Arachidonic acid (AA) itself seems to mediate the AGE-augmented neutrophil respiratory burst (ascertained by chemiluminescence). Inhibitors of the cyclooxygenase pathway (indomethacin) and lipoxygenase pathway (MK-886) do not impair this AGE effect, excluding a contribution from AA metabolites. Cytosolic phospholipase A2 (cPLA2) controls AA generation. Its inhibition by methyl arachidonyl fluorophosphonate abrogates the AGE-enhanced activated neutrophil respiratory burst, and it is demonstrably stimulated in AGE-expos...

Impact of extramedullary disease in patients with newly diagnosed multiple myeloma undergoing autologous stem cell transplantation: a study from the Chronic Malignancies Working Party of the EBMT.

Abstract: We investigated extramedullary disease in newly diagnosed multiple myeloma patients and its impact on outcome following first-line autologous stem cell transplantation. We identified 3744 adult myeloma patients who received up-front single (n=3391) or tandem transplantation (n=353) between 2005 and 2014 with available data on extramedullary involvement at diagnosis. The overall incidence of extramedullary disease was 18.2% (n=682) and increased per year from 6.5% (2005) to 23.7% (2014). Paraskeletal involvement was found in 543 (14.5%) and extramedullary organ involvement in 139 (3.7%). More patients with extramedullary organ involvement had multiple involved sites (≥2; P<0.001). In a comparison of patients with single sites with patients without the disease, up-front transplantation resulted in at least similar 3-year progression-free survival (paraskeletal: P=0.86, and extramedullary organ: P=0.88). In single paraskeletal involvement, this translated less clearly into worse 3-year overall survival (P=0.07) while single organ involvement was significantly worse (P=0.001). Multiple organ sites were associated with worse outcome (P<0.001 and P=0.01). First-line treatment with tandem compared with single transplantation resulted in similar survival in patients with extramedullary disease at diagnosis (P=0.13 for both).