• The inpatient burden of abdominal and gynecological adhesiolysis in the US.

      Sikirica, V; Bapat, B; Candrilli, S D; Davis, K L; Wilson, Malcolm S; Johns, A; Shire Pharmaceuticals, Wayne, PA 19087, USA. (2011)
      Adhesions are fibrous bands of scar tissue, often a result of surgery, that form between internal organs and tissues, joining them together abnormally. Postoperative adhesions frequently occur following abdominal surgery, and are associated with a large economic burden. This study examines the inpatient burden of adhesiolysis in the United States (i.e., number and rate of events, cost, length of stay [LOS]).
    • Insulin analogues and cancer risk: the emergence of second-generation studies.

      Renehan, Andrew G; School of Cancer and Enabling Sciences, University of Manchester, Manchester Academic Health Science Centre, The Christie NHS Foundation Trust, Wilmslow Road, Manchester, M20 4BX, UK. arenehan@picr.man.ac.uk (2012-01)
      A number of observational studies have linked insulin glargine (A21Gly,B31Arg,B32Arg human insulin) with a putative increased cancer risk, particularly breast cancer, but many of these 'first generation' studies had study design and analysis flaws, and were inconclusive. A small number of 'second generation' studies are now emerging in which the applied pharmaco-epidemiological principles are more robust. For example, when Ruitar and colleagues (Diabetologia DOI: 10.1007/s00125-011-2312-4 ) focused specifically on breast cancer rather than all incident cancer risk, they were able to show a positive association with insulin glargine for breast cancer although there was no association with all incident cancer risk. A list of preferred qualities for pharmaco-epidemiological studies is presented.
    • Interpreting the epidemiological evidence linking obesity and cancer: A framework for population-attributable risk estimations in Europe.

      Renehan, Andrew G; Soerjomataram, Isabelle; Leitzmann, Michael F; Department of Surgery, The Christie NHS Foundation Trust, School of Cancer and Enabling Sciences, University of Manchester, UK. arenehan@picr.man.ac.uk (2010-09)
      Standard approaches to estimating population-attributable risk (PAR) include modelling estimates of exposure prevalence and relative risk. Here, we examine the associations between body mass index (BMI) and cancer risk and how effect modifications of these associations impact on PAR estimates. In 2008, sex- and population-specific risk estimates were determined for associations with BMI in a standardised meta-analysis for 20 cancer types. Since then, refinements of these estimates have emerged: (i) absence of menopausal hormonal therapy (MHT) is associated with elevated BMI associations in post-menopausal breast, endometrial and ovarian cancers; (ii) current smoking attenuates the BMI associations in oesophageal squamous cell carcinoma, lung and pancreatic cancers; (iii) prostate screening attenuates BMI associations when all prostate cancers are considered together; and (iv) BMI is differentially associated with different histological subtypes within the same cancer group. Using secondary analyses of the aforementioned meta-analysis, we show 2-3-fold shifts in PAR estimations for breast and endometrial cancers depending on the MHT usage in European countries. We also critically examine how to best handle exposures (in this example, BMI distributions) and relative risk estimates in PAR models, and argue in favour of a counterfactual approach based around BMI means. From these observations, we develop a research framework in which to optimally evaluate future trends in numbers of new cancers attributable to excess BMI. Overall, this framework gives conservative estimates for PAR - nonetheless, the numbers of avoidable cancers across Europe through avoidance of excess weight are substantial.
    • Joint practice guidelines for radionuclide lymphoscintigraphy for sentinel node localization in oral/oropharyngeal squamous cell carcinoma.

      Alkureishi, Lee W T; Burak, Zeynep; Alvarez, Julio A; Ballinger, James; Bilde, Anders; Britten, Alan J; Calabrese, Luca; Chiesa, Carlo; Chiti, Arturo; de Bree, Remco; et al. (2009-11)
      Involvement of the cervical lymph nodes is the most important prognostic factor for patients with oral/oropharyngeal squamous cell carcinoma (OSCC), and the decision whether to electively treat patients with clinically negative necks remains a controversial topic. Sentinel node biopsy (SNB) provides a minimally invasive method of determining the disease status of the cervical node basin, without the need for a formal neck dissection. This technique potentially improves the accuracy of histological nodal staging and avoids over-treating three-quarters of this patient population, minimizing associated morbidity. The technique has been validated for patients with OSCC, and larger-scale studies are in progress to determine its exact role in the management of this patient population. This article was designed to outline the current best practice guidelines for the provision of SNB in patients with early-stage OSCC, and to provide a framework for the currently evolving recommendations for its use. These guidelines were prepared by a multidisciplinary surgical/nuclear medicine/pathology expert panel under the joint auspices of the European Association of Nuclear Medicine (EANM) Oncology Committee and the Sentinel European Node Trial Committee.
    • Lifestyle factors and colorectal cancer risk (1): systematic review and meta-analysis of associations with body mass index.

      Harriss, D J; Atkinson, G; George, K; Cable, N Tim; Reilly, Thomas; Haboubi, Najib; Zwahlen, Marcel; Egger, Matthias; Renehan, Andrew G; Research Institute for Sport and Exercise Sciences, Liverpool John Moores University, Henry Cotton Campus, Liverpool, UK. (2009-07)
      OBJECTIVE: Excess body weight, defined by body mass index (BMI), may increase the risk of colorectal cancer. As a prerequisite to the determination of lifestyle attributable risks, we undertook a systematic review and meta-analysis of prospective observational studies to quantify colorectal cancer risk associated with increased BMI and explore for differences by gender, sub-site and study characteristics. METHOD: We searched MEDLINE and EMBASE (to December 2007), and other sources, selecting reports based on strict inclusion criteria. Random-effects meta-analyses and meta-regressions of study-specific incremental estimates were performed to determine the risk ratio (RR) and 95% confidence intervals (CIs) associated with a 5 kg/m(2) increase in BMI. RESULTS: We analysed 29 datasets from 28 articles, including 67,361 incident cases. Higher BMI was associated with colon (RR 1.24, 95% CIs: 1.20-1.28) and rectal (1.09, 1.05-1.14) cancers in men, and with colon cancer (1.09, 1.04-1.12) in women. Associations were stronger in men than in women for colon (P < 0.001) and rectal (P = 0.005) cancers. Associations were generally consistent across geographic populations. Study characteristics and adjustments accounted for only moderate variations of associations. CONCLUSION: Increasing BMI is associated with a modest increased risk of developing colon and rectal cancers, but this modest risk may translate to large attributable proportions in high-prevalence obese populations. Inter-gender differences point to potentially important mechanistic differences, which merit further research.
    • Lifestyle factors and colorectal cancer risk (2): a systematic review and meta-analysis of associations with leisure-time physical activity.

      Harriss, D J; Atkinson, G; Batterham, A; George, K; Cable, N Tim; Reilly, Thomas; Haboubi, Najib; Renehan, Andrew G; Research Institute for Sport and Exercise Sciences, Liverpool John Moores University, Liverpool, UK. (2009-09)
      OBJECTIVE: Increased physical activity may decrease the risk of colorectal cancer. As a prerequisite to the determination of lifestyle attributable risks, we performed a systematic review and meta-analysis of prospective observational studies to quantify gender-specific risk associated with increased leisure-time physical activity (LT-PA). METHOD: We searched MEDLINE and EMBASE (to December 2007), and other sources, selecting reports based on strict inclusion criteria. We used random-effects meta-analyses to estimate summary risk ratios (RR) and 95% confidence intervals (95% CI) for uppermost vs lowermost categories of physical activity. To investigate dose-response, we explored risks ratios as a function of cumulative percentiles of physical activity distribution. RESULTS: Fifteen datasets from 14 articles, including 7873 incident cases, were identified. For colon cancer, there were inverse associations with LT-PA for men (RR: 0.80; 95% CI: 0.67-0.96) and women (0.86; 0.76-0.98). LT-PA did not influence risk of rectal cancer. The dose-response analysis was consistent with linear pattern reductions in risk of colon cancer in both genders. There was evidence of moderate between-study heterogeneity but summary estimates were broadly consistent across potential confounding factors. CONCLUSION: Increased LT-PA is associated with a modest reduction in colon but not rectal cancer risk; a risk reduction, which previously may have been overstated. LT-PA only interventions in public health cancer prevention strategies are unlikely to impact substantially on colorectal cancer incidences.
    • The long road towards cancer prevention: 4 steps backward and 8 forward.

      Coebergh, Jan-Willem; Martin-Moreno, Jose M; Soerjomataram, Isabelle; Renehan, Andrew G; Department of Public Health, Erasmus MC, Rotterdam, The Netherlands. j.coebergh@erasmusmc.nl (2010-09)
    • Management of local disease relapse.

      Renehan, Andrew G; O'Dwyer, Sarah T; Department of Surgery, Christie NHS Foundation Trust, Manchester, UK. (2011-02)
    • The management of vulval cancer.

      Crosbie, Emma J; Slade, Richard J; Ahmed, Ahmed S; The Christie NHS Foundation Trust, Wilmslow Road, Manchester, M20 4BX, United Kingdom. Emma.Crosbie@Manchester.ac.uk (2009-11)
      Referral of women with vulval carcinoma to tertiary centres is now established practise in the UK. The centralisation of care for these women promotes the development of specialist teams of gynaecological oncologists, clinical oncologists, pathologists and clinical nurse specialists with expertise in the management of this relatively rare tumour. The primary care physician plays an essential role in the early detection and subsequent urgent referral of women with suspicious vulval lesions. Improved education and awareness campaigns may encourage women to report vulval symptoms early. Where vulval carcinoma is diagnosed at an early stage, surgical excision is likely to be curative. There is, however, a move away from radical surgery for all patients irrespective of stage of disease towards an individualised approach, which takes into account the size and position of the tumour. The challenge is to reduce morbidity associated with treatment without compromising on cure rates. Restricting groin lymphadenectomy to women with lymph node metastases may be possible with the advent of sentinel node technology and it is anticipated that expertise in this area will show significant advances over the coming years. There is still a place for radical surgery, often in combination with other treatment modalities, in the management of advanced or recurrent disease. This article will review the evidence for the current management of vulval carcinoma.
    • Meta-analysis in medical research: potentials and limitations.

      Zwahlen, Marcel; Renehan, Andrew G; Egger, Matthias; Department of Social and Preventive Medicine, University of Berne, Berne, Switzerland. zwahlen@ispm.unibe.ch (2009-05-12)
      Meta-analysis, the statistical combination of results from several studies to produce a single estimate of a treatment effect or size of an association, continues to attract controversy. We illustrate and discuss the promises and limitations of meta-analysis. Meta-analysis of clinical trials can prevent delays in the introduction of effective treatments or lead to the timely identification of adverse effects. However, meta-analyses are liable to numerous biases, both at the level of the individual study and the selection of studies for inclusion in meta-analysis. The biases and confounding factors that threaten the validity of individual studies will also affect meta-analyses of observational studies. We argue that meta-analyses should only be performed within the framework of systematic reviews that have been prepared using methods that minimize bias and address the combinability of studies.
    • Micrometastases and isolated tumour cells in sentinel lymph nodes in oral and oropharyngeal squamous cell carcinoma.

      Atula, T; Hunter, K D; Cooper, L A; Shoaib, T; Ross, Gary L; Soutar, D S; Canniesburn Plastic Surgery Unit, Jubilee Building, Glasgow Royal Infirmary, 84 Castle Street, Glasgow G4 0SF, United Kingdom. timo.atula@hus.fi (2009-05)
      BACKGROUND: The occurrence of micrometastases (MMs) and isolated tumour cells (ITCs) in oral sentinel lymph node (SLN) biopsy is poorly known, and the definitions and clinical significance of MMs and ITCs in SLN biopsy are controversial. We compared the UICC/TNM definitions of MMs and ITCs with our previously published sentinel node protocol to assess how the adoption of the UICC/TNM criteria would affect the staging of nodal micrometastatic disease. METHODS: Of 107 patients who had a SLN biopsy and pathology at 150 microm intervals, 35 with metastatic tumour were included. Eighty-six SLNs were reassessed using the UICC/TNM definitions for MMs and ITCs. Findings were linked to the final pathology in the subsequent neck dissection. RESULTS: Initial H&E sections showed metastases in 24 patients (in 34 out of 61 SLN), 8 of whom (9 SLNs) had MMs. Additional step serial sections revealed metastatic deposits in a further 11 patients (15 out of 25 SLNs were positive) which were reassessed as MMs (6 patients) or ITCs (5 patients). Subsequent neck dissection revealed additional metastases in 46% of patients with MM, whilst one of the ITC patients had subsequent neck metastases (20%). CONCLUSION: Despite some limitations, the UICC/TNM classification provides an objective, uniform method of detecting MMs and ITC's. Unlike in cases with ITC, metastases in other non-SLNs were common when a micrometastasis was detected in a SLN, indicating need for further treatment of the neck.
    • Mitochondrial DNA mutations in head and neck cancer are infrequent and lack prognostic utility.

      Challen, C; Brown, H; Cai, C; Betts, Guy N J; Paterson, I; Sloan, P; West, Catharine M L; Birch-Machin, M; Robinson, M; Centre for Oral Health Research, School of Dental Sciences, Newcastle University, Framlington Place, Newcastle-upon-Tyne NE2 4BW, UK (2011)
    • Oncoplastic surgery for breast cancer.

      Baildam, Andrew D; University Hospital of South Manchester Foundation Trust and the Christie Hospital, Manchester M20 4BX, UK. aetab2@btinternet.com (2008-01)
    • Perfusion Estimated with Rapid Dynamic Contrast-Enhanced Magnetic Resonance Imaging Correlates Inversely with Vascular Endothelial Growth Factor Expression and Pimonidazole Staining in Head-and-Neck Cancer: A Pilot Study.

      Donaldson, Stephanie B; Betts, Guy N J; Bonington, Suzanne C; Homer, Jarrod J; Slevin, Nicholas J; Kershaw, Lucy E; Valentine, Helen R; West, Catharine M L; Buckley, David L; School of Cancer and Enabling Sciences, University of Manchester, Manchester, United Kindom; North Western Medical Physics, The Christie, Manchester, United Kingdom. (2011-05-04)
      PURPOSE: To analyze, in a pilot study, rapidly acquired dynamic contrast-enhanced (DCE)-MRI data with a general two-compartment exchange tracer kinetic model and correlate parameters obtained with measurements of hypoxia and vascular endothelial growth factor (VEGF) expression in patients with squamous cell carcinoma of the head and neck. METHODS AND MATERIALS: Eight patients were scanned before surgery. The DCE-MRI data were acquired with 1.5-s temporal resolution and analyzed using the two-compartment exchange tracer kinetic model to obtain estimates of parameters including perfusion and permeability surface area. Twelve to 16 h before surgery, patients received an intravenous injection of pimonidazole. Samples taken during surgery were used to determine the level of pimonidazole staining using immunohistochemistry and VEGF expression using quantitative real-time polymerase chain reaction. Correlations between the biological and imaging data were examined. RESULTS: Of the seven tumors fully analyzed, those that were poorly perfused tended to have high levels of pimonidazole staining (r = -0.79, p = 0.03) and VEGF expression (r = -0.82, p = 0.02). Tumors with low permeability surface area also tended to have high levels of hypoxia (r = -0.75, p = 0.05). Hypoxic tumors also expressed higher levels of VEGF (r = 0.82, p = 0.02). CONCLUSIONS: Estimates of perfusion obtained with rapid DCE-MRI data in patients with head-and-neck cancer correlate inversely with pimonidazole staining and VEGF expression.
    • A phase II study evaluating the use of concurrent mitomycin C and capecitabine in patients with advanced unresectable pseudomyxoma peritonei.

      Farquharson, Adam L; Pranesh, Nagarajan; Witham, Gary; Swindell, Ric; Taylor, Malcolm B; Renehan, Andrew G; Rout, Shantanu; Wilson, Malcolm S; O'Dwyer, Sarah T; Saunders, Mark P; et al. (2008-08-19)
      Pseudomyxoma peritonei (PMP) is a rare neoplastic process characterised by progressive intra-abdominal dissemination of mucinous tumour, and generally considered resistant to systemic chemotherapy. A phase II study in patients with advanced unresectable PMP was undertaken to evaluate the combination of systemic concurrent mitomycin C (7 mg m(-2) i.v. on day 1) and capecitabine (1250 mg m(-2) b.d. on days 1-14) in a 3-weekly cycle (MCap). Response was determined by semiquantitative assessment of disease volume on serial computed tomographic (CT) scans and serum tumour marker (CEA, CA125, CA19-9) changes at 12 weeks. Between 2003 and 2006, 40 patients were recruited through a national centre for the treatment of peritoneal surface tumours. At baseline, 23 patients had progressive disease and 17 had stable disease. Of 39 assessable patients, 15 (38%, 95% confidence intervals (CIs): 25, 54%) benefited from chemotherapy in the form of either reductions in mucinous deposition or stabilisation of progressive pretreatment disease determined on CT scan. Notably, two patients, originally considered unresectable, following MCap and re-staging underwent potentially curative cytoreductive surgery. Grade 3/4 toxicity rates were low (6%, 95% CIs: 4, 9%). Twenty out of 29 assessed patients (69%, 95% CIs: 51, 83%) felt that their Global Health Status improved during chemotherapy. This is the first trial to demonstrate an apparent benefit of systemic chemotherapy in patients with advanced unresectable PMP.
    • Predictive factors for failure to identify sentinel nodes in head and neck squamous cell carcinoma.

      Hornstra, Marije T; Alkureishi, Lee W T; Ross, Gary L; Shoaib, Taimur; Soutar, David S; Plastic Surgery Unit, Canniesburn Hospital, Glasgow Royal Infirmary, Glasgow, United Kingdom. (2008-07)
      BACKGROUND: The aim of this study was to ascertain which factors determine success of sentinel node biopsy (SNB). METHODS: We conducted a retrospective review of 121 patients with head and neck squamous cell carcinoma undergoing SNB to stage the neck. All patients underwent the triple-diagnostic procedure of preoperative lymphoscintigraphy, intraoperative blue dye, and a gamma probe. Factors contributing to failure of SNB were identified. RESULTS: SNB was unsuccessful in 12 of 121 patients (10%). Seven of the 12 patients had cT1/cT2 tumors, and 6 of these were located in the floor of mouth. SN identification was more likely to be successful in patients with cN0 necks, but this did not reach statistical significance (92% vs 84%, p = .268). Factors associated with failure included T classification (p = .01), tumor site (p = .05), and negative preoperative lymphoscintigraphy (p = .0174). CONCLUSION: Successful sentinel lymph node harvest is related to primary tumor site, T classification, and the presence of nodes on preoperative lymphoscintigraphy.
    • Radiotherapy for the treatment of longstanding head and neck hemangioma.

      Douglas, Catriona Mairi; Ho, Kean F; Homer, Jarrod J; Slevin, Nicholas J; Department of Otolaryngology-Head and Neck Surgery, Christie Hospital, Manchester, UK. Catriona.douglas@christie.nhs.uk (2009-08)
    • Re: Squamous cell carcinoma of the oral tongue in patients younger than 30 years.

      Mani, Navin; Homer, Jarrod J; Department of Head and Neck Surgery, The Christie Hospital, Manchester, UK (2011-02)
    • Reciprocal relationship between expression of hypoxia inducible factor 1alpha (HIF-1alpha) and the pro-apoptotic protein bid in ex vivo colorectal cancer.

      Seenath, M M; Roberts, Darren L; Cawthorne, Christopher; Saunders, Mark P; Armstrong, G; O'Dwyer, Sarah T; Stratford, Ian J; Dive, Caroline; Renehan, Andrew G; Clinical and Experimental Pharmacology, Paterson Institute of Cancer Research, Manchester, UK. (2008-08-05)
      Hypoxia inducible factor 1 (HIF-1) represses the transcription of pro-apoptotic bid in colorectal cancer cells in vitro. To assess the clinical relevance of this observation, HIF-1alpha and Bid were assessed in serial sections of 39 human colorectal adenocarcinomas by immunohistochemistry. In high HIF-1alpha nuclear-positive cell subpopulations, there was a significant reduction in Bid expression (ANOVA, P=0.04). Given the role of Bid in drug-induced apoptosis, these data add impetus to strategies targeting HIF-1 for therapeutic gain.
    • Response and resistance to the endocrine prevention of breast cancer.

      Howell, Anthony; Bundred, Nigel J; Cuzick, Jack; Allred, D Craig; Clarke, Robert B; CRC Department Medical Oncology, University of Manchester Christie Hospital and Holt Radium Inst., Manchester, UK. (2008)
      The data from observational studies and clinical trials indicates that it is possible to prevent BC for prolonged periods using various endocrine manipulations. Ovarian suppression is thought to give lifelong protection and recent data indicate that the effectiveness of Tam continues after cessation of treatment at 5-8 years. It is clear from three randomised trials that SERMs prevent ERalpha+ tumors only in women at increased risk and at population risk of BC entered into these trials. The data from the Ral trials also suggests that this agent appears less effective than Tam in preventing DCIS. This is surprising since a large proportion of DCIS is ERalpha+. Equally surprising is the effectiveness of oophorectomy and Tam in mutation carriers, particularly BRCA1, which is associated with ERalpha+ tumors. The fact that ERT can be given without apparently abrogating the effect of oophorectomy and also to naturally postmenopausal women without increasing BC risk suggests that cyclical estrogen or estrogen + progestin are important for BC initiation and/or progression. The question arises whether the information we have concerning the responsiveness of ERalpha+ cells in TDLU, premalignant lesions, and invasive cancers give an indication of the targets for endocrine prevention. Data summarised in Table 1 indicate that TDLU are responsive to estrogen, ED, and SERMs/SERDs in premenopausal women and there may be the targets for the preventative effect of early oophorectomy particularly in BRCA1 carriers where we have demonstrated endocrine responsiveness of TDLU, which at this heterozygote stage are ERalpha+. The decline in numbers of atypical lobules in breasts without invasive cancer suggests that these are targets for the 'preventive' effect of the menopause, as suggested by Wellings. The data also suggest that ERalpha+ DCIS is responsive to estrogen and ED supporting premalignant lesions is a target as does the data from the NSABP P1 trial indicating a marked preventive effect of Tam in women previously diagnosed with atypical ductal hyperplasia and a preventative effect on CIS.