Showing papers by "Royal Surrey County Hospital published in 2012"

Comparative analysis of prostate-specific antigen free survival outcomes for patients with low, intermediate and high risk prostate cancer treatment by radical therapy. Results from the Prostate Cancer Results Study Group.

Abstract: What's known on the subject? and What does the study add? Very few comparative studies to date evaluate the results of treatment options for prostate cancer using the most sensitive measurement tools. PSA has been identified as the most sensitive tool for measuring treatment effectiveness. To date, comprehensive unbiased reviews of all the current literature are limited for prostate cancer. This is the first large scale comprehensive review of the literature comparing risk stratified patients by treatment option and with long-term follow-up. The results of the studies are weighted, respecting the impact of larger studies on overall results. The study identified a lack of uniformity in reporting results amongst institutions and centres. A large number of studies have been conducted on the primary therapy of prostate cancer but very few randomized controlled trials have been conducted. The comparison of outcomes from individual studies involving surgery (radical prostatectomy or robotic radical prostatectomy), external beam radiation (EBRT) (conformal, intensity modulated radiotherapy, protons), brachytherapy, cryotherapy or high intensity focused ultrasound remains problematic due to the non-uniformity of reporting results and the use of varied disease outcome endpoints. Technical advances in these treatments have also made long-term comparisons difficult. The Prostate Cancer Results Study Group was formed to evaluate the comparative effectiveness of prostate cancer treatments. This international group conducted a comprehensive literature review to identify all studies involving treatment of localized prostate cancer published during 2000-2010. Over 18,000 papers were identified and a further selection was made based on the following key criteria: minimum/median follow-up of 5 years; stratification into low-, intermediate- and high-risk groups; clinical and pathological staging; accepted standard definitions for prostate-specific antigen failure; minimum patient number of 100 in each risk group (50 for high-risk group). A statistical analysis (standard deviational ellipse) of the study outcomes suggested that, in terms of biochemical-free progression, brachytherapy provides superior outcome in patients with low-risk disease. For intermediate-risk disease, the combination of EBRT and brachytherapy appears equivalent to brachytherapy alone. For high-risk patients, combination therapies involving EBRT and brachytherapy plus or minus androgen deprivation therapy appear superior to more localized treatments such as seed implant alone, surgery alone or EBRT. It is anticipated that the study will assist physicians and patients in selecting treatment for men with newly diagnosed prostate cancer.

Efficacy and Safety of Exenatide Once Weekly Versus Metformin, Pioglitazone, and Sitagliptin Used as Monotherapy in Drug-Naive Patients With Type 2 Diabetes (DURATION-4): A 26-week double-blind study

Abstract: OBJECTIVE To test the safety and efficacy of exenatide once weekly (EQW) compared with metformin (MET), pioglitazone (PIO), and sitagliptin (SITA) over 26 weeks, in suboptimally treated (diet and exercise) drug-naive patients with type 2 diabetes. RESEARCH DESIGN AND METHODS Patients were randomized to subcutaneous (SC) EQW 2.0 mg + oral placebo ( n = 248), MET 2,000 mg/day + SC placebo ( n = 246), PIO 45 mg/day + SC placebo ( n = 163), or SITA 100 mg/day + SC placebo ( n = 163) for 26 weeks. MET and PIO therapies were increased to maximum-tolerated dosages. Injections with EQW or placebo were administered weekly, while oral medication or placebo was administered daily. RESULTS Baseline characteristics were as follows: 59% men, 67% Caucasian, mean age 54 years, HbA 1c 8.5%, fasting serum glucose 9.9 mmol/L, body weight 87.0 kg, and diabetes duration 2.7 years. HbA 1c reductions (%) at 26 weeks (least-squares means) with EQW versus MET, PIO, and SITA were −1.53 vs. −1.48 ( P = 0.620), −1.63 ( P = 0.328), and −1.15 ( P P = 0.892), +1.5 ( P P CONCLUSIONS EQW was noninferior to MET but not PIO and superior to SITA with regard to HbA 1c reduction at 26 weeks. Of the agents studied, EQW and MET provided similar improvements in glycemic control along with the benefit of weight reduction and no increased risk of hypoglycemia.

Conventional versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: preliminary safety results from the CHHiP randomised controlled trial

Abstract: Summary Background Prostate cancer might have high radiation-fraction sensitivity, implying a therapeutic advantage of hypofractionated treatment. We present a pre-planned preliminary safety analysis of side-effects in stages 1 and 2 of a randomised trial comparing standard and hypofractionated radiotherapy. Methods We did a multicentre, randomised study and recruited men with localised prostate cancer between Oct 18, 2002, and Aug 12, 2006, at 11 UK centres. Patients were randomly assigned in a 1:1:1 ratio to receive conventional or hypofractionated high-dose intensity-modulated radiotherapy, and all were given with 3–6 months of neoadjuvant androgen suppression. Computer-generated random permuted blocks were used, with risk of seminal vesicle involvement and radiotherapy-treatment centre as stratification factors. The conventional schedule was 37 fractions of 2 Gy to a total of 74 Gy. The two hypofractionated schedules involved 3 Gy treatments given in either 20 fractions to a total of 60 Gy, or 19 fractions to a total of 57 Gy. The primary endpoint was proportion of patients with grade 2 or worse toxicity at 2 years on the Radiation Therapy Oncology Group (RTOG) scale. The primary analysis included all patients who had received at least one fraction of radiotherapy and completed a 2 year assessment. Treatment allocation was not masked and clinicians were not blinded. Stage 3 of this trial completed the planned recruitment in June, 2011. This study is registered, number ISRCTN97182923. Findings 153 men recruited to stages 1 and 2 were randomly assigned to receive conventional treatment of 74 Gy, 153 to receive 60 Gy, and 151 to receive 57 Gy. With 50·5 months median follow-up (IQR 43·5–61·3), six (4·3%; 95% CI 1·6–9·2) of 138 men in the 74 Gy group had bowel toxicity of grade 2 or worse on the RTOG scale at 2 years, as did five (3·6%; 1·2–8·3) of 137 men in the 60 Gy group, and two (1·4%; 0·2–5·0) of 143 men in the 57 Gy group. For bladder toxicities, three (2·2%; 0·5–6·2) of 138 men, three (2·2%; 0·5–6·3) of 137, and none (0·0%; 97·5% CI 0·0–2·6) of 143 had scores of grade 2 or worse on the RTOG scale at 2 years. Interpretation Hypofractionated high-dose radiotherapy seems equally well tolerated as conventionally fractionated treatment at 2 years. Funding Stage 1 was funded by the Academic Radiotherapy Unit, Cancer Research UK programme grant; stage 2 was funded by the Department of Health and Cancer Research UK.

A phase II study of afatinib (BIBW 2992), an irreversible ErbB family blocker, in patients with HER2-positive metastatic breast cancer progressing after trastuzumab

Abstract: Afatinib is an oral, ErbB family blocker, which covalently binds and irreversibly blocks all kinase-competent ErbB family members. This phase II, open-label, single-arm study explored afatinib activity in human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients progressing after trastuzumab treatment. Patients had stage IIIB/IV HER2-positive metastatic breast cancer, with progression following trastuzumab or trastuzumab intolerance and an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2. Patients received 50 mg afatinib once-daily until disease progression. Primary endpoint was objective response rate (Response Evaluation Criteria in Solid Tumors 1.0), with tumor assessments every 8 weeks. Forty-one patients were treated. Patients had received a median of three prior chemotherapy lines (range, 0–15) and 68.3% had received trastuzumab for >1 year. Four patients (10% of 41 treated; 11% of evaluable patients) had partial response. Fifteen patients (37% of 41) had stable disease as best response and 19 (46% of 41) achieved clinical benefit. Median progression-free survival was 15.1 weeks (95% confidence interval [CI]: 8.1–16.7); median overall survival was 61.0 weeks (95% CI: 56.7–not evaluable). Most frequent common terminology criteria for adverse events grade 3 treatment-related adverse events were diarrhea (24.4%) and rash (9.8%). Afatinib monotherapy was associated with promising clinical activity in extensively pretreated HER2-positive breast cancer patients who had progressed following trastuzumab treatment.

First-line erlotinib in patients with advanced non-small-cell lung cancer unsuitable for chemotherapy (TOPICAL): a double-blind, placebo-controlled, phase 3 trial

Abstract: Summary Background Many patients with advanced non-small-cell lung cancer (NSCLC) receive only active supportive care because of poor performance status or presence of several comorbidities. We investigated whether erlotinib improves clinical outcome in these patients. Methods TOPICAL was a double-blind, randomised, placebo-controlled, phase 3 trial, done at 78 centres in the UK. Eligibility criteria were newly diagnosed, pathologically confirmed NSCLC; stage IIIb or IV; chemotherapy naive; no symptomatic brain metastases; deemed unsuitable for chemotherapy because of poor (≥2) Eastern Cooperative Oncology Group performance status or presence of several comorbidities, or both; and estimated life expectancy of at least 8 weeks. Patients were randomly assigned (by phone call, in a 1:1 ratio, stratified by disease stage, performance status, smoking history, and centre, block size 10) to receive oral placebo or erlotinib (150 mg per day) until disease progression or unacceptable toxicity. Investigators, clinicians, and patients were masked to assignment. The primary endpoint was overall survival. Analyses were by intention to treat, and prespecified subgroup analyses included development of a rash due to erlotinib within 28 days of starting treatment. This study is registered, number ISRCTN 77383050. Findings Between April 14, 2005, and April 1, 2009, we randomly assigned 350 patients to receive erlotinib and 320 to receive placebo. We followed up patients until March 31, 2011. 657 patients died; median overall survival did not differ between groups (erlotinib, 3·7 months, 95% CI 3·2–4·2, vs placebo, 3·6 months, 3·2–3·9; unadjusted hazard ratio [HR] 0·94, 95% CI 0·81–1·10, p=0·46). 59% (178 of 302) of patients assigned erlotinib and who were assessable at 1 month developed first-cycle rash, which was the only independent factor associated with overall survival. Patients with first-cycle rash had better overall survival (HR 0·76, 95% CI 0·63–0·92, p=0·0058), compared with placebo. Compared with placebo, overall survival seemed to be worse in the group that did not develop first-cycle rash (1·30, 1·05–1·61, p=0·017). Grade 3 or 4 diarrhoea was more common with erlotinib than placebo (8% [28 of 334] vs 1% [four of 313], p=0·0001), as was high-grade rash (23% [79 of 334] vs 2% [five of 313], p Interpretation Patients with NSCLC who are deemed unsuitable for chemotherapy could be given erlotinib. Patients who develop a first-cycle rash should continue to receive erlotinib, whereas those who do not have a rash after 28 days should discontinue erlotinib, because of the possibility of decreased survival. Funding Cancer Research UK, Roche.

A prospective, randomized pilot study evaluating the effects of metformin and lifestyle intervention on patients with prostate cancer receiving androgen deprivation therapy

Abstract: Study Type - Therapy (RCT) Level of Evidence 1b What's known on the subject? and What does the study add? Men with prostate cancer have higher rates of non-cancer mortality and CV morbidity and some of that excess risk has been attributed to the treatment they receive. ADT is an established treatment option for men with locally-advanced and metastatic prostate cancer and, although it has been shown to confer a disease-free survival advantage, it has also been associated with an increased incidence of CV disease and the metabolic syndrome (characterized by a cluster of CV risk factors, including insulin resistance). The benefits of the insulin sensitizer metformin and lifestyle intervention for reducing the incidence of metabolic syndrome have been shown in patients with impaired glucose tolerance. At the time of writing, the present study is the first to use metformin and lifestyle intervention in men with prostate cancer with the aim of reducing the risk of developing ADT-related CV morbidity and the metabolic syndrome. The study shows that lifestyle changes and metformin may indeed reduce the complications of androgen suppression in these men. Although further investigations are needed to establish which of the two interventions may be most beneficial, the favourable effects of a combination of these interventions on patients' quality of life and the potential for improved overall survival are of clinical significance.

European guidelines for quality assurance in colorectal cancer screening and diagnosis. First Edition Faecal occult blood testing

Abstract: Multidisciplinary, evidence-based guidelines for quality assurance in colorectal cancer screening and diagnosis have been developed by experts in a project coordinated by the International Agency for Research on Cancer. The full guideline document covers the entire process of population-based screening. It consists of 10 chapters and over 250 recommendations, graded according to the strength of the recommendation and the supporting evidence. The 450-page guidelines and the extensive evidence base have been published by the European Commission. The chapter on faecal occult blood testing includes 21 graded recommendations. The content of the chapter is presented here to promote international discussion and collaboration by making the principles and standards recommended in the new EU Guidelines known to a wider professional and scientific community. Following these recommendations has the potential to enhance the control of colorectal cancer through improvement in the quality and effectiveness of screening programmes and services.

Report of a consensus meeting on focal low dose rate brachytherapy for prostate cancer

Abstract: What's known on the subject? and What does the study add? Whole gland brachytherapy has been used to successfully treat prostate cancer but the protocol for focal therapy has not previously been established. The consensus findings provide guidance on patient selection for focal brachytherapy as well as recommendations for conducting therapy and patient follow-up. Low dose rate prostate brachytherapy is an effective treatment for localized prostate cancer. Recently, it has been considered for use in a focused manner whereby treatment is targeted only to areas of prostate cancer. The objective of focal brachytherapy is to provide effective cancer control for low-risk disease but with reduced genitourinary and rectal side-effects in a cost-effective way. We report on the outputs of a consensus meeting of international experts in brachytherapy and focal therapy convened to consider the feasibility and potential development of focal brachytherapy. A number of factors were considered for focal brachytherapy including optimal patient selection, disease characterization and localization, treatment protocols and outcome measures. The consensus meeting also addressed the design of a clinical trial that would assess the oncological outcomes and side-effect profiles resulting from focal brachytherapy.

Do CYP2D6 genotypes reflect oxycodone requirements for cancer patients treated for cancer pain? A cross-sectional multicentre study

Abstract: Objective Opioids are recommended by the World Health Organization for moderate to severe cancer pain. Oxycodone is one of the most commonly used opioids and is metabolized in the liver by CYP3A4 and CYP2D6 enzymes. The aim of this cross-sectional study was to assess the relationship between oxycodone pharmacokinetics, pharmacodynamics and the CYP2D6 genotypes “poor metaboliser” (PM), “extensive metaboliser” (EM) and “ultra-rapid metaboliser” (URM) in a cohort of patients with cancer pain.

Impact of a multidisciplinary standardized clinical pathway on perioperative outcomes in patients with oesophageal cancer.

Abstract: Background: Defined clinical pathways can contribute to improved outcomes in patients undergoing oesophageal cancer surgery. A standardized oesophagectomy clinical pathway (SOCP) established at the Virginia Mason Medical Center (VMMC) in Seattle, Washington, USA was introduced into the Royal Surrey County Hospital (RSCH), Guildford, UK in 2011. The aim of this study was to see whether transfer and implementation of an oesophagectomy care pathway could change postoperative outcomes significantly. Methods: Three consecutively accrued study groups were examined at the RSCH: patients operated on immediately before the introduction of the SOCP (group 1), patients operated on after the introduction of the SOCP but not included in the pathway (group 2), and patients managed according to the SOCP (group 3). Outcomes were compared with those of patients who had surgery at the VMMC between 2009 and 2011 using the SOCP (group 4). Results: There were 12 patients in each of the first three groups and 74 in group 4. All groups were similar with respect to body mass index, medical co-morbidities and clinical stage. The median age of patients in group 3 was significantly lower than that in group 1, and median American Society of Anesthesiologists score was significantly better in group 3 compared with group 4. Following initiation of the SOCP there was an increase in immediate extubation (8 of 12 in group 1 versus 12 of 12 in group 3) and first-day mobilization (1 of 12 versus 12 of 12 respectively), and a reduction in complications (9 of 12 versus 4 of 12), length of critical care stay (4 (range 2–20) days in group 1 versus 3 (1–5) days in group 3) and length of hospital stay (17 (12–30) to 7 (6–37) days respectively). Patients not on the pathway but who had surgery during the same interval experienced small but non-significant improvements in length of critical care and hospital stay, and in first-day mobilization. Conclusion: The study demonstrated improvement in short-term outcomes after oesophagectomy following the adoption of an established multidisciplinary standardized postoperative pathway. Copyright © 2012 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.

Salivary duct carcinomas can be classified into luminal androgen receptor-positive, HER2 and basal-like phenotypes

Abstract: Di Palma S, Simpson R H W, Marchio C, Skalova A, Ungari M, Sandison A, Whitaker S, Parry S & Reis-Filho J S (2012) Histopathology 61, 629–643 Salivary duct carcinomas can be classified into luminal androgen receptor-positive, HER2 and basal-like phenotypes Aims: The aim of this study was to devise a molecular classification for salivary duct carcinomas (SDCs) based on the similarities between SDCs and breast carcinomas and on characteristics of the microarray-based gene expression profiling-defined molecular subtypes of breast cancer. Methods and results: Forty-two pure salivary duct carcinomas, 35 of which contained an in-situ component as defined by histological review and/or immunohistochemical analysis, were stained with antibodies for oestrogen receptor (ER), progesterone receptor (PR), androgen receptor (AR), human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor (EGFR) and cytokeratin (CK) 5/6. Based on these markers, tumours were classified into HER2, luminal androgen receptor-positive, basal-like, luminal and indeterminate phenotype. Analysis revealed that 16.7%, 69%, 4.8%, 9.5% and 0% were of HER2, luminal androgen receptor-positive, basal-like, indeterminate and luminal phenotype, respectively. The in-situ and invasive components displayed the same molecular subtype in all but one case. Conclusions: Salivary duct carcinomas can be classified into molecular subgroups approximately equivalent to those in the breast. We also report on the existence of a subgroup of bona fide pure salivary duct carcinomas that have a ‘basal-like’ phenotype. Understanding the phenotypic complexity of SDCs may help to expedite the identification of novel therapeutic targets for these aggressive tumours.

Retrospective analysis of the effect of postoperative analgesia on survival in patients after laparoscopic resection of colorectal cancer

Abstract: postoperative analgesic technique may influence cancer surgery outcome. † Retrospective analysis of 424 patients undergoing laparoscopic colonic resection. Background. Surgical excision of colorectal cancer can reduce immune function during the postoperative period, which may affect long-term survival. There is evidence that regional analgesia may attenuate the immunosuppressive effect of surgery. Opioid analgesia also suppresses cell-mediated immunity, notably natural killer cell activity. Therefore, using either epidural or spinal analgesia rather than systemic opioids during the postoperative period could affect long-term survival and disease recurrence. Methods. A retrospective analysis of a prospective database of all patients undergoing laparoscopic colorectal resection for adenocarcinoma between October 2003 and December 2010 was performed. Patients received either an epidural, spinal block, or a morphine patient-controlled analgesia (PCA) for their primary postoperative analgesia. Overall survival and disease-free survival were analysed. Results. A total of 457 laparoscopic colorectal resections were performed during the period analysed; 424 cases were suitable for analysis (epidural¼107, spinal¼144, and PCA¼173). There was no significant difference between the groups for age, gender, conversion rate, operation performed, TNM stage, tumour differentiation, extramural venous, or lymphovascular invasion. The epidural group had significantly more ASA category III patients (P¼0.006). The median length of stay was significantly longer in the epidural group at 5 days compared with 3 days for spinal and PCA (P,0.0005). There was no significant difference in overall survival (P¼0.622) or disease-free survival (P¼0.490) at 5 yr between the groups. Conclusions. In this study, there appears to be no significant advantage to be gained in overall or disease-free survival with the use of regional analgesia compared with opioid analgesia after laparoscopic colorectal resection.

Effect of image quality on calcification detection in digital mammography.

Abstract: Purpose: This study aims to investigate if microcalcification detection varies significantly when mammographicimages are acquired using different image qualities, including: different detectors,dose levels, and different image processing algorithms. An additional aim was to determine how the standard European method of measuring image quality using threshold gold thickness measured with a CDMAM phantom and the associated limits in current EU guidelines relate to calcification detection. Methods: One hundred and sixty two normal breast images were acquired on an amorphous selenium direct digital (DR) system. Microcalcification clusters extracted from magnified images of slices of mastectomies were electronically inserted into half of the images. The calcification clusters had a subtle appearance. All images were adjusted using a validated mathematical method to simulate the appearance of images from a computed radiography(CR)imagingsystem at the same dose, from both systems at half this dose, and from the DR system at quarter this dose. The original 162 images were processed with both Hologic and Agfa (Musica-2) image processing. All other image qualities were processed with Agfa (Musica-2) image processing only. Seven experienced observers marked and rated any identified suspicious regions. Free response operating characteristic (FROC) and ROC analyses were performed on the data. The lesion sensitivity at a nonlesion localization fraction (NLF) of 0.1 was also calculated. Images of the CDMAM mammographic test phantom were acquired using the automatic setting on the DR system. These images were modified to the additional image qualities used in the observer study. The images were analyzed using automated software. In order to assess the relationship between threshold gold thickness and calcification detection a power law was fitted to the data. Results: There was a significant reduction in calcification detection using CR compared with DR: the alternative FROC (AFROC) area decreased from 0.84 to 0.63 and the ROC area decreased from 0.91 to 0.79 (p 0.05). It was additionally found that lower threshold gold thickness from CDMAM analysis implied better cluster detection. The measured threshold gold thickness passed the acceptable limit set in the EU standards for all image qualities except half doseCR. However, calcification detection varied significantly between image qualities. This suggests that the current EU guidelines may need revising. Conclusions: Microcalcification detection was found to be sensitive to detector and dose used. Standard measurements of image quality were a good predictor of microcalcification cluster detection.

How are medical devices regulated in the European Union

Abstract: Medical devices cannot be placed on the European market without conforming to the strict safety requirements of the European Union; one of these requirements is the affixation of the CE conformity mark. This article is an overview of the CE marking process only; it is not a document that should be referred to on its own. All manufacturers wishing to gain a CE mark should refer to the official documents.

Use of sugammadex in a ‘can't intubate, can't ventilate’ situation

Abstract: A 78-yr-old woman presented for a panendoscopy to investigate dysphonia and dysphagia. Intubation was anticipated to be difficult but possible, and mask ventilation was anticipated to be possible. After induction of anaesthesia and after three attempts at intubation, a ‘can't intubate, can ventilate' situation deteriorated to a ‘can't intubate, can't ventilate' (CICV) situation. Rocuronium-induced neuromuscular block was successfully reversed with sugammadex, as evidenced by the restoration of diaphragmatic movement, the ability of the patient to move her limbs, and the presence of a train-of-four nerve stimulation with no fade; however, ventilation was still not possible. A cricothyroid puncture using a Ravussin needle was performed successfully to provide emergency oxygenation. A tracheostomy was performed to allow the panendoscopy. CICV situations are rare anaesthetic emergencies. While sugammadex can be relied upon to reverse rocuronium-induced neuromuscular block, it should not be relied upon to rescue all CICV events, especially where airway instrumentation has led to airway swelling. The availability of sugammadex does not obviate the need for emergency tracheal access in the event of failed oxygenation. The presence of head and neck pathology should lead to the consideration of securing the airway awake.

Miscoding, misclassification and misdiagnosis of diabetes in primary care

Abstract: Aims: To determine the effectiveness of self-audit tools designed to detect miscoding, misclassification and misdiagnosis of diabetes in primary care. Methods: We developed six searches to identify people with diabetes with potential classification errors. The search results were automatically ranked from most to least likely to have an underlying problem. Eight practices with a combined population of 72 000 and diabetes prevalence 2.9% (n = 2340) completed audit forms to verify whether additional information within the patients' medical record confirmed or refuted the problems identified. Results: The searches identified 347 records, mean 42 per practice. Pre-audit 20% (n = 69) had Type 1 diabetes, 70% (n = 241) had Type 2 diabetes, 9% (n = 30) had vague codes that were hard to classify, 2% (n = 6) were not coded and one person was labelled as having gestational diabetes. Of records, 39.2% (n = 136) had important errors: 10% (n = 35) had coding errors; 12.1% (42) were misclassified; and 17.0% (59) misdiagnosed as having diabetes. Thirty-two per cent (n = 22) of people with Type 2 diabetes (n = 69) were misclassified as having Type 1 diabetes; 20% (n = 48) of people with Type 2 diabetes (n = 241) did not have diabetes; of the 30 patients with vague diagnostic terms, 50% had Type 2 diabetes, 20% had Type 1 diabetes and 20% did not have diabetes. Examples of misdiagnosis were found in all practices, misclassification in seven and miscoding in six. Conclusions: Volunteer practices successfully used these self-audit tools. Approximately 40% of patients identified by computer searches (5.8% of people with diabetes) had errors; misdiagnosis is commonest, misclassification may affect treatment options and miscoding in omission from disease registers and the potential for reduced quality of care.

The role of transperineal template prostate biopsies in restaging men with prostate cancer managed by active surveillance

Abstract: Study Type – Diagnostic (exploratory cohort) Level of Evidence 3b What's known on the subject? and What does the study add? The optimal method of active surveillance in prostate cancer remains unknown. This study is one of the first to report on the role of transperineal template prostate biopsies in active surveillance. It demonstrates that around one third of men are reclassified with more significant prostate cancer at an early stage in their management. This is a higher proportion than reported in contemporary cancers using standard transrectal biopsies for restaging. OBJECTIVE • To evaluate the role of transperineal template prostate biopsies in men on active surveillance. PATIENTS AND METHODS • In all, 101 men on active surveillance for prostate cancer underwent restaging transperineal template prostate biopsies at a single centre. • Criteria for active surveillance were ≤75 years, Gleason ≤3+3, prostate-specific antigen (PSA) ≤15 ng/mL, clinical stage T1–2a and ≤50% ultrasound-guided transrectal biopsy cores positive for cancer with ≤10 mm of disease in a single core. • The number of men with an increase in disease volume or Gleason grade on transperineal template biopsy and the number of men who later underwent radical treatment were assessed. • The role of PSA and PSA kinetics were studied. RESULTS • In all, 34% of men had more significant prostate cancer on restaging transperineal template biopsies compared with their transrectal biopsies. • Of these men, 44% had disease predominantly in the anterior part of the gland, an area often under-sampled by transrectal biopsies. • In the group of men who had their restaging transperineal template biopsies within 6 months of commencing active surveillance 38% had more significant disease. • There was no correlation with PSA velocity or PSA doubling time. • In total, 33% of men stopped active surveillance and had radical treatment. CONCLUSIONS • Around one-third of men had more significant prostate cancer on transperineal template biopsies. • This probably reflects under-sampling by initial transrectal biopsies rather than disease progression.

Recent advances in incretin‐based therapies

Abstract: The global burden of type 2 diabetes is growing. Traditional therapies are suboptimal and there is a clear unmet need for treatments that offer effective glucose control while addressing the comorbid factors associated with diabetes, such as obesity and risk of cardiovascular disease, without the fear of hypoglycaemia. Glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors offer a novel way of reducing hyperglycaemia by targeting the incretin system. This review provides an overview of the development of incretin-based therapies and explains their differing modes of action compared with traditional interventions. A comparison of the clinical profiles of current glucagon-like peptide-1 receptor agonists [liraglutide and exenatide (twice-daily and once-weekly)] and dipeptidyl peptidase-4 inhibitors (sitagliptin, saxagliptin, vildagliptin and linagliptin) is performed alongside a discussion of the placement of incretin-based therapies in treatment guidelines. Further improvements in this class are expected, and we will examine some of the novel glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors currently under development.

Therapeutic application of monoclonal antibodies in cancer: advances and challenges

Abstract: IntroductionMonoclonal antibody (mAb)-based products are highly specific for a particular antigen. This characteristic feature of the molecules makes them an ideal tool for many applications including cancer diagnosis and therapy.Sources of dataWe performed comprehensive searches of PubMed, Medline and the Food and Drug Administration website using keywords such as 'therapeutic antibodies' and 'anti-cancer antibodies'.Areas of agreementTreatment of cancer patients with antibodies when used alone or in combination with chemotherapy and radiotherapy, or conjugated to drugs or radioisotopes, prolongs overall survival in cancer patients. Currently, there are 14 mAb-based drugs that have been approved for the treatment of cancer patients.Areas of controversyThe response of cancer patients to antibody therapy can be of short duration. Therapeutic antibodies are expensive and may have side effects. There are no reliable predictive biomarkers for sensitivity or resistance to certain therapeutic antibodies.Future focusThere should be additional studies to discover novel therapeutic targets, to develop more effective antibody-based drugs with fewer side effects, to identify more reliable predictive biomarker(s) for response to therapy with antibody-based drugs and to develop alternative strategies (e.g. transgenic plants, transgenic farm animals) for production of large quantities and more affordable batches of therapeutic antibodies.Areas timely for developing researchA better understanding of cancer biology, the hallmarks of human cancers and the immune system would lead to identification of additional cell surface biomarkers. These in turn would facilitate the development of novel and biosimilar antibody-based drugs and their routine use as 'magic bullets' for the targeted therapy of human cancers.

Regulation of medical devices outside the European Union

Abstract: The regulation of medical devices across the world is very varied, ranging from comprehensive to none. Over the past two decades, the number, range, and complexity of medical devices has increased. Regulation of these devices has also evolved due to an increasing awareness of the need for a more consistent approach to regulatory documentation. This will aid both manufacturers selling a product in more than one country, and the countries introducing regulation. Current initiatives are working towards manufacturers being able to produce a single set of documents that will fulfil the requirements of all regulatory authorities. In 2001 the World Health Organization (WHO) published ‘A model regulatory programme for medical devices: An international guide’1 which provided a framework to assist member states in establishing regulatory programmes for medical devices. The guide was based on experiences from areas that had already established comprehensive regulatory programmes. The aim was to provide information to nations without medical device regulatory systems that would enable the production of internationally compatible regulations. In 2003 the WHO published ‘Medical device regulations. Global overview and guiding principles’,2 in which it highlighted the complexity of the medical device industry and identified issues related to regulation. This document provided guidance to member states wishing to create or modify their regulatory systems for medical devices. The WHO is continually prompting harmonized medical device regulation through a range of initiatives, the most recent being the First Global Forum on Medical Devices held in Bangkok during September 2010. At the Bangkok meeting it was reported that: approximately 30% of countries have a developed framework for regulation of medical devices; approximately 30% of countries only have partial regulation of medical devices; remaining countries are either developing a framework or do not yet have any regulation.3 The Global Harmonization Task Force (GHTF) was founded in 1992 in response to a growing need for international harmonization of medical device regulation. This is a voluntary group comprised originally of representatives from the medical device regulatory authorities of the five founding members USA, European Union (EU), Japan, Australia and Canada. In 2006, membership was expanded to include the AHWP, International Organization for standardization (ISO), and the International Electrotechnical Commission (IEC). The International Organization for Standardization (ISO) was set-up in 1946 to facilitate the international coordination and unification of industrial standards. ISO is a network of national standards institutes in 163 countries, and is now the world's largest developer and publisher of voluntary international standards. ISO standards are widely adopted at regional and national level, and underpin the procedures and practices of medical device development, manufacture, quality control and conformity assessment requirements. In the global market these standards provide governments with a technical base for health, safety and environmental requirements, and aid the transfer of good practice and knowledge to developing countries. Standards can be obtained from the ISO website (http://www.iso.org/iso/home.html). There are a large number of standards that relate to medical devices and some of the most important include: ISO 13485 Medical devices – Quality management systems – Requirements for regulatory processes (this is a specific medical device standard based on ISO 9001); ISO 10993 Biological evaluation of medical devices; ISO 14155 Clinical investigation of medical devices for human subjects; ISO 14971 Medical devices – Application of risk management to medical devices.

Socioeconomic variation in uptake of colonoscopy following a positive faecal occult blood test result: a retrospective analysis of the NHS Bowel Cancer Screening Programme.

Abstract: Bowel cancer is a serious health burden and its early diagnosis improves survival. The Bowel Cancer Screening Programme (BCSP) in England screens with the Faecal Occult Blood test (FOBt), followed by colonoscopy for individuals with a positive test result. Socioeconomic inequalities have been demonstrated for FOBt uptake, but it is not known whether they persist at the next stage of the screening pathway. The aim of this study was to assess the association between colonoscopy uptake and area socioeconomic deprivation, controlling for individual age and sex, and area ethnic diversity, population density, poor self-assessed health, and region. Logistic regression analysis of colonoscopy uptake using BCSP data for England between 2006 and 2009 for 24 180 adults aged between 60 and 69 years. Overall colonoscopy uptake was 88.4%. Statistically significant variation in uptake is found between quintiles of area deprivation (ranging from 86.4 to 89.5%), as well as age and sex groups (87.9–89.1%), quintiles of poor self-assessed health (87.5–89.5%), non-white ethnicity (84.6–90.6%) and population density (87.9–89.3%), and geographical regions (86.4–90%). Colonoscopy uptake is high. The variation in uptake by socioeconomic deprivation is small, as is variation by subgroups of age and sex, poor self-assessed health, ethnic diversity, population density, and region.

I. Enhanced recovery: more than just reducing length of stay?

Abstract: The concept of enhanced recovery (ER) after surgery is not new. It was pioneered in Denmark in the 1990s and in that time has been practiced under various names, including fasttrack surgery and accelerated recovery. Currently, NHS improvement is leading a major initiative in the UK to implement ER across a number of specialities, including colorectal, musculoskeletal, urology, gynaecology, and breast surgery (http:// www.dh.gov.uk/prod_consum_dh/groups/dh_digitalassets/@dh/ @en/@ps/documents/digitalasset/dh_115156.pdf). The major evidence base to date is from colorectal surgery. It is noteworthy that in spite of anaesthesia having a pivotal role in driving ER forward, many of the publications are found in surgical journals. There are many traditionally perceived benefits from ER, for patients, healthcare professionals, and hospital managers. Patients recover from surgery more swiftly and are able to resume their normal lifestyle more quickly. For healthcare professionals and managers, patients spend less time in hospital resulting in either more capacity or a reduced requirement for hospital beds and therefore cost. Of the many criteria used to judge ER, length of stay (LOS) is the most commonly used. It is widely collected and allows easy comparisons between units. Dramatic reductions in LOS have been described including 23 h stay laparoscopic colectomy. However, there are several pitfalls associated with LOS. Time fit for medical discharge is probably a better marker but may not be the same in all hospitals and is not always the same as LOS, as it is recognized that patients may remain in hospital for reasons other than medical ones. In addition, some use the mean LOS, while others use the median LOS. This can be misleading; for example, in a group of patients in which a small number have a very prolonged LOS, the median LOS effectively ignores these patients. Despite these points, LOS (mean or median) is still so widely used that a reduction in LOS is almost seen as the raison d’etre of ER. There are, however, potentially more benefits other than having patients in hospital for less time. ER allows patients to recover quicker, using a number of techniques including preoperative carbohydrate loading, small incision surgery, reduced tubes, drains, etc., minimal use of opioid analgesia, avoidance of sodium and/or fluid overload, early resumption of enteral feeding, and early mobilization. This has been encompassed into a protocol-driven care pathway ensuring great consistency in patient treatment, from the preoperative phase through to discharge. Importantly, it has been demonstrated that the greater adherence to ER protocols, the greater the improvement in clinical outcome. Of all the steps that are important in colorectal surgery (some 20 in all), we have simplified them to analgesia, goal-directed fluid therapy (GDFT), and ‘all the others’ in the ER pathway and have termed this the trimodal approach. Perioperative analgesia and i.v. fluid therapy are generally under the control of the anaesthetist. The rewards are great if these processes are performed well but can be disastrous for patients if they are poorly conducted. Inadequate analgesia can result in poor mobilization, sleep deprivation, and ultimately an exaggerated stress response, or side-effects from excessive or inappropriate medication. The optimum analgesic regimen for many types of surgery is often contested. Volume 109, Number 5, November 2012

Urinary engrailed-2 (EN2) levels predict tumour volume in men undergoing radical prostatectomy for prostate cancer.

Abstract: What's known on the subject? and What does the study add? There are a lot of potential prostate cancer biomarkers being evaluated. All aim to improve on the sensitivity and specificity of PSA. EN2 was recently shown by our group to have better sensitivity and specificity than PSA. EN2 is a simple ELISA test and is not dependent on other parameters, even PSA, unlike all the other current biomarkers under evaluation. To date, no marker correlates with the amount of cancer present - the present study shows this positive correlation with EN2 in men undergoing prostatectomy. The potential utility of this work is that by knowing that the level of EN2 corresponds to the amount of cancer present, irrelevant of tumour grade and number of cancer foci, we can define an EN2 level corresponding to small cancers, which can then undergo surveillance. We are conducting a further study that is aimed at determining whether the levels of EN2 in urine can indicate 'significant' vs 'non-significant cancer' using the threshold of 0.5 mL cancer (after Epstein's work).

Conversion of mammographic images to appear with the noise and sharpness characteristics of a different detector and x-ray system

Abstract: Purpose: Undertaking observer studies to compare imaging technology using clinical radiological images is challenging due to patient variability. To achieve a significant result, a large number of patients would be required to compare cancer detection rates for different image detectors and systems. The aim of this work was to create a methodology where only one set of images is collected on one particular imaging system. These images are then converted to appear as if they had been acquired on a different detector and x-ray system. Therefore, the effect of a wide range of digital detectors on cancer detection or diagnosis can be examined without the need for multiple patient exposures. Methods: Three detectors and x-ray systems [Hologic Selenia (ASE), GE Essential (CSI), Carestream CR (CR)] were characterized in terms of signal transfer properties, noise power spectra (NPS), modulation transfer function, and grid properties. The contributions of the three noise sources (electronic, quantum, and structure noise) to the NPS were calculated by fitting a quadratic polynomial at each spatial frequency of the NPS against air kerma. A methodology was developed to degrade the images to have the characteristics of a different (target) imaging system. The simulated images were created by firstmore » linearizing the original images such that the pixel values were equivalent to the air kerma incident at the detector. The linearized image was then blurred to match the sharpness characteristics of the target detector. Noise was then added to the blurred image to correct for differences between the detectors and any required change in dose. The electronic, quantum, and structure noise were added appropriate to the air kerma selected for the simulated image and thus ensuring that the noise in the simulated image had the same magnitude and correlation as the target image. A correction was also made for differences in primary grid transmission, scatter, and veiling glare. The method was validated by acquiring images of a CDMAM contrast detail test object (Artinis, The Netherlands) at five different doses for the three systems. The ASE CDMAM images were then converted to appear with the imaging characteristics of target CR and CSI detectors. Results: The measured threshold gold thicknesses of the simulated and target CDMAM images were closely matched at normal dose level and the average differences across the range of detail diameters were -4% and 0% for the CR and CSI systems, respectively. The conversion was successful for images acquired over a wide dose range. The average difference between simulated and target images for a given dose was a maximum of 11%. Conclusions: The validation shows that the image quality of a digital mammography image obtained with a particular system can be degraded, in terms of noise magnitude and color, sharpness, and contrast to account for differences in the detector and antiscatter grid. Potentially, this is a powerful tool for observer studies, as a range of image qualities can be examined by modifying an image set obtained at a single (better) image quality thus removing the patient variability when comparing systems.« less