Showing papers by "St Bartholomew's Hospital published in 2012"

Maintenance of sinus rhythm with an ablation strategy in patients with atrial fibrillation is associated with a lower risk of stroke and death

Abstract: Objective To investigate whether catheter ablation of atrial fibrillation (AF) reduces stroke rate or mortality. Methods An international multicentre registry was compiled from seven centres in the UK and Australia for consecutive patients undergoing catheter ablation of AF. Long-term outcomes were compared with (1) a cohort with AF treated medically in the Euro Heart Survey, and (2) a hypothetical cohort without AF, age and gender matched to the general population. Analysis of stroke and death was carried out after the first procedure (including peri-procedural events) regardless of success, on an intention-to-treat basis. Results 1273 patients, aged 58±11 years, 56% paroxysmal AF, CHADS 2 score 0.7±0.9, underwent 1.8±0.9 procedures. Major complications occurred in 5.4% of procedures, including stroke/TIA in 0.7%. Freedom from AF following the last procedure was 85% (76% off antiarrhythmic drugs) for paroxysmal AF, and 72% (60% off antiarrhythmic drugs) for persistent AF. During 3.1 (1.0–9.6) years from the first procedure, freedom from AF predicted stroke-free survival on multivariate analysis (HR=0.30, CI 0.16 to 0.55, p Conclusion Restoration of sinus rhythm by catheter ablation of AF is associated with lower rates of stroke and death compared with patients treated medically.

Adjuvant radiotherapy for Stage I endometrial cancer

Abstract: Background This is an updated version of the original Cochrane review published in Issue 2, 2007. The role of radiotherapy (both pelvic external beam radiotherapy (EBRT) and vaginal intracavity brachytherapy (VBT)) in stage I endometrial cancer following hysterectomy remains controversial. Objectives To assess the efficacy of adjuvant radiotherapy following surgery for stage I endometrial cancer. Search methods We searched The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and the Specialised Register to end-2005 for the original review, and extended the search to January 2012 for the update. Selection criteria We included randomised controlled trials (RCTs) that compared post-operative adjuvant radiotherapy (either EBRTor VBT, or both) versus no radiotherapy or VBT in women with stage I endometrial cancer. Data collection and analysis Two review authors independently assessed trials and extracted data to a specifically designed data collection form. The primary outcome was overall survival. Secondary outcomes were endometrial cancer-related deaths, locoregional recurrence and distant recurrence. Meta-analyses were performed using Cochrane Review Manager Software 5.1. Main results We included eight trials. Seven trials (3628 women) compared EBRT with no EBRT (or VBT), and one trial (645 women) compared VBTwith no additional treatment. We considered six of the eight trials to be of a high quality. Time-to-event data were not available for all trials and all outcomes. EBRT (with or without VBT) compared with no EBRT (or VBT alone) for stage I endometrial carcinoma significantly reduced locoregional recurrence (time-to-event data: five trials, 2965 women; Hazard Ratio (HR) 0.36, 95% Confidence Interval (CI) 0.25 to 0.52; and dichotomous data: seven trials, 3628 women; Risk Ratio (RR) 0.33, 95% CI 0.23 to 0.47). This reduced risk of locoregional recurrence did not translate into improved overall survival (time-to-event data: five trials, 2,965 women; HR 0.99, 95% CI 0.82 to1.20; and dichotomous data: seven trials, 3628 women; RR 0.98, 95% CI 0.83 to 1.15) or improved endometrial cancer-related survival (time-to-event data: five trials, 2965 women; HR 0.96, 95% CI 0.72 to 1.28; and dichotomous data: seven trials, 3628 women; RR 1.02, 95% CI 0.81 to 1.29) or improved distant recurrence rates (dichotomous data: seven trials, 3628 women; RR 1.04, 95% CI 0.80 to1.35). EBRT did not improve survival outcomes in either the intermediate-risk or high-risk subgroups, although high-risk data were limited, and a benefit of EBRT for high-risk women could not be excluded. One trial (PORTEC-2) compared EBRT with VBT in the high-intermediate risk group and reported that VBT was effective in ensuring vaginal control with a non-significant difference in loco-regional relapse rate compared to EBRT (5.1% versus 2.1%; HR 2.08, 95% CI 0.71 to 6.09; P = 0·17). In the subgroup of low-risk patients (IA/B and grade 1/2), EBRT increased the risk of endometrial carcinoma-related deaths (including treatment-related deaths) (two trials, 517 women; RR 2.64, 95% CI 1.05 to 6.66) but there was a lack of data on overall survival. We considered the evidence for the low-risk subgroup to be of a low quality. EBRT was associated with significantly increased severe acute toxicity (two trials, 1328 patients, RR 4.68, 95% CI 1.35 to 16.16), increased severe late toxicity (six trials, 3501 women; RR 2.58, 95% CI 1.61 to 4.11) and significant reductions in quality of life scores and rectal and bladder function more than 10 years after randomisation (one trial, 351 women) compared with no EBRT. One trial of VBT versus no additional treatment in women with low-risk lesions reported a non-significant reduction in locoregional recurrence in the VBT group compared with the no additional treatment group (RR 0.39, (95% CI 0.14 to 1.09). There were no significant differences in survival outcomes in this trial. Authors' conclusions EBRT reduces the risk of locoregional recurrence but has no significant impact on cancer-related deaths or overall survival. It is associated with significant morbidity and a reduction in quality of life. There is no demonstrable survival advantage from adjuvant EBRT for high-risk stage I endometrial cancer, however, the meta-analyses of this subgroup were underpowered and also included high-intermediate risk women, therefore we cannot exclude a small benefit in the high-risk subgroup. EBRT may have an adverse effect on endometrial cancer survival when used to treat uncomplicated low-risk (IA/B grade 1/2) endometrial cancer. For the intermediate to high-intermediate risk group, VBT alone appears to be adequate in ensuring vaginal control compared to EBRT. Further research is needed to guide practice for lesions that are truly high risk. In addition, the definitions of risk should be standardised.

A placebo-controlled, parallel-group, randomized withdrawal study of subjects with symptoms of spasticity due to multiple sclerosis who are receiving long-term Sativex® (nabiximols):

Abstract: Background: Open-label studies are not ideal for providing robust evidence for long-term maintenance of efficacy of medicines, especially where medicines provide symptom relief and where long-term use of a placebo may be problematic and not ethical.Objective: To evaluate the maintenance of efficacy of Sativex in subjects who have gained long-term symptomatic relief of spasticity in multiple sclerosis (MS), and to assess the impact of sudden medicine withdrawal.Methods: An enriched enrolment randomized withdrawal study design was used. Eligible subjects with ongoing benefit from Sativex for at least 12 weeks entered this 5-week placebo-controlled, parallel-group, randomized withdrawal study. Each subjects’ previous effective and tolerated dose was continued.Results: A total of 18 subjects per group were enrolled. Demographics showed a mean duration of MS of 16.4 years, spasticity 12.7 years, mean duration of Sativex use of 3.6 years (median 3.4 years) and a mean daily dose of 8.25 sprays. Primary outcome o...

Targeting the FMS-like tyrosine kinase 3 in acute myeloid leukemia

Abstract: Acute myeloid leukemia (AML) is a highly heterogenous disease with multiple signaling pathways contributing to its pathogenesis. A key driver of AML is the FMS-like tyrosine kinase receptor-3 (FLT3). Activating mutations in FLT3, primarily the FLT3-internal tandem duplication (FLT3-ITD), are associated with decreased progression-free and overall survival. Identification of the importance of FLT3-ITD and the FLT3 pathway in the prognosis of patients with AML has stimulated efforts to develop therapeutic inhibitors of FLT3. Although these inhibitors have shown promising antileukemic activity, they have had limited efficacy to date as single agents and may require use in combination with cytotoxic chemotherapies. Here, we review clinical and preclinical results for the clinically mature FLT3 inhibitors currently in development. We conclude that multitargeted FLT3 inhibitors may have more utility earlier in the course of disease, when in vitro evidence suggests that AML cells are less dependent on FLT3 signaling, perhaps because of upregulation of multiple other signaling pathways. More potent agents may have greater utility in relapsed and heavily pretreated patients, in whom high levels of circulating FLT3 ligand may necessitate use of an agent with a very favorable pharmacokinetic/pharmacodynamic profile. Novel combination regimens are also discussed.

Imaging Strategy for Early Ovarian Cancer: Characterization of Adnexal Masses with Conventional and Advanced Imaging Techniques

Abstract: Imaging strategies used to diagnose early ovarian cancer are discussed, with a focus on characterizing adnexal masses with emerging dynamic contrast material-enhanced and diffusion-weighted MR imaging techniques.

Left Atrial Wall Stress Distribution and Its Relationship to Electrophysiologic Remodeling in Persistent Atrial Fibrillation

Abstract: Background— Atrial stretch causes remodeling that predisposes to atrial fibrillation. We tested the hypothesis that peaks in left atrial (LA) wall stress are associated with focal remodeling. Methods and Results— Nineteen patients underwent LA mapping before catheter ablation for persistent atrial fibrillation. Finite Element Analysis was used to predict wall stress distribution based on LA geometry from CT. The relationship was assessed between wall stress and (1) electrogram voltage and (2) complex fractionated atrial electrograms (CFAE), using CFAE mean (the mean interval between deflections). Wall stress varied widely within atria and between subjects (median, 36 kPa; interquartile range, 26–51 kP). Peaks in wall stress (≥90th percentile) were common at the pulmonary vein (PV) ostia (93%), the appendage ridge (100%), the high posterior wall (84%), and the anterior wall and septal regions (42–84%). Electrogram voltage showed an inverse relationship across quartiles for wall stress (19% difference across quartiles, P =0.016). There was no effect on CFAE mean across quartiles of wall stress. Receiver operating characteristic analysis showed high wall stress was associated with low voltage (ie, <0.5 mV) and electrical scar (ie, <0.05 mV; both P <0.0001) and with absence of CFAE (ie, CFAE mean <120 ms; P <0.0001). However, peaks in wall stress and CFAE were found at 88% of PV ostia. Conclusions— Peaks in wall stress were associated with areas of low voltage, suggestive of focal remodeling. Although peaks in wall stress were not associated with LA CFAE, the PV ostia may respond differently.

Effectiveness of semi-quantitative multiphase dynamic contrast-enhanced MRI as a predictor of malignancy in complex adnexal masses: radiological and pathological correlation

Abstract: To determine whether threshold criteria using semi-quantitative multiphase-dynamic contrast-enhanced magnetic resonance imaging (DCE- MRI) can improve prediction of malignancy in complex adnexal masses. MRI features of 70 complex adnexal masses with enhancing components in 63 patients were reviewed and correlated with histopathology (n = 67) or radiological follow-up (n = 3). Masses were categorised as benign (n = 34) or borderline/invasive malignant (n = 36). Borderline lesions (n = 6) were also analysed separately. Using the semi-quantitative breast analysis software, regions of interest were drawn around the most avidly enhancing component of each lesion. Maximum absolute enhancement of signal intensities (SImax), maximum relative enhancement (SIrel) and wash-in rate (WIR) were recorded. Optimal threshold criteria were established to predict borderline/invasive malignancy. There was a significant difference in mean SImax (P < 0.05), SIrel (P < 0.01) and WIR (P < 0.001) between benign and borderline/invasive malignant groups. A cut-off WIR ≥9.5 l/s had a specificity of 88% and positive predictive value of 86% for predicting malignancy, significantly better than conventional MRI (62%, P < 0.01). WIR <8.2 l/s had a negative predictive value of 94%. Threshold criteria using semi-quantitative multiphase DCE-MRI improves specificity in the prediction of malignancy in complex adnexal masses with enhancing components and is complementary to standard qualitative assessment. • Semi-quantitative DCE-MRI threshold criteria are effective for predicting ovarian malignancy • The surgical approach may be altered depending on DCE-MRI threshold criteria analysis • Borderline tumours demonstrate significant overlap with benign lesions using DCE-MRI threshold criteria

Effective Combination Treatment with Cabergoline and Low-Dose Pegvisomant in Active Acromegaly: A Prospective Clinical Trial

Abstract: Context: With adequate dose titration, pegvisomant normalizes IGF-I in up to 97% of patients with acromegaly. Pegvisomant is indicated for treatment-resistant disease but is expensive, particularly at a high dose. It has been used successfully in combination with somatostatin analogs. However, there are no therapeutic reports of pegvisomant in combination with dopamine agonists. Cabergoline is orally active, well-tolerated, and relatively inexpensive, and as monotherapy for acromegaly it is reported to normalize IGF-I in up to 30% of patients. Objective: The aim of the study was to investigate the efficacy of cabergoline monotherapy and pegvisomant in combination with cabergoline to control serum IGF-I in patients with active acromegaly. Twenty-four patients were recruited into a United Kingdom, multicenter, open-label, prospective clinical trial. Main Outcome Measure: We measured the change in serum IGF-I. Results: After 18 wk of dose titration to a maximum dose of 0.5 mg once daily, cabergoline monother...

European Perspective on Multiple Myeloma Treatment Strategies: Update Following Recent Congresses

Abstract: The management of multiple myeloma has undergone profound changes over the recent past as a result of advances in our understanding of the disease biology as well as improvements in treatment and supportive care strategies. Notably, recent years have seen a surge in studies incorporating the novel agents thalidomide, bortezomib, and lenalidomide into treatment for different disease stages and across different patient groups. This article presents an update to a previous review of European treatment practices and is based on discussions during an expert meeting that was convened to review novel agent data published or presented at medical meetings until the end of 2011 and to assess their impact on treatment strategies.

Risk of epithelial ovarian cancer in asymptomatic women with ultrasound-detected ovarian masses: a prospective cohort study within the UK collaborative trial of ovarian cancer screening (UKCTOCS).

Abstract: Objective. To estimate the risk of primary epithelial ovarian cancer (EOC) and slow growing borderline or Type I and aggressive Type II EOC in postmenopausal women with adnexal abnormalities on ultrasound. Methods. This was a prospective cohort study in the ultrasound group of the UK Collaborative Trial of Ovarian Cancer Screening of postmenopausal women with ultrasound-detected abnormal adnexal (unilocular, multilocular, unilocular solid and multilocular solid, solid) morphology on their first scan. Women were followed up through the national cancer registries and by postal questionnaires. Absolute risks of EOC and borderline, Type I and Type II EOC within 3 years of initial scan were calculated. Results. Of 48 053 women who underwent ultrasound examination and had complete scan data, 4367 (9.1% (95% CI, 8.8–9.3%)) had abnormal adnexal morphology. Median follow-up was 7.09 (25th–75th centiles, 6.03–7.92) years. Forty-seven (32 borderline or Type I, 15 Type II) were diagnosed with EOC. The overall absolute risk of EOC associated with abnormal adnexal morphology was 1.08% (95% CI, 0.79–1.43%); for borderline and Type I it was 0.73% (95% CI, 0.5–1.03%); and for Type II it was 0.34% (95% CI, 0.33–0.79%). In the subgroup (n = 741) with solid elements (unilocular solid, multilocular solid and solid) overall absolute risk was 4.45% (95% CI, 3.08–6.20%), for borderline and Type I it was 3.1% (95% CI, 1.9–4.6%) and for Type II it was 1.3% (95% CI, 0.6–2.4%). 11 982 women had both ovaries visualized and normal annual scans throughout the 3-year follow-up period. In this group, no borderline or Type I and eight Type II cancers were diagnosed. Conclusion. Asymptomatic postmenopausal women with ultrasound-detected adnexal abnormalities with solid elements have a 1 in 22 risk for EOC. Despite the higher prevalence of Type II EOC, the risk of borderline or Type I cancer in women with ultrasound abnormalities seems to be higher than does the risk of Type II cancer. This has important immediate implications for patients with incidental adnexal findings as well as for any future ultrasound-based screening.

Efficacy of bimonthly extracorporeal photopheresis in refractory chronic mucocutaneous GVHD

Abstract: Extracorporeal photopheresis (ECP) has become a recognised treatment for steroid-refractory chronic GVHD (cGVHD), but the optimal frequency and duration of treatment are yet to be established. We report on 82 consecutive patients with mucocutaneous cGVHD who received a bimonthly regimen of ECP treatment for two consecutive days, which could be subsequently tapered to a monthly regimen depending on response. Patients were steroid-refractory, steroid-dependent or steroid-intolerant, and 29 (35%) had multiorgan involvement. The median duration of treatment was 330 days (42-987). The median number of ECP cycles was 15 (1.5-32). Response was assessed by clinical assessment and reduction in immunosuppression after 6 months. 69/82 (84%) had completed 6 months of ECP and 65/69 (94%) had ≥ 50% improvement in symptoms and signs of cGVHD. A total of 77% of patients who completed 6 months of ECP had a reduction in immunosuppression dose and 80% had decreased their steroid dose (27.5% stopped, 30% had ≥ 75% reduction, 17.5% had ≥ 50% reduction and 25% had <50% reduction). OS at 3 years from the start of ECP was 69%. This study reports the largest series of patients receiving bimonthly ECP treatment for cGVHD, and confirms that ECP allows successful reduction of immunosuppression.

Radiological appearances of gynaecological emergencies

Abstract: The role of various gynaecological imaging modalities is vital in aiding clinicians to diagnose acute gynaecological disease, and can help to direct medical and surgical treatment where appropriate. It is important to interpret the imaging findings in the context of the clinical signs and patient's pregnancy status. Ultrasound and Doppler are readily available in the emergency department, and demonstrate features of haemorrhagic follicular cysts, ovarian cyst rupture, endometriotic cysts and pyosalpinx. Adnexal torsion may also be identified using ultrasound and Doppler, although the diagnosis cannot be safely excluded based on imaging alone. Computed tomography (CT) is not routinely employed in diagnosing acute gynaecological complications. However due to similar symptoms and signs with gastrointestinal and urinary tract pathologies, it is frequently used as the initial imaging modality and recognition of features of gynaecological complications on CT is important. Although MRI is not frequently used in the emergency setting, it is an important modality in characterising features that are unclear on ultrasound and CT. MRI is particularly helpful in identifying the site of origin of large pelvic masses, such as haemorrhagic uterine fibroid degeneration and fibroid prolapse or torsion. In this article, we review the imaging appearances of gynaecological emergencies in non-pregnant patients. • Ultrasonography is easily accessible and can identify life-threatening gynaecological complications. • Tomography scanners and computed radiography are not routinely used but are important to recognise key features. • MRI is used for the characterisation of acute gynaecological complications. • Recognition of the overlap in symptoms between gastrointestinal and gynaecological conditions is essential.

A MIQE-compliant real-time PCR assay for Aspergillus detection.

Abstract: The polymerase chain reaction (PCR) is widely used as a diagnostic tool in clinical laboratories and is particularly effective for detecting and identifying infectious agents for which routine culture and microscopy methods are inadequate. Invasive fungal disease (IFD) is a major cause of morbidity and mortality in immunosuppressed patients, and optimal diagnostic criteria are contentious. Although PCR-based methods have long been used for the diagnosis of invasive aspergillosis (IA), variable performance in clinical practice has limited their value. This shortcoming is a consequence of differing sample selection, collection and preparation protocols coupled with a lack of standardisation of the PCR itself. Furthermore, it has become clear that the performance of PCR-based assays in general is compromised by the inadequacy of experimental controls, insufficient optimisation of assay performance as well as lack of transparency in reporting experimental details. The recently published “Minimum Information for the publication of real-time Quantitative PCR Experiments” (MIQE) guidelines provide a blueprint for good PCR assay design and unambiguous reporting of experimental detail and results. We report the first real-time quantitative PCR (qPCR) assay targeting Aspergillus species that has been designed, optimised and validated in strict compliance with the MIQE guidelines. The hydrolysis probe-based assay, designed to target the 18S rRNA DNA sequence of Aspergillus species, has an efficiency of 100% (range 95–107%), a dynamic range of at least six orders of magnitude and limits of quantification and detection of 6 and 0.6 Aspergillus fumigatus genomes, respectively. It does not amplify Candida, Scedosporium, Fusarium or Rhizopus species and its clinical sensitivity is demonstrated in histological material from proven IA cases, as well as concordant PCR and galactomannan data in matched broncho-alveolar lavage and blood samples. The robustness, specificity and sensitivity of this assay make it an ideal molecular diagnostic tool for clinical use.

Archie Brain: celebrating 30 years of development in laryngeal mask airways.

Abstract: The practice of anaesthesia was revolutionised by the ideas of Archie Brain. The routine use of a facemask to manage the airway was not a hands-free technique, despite the development of various harnesses, and made adequate record-keeping difficult. The tracheal tube was associated with some morbidity, which some felt was unsuitable for day surgery. Brain developed an airway management device that was less stressful to the patient than tracheal intubation, and was, however, as safe as using a facemask and airway. Brain also hoped his device would function for cases where mask ventilation was particularly difficult and thus give anaesthetists a safer alternative to a complex intubation, especially in emergency scenarios.

A randomized multicenter trial of epirubicin, oxaliplatin, and capecitabine (EOC) plus panitumumab in advanced esophagogastric cancer (REAL3).

Abstract: LBA4000 Background: EGFR overexpression occurs in 27-50% of esophagogastric adenocarcinomas (OGA), and correlates with poor prognosis. The REAL3 trial evaluated the addition of the anti-EGFR antibody panitumumab (P) to epirubicin, oxaliplatin and capecitabine (EOC) in advanced OGA. Methods: Patients with untreated, metastatic or locally advanced OGA were randomised to EOC (E 50mg/m2, O 130mg/m2, C 1250mg/m2/day) or mEOC+P (E 50mg/m2, O 100mg/m2, C 1000mg/m2/day, P 9mg/kg). Primary endpoint was overall survival (OS); secondary endpoints were progression-free survival (PFS), response rate (RR), toxicity, and biomarker evaluation. Response was evaluated by RECIST after 4 and 8 cycles. Following IDMC review in October 2011 trial recruitment was halted and panitumumab withdrawn. Data for patients on treatment were censored at this timepoint. Results: 553 patients were recruited (EOC 275, mEOC+P 278), with median follow-up 5.0 and 5.2 months respectively. Median OS was 11.3 months with EOC compared to 8.8 month...

Extracellular fluid volume and glomerular filtration rate in 1878 healthy potential renal transplant donors: effects of age, gender, obesity and scaling

Abstract: Aim. The aim of this study was to investigate the influence of age, gender, obesity and scaling on glomerular filtration rate (GFR) and extracellular fluid volume (ECV) in healthy subjects. Methods. This is a retrospective multi-centre study of 1878 healthy prospective kidney transplant donors (819 men) from 15 centres. Age and body mass index (BMI) were not significantly different between men and women. Slope-intercept GFR was measured (using Cr-51-EDTA in 14 centres; Tc-99m-DTPA in one) and scaled to body surface area (BSA) and lean body mass (LBM), both estimated from height and weight. GFR was also expressed as the slope rate constant, with one-compartment correction (GFR/ECV). ECV was measured as the ratio, GFR to GFR/ECV. Results. ECV was age independent but GFR declined with age, at a significantly faster rate in women than men. GFR/BSA was higher in men but GFR/ECV and GFR/LBM were higher in women. Young women ( 65 years). There was no difference in GFR between obese (BMI > 30 kg/m2) and non-obese men. Obese women, however, had lower GFR than non-obese women and negative correlations were observed between GFR and both BMI and %fat. The decline in GFR with age was no faster in obese versus non-obese subjects. ECV/BSA was higher in men but ECV/LBM was higher in women. ECV/weight was almost gender independent, suggesting that fat-free mass in women contains more extracellular water. BSA is therefore a misleading scaling variable. Conclusion. There are several significant differences in GFR and ECV between healthy men and women.

Detection of Invasive Pulmonary Aspergillosis in Haematological Malignancy Patients by using Lateral-flow Technology

Abstract: Invasive pulmonary aspergillosis (IPA) is a leading cause of morbidity and mortality in haematological malignancy patients and hematopoietic stem cell transplant recipients1. Detection of IPA represents a formidable diagnostic challenge and, in the absence of a 'gold standard', relies on a combination of clinical data and microbiology and histopathology where feasible. Diagnosis of IPA must conform to the European Organization for Research and Treatment of Cancer and the National Institute of Allergy and Infectious Diseases Mycology Study Group (EORTC/MSG) consensus defining "proven", "probable", and "possible" invasive fungal diseases2. Currently, no nucleic acid-based tests have been externally validated for IPA detection and so polymerase chain reaction (PCR) is not included in current EORTC/MSG diagnostic criteria. Identification of Aspergillus in histological sections is problematic because of similarities in hyphal morphologies with other invasive fungal pathogens3, and proven identification requires isolation of the etiologic agent in pure culture. Culture-based approaches rely on the availability of biopsy samples, but these are not always accessible in sick patients, and do not always yield viable propagules for culture when obtained. An important feature in the pathogenesis of Aspergillus is angio-invasion, a trait that provides opportunities to track the fungus immunologically using tests that detect characteristic antigenic signatures molecules in serum and bronchoalveolar lavage (BAL) fluids. This has led to the development of the Platelia enzyme immunoassay (GM-EIA) that detects Aspergillus galactomannan and a 'pan-fungal' assay (Fungitell test) that detects the conserved fungal cell wall component (1 →3)-β-D-glucan, but not in the mucorales that lack this component in their cell walls1,4. Issues surrounding the accuracy of these tests1,4-6 has led to the recent development of next-generation monoclonal antibody (MAb)-based assays that detect surrogate markers of infection1,5. Thornton5 recently described the generation of an Aspergillus-specific MAb (JF5) using hybridoma technology and its use to develop an immuno-chromatographic lateral-flow device (LFD) for the point-of-care (POC) diagnosis of IPA. A major advantage of the LFD is its ability to detect activity since MAb JF5 binds to an extracellular glycoprotein antigen that is secreted during active growth of the fungus only5. This is an important consideration when using fluids such as lung BAL for diagnosing IPA since Aspergillus spores are a common component of inhaled air. The utility of the device in diagnosing IPA has been demonstrated using an animal model of infection, where the LFD displayed improved sensitivity and specificity compared to the Platelia GM and Fungitell (1 → 3)-β-D-glucan assays7. Here, we present a simple LFD procedure to detect Aspergillus antigen in human serum and BAL fluids. Its speed and accuracy provides a novel adjunct point-of-care test for diagnosis of IPA in haematological malignancy patients.

Controversies and advances in non-steroidal anti-inflammatory drug (NSAID) analgesia in chronic pain management

Abstract: Chronic pain can lead to significant disability with social and economic implications in the community. Traditional non-steroidal anti-inflammatory drugs (NSAIDs) have been part of the management of chronic pain. The risk of adverse events with traditional NSAIDs has led to the development of alternative therapeutic options. Differential blockade of the enzymes involved in pain and inflammation can offer therapeutic options without the gastrointestinal side effects. However, this may be at the expense of other major cardiovascular side effects. Pain pathways that involve peripheral transmission may be altered by local application of analgesia to the skin overlying the painful area. Recent guidelines for osteoarthritis treatment from the National Institute for Health and Clinical Excellence highlight the importance of topical NSAIDs in the armamentarium of pain management. NSAID combination drugs with gastric protection have provided alternatives to traditional NSAIDs, but the long-term sequelae are unknown.

Impact of the revised (2008) EORTC/MSG definitions for invasive fungal disease on the rates of diagnosis of invasive aspergillosis.

Abstract: Diagnosis of invasive aspergillosis (IA) remains a challenge as the clinical manifestations are not specific, and a histological diagnosis is often unfeasible. The 2002 European Organization for Research and Treatment of Cancer (EORTC) and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (MSG) criteria for classification of cases into possible, probable or proven were revised in 2008. Our objective was to analyze the impact of these revisions on the diagnosis of IA. A retrospective analysis of 589 high risk patient-episodes revealed that 125 of 155 'possible' (81%) and 12 of 16 'probable' (75%) cases of IA should be changed to 'non-classifiable' when the new criteria were applied. We concluded, as expected, that the 2008 EORTC/MSG revised definitions reduced the number of cases classified as 'possible' IA, but additionally, there has been a dramatic reduction in 'probable' cases. These changes have significant implications on the interpretation of clinical trial data based on EORTC/MSG classifications.

Multispectral imaging flow cytometry reveals distinct frequencies of γ‐H2AX foci induction in DNA double strand break repair defective human cell lines

Abstract: Copyright @ 2012 International Society for Advancement of Cytometry. The article can be accessed from the links below.

The role of FDG-PET/CT in gynaecological cancers

Abstract: There is now a growing body of evidence supporting the use of fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) in gynaecological malignancies. Although this molecular imaging technique is becoming increasingly available, PET/CT remains an expensive imaging tool. It is essential to be familiar with the circumstances in which FDG-PET/CT can add value and contribute to patient management and indeed to know when it is unlikely to be of benefit. It is also important to understand and recognize the potential pitfalls. FDG-PET/CT has been most widely adopted for staging patients with suspected advanced disease or in suspected recurrence, offering a whole-body imaging approach. However, there is great potential for this technique to act as a predictive biomarker of response to treatment, as well as a prognostic biomarker. In addition, FDG-PET images may now be incorporated into radiotherapy planning in order to refine the delineation of dose according to metabolically active sites of disease. This article reviews the literature that provides the evidence for the use of FDG-PET in gynaecological malignancies, identifies areas of real benefit and future potential, and highlights circumstances where there is limited value.

Tramadol/paracetamol fixed-dose combination in the treatment of moderate to severe pain

Abstract: Pain is the most common reason patients seek medical attention and pain relief has been put forward as an ethical obligation of clinicians and a fundamental human right. However, pain management is challenging because the pathophysiology of pain is complex and not completely understood. Widely used analgesics such as nonsteroidal anti-inflammatory drugs (NSAIDs) and paracetamol (acetaminophen) have been associated with adverse events. Adverse event rates are of concern, especially in long-term treatment or at high doses. Paracetamol and NSAIDs are available by prescription, over the counter, and in combination preparations. Patients may be unaware of the risk associated with high dosages or long-term use of paracetamol and NSAIDs. Clinicians should encourage patients to disclose all medications they take in a "do ask, do tell" approach that includes patient education about the risks and benefits of common pain relievers. The ideal pain reliever would have few risks and enhanced analgesic efficacy. Fixed-dose combination analgesics with two or more agents may offer additive or synergistic benefits to treat the multiple mechanisms of pain. Therefore, pain may be effectively treated while toxicity is reduced due to lower doses. One recent fixed-dose combination analgesic product combines tramadol, a centrally acting weak opioid analgesic, with low-dose paracetamol. Evidence-based guidelines recognize the potential value of combination analgesics in specific situations. The current guideline-based paradigm for pain treatment recommends NSAIDs for ongoing use with analgesics such as opioids to manage flares. However, the treatment model should evolve how to use low-dose combination products to manage pain with occasional use of NSAIDs for flares to avoid long-term and high-dose treatment with these analgesics. A next step in pain management guidelines should be targeted therapy when possible, or low-dose combination therapy or both, to achieve maximal efficacy with minimal toxicity.

A prospective evaluation of postural stimulation testing, computed tomography and adrenal vein sampling in the differential diagnosis of primary aldosteronism.

Abstract: Summary Context In primary aldosteronism (PA), discriminating unilateral from bilateral disease is crucial because adrenalectomy is frequently curative in the former case but rarely helps in the latter. Various series have reported the utility of postural stimulation testing (PST), cross-sectional imaging and adrenal vein sampling (AVS) in the assessment of PA, but most of these studies were retrospective. Objective To prospectively determine the diagnostic utility of PST, AVS and computed tomography (CT) using a radiological scoring system in the assessment of PA in a tertiary centre, as well as to document the incidence of autonomous cortisol cosecretion. Design and Setting Fifty consecutive patients with PA underwent PST, CT, AVS and a low-dose dexamethasone suppression test with measurement of serum cortisol at 48 h. For patients who underwent surgery, histological confirmation, and a normal postoperative serum aldosterone concentration and plasma renin activity were taken as evidence for unilateral disease. For other patients, results from successful adrenal vein sampling were the diagnostic evidence against which CT and PST were assessed. Results Postural stimulation testing had a sensitivity and specificity of 44–56% and 71–75%, respectively. CT had an overall sensitivity and specificity of 77% and 80%, respectively, rising to 100% sensitivity and specificity if there was a single, discrete macronodule with an unequivocally normal contralateral gland. Evidence of cosecretion of cortisol occurred in 14% of patients. Conclusions Preliminary experience is presented of an objective radiological scoring system for selecting patients with PA for AVS. PST provides little, if any, useful additional information. A significant minority of patients with PA exhibit evidence of cortisol cosecretion, which may have implications for perioperative management.

Does minimally invasive surgery for endometriosis improve pelvic symptoms and quality of life

Abstract: Purpose of review Endometriosis is a common gynaecological disorder estimated to affect over 70 million women worldwide. In this review we aim to give an overview of postoperative symptoms and look at factors influencing therapeutic choices and surgical techniques. Recent findings A wide range of physical and psychological factors contribute to the symptoms of disease. Patients suffer from impaired quality of life, depression, anxiety and chronic and acute pain. Validated questionnaires have been used to assess patient response. Surgical excision of endometriosis improves dyspareunia and the quality of sex life of patients. It is superior in outcomes to medical therapy in achieving increased pregnancy rates. Catastrophizing and biopsychosocial variables are implicated in the severity of pain experienced in patients with endometriosis. Patients with endometriosis score lower on quality of life assessments and the addition of psychosomatic therapy to medical treatments has shown to improve the emotional status of patients with improved treatment outcomes. Summary Despite its prevalence, there is no optimal treatment for endometriosis; recurrence of disease is a common problem. Laparoscopic surgery compared with medical therapies shows improved patient satisfaction outcomes in general health, quality of life and emotional wellbeing. Management of this varied aetiology improves in the context of a multidisciplinary team.

A distinct DNA methylation profile associated with microsatellite and chromosomal stable sporadic colorectal cancers

Abstract: Aberrant DNA methylation, microsatellite instability (MSI) and chromosomal instability (CIN) are well-characterised molecular features of sporadic colorectal cancers (CRCs). In addition to CpG island methylator phenotype (CIMP) associated with MSI, an intermediate methylation subgroup is also a feature of non-MSI cancers. A large proportion of CRCs have no evidence of either MSI or CIN, here called Microsatellite and Chromosomal Stable (MACS), and require their methylation profile to be established. The clinical and molecular features of 170 sporadic CRC patients were investigated and stratified into MSI, CIN and MACS groups. MACS were most often found in the left colon and had a significantly lower BRAF mutation frequency (p < 0.001) compared with MSI. MACS had better survival [hazard ratio (HR) = 0.244, p = 0.017] compared with CIN, but were similar to MSI. The methylation status of 1,505 CpG loci from cancer-related genes was analysed in a subset of CRCs (n = 44 normal-tumour pairs) and compared with CIN, MSI and MACS status. Using two-way hierarchical clustering, three subgroups were identified, which associated with CIN, MSI and MACS status. Using significance analysis of microarray, 16 CpG loci demonstrating methylation changes associated with MACS were identified. A combination of six loci identified MACS with 81% sensitivity and 93% specificity. This result now requires independent validation. Hypomethylation of a CpG locus within the sonic hedgehog (SHH) promoter correlated with increased gene expression and was associated significantly with MACS cancers. In conclusion, we propose that MACS have distinct clinicopathological features and can be distinguished from other CRCs by a specific set of methylation loci.