• 6 versus 12 months of adjuvant trastuzumab for HER2-positive early breast cancer (PERSEPHONE): 4-year disease-free survival results of a randomised phase 3 non-inferiority trial.

      Woodings, P (2019-06)
      BACKGROUND: Adjuvant trastuzumab significantly improves outcomes for patients with HER2-positive early breast cancer. The standard treatment duration is 12 months but shorter treatment could provide similar efficacy while reducing toxicities and cost. We aimed to investigate whether 6-month adjuvant trastuzumab treatment is non-inferior to the standard 12-month treatment regarding disease-free survival. METHODS: This study is an open-label, randomised phase 3 non-inferiority trial. Patients were recruited from 152 centres in the UK. We randomly assigned patients with HER2-positive early breast cancer, aged 18 years or older, and with a clear indication for chemotherapy, by a computerised minimisation process (1:1), to receive either 6-month or 12-month trastuzumab delivered every 3 weeks intravenously (loading dose of 8 mg/kg followed by maintenance doses of 6 mg/kg) or subcutaneously (600 mg), given in combination with chemotherapy (concurrently or sequentially). The primary endpoint was disease-free survival, analysed by intention to treat, with a non-inferiority margin of 3% for 4-year disease-free survival. Safety was analysed in all patients who received trastuzumab. This trial is registered with EudraCT (number 2006-007018-39), ISRCTN (number 52968807), and ClinicalTrials.gov (number NCT00712140). FINDINGS: Between Oct 4, 2007, and July 31, 2015, 2045 patients were assigned to 12-month trastuzumab treatment and 2044 to 6-month treatment (one patient was excluded because they were double randomised). Median follow-up was 5·4 years (IQR 3·6-6·7) for both treatment groups, during which a disease-free survival event occurred in 265 (13%) of 2043 patients in the 6-month group and 247 (12%) of 2045 patients in the 12-month group. 4-year disease-free survival was 89·4% (95% CI 87·9-90·7) in the 6-month group and 89·8% (88·3-91·1) in the 12-month group (hazard ratio 1·07 [90% CI 0·93-1·24], non-inferiority p=0·011), showing non-inferiority of the 6-month treatment. 6-month trastuzumab treatment resulted in fewer patients reporting severe adverse events (373 [19%] of 1939 patients vs 459 [24%] of 1894 patients, p=0·0002) or stopping early because of cardiotoxicity (61 [3%] of 1939 patients vs 146 [8%] of 1894 patients, p<0·0001). INTERPRETATION: We have shown that 6-month trastuzumab treatment is non-inferior to 12-month treatment in patients with HER2-positive early breast cancer, with less cardiotoxicity and fewer severe adverse events. These results support consideration of reduced duration trastuzumab for women at similar risk of recurrence as to those included in the trial. FUNDING: UK National Institute for Health Research, Health Technology Assessment Programme.
    • A comparison of the natural history and outcome of treatment for Asian and non-Asian hepatitis C-infected patients.

      Lawson, A (2011-07)
      Ethnicity is an important host variable, but its impact on disease progression and response to therapy in Hepatitis C infection is unclear. Here we compare the natural history and outcome of therapy in white and Asian (Indian subcontinent) Hepatitis C infected patients. A total of 2123 White and 120 Asian HCV infected patients were identified within the Trent HCV study. Response to therapy was assessed in 224 white and 46 Asian patients with genotype 3 infection who received pegylated interferon and ribavirin. Asian patients were more likely to be older, female, infected with genotype 3 and to consume no alcohol. At time of first biopsy, fibrosis stage was significantly higher in Asian patients than in Whites (3.0 ± 2.3 vs 1.8 ± 2.0, P < 0.001), as were necro-inflammation and steatosis scores. However, in those patients where duration of infection could be estimated, fibrosis progression was similar for both groups (0.25 ± 0.31 vs. 0.16 ± 0.54 Ishak points/year, P = 0.068). 78.3% of Asian and 67.9% of White genotype 3 patients had a sustained virological response following Pegylated Interferon and Ribavirin. Cirrhosis and increased levels of GGT, but not ethnicity were associated with a reduction in the likelihood of a sustained virological response on multivariate analysis. Asian patients with Hepatitis C are more likely to be female, less likely to give a history of risk factors, present to medical services at an older age, and have more severe liver disease at diagnosis, but disease progression and response to treatment are similar to white patients.
    • A diagnostic head and neck fine needle aspiration service can be provided using liquid-based cytology only.

      Robinson, Ivan (2016-06)
      OBJECTIVE: Liquid-based cytology (LBC) has been used for non gynaecological specimens since its introduction into routine use in cervical cytology in the mid-1990s. There are still relatively few large studies comparing performance in reporting the head and neck fine-needle aspirations (H&N FNA) processed by LBC only to conventional direct smears (CDS). METHODS: This study compared 686 H&N FNAs processed by LBC only with 3719 CDS. All were taken under ultrasound (US) guidance by a small cohort of three consultant radiologists and reported by the author. RESULTS: The (smaller) LBC sample was statistically representative of the larger CDS population at an alpha level of 0.05. There was no difference between CDS and LBC at a 95% confidence interval (CI) when comparing specificity and sensitivity (specificity: 94.8-96.5% versus 90.2-95.4%; sensitivity: 91.4-94.1% versus 86.8-93.4%). The inadequate rate between the two techniques was similar, 0.5-1.0% for CDS versus 0.7-2.5% for LBC. The significance difference was in the suspicious rate which was greater at 2.8-5.8% for LBC versus 1.7-2.6% for CDS. Consequently, there was a slight but non-significant difference between the two populations with respect to the overall accuracy: 93.5-95.1% for CDS versus 89.4-93.7% for LBC. CONCLUSIONS: While there are morphological differences between LBC and CDS in H&N FNAs, once a degree of familiarity is achieved, the two techniques have equivalent sensitivity, specificity and inadequate rates.
    • A preliminary randomized controlled study to determine the application frequency of a new lymphoedema bandaging system.

      Moffatt, Christine (2012-03)
      BACKGROUND:  Bandaging plays an important role in the treatment of lymphoedema. OBJECTIVE: To investigate efficacy and safety of the 3M™ Coban™ 2 compression system (Coban 2 system) with different application frequencies in comparison to short-stretch bandaging. METHODS: A multicentre, randomized, prospective study was performed with 82 patients suffering from arm or leg lymphoedema stage II or late stage II. Patients were allocated to traditional short-stretch bandaging five times per week or to the Coban 2 system applied two, three or five times per week for 19 days. Limb volume and adverse events were recorded at each study visit. The primary endpoint was percentage volume reduction. RESULTS: The highest lymphoedema volume reduction was achieved with the Coban 2 system applied two times per week. A mean reduction of 18•7% (SD 14•5) in legs and 10•5% (SD 8•3) in arms was achieved. More frequent bandage changes of three and five times per week did not demonstrate additional benefits. Short-stretch bandaging five times per week showed a mean volume reduction of 10•9% (SD 5•2) and 8•2% (SD 3•1) for legs and arms, respectively. Bandage slippage was low for all treatment groups. A relevant change in overall mobility was achieved during the use of the Coban 2 system. The adverse reactions were in agreement with already known side-effects and did not differ remarkably between the treatment groups. CONCLUSION: The 3M™ Coban™ 2 compression system applied twice weekly demonstrated a high rate of volume reduction and a good safety profile. Oedema reduction was still effective with 4 days between bandage change, which allows a constant therapeutic effect in routine practice. This should give the patient a high degree of independence and mobility.
    • A questionnaire survey comparing the educational priorities of patients and medical students in the management of multiple sclerosis.

      Gibson, Jeremy; Fakis, Apostolos (2014-12)
      OBJECTIVE: To compare the educational priorities patients and students raise concerning the management of multiple sclerosis (MS). DESIGN/SETTING: A single-centre comparative questionnaire survey conducted in a foundation trust hospital which provides teaching for one UK medical school. PARTICIPANTS: A total of 255 people with multiple sclerosis (pwMS) and 125 final year medical students attending a mandatory module were invited to participate. MAIN OUTCOME MEASUREMENTS: Questionnaires were developed and piloted for thisstudy and analysed on the basis of the International Classification of Functioning, Disability and Health terminology. RESULTS: Questionnaires were returned by 125 (50%) pwMS (age range 36-86 years; median 58) and 96 (77%) medical students (age range 22-37 years; median 23). The most commonly reported priority listed by people with MS and students concerned 'environmental contextual factors' (95.5% and 99%, respectively). PwMS focused primarily on the 'social and attitudinal aspects' of the environment (53.6%), while students expressed greater interest in the use of medications (91.7%) and investigations (14.6%) (p < 0.001). People with greater psychological or physical impact of the condition were more likely to prioritise 'health condition' topics. CONCLUSIONS: PwMS and medical students identify different topics when asked to list aspects of management of MS which they deem to be important for medical student teaching. These differences in educational priorities should be taken into consideration when teaching students about MS. The findings may also apply to other long-term neurological conditions and warrant further investigation.
    • A randomised controlled feasibility study investigating the use of eccentric and concentric strengthening exercises in the treatment of rotator cuff tendinopathy.

      Bateman, Marcus (2014-01)
      OBJECTIVES: To conduct a feasibility study to compare concentric and eccentric rotator cuff strengthening exercises for rotator cuff tendinopathy. METHODS: A total of 11 patients with rotator cuff tendinopathy who were on the waiting list for arthroscopic subacromial decompression surgery were randomised to perform eccentric rotator cuff strengthening exercises, concentric strengthening exercises or no exercises. Patients were evaluated in terms of levels of pain and function using the Oxford Shoulder Score and a Visual Analogue Scale initially, at 4 weeks and at 8 weeks. RESULTS: The study design was found to be acceptable to patients and achieved a high level of 86% compliance. The drop-out rate was 0%. Two patients performing eccentric strengthening exercises improved sufficiently to cancel their planned surgery. CONCLUSION: Further research in this area is recommended. The study design was feasible and power calculations have been conducted to aid future research planning.
    • A Transcriptional Signature of Fatigue Derived from Patients with Primary Sjögren's Syndrome.

      Regan, Marian (2015-12)
      BACKGROUND: Fatigue is a debilitating condition with a significant impact on patients' quality of life. Fatigue is frequently reported by patients suffering from primary Sjögren's Syndrome (pSS), a chronic autoimmune condition characterised by dryness of the eyes and the mouth. However, although fatigue is common in pSS, it does not manifest in all sufferers, providing an excellent model with which to explore the potential underpinning biological mechanisms. METHODS: Whole blood samples from 133 fully-phenotyped pSS patients stratified for the presence of fatigue, collected by the UK primary Sjögren's Syndrome Registry, were used for whole genome microarray. The resulting data were analysed both on a gene by gene basis and using pre-defined groups of genes. Finally, gene set enrichment analysis (GSEA) was used as a feature selection technique for input into a support vector machine (SVM) classifier. Classification was assessed using area under curve (AUC) of receiver operator characteristic and standard error of Wilcoxon statistic, SE(W). RESULTS: Although no genes were individually found to be associated with fatigue, 19 metabolic pathways were enriched in the high fatigue patient group using GSEA. Analysis revealed that these enrichments arose from the presence of a subset of 55 genes. A radial kernel SVM classifier with this subset of genes as input displayed significantly improved performance over classifiers using all pathway genes as input. The classifiers had AUCs of 0.866 (SE(W) 0.002) and 0.525 (SE(W) 0.006), respectively. CONCLUSIONS: Systematic analysis of gene expression data from pSS patients discordant for fatigue identified 55 genes which are predictive of fatigue level using SVM classification. This list represents the first step in understanding the underlying pathophysiological mechanisms of fatigue in patients with pSS.
    • Abiraterone acetate and prednisolone with or without enzalutamide for high-risk non-metastatic prostate cancer: a meta-analysis of primary results from two randomised controlled phase 3 trials of the STAMPEDE platform protocol.

      Das, P
      BACKGROUND: Men with high-risk non-metastatic prostate cancer are treated with androgen-deprivation therapy (ADT) for 3 years, often combined with radiotherapy. We analysed new data from two randomised controlled phase 3 trials done in a multiarm, multistage platform protocol to assess the efficacy of adding abiraterone and prednisolone alone or with enzalutamide to ADT in this patient population. METHODS: These open-label, phase 3 trials were done at 113 sites in the UK and Switzerland. Eligible patients (no age restrictions) had high-risk (defined as node positive or, if node negative, having at least two of the following: tumour stage T3 or T4, Gleason sum score of 8-10, and prostate-specific antigen [PSA] concentration ≥40 ng/mL) or relapsing with high-risk features (≤12 months of total ADT with an interval of ≥12 months without treatment and PSA concentration ≥4 ng/mL with a doubling time of <6 months, or a PSA concentration ≥20 ng/mL, or nodal relapse) non-metastatic prostate cancer, and a WHO performance status of 0-2. Local radiotherapy (as per local guidelines, 74 Gy in 37 fractions to the prostate and seminal vesicles or the equivalent using hypofractionated schedules) was mandated for node negative and encouraged for node positive disease. In both trials, patients were randomly assigned (1:1), by use of a computerised algorithm, to ADT alone (control group), which could include surgery and luteinising-hormone-releasing hormone agonists and antagonists, or with oral abiraterone acetate (1000 mg daily) and oral prednisolone (5 mg daily; combination-therapy group). In the second trial]
    • Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy.

      Chakraborti, Prabir (2017-06)
      Background Abiraterone acetate plus prednisolone improves survival in men with relapsed prostate cancer. We assessed the effect of this combination in men starting long-term androgen-deprivation therapy (ADT), using a multigroup, multistage trial design. Methods We randomly assigned patients in a 1:1 ratio to receive ADT alone or ADT plus abiraterone acetate (1000 mg daily) and prednisolone (5 mg daily) (combination therapy). Local radiotherapy was mandated for patients with node-negative, nonmetastatic disease and encouraged for those with positive nodes. For patients with nonmetastatic disease with no radiotherapy planned and for patients with metastatic disease, treatment continued until radiologic, clinical, or prostate-specific antigen (PSA) progression; otherwise, treatment was to continue for 2 years or until any type of progression, whichever came first. The primary outcome measure was overall survival. The intermediate primary outcome was failure-free survival (treatment failure was defined as radiologic, clinical, or PSA progression or death from prostate cancer). Results A total of 1917 patients underwent randomization from November 2011 through January 2014. The median age was 67 years, and the median PSA level was 53 ng per milliliter. A total of 52% of the patients had metastatic disease, 20% had node-positive or node-indeterminate nonmetastatic disease, and 28% had node-negative, nonmetastatic disease; 95% had newly diagnosed disease. The median follow-up was 40 months. There were 184 deaths in the combination group as compared with 262 in the ADT-alone group (hazard ratio, 0.63; 95% confidence interval [CI], 0.52 to 0.76; P<0.001); the hazard ratio was 0.75 in patients with nonmetastatic disease and 0.61 in those with metastatic disease. There were 248 treatment-failure events in the combination group as compared with 535 in the ADT-alone group (hazard ratio, 0.29; 95% CI, 0.25 to 0.34; P<0.001); the hazard ratio was 0.21 in patients with nonmetastatic disease and 0.31 in those with metastatic disease. Grade 3 to 5 adverse events occurred in 47% of the patients in the combination group (with nine grade 5 events) and in 33% of the patients in the ADT-alone group (with three grade 5 events). Conclusions Among men with locally advanced or metastatic prostate cancer, ADT plus abiraterone and prednisolone was associated with significantly higher rates of overall and failure-free survival than ADT alone. (Funded by Cancer Research U.K. and others; STAMPEDE ClinicalTrials.gov number, NCT00268476 , and Current Controlled Trials number, ISRCTN78818544
    • Accuracy of classification of invasive lobular carcinoma on needle core biopsy of the breast.

      Deb, Rahul (2016-08)
      Although the UK National Institute for Health and Care Excellence guidelines recommend that in patients with biopsy-proven invasive lobular carcinoma (ILC), preoperative MRI scan is considered, the accuracy of diagnosis of ILC in core biopsy of the breast has not been previously investigated. Eleven pathology laboratories from the UK and Ireland submitted data on 1112 cases interpreted as showing features of ILC, or mixed ILC and IDC/no special type (NST)/other tumour type, on needle core biopsy through retrieval of histology reports. Of the total 1112 cases, 844 were shown to be pure ILC on surgical excision, 154 were mixed ILC plus another type (invariably ductal/NST) and 113 were shown to be ductal/NST. Of those lesions categorised as pure ILC on core, 93% had an element of ILC correctly identified in the core biopsy sample and could be considered concordant. Of cores diagnosed as mixed ILC plus another type on core, complete agreement between core and excision was 46%, with 27% cases of pure ILC, whilst 26% non-concordant. These data indicate that there is not a large excess of expensive MRIs being performed as a result of miscategorisation histologically. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/ DOI: 10.1136/jclinpath-2016-203886 PMID: 27510520 [PubMed - as supplied by publisher] 2. Curr Opin Nephrol Hypertens. 2015 Nov;24(6):511-6. doi: 10.1097/MNH.0000000000000168. Acute kidney: improving the pathway of care for patients and across healthcare. Fluck RJ(1). Author information: (1)Department of Renal Medicine, Royal Derby Hospital, Derby, United Kingdom. PURPOSE OF REVIEW: Acute kidney injury (AKI) is common, harmful and of global concern. There is a need to understand the pathway of the management of AKI in order to identify potential areas where care can be improved, for the individual and for healthcare systems. RECENT FINDINGS: There has been considerable focus on risk assessment and earlier detection using changes in serum creatinine. There is less understanding of optimal management, enhanced and long-term recovery, and education to support better care. Using Kidney Disease Improving Global Outcomes-based criteria to improve the detection of AKI improves its detection, but requires supportive training and education to deliver better outcomes.Policy makers need to understand the personal and economic burden that results from AKI. There is a need to provide commissioning support, improvement methodologies, and registry initiatives with research investment to sustain progress in overall management. SUMMARY: There is clear evidence of harm related to AKI and a need to improve the reliability of care. The prevalence is high, with the potential to significantly improve short-term and long-term care by addressing all the elements in the pathway, at both patient and system level, assessing risk, detection, treatment, and recovery
    • Accuracy of clinical diagnosis in tremulous parkinsonian patients: A blinded video study

      Bajaj, Nin; Gontu, Vamsi; Birchall, James (2010-11)
      Background: This study examines the clinical accuracy of movement disorder specialists in distinguishing tremor dominant Parkinson's disease (TDPD) from other tremulous movement disorders by the use of standardised patient videos. Patients and methods: Two movement disorder specialists were asked to distinguish TDPD from patients with atypical tremor and dystonic tremor, who had no evidence of presynaptic dopaminergic deficit (subjects without evidence of dopaminergic deficit (SWEDDs)) according to ¹²³I-N-ω-fluoro-propyl- 2β-carbomethoxy-3β-(4-iodophenyl) nortropane ([¹²³I] FP-CIT) single photon emission computed tomography (SPECT), by ‘blinded’ video analysis in 38 patients. A diagnosis of parkinsonism was made if the step 1 criteria of the Queen Square Brain Bank criteria for Parkinson's disease were fulfilled. The reviewer diagnosis was compared with the working clinical diagnosis drawn from the medical history, SPECT scan result, long term follow-up and in some cases the known response to dopaminergic medications. This comparison allowed a calculation for false positive and false negative rate of diagnosis of PD. Results: High false positive (17.4-26.1%) and negative (6.7-20%) rates were found for the diagnosis of PD. The diagnostic distinction of TDPD from dystonic tremor was reduced by the presence of dystonic features in treated and untreated PD patients. Conclusion: Clinical distinction of TDPD from atypical tremor, monosymptomatic rest tremor and dystonic tremor can be difficult due to the presence of parkinsonian features in tremulous SWEDD patients. The diagnosis of bradykinesia was particularly challenging. This study highlights the difficulty of differentiation of some cases of SWEDD from PD.
    • Accuracy of GE digital breast tomosynthesis vs supplementary mammographic views for diagnosis of screen-detected soft-tissue breast lesions.

      Turnbull, Anne (2016-06)
      OBJECTIVE: To compare the accuracy of standard supplementary views and GE digital breast tomosynthesis (DBT) for assessment of soft-tissue mammographic abnormalities. METHODS: Women recalled for further assessment of soft-tissue abnormalities were recruited and received standard supplementary views (typically spot compression views) and two-view GE DBT. The added value of DBT in the assessment process was determined by analysing data collected prospectively by radiologists working up the cases. Following anonymization of cases, there was also a retrospective multireader review. The readers first read bilateral standard two-view digital mammography (DM) together with the supplementary mammographic views and gave a combined score for suspicion of malignancy on a five-point scale. The same readers then read bilateral standard two-view DM together with two-view DBT. Pathology data were obtained. Differences were assessed using receiver operating characteristic analysis. RESULTS: The study population was 342 lesions in 322 patients. The final diagnosis was malignant in 113 cases (33%) and benign/normal in 229 cases (67%). In the prospective analysis, the performance of two-view DM plus DBT was at least equivalent to the performance of two-view DM and standard mammographic supplementary views-the area under the curve (AUC) was 0.946 and 0.922, respectively, which did not reach statistical significance. Similar results were obtained for the retrospective review-AUC was 0.900 (DBT) and 0.873 (supplementary views), which did not reach statistical significance. CONCLUSION: The accuracy of GE DBT in the assessment of screen detected soft-tissue abnormalities is equivalent to the use of standard supplementary mammographic views. ADVANCES IN KNOWLEDGE: The vast majority of evidence relating to the use of DBT has been gathered from research using Hologic equipment. This study provides evidence for the use of the commercially available GE DBT system demonstrating that it is at least equivalent to supplementary mammographic views in the assessment of soft-tissue screen-detected abnormalities.
    • Adding abiraterone or docetaxel to long-term hormone therapy for prostate cancer: directly randomised data from the STAMPEDE multi-arm, multi-stage platform protocol.

      Chakraborti, Prabir (2018-02)
      Background: Adding abiraterone acetate with prednisolone (AAP) or docetaxel with prednisolone (DocP) to standard-of-care (SOC) each improved survival in STAMPEDE: a multi-arm multi-stage platform randomised controlled protocol recruiting patients with high-risk locally advanced or metastatic PCa starting long-term androgen deprivation therapy (ADT). The protocol provides the only direct, randomised comparative data of SOC+AAP vs SOC+DocP. Method: Recruitment to SOC+DocP and SOC+AAP overlapped Nov-2011─Mar-2013. SOC was long-term ADT or, for most non-metastatic cases, ADT for ≥2yrs and RT to the primary tumour. Stratified randomisation allocated pts 2:1:2 to SOC; SOC+docetaxel 75mg/m2 3-weekly x6 + prednisolone 10mg daily; or SOC+abiraterone acetate 1000mg + prednisolone 5mg daily. AAP duration depended on stage & intent to give radical RT. The primary outcome measure was death from any cause. Analyses used Cox proportional hazards & flexible parametric models, adjusted for stratification factors. This was not a formally-powered comparison. A hazard ratio (HR)<1 favours SOC+AAP, HR > 1 favours SOC+DocP. Results: 566 consenting patients were contemporaneously randomised: 189 SOC+DocP, 377 SOC+AAP. The patients, balanced by allocated treatment were: 342 (60%) M1; 429 (76%) Gleason 8-10; 449 (79%) WHO performance status 0; median age 66yr & median PSA 56ng/ml. With median follow-up 4 years, 149 deaths were reported. For overall survival, HR = 1·16 (95%CI 0·82-1·65); failure-free survival HR = 0·51 (95%CI 0·39-0·67); progression-free survival HR = 0·65 (95%CI 0·48-0·88); metastasis-free survival HR = 0·77 (95%CI 0·57-1·03); prostate cancer-specific survival HR = 1·02 (0·70-1·49); and symptomatic skeletal events HR = 0·83 (95%CI 0·55-1·25). In the safety population, the proportion reporting ≥1 grade 3, 4 or 5 adverse events ever was 36%, 13% and 1% SOC+DocP, & 40%, 7% and 1% SOC+AAP; prevalence 11% at 1 and 2yrs on both arms. Relapse treatment patterns varied by arm. Conclusions: This direct, randomised comparative analysis of two new treatment standards for hormone-naïve prostate cancer (HNPC) showed no evidence of a difference in overall or prostate cancer-specific survival, nor in other important outcomes such as symptomatic skeletal events, suggesting that Worst toxicity grade over entire time on trial was similar but comprised different toxicities in line with the known properties of the drugs. Trial registration: Clinicaltrials.gov: NCT00268476.
    • Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial.

      Chakraborti, Prabir (2016-03)
      BACKGROUND: Long-term hormone therapy has been the standard of care for advanced prostate cancer since the 1940s. STAMPEDE is a randomised controlled trial using a multiarm, multistage platform design. It recruits men with high-risk, locally advanced, metastatic or recurrent prostate cancer who are starting first-line long-term hormone therapy. We report primary survival results for three research comparisons testing the addition of zoledronic acid, docetaxel, or their combination to standard of care versus standard of care alone. METHODS: Standard of care was hormone therapy for at least 2 years; radiotherapy was encouraged for men with N0M0 disease to November, 2011, then mandated; radiotherapy was optional for men with node-positive non-metastatic (N+M0) disease. Stratified randomisation (via minimisation) allocated men 2:1:1:1 to standard of care only (SOC-only; control), standard of care plus zoledronic acid (SOC + ZA), standard of care plus docetaxel (SOC + Doc), or standard of care with both zoledronic acid and docetaxel (SOC + ZA + Doc). Zoledronic acid (4 mg) was given for six 3-weekly cycles, then 4-weekly until 2 years, and docetaxel (75 mg/m(2)) for six 3-weekly cycles with prednisolone 10 mg daily. There was no blinding to treatment allocation. The primary outcome measure was overall survival. Pairwise comparisons of research versus control had 90% power at 2·5% one-sided α for hazard ratio (HR) 0·75, requiring roughly 400 control arm deaths. Statistical analyses were undertaken with standard log-rank-type methods for time-to-event data, with hazard ratios (HRs) and 95% CIs derived from adjusted Cox models. This trial is registered at ClinicalTrials.gov (NCT00268476) and ControlledTrials.com (ISRCTN78818544). FINDINGS: 2962 men were randomly assigned to four groups between Oct 5, 2005, and March 31, 2013. Median age was 65 years (IQR 60-71). 1817 (61%) men had M+ disease, 448 (15%) had N+/X M0, and 697 (24%) had N0M0. 165 (6%) men were previously treated with local therapy, and median prostate-specific antigen was 65 ng/mL (IQR 23-184). Median follow-up was 43 months (IQR 30-60). There were 415 deaths in the control group (347 [84%] prostate cancer). Median overall survival was 71 months (IQR 32 to not reached) for SOC-only, not reached (32 to not reached) for SOC + ZA (HR 0·94, 95% CI 0·79-1·11; p=0·450), 81 months (41 to not reached) for SOC + Doc (0·78, 0·66-0·93; p=0·006), and 76 months (39 to not reached) for SOC + ZA + Doc (0·82, 0·69-0·97; p=0·022). There was no evidence of heterogeneity in treatment effect (for any of the treatments) across prespecified subsets. Grade 3-5 adverse events were reported for 399 (32%) patients receiving SOC, 197 (32%) receiving SOC + ZA, 288 (52%) receiving SOC + Doc, and 269 (52%) receiving SOC + ZA + Doc. INTERPRETATION: Zoledronic acid showed no evidence of survival improvement and should not be part of standard of care for this population. Docetaxel chemotherapy, given at the time of long-term hormone therapy initiation, showed evidence of improved survival accompanied by an increase in adverse events. Docetaxel treatment should become part of standard of care for adequately fit men commencing long-term hormone therapy. FUNDING: Cancer Research UK, Medical Research Council, Novartis, Sanofi-Aventis, Pfizer, Janssen, Astellas, NIHR Clinical Research Network, Swiss Group for Clinical Cancer Research.
    • Adequacy of percutaneous non-targeted liver biopsy under real-time ultrasound guidance when comparing the Biopince™ and Achieve™ biopsy needle.

      Hall, Thomas; Deakin, Claire; Atwal, Gurprit; Singh, Rajeev (2017-10)
      AIM: The purpose of this study was to compare the adequacy rates of percutaneous liver biopsies, in parenchymal liver disease, using the Biopince™ 16G and Achieve™ 18G biopsy needles in relation to the Royal College of Pathologists guidelines and to assess risk of complications. METHOD: Data for all percutaneous non-targeted 'medical' liver biopsies using the Biopince™ 16G and Achieve™ 18G biopsy needles were collected retrospectively over a 2-year period. Total biopsy core length and number of portal tracts was recorded along with adequacy of biopsy as assessed according to RCPath criteria. RESULTS: In total 194 percutaneous liver biopsies met the inclusion criteria; 53 using the Biopince™ needle and 141 using the Achieve™ needle.The mean total core length was 23mm (SD 4.1) and 20mm (SD 6.8) for the Biopince™ and Achieve™ needles respectively (p=0.0005). The mean number of portal tracts was 11 (SD 4.2) and 7 (SD 3.4) for the Biopince™ and Achieve™ needles respectively (p<0.0001). An adequate biopsy was obtained in 15 (31.3%) and 1 (1.3%) case using the Biopince™ and Achieve™ needles respectively (p<0.001). Compromised biopsies were obtained in 32 (66.7%) and 39 (50.6%) cases using the Biopince™ and Achieve™ needles respectively. Inadequate biopsies were obtained in 1 (2%) and 37 (48.1%) cases using the Biopince™ and Achieve™ needles respectively. CONCLUSION: The Biopince™ 16G needle, when compared with the Achieve™ 18G needle, acquires a significantly greater total core length and number of portal tracts with significantly improved adequacy rates. There were no major complications associated with its use. Advances in knowledge: The Biopince™ 16G needle achieves significantly better specimen adequacy, when compared with the Achieve™ 18G needle and with no added major complications associated with its use.
    • Adjuvant chemotherapy in upper tract urothelial carcinoma (the POUT trial): a phase 3, open-label, randomised controlled trial.

      Chakraborti, Prabir (2020-04)
      BACKGROUND: Urothelial carcinomas of the upper urinary tract (UTUCs) are rare, with poorer stage-for-stage prognosis than urothelial carcinomas of the urinary bladder. No international consensus exists on the benefit of adjuvant chemotherapy for patients with UTUCs after nephroureterectomy with curative intent. The POUT (Peri-Operative chemotherapy versus sUrveillance in upper Tract urothelial cancer) trial aimed to assess the efficacy of systemic platinum-based chemotherapy in patients with UTUCs. METHODS: We did a phase 3, open-label, randomised controlled trial at 71 hospitals in the UK. We recruited patients with UTUC after nephroureterectomy staged as either pT2-T4 pN0-N3 M0 or pTany N1-3 M0. We randomly allocated participants centrally (1:1) to either surveillance or four 21-day cycles of chemotherapy, using a minimisation algorithm with a random element. Chemotherapy was either cisplatin (70 mg/m2) or carboplatin (area under the curve [AUC]4•5/AUC5, for glomerular filtration rate <50 mL/min only) administered intravenously on day 1 and gemcitabine (1000 mg/m2) administered intravenously on days 1 and 8; chemotherapy was initiated within 90 days of surgery. Follow-up included standard cystoscopic, radiological, and clinical assessments. The primary endpoint was disease-free survival analysed by intention to treat with a Peto-Haybittle stopping rule for (in)efficacy. The trial is registered with ClinicalTrials.gov, NCT01993979. A preplanned interim analysis met the efficacy criterion for early closure after recruitment of 261 participants. FINDINGS: Between June 19, 2012, and Nov 8, 2017, we enrolled 261 participants from 57 of 71 open study sites. 132 patients were assigned chemotherapy and 129 surveillance. One participant allocated chemotherapy withdrew consent for data use after randomisation and was excluded from analyses. Adjuvant chemotherapy significantly improved disease-free survival (hazard ratio 0•45, 95% CI 0•30-0•68; p=0•0001) at a median follow-up of 30•3 months (IQR 18•0-47•5). 3-year event-free estimates were 71% (95% CI 61-78) and 46% (36-56) for chemotherapy and surveillance, respectively. 55 (44%) of 126 participants who started chemotherapy had acute grade 3 or worse treatment-emergent adverse events, which accorded with frequently reported events for the chemotherapy regimen. Five (4%) of 129 patients managed by surveillance had acute grade 3 or worse emergent adverse events. No treatment-related deaths were reported. INTERPRETATION: Gemcitabine-platinum combination chemotherapy initiated within 90 days after nephroureterectomy significantly improved disease-free survival in patients with locally advanced UTUC. Adjuvant platinum-based chemotherapy should be considered a new standard of care after nephroureterectomy for this patient population. FUNDING: Cancer Research UK.
    • An update of stabilisation exercises for low back pain: a systematic review with meta-analysis.

      Smith, Benjamin (2014-12)
      BACKGROUND: Non-specific low back pain (NSLBP) is a large and costly problem. It has a lifetime prevalence of 80% and results in high levels of healthcare cost. It is a major cause for long term sickness amongst the workforce and is associated with high levels of fear avoidance and kinesiophobia. Stabilisation (or 'core stability') exercises have been suggested to reduce symptoms of pain and disability and form an effective treatment. Despite it being the most commonly used form of physiotherapy treatment within the UK there is a lack of positive evidence to support its use. The aims of this systematic review update is to investigate the effectiveness of stabilisation exercises for the treatment of NSLBP, and compare any effectiveness to other forms of exercise. METHODS: A systematic review published in 2008 was updated with a search of PubMed, CINAHL, AMED, Pedro and The Cochrane Library, October 2006 to October 2013. Two authors independently selected studies, and two authors independently extracted the data. Methodological quality was evaluated using the PEDro scale. Meta-analysis was carried out when appropriate. RESULTS: 29 studies were included: 22 studies (n = 2,258) provided post treatment effect on pain and 24 studies (n = 2,359) provided post treatment effect on disability. Pain and disability scores were transformed to a 0 to 100 scale. Meta-analysis showed significant benefit for stabilisation exercises versus any alternative treatment or control for long term pain and disability with mean difference of -6.39 (95% CI -10.14 to -2.65) and -3.92 (95% CI -7.25 to -0.59) respectively. The difference between groups was clinically insignificant. When compared with alternative forms of exercise, there was no statistical or clinically significant difference. Mean difference for pain was -3.06 (95% CI -6.74 to 0.63) and disability -1.89 (95% CI -5.10 to 1.33). CONCLUSION: There is strong evidence stabilisation exercises are not more effective than any other form of active exercise in the long term. The low levels of heterogeneity and large number of high methodological quality of available studies, at long term follow-up, strengthen our current findings, and further research is unlikely to considerably alter this conclusion.
    • Analytical Performance Verification of the Beckman Coulter AU5800 Clinical Chemistry Analyser Against Recognized Quality Specifications Reveals Relevance of Method Harmonization

      Reynolds, Tim (2016)
      Analytical performance of 24 Beckman-Coulter AU 5800 methods was verified against recognized quality goals and manufacturer's expected imprecision and bias.AU5800 method imprecision, bias, agreement with a comparative method, and linearity were studied using CLSI protocols, commercial control material, patient samples, and linearity test kit solutions. Repeat patient testing and IQC were also used for imprecision. Commutability of control material was tested. Total analytical error (TAE) was estimated for each method and between the tested and the comparative method, the Beckman-Coulter Unicel DxC800.CLSI EP15 total imprecision CV (TCV) < 3.2%. Duplicate patient imprecision CV < 2.8%. IQC imprecision CV < 5.1%, except for low level ALP (CV = 7.4%). Sodium and urate IQC imprecision were higher than manufacturer's specifications. TAE for all methods met accepted quality goals. Correlation between methods was > 0.975, except for Cl (0.971), TP (0.964), and Na (0.948). Average bias versus Unicel DxC800 is high for ALP (17.3%), GGT (37%), LD (20%), TBIL (-23%), and TP (8%) and was confirmed in other laboratories. TAE between methods met allowable total error for 21 analytes. For GGT, between method TAE (23 to 51%) was predictable from expected bias and combined method imprecision. For LD and TP several between method differences were outside boundaries describing expected bias. Linearity was excellent with R2 > 0.997 and deviations met accepted goals.The Beckman-Coulter AU 5800 demonstrates good linearity, low imprecision, and good correlation with previous methods. Observed between method differences suggest ALP, GGT, LD, TBIL, and TP harmonization should be considered.
    • Anticholinergic Drug Burden Tools/Scales and Adverse Outcomes in Different Clinical Settings: A Systematic Review of Reviews.

      Gordon, Adam (2018-05)
      BACKGROUND: Cumulative anticholinergic exposure (anticholinergic burden) has been linked to a number of adverse outcomes. To conduct research in this area, an agreed approach to describing anticholinergic burden is needed. OBJECTIVE: This review set out to identify anticholinergic burden scales, to describe their rationale, the settings in which they have been used and the outcomes associated with them.METHODS: A search was performed using the Healthcare Databases Advanced Search of MEDLINE, EMBASE, Cochrane, CINAHL and PsycINFO from inception to October 2016 to identify systematic reviews describing anticholinergic burden scales or tools. Abstracts and titles were reviewed to determine eligibility for review with eligible articles read in full. The final selection of reviews was critically appraised using the ROBIS tool and pre-defined data were extracted; the primary data of interest were the anticholinergic burden scales or tools used. RESULTS: Five reviews were identified for analysis containing a total of 62 original articles. Eighteen anticholinergic burden scales or tools were identified with variation in their derivation, content and how they quantified the anticholinergic activity of medications. The Drug Burden Index was the most commonly used scale or tool in community and database studies, while the Anticholinergic Risk Scale was used more frequently in care homes and hospital settings. The association between anticholinergic burden and clinical outcomes varied by index and study. Falls and hospitalisation were consistently found to be associated with anticholinergic burden. Mortality, delirium, physical function and cognition were not consistently associated. CONCLUSIONS: Anticholinergic burden scales vary in their rationale, use and association with outcomes. This review showed that the concept of anticholinergic burden has been variably defined and inconsistently described using a number of indices with different content and scoring. The association between adverse outcomes and anticholinergic burden varies between scores and has not been conclusively established.
    • Are patients with cancers 'missed' on faecal occult blood (FOB) testing truly asymptomatic?-a multicentre analysis

      George, Anil Thomas (2015-06)
      Introduction We aimed to identify the symptomatology of patients who develop interval cancers (cancers diagnosed within 2 years of a negative FOBT screening) in the eligible population of the East Midlands region. Method Data from the National Bowel Cancer Audit Programme from three tertiary colorectal centres (Queens Medical Centre, Nottingham; Royal Derby Hospital and Sherwood Forest Hospitals ll) in the FOB testing age group (60-74 years) over 2 years (August 2011 to August 2013) were analysed and linked to the regional FOB hub to identify patients who had developed colorectal cancer after a negative FOBT in the screening interval (2 years) status. Tumours from and distal to the splenic flexure were classed as left sided tumours. Dukes C/D tumours were classed as advanced tumours. All three centres were in incident rounds of screening. Results The study covered a population of 2 million of which 200,000 were eligible for screening. 521 colorectal cancers were diagnosed in the above population (0.11%). Of these, 231 cancers (44%) were in patients who had declined screening,162 (31%) were picked up following on from a positive FOBT and 128 (25%) were picked up in patients who had a negative FOBT. Of these 128 patients (M: F; 84:44),median age 67 years (SD:3.8) the commonest presenting symptoms for these patients were change in bowel habits in 50(39%). Other presentations included bleeding per-rectum in 44 patients (34%), abdominal pain in 38 (30%) patients, anaemia in 36(28%) patients, loss of weight in14 (11%)patients, bowel obstruction in 13 (10%) patients, bowel perforation in 3(2%) patients. Only two patients were truly asymptomatic from the bowel cancer with this being identified in one patient during surgery for an ovarian cyst and during a trauma laparotomy in the other patient. In the 28% patients who had anaemia the blood picture included a Hb (mean)of 10.3gm;MCV of 82.4 and;MCH of 26.3. In 61% of anaemic patients, the cancer was located on the right side of the colon with an equal percentage being of advanced Duke's stage. The median interval between the negative FOB test and the diagnosis of cancer in these patients was 15 months (range 0.5-24 months). Conclusion Our findings suggest that the majority of patients with 'missed' interval cancers were symptomatic with 'red flag symptoms' inspite of the negative FOB test. We also raise the possibility of a natural bias of subjects volunteering for the FOB test in that some who opt for the test may not be 'truly' asymptomatic but may have bowel symptoms not yet discussed with their general practitioner. We highlight the need for improved awareness to reduce delays in symptomatic patients seeking medical advice against a background of a negative FOBT.