• 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 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.
    • 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
    • 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.
    • The association between hepatocellular carcinoma and direct-acting anti-viral treatment in patients with decompensated cirrhosis

      Lawson, A (2019-07)
      BACKGROUND: Direct-acting anti-viral therapy (DAA) has transformed hepatitis C virus (HCV) care, particularly in patients with decompensated cirrhosis. However, their impact on hepatocellular carcinoma (HCC) remains unclear. AIM: To use a national registry of patients with advanced liver disease to explore the relationship between DAA therapy and HCC. METHODS: All patients with de novo HCC post DAA therapy were frequency matched with patients who did not develop HCC. Demographic, clinical and laboratory data were obtained. Cross-sectional imaging and multidisciplinary team reports were reviewed for dates of HCC diagnosis and HCC progression. Patients were categorised by treatment outcome and time of HCC development. Data were examined by multivariable analysis and Kaplan-Meier estimation. RESULTS: Eighty patients with HCC were compared with 165 patients without HCC, treated between June 2014 and September 2015. Mean follow-up from start of DAA therapy was 32.4 months. Twenty-eight patients were diagnosed with early HCC (within 6 months of therapy) and 52 presented late. Baseline nonmalignant lesions (HR: 1.99), thrombocytopaenia (HR: 1.59) and diabetes (HR: 1.68) increased likelihood of HCC. Response to therapy was reduced in patients who developed liver cancer (SVR in patients with HCC = 54/80 (68%), SVR in patients without HCC = 143/165 (87%), P < 0.001, OR: 3.13, 95% CI: 1.64-5.99). We found no difference between tumour size, progression or survival between viraemic and nonviraemic patients. CONCLUSION: There is no alteration in prognosis or cancer progression following HCC development after HCV treatment. However, baseline nonmalignant liver lesions, diabetes and thrombocytopaenia increase the risk of HCC, and HCC is associated with a decreased SVR rate.
    • Cholesteryl ester storage disease: a rare and possibly treatable cause of premature vascular disease and cirrhosis

      Reynolds, Tim (2013-09)
      Cholesteryl ester storage disease (CESD) is an autosomal recessive lysosomal storage disorder caused by a variety of mutations of the LIPA gene. These cause reduced activity of lysosomal acid lipase, which results in accumulation of cholesteryl esters in lysosomes. If enzyme activity is very low/absent, presentation is in infancy with failure to thrive, malabsorption, hepatosplenomegaly and rapid early death (Wolman disease). With higher but still low enzyme activity, presentation is later in life with hepatic fibrosis, dyslipidaemia and early atherosclerosis.Identification of this rare disorder is difficult as it is essential to assay leucocyte acid phosphatase activity. An assay using specific inhibitors has now been developed that facilitates measurement in dried blood spots. Treatment of CESD has until now been limited to management of the dyslipidaemia, but this does not influence the liver effects. A new enzyme replacement therapy (Sebelipase) has now been developed that could change treatment options for the future.
    • Cytoplasmic PML promotes TGF-β-associated epithelial-mesenchymal transition and invasion in prostate cancer.

      Van Schalkwyk, Gerhard (2015-11)
      Epithelial-mesenchymal transition (EMT) is a key event that is involved in the invasion and dissemination of cancer cells. Although typically considered as having tumour-suppressive properties, transforming growth factor (TGF)-β signalling is altered during cancer and has been associated with the invasion of cancer cells and metastasis. In this study, we report a previously unknown role for the cytoplasmic promyelocytic leukaemia (cPML) tumour suppressor in TGF-β signalling-induced regulation of prostate cancer-associated EMT and invasion. We demonstrate that cPML promotes a mesenchymal phenotype and increases the invasiveness of prostate cancer cells. This event is associated with activation of TGF-β canonical signalling pathway through the induction of Sma and Mad related family 2 and 3 (SMAD2 and SMAD3) phosphorylation. Furthermore, the cytoplasmic localization of promyelocytic leukaemia (PML) is mediated by its nuclear export in a chromosomal maintenance 1 (CRM1)-dependent manner. This was clinically tested in prostate cancer tissue and shown that cytoplasmic PML and CRM1 co-expression correlates with reduced disease-specific survival. In summary, we provide evidence of dysfunctional TGF-β signalling occurring at an early stage in prostate cancer. We show that this disease pathway is mediated by cPML and CRM1 and results in a more aggressive cancer cell phenotype. We propose that the targeting of this pathway could be therapeutically exploited for clinical benefit.
    • Differential Diagnosis for Chronic Hypokalaemia.

      Stimson, Laura; Reynolds, Tim (2018-06)
      Doctors will often see patients with chronic hypokalaemia, frequently this is secondary to gastrointestinal losses, diuretics or renal disease. However, in this case report we review a rarer cause of chronic hypokalaemia-Gitelman syndrome (GS).GS is an uncommon genetic disorder which causes primary renal tubular hypokalaemic metabolic alkalosis with secondary hypomagnesaemia and hypocalciuria. Although rare, it is important to remember GS when considering differential diagnoses for chronic hypokalaemia. We report the case of a woman who presented to the ophthalmology department with sclerochoroidal calcification. An ophthalmologist was reviewing the medical literature, which prompted them to investigate for GS. A diagnosis was formed at that time based on the blood and urine chemistry results. However, later we were able to offer the patient genetic testing, which confirmed our provisional diagnosis.
    • Do the EULAR Sjögren's syndrome outcome measures correlate with health status in primary Sjögren's syndrome?

      Regan, Marian (2015-04)
      OBJECTIVE: This study sets out to investigate the relationship between health status [EuroQol five-dimensions questionnaire (EQ-5D)] in primary SS and three of the European League Against Rheumatism (EULAR) SS outcome measures-the disease activity index (ESSDAI), the patient reported index (ESSPRI) and the sicca score. In particular, the goal was to establish whether there is a relationship between the EULAR outcome measures and quality of life. METHODS: Health status was evaluated using a standardized measure developed by the EuroQol Group-the EQ5D. This permits calculation of two measures of health status: time trade-off (TTO) values and the EQ-5D visual analogue scale (VAS) scores. We used Spearman's rank correlation analysis to investigate the strength of association between health status and three EULAR measures of physician- and patient-reported disease activity in 639 patients from the UK primary SS registry (UKPSSR) cohort. RESULTS: This study demonstrates that the EULAR SS disease-specific outcome measures are significantly correlated with health outcome values (P < 0.001). Higher scores on the ESSDAI, EULAR sicca score and ESSPRI are associated with poorer health states-i.e. lower TTO values and lower VAS scores. While all three are significantly correlated with TTO values and EQ-5D VAS scores, the effect is strongest for the ESSPRI. CONCLUSION: This study provides further evidence supporting the use of ESSDAI, EULAR sicca score and ESSPRI measures in the clinic. We also discuss the need for disease-specific measures of health status and their comparison with standardized health outcome measures.
    • Eligibility for clinical trials in primary Sjögren's syndrome: lessons from the UK Primary Sjögren's Syndrome Registry.

      Regan, Marian (2016-03)
      OBJECTIVE: To identify numbers of participants in the UK Primary Sjögren's Syndrome Registry (UKPSSR) who would fulfil eligibility criteria for previous/current or potential clinical trials in primary SS (pSS) in order to optimize recruitment. METHODS: We did a retrospective analysis of UKPSSR cohort data of 688 participants who had pSS with evaluable data. RESULTS: In relation to previous/current trials, 75.2% fulfilled eligibility for the Belimumab in Subjects with Primary Sjögren's Syndrome study (Belimumab), 41.4% fulfilled eligibility for the Trial of Remicade in primary Sjögren's syndrome study (Infliximab), 35.4% for the Efficacy of Tocilizumab in Primary Sjögren's Syndrome study (Tocilizumab), 31.6% for the Tolerance and Efficacy of Rituximab in Sjögren's Disease study (Rituximab), 26.9% for the Trial of anti-B-cell therapy in pSS study (Rituximab) and 26.6% for the Efficacy and Safety of Abatacept in Patients With Primary Sjögren's Syndrome study (Abatacept). If recent measures of outcome, such as the EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) score ⩾5 (measure of patient symptoms) and the EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) score ⩾5 (measure of systemic disease activity) are incorporated into a study design, with requirements for an unstimulated salivary flow >0 and anti-Ro positivity, then the pool of eligible participants is reduced to 14.3%. CONCLUSION: The UKPSSR identified a number of options for trial design, including selection on ESSDAI ⩾5, ESSPRI ⩾5 and serological and other parameters.
    • Eltrombopag and Romiplostim: A snapshot from Derby Teaching Hospitals

      Khan, I; Lala, J; Smith, A; Millar, C; Addada, Jo (2018-04)
      Severe Idiopathic Thrombocytopenic Purpura (ITP) is a relatively common disorder with a small but definite associated mortality. For many years, first line therapy has consisted of steroid or Intravenous Immunoglobulin. A plethora of second line treatment options have traditionally included splenectomy, Rituximab, Mycophenolate, other immunosupressants & Danazol. Each has had its own risks and uncertain efficacy and treatment sequencing for refractory patients has always been very much at the discretion of individual clinicians. Recently the Thrombopoietin Receptor Agonists (TPO-RA) Romi-plostim and Eltrombopag have been available in the UK (NICE approved in 2011 and 2013 respectively). Both are regarded as highly effective but costly treatments. We present here our recent experience of using TPO-RA in a large clinical unit serving a population of 600,000. We audited patients on TPO-RA between March 2016 and April 2017. TPO-RAs were used in 34 episodes (30 patients, 4 patients required switching from one to other). Eltrombopag was used in 25 episodes and Romi-plostim in 9 episodes. Patient demographics were as follows: 21 females, 9 males; Age range 28-91 (median 65.4). 26 out of 30 patients were treated in accordance with NICE guidance. These patients were refractory to other standard treatment for ITP and/or had severe disease and a high risk of bleeding requiring frequent rescue therapy. Splenectomy was considered inappropriate in 20 out of 26 (76.9%) patients. 6 out of 26 (23%) patients were post splenectomy and had refractory ITP. 4 out of 30 patients were treated with TPO (Eltrombopag) out with NICE guidance. Splenectomised patients had a median of 5.5 previous treatment lines compared with non-splenectomised patients (1.36). Eltrombopag doses ranged from 25-75 mg/day. Romiplostim doses ranged from 2-10 mcg/kg/week. 4 patients switched between Romiplostim and Eltrombopag due to loss/failure of response. Doses were individualized to maintain platelet counts in a safe range. All patients showed a positive response to one or the other agent (defined as greater than 50 x 10/l) In general both treatments were well tolerated and no drug needed discontinuation due to side effects. Main side effects with Eltrombopag were fatigue (2 patients), headache (2) and grade 1 diarrhoea (1). Side effects experienced with Romiplastim were dyspepsia (1) and occasional mild headache (1). In our experience TPO-RA treatments are well tolerated and all patients audited showed an effective response. Furthermore, we also noticed that our clinicians do not consider splenectomy to be a favoured second line treatment in the era of TPO-RAs. This suggests that the current treatment paradigm should be reviewed.
    • Experience of romiplostin use in the management of ITP in a district general hospital setting-can fixed doses be used during stable phase to reduce wastage?

      Van Staden, Bernhard; Ahmad, Humayun (2014-05)
      The thrombopoetin receptor agonist, Romiplostim is indicated in chronic ITP patients with refractory ITP. We reviewed and analysed the data from two refractory ITP patients managed with Romiplostim. Using current manufacturer guidelines, we started with weekly dosing adjustments aiming for the recommended baseline platelet count of at least 50 9 109. Guidelines recommend an initiating dose of 1mcg/kg per week with increase in 1mcg increments to a maximum of 10 mcg/kg weekly until platelet count is stabilized above mentioned baseline. Hereafter, monthly blood tests are recommended and readjustment made if platelet count exceeds 200 x 109. Our patients commenced on 1mcg/kg, though once the platelet count was consistently above baseline, after a few dose adjustments, we found in both patients that during the stable phase, 250 mcg hence between 3 and 4 mcg/kg per patient respectively was an ideal maintenance dose that consistently kept the platelet count above 50 x 109 without requiring need for regular dose adjustment. Therefore these two patients have now been continued on this fixed dose and have shown an excellent response. Though our experience is limited, we have found a standard dose of 250 mcg to be an effective in maintenance of safe platelet counts. Also, as Romiplostim is available only in 250 and 500 mcg vials, variable doses will invariably lead to some wastage of this expensive drug. Given the economic climate and to simplify self-administration we propose further studies are required to assess whether a fixed dose of Romiplostim can be established for stable phase management of chronic ITP.
    • Health Assessment Questionnaire disability progression in early rheumatoid arthritis: systematic review and analysis of two inception cohorts.

      Deighton, Chris (2014-10)
      OBJECTIVE: The Health Assessment Questionnaire is widely used for patients with inflammatory polyarthritis (IP) and its subset, rheumatoid arthritis (RA). In this study, we evaluated the progression of HAQ scores in RA (i) by systematically reviewing the published literature on the methods used to assess changes in functional disability over time and (ii) to study in detail HAQ progression in two large prospective observational studies from the UK. METHODS: Data from two large inception cohorts, ERAS and NOAR, were studied to determine trajectories of HAQ progression over time by applying latent class growth models (LCGMs) to each dataset separately. Age, sex, baseline DAS28, symptom duration, rheumatoid factor, fulfilment of the 1987 ACR criteria and socio-economic status (SES) were included as potential predictors of HAQ trajectory subgroup membership. RESULTS: The literature search identified 49 studies showing that HAQ progression has mainly been based on average changes in the total study population. In the HAQ progression study, a LCGM with four HAQ trajectory subgroups was selected as providing the best fit in both cohorts. In both the cohorts, older age, female sex, longer symptom duration, fulfilment of the 1987 ACR criteria, higher DAS28 and lower SES were associated with increased likelihood of membership of subgroups with worse HAQ progression. CONCLUSION: Four distinct HAQ trajectory subgroups were derived from the ERAS and NOAR cohorts. The fact that the subgroups identified were nearly identical supports their validity. Identifying distinct groups of patients who are at risk of poor functional outcome may help to target therapy to those who are most likely to benefit.
    • Hepatitis C virus-infected patients with a persistently normal alanine aminotransferase: do they exist and is this really a group with mild disease?

      Lawson, A (2010-01)
      Opinion varies on whether or not hepatitis C virus (HCV) infected patients with persistently normal aminotransferase (PNALT) levels represent a group with mild disease. To evaluate the risk of ALT flare and fibrosis progression in patients with PNALT followed up as part of the Trent HCV cohort. Treatment-naïve patients with an elevated ALT (n = 1140) or PNALT, the latter defined as either an ALT < or = 30 IU/L (n = 43) or an ALT < or = 40 IU/L (n = 87) on > or =2 occasions in the 6 months following diagnosis, and no ALT > 40 U/L were included. The likelihood of maintaining a PNALT < or = 30 IU/L was 42.2% and PNALT < or = 40 IU/L 41.7% at 3 years. The Ishak fibrosis score was > or =3 in 3.7%, 8.3% and 29.6% of patients with PNALT < or = 30 IU/L, PNALT < or = 40 IU/L and elevated ALT, respectively. Fibrosis progression between paired biopsies was similar for patients with PNALT < or = 30 IU/L (0.33 +/- 0.94 Ishak fibrosis points/year), PNALT < or = 40 IU/L (0.35 +/- 0.82) and elevated ALT (0.19 +/- 0.48). The majority of those defined as PNALT subsequently have an abnormal ALT. They have a similar risk of disease progression to other HCV infected patients and, therefore, warrant the same consideration with regard to treatment.