Showing papers by "Leicester Royal Infirmary published in 2017"

European Respiratory Society guidelines for the diagnosis of primary ciliary dyskinesia.

Abstract: The diagnosis of primary ciliary dyskinesia is often confirmed with standard, albeit complex and expensive, tests. In many cases, however, the diagnosis remains difficult despite the array of sophisticated diagnostic tests. There is no "gold standard" reference test. Hence, a Task Force supported by the European Respiratory Society has developed this guideline to provide evidence-based recommendations on diagnostic testing, especially in light of new developments in such tests, and the need for robust diagnoses of patients who might enter randomised controlled trials of treatments. The guideline is based on pre-defined questions relevant for clinical care, a systematic review of the literature, and assessment of the evidence using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach. It focuses on clinical presentation, nasal nitric oxide, analysis of ciliary beat frequency and pattern by high-speed video-microscopy analysis, transmission electron microscopy, genotyping and immunofluorescence. It then used a modified Delphi survey to develop an algorithm for the use of diagnostic tests to definitively confirm and exclude the diagnosis of primary ciliary dyskinesia; and to provide advice when the diagnosis was not conclusive. Finally, this guideline proposes a set of quality criteria for future research on the validity of diagnostic methods for primary ciliary dyskinesia.

Mutation Analysis of Cell-Free DNA and Single Circulating Tumor Cells in Metastatic Breast Cancer Patients with High Circulating Tumor Cell Counts

Abstract: Purpose: The purpose of this study was to directly compare mutation profiles in multiple single CTCs and cfDNA isolated from the same blood samples taken from patients with metastaic breast cancer (MBC). We aimed to determine whether cell-free DNA would reflect the heterogeneity observed in 40 single CTCs. Experimental design: CTCs were enumerated by Cellsearch. CTC count was compared with the quantity of matched cfDNA and serum CA15-3 and alkaline phosphatase (ALP) in 112 patients with metastatic breast cancer. In 5 patients with {greater than or equal to}100 CTCs, multiple individual EpCAM-positive CTCs were isolated by DEPArray and compared with matched cfDNA and primary tumour tissue by targeted next generation sequencing (NGS) of ~2200 mutations in 50 cancer genes. Results: In the whole cohort, total cfDNA levels and cell counts ({greater than or equal to}5 CTCs) were both significantly associated with overall survival, unlike CA15-3 and ALP. NGS analysis of 40 individual EpCAM-positive CTCs from 5 patients with MBC revealed mutational heterogeneity in PIK3CA, TP53, ESR1 and KRAS genes between individual CTCs. In all 5 patients cfDNA profiles provided an accurate reflection of mutations seen in individual CTCs. ESR1 and KRAS gene mutations were absent from primary tumour tissue and therefore likely reflect either a minor sub-clonal mutation or were acquired with disease progression. Conclusion: Our results demonstrate that cfDNA reflects persisting EpCAM-positive CTCs in patients with high CTC counts and therefore may enable monitoring of the metastatic burden for clinical decision-making.

Arginine Deprivation With Pegylated Arginine Deiminase in Patients With Argininosuccinate Synthetase 1-Deficient Malignant Pleural Mesothelioma: A Randomized Clinical Trial.

Abstract: Importance Preclinical studies show that arginine deprivation is synthetically lethal in argininosuccinate synthetase 1 (ASS1)-negative cancers, including mesothelioma. The role of the arginine-lowering agent pegylated arginine deiminase (ADI-PEG20) has not been evaluated in a randomized and biomarker-driven study among patients with cancer. Objective To assess the clinical impact of arginine depletion in patients with ASS1-deficient malignant pleural mesothelioma. Design, Setting, and Participants A multicenter phase 2 randomized clinical trial, the Arginine Deiminase and Mesothelioma (ADAM) study, was conducted between March 2, 2011, and May 21, 2013, at 8 academic cancer centers. Immunohistochemical screening of 201 patients (2011-2013) identified 68 with advanced ASS1-deficient malignant pleural mesothelioma. Interventions Randomization 2:1 to arginine deprivation (ADI-PEG20, 36.8 mg/m 2 , weekly intramuscular) plus best supportive care (BSC) or BSC alone. Main Outcomes and Measures The primary end point was progression-free survival (PFS) assessed by modified Response Evaluation Criteria in Solid Tumors (RECIST) (target hazard ratio, 0.60). Secondary end points were overall survival (OS), tumor response rate, safety, and quality of life, analyzed by intention to treat. We measured plasma arginine and citrulline levels, anti–ADI-PEG20 antibody titer, ASS1 methylation status, and metabolic response by 18 F-fluorodeoxyglucose positron-emission tomography. Results Median (range) follow-up in 68 adults (median [range] age, 66 [48-83] years; 19% female) was 38 (2.5-39) months. The PFS hazard ratio was 0.56 (95% CI, 0.33-0.96), with a median of 3.2 months in the ADI-PEG20 group vs 2.0 months in the BSC group ( P = .03) (absolute risk, 18% vs 0% at 6 months). Best response at 4 months (modified RECIST) was stable disease: 12 of 23 (52%) in the ADI-PEG20 group vs 2 of 9 (22%) in the BSC group ( P = .23). The OS curves crossed, so life expectancy was used: 15.7 months in the ADI-PEG20 group vs 12.1 months in the BSC group (difference of 3.6 [95% CI, −1.0 to 8.1] months; P = .13). The incidence of symptomatic adverse events of grade at least 3 was 11 of 44 (25%) in the ADI-PEG20 group vs 4 of 24 (17%) in the BSC group ( P = .43), the most common being immune related, nonfebrile neutropenia, gastrointestinal events, and fatigue. Differential ASS1 gene-body methylation correlated with ASS1 immunohistochemistry, and longer arginine deprivation correlated with improved PFS. Conclusions and Relevance In this trial, arginine deprivation with ADI-PEG20 improved PFS in patients with ASS1-deficient mesothelioma. Targeting arginine is safe and warrants further clinical investigation in arginine-dependent cancers. Trial Registration clinicaltrials.gov Identifier:NCT01279967

British Association of Dermatologists' guidelines for the management of pemphigus vulgaris 2017.

Abstract: British Association of Dermatologists’ guidelines for the management of pemphigus vulgaris 2017* K.E. Harman, D. Brown, L.S. Exton, R.W. Groves, P.J. Hampton, M.F. Mohd Mustapa, J.F. Setterfield and P.D. Yesudian University Hospitals Leicester, Leicester Royal Infirmary, Infirmary Square, Leicester, LE1 5WW, U.K. St John’s Institute of Dermatology, Guy’s and St Thomas’ NHS Foundation Trust, St Thomas’ Hospital, Westminster Bridge Road, London SE1 7EH, U.K. British Association of Dermatologists, Willan House, 4 Fitzroy Square, London W1T 5HQ, U.K. St. John’s Institute of Dermatology, King’s College London, Guy’s Campus, Great Maze Pond, London SE1 9RT, U.K. Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne, Tyne and Wear NE1 4LP, U.K. Mucosal & Salivary Biology Division, King’s College London Dental Institute, Guy’s Campus, Great Maze Pond, London SE1 9RT, U.K Wrexham Maelor Hospital, Croesnewydd Road, Wrexham LL13 7TD, U.K.

Viscoelastometric-guided early fibrinogen concentrate replacement during postpartum haemorrhage: OBS2, a double-blind randomized controlled trial

Abstract: Background: Postpartum haemorrhage (PPH) can be exacerbated by haemostatic failure. We hypothesized that early fibrinogen replacement, guided by viscoelastometric testing, reduces blood product usage and bleed size. Methods: Women with PPH 1000–1500 ml were enrolled. If Fibtem A5 was ≤15 mm and bleeding continued, subjects were randomized to fibrinogen concentrate or placebo. The primary outcome compared the number of units of red blood cells, plasma, cryoprecipitate and platelets transfused. Results: Of 663 women enrolled 55 were randomized. The adjusted incidence rate ratio (IRR) (95% CI) for the number of allogeneic units transfused in the fibrinogen group compared with placebo was 0.72 (0.3–1.7), P=0.45. In pre-specified subgroup analyses, subjects who had a Fibtem A5 ≤12 mm at the time of randomization and who received fibrinogen concentrate received a median (25th–75th centile) of 1 (0–4.5) unit of allogeneic blood products and had an additional 300 (100–350) ml blood loss whereas those who received placebo also received 3 (0–6) units of allogeneic blood products and had 700 (200–1550) ml additional blood loss; these differences were not statistically significantly different. There was one thrombotic event in each group. Conclusions: Infusion of fibrinogen concentrate triggered by Fibtem A5 ≤15 mm did not improve outcomes in PPH. Pre-specified subgroup analyses suggest that fibrinogen replacement is not required if the Fibtem A5 is > 12 mm or Clauss fibrinogen >2 g litre−1, but an effect below these levels cannot be excluded. The raised fibrinogen at term appears to be a physiological buffer rather than required for haemostasis

BSACI guideline for the diagnosis and management of peanut and tree nut allergy

Abstract: Summary Peanut nut and tree nut allergy are characterised by IgE mediated reactions to nut proteins Nut allergy is a global disease Limited epidemiological data suggest varying prevalence in different geographical areas Primary nut allergy affects over 2% of children and 05% of adults in the UK Infants with severe eczema and/or egg allergy have a higher risk of peanut allergy Primary nut allergy presents most commonly in the first five years of life, often after the first known ingestion with typical rapid onset IgE-mediated symptoms The clinical diagnosis of primary nut allergy can be made by the combination of a typical clinical presentation and evidence of nut specifc IgE shown by a positive skin prick test (SPT) or specific IgE (sIgE) test Pollen food syndrome is a distinct disorder, usually mild, with oral/pharyngeal symptoms, in the context of hay fever or pollen sensitisation, which can be triggered by nuts It can usually be distinguish clinically from primary nut allergy The magnitude of a SPT or sIgE relates to the probability of clinical allergy, but does not relate to clinical severity SPT of ≥ 8 mm or sIgE ≥ 15 KU/L to peanut is highly predictive of clinical allergy Cut off values are not available for tree nuts Test results must be interpreted in the context of the clinical history Diagnostic food challenges are usually not necessary but may be used to confirm or refute a conflicting history and test result As nut allergy is likely to be a long-lived disease, nut avoidance advice is the cornerstone of management Patients should be provided with a comprehensive management plan including avoidance advice, patient specific emergency medication and an emergency treatment plan and training in administration of emergency medication Regular re-training is required

Thymus Transplantation for Complete Digeorge Syndrome: European Experience

Abstract: Background Thymus transplantation is a promising strategy for the treatment of athymic complete DiGeorge syndrome (cDGS). Methods Twelve patients with cDGS underwent transplantation with allogeneic cultured thymus. Objective We sought to confirm and extend the results previously obtained in a single center. Results Two patients died of pre-existing viral infections without having thymopoiesis, and 1 late death occurred from autoimmune thrombocytopenia. One infant had septic shock shortly after transplantation, resulting in graft loss and the need for a second transplant. Evidence of thymopoiesis developed from 5 to 6 months after transplantation in 10 patients. Median circulating naive CD4 counts were 44 × 10 6 /L (range, 11-440 × 10 6 /L) and 200 × 10 6 /L (range, 5-310 × 10 6 /L) at 12 and 24 months after transplantation and T-cell receptor excision circles were 2,238/10 6 T cells (range, 320-8,807/10 6 T cells) and 4,184/10 6 T cells (range, 1,582-24,596/10 6 T cells). Counts did not usually reach normal levels for age, but patients were able to clear pre-existing infections and those acquired later. At a median of 49 months (range, 22-80 months), 8 have ceased prophylactic antimicrobials, and 5 have ceased immunoglobulin replacement. Histologic confirmation of thymopoiesis was seen in 7 of 11 patients undergoing biopsy of transplanted tissue, including 5 showing full maturation through to the terminal stage of Hassall body formation. Autoimmune regulator expression was also demonstrated. Autoimmune complications were seen in 7 of 12 patients. In 2 patients early transient autoimmune hemolysis settled after treatment and did not recur. The other 5 experienced ongoing autoimmune problems, including thyroiditis (3), hemolysis (1), thrombocytopenia (4), and neutropenia (1). Conclusions This study confirms the previous reports that thymus transplantation can reconstitute T cells in patients with cDGS but with frequent autoimmune complications in survivors.

Clinical Practice Guideline on management of older patients with chronic kidney disease stage 3b or higher (eGFR<45 mL/min/1.73 m2): a summary document from the European Renal Best Practice Group.

Abstract: The population of patients with moderate and severe CKD is growing. Frail and older patients comprise an increasing proportion. Many studies still exclude this group, so the evidence base is limited. In 2013 the advisory board of ERBP initiated, in collaboration with European Union of Geriatric Medicine Societies (EUGMS), the development of a guideline on the management of older patients with CKD stage 3b or higher (eGFR >45 mL/min/1.73 m2). The full guideline has recently been published and is freely available online and on the website of ERBP (www.european-renal-best-practice.org). This paper summarises main recommendations of the guideline and their underlying rationales.

The evidence base for circulating tumour DNA blood-based biomarkers for the early detection of cancer: a systematic mapping review

Abstract: The presence of circulating cell-free DNA from tumours in blood (ctDNA) is of major importance to those interested in early cancer detection, as well as to those wishing to monitor tumour progression or diagnose the presence of activating mutations to guide treatment. In 2014, the UK Early Cancer Detection Consortium undertook a systematic mapping review of the literature to identify blood-based biomarkers with potential for the development of a non-invasive blood test for cancer screening, and which identified this as a major area of interest. This review builds on the mapping review to expand the ctDNA dataset to examine the best options for the detection of multiple cancer types. The original mapping review was based on comprehensive searches of the electronic databases Medline, Embase, CINAHL, the Cochrane library, and Biosis to obtain relevant literature on blood-based biomarkers for cancer detection in humans (PROSPERO no. CRD42014010827). The abstracts for each paper were reviewed to determine whether validation data were reported, and then examined in full. Publications concentrating on monitoring of disease burden or mutations were excluded. The search identified 94 ctDNA studies meeting the criteria for review. All but 5 studies examined one cancer type, with breast, colorectal and lung cancers representing 60% of studies. The size and design of the studies varied widely. Controls were included in 77% of publications. The largest study included 640 patients, but the median study size was 65 cases and 35 controls, and the bulk of studies (71%) included less than 100 patients. Studies either estimated cfDNA levels non-specifically or tested for cancer-specific mutations or methylation changes (the majority using PCR-based methods). We have systematically reviewed ctDNA blood biomarkers for the early detection of cancer. Pre-analytical, analytical, and post-analytical considerations were identified which need to be addressed before such biomarkers enter clinical practice. The value of small studies with no comparison between methods, or even the inclusion of controls is highly questionable, and larger validation studies will be required before such methods can be considered for early cancer detection.

The efficacy and safety of continued hydroxycarbamide therapy versus switching to ruxolitinib in patients with polycythaemia vera: a randomized, double-blind, double-dummy, symptom study (RELIEF)

Abstract: Summary The randomized, double-blind, double-dummy, phase 3b RELIEF trial evaluated polycythaemia vera (PV)-related symptoms in patients who were well controlled with a stable dose of hydroxycarbamide (also termed hydroxyurea) but reported PV-related symptoms. Patients were randomized 1:1 to ruxolitinib 10 mg BID (n = 54) or hydroxycarbamide (prerandomization dose/schedule; n = 56); crossover to ruxolitinib was permitted after Week 16. The primary endpoint, ≥50% improvement from baseline in myeloproliferative neoplasm -symptom assessment form total symptom score cytokine symptom cluster (TSS-C; sum of tiredness, itching, muscle aches, night sweats, and sweats while awake) at Week 16, was achieved by 43·4% vs. 29·6% of ruxolitinib- and hydroxycarbamide-treated patients, respectively (odds ratio, 1·82; 95% confidence interval, 0·82–4·04; P = 0·139). The primary endpoint was achieved by 34% of a subgroup who maintained their hydroxycarbamide dose from baseline to Weeks 13–16. In a post hoc analysis, the primary endpoint was achieved by more patients with stable screening-to-baseline TSS-C scores (ratio ≤ 2) receiving ruxolitinib than hydroxycarbamide (47·4% vs. 25·0%; P = 0·0346). Ruxolitinib treatment after unblinding was associated with continued symptom score improvements. Adverse events were primarily grades 1/2 with no unexpected safety signals. Ruxolitinib was associated with a nonsignificant trend towards improved PV-related symptoms versus hydroxycarbamide, although an unexpectedly large proportion of patients who maintained their hydroxycarbamide dose reported symptom improvement.

A systematic review of the prognostic value of lymph node ratio, number of positive nodes and total nodes examined in pancreatic ductal adenocarcinoma.

Abstract: BACKGROUND Pancreatic ductal adenocarcinoma is the most common pancreatic cancer. Five-year overall survival is currently 3.3-6.0%. The aim of this review was to evaluate the prognostic value of lymph node ratio, number of positive nodes and total nodes examined on overall survival rate following pancreatic resection. MATERIALS AND METHODS A literature search was conducted of MEDLINE, EMBASE, the Cochrane Library and Central Register of Controlled Trials and the Cochrane Database of Systematic Review databases, from January 1996 to January 2016. RESULTS Overall, 19 studies including 4,883 patients examined the relationship between lymph node ratio and overall survival. A high lymph node ratio was associated with decreased overall survival in 17 studies. A total of 12 studies examined the relationship between the number of positive nodes and overall survival, and 11 studies revealed that an increase in the number of positive nodes was associated with decreased overall survival. In 15 studies examining the relationship between the total nodes examined and overall survival, there was no association with overall survival in 12 studies. CONCLUSIONS Lymph node ratio and number of positive nodes are factors associated with overall survival in pancreatic ductal adenocarcinoma, but not total nodes examined.

Total Knee Arthroplasty for Osteoarthritis in Patients Less Than Fifty-Five Years of Age: A Systematic Review

Abstract: Background The proportion of younger patients undergoing total knee arthroplasty (TKA) is increasing and predictions state that the Methods The search identified 980 studies for title and abstract review. Forty-three full texts were then assessed. Thirteen studies underwent quality assessment and data extraction. Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were followed throughout. Outcomes extracted included pre-operative and post-operative functional scores, range of motion, and patient satisfaction. Clinical complications and survival were also recorded. Results Across 13 studies we were able to demonstrate 54-point improvement in clinical Knee Society Score and a 46-point improvement on functional Knee Society Score. A 2.9° improvement in range of motion was found at final follow-up. Satisfaction rate was 85.5%. Cumulative percentage all-cause revision rate was 5.4% across 1283 TKAs at a mean 10.8 years of follow-up. Ten-year survival, for aseptic loosening alone, was 98.2%. Conclusion TKA is an excellent treatment option for the young osteoarthritic knee with a >50% improvement in functional knee scores. Satisfaction is high and the revision rate remains 0.5% per year.

Viscoelastometry guided fresh frozen plasma infusion for postpartum haemorrhage: OBS2, an observational study.

Abstract: Background Postpartum haemorrhage (PPH) may be exacerbated by haemostatic failure. Based on data from trauma studies, empirical infusions of fresh frozen plasma (FFP) are often given during severe PPH if coagulation tests are unavailable. This study observed a cohort of women with moderate/severe PPH in whom FFP infusion was guided by the use of viscoelastometric point-of-care testing (VEPOCT) and clinical assessment. Methods Women were enrolled into this observational study when blood loss was measured or suspected to be about 1000 mL. If Fibtem A5 remained >15 mm, or bleeding stopped, FFP was withheld. If Fibtem A5 was ≤15 mm and bleeding ongoing women were randomised into an interventional study as previously reported. Clinical and laboratory outcomes were recorded. Results The study recruited 605 women and 98% had FFP withheld. The median (25th-75th centile) total blood loss was 1500 (1300-2000) mL with 300 (50-545) mL occurring after enrolment. Total blood loss was >2500 mL in 40/605 (6.6%) women. RBCs were transfused in 141/605 (23.3%) cases and 11 (1.8%) received ≥4 units. At least one invasive procedure was performed in 283/605 (46.8%) women. Level 3 care was required for 10/605 (1.7%) women. No women developed clinically significant haemostatic impairment. Conclusions A restrictive use of FFP guided by clinical assessment of bleeding and VE-POCT is feasible and did not result in clinically significant haemostatic impairment. Studies should compare the clinical and cost effectiveness of empirical FFP infusions, according to current guidelines, with a targeted use of FFP based on VE-POCT.

Contact allergy to preservatives: ESSCA* results with the baseline series, 2009–2012

Abstract: Background Allergic contact dermatitis caused by biocides is common, and causes significant patient morbidity. Objective To describe the current frequency and pattern of patch test reactivity to biocide allergens included in the baselines series of most European countries. Methods Data collected by the European Surveillance System on Contact Allergies (ESSCA) network between 2009 and 2012 from 12 European countries were analysed. Results Methylisothiazolinone 0.2% aq. produced the highest prevalence of sensitization during the study period, with an overall prevalence of 4.5%. The mixture methylchloroisothiazolinone/methylisothiazolinone tested at 0.02% aq. followed closely, with 4.1% of positive reactions. Other preservatives with lower rates of sensitisation, but still over 1%, include methyldibromo glutaronitrile (MDBGN) 0.5% pet. and iodopropynyl butylcarbamate (IPBC) 0.2% pet. Formaldehyde releasers and parabens yielded less than 1% positive reactions during the study period. Some regional differences in the prevalence of contact allergy to biocides among European countries were observed. Conclusions Contact allergy to biocides is common throughout Europe, and regional differences could be explained by differences in exposure or characteristics of the population tested. Timely regulatory action for isothiazolinones is required. Although MDBGN is banned from cosmetics products since 2005, sensitization prevalence has not appeared to plateau. IPBC is an emerging allergen with an increasing prevalence over the last few years, and its inclusion in the European baseline series may be appropriate. This article is protected by copyright. All rights reserved.

Randomized Prospective Biomarker Trial of ERCC1 for Comparing Platinum and Nonplatinum Therapy in Advanced Non-Small-Cell Lung Cancer: ERCC1 Trial (ET).

Abstract: Purpose Retrospective studies indicate that expression of excision repair cross complementing group 1 (ERCC1) protein is associated with platinum resistance and survival in non-small-cell lung cancer (NSCLC). We conducted the first randomized trial, to our knowledge, to evaluate ERCC1 prospectively and to assess the superiority of nonplatinum therapy over platinum doublet therapy for ERCC1-positive NSCLC as well as noninferiority for ERCC1-negative NSCLC. Patients and Methods This trial had a marker-by-treatment interaction phase III design, with ERCC1 (8F1 antibody) status as a randomization stratification factor. Chemonaive patients with NSCLC (stage IIIB and IV) were eligible. Patients with squamous histology were randomly assigned to cisplatin and gemcitabine or paclitaxel and gemcitabine; nonsquamous patients received cisplatin and pemetrexed or paclitaxel and pemetrexed. Primary end point was overall survival (OS). We also evaluated an antibody specific for XPF (clone 3F2). The target hazard ratio (HR) for patients with ERCC1-positive NSCLC was ≤ 0.78. Results Of patients, 648 were recruited (177 squamous, 471 nonsquamous). ERCC1-positive rates were 54.5% and 76.7% in nonsquamous and squamous patients, respectively, and the corresponding XPF-positive rates were 70.5% and 68.5%. Accrual stopped early in 2012 for squamous patients because OS for nonplatinum therapy was inferior to platinum therapy (median OS, 7.6 months [paclitaxel and gemcitabine] v 10.7 months [cisplatin and gemcitabine]; HR, 1.46; P = .02). Accrual for nonsquamous patients halted in 2013. Median OS was 8.0 (paclitaxel and pemetrexed) versus 9.6 (cisplatin and pemetrexed) months for ERCC1-positive patients (HR, 1.11; 95% CI, 0.85 to 1.44), and 10.3 (paclitaxel and pemetrexed) versus 11.6 (cisplatin and pemetrexed) months for ERCC1-negative patients (HR, 0.99; 95% CI, 0.73 to 1.33; interaction P = .64). OS HR was 1.09 (95% CI, 0.83 to 1.44) for XPF-positive patients, and 1.39 (95% CI, 0.90 to 2.15) for XPF-negative patients (interaction P = .35). Neither ERCC1 nor XPF were prognostic: among nonsquamous patients, OS HRs for positive versus negative were ERCC1, 1.11 ( P = .32), and XPF, 1.08 ( P = .55). Conclusion Superior outcomes were observed for patients with squamous histology who received platinum therapy compared with nonplatinum chemotherapy; however, selecting chemotherapy by using commercially available ERCC1 or XPF antibodies did not confer any extra survival benefit.

International Interlaboratory Digital PCR Study Demonstrating High Reproducibility for the Measurement of a Rare Sequence Variant.

Abstract: This study tested the claim that digital PCR (dPCR) can offer highly reproducible quantitative measurements in disparate laboratories. Twenty-one laboratories measured four blinded samples containing different quantities of a KRAS fragment encoding G12D, an important genetic marker for guiding therapy of certain cancers. This marker is challenging to quantify reproducibly using quantitative PCR (qPCR) or next generation sequencing (NGS) due to the presence of competing wild type sequences and the need for calibration. Using dPCR, 18 laboratories were able to quantify the G12D marker within 12% of each other in all samples. Three laboratories appeared to measure consistently outlying results; however, proper application of a follow-up analysis recommendation rectified their data. Our findings show that dPCR has demonstrable reproducibility across a large number of laboratories without calibration. This could enable the reproducible application of molecular stratification to guide therapy and, potentially, ...

Heavy menstrual bleeding on Rivaroxaban - Comparison with Apixaban

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Profiling tumour heterogeneity through circulating tumour DNA in patients with pancreatic cancer

Abstract: // Patricia Adamo 1, * , Caroline M. Cowley 1, * , Christopher P. Neal 2 , Vilas Mistry 1 , Karen Page 1 , Ashley R. Dennison 2 , John Isherwood 2 , Robert Hastings 3 , JinLi Luo 3 , David A. Moore 1 , J. Howard Pringle 1 , L. Miguel Martins 4 , Catrin Pritchard 1 , Margaret Manson 1 and Jacqui A. Shaw 1 1 Department of Cancer Studies, University of Leicester, Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, Leicester, UK 2 Department of Hepatobiliary and Pancreatic Surgery, Leicester General Hospital, Leicester, UK 3 Cancer Research UK Leicester Centre, University of Leicester, Leicester, UK 4 MRC Toxicology Unit, Leicester, UK * These authors have contributed equally to this work Correspondence to: Jacqui A. Shaw, email: js39@le.ac.uk Keywords: ctDNA, cfDNA, pancreatic ductal adenocarcinomas, KRAS, liquid biopsy Received: January 31, 2017 Accepted: July 14, 2017 Published: August 14, 2017 ABSTRACT The majority of pancreatic ductal adenocarcinomas (PDAC) are diagnosed late so that surgery is rarely curative. Earlier detection could significantly increase the likelihood of successful treatment and improve survival. The aim of the study was to provide proof of principle that point mutations in key cancer genes can be identified by sequencing circulating free DNA (cfDNA) and that this could be used to detect early PDACs and potentially, premalignant lesions, to help target early effective treatment. Targeted next generation sequencing (tNGS) analysis of mutation hotspots in 50 cancer genes was conducted in 26 patients with PDAC, 14 patients with chronic pancreatitis (CP) and 12 healthy controls with KRAS status validated by digital droplet PCR. A higher median level of total cfDNA was observed in patients with PDAC (585 ng/ml) compared to either patients with CP (300 ng/ml) or healthy controls (175 ng/ml). PDAC tissue showed wide mutational heterogeneity, whereas KRAS was the most commonly mutated gene in cfDNA of patients with PDAC and was significantly associated with a poor disease specific survival (p=0.018). This study demonstrates that tNGS of cfDNA is feasible to characterise the circulating genomic profile in PDAC and that driver mutations in KRAS have prognostic value but cannot currently be used to detect early emergence of disease. Importantly, monitoring total cfDNA levels may have utility in individuals “at risk” and warrants further investigation.

Germline variation in inflammation-related pathways and risk of Barrett's oesophagus and oesophageal adenocarcinoma.

Abstract: This work was principally supported by the National Institutes of Health (R21DK099804 to MMM and R01CA136725 to TLV and DCW). Support for studies related to the Oxford data set was granted by the Esophageal Adenocarcinoma GenE Consortia incorporating the ChOPIN project (grant C548/A5675) and Inherited Predisposition of neoplasia analysis of genomic DNA (IPOD) from AspECT and BOSS clinical trials project (grant MGAG1G7R); Cancer Research UK (AspECT, grants C548/A4584 and D9612L00090, and Histological AssessmeNt Determining EpitheliaL Response (HANDEL), grant C548/A9085); AstraZeneca UK educational grant; University Hospitals of Leicester R and D grant; and AspECT (T91 5211 University of Oxford grant HDRMJQ0).

Detection of structural mosaicism from targeted and whole-genome sequencing data.

Abstract: Structural mosaic abnormalities are large post-zygotic mutations present in a subset of cells and have been implicated in developmental disorders and cancer. Such mutations have been conventionally assessed in clinical diagnostics using cytogenetic or microarray testing. Modern disease studies rely heavily on exome sequencing, yet an adequate method for the detection of structural mosaicism using targeted sequencing data is lacking. Here, we present a method, called MrMosaic, to detect structural mosaic abnormalities using deviations in allele fraction and read coverage from next-generation sequencing data. Whole-exome sequencing (WES) and whole-genome sequencing (WGS) simulations were used to calculate detection performance across a range of mosaic event sizes, types, clonalities, and sequencing depths. The tool was applied to 4911 patients with undiagnosed developmental disorders, and 11 events among nine patients were detected. For eight of these 11 events, mosaicism was observed in saliva but not blood, suggesting that assaying blood alone would miss a large fraction, possibly >50%, of mosaic diagnostic chromosomal rearrangements.

Risk factors for intramedullary nail breakage in proximal femoral fractures: a 10-year retrospective review

Abstract: INTRODUCTION Intramedullary nailing is a common treatment for proximal femoral fractures. Fracture of the nail is a rare but devastating complication that exposes often frail patients to complex revision surgery. We investigated which risk factors predict nail failure. METHODS We reviewed all cases of nail breakage seen over a 10-year period in a single busy trauma unit; 22 nail fractures were seen in 19 patients. Comparison was made with a group of 209 consecutive patients who underwent intramedullary fixation of a proximal femur fracture with no nail breakage over a 2-year period. RESULTS In the fractured nail group, mean age was 70.4 years (range 55–88 years).The mean time to fracture was 10 months (range 2.5–23 months). Logistical regression was used to show that low American Society of Anesthesiologists (ASA) score, subtrochanteric fracture and pathological fracture were independent risk factors for nail fracture. CONCLUSIONSYoung patients with a low ASA score are at highest risk of nail breakage. We...

Recommendation to test limonene hydroperoxides 0·3% and linalool hydroperoxides 1·0% in the British baseline patch test series

Abstract: Background There is a significant rate of sensitisation worldwide to the oxidised fragrance terpenes limonene and linalool. Patch testing to oxidised terpenes is not routinely carried out; the ideal patch test concentration is unknown. Objectives To determine the best test concentrations for limonene and linalool hydroperoxides, added to the British baseline patch test series, to optimise detection of true allergy and minimise irritant reactions. Methods During 2013-2014, 4563 consecutive patients in 12 UK centres were tested to hydroperoxides of limonene in petrolatum (pet.) 0.3%, 0.2% and 0.1%, and hydroperoxides of linalool 1.0%, 0.5% and 0.25% pet. Irritant (IR) reactions were recorded separately from doubtful (?+) reactions. Concomitant reactions to other fragrance markers and clinical relevance were documented. Results Limonene hydroperoxide 0.3% gave positive reactions in 241 (5.3%) patients, irritant reactions in 93 (2.0%) and doubtful reactions in 110 (2.4%). Linalool hydroperoxide 1.0% gave positive reactions in 352 (7.7%), irritant reactions in 178 (3.9%), and doubtful reactions in 132 (2.9%). 119 patients with crescendo reactions to 0.3% limonene would have been missed if only tested with 0.1%. 131 patients with crescendo reactions to 1.0% linalool would have been missed if only tested with 0.25%. In almost two-thirds of patients with positive patch tests to limonene and linalool the reaction was clinically relevant. The majority of patients did not react to any fragrance marker in the baseline series. Conclusions We recommend that limonene hydroperoxides be tested at 0.3% and linalool hydroperoxides at 1.0% in the British baseline patch test series. This article is protected by copyright. All rights reserved.

Inclusion of diverse populations in genomic research and health services: Genomix workshop report.

Abstract: Clinical genetic services and genomic research are rapidly developing but, historically, those with the greatest need are the least to benefit from these advances. This encompasses low-income communities, including those from ethnic minority and indigenous backgrounds. The “Genomix” workshop at the European Society of Human Genetics (ESHG) 2016 conference offered the opportunity to consider possible solutions for these disparities from the experiences of researchers and genetic healthcare practitioners working with underserved communities in the USA, UK and Australia. Evident from the workshop and corresponding literature is that a multi-faceted approach to engaging communities is essential. This needs to be complemented by redesigning healthcare systems that improves access and raises awareness of the needs of these communities. At a more strategic level, institutions involved in funding research, commissioning and redesigning genetic health services also need to be adequately represented by underserved populations with intrinsic mechanisms to disseminate good practice and monitor participation. Further, as genomic medicine is mainstreamed, educational programmes developed for clinicians should incorporate approaches to alleviate disparities in accessing genetic services and improving study participation.