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1.
Front Neurosci ; 18: 1379658, 2024.
Article in English | MEDLINE | ID: mdl-38803685

ABSTRACT

Glioblastoma multiforme (GBM) is one of the most common and lethal forms of brain cancer, carrying a very poor prognosis (median survival of ~15 months post-diagnosis). Treatment typically involves invasive surgical resection of the tumour mass, followed by radiotherapy and adjuvant chemotherapy using the alkylating agent temozolomide, but over half of patients do not respond to this drug and considerable resistance is observed. Tumour heterogeneity is the main cause of therapeutic failure, where diverse progenitor glioblastoma stem cell (GSC) lineages in the microenvironment drive tumour recurrence and therapeutic resistance. The apelin receptor is a class A GPCR that binds two endogenous peptide ligands, apelin and ELA, and plays a role in the proliferation and survival of cancer cells. Here, we used quantitative whole slide immunofluorescent imaging of human GBM samples to characterise expression of the apelin receptor and both its ligands in the distinct GSC lineages, namely neural-progenitor-like cells (NPCs), oligodendrocyte-progenitor-like cells (OPCs), and mesenchymal-like cells (MES), as well as reactive astrocytic cells. The data confirm the presence of the apelin receptor as a tractable drug target that is common across the key cell populations driving tumour growth and maintenance, offering a potential novel therapeutic approach for patients with GBM.

2.
Biosci Rep ; 44(6)2024 Jun 26.
Article in English | MEDLINE | ID: mdl-38747277

ABSTRACT

Endothelin (ET) receptor antagonists are being investigated in combination with sodium-glucose co-transporter-2 inhibitors (SGLT-2i). These drugs primarily inhibit the SGLT-2 transporter that, in humans, is thought to be mainly restricted to the renal proximal convoluted tubule, resulting in increased glucose excretion favouring improved glycaemic control and diuresis. This action reduces fluid retention with ET receptor antagonists. Studies have suggested SGLT-2 may also be expressed in cardiomyocytes of human heart. To understand the potential of combining the two classes of drugs, our aim was to compare the distribution of ET receptor sub-types in human kidney, with SGLT-2. Secondly, using the same experimental conditions, we determined if SGLT-2 expression could be detected in human heart and whether the transporter co-localised with ET receptors. METHODS: Immunocytochemistry localised SGLT-2, ETA and ETB receptors in sections of histologically normal kidney, left ventricle from patients undergoing heart transplantation or controls. Primary antisera were visualised using fluorescent microscopy. Image analysis was used to measure intensity compared with background in adjacent control sections. RESULTS: As expected, SGLT-2 localised to epithelial cells of the proximal convoluted tubules, and co-localised with both ET receptor sub-types. Similarly, ETA receptors predominated in cardiomyocytes; low (compared with kidney but above background) positive staining was also detected for SGLT-2. DISCUSSION: Whether low levels of SGLT-2 have a (patho)physiological role in cardiomyocytes is not known but results suggest the effect of direct blockade of sodium (and glucose) influx via SGLT-2 inhibition in cardiomyocytes should be explored, with potential for additive effects with ETA antagonists.


Subject(s)
Receptor, Endothelin A , Receptor, Endothelin B , Sodium-Glucose Transporter 2 , Humans , Kidney/metabolism , Kidney Tubules, Proximal/metabolism , Kidney Tubules, Proximal/drug effects , Myocardium/metabolism , Receptor, Endothelin A/metabolism , Receptor, Endothelin B/metabolism , Sodium-Glucose Transporter 2/metabolism , Sodium-Glucose Transporter 2/genetics , Sodium-Glucose Transporter 2 Inhibitors/pharmacology
3.
Transplantation ; 108(6): 1403-1409, 2024 Jun 01.
Article in English | MEDLINE | ID: mdl-38419153

ABSTRACT

BACKGROUND: Normothermic ex situ liver perfusion (NESLiP) has the potential to increase organ utilization. Radiological evidence of localized liver injury due to compression at the time of NESLiP, termed cradle compression, is a recognized phenomenon but is poorly characterized. METHODS: A retrospective analysis of a prospectively collected database was performed of transplanted livers that underwent NESLiP and subsequently had a computed tomography performed within the first 14 d posttransplant. The primary study outcome was 1-y graft survival. RESULTS: Seventy livers (63%) were included in the analysis. Radiological evidence of cradle compression was observed in 21 of 70 (30%). There was no difference in rate of cradle compression between donor after circulatory death and donated after brain death donors ( P  = 0.37) or with duration of NESLiP. Univariate analysis demonstrated younger (area under the receiver operating characteristic, 0.68; P = 0.008; 95% confidence interval [CI], 0.55-0.82) and heavier (area under the receiver operating characteristic, 0.80; P  < 0.001; 95% CI, 0.69-0.91) livers to be at risk of cradle compression. Only liver weight was associated with cradle compression on multivariate analysis (odds ratio, 1.003; P  = 0.005; 95% CI, 1.001-1.005). There was no difference in 1-y graft survival (16/17 [94.1%] versus 44/48 [91.6%]; odds ratio, 0.69; P  = 0.75; 95% CI, 0.07-6.62). CONCLUSIONS: This is the first study assessing the impact of cradle compression on outcome. We have identified increased donor liver weight and younger age as risk factors for the development of this phenomenon. Increasing utilization of NESLiP will result in the increased incidence of cradle compression but the apparent absence of long-term sequelae is reassuring. Routine postoperative axial imaging may be warranted.


Subject(s)
Graft Survival , Liver Transplantation , Liver , Perfusion , Humans , Liver Transplantation/adverse effects , Retrospective Studies , Male , Perfusion/methods , Perfusion/adverse effects , Female , Middle Aged , Liver/diagnostic imaging , Liver/blood supply , Liver/pathology , Adult , Treatment Outcome , Risk Factors , Time Factors , Tomography, X-Ray Computed , Organ Preservation/methods , Organ Preservation/adverse effects , Multivariate Analysis , Aged , Tissue Donors , Organ Size
4.
Clin Gastroenterol Hepatol ; 20(2): e51-e63, 2022 02.
Article in English | MEDLINE | ID: mdl-33581357

ABSTRACT

BACKGROUND & AIMS: A non-endoscopic approach to Barrett's esophagus (BE) surveillance after radiofrequency ablation (RFA) would offer a less invasive method for monitoring. We assessed the test characteristics and cost-effectiveness of the Cytosponge (Medtronic, Minneapolis, MN) in post-RFA patients. METHODS: We performed a multicenter study of dysplastic BE patients after at least one round of RFA. A positive Cytosponge before endoscopy was defined as intestinal metaplasia (IM) on cytological assessment and/or TFF3 immunohistochemistry. Sensitivity, specificity, and receiver operator characteristic (ROC) curves were calculated. Multivariable regression was used to estimate the odds of a positive Cytosponge in BE. A microsimulation cost-effectiveness model was performed to assess outcomes of various surveillance strategies: endoscopy-only, Cytosponge-only, and alternating endoscopy/Cytosponge. RESULTS: Of 234 patients, Cytosponge adequately sampled the distal esophagus in 175 (75%). Of the 142 with both endoscopic and histologic data, 19 (13%) had residual/recurrent BE. For detecting any residual Barrett's, Cytosponge had a sensitivity of 74%, specificity of 85%, accuracy of 84%, and ROC curve showed an area under the curve of 0.74. The adjusted odds of a positive Cytosponge in BE were 17.1 (95% CI, 5.2-55.9). Cytosponge-only surveillance dominated all the surveillance strategies, being both less costly and more effective. Cytosponge-only surveillance required <1/4th the endoscopies, resulting in only 0.69 additional EAC cases/1000 patients, and no increase in EAC deaths when compared to currently-practiced endoscopy-only surveillance. CONCLUSIONS: A positive Cytosponge test was strongly associated with residual BE after ablation. While the assay needs further refinement in this context, it could serve as a cost-effective surveillance examination.


Subject(s)
Barrett Esophagus , Esophageal Neoplasms , Barrett Esophagus/complications , Barrett Esophagus/diagnosis , Barrett Esophagus/surgery , Cost-Benefit Analysis , Endoscopy, Gastrointestinal , Esophageal Neoplasms/pathology , Esophagoscopy , Humans , Metaplasia/complications
5.
J Clin Pathol ; 75(9): 620-626, 2022 Sep.
Article in English | MEDLINE | ID: mdl-34531287

ABSTRACT

AIMS: To determine the proportion of thyroid fine needle aspiration (FNA) and core needle biopsy (CNB) cases reported at a single institute into each UK Royal College of Pathologists (RCPath) Thy1-5 and local T category, respectively. Where subsequent histology was available, malignancy rates, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and diagnostic accuracy were compared for both procedures. METHODS: 1591 FNAs (2010-2018) and 514 CNBs (2013-2018) cases were identified, together with paired histology excision specimens. RESULTS: The FNA samples were classified as: Thy1: 45.3%, Thy2/Thy2c: 22.1%, Thy3a/Thy3f: 28%, Thy4: 1.6% and Thy5: 3%; while the CNB were classified as: T1: 7.2%, T2: 22.4%, T3 59.3%, T4: 1% and T5: 10.1%. Comparison of FNA and CNB classified as Thy5/T5 showed a 100% risk of malignancy (ROM), sensitivity (98% vs 100%), specificity (14.1% vs 12.1%), PPV (29.4% vs 29.4%), NPV (94.9% vs 100%) and accuracy (36.5% vs 35.6%), respectively, for a diagnosis of malignancy. ROMs for other categories were: Thy1/T1 (9% vs 6.7%), Thy2/T2 (5.1% vs 0%), Thy3/T3 (17.5% vs 18.4%) and Thy4/T4 (73.3% vs 100%). CONCLUSIONS: The proportion of cases in each RCPath Thy category has remained relatively stable during the 9-year study period, with the exception of the Thy3a category, which has increased over time. This finding is in line with other more recent reports in the literature and the proportion of T3 cases in the CNB group. The proportion of Thy2/Thy2c cases has also reduced over time, reflecting a local change in the triaging protocol for probable benign lesions. Both FNA and CNB showed comparable performance in our study.


Subject(s)
Thyroid Neoplasms , Thyroid Nodule , Biopsy, Fine-Needle/methods , Biopsy, Large-Core Needle , Humans , Pathologists , Retrospective Studies , Sensitivity and Specificity , Thyroid Neoplasms/diagnosis , Thyroid Neoplasms/pathology , Thyroid Nodule/diagnosis , Thyroid Nodule/pathology
6.
J R Coll Physicians Edinb ; 51(4): 373-376, 2021 Dec.
Article in English | MEDLINE | ID: mdl-34882137

ABSTRACT

Paraneoplastic glomerular disease is well recognised, although it most frequently presents with clinical features of the nephrotic syndrome. This case describes a 74-year-old male with metastatic rectal adenocarcinoma treated surgically with anterior resection followed by adjuvant capecitabine chemotherapy. Having previously had normal renal function, he developed an acute kidney injury with active urinary sediment following the discovery of liver metastases. A renal biopsy was performed, which revealed an active crescentic pauci-immune glomerulonephritis. The patient was treated with high dose oral corticosteroids which led to some improvement in renal function, although he was still left with significant kidney impairment, which limited further safe oncological treatment. This case highlights a rare presentation of glomerular disease in the setting of malignancy and also demonstrates the adverse impact that kidney impairment can have on outcomes in patients with cancer.


Subject(s)
Carcinoma , Glomerulonephritis , Adrenal Cortex Hormones , Aged , Autoantibodies , Humans , Male
7.
Chest ; 160(6): e609-e611, 2021 12.
Article in English | MEDLINE | ID: mdl-34872672

ABSTRACT

Malignant pleural effusion is common in mesothelioma. We report a case of viscous recurrent malignant mesothelioma pleural effusion. The viscosity was due to the presence of hyaluronic acid and resulted in prolonged drainage time. The use of intrapleural hyaluronidase significantly reduced fluid viscosity and drainage duration. No adverse reactions were noted. This novel case highlights the feasibility and safety of the use of intrapleural hyaluronidase in the management of hyaluronic acid-rich viscous malignant pleural effusion.


Subject(s)
Exudates and Transudates/drug effects , Hyaluronoglucosaminidase/therapeutic use , Mesothelioma, Malignant/therapy , Pleural Effusion, Malignant/therapy , Pleural Neoplasms/therapy , Aged , Combined Modality Therapy , Drainage , Humans , Male
8.
Sci Rep ; 11(1): 24336, 2021 12 21.
Article in English | MEDLINE | ID: mdl-34934117

ABSTRACT

ACE2 is a membrane protein that regulates the cardiovascular system. Additionally, ACE2 acts as a receptor for host cell infection by human coronaviruses, including SARS-CoV-2 that emerged as the cause of the on-going COVID-19 pandemic and has brought unprecedented burden to economy and health. ACE2 binds the spike protein of SARS-CoV-2 with high affinity and shows little variation in amino acid sequence meaning natural resistance is rare. The discovery of a novel short ACE2 isoform (deltaACE2) provides evidence for inter-individual differences in SARS-CoV-2 susceptibility and severity, and likelihood of developing subsequent 'Long COVID'. Critically, deltaACE2 loses SARS-CoV-2 spike protein binding sites in the extracellular domain, and is predicted to confer reduced susceptibility to viral infection. We aimed to assess the differential expression of full-length ACE2 versus deltaACE2 in a panel of human tissues (kidney, heart, lung, and liver) that are implicated in COVID-19, and confirm ACE2 protein in these tissues. Using dual antibody staining, we show that deltaACE2 localises, and is enriched, in lung airway epithelia and bile duct epithelia in the liver. Finally, we also confirm that a fluorescently tagged SARS-CoV-2 spike protein monomer shows low binding at lung and bile duct epithelia where dACE2 is enriched.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/metabolism , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/genetics , Bile Ducts/metabolism , Bile Ducts/virology , Binding Sites , COVID-19/pathology , COVID-19/virology , Humans , Lung/metabolism , Lung/virology , Microscopy, Fluorescence, Multiphoton , Protein Binding , Protein Isoforms/chemistry , Protein Isoforms/genetics , Protein Isoforms/metabolism , Receptors, Virus/chemistry , Receptors, Virus/metabolism , SARS-CoV-2/isolation & purification , Spike Glycoprotein, Coronavirus/chemistry , Virus Internalization
12.
Br J Cancer ; 123(5): 793-802, 2020 09.
Article in English | MEDLINE | ID: mdl-32555365

ABSTRACT

BACKGROUND: PTEN loss is a putative driver in histotypes of ovarian cancer (high-grade serous (HGSOC), endometrioid (ENOC), clear cell (CCOC), mucinous (MOC), low-grade serous (LGSOC)). We aimed to characterise PTEN expression as a biomarker in epithelial ovarian cancer in a large population-based study. METHODS: Tumours from 5400 patients from a multicentre observational, prospective cohort study of the Ovarian Tumour Tissue Analysis Consortium were used to evaluate associations between immunohistochemical PTEN patterns and overall survival time, age, stage, grade, residual tumour, CD8+ tumour-infiltrating lymphocytes (TIL) counts, expression of oestrogen receptor (ER), progesterone receptor (PR) and androgen receptor (AR) by means of Cox proportional hazard models and generalised Cochran-Mantel-Haenszel tests. RESULTS: Downregulation of cytoplasmic PTEN expression was most frequent in ENOC (most frequently in younger patients; p value = 0.0001) and CCOC and was associated with longer overall survival in HGSOC (hazard ratio: 0.78, 95% CI: 0.65-0.94, p value = 0.022). PTEN expression was associated with ER, PR and AR expression (p values: 0.0008, 0.062 and 0.0002, respectively) in HGSOC and with lower CD8 counts in CCOC (p value < 0.0001). Heterogeneous expression of PTEN was more prevalent in advanced HGSOC (p value = 0.019) and associated with higher CD8 counts (p value = 0.0016). CONCLUSIONS: PTEN loss is a frequent driver in ovarian carcinoma associating distinctly with expression of hormonal receptors and CD8+ TIL counts in HGSOC and CCOC histotypes.


Subject(s)
PTEN Phosphohydrolase/biosynthesis , Adenocarcinoma, Clear Cell/enzymology , Adenocarcinoma, Clear Cell/mortality , Adenocarcinoma, Clear Cell/pathology , Age Factors , Biomarkers, Tumor/biosynthesis , Biomarkers, Tumor/genetics , Carcinoma, Ovarian Epithelial/enzymology , Carcinoma, Ovarian Epithelial/genetics , Carcinoma, Ovarian Epithelial/mortality , Carcinoma, Ovarian Epithelial/pathology , Cohort Studies , Down-Regulation , Female , Gene Knockout Techniques , Humans , Middle Aged , Neoplasm Staging , Ovarian Neoplasms/enzymology , Ovarian Neoplasms/genetics , Ovarian Neoplasms/mortality , Ovarian Neoplasms/pathology , PTEN Phosphohydrolase/deficiency , PTEN Phosphohydrolase/genetics , Prospective Studies , Receptors, Androgen/biosynthesis , Receptors, Estrogen/biosynthesis , Receptors, Progesterone/biosynthesis , Tissue Array Analysis , Tumor Suppressor Proteins/biosynthesis , Tumor Suppressor Proteins/deficiency
13.
Cells ; 9(2)2020 02 14.
Article in English | MEDLINE | ID: mdl-32075097

ABSTRACT

Identifying cancer drivers and actionable mutations is critical for precision oncology. In epithelial ovarian cancer (EOC) the majority of mutations lack biological or clinical validation. We fully characterized 43 lines of Patient-Derived Xenografts (PDXs) and performed copy number analysis and whole exome sequencing of 12 lines derived from naïve, high grade EOCs. Pyrosequencing allowed quantifying mutations in the source tumours. Drug response was assayed on PDX Derived Tumour Cells (PDTCs) and in vivo on PDXs. We identified a PIK3R1W624R variant in PDXs from a high grade serous EOC. Allele frequencies of PIK3R1W624R in all the passaged PDXs and in samples of the source tumour suggested that it was truncal and thus possibly a driver mutation. After inconclusive results in silico analyses, PDTCs and PDXs allowed the showing actionability of PIK3R1W624R and addiction of PIK3R1W624R carrying cells to inhibitors of the PI3K/AKT/mTOR pathway. It is noteworthy that PIK3R1 encodes the p85α regulatory subunit of PI3K, that is very rarely mutated in EOC. The PIK3R1W624R mutation is located in the cSH2 domain of the p85α that has never been involved in oncogenesis. These data show that patient-derived models are irreplaceable in their role of unveiling unpredicted driver and actionable variants in advanced ovarian cancer.


Subject(s)
Carcinoma, Ovarian Epithelial/genetics , Class Ia Phosphatidylinositol 3-Kinase/genetics , Cystadenocarcinoma, Serous/genetics , Ovarian Neoplasms/genetics , Animals , Carcinoma, Ovarian Epithelial/drug therapy , Carcinoma, Ovarian Epithelial/enzymology , Cell Line, Tumor , Class Ia Phosphatidylinositol 3-Kinase/metabolism , Cystadenocarcinoma, Serous/drug therapy , Cystadenocarcinoma, Serous/enzymology , Female , Heterografts , Humans , Mice , Mice, Inbred NOD , Mice, SCID , Molecular Targeted Therapy , Mutation , Neoplasm Grading , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/enzymology , Random Allocation
14.
Diagn Cytopathol ; 48(3): 253-264, 2020 Mar.
Article in English | MEDLINE | ID: mdl-31814330

ABSTRACT

The incidence of esophageal carcinoma continues to increase whilst its prognosis remains poor. The most dramatic reduction in mortality is likely to follow early diagnosis of the preinvasive precursor lesion, Barrett's esophagus (BE), coupled with treatment of dysplastic lesions. The major risk factor for BE is gastroesophageal reflux disease, however this is highly prevalent and only a small proportion of individuals have BE, therefore an endoscopy-based screening strategy to detect BE is unfeasible. Minimally invasive esophageal sampling devices offer an alternative, cost-effective strategy which can be deployed within an at-risk population in a primary care setting to identify individuals with probable BE who can then be referred for endoscopic confirmation. The device that has currently progressed furthest in clinical trials is the CytospongeTM which collects cells from the gastric cardia, gastroesophageal junction and along the whole esophageal length. The cell sample is processed into a formalin-fixed paraffin-embedded block and sections assessed for the presence of intestinal metaplasia. TFF3 immunohistochemistry has consistently been shown to be a valuable adjunct that increases the accuracy of the CytospongeTM test by highlighting early goblet cells which may be missed on morphological assessment and by allowing pseudogoblet cells to be differentiated from true goblet cells.


Subject(s)
Barrett Esophagus , Endoscopy, Digestive System/instrumentation , Esophagus , Goblet Cells , Barrett Esophagus/diagnosis , Barrett Esophagus/metabolism , Barrett Esophagus/pathology , Esophagus/metabolism , Esophagus/pathology , Goblet Cells/metabolism , Goblet Cells/pathology , Humans , Immunohistochemistry/instrumentation , Metaplasia
15.
Eur J Haematol ; 102(6): 472-478, 2019 Jun.
Article in English | MEDLINE | ID: mdl-30844104

ABSTRACT

OBJECTIVES: To explore the frequency, context and diagnostic impact of B- and T-lymphocyte clonality assay use in the assessment of possible lymphoproliferative disorders at a central haematopathology diagnostics hub. METHODS: All cases reported by haematopathologists over a sixteen-month period were identified, n = 4462, and those which had clonality studies undertaken analysed further. RESULTS: Clonality studies were requested in 9% of cases, directly contributing to a diagnosis being made in 79%. They were most frequently used to help distinguish reactive lymphoid infiltrates from low-grade B-cell lymphomas and in cases of possible T-cell lymphoma, facilitating a diagnosis being made in over 90% of these. In contrast when clonality assays were requested as a diagnostic adjunct in cases with an atypical cutaneous lymphoid infiltrate, and in occasional cases of lymphoid proliferations with Hodgkin-like cells or EBV-driven proliferations, a definitive final diagnosis was possible in less than 60% of cases. CONCLUSIONS: Clonality studies were used in 9% of cases assessed for a possible lymphoproliferative disorder and had a differing impact depending on the differential diagnoses being considered. These findings can be used to guide access to clonality assays by highlighting the likelihood of an informative result in different diagnostic settings.


Subject(s)
Clonal Evolution , Lymphoproliferative Disorders/diagnosis , Lymphoproliferative Disorders/etiology , B-Lymphocytes/metabolism , B-Lymphocytes/pathology , Disease Management , Disease Susceptibility , Epstein-Barr Virus Infections/complications , Epstein-Barr Virus Infections/virology , Female , Gene Rearrangement , Genetic Predisposition to Disease , Humans , Immunophenotyping , T-Lymphocytes/metabolism , T-Lymphocytes/pathology
16.
Br J Haematol ; 185(2): 261-265, 2019 04.
Article in English | MEDLINE | ID: mdl-30681735

ABSTRACT

Identification of clonal IGH, IGK and IGL gene rearrangements offers diagnostic adjunct in suspected B-cell neoplasms. However, many centres omit IGL analysis as its value is uncertain. A review of 567 cases with IGH, IGK and IGL rearrangement assessed using BIOMED-2 assays showed clonal immunoglobulin gene rearrangement in 54% of cases, of which 24% had a clonal IGL rearrangement. In two cases, the clonal rearrangement was detected exclusively by IGL analysis. This finding demonstrates the added value of IGL analysis for clonality assessment, especially in suspected B-cell neoplasms in which a clonal IGH and/or IGK rearrangement is not detected or is equivocal.


Subject(s)
Gene Rearrangement, B-Lymphocyte, Light Chain , Genes, Immunoglobulin Light Chain/genetics , Immunoglobulin lambda-Chains/genetics , Lymphoma, B-Cell/diagnosis , Lymphoma, B-Cell/genetics , Aged , Female , Genes, Neoplasm , Humans , Immunoglobulin Heavy Chains/genetics , Immunoglobulin kappa-Chains/genetics , Lymphoma, B-Cell/pathology , Neoplasm Grading , Neoplastic Stem Cells/pathology , Polymerase Chain Reaction/methods
18.
Histopathology ; 70(2): 203-210, 2017 Jan.
Article in English | MEDLINE | ID: mdl-27417524

ABSTRACT

AIMS: Reflux symptoms are highly prevalent and non-specific; hence, in the absence of alarm symptoms, endoscopy referral decisions are challenging. This study evaluated whether a non-endoscopic Cytosponge could detect benign oesophageal pathologies and thus have future potential in triaging patients with persistent symptoms. METHODS AND RESULTS: Two complementary cohorts were recruited: (i) patients with reflux symptoms and no prior endoscopy (n = 409), and (ii) patients with reflux symptoms referred for endoscopy (n = 411). All patients were investigated using the Cytosponge and endoscopy. Significant epithelial inflammation was present in 130 (16%) Cytosponge samples, 32 of which had ulcer slough. Candida and significant inflammation was detected in a further 22 (2.3%) cases; epithelial infiltration with >15 eosinophils/high-power field reflecting possible eosinophilic oesophagitis (EOE) in five (0.6%); and viral inclusions suggestive of herpes oesophagitis in one (0.1%). No significant pathology was detected in the majority, 662 (81%), of Cytosponge samples. Cytosponge and endoscopy findings were in agreement in 574 (70%) cases, in 165 (67%) of the discordant cases one investigation showed mild inflammation while the other was negative, with an additional 22 (8.9%) differing on the extent of inflammation. Eighteen cases with severe inflammation, six with candida and two with EOE were detected only at endoscopy, while 18 with candida and significant inflammation, 13 with ulcer slough, one probable EOE and one viral oesophagitis were identified on the Cytosponge only. CONCLUSIONS: The Cytosponge detects a range of benign oesophageal pathologies, and therefore has potential clinical utility in the triaging of patients with troublesome reflux symptoms. This warrants further investigation.


Subject(s)
Cytodiagnosis/instrumentation , Cytodiagnosis/methods , Gastroesophageal Reflux/diagnosis , Adult , Aged , Esophagus/pathology , Female , Humans , Male , Middle Aged
19.
Br J Cancer ; 115(2): 223-7, 2016 Jul 12.
Article in English | MEDLINE | ID: mdl-27336602

ABSTRACT

BACKGROUND: Determining the BRAF mutation status of patients with advanced metastatic melanoma is essential in order to assess patients' eligibility for targeted BRAF inhibitor therapy. The aim of this study was to validate the utility of immunohistochemistry (IHC) to rapidly obtain the BRAF status in the UK cancer centre setting. METHODS: All samples sent for molecular testing for detection of the BRAF mutation over a 26-month period were prospectively tested using the VE1 monoclonal antibody IHC stain. RESULTS: Two-hundred and nineteen samples from 214 patients were identified. All patients were AJCC stage III/IV, except one. There was an overall 95.0% (208/219) concordance rate, with a sensitivity of 94.4% (84/89) and a specificity of 95.4% (124/130) when using genomic assays as the gold standard. Discordance resulted from the inability of the molecular technique to detect the V600E2 mutation and an inability of the IHC staining technique to detect non-V600E mutations. Molecular testing on smaller tumour deposits was also unreliable. CONCLUSIONS: IHC staining has good sensitivity and excellent specificity for BRAF V600E mutations. BRAF IHC can be incorporated into a BRAF mutation testing algorithm for UK cancer centres to as a feasible first-line assay and identify a subset of cases that require subsequent genomic testing. It has the additional major advantages of reduced cost and rapid turnaround time.


Subject(s)
Antibodies, Monoclonal/immunology , Melanoma/genetics , Mutation , Neoplasm Metastasis , Proto-Oncogene Proteins B-raf/genetics , Feasibility Studies , Humans , Immunohistochemistry , Melanoma/pathology , United Kingdom
20.
Histopathology ; 69(2): 315-21, 2016 Aug.
Article in English | MEDLINE | ID: mdl-26826338

ABSTRACT

AIMS: Liver pathology is a challenging subspeciality, with histopathologists frequently seeking specialist opinions. This study aims to determine the impact of specialist reviews on the final diagnosis and patient management. METHODS AND RESULTS: Agreement with the initial reporting centre in the histopathological diagnosis of 1265 liver biopsies was determined. The nature of differences was explored in more depth for 103 discrepant cases. Differences in the histopathological interpretation were present in 749 of 1265 (59%) biopsies, of which 505 of 749 (67%) were predicted at the time of reporting to impact upon patient management. Agreement was good in cases with chronic viral hepatitis, fatty liver disease, malignancy and minimal pathological changes, while diagnostic differences occurred in more than 70% with biliary disease, autoimmune hepatitis or vascular/architectural changes. A clinical review of a subset of reports with histopathological differences predicted changes in patient management in 63 of 103 (61%). CONCLUSIONS: Clinically significant differences in liver biopsy interpretation between local pathologists and subspecialists are common. Diagnoses with frequent discrepancies, such as biliary disease, may benefit from a specialist review as standard when diagnosed initially, while cases requiring specialist advice from disease subgroups where discrepancies are less common, such as chronic viral hepatitis, could be selected during the clinicopathological conference process.


Subject(s)
Fatty Liver/diagnosis , Hepatitis, Autoimmune/diagnosis , Liver Diseases/diagnosis , Liver/pathology , Referral and Consultation/standards , Biopsy , Diagnostic Errors/prevention & control , Fatty Liver/pathology , Hepatitis, Autoimmune/pathology , Humans , Liver Diseases/pathology , Specialization
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