Showing papers in "Journal of Clinical Pathology in 2010"
TL;DR: The application of these glycosylation modifications as biomarkers for cancer detection in tumour tissues and serological assays is summarised.
Abstract: Glycoconjugates constitute a major class of biomolecules which include glycoproteins, glycosphingolipids and proteoglycans. Glycans are involved in several physiological and pathological conditions, such as host-pathogen interactions, cell differentiation, migration, tumour invasion and metastisation, cell trafficking and signalling. Cancer is associated with glycosylation alterations in glycoproteins and glycolipids. This review describes various aspects of protein glycosylation with the focus on alterations associated with human cancer. The application of these glycosylation modifications as biomarkers for cancer detection in tumour tissues and serological assays is summarised.
410 citations
TL;DR: Based on significant age differences between groups, there appears to be a stepwise progression of dysplasia and carcinoma in SSAs over 10 to 15 years, a period two to three times longer than that for conventional adenomas.
Abstract: Background and aims Sessile serrated adenomas (SSAs) are recognised as precursors to microsatellite unstable adenocarcinomas. This study attempts to estimate the progression rate of SSAs based upon the epidemiology of a large cohort as well as identify relationships to other colorectal polyps. Methods Pathological reports generated at Caris Diagnostics from 290810 colonoscopic specimens on 179111 patients were analysed using computerised algorithms. Results SSAs with or without dysplasia/carcinoma (SSA +/e) were identified in 2416 specimens from 2139 patients (54% women). The distribution of SSA+/e was: right-sided (81.2%); left-sided (11.2%); both rightand left-sided (3.2%); not specified (4.3%). There were 1816 (85%) patients without dysplasia (SSAe), 257 (12%) with low-grade dysplasia (SSA-LD), 45 (2%) with high-grade dysplasia (SSA-HD) and 21 (1%) with adenocarcinoma (SSA-CA). The difference in median age between almost all groups was significant (SSAe¼61 years versus SSA-LD¼66 years (p<0.001) vs SSA-HD¼72 years (p¼0.002) vs SSA-CA¼76 years (p¼0.07, NS)). Women comprised 53% of the SSAe group (968/1816), 57% of the SSA-LD group (147/257), 69% of the SSA-HD group (31/45) and 76% of the SSACA group (16/21), being more likely to have high-grade dysplasia (OR 1.94, 95% CI 1.03 to 3.67) and adenocarcinoma (OR 2.80, 95% CI 1.02 to 7.68). Conclusions 1.7% of patients with mucosal polyps had SSAs (with and without dysplasia), more commonly in women and primarily in the right colon. Dysplasia or carcinoma was identified in 15% of patients and significantly disproportionately among women. Based on significant age differences between groups, there appears to be a stepwise progression of dysplasia and carcinoma in SSAs over 10 to 15 years, a period two to three times longer than that for conventional adenomas.
283 citations
TL;DR: A large number of cases of NMCs uniformly present in the midline, most commonly in the head, neck or mediastinum, as poorly differentiated carcinomas with variable degrees of squamous differentiation go unrecognised.
Abstract: NUT midline carcinoma (NMC) is a rare, highly lethal cancer that occurs in children and adults of all ages. NMCs uniformly present in the midline, most commonly in the head, neck or mediastinum, as poorly differentiated carcinomas with variable degrees of squamous differentiation. This tumour is defined by rearrangement of the nuclear protein in testis ( NUT ) gene on chromosome 15q14. In most cases, NUT is involved in a balanced translocation with the BRD4 gene on chromosome 19p13.1, an event that creates a BRD4–NUT fusion gene. Variant rearrangements, some involving the BRD3 gene, occur in the remaining cases. NMC is diagnosed by detection of NUT rearrangement by fluorescence in situ hybridisation or reverse transcriptase PCR. Due its rarity and lack of characteristic histological features, most cases of NMC currently go unrecognised.
181 citations
TL;DR: This is a review of the role of ureases in H pylori and Proteus species infections, focussing on the biochemical and clinical aspects of the most promising and/or potent urease inhibitors for the treatment of gastric and urinary tract infections.
Abstract: Urease is known to be a major contributor to pathologies induced by Helicobacter pylori and Proteus species. In H pylori, urease allows the bacteria to survive in an acidic gastric environment during colonisation, playing an important role in the pathogenesis of gastric and peptic ulcers. Ureolytic activity also results in the production of ammonia in close proximity to the gastric epithelium, causing cell damage and inflammation. In the case of Proteus species (notably Proteus mirabilis) infection, stones are formed due to the presence of ammonia and carbon dioxide released by urease action. In addition, the ammonia released is able to damage the glycosaminoglycan layer, which protects the urothelial surface against bacterial infection. In this context, the administration of urease inhibitors may be an effective therapy for urease-dependent pathogenic bacteria. This is a review of the role of ureases in H pylori and Proteus species infections, focussing on the biochemical and clinical aspects of the most promising and/or potent urease inhibitors for the treatment of gastric and urinary tract infections.
143 citations
TL;DR: EML4-ALK-positive lung adenocarcinoma has a tendency to express a characteristic morphological pattern and the combined use of morphological feature analysis and immunohistochemistry may be a useful and cost effective screening method.
Abstract: Background A subset of lung cancers harbours the fusion gene echinoderm microtubule-associated protein-like-4–anaplastic lymphoma kinase (EML4-ALK). Recently, immunohistochemistry for ALK has shown sensitivity for the detection of EML4-ALK-positive lung adenocarcinoma almost equal to that of the fluorescence in situ hybridisation (FISH) assay. Aims To study the clinicopathological features of EML4-ALK-positive lung adenocarcinoma in a large number of surgically resected samples using immunohistochemistry, in order to establish a useful screening method for EML4-ALK-positive lung adenocarcinoma. Methods Immunohistochemistry for ALK was used to screen for EML4-ALK-positive lung adenocarcinomas in 254 cases of surgically resected samples. Results EML4-ALK-positive cases were detected in 3.1% of lung adenocarcinomas (8/254). EML4-ALK-positive lung adenocarcinomas showed significant associations with intra- and/or extra-cytoplasmic mucin (p=0.0001), and cribriform pattern with excessive extracytoplasmic mucin (p Conclusion EML4-ALK-positive lung adenocarcinoma has a tendency to express a characteristic morphological pattern. The combined use of morphological feature analysis and immunohistochemistry may be a useful and cost effective screening method for EML4-ALK lung adenocarcinoma.
133 citations
TL;DR: While salivary gland lesions have a relatively high proclivity to metastasise, patients with breast AdCCs have an excellent outcome; here the clinical, morphological and molecular features, and potential therapeutic targets of salivARY gland and breast Ad CCs are reviewed.
Abstract: Adenoid cystic carcinoma (AdCC) is a tumour with myoepithelial differentiation and characterised by the presence of a dual population of basaloid and luminal cells arranged in specific growth patterns. These tumours, regardless of the anatomical site, are characterised by expression of the proto-oncogene and therapeutic target c-KIT, and seem to harbour a specific chromosomal translocation t(6;9) leading to the fusion gene MYB-NFIB and overexpression of the oncogene MYB. However, the clinical behaviour of salivary gland and breast AdCC differs; while salivary gland lesions have a relatively high proclivity to metastasise, patients with breast AdCCs have an excellent outcome. Here the clinical, morphological and molecular features, and potential therapeutic targets of salivary gland and breast AdCCs are reviewed.
125 citations
TL;DR: The paper highlights the most common practical diagnostic difficulties that a pathologist is faced with in dealing with pretreated nephroblastomas and emphasises the importance of a systematic, step-by-step analysis based on adequately sampled material in order to accurately sub-classify a nephROblastoma as a low, intermediate or high risk tumour and assign its genuine stage.
Abstract: In the International Society of Paediatric Oncology renal tumour trials, preoperative chemotherapy has been successfully applied with resulting reduction of tumour rupture and increased favourable stage distribution of nephroblastoma. Postoperative treatment includes chemotherapy and sometimes radiotherapy in a risk-adapted approach based on histological sub-classification and stage of the tumour. However, preoperative chemotherapy alters the tumour's histological features and distribution of subtypes, and makes staging more difficult. The paper highlights the most common practical diagnostic difficulties that a pathologist is faced with in dealing with pretreated nephroblastomas. It emphasises the importance of a systematic, step-by-step analysis based on adequately sampled material, in order to accurately sub-classify a nephroblastoma as a low, intermediate or high risk tumour and assign its genuine stage. Finally, it outlines the standard operating procedure for submission of renal tumours for rapid central pathology review which allows the treating oncologists to apply the optimal treatment protocol.
122 citations
TL;DR: The National Health Service now has access to cost-effective and timely TPMT assay services, with two laboratories undertaking the majority of the work at national level and with several local services developing.
Abstract: Thiopurine S-methyltransferase (TPMT) is involved in the metabolism of thiopurine drugs. Patients that due to genetic variation lack this enzyme or have lower levels than normal, can be adversely affected if normal doses of thiopurines are prescribed. The evidence for measuring TPMT prior to starting patients on thiopurine drug therapy has been reviewed and the various approaches to establishing a service considered. Until recently clinical guidelines on the use of the TPMT varied by medical specialty. This has now changed, with clear guidance encouraging clinicians to use the TPMT test prior to starting any patient on thiopurine therapy. The TPMT test is the first pharmacogenomic test that has crossed from research to routine use. Several analytical approaches can be taken to assess TPMT status. The use of phenotyping supported with genotyping on selected samples has emerged as the analytical model that has enabled national referral services to be developed to a high level in the UK. The National Health Service now has access to cost-effective and timely TPMT assay services, with two laboratories undertaking the majority of the work at national level and with several local services developing. There appears to be adequate capacity and an appropriate internal market to ensure that TPMT assay services are commensurate with the clinical demand.
117 citations
TL;DR: It is concluded that multicentric Castleman's disease sometimes occurs with abundant IgG 4-positive cells and elevated serum IgG4 levels, therefore, the two diseases cannot be differentially diagnosed by immunohistochemical staining alone.
Abstract: Background Differentiation between multicentric Castleman9s disease and systemic immunoglobulin (Ig) G4-related lymphadenopathy is sometimes difficult. It has been suggested that measurement of the IgG4-/IgG-positive cell ratio is useful for the differential diagnosis of the two diseases. However, the authors present a detailed report of six patients with multicentric Castleman9s disease with abundant IgG4-positive cells (IgG4-/IgG-positive cell ratio, >40%). Results In the present series, the patients showed systemic lymphadenopathy, polyclonal hypergammaglobulinaemia and elevated serum interleukin-6 (IL-6) and C-reactive protein levels. Further, anaemia, hypoalbuminaemia, hypocholesterolaemia and thrombocytosis were observed. These findings were consistent with those of multicentric Castleman9s disease. Although five patients showed elevated serum IgG4 levels, only two patients showed an increased serum IgG4/IgG ratio. However, the two patients showed highly elevated serum IgG4 levels, but the serum IgG4/IgG ratios were, although increased, not very high. Also, a patient with increased serum IgG4/IgG ratio showed a good response to antihuman IL-6 receptor monoclonal antibody (tocilizumab). Histologically, the germinal centres were mostly small and regressive, and frequently penetrated by hyalinised blood vessels, and there was no eosinophil infiltration. These findings were different from those of IgG4-related lymphadenopathy. Conclusions The authors conclude that multicentric Castleman9s disease sometimes occurs with abundant IgG4-positive cells and elevated serum IgG4 levels. Therefore, the two diseases cannot be differentially diagnosed by immunohistochemical staining alone. Laboratory findings, especially IL-6 level, C-reactive protein level and platelet count, are important for the differential diagnosis of the two diseases.
115 citations
TL;DR: Results suggest the need to rigorously evaluate CISH as an independent reference standard for assessment of HER2 amplification in gastric cancers, and corroborating existing reports that discrepancies exist between HER2 ISH and IHC assays.
Abstract: Background Gastric cancer is a leading cause of cancer-related mortality, and current treatment outcomes for advanced disease remain poor. HER2 has been identified as a potential candidate for targeted therapy in gastric cancers displaying HER2 gene amplification and protein overexpression. Aims To study the prevalence rate of HER2 gene amplification/overexpression in a local population, and determine the concordance rate between the various modalities. Methods 128 gastric cancer samples were analysed by fluorescence (FISH) and chromogenic (CISH) in situ hybridisation and immunohistochemistry (IHC). The relation between HER2 status and various clinicopathological parameters was also analysed. Results 11.7% (15/128) and 9.4% (12/128) of gastric cancers displayed HER2 gene amplification and protein overexpression (score 3+), respectively, with a perfect correlation between the FISH and CISH analyses. There was also a significant inverse correlation between overall survival and HER2 protein overexpression in intestinal-type gastric carcinomas (p Conclusion Results, besides corroborating existing reports that discrepancies exist between HER2 ISH and IHC assays, also suggest the need to rigorously evaluate CISH as an independent reference standard for assessment of HER2 amplification in gastric cancers.
113 citations
TL;DR: The data suggest that there has been an increasing resistance trend to the first-line antibiotics like trimethoprim and Augmentin against E coli, and each region should monitor resistance patterns to urinary pathogens on a regular basis and use antibiotics with a low resistance pattern.
Abstract: Background Epidemiology and resistance patterns of bacterial pathogens in paediatric urinary tract infections (UTIs) show large inter-regional variability, and rates of bacterial resistance are changing due to different antibiotic treatment. Empiric therapy to treat UTI should be tailored to the surveillance data on the epidemiology and resistance patterns of common uropathogens to reduce treatment failures and emergence of bacterial resistance within the community. Objective A retrospective data review was carried out to evaluate the resistance patterns to commonly used antibiotics in children with culture proven UTIs. Methods All infants and children with culture proven UTI from 2002 to 2008 were included. Urine culture was deemed positive with a pure growth >10 5 (single organism). Results A total of 547 UTIs were confirmed on urine cultures in 337 patients. An average of 78 cases were diagnosed each year. E coli was the most commonly grown pathogen (92%). From 2002 to 2008, rising resistance patterns were noted for trimethoprim (p≤0.05) and Augmentin (p≤0.001). In contrast, resistance to cefalexin and nitrofurantoin remained relatively low (11% and 7%, respectively, in 2008). Conclusion Our data suggest that there has been an increasing resistance trend to the first-line antibiotics like trimethoprim and Augmentin against E coli . In accordance with NICE (National Institute for Health and Clinical Excellence) guidance, each region should monitor resistance patterns to urinary pathogens on a regular basis and use antibiotics with a low resistance pattern. Further studies are required from other centres in the UK to look at similar data.
TL;DR: The various grading systems that have been proposed for use with endometrioid endometrial carcinoma are reviewed, and the recent progress in cell type assignment is discussed, including the use of immunohistochemistry as a diagnostic adjunct.
Abstract: Histopathological assessment of tumour grade and cell type is central to the management of endometrial carcinoma, guiding the extent of surgery and the use of adjuvant radiation therapy and chemotherapy. Endometrioid carcinomas are usually low grade but high-grade examples are encountered, and they have a significantly worse prognosis, similar to that of high-grade subtypes such as serous and clear cell carcinoma. This article reviews the various grading systems that have been proposed for use with endometrioid endometrial carcinoma, and discusses the recent progress in cell type assignment, including the use of immunohistochemistry as a diagnostic adjunct.
TL;DR: Perinuclear LC3A accumulation in colorectal tumour cells is a marker of good prognosis, presumably reflecting a basal autophagic activity.
Abstract: Aims The microtubule-associated protein 1 light chain 3 (LC3A) is an essential component of the autophagic vacuoles, forming a reliable marker of autophagic activity In a previous study, the authors showed that LC3A immunohistochemistry renders three patterns of autophagic expression in breast carcinomas: diffuse cytoplasmic, perinuclear and ‘stone-like’ intracellular structures (SLS), each with a distinct prognostic relevance Methods Tumour tissues from 155 patients with stage IIA–III colorectal adenocarcinomas, treated with surgery alone, were assessed immunohistochemically for LC3A Median values were used as cut-off points to separate groups into low and high autophagic activity Associations with prognosis and with lactate dehydrogenase-5 (LDH5) were sought Results High SLS counts were associated with metastases and poor prognosis, while the prominence of the perinuclear pattern was linked to localised disease and good prognosis The cytoplasmic pattern was irrelevant Furthermore, patients with increased SLS numbers, but suppressed perinuclear expression, were associated with LDH5 overexpression and had an extremely poor prognosis (3-year survival 165%) The prognosis improved considerably when high SLS counts were accompanied by intense perinuclear expression (3-year survival 67%) and were optimal when SLS numbers dropped below median values, irrespective of perinuclear status (3-year survival 94–100%) Multivariate analysis showed that SLS and perinuclear patterns were independent predictors of death events Conclusions Perinuclear LC3A accumulation in colorectal tumour cells is a marker of good prognosis, presumably reflecting a basal autophagic activity An abnormal or excessive autophagic response, as indicated by increased numbers of SLS, is linked to metastasis and poor prognosis
TL;DR: The ‘osteoclast-rich tumour of the gastrointestinal tract with features resembling clear cell sarcoma of soft parts’ is an extraordinarily rare gastrointestinal neoplasm that shares some features of CCS, but differs from it in other ways.
Abstract: Clear cell sarcoma (CCS) is a rare, distinctive soft tissue neoplasm, typically occurring in the distal extremities of young adult patients. Although CCS shows melanocytic differentiation, it is now clear that it is clinicopathologically and genetically distinct from conventional malignant melanoma. The 'osteoclast-rich tumour of the gastrointestinal tract with features resembling clear cell sarcoma of soft parts' is an extraordinarily rare gastrointestinal neoplasm that shares some features of CCS, but differs from it in other ways. The historical, histopathological, ultrastructural, immunohistochemical and genetic aspects of these two tumours are reviewed in this article.
TL;DR: PMBCs with a micropapillary pattern were more frequently associated with nodal disease and axillary staging by sentinel lymph node biopsy is recommended in PMBCs.
Abstract: Background Pure mucinous breast carcinoma (PMBC) is uncommon and associated with better prognosis than mixed mucinous breast carcinoma (MMBC). A micropapillary pattern in PMBC has been identified although its prognostic significance is questionable. Methods A retrospective review of 100 cases of mucinous carcinoma diagnosed between 2000 and 2009 was conducted. Two broad categories were studied: PMBC (more than 90% mucinous component; n=45) and MMBC (less than 90% mucinous component; n=55). PMBC was further subclassified as hypocellular/type A (n=37) and cellular/type B (n=8). Receptor status, clinicomorphological and prognostic features were compared without patient follow-up. Results Mean age at diagnosis in PMBC and MMBC was 60 and 63 years, while mean tumour size was 1.65 and 2.5 cm, respectively. Mean age in type A and type B PMBC patients was 75 and 55 years, respectively. The majority of PMBCs were well differentiated, with two poorly differentiated cases as well. The majority of MMBCs were moderately differentiated. A micropapillary pattern was seen in 20% of PMBCs. Sentinel lymph nodes were positive in 18.5% of PMBCs and 16% of MMBCs. Non-sentinel lymph nodes were positive in 14% of PMBCs and 39% of MMBCs. A micropapillary pattern was seen in 60% of LN positive PMBCs and 14% of LN negative PMBCs. Furthermore, 95% of PMBCs were ER(+), 84% were PR(+) and 9% were Her-2(+); 91% of MMBCs were ER(+), 87% were PR(+) and 33% were Her-2(+). Conclusions PMBCs with a micropapillary pattern were more frequently associated with nodal disease. PMBCs with axillary disease had one or more of the following: micropapillary pattern, high nuclear grade, Her-2 positivity, smaller tumour size or younger age. Hence, axillary staging by sentinel lymph node biopsy is recommended in PMBCs.
TL;DR: This study confirms the involvement of these genes in CFS/ME, and reveals genomic subtypes with distinct differences in SF36 scores, clinical phenotypes, severity and geographical distribution.
Abstract: Background The authors have previously reported genomic subtypes of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) based on expression of 88 human genes. Aim To attempt to reproduce these findings, determine the specificity of this signature to CFS/ME, and test for associations between CFS/ME subtype and infection. Methods Expression levels of 88 human genes were determined in blood of 62 new patients with idiopathic CFS/ME (according to Fukuda criteria), six patients with Q-fever-associated CFS/ME from the Birmingham Q-fever outbreak (according to Fukuda criteria), 14 patients with endogenous depression (according to DSM-IV criteria) and 29 normal blood donors. Results In patients with CFS/ME, differential expression was confirmed for all 88 genes. Q-CFS/ME had similar patterns of gene expression to idiopathic CFS/ME. Gene expression in patients with endogenous depression was similar to that in the normal controls, except for upregulation of five genes (APP, CREBBP, GNAS, PDCD2 and PDCD6). Clustering of combined gene data in CFS/ME patients for this and the authors’ previous study (117 CFS/ME patients) revealed genomic subtypes with distinct differences in SF36 scores, clinical phenotypes, severity and geographical distribution. Antibody testing for EpsteineBarr virus, enterovirus, Coxiella burnetii and parvovirus B19 revealed evidence of subtype-specific relationships for EpsteineBarr virus and enterovirus, the two most common infectious triggers of CFS/ME. Conclusions This study confirms the involvement of these genes in CFS/ME.
TL;DR: Distinction between benign and malignant mesothelial proliferations can be diagnostically challenging and FISH for p16/CDKN2A deletion is a useful test for confirming the diagnosis of MPM.
Abstract: Aims To develop a fluorescence in-situ hybridisation (FISH) assay for detecting p16/CDKN2A deletion on paraffin tissue sections for use as an ancillary test to distinguish reactive from malignant mesothelial proliferations.
Method Dual-colour FISH for p16/CDKN2A and chromosome 9 (CEP-9) was performed on 11 benign mesothelial proliferations and 54 malignant pleural mesothelioma (MPM) cases to establish cut-off values for p16/CDKN2A deletion. A third MYC probe was used to verify cases showing homozygous deletion. Eight equivocal biopsies were used for assay testing.
Results Cut-off values for p16/CDKN2A deletion were calculated based on FISH signalling patterns obtained from the benign controls (mean percent nuclei plus three standard deviations). Hemizygous deletion was defined as >44% of nuclei showing the hemizygous (one p16/CDKN2A , two CEP-9 signals) or >15% of nuclei showing the monosomy (one p16/CDKN2A , one CEP-9 signal) deletion patterns. None of the benign cases showed a homozygous deletion pattern (no p16/CDKN2A , at least one CEP-9 signal). In the malignant cases, the percentage of nuclei showing homozygous deletion ranged from 1% to 87%. Therefore, the cut-off value for homozygous deletion was defined as >10%. P16/CDKN2A deletion was detected in 61% (33/54) of MPM cases. Among the equivocal biopsies, four showed homozygous and one showed hemizygous p16/CDKN2A deletion. Age over 60 years, asbestos exposure and p16/CDKN2A deletion were associated with a worse prognosis.
Conclusion Distinction between benign and malignant mesothelial proliferations can be diagnostically challenging. FISH for p16/CDKN2A deletion is a useful test for confirming the diagnosis of MPM.
TL;DR: Bacteroides, Bifidobacterium and LAB populations in the duodenum of Spanish children with typical coeliac disease (active and treated) and controls differ in diversity and species composition; this could contribute to features of the disease.
Abstract: Aims To characterise the predominant species of bacterial populations associated with duodenal biopsies of paediatric patients with active and treated coeliac disease. Methods 20 biopsy specimens from patients with active coeliac disease, 12 from patients with treated coeliac disease, and eight from age-matched controls were evaluated for comparative purposes. Bacteroides, Bifidobacterium and lactic acid bacteria (LAB) populations were analysed by PCR-denaturing gradient gel electrophoresis using group-specific primers. Results Bacteroides diversity was higher in biopsy specimens from controls than in those from patients with active and treated coeliac disease. Bacteroides distasonis, Bacteroides fragilis/Bacteroides thetaiotaomicron, Bacteroides uniformis and Bacteroides ovatus were more abundant in controls than in patients with coeliac disease (p<0.05). Bacteroides vulgatus was more frequently detected in controls than in patients with treated coeliac disease (p<0.01). Bacteroides dorei was more common in patients with active coeliac disease than in those with treated coeliac disease and control children (p<0.01). Bifidobacterium diversity was higher in patients with coeliac disease than in controls. Bifidobacterium adolescentis and Bifidobacterium animalis subsp lactis were more prevalent in patients with active coeliac disease than in patients with treated coeliac disease and control children. A higher LAB diversity was found in patients with treated coeliac disease and controls than in patients with active coeliac disease. Weissella spp and Lactobacillus fermentum were more frequently detected in patients with treated coeliac disease than in controls and patients with active coeliac disease. Conclusions Bacteroides, Bifidobacterium and LAB populations in the duodenum of Spanish children with typical coeliac disease (active and treated) and controls differ in diversity and species composition; this could contribute to features of the disease.
TL;DR: It is demonstrated that additive use of p16INK4a immunohistochemistry significantly improves the accuracy of grading CIN lesions by a single pathologist, equalling an expert consensus diagnosis.
Abstract: Background Histomorphological grading of cervical intraepithelial neoplasia (CIN) is crucial for clinical management. CIN grading is however subjective and affected by substantial rates of discordance among pathologists, which may lead to overtreatment. To minimise this problem, a histology review of CIN lesions by a consensus panel of pathologists is often used. Diffuse strong p16 INK4a immunostaining has been proposed to aid the identification of true high-grade cervical lesions (ie, CIN2/3). Aim To assess the value of additional interpretation of p16 INK4a immunostains for making a more reproducible diagnosis of CIN2/3 lesions. Methods The authors used a series of 406 biopsies of cervical lesions, with known HPV status, stained for both H&E- and p16 INK4a . First, in a randomly selected set of 49 biopsies, we examined the effect of additional interpretation of p16 INK4a immunostained slides, on the agreement of CIN diagnosis among three pathologists. Second, the full series of samples was used to assess the accuracy of p16 INK4a -supported lesion grading by a single pathologist, by evaluating the degree of diagnostic agreement with the consensus diagnosis of expert pathologists based on H&E-stained sections only. Results The study shows that the interobserver agreement between three pathologists for the routine H&E-based diagnosis ranged from fair (weighted kappa 0.44 (95% CI 0.19 to 0.64)) to moderate (weighted kappa 0.66 (95% CI 0.47 to 0.79)). The concordance increased substantially for p16 INK4a -supported grading (mean weighted kappa 0.80 (95% CI 0.66 to 0.89)). Furthermore, an almost perfect agreement was found between the p16 INK4a -supported diagnosis of a single pathologist and the consensus diagnosis of an expert pathology panel (kappa 0.88 (95% CI 0.85 to 0.89)). Conclusions These data demonstrate that additive use of p16 INK4a immunohistochemistry significantly improves the accuracy of grading CIN lesions by a single pathologist, equalling an expert consensus diagnosis. Hence, the authors advocate the combined use of p16 INK4a -stained slides and conventional H&E sections in routine histopathology to improve accuracy of diagnosis.
TL;DR: A review of recent advances in the understanding of the molecular basis of PDB with particular emphasis on findings since 2008, and focus on newly defined functions of the p62 protein upon which SQSTM1 mutations may impact in the development of the pagetic phenotype.
Abstract: Paget disease of bone (PDB) is a relatively common disorder characterised by increased bone turnover within discrete lesions throughout the skeleton. The condition has a strong genetic component, with mutations affecting the SQSTM1 gene that encodes the p62 protein often found in PDB patients, although environmental factors also play an important role in disease aetiology. The precise disease mechanism(s) in familial forms and sporadic forms of PDB is unclear, although defective RANK-NF-κB signalling has been suggested to contribute to the increased activity of pagetic osteoclasts in the former. Here, there is a review of recent advances in the understanding of the molecular basis of PDB with particular emphasis on findings since 2008, and focus on newly defined functions of the p62 protein upon which SQSTM1 mutations may impact in the development of the pagetic phenotype.
TL;DR: Aptamers are synthetic oligonucleotide ligands or peptides that can be isolated in vitro against diverse targets including toxins, bacterial and viral proteins, virus-infected cells, cancer cells and whole pathogenic microorganisms as mentioned in this paper.
Abstract: Aptamers, simply described as chemical antibodies, are synthetic oligonucleotide ligands or peptides that can be isolated in vitro against diverse targets including toxins, bacterial and viral proteins, virus-infected cells, cancer cells and whole pathogenic microorganisms. Aptamers assume a defined three-dimensional structure and generally bind functional sites on their respective targets. They possess the molecular recognition properties of monoclonal antibodies in terms of their high affinity and specificity. The applications of aptamers range from diagnostics and biosensing, target validation, targeted drug delivery, therapeutics, templates for rational drug design to biochemical screening of small molecule leads compounds. This review describes recent progress made in the application of biomedically relevant aptamers and relates them to their future clinical prospects.
TL;DR: It is suggested that ocular adnexal MZBLs with IgG4-positive plasma cells have unique histological and serological characteristics that overlap those of ocularAdnexal IgG 4-related lymphoplasmacytic infiltrative disorder and systemic conditions.
Abstract: Aims To report the clinicopathological characteristics of patients with ocular adnexal marginal zone B cell lymphoma (MZBL) with IgG4-positive plasma cells. Methods 114 biopsy samples of ocular adnexal MZBLs were analysed. MZBLs with IgG4-positive plasma cells were included when the IgG4:IgG ratio was >40% (IgG4-related group). The serum levels of each subclass of immunoglobulins and soluble interleukin-2 receptor in the IgG4-related group were compared with those in 61 consecutive patients having MZBL without IgG4-positive plasma cells (IgG4-unrelated group). They were also compared with those in 10 patients having ocular adnexal IgG4-related lymphoplasmacytic disorder (IgG4-related inflammatory group). Results Ten (9%) of the patients were diagnosed with MZBL with IgG4-positive plasma cells. The IgG4-related group had a significantly greater degree of sclerosis and reactive follicles in the MZBLs (p=0.0004 and p=0.01, respectively). The serum levels of IgG, IgG1, IgG4, IgE and soluble interleukin 2 receptor in the IgG4-related group were significantly higher than those in the IgG4-unrelated group (p=0.003, p=0.009, p Conclusions IgG4-positive plasma cells had infiltrated into ocular adnexal MZBLs in 9% of cases. It is suggested that ocular adnexal MZBLs with IgG4-positive plasma cells have unique histological and serological characteristics that overlap those of ocular adnexal IgG4-related lymphoplasmacytic infiltrative disorder and systemic conditions.
TL;DR: This introductory review provides a brief summary of the immunobiology of the HLA system and methodology for HLA typing, antibody screening and patient-donor cross-matching and constitutes a basis for consideration of the importance of these procedures in the system-specific reviews which follow.
Abstract: The Human Leukocyte Antigen (HLA) system plays a critical role in regulating the immune response. As a consequence of its role in immune regulation and exquisite polymorphism, the HLA system also constitutes an immunological barrier which must be avoided or otherwise overcome in clinical transplantation. This introductory review provides a brief summary of the immunobiology of the HLA system and methodology for HLA typing, antibody screening and patient-donor cross-matching. This constitutes a basis for consideration of the importance of these procedures in the system-specific reviews which follow.
TL;DR: This review provides a practical approach to the interpretation of these challenging biopsies of new-onset/de novo post-transplant abnormalities (early and late), rejection, and recurrence of original disease.
Abstract: The spectrum of diseases encountered in post-transplant liver pathology biopsies is broad. In this review, these have been divided as belonging to one of three categories: (1) new-onset/de novo post-transplant abnormalities (early and late), (2) rejection, and (3) recurrence of original disease. The clinical and pathological features of the entities making up each category, with the relevant differential diagnosis and overlaps between and within these groups, are discussed and illustrated. Recurrent or de novo neoplasms make up a fourth category not included in this review. Early new-onset conditions are mostly related to surgical complications, donor factors and ischaemia to the graft. These include reperfusion/preservation injury, lipopeliosis, small-for-size-syndrome, biliary sludge syndrome and hepatic artery thrombosis. The various forms of rejection (cellular, chronic, antibody-mediated, and late atypical rejection) are detailed. Most chronic liver diseases can and do recur in the graft. They may display features that overlap with de novo conditions (eg, primary sclerosing cholangitis versus chronic rejection). As with most cases of allograft biopsy interpretation, accurate diagnosis rests with careful correlation of histological features with clinical, imaging and laboratory findings, and often comparison with previous sequential and follow-up biopsies. Late-onset new diseases include biliary strictures, idiopathic chronic hepatitis and de novo autoimmune hepatitis, among others. This review provides a practical approach to the interpretation of these challenging biopsies. Selected difficult scenarios or conundrums are identified and discussed in the relevant sections.
TL;DR: These results provide useful information both about the frequency of these conditions and the carrier state and their geographic and ethnic distribution across England and can be used to refine counselling information and are also useful to target and plan services and public information.
Abstract: Aims The overall aim of the new national newborn programme is to identify infants at risk of sickle cell disease to allow early detection and to minimise deaths and complications. Methods Universal screening for sickle cell disease was introduced in England between September 2003 and July 2006. The 13 newborn laboratories each screen between 25 000 and 110 000 babies a year using the existing dried bloodspot cards. The specified conditions to be screened for include sickle cell anaemia (Hb SS), Hb SC disease, Hb S/ β thalassaemia, Hb S/D Punjab and Hb S/O Arab . Data are reported on screening results by ethnic group and geographical area. Results The prevalence of screen positive results across England is 1:2000. There is a 25-fold variation by geographical area. African babies make up 61% of all screen positive results despite representing only 4% of total births. Combined carrier rates vary widely by ethnicity, from 1.85 per 1000 (1:540) in ‘White British’ to 145 per 1000 (1:7) in ‘African’ babies. Refusal rates for screening show variation by ethnicity. Conclusions These results provide useful information both about the frequency of these conditions and the carrier state and their geographic and ethnic distribution across England. This can be used to refine counselling information and are also useful to target and plan services and public information.
TL;DR: SP6 and MIB1 provide highly comparable measures of Ki67 that predict progression of advanced disease similarly and SP6 is substantially better suited than M IB1 to image analysis.
Abstract: Aim To compare SP6 and MIB1 antibodies for Ki67 staining in breast cancer. Background Immunohistochemical detection of Ki67 has been widely used to assess the proliferative fraction in breast cancer. Ki67 is used prognostically and is the primary end-point for some presurgical trials. MIB1 has been the preferred antibody, but SP6 has become available, with apparently improved performance. The importance of Ki67 led us to systematically compare SP6 with MIB1. Methods Two sets of tissue microarrays were used. These were constructed from formalin-fixed paraffin-embedded breast cancers: (i) 177 cancers with data on response to an aromatase inhibitor for advanced disease (cohort 1); (ii) 200 mainly oestrogen-receptor-positive cancers without response data (cohort 2). Twenty-eight pairs of core-cut biopsies taken before and after aromatase inhibitor treatment were also assessed (cohort 3). Stained sections were examined either visually or by using an image analysis system (Ariol). Results There was a strong correlation between the two antibodies in all cohorts of samples scored visually (cohort 1: n=161, r=0.93, p Conclusions SP6 and MIB1 provide highly comparable measures of Ki67 that predict progression of advanced disease similarly. SP6 is substantially better suited than MIB1 to image analysis.
TL;DR: Evidence is provided of very high D-dimer levels in patients with cancer who do not have VTE and malignancy, which suggests that elevated D-Dimer levelsIn patients with VTE are not solely due to presence of thrombus.
Abstract: Background D-dimers are used in conjunction with clinical probability scores in the assessment of venous thromboembolism (VTE), and they are elevated in other conditions, including malignancy, infection and arrhythmias. High levels of D-dimers in VTE are associated with adverse outcomes, including increased mortality. Their significance in patients without VTE has not previously been established. Aims To establish the clinical significance of elevated D-dimer levels in patients without VTE. Methods This prospective study included 2263 patient episodes of suspected deep vein thrombosis, which were excluded radiologically. Patients were followed up for survival and adverse events for a median of 22 months. Results D-dimer levels greater than 4000 ng FEU/ml (4.9% of patients), and greater than 8000 ng FEU/ml (1.8%) were associated with a reduced overall survival. D-dimer levels greater than 8000 ng FEU/ml and age over 60 years were independent poor prognostic factors for overall survival (p Conclusions This study provides evidence of very high D-dimer levels in patients with cancer who do not have VTE. This suggests that elevated D-dimer levels in patients with VTE and malignancy are not solely due to presence of thrombus. High D-dimer levels in malignancy are likely to reflect the biology of the underlying tumour, with higher levels observed in breast, prostate and bowel cancers.
TL;DR: The basaloid subtype of SCC, owing to its particular behaviour, should be systematically investigated along with HPV and smoking status, as those factors may be determinant in the response to treatment.
Abstract: Basaloid squamous cell carcinoma (BSCC) is a rare variant of squamous cell carcinoma (SCC) of the head and neck. Wain's criteria (peripheral palisading, association with SCC, high nuclear-cytoplasmic ratio, high mitotic rate, solid growth), anti-34BE12 and CK 5/6 staining, and absence of neuroendocrine markers are mandatory for the diagnosis of BSCC. Its increasing incidence parallels that of human papilloma virus (HPV)-positive tumours for the oropharyngeal subsite. On the other hand, BSCC is frequently considered a high-grade carcinoma of poorer prognosis than its SCC counterparts, mostly due to a higher rate of distant metastases. However, BSCC has similar or better locoregional control rates and a relatively better radiosensitivity than SCC. BSCC seems to have a dual behaviour depending, at least partly, on its recently described association with HPV. The basaloid subtype of SCC, owing to its particular behaviour, should be systematically investigated along with HPV and smoking status, as those factors may be determinant in the response to treatment.
TL;DR: After acute infections, enteroviruses can persist in patients resulting in manifestation of ME/CFS, and chronic enterovirus infection in an immunocompetent host may be an example of a stalemate between attenuated, intracellular viruses and an ineffective immune response.
Abstract: Aims Enteroviruses are well-known causes of acute respiratory and/or gastrointestinal infections and non-specific flu-like illness. Although enterovirus protein, RNA and non-cytopathic viruses have been demonstrated in the stomach biopsies of patients with myalgia encephalomyelitis/chronic fatigue syndrome (ME/CFS), causality for chronic diseases is difficult to establish without having well-documented cases of acute enterovirus infections. The aim of this study was to link acute enteroviral infection to viral persistence in patients with ME/CFS. Method Patients admitted to the hospital with acute febrile illnesses were screened for enteroviral infections. Acutely infected patients were followed longitudinally, and those who developed symptoms of ME/CFS underwent oesophagogastroduodenoscopy and biopsies of the antrum to document viral persistence by immunoperoxidase staining for viral protein and viral RNA assay. Results Three representative patients with different manifestations of acute enterovirus infections progressed to have chronic symptoms of ME/CFS. Persistent viral infection was demonstrated in the antrum years later. Conclusion After acute infections, enteroviruses can persist in patients resulting in manifestation of ME/CFS. Chronic enterovirus infection in an immunocompetent host may be an example of a stalemate between attenuated, intracellular viruses and an ineffective immune response.
TL;DR: Two adult patients with pre-existing primary antibody deficiency who presented with recurrent infections immediately following rituximab use for the treatment of refractory idiopathic thrombocytopenic purpura are described, suggesting that ritUXimab has accelerated the presentation of immune deficiency in these patients.
Abstract: Rituximab, an anti-CD20 chimeric antibody, is the first monoclonal agent to be used in the therapy of cancer. It has been hailed as one of the most important therapeutic developments of the decade. While transient peripheral B cell depletion is common after rituximab therapy, immunoglobulin levels are generally not affected. This is because CD20 is expressed on pre-B and mature B lymphocytes but not on stem cells or plasma cells. Two adult patients with pre-existing primary antibody deficiency who presented with recurrent infections immediately following rituximab use for the treatment of refractory idiopathic thrombocytopenic purpura (ITP) are described. Both were previously treated with various immunosuppressive agents without any notable infective problems. However, a few weeks after treatment with rituximab, these patients presented with clinically significant immunodeficiency requiring intravenous immunoglobulin replacement therapy. This striking temporal relationship between rituximab administration and onset of infections suggests that rituximab has accelerated the presentation of immune deficiency in these patients. Increased vigilance around the use of newer immunomodulatory agents such as rituximab is recommended.