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1.	Akgul, M, et al. (författare) Diagnostic approach in TFE3-rearranged renal cell carcinoma: a multi-institutional international survey 2021 Ingår i: Journal of clinical pathology. - : BMJ. - 1472-4146 .- 0021-9746. ; 74:5, s. 291-299 Tidskriftsartikel (refereegranskat)abstract Transcription factor E3-rearranged renal cell carcinoma (TFE3-RCC) has heterogenous morphologic and immunohistochemical (IHC) features.131 pathologists with genitourinary expertise were invited in an online survey containing 23 questions assessing their experience on TFE3-RCC diagnostic work-up.Fifty (38%) participants completed the survey. 46 of 50 participants reported multiple patterns, most commonly papillary pattern (almost always 9/46, 19.5%; frequently 29/46, 63%). Large epithelioid cells with abundant cytoplasm were the most encountered cytologic feature, with either clear (almost always 10/50, 20%; frequently 34/50, 68%) or eosinophilic (almost always 4/49, 8%; frequently 28/49, 57%) cytology. Strong (3+) or diffuse (>75% of tumour cells) nuclear TFE3 IHC expression was considered diagnostic by 13/46 (28%) and 12/47 (26%) participants, respectively. Main TFE3 IHC issues were the low specificity (16/42, 38%), unreliable staining performance (15/42, 36%) and background staining (12/42, 29%). Most preferred IHC assays other than TFE3, cathepsin K and pancytokeratin were melan A (44/50, 88%), HMB45 (43/50, 86%), carbonic anhydrase IX (41/50, 82%) and CK7 (32/50, 64%). Cut-off for positive TFE3 fluorescent in situ hybridisation (FISH) was preferably 10% (9/50, 18%), although significant variation in cut-off values was present. 23/48 (48%) participants required TFE3 FISH testing to confirm TFE3-RCC regardless of the histomorphologic and IHC assessment. 28/50 (56%) participants would request additional molecular studies other than FISH assay in selected cases, whereas 3/50 participants use additional molecular cases in all cases when TFE3-RCC is in the differential.Optimal diagnostic approach on TFE3-RCC is impacted by IHC and/or FISH assay preferences as well as their conflicting interpretation methods.
2.	Algaba, F, et al. (författare) Handling and reporting of nephrectomy specimens for adult renal tumours: a survey by the European Network of Uropathology 2012 Ingår i: Journal of clinical pathology. - : BMJ. - 1472-4146 .- 0021-9746. ; 65:2, s. 106-113 Tidskriftsartikel (refereegranskat)
3.	Ben-Yosef, Yaara, et al. (författare) The HemoScreen, a novel haematology analyser for the point of care 2016 Ingår i: Journal of Clinical Pathology. - : BMJ. - 0021-9746 .- 1472-4146. ; 69:8, s. 720-725 Tidskriftsartikel (refereegranskat)abstract BACKGROUND AND AIMS: A haematology analyser, based on a new technology, is presented herein. The analyser that provides a complete blood count (CBC) and five-part differential accepts disposable cartridges containing all required reagents, making it maintenance-free and ideal for point-of-care (POC) settings. The test reproducibility and imperviousness to analytical errors are attributed to the imaging-based analysis employed. Imaging enables cell-morphology-based differentiation, which is analogous to the gold standard microscopic analysis. This article presents the HemoScreen new technology and evaluates its performance through a small-scale study conducted in its designated clinical settings.METHODS: Thirty anticoagulated whole blood samples were analysed on the HemoScreen and Sysmex XE-2100. Linear regression was performed for the methods comparison. Two samples with 15 replicates were processed for imprecision. Ease of use of the device was also considered.RESULTS: The HemoScreen demonstrated acceptable imprecision and good agreement with the Sysmex XE-2100. The white blood cells (WBCs), red blood cells (RBCs), haemoglobin (HGB), haematocrit (HCT), platelets (PLT), neutrophils, lymphocytes and eosinophils have coefficients of correlation (r) >0.97. For mean cell volume (MCV), mean cell HGB (MCH) and RBC distribution width (RDW), r values ranged from 0.92 to 0.96. For mean cell HGB concentration (MCHC) and monocytes r=0.82 was demonstrated. User-friendliness and suitability of the device for operation in the designated POC settings was also confirmed.CONCLUSIONS: The HemoScreen employs innovative technologies of viscoelastic focusing and microfluidics within a disposable cartridge for an image-based blood cell analysis. By providing accurate and repeatable CBC and five-part differential results within minutes and maintaining the simplicity of operation, the HemoScreen could have far-reaching implications for use at POC. Further extended evaluation is in progress.
4.	Berglund, Pontus, et al. (författare) Cyclin E confers a prognostic value in premenopausal breast cancer patients with tumours exhibiting an infiltrative growth pattern 2008 Ingår i: Journal of Clinical Pathology. - : BMJ. - 0021-9746 .- 1472-4146. ; 61:2, s. 184-191 Tidskriftsartikel (refereegranskat)abstract Aims: To investigate the prognostic value of cyclin E in relation to tumour growth pattern by analysing stage II primary breast cancers from premenopausal women not subjected to any further adjuvant treatment. To analyse the value of cyclin E as a predictor of tamoxifen response, by comparing untreated and treated patients with oestrogen receptor positive tumours. Methods: Breast cancer samples, assembled in tissue microarrays, were immunohistochemically stained for cyclin E and evaluated regarding the presence of nuclear staining. The overall growth characteristics of each tumour were assessed using whole tissue sections. Results: Tumours displaying a pushing margin phenotype were strongly associated with high cyclin E levels, lymph node negative disease, a high histological grade and oestrogen receptor negativity, and exhibited a better prognosis compared to tumours with an infiltrative growth pattern. In the total cohort of non-treated patients (n = 187), cyclin E was not associated with recurrence free survival (RFS). However, when analysing the subgroup of tumours lacking a pushing growth pattern (n = 141), cyclin E was significantly associated with RFS, independent of histological grade and node status. There was no significant difference in tamoxifen response with regard to different cyclin E levels. Conclusion: The prognostic value of cyclin E in premenopausal breast cancer is limited to patients with breast carcinomas exhibiting an exclusively infiltrative growth pattern. This limitation could be explained by the presence of a small but distinct subgroup of cyclin E-high breast cancers with a pushing margin phenotype and a more favourable outcome.
5.	Borgquist, Signe, et al. (författare) Oestrogen receptors alpha and beta show different associations to clinicopathological parameters and their co-expression might predict a better response to endocrine treatment in breast cancer. 2008 Ingår i: Journal of Clinical Pathology. - : BMJ. - 1472-4146 .- 0021-9746. ; 61:2, s. 197-202 Tidskriftsartikel (refereegranskat)abstract AIMS: The majority of all breast cancers are hormone responsive, traditionally defined by the expression of oestrogen receptor (ER) alpha and/or progesterone receptors. In contrast to ERalpha, the clinical significance of the relatively recently identified ERbeta is still unclear. This study aimed to define the relationship between ERbeta and clinicopathological parameters in a mixed cohort of breast cancer and, furthermore, to investigate the impact of ERbeta expression on disease outcome. METHODS: The immunohistochemical expression of ERalpha and ERbeta was analysed in tissue microarrays containing a total number of 512 tumours with all incident breast cancers diagnosed at the Malmö University Hospital between 1988 and 1992. RESULTS: 78% of the tumours were ERalpha positive and 50% were ERbeta positive. ERbeta correlated positively with ERalpha (p = 0.001). In contrast to ERalpha, ERbeta was not associated with any important clinicopathological variables. Furthermore, no overall prognostic significance could be demonstrated for ERbeta. In the ERalpha-positive subgroup, however, a low expression of ERbeta correlated with a decreased disease-free survival in patients receiving endocrine treatment (p = 0.003). CONCLUSIONS: Although interrelated, ERalpha and ERbeta seem to be differentially associated to clinicopathological parameters, and this would support the fact that they might have different functions in vivo. Furthermore, ERbeta might be a predictive marker of response to endocrine therapy, although this needs to be confirmed in additional studies, preferably randomised trials.
6.	Burger, Gerard, et al. (författare) Natural language processing in pathology: a scoping review 2016 Ingår i: Journal of Clinical Pathology. - : BMJ PUBLISHING GROUP. - 0021-9746 .- 1472-4146. ; 69:11, s. 949-955 Forskningsöversikt (refereegranskat)abstract Background Encoded pathology data are key for medical registries and analyses, but pathology information is often expressed as free text. Objective We reviewed and assessed the use of NLP (natural language processing) for encoding pathology documents. Materials and methods Papers addressing NLP in pathology were retrieved from PubMed, Association for Computing Machinery (ACM) Digital Library and Association for Computational Linguistics (ACL) Anthology. We reviewed and summarised the study objectives; NLP methods used and their validation; software implementations; the performance on the dataset used and any reported use in practice. Results The main objectives of the 38 included papers were encoding and extraction of clinically relevant information from pathology reports. Common approaches were word/phrase matching, probabilistic machine learning and rule-based systems. Five papers (13%) compared different methods on the same dataset. Four papers did not specify the method(s) used. 18 of the 26 studies that reported F-measure, recall or precision reported values of over 0.9. Proprietary software was the most frequently mentioned category (14 studies); General Architecture for Text Engineering (GATE) was the most applied architecture overall. Practical system use was reported in four papers. Most papers used expert annotation validation. Conclusions Different methods are used in NLP research in pathology, and good performances, that is, high precision and recall, high retrieval/removal rates, are reported for all of these. Lack of validation and of shared datasets precludes performance comparison. More comparative analysis and validation are needed to provide better insight into the performance and merits of these methods.
7.	Carneiro, Ana, et al. (författare) Ezrin expression predicts local recurrence and development of metastases in soft tissue sarcomas. 2011 Ingår i: Journal of Clinical Pathology. - : BMJ. - 1472-4146 .- 0021-9746. ; 64, s. 689-694 Tidskriftsartikel (refereegranskat)abstract Background Ezrin is a cytoskeletal protein involved in tumour growth and invasion. Ezrin expression has been suggested to play a role in metastasis in paediatricosteosarcoma and rhabdomyosarcoma. Aim To evaluate the prognostic role of ezrin in a large series of soft tissue sarcoma of the extremities and trunk wall. Methods Ezrin expression was evaluated by immunohistochemistry on tissue microarrays from a mixed series of 256 soft tissue sarcomas. The expression patterns were correlated to local recurrence and metastasis as well as to established prognostic factors in soft tissue sarcoma. Results Increased ezrin expression predicted development of metastasis (HR=1.8, 95% CI 1.1 to 2.8; p=0.007) and local recurrence, also after adjustment for surgical margin (HR=2.4, 95% CI 1.4 to 4.3; p=0.02). Correlations to established prognostic factors showed strong associations between ezrin and necrosis (OR=3.9, p<0.0001) and ezrin and growth pattern (OR=3.1, p=0.03). Conclusions Ezrin independently predicts development of local recurrences and metastases in soft tissue sarcomas. The possibility of preoperative evaluation makes ezrin a potential marker for identification of high-risk sarcoma patients who would benefit from neoadjuvant therapy.
8.	Craven, Claudia Louise, et al. (författare) Lumbar drains can affect CSF biomarker levels. 2018 Ingår i: Journal of clinical pathology. - : BMJ. - 1472-4146 .- 0021-9746. ; 72:1 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
9.	Cree, I. A., et al. (författare) Guidance for laboratories performing molecular pathology for cancer patients 2014 Ingår i: Journal of Clinical Pathology. - : BMJ. - 0021-9746 .- 1472-4146. ; 67:11, s. 923-931 Tidskriftsartikel (refereegranskat)abstract Molecular testing is becoming an important part of the diagnosis of any patient with cancer. The challenge to laboratories is to meet this need, using reliable methods and processes to ensure that patients receive a timely and accurate report on which their treatment will be based. The aim of this paper is to provide minimum requirements for the management of molecular pathology laboratories. This general guidance should be augmented by the specific guidance available for different tumour types and tests. Preanalytical considerations are important, and careful consideration of the way in which specimens are obtained and reach the laboratory is necessary. Sample receipt and handling follow standard operating procedures, but some alterations may be necessary if molecular testing is to be performed, for instance to control tissue fixation. DNA and RNA extraction can be standardised and should be checked for quality and quantity of output on a regular basis. The choice of analytical method(s) depends on clinical requirements, desired turnaround time, and expertise available. Internal quality control, regular internal audit of the whole testing process, laboratory accreditation, and continual participation in external quality assessment schemes are prerequisites for delivery of a reliable service. A molecular pathology report should accurately convey the information the clinician needs to treat the patient with sufficient information to allow for correct interpretation of the result. Molecular pathology is developing rapidly, and further detailed evidence-based recommendations are required for many of the topics covered here.
10.	DaCosta, R. S., et al. (författare) Autofluorescence characterisation of isolated whole crypts and primary cultured human epithelial cells from normal, hyperplastic, and adenomatous colonic mucosa 2005 Ingår i: Journal of Clinical Pathology. - : BMJ. - 0021-9746 .- 1472-4146. ; 58:7, s. 766-774 Tidskriftsartikel (refereegranskat)abstract Background/Aims: In vivo autofluorescence endoscopic imaging and spectroscopy have been used to detect and differentiate benign ( hyperplastic) and preneoplastic ( adenomatous) colonic lesions. This fluorescence is composed of contributions from the epithelium, lamina propria, and submucosa. Because epithelial autofluorescence in normal and diseased tissues is poorly understood, this was the focus of the present study. Methods: Whole colonic crypts were isolated, and short term primary cultures of epithelial cells were established from biopsies of normal, hyperplastic, and adenomatous colon. Autofluorescence ( 488 nm excitation) was examined by confocal fluorescence microscopy. Fluorescently labelled organelle probes and transmission electron microscopy were used to identify subcellular sources of fluorescence. Results: Mitochondria and lysosomes were identified as the main intracellular fluorescent components in all cell types. Normal and hyperplastic epithelial cells were weakly autofluorescent and had similar numbers of mitochondria and lysosomes, whereas adenomatous ( dysplastic) epithelial cells showed much higher autofluorescence, and numerous highly autofluorescent lysosomal ( lipofuscin) granules. Conclusions: Short term primary cell cultures from endoscopic biopsies provide a novel model to understand differences in colonic tissue autofluorescence at the glandular ( crypt) and cellular levels. The differences between normal, hyperplastic, and adenomatous epithelial cells are attributed in part to differences in the intrinsic numbers of mitochondria and lysosomes. This suggests that the detection of colonic epithelial fluorescence alone, if possible, may be sufficient to differentiate benign ( hyperplastic) from preneoplastic and neoplastic ( adenomatous) colonic intramucosal lesions during in vivo fluorescence endoscopy. Furthermore, highly orange/red autofluorescent intracellular granules found only in dysplastic epithelial cells may serve as a potential biomarker.
11.	Dessauvagie, Benjamin F., et al. (författare) Interobserver variation in the diagnosis of fibroepithelial lesions of the breast: a multicentre audit by digital pathology 2018 Ingår i: Journal of Clinical Pathology. - : BMJ PUBLISHING GROUP. - 0021-9746 .- 1472-4146. ; 71:8, s. 672-679 Tidskriftsartikel (refereegranskat)abstract Aim Fibroepithelial lesions (FELs) of the breast span a morphological continuum including lesions where distinction between cellular fibroadenoma (FA) and benign phyllodes tumour (PT) is difficult. The distinction is clinically important with FAs managed conservatively while equivocal lesions and PTs are managed with surgery. We sought to audit core biopsy diagnoses of equivocal FELs by digital pathology and to investigate whether digital point counting is useful in clarifying FEL diagnoses. Method Scanned slide images from cores and subsequent excisions of 69 equivocal FELs were examined in a multicentre audit by eight pathologists to determine the agreement and accuracy of core needle biopsy (CNB) diagnoses and by digital point counting of stromal cellularity and expansion to determine if classification could be improved. Results Interobserver variation was high on CNB with a unanimous diagnosis from all pathologists in only eight cases of FA, diagnoses of both FA and PT on the same CNB in 15 and a weak mean kappa agreement between pathologists (k=0.36). Moderate agreement was observed on CNBs among breast specialists (k=0.44) and on excision samples (k=0.49). Up to 23% of lesions confidently diagnosed as FA on CNB were PT on excision and up to 30% of lesions confidently diagnosed as PT on CNB were FA on excision. Digital point counting did not aid in the classification of FELs. Conclusion Accurate and reproducible diagnosis of equivocal FELs is difficult, particularly on CNB, resulting in poor interobserver agreement and suboptimal accuracy. Given the diagnostic difficulty, and surgical implications, equivocal FELs should be reported in consultation with experienced breast pathologists as a small number of benign FAs can be selected out from equivocal lesions.
12.	Ericson Lindquist, Kajsa, et al. (författare) Difficulties in diagnostics of lung tumours in biopsies : an interpathologist concordance study evaluating the international diagnostic guidelines 2022 Ingår i: Journal of Clinical Pathology. - : BMJ Publishing Group Ltd. - 0021-9746 .- 1472-4146. ; 75:5, s. 302-309 Tidskriftsartikel (refereegranskat)abstract AIMS: Accurate and reliable diagnosis is essential for lung cancer treatment. The study aim was to investigate interpathologist diagnostic concordance for pulmonary tumours according to WHO diagnostic criteria.METHODS: Fifty-two unselected lung and bronchial biopsies were diagnosed by a thoracic pathologist based on a broad spectrum of immunohistochemical (IHC) stainings, molecular data and clinical/radiological information. Slides stained with H&E, thyroid transcription factor-1 (TTF-1) clone SPT24 and p40 were scanned and provided digitally to 20 pathologists unaware of reference diagnoses. The pathologists independently diagnosed the cases and stated if further diagnostic markers were deemed necessary.RESULTS: In 31 (60%) of the cases, ≥80% of the pathologists agreed with each other and with the reference diagnosis. Lower agreement was seen in non-small cell neuroendocrine tumours and in squamous cell carcinoma with diffuse TTF-1 positivity. Agreement with the reference diagnosis ranged from 26 to 45 (50%-87%) for the individual pathologists. The pathologists requested additional IHC staining in 15-44 (29%-85%) of the 52 cases. In nearly half (17 of 36) of the malignant cases, one or more pathologist advocated for a different final diagnosis than the reference without need of additional IHC markers, potentially leading to different clinical treatment.CONCLUSIONS: Interpathologist diagnostic agreement is moderate for small unselected bronchial and lung biopsies based on a minimal panel of markers. Neuroendocrine morphology is sometimes missed and TTF-1 clone SPT24 should be interpreted with caution. Our results suggest an intensified education need for thoracic pathologists and a more generous use of diagnostic IHC markers.
13.	Feakins, R, et al. (författare) Survey of UK histopathologists' approach to the reporting of resection specimens for carcinomas of the pancreatic head 2013 Ingår i: Journal of clinical pathology. - : BMJ. - 1472-4146 .- 0021-9746. ; 66:8, s. 715-717 Tidskriftsartikel (refereegranskat)
14.	Fiore, Christopher, et al. (författare) Utility of multispectral imaging in automated quantitative scoring of immunohistochemistry 2012 Ingår i: Journal of Clinical Pathology. - London, United Kingdom : BMJ Publishing Group Ltd. - 0021-9746 .- 1472-4146. ; 65:6, s. 496-502 Tidskriftsartikel (refereegranskat)abstract Background: Automated scanning devices and image analysis software provide a means to overcome the limitations of manual semiquantitative scoring of immunohistochemistry. Common drawbacks to automated imaging systems include an inability to classify tissue type and an inability to segregate cytoplasmic and nuclear staining.Methods: Immunohistochemistry for the membranous marker a-catenin, the cytoplasmic marker stathmin and the nuclear marker Ki-67 was performed on tissue microarrays (TMA) of archival formalin-fixed paraffin-embedded tissue comprising 471 (alpha-catenin and stathmin) and 511 (Ki-67) cases of prostate adenocarcinoma. These TMA were quantitatively analysed using two commercially available automated image analysers, the Ariol SL-50 system and the Nuance system from CRi. Both systems use brightfield microscopy for automated, unbiased and standardised quantification of immunohistochemistry, while the Nuance system has spectral deconvolution capabilities. Results Overall concordance between scores from both systems was excellent (r=0.90; 0.83-0.95). The software associated with the multispectral imager allowed accurate automated classification of tissue type into epithelial glandular structures and stroma, and a single-step segmentation of staining into cytoplasmic or nuclear compartments allowing independent evaluation of these areas. The Nuance system, however, was not able to distinguish reliably between tumour and non-tumour tissue. In addition, variance in the labour and time required for analysis between the two systems was also noted.Conclusion: Despite limitations, this study suggests some beneficial role for the use of a multispectral imaging system in automated analysis of immunohistochemistry.
15.	Flach, RN, et al. (författare) Use of the ISUP e-learning module improves interrater reliability in prostate cancer grading 2024 Ingår i: Journal of clinical pathology. - : BMJ. - 1472-4146 .- 0021-9746. ; 77:1, s. 22-26 Tidskriftsartikel (refereegranskat)abstract Prostate cancer (PCa) grading is an important prognostic parameter, but is subject to considerable observer variation. Previous studies have shown that interobserver variability decreases after participants were trained using an e-learning module. However, since the publication of these studies, grading of PCa has been enhanced by adopting the International Society of Urological Pathology (ISUP) 2014 grading classification. This study investigates the effect of training on interobserver variability of PCa grading, using the ISUP Education web e-learning on Gleason grading.MethodsThe ISUP Education Prostate Test B Module was distributed among Dutch pathologists. The module uses images graded by the ISUP consensus panel consisting of 24 expert uropathologists. Participants graded the same 10 images before and after e-learning. We included those who completed the tests before and after training. We evaluated variation in PCa grading in a fully crossed study design, using linearly weighted kappa values for each pathologist, comparing them to other pathologists and to the ISUP consensus panel. We analysed the improvement in median weighted kappas before and after training, using Wilcoxon’s signed rank-test.ResultsWe included 42 pathologists. Inter-rater reliability between pathologists improved from 0.70 before training to 0.74 after training (p=0.01). When compared with the ISUP consensus panel, five pathologists improved significantly, whereas the kappa of one pathologist was significantly lower after training. All pathologists who improved significantly, graded with less than substantial agreement before training.ConclusionsISUP Prostate Test B e-learning reduces variability in PCa grading. E-learning is a cost-effective method for standardisation of pathology.
16.	Gräns, Hanna, et al. (författare) Reduced levels of oestrogen receptor beta mRNA in Swedish patients with chronic fatigue syndrome. 2007 Ingår i: Journal of Clinical Pathology. - : BMJ. - 0021-9746 .- 1472-4146. ; 60:2, s. 195-8 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: Chronic fatigue syndrome (CFS) is an illness with unknown aetiology and pathophysiology. The difference in incidence by sex observed for CFS indicates a role for oestrogen and oestrogen receptors in disease development. Furthermore, an immunomediated pathogenesis has been suggested for CFS, providing an additional connection to oestrogen, which displays immunomodular functions. AIMS: To investigate a possible association of oestrogen receptor (ER) mRNAs and two ERbeta single-nucleotide polymorphisms (SNPs) with CFS. METHODS: Messenger RNA levels of ERalpha, ERbeta wt and ERbeta cx were investigated in peripheral blood mononuclear cells from 30 patients with CFS and 36 healthy controls by quantitative real-time polymerase chain reaction. Two ERbeta SNPs were scored in the same material. RESULTS: The CFS group showed significantly lower mRNA expression levels of ERbeta wt compared with the healthy control group. No differences were observed for ERalpha or ERbeta cx between patients and controls. There were no significant differences in frequency for the investigated ERbeta SNPs between cases and controls. CONCLUSIONS: The reduced ERbeta wt expression level observed in this study is consistent with an immune-mediated pathogenesis of CFS. Additionally, the observation that ERbeta wt expression is decreased in CFS could provide an entry point to identify interesting, potentially disease-causing, candidate molecules for further study. A possible connection between oestrogen, oestrogen receptors and CFS should be evaluated further.
17.	Gulyas, Miklos, et al. (författare) Use of cholesterol and soluble tumour markers CEA and syndecan-2 in pleural effusions in cases of inconclusive cytology 2019 Ingår i: Journal of Clinical Pathology. - : BMJ PUBLISHING GROUP. - 0021-9746 .- 1472-4146. ; 72:8, s. 529-535 Tidskriftsartikel (refereegranskat)abstract Aims In order to improve diagnostics in pleural effusions, additional value of effusion cholesterol, carcinoembryonic antigen (CEA) and syndecan-2 assays to cytology was studied. Methods Biomarkers were measured in effusion supernatants from 247 patients, of whom 126 had malignant pleural involvement, and their additional diagnostic efficacy to cytology was assessed. Results Syndecan-2 measurement, although gave detectable concentrations in all effusions with highest median value in mesotheliomas, was non-discriminative between different pathological conditions. CEA concentrations exceeding 5 ng/mL cut-off point indicated carcinomas, regardless of pleural involvement, which gave a sensitivity of 62% and specificity of 100% for carcinoma. Cholesterol concentration over 1.21 mmol/L cut-off value indicated neoplastic pleural involvement with 99% sensitivity and 'merely' 69% specificity, the latter mainly due to raised levels being associated also with benign inflammatory effusions. Combined CEA and cholesterol determinations increased the sensitivity for diagnosing carcinomatosis from 70% with cytology alone to 84% and established the correct diagnosis in 16 of 31 carcinomatosis cases with inconclusive cytology. Cholesterol measurement alone, with elevated level, in combination with absence of substantial number of inflammatory cells in effusion sediment proved to be a magnificent marker for neoplastic pleural involvement with 99% efficacy, and recognised all 36 such cases with inconclusive cytology. Conclusions Simultaneous measurement of CEA and cholesterol concentrations in effusion, or at least cholesterol alone, in combination with non-inflammatory fluid cytology, provides additional specific information about neoplastic pleural involvement, and can therefore be used as an adjunct to cytology, above all, in inconclusive cases.
18.	Haeggblom, L, et al. (författare) Human polyomavirus DNA detection in keratoacanthoma and Spitz naevus: no evidence for a causal role 2017 Ingår i: Journal of clinical pathology. - : BMJ. - 1472-4146 .- 0021-9746. ; 70:5, s. 451-453 Tidskriftsartikel (refereegranskat)
19.	Halvarsson, Britta, et al. (författare) Phenotypic heterogeneity in hereditary nonpolyposis colorectal cancer: identical germline mutations associated with variable tumor morphology and immunohistochemical expression. 2007 Ingår i: Journal of Clinical Pathology. - : BMJ. - 1472-4146 .- 0021-9746. ; 60:7, s. 781-786 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: Hereditary non-polyposis colorectal cancer (HNPCC) is associated with high risks for colorectal and endometrial cancer, young age at onset and an increased risk of multiple primary tumours. Colorectal cancer in HNPCC is characterised by poor tumour differentiation, an expanding growth pattern, and a pronounced lymphocytic reaction with tumour-infiltrating lymphocytes. Aims and METHODS: The mutation spectrum in HNPCC is diverse and in order to clarify whether the HNPCC tumour phenotype is influenced by the underlying genetic alteration, 29 colorectal cancers and 12 adenomas from 24 individuals in two HNPCC families were morphologically and immunohistochemically characterised. RESULTS: The tumour morphology as well as the immunohistochemical expression of beta-catenin varied extensively within the families as well as between synchronous/metachronous colorectal cancers from the same individual. Poor tumour differentiation, an expanding growth pattern, and tumour-infiltrating lymphocytes occurred at higher frequencies in proximal tumours, whereas distal colorectal cancers often lacked distinct HNPCC-associated morphological features. CONCLUSIONS: The clinical, morphological and immunohistochemical variability observed within these families indicates that other mechanisms than the underlying germline mutation influence the HNPCC phenotype. Since morphological features linked to HNPCC are less frequent in distal cancers, it may be particularly relevant to obtain family history and age of onset in these tumours in order to identify individuals with HNPCC.
20.	Hedner, Charlotta, et al. (författare) Expression and prognostic significance of human epidermal growth factor receptors 1, 2 and 3 in oesophageal and gastric adenocarcinomas preneoadjuvant and postneoadjuvant treatment 2018 Ingår i: Journal of Clinical Pathology. - : BMJ. - 1472-4146 .- 0021-9746. ; 71:5, s. 451-462 Tidskriftsartikel (refereegranskat)abstract AIMS: Neoadjuvant treatment has now become the standard of care for oesophageal and gastric cancer. The aim of this study was to investigate the influence of neoadjuvant therapy on the expression of human epidermal growth factor receptor 1 (HER1/EGFR), HER2 and HER3, in oesophageal and gastric adenocarcinoma.METHODS: Immunohistochemical expression of EGFR, HER2 and HER3 was examined and compared in pretreatment biopsies, post-treatment surgical resection specimens and metastases in a retrospective cohort of 166 patients with adenocarcinoma of the oesophagus or stomach. The relationship between expression of the investigative markers and histopathological response to neoadjuvant treatment, overall survival (OS) and recurrence free survival (RFS) was analysed.RESULTS: Conversion of protein expression between pretreatment biopsy and post-treatment surgical resection was seen in 4.6% of the cases for EGFR, 5.9% for HER2% and 19.4% for HER3. Histopathological response to neoadjuvant treatment was significantly and stepwise associated with OS and RFS . High HER3 protein expression in post-treatment surgical resection specimens was significantly associated with a prolonged OS in univariable analysis (HR=0.39; 95% CI 0.17 to 0.93), but did not remain significant in multivariable analysis. Expression of EGFR and HER2 in post-treatment surgical resection specimens was not prognostic. No correlation between pretreatment HER-protein expression and histopathological response was seen.CONCLUSIONS: The results from this study underscore the need for further studies on the influence of neoadjuvant treatment on biomarker expression, as this may influence treatment strategy as well as prognosis. Histopathological response is validated as a useful prognostic factor.
21.	Hellgren, LS, et al. (författare) Nuclear-specific accumulation of telomerase reverse transcriptase (TERT) mRNA in TERT promoter mutated follicular thyroid tumours visualised by in situ hybridisation: a possible clinical screening tool? 2022 Ingår i: Journal of clinical pathology. - : BMJ. - 1472-4146 .- 0021-9746. ; 75:10, s. 658-662 Tidskriftsartikel (refereegranskat)abstract Upregulation of the telomerase reverse transcriptase (TERT) gene is a frequent finding in follicular thyroid carcinomas (FTCs) with metastatic features. The augmented expression is usually caused by TERT promoter mutations. As TERT protein immunohistochemistry might not correlate to TERT mRNA levels in follicular thyroid tumours, we therefore sought to determine if visualisation of TERT mRNA through in situ hybridisation could highlight high-risk cases.MethodsWe collected formalin-fixated paraffin-embedded tissues from 26 follicular thyroid tumours; 7 FTCs, 2 follicular thyroid tumours of uncertain malignant potential (FT-UMPs) and a single Hürthle cell carcinoma with established TERT promoter mutations and gene expression, as well as 16 FTCs with no TERT gene aberrancy or gene expression, and assessed them using RNA Scope in situ hybridisation (ISH) and TERT probes targeting the two main TERT transcripts (TERT1 and TERT2).ResultsTERT 1 and/or 2 mRNA was found by ISH in 8/10 cases with established promoter mutations and mRNA expression, whereas all 16 cases without TERT gene aberrancies or gene expression were negative (Fisher’s exact p<0.001). Strikingly, TERT mRNA was visualised in the nuclear compartment only, thereby corroborating earlier studies suggesting a non-conventional role for TERT in tumour biology. Moreover, TERT mRNA expression was scattered across the tissue sections and only found in a few percentages of tumour nuclei.ConclusionsTERT mRNA seems to be focally expressed and localised exclusively to the nucleus in TERT promoter mutated follicular thyroid tumours, possibly reflecting a true biological and unorthodox phenomenon worthy of further investigations.
22.	Henriksson, Anders E., et al. (författare) Neuroendocrine tumour cells in the wall of a splenic artery aneurysm 2007 Ingår i: Journal of Clinical Pathology. - : BMJ. - 0021-9746 .- 1472-4146. ; 60:7, s. 837-838 Tidskriftsartikel (refereegranskat)abstract Neuroendocrine tumours are reported from the alimentary and respiratory tracts. A case of a 57-year-old man with an unsuspected histopathological finding of neuroendocrine tumour cells in the wall of a splenic artery aneurysm is reported. Visceral artery aneurysms are uncommon but clinically important owing to the risk of rupture and of intra-abdominal bleeding.1 There are several possible aetiologies, atherosclerosis being one, and often the cause is unknown or at least not stated.1 The case of a patient with two visceral artery aneurysms and unsuspected histopathological finding is reported.
23.	Jatta, Ken, et al. (författare) Overexpression of von Hippel-Lindau protein in skeletal muscles of patients with chronic obstructive pulmonary disease 2009 Ingår i: Journal of Clinical Pathology. - London : BMJ Publishing Group Ltd. - 0021-9746 .- 1472-4146. ; 62:1, s. 70-76 Tidskriftsartikel (refereegranskat)abstract Background/aim: A Significant number of patients with chronic obstructive pulmonary disease (COPD) exhibit skeletal muscle wasting and decreased capillary area formation which have been correlated to increased mortality. The current study aimed to determine the molecular mechanisms mediating decreased capillary formation in COPD.Methods: Twenty-four COPD patients and twelve matching controls were recruited. COPD patients were divided into mild, moderate and severe groups according to GOLD (Global Initiative for Chronic Obstructive Lung Disease) criteria. Skeletal muscle biopsies were obtained from the tibialis anterior muscle. Fibre typing and capillary formation together with messenger RNA (mRNA) expression of hypoxia-inducible factors (HIF-1á and HIF-3á ), vascular endothelial growth factors (VEGF-A, -B and -C isoforms) and von Hippel Lindau (VHL) were determined. VHL expression and localization was further studied by immunohistochemistry.Results: Skeletal muscle capillary formation was significantly decreased with ascending disease severity. Compared to controls, a tendency to mRNA overexpression of HIF-1á, HIF-3á and VEGF isoforms was observed at mild and moderate COPD that decreased at the severe stage. By contrast, skeletal muscle biopsies from COPD patients exhibited significant overexpression of VHL both on the mRNA and protein levels by immunohistochemistry. VHL protein was further determined to be localized to satellite cells.Conclusions: Overexpression of VHL was identified in the skeletal muscle of patients with COPD. Increased VHL activity may exert a negative impact on transducing the hypoxic signal and may contribute to decreased capillarization in skeletal muscles of patients with COPD.
24.	Jirström, Karin, et al. (författare) Pathology parameters and adjuvant tamoxifen response in a randomised premenopausal breast cancer trial 2005 Ingår i: Journal of Clinical Pathology. - : BMJ. - 0021-9746 .- 1472-4146. ; 58:11, s. 1135-1142 Tidskriftsartikel (refereegranskat)abstract Background: Subgroups of breast cancer that have an impaired response to endocrine treatment, despite hormone receptor positivity, are still poorly defined. Breast cancer can be subdivided according to standard pathological parameters including histological type, grade, and assessment of proliferation. These parameters are the net result of combinations of genetic alterations effecting tumour behaviour and could potentially reflect subtypes that respond differently to endocrine treatment.Aims: To investigate the usefulness of these parameters as predictors of the response to tamoxifen in premenopausal women with breast cancer.Materials/methods: Clinically established pathological parameters were assessed and related to the tamoxifen response in 500 available tumour specimens from 564 premenopausal patients with breast cancer randomised to either two years of tamoxifen or no treatment with 14 years of follow up. Proliferation was further evaluated by immunohistochemical Ki-67 expression.Results: Oestrogen receptor positive ductal carcinomas responded as expected to tamoxifen, whereas the difference in recurrence free survival between control and tamoxifen treated patients was less apparent in the relatively few lobular carcinomas. For histological grade, there was no obvious difference in treatment response between the groups. The relation between proliferation and tamoxifen response seemed to be more complex, with a clear response in tumours with high and low proliferation, whereas tumours with intermediate proliferation defined by Ki-67 responded more poorly.Conclusions: Clinically established pathology parameters seem to mirror the endocrine treatment response and could potentially be valuable in future treatment decisions for patients with breast cancer.
25.	Jones, A Wayne, 1945-, et al. (författare) Uncertainty in estimating blood ethanol concentrations by analysis of vitreous humour 2001 Ingår i: Journal of Clinical Pathology. - 0021-9746 .- 1472-4146. ; 54:9, s. 699-702 Tidskriftsartikel (refereegranskat)abstract Aims - To determine the concentrations of ethanol in femoral venous blood (FVB) and vitreous humour (VH) obtained during forensic necropsies. The ratios of ethanol concentrations in VH and FVB, the reference interval, and the associated confidence limits were calculated to provide information about the uncertainty in estimating FVB ethanol concentrations indirectly from that measured in VH. Methods - Ethanol concentrations were determined in specimens of FVB and VH obtained from 706 forensic necropsies. The specimens were analysed in duplicate by headspace gas chromatography (HS-GC), with a precision (coefficient of variation) of 1.5% at a mean ethanol concentration of 500 mg/litre. The limit of detection of ethanol in body fluids by HS-GC in routine casework was 100 mg/litre. Results - In 34 instances, ethanol was present in VH at a mean concentration of 154 mg/litre, whereas the FVB ethanol concentration was reported as negative (< 100 mg/litre). These cases were excluded from the statistical analysis. The concentration of ethanol in FVB was higher than in VH in 93 instances, with a mean difference of 160 mg/litre (range 0 to 900). The mean concentration of ethanol in FVB (n = 672) was 1340 mg/litre (SD, 990) compared with 1580 mg/litre (SD, 1190) in VH. The arithmetic mean VH/FVB ratio of ethanol was 1.19 (SD, 0.285) and the 95% range was 0.63 to 1.75. The mean and SD of the differences (log VH - log FVB) was 0.063 (SD, 0.109), which gives 95% limits of agreement (LOA) from -0.149 to 0.276. Transforming back to the original scale of measurement gives a geometric mean VH/FVB ratio of 1.16 and 95% LOA from 0.71 to 1.89. These parametric estimates are in good agreement, with a median VH/FVB ratio of 1.18 and 2.5th and 97.5th centiles of 0.63 and 1.92. Conclusions - The ethanol distribution ratios (VH/FVB) show wide variation and this calls for caution when results of analysing VH at necropsy are used to estimate the concentration in FVB. Dividing the ethanol concentration in VH by 2.0 would provide a very conservative estimate of the ethanol content in FVB, being less than the true value, with a high degree of confidence.
26.	Kallner, A (författare) Estimated GFR. Comparison of five algorithms:implications for drug dosing 2014 Ingår i: Journal of clinical pathology. - : BMJ. - 1472-4146 .- 0021-9746. ; 67:7, s. 609-613 Tidskriftsartikel (refereegranskat)
27.	Klarskov, Louise, et al. (författare) Hereditary colorectal cancer diagnostics: morphological features of familial colorectal cancer type X versus Lynch syndrome 2012 Ingår i: Journal of Clinical Pathology. - : BMJ. - 1472-4146 .- 0021-9746. ; 65:4, s. 352-356 Tidskriftsartikel (refereegranskat)abstract Background The hereditary non-polyposis colorectal cancer (HNPCC) subset of tumours can broadly be divided into tumours caused by an underlying mismatch-repair gene mutation, referred to as Lynch syndrome, and those that develop in families with similar patterns of heredity but without disease-predisposing germline mismatch repair mutations, referred to as familial colorectal cancer type X (FCCTX). Recognition of HNPCC-associated colorectal cancers is central since surveillance programmes effectively reduce morbidity and mortality. The characteristic morphological features linked to Lynch syndrome can aid in the identification of this subset, whereas the possibility to use morphological features as an indicator of FCCTX is uncertain. Objective and methods To perform a detailed morphological evaluation of HNPCC-associated colorectal cancers and demonstrate significant differences between tumours associated with FCCTX and Lynch syndrome. Results The morphological features associated with Lynch syndrome, that is, right-sided tumour location, poor differentiation, expansive growth pattern, tumour-infiltrating lymphocytes, peritumorous lymphocytes, Crohn-like reactions, and lack of dirty necrosis, were significantly less often observed in FCCTX tumours. Discussion The less typical morphology in FCCTX implies that family history of cancer needs to be taken into account since these tumours cannot readily be recognised based on histopathological features.
28.	Lawson, J S, et al. (författare) Presence of mouse mammary tumour-like virus gene sequences may be associated with morphology of specific human breast cancer 2006 Ingår i: Journal of Clinical Pathology. - : BMJ. - 1472-4146 .- 0021-9746. ; 59:12, s. 1287-1292 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: Mouse mammary tumour virus (MMTV) has a proven role in breast carcinogenesis in wild mice and genetically susceptible in-bred mice. MMTV-like env gene sequences, which indicate the presence of a replication-competent MMTV-like virus, have been identified in some human breast cancers, but rarely in normal breast tissues. However, no evidence for a causal role of an MMTV-like virus in human breast cancer has emerged, although there are precedents for associations between specific histological characteristics of human cancers and the presence of oncogenic viruses. AIM: To investigate the possibility of an association between breast cancer and MMTV-like viruses. METHODS: Histological characteristics of invasive ductal human breast cancer specimens were compared with archival MMTV-associated mammary tumours from C3H experimental mice. The presence of MMTV-like env DNA sequences in the human breast cancer specimens was determined by polymerase chain reaction and confirmed by Southern hybridisation. RESULTS: MMTV-like env gene sequences were identified in 22 of 59 (37.3%) human breast cancer specimens. Seventeen of 43 (39.5%) invasive ductal carcinoma breast cancer specimens and 4 of 16 (25%) ductal carcinoma in situ specimens had some histological characteristics, which were similar to MMTV-associated mouse mammary tumours. However, these similarities were not associated with the presence or absence of MMTV-like gene sequences in the human breast tumour specimens. A significant (p = 0.05) correlation was found between the grade of the human breast cancer and similarity to the mouse mammary tumours. The lower the grade, the greater the similarity. CONCLUSION: Some human breast cancer specimens, in which MMTV-like env DNA sequences have been identified, were shown to have histological characteristics (morphology) similar to MMTV-associated mouse mammary tumours. These observations are compatible with, but not conclusive of, an association between the presence of MMTV-like env DNA sequences and some human breast cancers.
29.	Lin, YB, et al. (författare) Telomerase promoter mutations and copy number alterations in solitary fibrous tumours 2018 Ingår i: Journal of clinical pathology. - : BMJ. - 1472-4146 .- 0021-9746. ; 71:9, s. 832-839 Tidskriftsartikel (refereegranskat)abstract Solitary fibrous tumour (SFT) is an infrequently metastasising mesenchymal tumour defined by the NAB2–STAT6 fusion gene. Activating mutations in the telomerase reverse transcriptase (hTERT) gene promoter has been reported to associate with adverse patient outcome in SFTs.MethodsWe analysed the hTERT gene for promoter mutations and copy number alterations in 43 primary extrameningeal SFTs (9 malignant and 34 benign tumours according to WHO 2013 criteria), six local recurrences and three metastatic lesions.ResultsActivating −124 C>T (n=12) or −148 C>T (n=2) mutations were found in 33% of the tumours and associated with older age (P=0.006), necrosis (P=0.009), higher mitotic rate (P=0.003), nuclear atypia (P=0.002), malignant histological diagnosis (P=0.04) and worse progression-free survival (P=0.023). We also observed frequent (24%) hTERT promoter mutations in histologically benign tumours without metastasis (mean follow-up >9 years), and in 14%–18% of low-risk SFTs as determined by three risk-stratification models. Mutations were seen in 2/6 metastatic tumours and metastatic lesions. hTERT copy number gain was seen in 11/28 hTERT promoter wild-type cases.ConclusionsActivating hTERT promoter mutations associate with aggressive histopathological features, indicating a role in tumour progression. Given the comparatively high prevalence of hTERT promoter mutations in low-risk and non-metastasising lesions, further studies are required to clarify the prognostic value of hTERT promoter analysis before implementing the analysis in clinical diagnostics.
30.	Linder, Nina, et al. (författare) Deep learning for detecting tumour-infiltrating lymphocytes in testicular germ cell tumours 2019 Ingår i: Journal of Clinical Pathology. - : BMJ Publishing Group Ltd. - 0021-9746 .- 1472-4146. ; 72:2, s. 157-164 Tidskriftsartikel (refereegranskat)abstract AIMS: To evaluate if a deep learning algorithm can be trained to identify tumour-infiltrating lymphocytes (TILs) in tissue samples of testicular germ cell tumours and to assess whether the TIL counts correlate with relapse status of the patient.METHODS: TILs were manually annotated in 259 tumour regions from 28 whole-slide images (WSIs) of H&E-stained tissue samples. A deep learning algorithm was trained on half of the regions and tested on the other half. The algorithm was further applied to larger areas of tumour WSIs from 89 patients and correlated with clinicopathological data.RESULTS: A correlation coefficient of 0.89 was achieved when comparing the algorithm with the manual TIL count in the test set of images in which TILs were present (n=47). In the WSI regions from the 89 patient samples, the median TIL density was 1009/mm2. In seminomas, none of the relapsed patients belonged to the highest TIL density tertile (>2011/mm2). TIL quantifications performed visually by three pathologists on the same tumours were not significantly associated with outcome. The average interobserver agreement between the pathologists when assigning a patient into TIL tertiles was 0.32 (Kappa test) compared with 0.35 between the algorithm and the experts, respectively. A higher TIL density was associated with a lower clinical tumour stage, seminoma histology and lack of lymphovascular invasion.CONCLUSIONS: Deep learning-based image analysis can be used for detecting TILs in testicular germ cell cancer more objectively and it has potential for use as a prognostic marker for disease relapse.
31.	Madrigal, Irene, et al. (författare) Efficient application of next-generation sequencing for the diagnosis of rare genetic syndromes 2014 Ingår i: Journal of Clinical Pathology. - : BMJ. - 0021-9746 .- 1472-4146. ; 67:12, s. 1099-1103 Tidskriftsartikel (refereegranskat)abstract Aims The causes of intellectual disability, which affects 1%-3% of the general population, are highly heterogeneous and the genetic defect remains unknown in around 40% of patients. The application of next-generation sequencing is changing the nature of biomedical diagnosis. This technology has quickly become the method of choice for searching for pathogenic mutations in rare uncharacterised genetic diseases. Methods Whole-exome sequencing was applied to a series of families affected with intellectual disability in order to identify variants underlying disease phenotypes. Results We present data of three families in which we identified the disease-causing mutations and which benefited from receiving a clinical diagnosis: Cornelia de Lange, Cohen syndrome and Dent-2 disease. The genetic heterogeneity and the variability in clinical presentation of these disorders could explain why these patients are difficult to diagnose. Conclusions The accessibility to next-generation sequencing allows clinicians to save much time and cost in identifying the aetiology of rare diseases. The presented cases are excellent examples that demonstrate the efficacy of next-generation sequencing in rare disease diagnosis.
32.	Malapelle, Umberto, et al. (författare) Predictive molecular pathology in the time of coronavirus disease (COVID-19) in Europe 2021 Ingår i: Journal of Clinical Pathology. - : BMJ. - 0021-9746 .- 1472-4146. ; 74:6, s. 391-395 Tidskriftsartikel (refereegranskat)abstract Aims Lung cancer predictive biomarker testing is essential to select advanced-stage patients for targeted treatments and should be carried out without delays even during health emergencies, such as the coronavirus (COVID-19) outbreak. Methods Fifteen molecular laboratories from seven different European countries compared 4 weeks of national lockdown to a corresponding period in 2019, in terms of tissue and/or plasma-based molecular test workload, analytical platforms adopted, number of cases undergoing programmed death-ligand1 (PD-L1) expression assessment and DNA-based molecular tests turnaround time. Results In most laboratories (80.0%), tissue-based molecular test workload was reduced. In 40.0% of laboratories (6/15), the decrease was >25%, and in one, reduction was as high as 80.0%. In this instance, a concomitant increase in liquid biopsy was reported (60.0%). Remarkably, in 33.3% of the laboratories, real-time PCR (RT-PCR)-based methodologies increased, whereas highly multiplexing assays approaches decreased. Most laboratories (88.9%) did not report significant variations in PD-L1 volume testing. Conclusions The workload of molecular testing for patients with advanced-stage lung cancer during the lockdown showed little variations. Local strategies to overcome health emergency-related issues included the preference for RT-PCR tissue-based testing methodologies and, occasionally, for liquid biopsy.
33.	Malapelle, Umberto, et al. (författare) Reference standards for gene fusion molecular assays on cytological samples : an international validation study 2023 Ingår i: Journal of Clinical Pathology. - : BMJ. - 0021-9746 .- 1472-4146. ; 76:1, s. 47-52 Tidskriftsartikel (refereegranskat)abstract Aims Gene fusions assays are key for personalised treatments of advanced human cancers. Their implementation on cytological material requires a preliminary validation that may make use of cell line slides mimicking cytological samples. In this international multi-institutional study, gene fusion reference standards were developed and validated. Methods Cell lines harbouring EML4(13)–ALK(20) and SLC34A2(4)–ROS1(32) gene fusions were adopted to prepare reference standards. Eight laboratories (five adopting amplicon-based and three hybridisation-based platforms) received, at different dilution points two sets of slides (slide A 50.0%, slide B 25.0%, slide C 12.5% and slide D wild type) stained by Papanicolaou (Pap) and May Grunwald Giemsa (MGG). Analysis was carried out on a total of 64 slides. Results Four (50.0%) out of eight laboratories reported results on all slides and dilution points. While 12 (37.5%) out of 32 MGG slides were inadequate, 27 (84.4%) out of 32 Pap slides produced libraries adequate for variant calling. The laboratories using hybridisation-based platforms showed the highest rate of inadequate results (13/24 slides, 54.2%). Conversely, only 10.0% (4/40 slides) of inadequate results were reported by laboratories adopting amplicon-based platforms. Conclusions Reference standards in cytological format yield better results when Pap staining and processed by amplicon-based assays. Further investigation is required to optimise these standards for MGG stained cells and for hybridisation-based approaches.
34.	McGenity, Clare, et al. (författare) Survey of liver pathologists to assess attitudes towards digital pathology and artificial intelligence 2023 Ingår i: Journal of Clinical Pathology. - : BMJ PUBLISHING GROUP. - 0021-9746 .- 1472-4146. Tidskriftsartikel (refereegranskat)abstract AimsA survey of members of the UK Liver Pathology Group (UKLPG) was conducted, comprising consultant histopathologists from across the UK who report liver specimens and participate in the UK National Liver Pathology External Quality Assurance scheme. The aim of this study was to understand attitudes and priorities of liver pathologists towards digital pathology and artificial intelligence (AI). MethodsThe survey was distributed to all full consultant members of the UKLPG via email. This comprised 50 questions, with 48 multiple choice questions and 2 free-text questions at the end, covering a range of topics and concepts pertaining to the use of digital pathology and AI in liver disease. ResultsForty-two consultant histopathologists completed the survey, representing 36% of fully registered members of the UKLPG (42/116). Questions examining digital pathology showed respondents agreed with the utility of digital pathology for primary diagnosis 83% (34/41), second opinions 90% (37/41), research 85% (35/41) and training and education 95% (39/41). Fatty liver diseases were an area of demand for AI tools with 80% in agreement (33/41), followed by neoplastic liver diseases with 59% in agreement (24/41). Participants were concerned about AI development without pathologist involvement 73% (30/41), however, 63% (26/41) disagreed when asked whether AI would replace pathologists. ConclusionsThis study outlines current interest, priorities for research and concerns around digital pathology and AI for liver pathologists. The majority of UK liver pathologists are in favour of the application of digital pathology and AI in clinical practice, research and education.
35.	Nyström, H., et al. (författare) Hypoxia-inducible factor 1a predicts recurrence in high-grade soft tissue sarcoma of extremities and trunk wall 2017 Ingår i: Journal of Clinical Pathology. - : BMJ. - 0021-9746 .- 1472-4146. ; 70:10, s. 879-885 Tidskriftsartikel (refereegranskat)abstract Background and aim Sarcomas are of mesenchymal origin and typically show abundant tumour stroma and presence of necrosis. In search for novel biomarkers for personalised therapy, we determined the prognostic impact of stromal markers, hypoxia and neovascularity in high-grade soft tissue leiomyosarcoma and pleomorphic undifferentiated sarcoma. Method We evaluated CD163, colony-stimulating factor (CSF)-1, CD16 and hypoxia-inducible factor 1 (HIF-1)a using immunohistochemical staining and assessed microvessel density using CD31 in 73 highgrade leiomyosarcomas and undifferentiated pleomorphic sarcomas of the extremities and the trunk wall. The results were correlated to metastasis-free and overall survival. Results Expression of HIF-1a was associated with the presence of necrosis and independently predicted shorter metastasis-free survival (HR 3.2, CI 1.4 to 7.0, p=0.004), whereas neither expression of the stromal markers CD163, CD16 and CSF-1 nor microvessel density was prognostically relevant in this series. Conclusions There is increasing evidence for the prognostic role of hypoxia in high-grade soft tissue sarcoma, and these data suggest that HIF-1a expression represents a candidate prognostic biomarker for clinical application in high-grade leiomyosarcoma and undifferentiated pleomorphic sarcoma.
36.	Palomino, J, et al. (författare) Computer graphics for the microscopist 2018 Ingår i: Journal of clinical pathology. - : BMJ. - 1472-4146 .- 0021-9746. ; 71:1, s. e1-e2 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
37.	Robertson, S, et al. (författare) Prognostic value of Ki67 analysed by cytology or histology in primary breast cancer 2018 Ingår i: Journal of clinical pathology. - : BMJ. - 1472-4146 .- 0021-9746. ; 71:9, s. 787-794 Tidskriftsartikel (refereegranskat)abstract The accuracy of biomarker assessment in breast pathology is vital for therapy decisions. The therapy predictive and prognostic biomarkers oestrogen receptor (ER), progesterone receptor, HER2 and Ki67 may act as surrogates to gene expression profiling of breast cancer. The aims of this study were to investigate the concordance of consecutive biomarker assessment by immunocytochemistry on preoperative fine-needle aspiration cytology versus immunohistochemistry (IHC) on the corresponding resected breast tumours. Further, to investigate the concordance with molecular subtype and correlation to stage and outcome.MethodsTwo retrospective cohorts comprising 385 breast tumours with clinicopathological data including gene expression-based subtype and up to 10-year overall survival data were evaluated.ResultsIn both cohorts, we identified a substantial variation in Ki67 index between cytology and histology and a switch between low and high proliferation within the same tumour in 121/360 cases. ER evaluations were discordant in only 1.5% of the tumours. From cohort 2, gene expression data with PAM50 subtype were used to correlate surrogate subtypes. IHC-based surrogate classification could identify the correct molecular subtype in 60% and 64% of patients by cytology (n=63) and surgical resections (n=73), respectively. Furthermore, high Ki67 in surgical resections but not in cytology was associated with poor overall survival and higher probability for axillary lymph node metastasis.ConclusionsThis study shows considerable differences in the prognostic value of Ki67 but not ER in breast cancer depending on the diagnostic method. Furthermore, our findings show that both methods are insufficient in predicting true molecular subtypes.
38.	Rubio, CA, et al. (författare) Asymmetric crypt fission in colectomy specimens in patients with ulcerative colitis 2021 Ingår i: Journal of clinical pathology. - : BMJ. - 1472-4146 .- 0021-9746. ; 74:9, s. 577-581 Tidskriftsartikel (refereegranskat)abstract We previously found colonic crypts with asymmetric fission bordering regenerating ulcers in ulcerative colitis (UC). The present objective was to assess the frequency of asymmetric crypt-fission in colectomy specimens from patients with long-lasting UC.MethodsH&E-stained sections from seven colectomies from patients with UC without dysplasia or carcinoma were investigated. Symmetric fission was characterised by branched colon crypts showing ≥2 identical crypts, whereas asymmetric fission exhibited branched colon crypt portraying ≥2 dissimilar crypts, differing in diameter, length and/or shape.ResultsThe number of crypts in fission in the 89 sections was 3586; of those, 2930 (81.7%) were asymmetric and the remaining 656 (18.3%), symmetric. Out of 927 vertically-cut crypts (in well-oriented sections), 912 (98.4%) were asymmetric, and the remaining 14 (1.6%), symmetric, and out 2660, cross-cut (transected) crypts in fission, 2018 (75.9%) were asymmetric and the remaining 642 (24.1%), symmetric.ConclusionCrypt fission is rarely found in the normal colon in adults. Symmetric crypt fission found in UC is possibly triggered by a compensatory homeostatic mechanism of crypt production in mucosal areas replaced by chronic inflammation. But asymmetric crypt fission is a pathological aberration that affects crypts in patients with a particular predisposition to develop mucosal dysplasia. It is suggested that this previously unattended histological parameter be included in the pathological descriptions of colectomy specimens from patients with UC.
39.	Rubio, CA, et al. (författare) Asymmetric crypt fission in sessile serrated lesions 2021 Ingår i: Journal of clinical pathology. - : BMJ. - 1472-4146 .- 0021-9746. ; 74:11, s. 712-717 Tidskriftsartikel (refereegranskat)abstract Sessile serrated lesions without dysplasia (SSL-ND) are epitomised by dilated crypts with epithelial serrations and architectural distortions portraying boot-shapes, L-shapes or inverted-T shapes. Recently, crypts in asymmetric fission were detected in SSL-ND. The purpose was to assess the frequency of crypts in asymmetric fission in a cohort of SSL-ND.MethodsThe frequency of crypts in fission was assessed in 60 SSL-ND, the distribution of cell proliferation in 48 SSL-ND and the expression of maspin, a tumour-suppressor protein, in 29 SSL-ND.ResultsOut of the 60 SSL-ND, 40 (66.7%) showed crypts in fission: 39 (65%) SSL-ND had crypts in asymmetric fission and one SSL-ND (1.7%), in symmetric fission (p<0.05). Of 1495 crypts recorded in the 60 SSL-ND, 73 (4.9%) were in asymmetric fission but only one (0.06%), in symmetric fission (p<0.05). Out of the 48 Ki67-immunostained SSL-ND,15 (31%) showed randomly distributed proliferating cell-domains. All 29 SSL-ND revealed maspin-upregulation (including crypts in asymmetric and symmetric fission). In contrast, the normal colon mucosa showed occasional single crypts in symmetric fission, proliferating cell-domains limited to the lower thirds of the crypts, absence of crypts in asymmetric fission and remained maspin negative.ConclusionsSSL-ND thrive with crypts in asymmetric fission displaying randomly distributed proliferating cell-domains and maspin-upregulation. These histo-biological aberrations disclose pathological cryptogenesis and suggest possibly unfolding somatic mutations in SSL-ND. The present findings may open new vistas on the parameters pertinent to the susceptibility of SSL-ND to develop dysplasia and carcinoma.
40.	Rubio, CA, et al. (författare) Compound traditional serrated adenoma and sessile serrated adenoma 2016 Ingår i: Journal of clinical pathology. - : BMJ. - 1472-4146 .- 0021-9746. ; 69:8, s. 745-746 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
41.	Rubio, CA, et al. (författare) Frequency of epithelioid granulomas in colonoscopic biopsy specimens from paediatric and adult patients with Crohn's colitis 2007 Ingår i: Journal of clinical pathology. - : BMJ. - 1472-4146 .- 0021-9746. ; 60:11, s. 1268-1272 Tidskriftsartikel (refereegranskat)
42.	Rubio, CA, et al. (författare) Lymphocytic oesophagitis, eosinophilic oesophagitis and compound lymphocytic-eosinophilic oesophagitis I: histological and immunohistochemical findings 2017 Ingår i: Journal of clinical pathology. - : BMJ. - 1472-4146 .- 0021-9746. ; 70:3, s. 208-216 Tidskriftsartikel (refereegranskat)
43.	Rubio, CA (författare) Lysozyme expression in microscopic colitis 2011 Ingår i: Journal of clinical pathology. - : BMJ. - 1472-4146 .- 0021-9746. ; 64:6, s. 510-515 Tidskriftsartikel (refereegranskat)abstract To audit the cellular expression of the innate antibacterial enzyme lysozyme in colonic biopsies from a cohort of patients having microscopic colitis (MC—collagenous colitis (CC) or lymphocytic colitis (LC)). Results were compared with those recorded in patients with inflammatory bowel disease (IBD) of the colon (ulcerative colitis (UC) or Crohn's colitis).MethodsFifty-five consecutive cases having biopsies from the left colon were investigated: 27 MC (14 CC and 13 LC) and 28 IBD (14 UC and 14 Crohn's colitis). Sections were stained with antilysozyme antibody. Twelve cases (3 CC, 3 LC, 3 UC and 3 Crohn's colitis) were challenged with the macrophage marker CD68 (clone PG-M1).ResultsIn MC, marked lysozyme expression in the colonic crypts was recorded in CC (p<0.05). The number of cases with metaplastic Paneth cells was higher in CC than in LC (p<0.05). In IBD, only active Crohn's colitis displayed marked lysozyme expression in the colonic crypts. Marked lysozyme immune-reactivity in subepitheliallamina propria mucosa (lpm)macrophages was found in LC (LC vs CC p<0.05).ConclusionsThe increased production of the antibacterial enzyme lysozyme in CC and LC supports a bacterial aetiology for these two diseases. Lysozyme upregulation in different cell types (epithelial vs macrophages) supports the notion that CC and LC might be two different maladies.
44.	Rubio, CA, et al. (författare) Novel histological repertoire of crypt-associated anomalies in inflamed colon mucosa 2023 Ingår i: Journal of clinical pathology. - : BMJ. - 1472-4146 .- 0021-9746. ; 76:8, s. 531-535 Tidskriftsartikel (refereegranskat)abstract Studying crypt branching in ulcerative colitis (UC) and in infectious colitis (IC), we detected previously unreported crypt-associated anomalies (CAAs). The objective was to describe, illustrate and assess the frequency of CAAs in inflamed colon mucosa in patients with UC and IC.MethodsSections from 100 consecutive biopsies with UC, in 50 with IC and in 27 with UC in remission (UCR) were reviewed. The following CAAs were identified: crypt eosinophilia, intracryptal epithelial hyperplasia, intracryptal epithelial budding, intracryptal supernumerary crypts, intracryptal epithelial bridges, crypt rings in rows and off-centre epithelial budding.ResultsThe frequency of crypts with extensive crypt eosinophilia and with intracryptal epithelial budding was significantly higher in UC than in IC and UCR (p<0.05); the frequency in the remaining histological parameters was similar in UC, IC and UCR.ConclusionsCAAs were found interspersed with branching crypts. CAAs persisted in long-lasting UC mucosal inflammation, but declined when the inflammation waned. Since similar anomalies are not present in normal colon mucosa, the results suggest that CAAs had been boosted by the ongoing mucosal inflammation. The development of these previously unreported CAAs in the colon mucosa with inflammation might embody pathological aberrations of cryptogenesis.
45.	Rubio, CA, et al. (författare) The third pathway of colorectal carcinogenesis 2018 Ingår i: Journal of clinical pathology. - : BMJ. - 1472-4146 .- 0021-9746. ; 71:1, s. 7-11 Tidskriftsartikel (refereegranskat)abstract The majority of the colorectal carcinomas (CRC) arise in a vast mucosal area built with columnar cells and mucus-producing goblet cells. These carcinomas evolve via the conventional (tubular/villous) adenoma–carcinoma pathway, or the serrated adenoma–carcinoma pathway. Much less frequently CRC arise in the gut-associated lymphoid tissue (GALT) mucosal domain via the third pathway of colorectal carcinogenesis.MethodsAll publications on human colorectal GALT carcinomas in the literature were reviewed.ResultsOnly 23 GALT-carcinomas found in 20 patients are in record. The GALT carcinomas were detected at surveillance colonoscopic biopsy in 11 patients (four had ulcerative colitis, two were members of a Lynch syndrome family, two of a CRC family, one had familial adenomatous polyposis (FAP), one prior colon adenomas and one a submucosal tumour), or at diagnostic colonoscopic biopsy in the remaining nine patients (three had rectal bleedings, two abdominal pains, one diverticular disease and one protracted constipation. In three, no ground disease or symptoms were provided). In six of the 23 GALT carcinomas, the luminal surface showed tumour cells, ulcerations or no descriptions were given. Ten (66.7%) of the remaining 15 GALT carcinomas showed on top, adenomas (n=8) or high-grade dysplasia (n=2).ConclusionsThe low frequency of GALT carcinomas might be explained by the fact that the colorectal mucosal areas occupied by GALT domains are minute. The finding that two-thirds of the 15 remaining GALT carcinomas (vide supra) were covered by high-grade dysplasia or by conventional adenomas strongly suggest that conventional non-invasive neoplasias might have preceded the majority of the GALT carcinomas in record.
46.	Rubio, CA (författare) Traditional serrated adenomas and serrated carcinomas in carcinogen-treated rats 2017 Ingår i: Journal of clinical pathology. - : BMJ. - 1472-4146 .- 0021-9746. ; 70:4, s. 301-307 Tidskriftsartikel (refereegranskat)abstract A recent review of archived sections from early experiments in rats showed neoplasias exhibiting serrated configurations. The aim was to assess the frequency of serrated neoplasias in the colon and small intestine of carcinogen-treated rats.MethodsWhile reviewing archival sections from early experiments in Sprague-Dawley (SD) and Fisher-344 (F-344) rats, we recently detected colonic and intestinal traditional serrated adenomas (displaying serrated or microtubular patterns) and serrated carcinomas. SD rats were injected 1,2-dimethylhydrazine (DMH) for 27 weeks whereas F-344 rats were fed with a pyrolysate (GLU-1) for 24 months. Filed sections from 358 colonic and small intestinal neoplasias were re-evaluated.ResultsDMH-treated SD rats had 215 colonic neoplasias (1.4% were serrated adenomas, 7.9% microtubular adenomas, 2.8% serrated carcinomas and 2.8% microtubular carcinomas). GLU1-treated F-344 rats had 53 colonic neoplasias (1.9% were serrated adenomas and 20.8% microtubular adenomas), and 89 small intestinal neoplasias (1.1% were serrated adenomas, 42.7% microtubular adenomas and 6.7%, microtubular carcinomas).ConclusionsDMH/SD-rats develop serrated and microtubular adenomas and carcinomas in the colon, whereas GLU1/F-344 rats develop microtubular adenomas in the colon and microtubular adenomas and carcinomas in the small intestine. The two rat-settings emerge as suitable models to study the molecular attributes of serrated and microtubular neoplasias under the standard conditions of the laboratory. This study is the first showing that a substantial number of serrated and particularly microtubular adenomas and carcinomas develop in the colon and small intestine of experimental rats. Importantly, serrated and microtubular neoplasias in rats recreate the histology of duodenal and colonic traditional serrated neoplasias in human beings.
47.	Sapkota, D., et al. (författare) COVID-19 salivary signature: diagnostic and research opportunities 2021 Ingår i: Journal of Clinical Pathology. - : BMJ. - 0021-9746 .- 1472-4146. ; 74:6, s. 344-349 Tidskriftsartikel (refereegranskat)abstract The COVID-19 (caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)) epidemic started in Wuhan (Hubei Province, China) in mid-December 2019 and quickly spread across the world as a pandemic. As a key to tracing the disease and to implement strategies aimed at breaking the chain of disease transmission, extensive testing for SARS-CoV-2 was suggested. Although nasopharyngeal/oropharyngeal swabs are the most commonly used biological samples for SARS-CoV-2 diagnosis, they have a number of limitations related to sample collection and healthcare personnel safety. In this context, saliva is emerging as a promising alternative to nasopharyngeal/oropharyngeal swabs for COVID-19 diagnosis and monitoring. Saliva collection, being a non-invasive approach with possibility for self-collection, circumvents to a great extent the limitations associated with the use of nasopharyngeal/oropharyngeal swabs. In addition, various salivary biomarkers including the salivary metabolomics offer a high promise to be useful for better understanding of COVID-19 and possibly in the identification of patients with various degrees of severity, including asymptomatic carriers. This review summarises the clinical and scientific basis for the potential use of saliva for COVID-19 diagnosis and disease monitoring. Additionally, we discuss saliva-based biomarkers and their potential clinical and research applications related to COVID-19.
48.	Sjöström, Martin, et al. (författare) Stem cell biomarker ALDH1A1 in breast cancer shows an association with prognosis and clinicopathological variables that is highly cut-off dependent. 2015 Ingår i: Journal of Clinical Pathology. - : BMJ. - 1472-4146 .- 0021-9746. ; 68:12, s. 1012-1019 Tidskriftsartikel (refereegranskat)abstract Aldehyde dehydrogenase family 1 member A1 (ALDH1A1) is a putative marker of breast cancer stem cells (CSCs) with prognostic implications when expressed in cancer or stroma. However, previous results are contradictory and we therefore aimed to further evaluate the impact of ALDH1A1 on distant disease-free survival (DDFS) and correlation with clinicopathological variables in breast cancer, specifically by evaluating different cut-offs.
49.	Strom, P, et al. (författare) Prognostic value of perineural invasion in prostate needle biopsies: a population-based study of patients treated by radical prostatectomy 2020 Ingår i: Journal of clinical pathology. - : BMJ. - 1472-4146 .- 0021-9746. ; 73:10, s. 630-635 Tidskriftsartikel (refereegranskat)abstract Despite being one of the major pathways for the spread of malignant tumours, perineural invasion (PNI) has not conclusively been shown to have an independent prognostic value for prostate cancer. Prostatic biopsy constitutes the major pathology workload in prostate cancer and is the foundation for primary treatment decisions and for this reason we aimed to estimate the prognostic value of PNI in biopsies.MethodsWe followed 918 men who underwent radical prostatectomy (RP) from the prospective and population based STHLM3 study until biochemical recurrence with a median follow-up of 4.1 years. To strengthen the evidence, we combined the estimates from the largest studies targeting the prognostic value of PNI in the biopsy. We also estimated the OR of advanced stage as radical prostatectomy for PNI positive and negative men.ResultsThe estimated prognostic value based on our data suggested an approximately 50% increased risk of biochemical recurrence if PNI was present in the biopsy (p=0.06). Even though not statistically significant on the 5% level, this estimate is consistent with similar studies, and by combining the estimates there is in fact strong evidence in support of an independent prognostic value of PNI in the biopsy (p<0.0001). There was also an independent increased risk of advanced stage at RP for positive men (OR 1.85, p=0.005).ConclusionsThe evidence supporting a clinically relevant and independent prognostic value of PNI is strong enough to be considered for pathology reporting guidelines.
50.	Sundbom, Marcus, et al. (författare) Alteration in human defensin-5 expression following gastric bypass surgery 2007 Ingår i: Journal of Clinical Pathology. - : BMJ. - 0021-9746 .- 1472-4146. ; 60:9, s. 1029-1034 Tidskriftsartikel (refereegranskat)abstract Background: Roux-en-Y gastric bypass surgery provides a novel human model to investigate small bowel mucosal innate immunity, in which there is loss of gastric acid-mediated protection against orally-acquired microorganisms. Aim: To study changes in jejunal mucosal immunoreactivity of human defensin (HD)-5,an antimicrobial peptide normally produced by Paneth cells. Methods: Mucosal samples were obtained from 18 female patients ( 24 - 54 years), from the same segment of jejunum during and after gastric bypass surgery. Samples were used for bacterial culture and immunohistochemistry using anti-HD-5 antibody. The number of immunoreactive cells per crypt and villus were determined and expressed as mean (SD). Results: No bacteria were cultured from any of the perioperative jejunal samples but colonies of bacteria normally present in the pharynx were identified during culture of all postoperative jejunal biopsy specimens (1-> 100 colonies). Paneth cell numbers per crypt were unchanged after gastric bypass ( 4.16 (0.71) vs 4.24 (0.78)). However, following surgery, there was an increase in HD-5-positive intermediate cells per crypt (0.25 (0.41) vs 1.12 (0.66), p < 0.01), HD-5 staining enterocytes per crypt ( 0.03 ( 0.09) vs 1.38 ( 1.10), p < 0.01), HD-5 staining material in the crypt lumen (crypt lumens: 5.0% ( 10.9%) vs 68.1% ( 27.9%), p < 0.01) and HD-5 immunoreactivity coating the luminal surface of villus enterocytes ( villi sampled: 15.0% ( 31.0%) vs 67.5% ( 42.0%), p < 0.01). Conclusions: Bacteria normally resident in the pharynx were present in the proximal jejunal mucosa following Roux-en-Y gastric bypass surgery. After gastric bypass, there was increased secretion of HD-5 and an increase in HD-5 expressing intermediate cells and enterocytes in the crypt. The increase in HD-5 expression in the jejunal mucosa following gastric bypass surgery is likely to be secondary to exposure to orally-acquired microorganisms.

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