Pathology

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LB1663 A multi-gene prognostic signature associated with cutaneous squamous cell carcinoma metastasis
(Elsevier, 2023-08-21) Wang, Jun; Harwood, Catherine; Bailey, Edmund; Bewicke-Copley, Charlotte; Anene, Chinedu; Thomson, Jason; Qamar, Muhammad; Nourse, Craig; Schoenherr, Christina; Treanor-Taylor, Mairi; Healy, Eugene; Lai, Chester; Craig, Paul; Moyes, Colin; Rickaby, William; Martin, Joanne; Proby, Charlotte; Inman, Gareth; Leigh, Irene; Craig, Paul; Medical and Dental
cSCC staging methods are reported to have sub-optimal performances in metastasis prediction. Accurate identification of patients with tumors at high risk of metastasis would have a significant impact on management. Archival FFPE tissue from primary cSCC with perilesional normal tissue from 237 immunocompetent patients (151 non-metastasizing and 86 metastasizing) were collected retrospectively from four centers. All pathology was centrally reviewed and T-staged by consensus. TempO-seq was used to probe the whole transcriptome and machine learning algorithms were applied to derive predictive signatures, with a 75%:25% split for training and testing datasets. A 20-gene prognostic model was developed and validated, with an accuracy of 86.0%, sensitivity of 85.7%, specificity of 86.1%, and positive predictive value of 78.3% in the testing set. A linear predictor was also developed, significantly correlating with metastatic risk. This has provided biological insights into the process of metastasis and potential therapeutic targets. There are biological and genomic mechanisms common to cSCC across different tissue types and the prognostic signature may provide further insights into common differentiation and stem-like pathways underpinning cSCC. Ultimately, the 20-gene prognostic signature has the potential to be incorporated into clinical workflows for cSCC to significantly improve risk stratification, identify patients with high-risk cSCC who may benefit from adjuvant treatment and reduce overtreatment for patients with low-risk cSCC.
AI is quicker and more accurate than pathologists at SNOMED coding pathology reports
(BMJ Publishing Group, 2025-10-13) Mayall, Charles; Mayall, Henry; Mayall, Frederick; Perring, Laura; Truman, Derek; Bodger, Ian; Perring, Laura; Medical and Dental
No abstract available
Diagnosis and Management of UTI in Primary Care Settings—A Qualitative Study to Inform a Diagnostic Quick Reference Tool for Women Under 65 Years
(MDPI, 2020-09-07) Cooper, Emily; Jones, Leah; Joseph, Annie; Allison, Rosie; Gold, Natalie; Larcombe, James; Moore, Philippa; McNulty, Cliodna Ann Miriam; Moore, Philippa; Additional Professional Scientific and Technical
Background: To inform interventions to improve antimicrobial use in urinary tract infections (UTIs) and contribute to a reduction in Escherichia coli bloodstream infection, we explored factors influencing the diagnosis and management of UTIs in primary care. Design: Semi-structured focus groups informed by the Theoretical Domains Framework. Setting: General practice (GP) surgeries in two English clinical commissioning groups (CCGs), June 2017 to March 2018. Participants: A total of 57 GP staff within 8 focus groups. Results: Staff were very aware of common UTI symptoms and nitrofurantoin as first-line treatment, but some were less aware about when to send a urine culture, second-line and non-antibiotic management, and did not probe for signs and symptoms to specifically exclude vaginal causes or pyelonephritis before prescribing. Many consultations were undertaken over the phone, many by nurse practitioners, and followed established protocols that often included urine dipsticks and receptionists. Patient expectations increased use of urine dipsticks, and immediate and 5 days courses of antibiotics. Management decisions were also influenced by patient co-morbidities. No participants had undertaken recent UTI audits. Patient discussions around antibiotic resistance and back-up antibiotics were uncommon compared to consultations for respiratory infections. Conclusions: Knowledge and skill gaps could be addressed with education and clear, accessible, UTI diagnostic and management guidance and protocols that are also appropriate for phone consultations. Public antibiotic campaigns and patient-facing information should cover UTIs, non-pharmaceutical recommendations for “self-care”, prevention and rationale for 3 days antibiotic courses. Practices should be encouraged to audit UTI management.
APOE gene testing in FH referrals – the story so far
(Elsevier, 2021-09-28) Duff-Farrier, Celia; Pennock, Melanie; Forrester, Natalie; Honeychurch, Julie; Aungraheeta, Riyaad; George, Esther; David, Alessia; Williams, Maximillian; Balasubramani, Mathangi; Gan, Kwok-Swee; Balasubramani, Mathangi; Gan, Kwok-Swee; Medical and Dental
Over 13,000 FH patients from >100 UK referral centres have been tested at Bristol for monogenic and polygenic hypercholesterolaemia using a high throughput NGS panel approach. A monogenic cause was identified in ∼21% of patients, and 80% of monogenic negative patients have a high or intermediate likelihood of a polygenic aetiology. The apolipoprotein E gene (APOE) is a new cause of Autosomal Dominant Familial Hypercholesterolaemia [1]; a common 3bp in-frame deletion, p.(Leu167del), removes a leucine residue in the Low Density Lipoprotein Receptor (LDLR)-binding region of the apo E protein. In vitro cellular studies show a “gain of function” mechanism, whereby very low-density lipoprotein (VLDL) carrying mutant apoE ‘produces LDLR downregulation, thereby raising plasma low-density lipoprotein cholesterol levels’ [2]. APOE has not been widely tested in UK diagnostic laboratories, and as such, there is little data on UK prevalence and penetrance, and the pathogenicity of other variants beyond p.(Leu167del). In a collaborative multicentre pilot study (Bristol, Bath, Gloucester, Wessex, Sheffield, St Georges, West Midlands and Plymouth) 3/317 consented selected patients negative for LDLR, APOB, PCSK9, and LDLRAP1 variants were found to be positive for APOE p.(Leu167del) indicating a prevalence of 0.95%. A further 5 cases, previously tested in Bristol, were detected through the 100,000 genomes project. APOE was incorporated into the Bristol FH v4 assay in Dec 19. Since its introduction, 17/ 4242 FH index patients have tested positive for the APOE p.(Leu167del) variant, indicating a prevalence of 0.4%. To date, APOE p.(Leu167del) cascade testing at Bristol has been undertaken in 29 relatives from 10 families, with 14 further positive cases identified. Examples of non-segregation, in families, indicate that this variant may display non–penetrance, and lifestyle choices may be relevant for disease presentation. A recent report evidences good statin response in APOE p.(Leu167del) patients [3], advocating the benefits of genetic testing. Two FH patients have APOE variants of uncertain significance; c.481A>G p.(Lys161Glu) also located in the LDLR-binding domain and potentially compatible with the proposed gene mechanism, and c.687del p.(Glu230Serfs*21), a likely loss of function variant more compatible with Type III hyperlipoproteinaemia. Our experience of APOE gene testing and recommendations for variant reporting will be presented.
Deep learning for prediction of colorectal cancer outcome: a discovery and validation study
(Elsevier, 2020-02-01) Skrede, Ole-Johan; De Raedt, Sepp; Kleppe, Andreas; Hveem, Tarjei; Liestol, Knut; Maddison, John; Askautrud, Hanne; Pradham, Manohar; Nesheim, John; Albregtsen, Fritz; Farstad, Inger; Domingo, Enric; Church, David; Nesbakken, Arild; Shepherd, Neil; Tomlinson, Ian; Kerr, Rachel; Novelli, Marco; Kerr, David; Danielsen, Havard; Shepherd, Neil; Medical and Dental
Background: Improved markers of prognosis are needed to stratify patients with early-stage colorectal cancer to refine selection of adjuvant therapy. The aim of the present study was to develop a biomarker of patient outcome after primary colorectal cancer resection by directly analysing scanned conventional haematoxylin and eosin stained sections using deep learning. Methods: More than 12 000 000 image tiles from patients with a distinctly good or poor disease outcome from four cohorts were used to train a total of ten convolutional neural networks, purpose-built for classifying supersized heterogeneous images. A prognostic biomarker integrating the ten networks was determined using patients with a non-distinct outcome. The marker was tested on 920 patients with slides prepared in the UK, and then independently validated according to a predefined protocol in 1122 patients treated with single-agent capecitabine using slides prepared in Norway. All cohorts included only patients with resectable tumours, and a formalin-fixed, paraffin-embedded tumour tissue block available for analysis. The primary outcome was cancer-specific survival. Findings: 828 patients from four cohorts had a distinct outcome and were used as a training cohort to obtain clear ground truth. 1645 patients had a non-distinct outcome and were used for tuning. The biomarker provided a hazard ratio for poor versus good prognosis of 3·84 (95% CI 2·72-5·43; p<0·0001) in the primary analysis of the validation cohort, and 3·04 (2·07-4·47; p<0·0001) after adjusting for established prognostic markers significant in univariable analyses of the same cohort, which were pN stage, pT stage, lymphatic invasion, and venous vascular invasion. Interpretation: A clinically useful prognostic marker was developed using deep learning allied to digital scanning of conventional haematoxylin and eosin stained tumour tissue sections. The assay has been extensively evaluated in large, independent patient populations, correlates with and outperforms established molecular and morphological prognostic markers, and gives consistent results across tumour and nodal stage. The biomarker stratified stage II and III patients into sufficiently distinct prognostic groups that potentially could be used to guide selection of adjuvant treatment by avoiding therapy in very low risk groups and identifying patients who would benefit from more intensive treatment regimes.
Global and mitosis-specific interobserver variation in mitotic count scoring and implications for malignant melanoma staging
(Wiley, 2020-04-16) Saldanha, Gerald; Ali, Rokiah; Bakshi, Arti; Basiouni, Ahmed; Bishop, Rachael; Colloby, Peter; Craig, Paul; Da Forno, Philip; Edward, Sara; Espinosa de Los Monteros, Olivia; Evans, Alan; Jamieson, Lynne; Rytina, Ed; Bamford, Mark; Craig, Paul; Medical and Dental
Aims: Staging is the gold standard for predicting malignant melanoma outcome but changes in its criteria over time indicate ongoing evolution. One notable recent change from the 8th edition of the American Joint Committee on Cancer (AJCC) staging manual was removal of mitotic count. We explore the extent to which this feature is limited by interobserver error in order to find ways to improve its fitness for use should it be revisited in future staging versions. Methods and results: In a cohort of 476 patients with melanoma ≤1.0 mm, a mitotic count of 0 versus 1 was significant for metastasis-free survival, but not melanoma-specific or overall survival. In 10 melanomas that were 0.9-1.0 mm thick, the mitotic count intraclass correlation coefficient for histopathologists was 0.58 (moderate agreement). Uniquely, we also assessed agreement for specific putative mitotic figures, identifying precise reasons why specific mitotic figures qualified for scoring or elimination. A kappa score was 0.54 (moderate agreement). We also gathered data on other staging features. Breslow thickness had an intraclass correlation coefficient of 0.41 (moderate agreement) and there was a systematic difference between histopathologists among cases (P = 0.04). Every case had a range that crossed the AJCC8 0.8-mm pT1a/pT1b staging boundary. Ulceration was only identified in two of the 10 cases. For ulceration, kappa agreement score was 0.31 (fair). Conclusion: This study supports the removal of mitotic count from staging, but shows that its scoring is substantially affected by interobserver variation, suggesting that more prescriptive guidelines might have a beneficial impact on its prognostic value.
In Situ Metabolomics Expands the Spectrum of Renal Tumours Positive on 99mTc-sestamibi Single Photon Emission Computed Tomography/Computed Tomography Examination
(Elsevier, 2020-11-27) Papathomas, Thomas; Tzortzakakis, Antonios; Sun, Na; Erlmeier, Franziska; Feuchtinger, Annette; Trpkov, Kiril; Bazarova, Alina; Arvanitis, Alexandros; Wang, Wanzhong; Bozoky, Bela; Kokaraki, Georgia; Axelsson, Rimma; Walch, Axel; Papathomas, Thomas; Medical and Dental
Background Definite noninvasive characterisation of renal tumours positive on 99mTc-sestamibi single photon emission computed tomography/computed tomography (SPECT/CT) examination including renal oncocytomas (ROs), hybrid oncocytic chromophobe tumours (HOCTs), and chromophobe renal cell carcinoma (chRCC) is currently not feasible. Objective To investigate whether combined 99mTc-sestamibi SPECT/CT and in situ metabolomic profiling can accurately characterise renal tumours exhibiting 99mTc-sestamibi uptake. Design, setting, and participants A tissue microarray analysis of 33 tumour samples from 28 patients was used to investigate whether their in situ metabolomic status correlates with their features on 99mTc-sestamibi SPECT/CT examination. In order to validate emerging data, an independent cohort comprising 117 tumours was subjected to matrix-assisted laser desorption/ionisation mass spectrometry imaging (MALDI MSI). Outcome measurements and statistical analysis MALDI MSI data analysis and image generation were facilitated by FlexImaging v. 4.2, while k-means analysis by SCiLS Lab software followed by R-package CARRoT analysis was used for assessing the highest predictive power in the differential of RO versus chRCC. Heatmap-based clustering, sparse partial least-squares discriminant analysis, and volcano plots were created with MetaboAnalyst 3.0. Results and limitations We identified a discriminatory metabolomic signature for 99mTc-sestamibi SPECT/CT–positive Birt-Hogg-Dubè–associated HOCTs versus other renal oncocytic tumours. Metabolomic differences were also evident between 99mTc-sestamibi–positive and 99mTc-sestamibi–negative chRCCs, prompting additional expert review; two of three 99mTc-sestamibi–positive chRCCs were reclassified as low-grade oncocytic tumours (LOTs). Differences were identified between distal-derived tumours from those of proximal tubule origin, including differences between ROs and chRCCs. Conclusions The current study expands the spectrum of 99mTc-sestamibi SPECT/CT–positive renal tumours, encompassing ROs, HOCTs, LOTs, and chRCCs, and supports the feasibility of in situ metabolomic profiling in the diagnostics and classification of renal tumours.
Low-grade Serous Carcinoma Arising in Inguinal Nodal Endosalpingiosis: Report of 2 Cases and Literature Review
(Lippincott, Williams & Wilkins, 2020-05) Sah, Shatrughan; Fulmali, Rahul; McCluggage, Glenn; Fulmali, Rahul; Medical and Dental
We report 2 cases of low-grade serous carcinoma probably arising from endosalpingiosis within inguinal lymph nodes. The neoplasms occurred in 51- and 58-yr old women in the absence of tumor within the adnexa, peritoneum or elsewhere. These represent the first reported examples of low-grade serous carcinoma arising within and confined to inguinal nodes. We review the pertinent literature regarding primary nodal low-grade serous carcinoma.
Merkel Cell Carcinoma
(Oxford University Press, 2021-06-16) Mistry, Khaylen; Levell, Nick; Craig, Paul; Steven, Neil; Venables, Zoe; Craig, Paul; Medical and Dental
Merkel cell carcinoma (MCC) is a rare neuroendocrine carcinoma. The cellular origin of MCC may include Merkel cell precursors. The incidence of MCC has increased significantly however trends may have been confounded by evolving diagnostic criteria. The two key aetiologies of MCC are ultraviolet radiation and Merkel cell polyoma virus (MCPyV). Both have unique mechanisms of carcinogenesis. MCC presents non-specifically as a rapidly growing, red-to-violet nodule on sun-exposed areas. Diagnostic accuracy has improved through immunohistochemical markers such as CK-20. Lymph nodes should be evaluated in MCC through examination and sentinel biopsy. USS, CT, MRI and CT-PET may be useful in staging. Management depends on tumour location, stage and comorbidities. MCPyV status may guide treatment strategy in the future. Treatment for the primary MCC is commonly wide local excision followed by radiotherapy, guided by anatomical constraints. There is uncertainty about surgical margins. Treatments for nodal disease have not been determined through trials. They include nodal dissection or radiotherapy for clinically or radiologically apparent disease, and adjuvant nodal irradiation for negative nodes, microscopic disease or following nodal dissection for definite disease. Patients with loco-regional advanced inoperable disease should be considered for combination therapy including chemotherapy, radiotherapy, surgery and immunotherapy. Systemic therapy for advanced disease includes immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway. Avelumab can improve survival in metastatic MCC. Immunotherapy may result in longer disease control. Various other immunotherapeutic and molecular agents are undergoing trials. MCC continues to have a high mortality characterized by high recurrence and early metastases.
Exploration of colonic looping patterns in undisturbed cadaveric specimens
(Wiley, 2020-11-24) Lam, Jacob; Wilkinson, James; Brown, Jonathan; Spear, Michelle; Brassett, Cecilia; Brown, Jonathan; Medical and Dental
Introduction: This study examines sex differences in the disposition of the sigmoid and transverse segments of the colon in undisturbed cadaveric abdomens and relates these findings to the anecdotal observation that colonoscopy is more challenging in females through the formation of tortuous bowel loops. Materials and methods: One hundred and twenty two undisturbed cadaveric abdomens were inspected. Three distinct configuration grades were separately assigned to the sigmoid and transverse segments of the colon on the basis of the pattern of the bowel loops observed in situ. Pearson's chi-squared test was used to analyze sex differences in bowel loop configuration and Spearman's rank correlation coefficient was calculated to identify co-occurrence of configuration grades in the subjects. Results: For the transverse segment, females had higher configuration grades corresponding to longer bowel loops with greater redundancy, compared to males (p = .000047). There was no sex difference in the sigmoid segment grade (p = .21636). Sigmoid and transverse segment grades were highly correlated in the subjects (coefficient = 0.9994). Conclusion: Sex differences in the configuration grades of the sigmoid or transverse colonic segments may be a significant contributing factor to increased difficulty of colonoscopy in females.
Current dilemmas in the pathological staging of colorectal cancer: the results of a national survey
(Wiley, 2020-11-05) Wong, Newton; Bracey, Tim; Mozayani, Behrang; Bateman, Adrian; Novelli, Marco; Shepherd, Neil; Shepherd, Neil; Medical and Dental
Aims: Accurate and consistent pathological staging of colorectal carcinoma (CRC) in resection specimens is especially crucial to guide adjuvant therapy. The aim of this study was to assess whether certain staging scenarios yield discordant opinions in the setting of current international and UK national guidelines. Methods and results: Members of the UK Gastrointestinal Pathology External Quality Assurance Scheme were invited to complete an anonymous, on-line survey that presented 15 scenarios related to pT or pR staging of CRC, and three questions about the respondent. The survey invitation was e-mailed to 405 pathologists, and 184 (45%) responses were received. The respondents had discordant opinions on whether and how CRC pT or pR staging is affected by: acellular mucin lakes and duration after short-course radiotherapy; the nature of the carcinoma at a resection margin or peritoneal surface; and microscopic evidence of perforation. This discordance was rarely related to the respondent's occupation type, and was not related to duration of work as a consultant or the staging guidelines used. Conclusions: This survey confirms that there remain several clinically critical but unresolved pT and pR staging issues for CRC. These issues therefore deserve attention in future versions of international and national staging guidelines.
Association between self-reported signs and symptoms and SARS-CoV-2 antibody detection in UK key workers
(Elsevier, 2021-03-26) Mulchandani, Ranya; Taylor-Philips, Sian; Jones, Hayley; Ades, A; Borrow, Ray; Linley, Ezra; Kirwan, Peter; Stewart, Richard; Moore, Philippa; Boyes, John; Moore, Philippa; Boyes, John; Medical and Dental
Background: Screening for SARS-CoV-2 antibodies is under way in some key worker groups; how this adds to self-reported COVID-19 illness is unclear. In this study, we investigate the association between self-reported belief of COVID-19 illness and seropositivity. Methods: Cross-sectional study of three key worker streams comprising (A) Police and Fire & Rescue (2 sites) (B) healthcare workers (1 site) and (C) healthcare workers with previously positive PCR result (5 sites). We collected self-reported signs and symptoms of COVID-19 and compared this with serology results from two SARS-CoV-2 immunoassays (Roche Elecsys® and EUROIMMUN). Results: Between 01 and 26 June, we recruited 2847 individuals (Stream A: 1,247, Stream B: 1,546 and Stream C: 154). Amongst those without previous positive PCR tests, 687/2,579 (26%) reported belief they had COVID-19, having experienced compatible symptoms; however, only 208 (30.3%) of these were seropositive on both immunoassays. Both immunoassays had high sensitivities relative to previous PCR positivity (>93%); there was also limited decline in antibody titres up to 110 days post symptom onset. Symptomatic but seronegative individuals had differing symptom profiles and shorter illnesses than seropositive individuals. Conclusion: Non-COVID-19 respiratory illness may have been mistaken for COVID-19 during the outbreak; laboratory testing is more specific than self-reported key worker beliefs in ascertaining past COVID-19 disease.
What Have We Learned from Molecular Biology of Paragangliomas and Pheochromocytomas?
(Springer, 2021-01-12) Papathomas, Thomas; Suurd, Diederik; Pacak, Karel; Tischler, Arthur; Vriens, Menno; Lam, Alfred; Krijger, Ronald; Papthomas, Thomas; Healthcare Scientists
Recent advances in molecular genetics and genomics have led to increased understanding of the aetiopathogenesis of pheochromocytomas and paragangliomas (PPGLs). Thus, pan-genomic studies now provide a comprehensive integrated genomic analysis of PPGLs into distinct molecularly defined subtypes concordant with tumour genotypes. In addition, new embryological discoveries have refined the concept of how normal paraganglia develop, potentially establishing a developmental basis for genotype–phenotype correlations for PPGLs. The challenge for modern pathology is to translate these scientific discoveries into routine practice, which will be based largely on histopathology for the foreseeable future. Here, we review recent progress concerning the cell of origin and molecular pathogenesis of PPGLs, including pathogenetic mechanisms, genetic susceptibility and molecular classification. The current roles and tools of pathologists are considered from a histopathological perspective, including differential diagnoses, genotype–phenotype correlations and the use of immunohistochemistry in identifying hereditary predisposition and validating genetic variants of unknown significance. Current and potential molecular prognosticators are also presented with the hope that predictive molecular biomarkers will be integrated into risk stratification scoring systems to assess the metastatic potential of these intriguing neoplasms and identify potential drug targets.
CPC13: Comparative study of p16, p53 and Ki67 immunostaining indicates that keratoacanthoma and cutaneous squamous cell carcinoma are clinicopathologically distinct entities
(Oxford University Press, 2022-07-01) Shpadaruk, Volha; Carr, Richard; Mesiano, Domenico; Heffron, Cinthia; Radonic, Teodora; Wiggings, James; Tso, Simon; Agrawal, Rishi; Cheung, Elaine; Slater, David; Craig, Paul; Craig, Paul; Medical and Dental
Keratoacanthoma (KA) is widely considered a benign, usually self‐resolving entity distinct from cutaneous squamous cell carcinoma (cSCC), while some consider KA to be indistinguishable histologically from cSCC. Published studies have indicated a use for p16, p53 and Ki67 immunohistochemistry in the assessment of KA and cSCC. We carried out an audit of comparative clinical features and staining patterns for p16, p53 and Ki67 used in the routine reporting of fully excised KA (excluding late regressing lesions), cSCC with KA‐like features (cSCC‐KAL) and other cSCC (cSCC‐OTHER). Cases were classified according to the Royal College of Pathologists Dataset for reporting cSCC. To ensure diagnostic concordance, all cases were reviewed by three dermatopathologists. There were 25 cases of KA, 37 of cSCC‐KAL (all considered follicular type) and 44 of SCC‐OTHER comprising 18 (41%) pure follicular, 15 (34%) hybrid follicular/surface neoplasms, five (11.4%) cSCC arising in Bowenoid actinic keratosis and six (13.6%) cSCC not otherwise specified. Clinical differences between KA, cSCC‐KAL and cSCC‐OTHER were found for median age (75, 81 and 81.5 years, respectively), head and neck location (20%, 86% and 84%, respectively) and duration < 5 months (95%, 63% and 36%, respectively). KA show a mosaic pattern for p16 (> 25–90% of neoplasm area) and a peripheral graded pattern for p53 (up to 50% moderate and strong nuclear staining) in 92% vs. 0% of cSCC‐KAL and 0% of cSCC‐OTHER. In contrast, a highly aberrant pattern (usually null) for one or both p16 and p53 was present in 0% of KA, 83.8% of cSCC‐KAL and 90.9% of cSCC‐OTHER. Abnormal distribution of Ki67 beyond the 1–3 peripheral cells was uncommon in KA (4.2%), and common in cSCC‐KAL (67.6%) and cSCC‐OTHER (88.4%). Our findings indicate that KA is clinicopathologically distinct from cSCC. The absence of highly aberrant protein expression patterns for two major tumour suppressor pathways (p16/CDNK2A and p53) and the regular peripheral Ki67 proliferation pattern in KA, compared with the prevalent aberrant patterns in cSCC, suggests that KA is a distinct entity from the malignant tumour pathway of cSCC. Combining the refined clinical, histological and immunohistochemistry features in our study should help to reduce the risk of diagnostic error and inform future studies to determine the molecular basis of KA.
99mTc-Sestamibi SPECT/CT and histopathological features of oncocytic renal neoplasia
(Medical Journals Sweden, 2022-11-02) Tzortzakakis, Antonios; Papathomas, Thomas; Gustafsson, Ove; Gabrielson, Stefan; Trpkov, Kiril; Ekström-Ehn, Linnea; Arvanitis, Alexandros; Holstensson, Maria; Karlsson, Mattias; Kokaraki, Georgia; Axelsson, Rimma; Papathomas, Thomas; Medical and Dental
Abstract Background 99mTc-Sestamibi Single Photon Emission Computed Tomography/Computed Tomography (SPECT/CT) contributes to the non-invasive differentiation of renal oncocytoma (RO) from renal cell carcinoma (RCC) by characterising renal tumours as Sestamibi positive or Sestamibi negative regarding their 99mTc-Sestamibi uptake compared to the non-tumoral renal parenchyma. Purpose To determine whether 99mTc- Sestamibi uptake in renal tumour and the non-tumoral renal parenchyma measured using Standard Uptake Value (SUV) SPECT, has a beneficial role in differentiating RO from RCC. Material and Methods Fifty-seven renal tumours from 52 patients were evaluated. In addition to visual evaluation of 99mTc-Sestamibi uptake, SUVmax measurements were performed in the renal tumour and the ipsilateral non-tumoral renal parenchyma. Analysis of the area under the receiver operating characteristic curve identified an optimal cut-off value for detecting RO, based on the relative ratio of 99mTc- Sestamibi uptake. Results Semiquantitative evaluation of 99mTc-Sestamibi uptake did not improve the performance of 99mTc- Sestamibi SPECT/CT in detecting RO. 99mTc- Sestamibi SPECT/CT identifies a group of mostly indolent Sestamibi-positive tumours with low malignant potential containing RO, Low-Grade Oncocytic Tumours, Hybrid Oncocytic Tumours, and a subset of chromophobe RCCs. Conclusion The imaging limitations for accurate differentiation of Sestamibi-positive renal tumours mirror the recognised diagnostic complexities of the histopathologic evaluation of oncocytic neoplasia. Patients with Sestamibi-positive renal tumours could be better suited for biopsy and follow-up, according to the current active surveillance protocols.
A clinical decision support system optimising adjuvant chemotherapy for colorectal cancers by integrating deep learning and pathological staging markers: a development and validation study
(Elsevier) Kleppe, Andreas; Skrede, Ole-Johan; De Raedt, Sepp; Hveem, Tarjei; Askautrud, Hanne; Jacobsen, Jørn; Church, David; Nedbakken, Arild; Shepherd, Neil; Novelli, Marco; Kerr, Rachel; Liestøl, Knut; Kerr, David; Danielsen, Håvard; Shepherd, Neil; Medical and Dental
Background: The DoMore-v1-CRC marker was recently developed using deep learning and conventional haematoxylin and eosin-stained tissue sections, and was observed to outperform established molecular and morphological markers of patient outcome after primary colorectal cancer resection. The aim of the present study was to develop a clinical decision support system based on DoMore-v1-CRC and pathological staging markers to facilitate individualised selection of adjuvant treatment. Methods: We estimated cancer-specific survival in subgroups formed by pathological tumour stage (pT<4 or pT4), pathological nodal stage (pN0, pN1, or pN2), number of lymph nodes sampled (≤12 or >12) if not pN2, and DoMore-v1-CRC classification (good, uncertain, or poor prognosis) in 997 patients with stage II or III colorectal cancer considered to have no residual tumour (R0) from two community-based cohorts in Norway and the UK, and used these data to define three risk groups. An external cohort of 1075 patients with stage II or III R0 colorectal cancer from the QUASAR 2 trial was used for validation; these patients were treated with single-agent capecitabine. The proposed risk stratification system was evaluated using Cox regression analysis. We similarly evaluated a risk stratification system intended to reflect current guidelines and clinical practice. The primary outcome was cancer-specific survival. Findings: The new risk stratification system provided a hazard ratio of 10·71 (95% CI 6·39-17·93; p<0·0001) for high-risk versus low-risk patients and 3·06 (1·73-5·42; p=0·0001) for intermediate versus low risk in the primary analysis of the validation cohort. Estimated 3-year cancer-specific survival was 97·2% (95% CI 95·1-98·4; n=445 [41%]) for the low-risk group, 94·8% (91·7-96·7; n=339 [32%]) for the intermediate-risk group, and 77·6% (72·1-82·1; n=291 [27%]) for the high-risk group. The guideline-based risk grouping was observed to be less prognostic and informative (the low-risk group comprised only 142 [13%] of the 1075 patients). Interpretation: Integrating DoMore-v1-CRC and pathological staging markers provided a clinical decision support system that risk stratifies more accurately than its constituent elements, and identifies substantially more patients with stage II and III colorectal cancer with similarly good prognosis as the low-risk group in current guidelines. Avoiding adjuvant chemotherapy in these patients might be safe, and could reduce morbidity, mortality, and treatment costs.
A national cohort study of melanoma BRAF status, testing patterns, patient and tumour characteristics, treatment and survival in England 2016-21
(Oxford University Press, 2025-09-03) Mistry, Khaylen; Jeffrey, Polly; Levell, Nick; Kennedy, Oliver; Richardson, Kathryn; Craig, Paul; Bright, Chloe; Taylor, Siobhan; Ragan, John; Karponis, Dimitrios; Pethick, Joanna; Lavelle, Katrina; McRonald, Fiona; Hardy, Steven; Vernon, Sally; Lorigan, Paul; Venables, Zoe; Craig, Paul; Taylor, Siobhan; Medical and Dental; Healthcare Scientists
Background: Inadequacy of testing for melanoma BRAF status results in delayed access to systemic therapy. BRAF mutations and their association with patient/tumour characteristics and survival is poorly understood. Objectives: To report national data from England on the (1) frequency of molecular BRAF testing, (2) association of patient/tumour characteristics with BRAF mutations and (3) treatment received and survival of patients with BRAF mutations. Methods: This national retrospective cohort study identified all new melanomas and molecular BRAF testing in England diagnosed from 2016 to 2021 using population-based data from the National Disease Registration Service. Multivariate logistic regression determined the association between a) BRAF testing with patient/tumour characteristics, b) BRAF genotype with patient/tumour characteristics. Age-standardised net survival (NS) analysed melanoma-specific mortality by BRAF genotype. Results: Of new melanomas diagnosed, 14.4% (13138/91415) had a BRAF test registered. The proportion of successfully tested tumours that were BRAF mutated was 34.0% (4424/13012). The West Midlands tested the highest proportion of cutaneous tumours (22.6% (1783/7901)) compared to the lowest in Yorkshire and the Humber (11.0% (856/7760)). Females (OR 0.82, 95%CI 0.79-0.86) and patients >80 years old (OR 0.88, 95%CI 0.83-0.93) were less likely to be tested for BRAF. BRAF mutations were associated with being female (OR 1.16, 95%CI 1.07-1.26). Patients >80 years (OR 0.36, 95%CI 0.32-0.40) had lower odds of being BRAF mutated. Patients with BRAF mutations had a lower five-year NS (BRAF-mutated 5-year NS 55.9%, 95%CI 52.7-59.2 vs BRAF WT 5-year NS 66.5%, 95%CI 62.1-60.1), particularly in stage II disease. Conclusions: This study presents the largest dataset on national melanoma BRAF status published to date. The data highlight geographic and demographic variations in BRAF testing and the impact of BRAF mutations on survival rates, particularly stage II patients. This highlights the critical role of consistent, early and accurate testing to ensure equal care, guide treatment decisions and understand prognosis.
Enhanced metastasis risk prediction in cutaneous squamous cell carcinoma using deep learning and computational histopathology
(Nature Research, 2025-09-02) Peleva, Emilia; Chen, Yue; Finke, Bernhard; Rizvi, Hasan; Healy, Eugene; Lai, Chester; Craig, Paul; Rickaby, William; Schoenherr, Christina; Nourse, Craig; Proby, Charlotte; Inman, Gareth; Leigh, Irene; Harwood, Catherine; Wang, Jun; Craig, Paul; Medical and Dental
Cutaneous squamous cell carcinoma (cSCC) is the most common skin cancer with metastatic potential and development of metastases carries a poor prognosis. To address the need for reliable risk stratification, we developed cSCCNet, a deep learning model using digital pathology of primary cSCC to predict metastatic risk. A retrospective cohort of 227 primary cSCC from four centres is used for model development. cSCCNet automatically selects the tumour area in standard histopathological slides and then stratifies primary cSCC into high- vs. low-risk categories, with heatmaps indicating most predictive tiles contributing to explainability. On a 20% hold-out testing cohort, cSCCNet achieves an area under the curve (AUC) of 0.95 and 95% accuracy in predicting risk of metastasis, outperforming gene expression-based tools and clinicopathologic classifications. Multivariate analysis including common clinicopathologic classifications confirms cSCCNet as an independent predictor for metastasis, implying it identifies predictive features beyond known clinicopathologic risk factors. Histopathological analysis including multiplex immunohistochemistry suggests that tumour differentiation, acantholysis, desmoplasia, and the spatial localisation of lymphocytes relative to tumour tissue may be important in predicting risk of developing metastasis. Although further validation including prospective evaluation is required, cSCCNet has potential as a reliable and accurate tool for metastatic risk prediction that could be easily integrated into existing histopathology workflows.
The Bowel Cancer Screening Programme Expert Board: an analysis of activity during 2017–2020
(Wiley, 2021-11-12) Bateman, Adrian; Kurn, Octavia; Novelli, Marco; Rodriguez-Justo, Manuel; Shepherd, Neil; Wong, Newton; Shepherd, Neil; Medical and Dental
Aims: The inception of the National Health Service Bowel Cancer Screening Programme in England in 2006 highlighted the fact that the differential diagnosis between the presence of epithelial misplacement and adenocarcinoma occurring in colorectal adenomas is problematic. The pathology Expert Board (EB) was created to facilitate the review of difficult cases by a panel of three experienced gastrointestinal pathologists. This article describes a review of the work of the EB over a 4-year period (2017-2020). Methods and results: Four hundred and thirty polyps were referred to the EB from 193 pathologists and 76 hospitals during this time. The EB diagnosis was benign for 67%, malignant for 28%, and equivocal for 2% (with no consensus in the remainder). The most common diagnosis change made by the EB was from malignant to benign-made in 50% of polyps referred with an initially malignant diagnosis. The level of agreement between the individual EB members was 'good' (kappa score of 0.619) but that between the EB and the referring diagnosis was 'poor' (kappa score of 0.149). Data from one EB member indicated that the presence of lamina propria, features of torsion and cytological similarity between the superficial and deep glands were predictors of a benign diagnosis, whereas the presence of irregular neoplastic glands, a desmoplastic reaction and lymphovascular invasion were commonly observed features in polyps with a malignant diagnosis. Conclusion: Diagnostic agreement between EB members is better than that between the EB and referring pathologists. There was a consistent trend for the EB to change diagnoses from malignant to benign.
Podocyte protease activated receptor 1 stimulation in mice produces focal segmental glomerulosclerosis mirroring human disease signaling events
(Elsevier, 2023-03-20) May, Carl; Chesor, Musleeha; Hunter, Sarah; Hayes, Bryony; Barr, Rachel; Roberts, Tim; Barrington, Fern; Farmer, Louise; Ni, Lan; Jackson, Maisie; Snethen, Heidi; Tavakolidakhrabadi, Nadia; Goldstone, Max; Gilbert, Rodney; Beesley, Matthew; Lennon, Rachel; Foster, Rebecca; Coward, Richard; Welsh, Gavin; Saleem, Moin; Beesley, Matthew; Medical and Dental
About 30% of patients who have a kidney transplant with underlying nephrotic syndrome (NS) experience rapid relapse of disease in their new graft. This is speculated to be due to a host-derived circulating factor acting on podocytes, the target cells in the kidney, leading to focal segmental glomerulosclerosis (FSGS). Our previous work suggests that podocyte membrane protease receptor 1 (PAR-1) is activated by a circulating factor in relapsing FSGS. Here, the role of PAR-1 was studied in human podocytes in vitro, and using a mouse model with developmental or inducible expression of podocyte-specific constitutively active PAR-1, and using biopsies from patients with nephrotic syndrome. In vitro podocyte PAR-1 activation caused a pro-migratory phenotype with phosphorylation of the kinase JNK, VASP protein and docking protein Paxillin. This signaling was mirrored in podocytes exposed to patient relapse-derived NS plasma and in patient disease biopsies. Both developmental and inducible activation of transgenic PAR-1 (NPHS2 Cre PAR-1Active+/-) caused early severe nephrotic syndrome, FSGS, kidney failure and, in the developmental model, premature death. We found that the non-selective cation channel protein TRPC6 could be a key modulator of PAR-1 signaling and TRPC6 knockout in our mouse model significantly improved proteinuria and extended lifespan. Thus, our work implicates podocyte PAR-1 activation as a key initiator of human NS circulating factor and that the PAR-1 signaling effects were partly modulated through TRPC6.

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