Recent Submissions

  • Clinical, histopathologic features and outcome of breast cancer in UK women of ethnic origin.

    Zaakouk, Mohamed; Longworth, Aisling; El Deftar, Mervat; Ezzat, Noha; Elgemeie, Emad; Shaaban, Abeer M; Shaaban, Abeer M; Histopathology; Medical and Dental (Asian Pacific Organization for Cancer Prevention, 2022-05-01)
    Objective: Breast cancer (BC) in non-Caucasian females is understudied and its management is based on Caucasian data. 30 % of the West Midlands females are non-Caucasian. We aimed to elucidate the pathologic features, molecular profile, and outcome of non-Caucasian breast cancer. Methods: Breast cancers (BCs) of different ethnic origins diagnosed at a large Birmingham tertiary referral hospital between 2000 and 2016 were identified. Detailed clinical and histological data were collected and statistically analyzed. Results: Out of 7554 BC cases, 749 were of ethnic ancestry and median age of 51 years. These comprised 47 in-situ and 702 invasive carcinomas of presenting symptomatically in 86.2% of patients. 53.4% of the invasive carcinomas measured >20 mm. Cancers were predominantly of grade 3 (45%), and grade 2 (42.4%). Median NPI was 4.35. 65.1% of the ethnic carcinomas were of luminal subtype, 18.6% were Her2 positive and 16.2% triple-negative. Median overall survival was 62 months. Five and ten-year survival was 81.7% & 68.4% respectively. Ethnicity correlated with higher NPI (p <0.001), larger tumour size (p= 0.001) and larger number of positive axillary nodes (p=0.007). Negative correlations were found between age at diagnosis and both invasive tumour size & grade (p< 0.001) and between tumour grade and overall survival (p= 0.006). Conclusion: Compared with Caucasian breast cancer, non-Caucasian tumours presented predominantly symptomatically at younger age, were of larger size, higher grade with more unfavorable phenotypes and shorter survival. This is important in counselling, planning management and follow up of non-Caucasian patients.
  • In situ follicular neoplasia with translocation of BCL6 - a new variant with different immunohistochemical properties.

    Rudzki, Zbigniew; Starczynski, Jane; Dowds, James; Pemberton, Nicholas; Rudzk, Zbigniew; Dowds, James; Pathology; Additional Professional Scientific and Technical Field; Medical and Dental (Wiley-Blackwell, 2021-05-15)
    No abstract available
  • In vitro activity of cefiderocol and comparators against Gram-negative bacterial isolates from a series of surveillance studies in England: 2014-2018.

    Gant, Vanya; Hussain, Abid; Bain, Malcolm; Longshaw, Christopher; Henriksen, Anne Santerre; Hussain, Abid; Pathology; Medical and Dental (Elsevier, 2021-07-27)
    Objectives: The prevalence of Gram-negative bacteria (GNB) demonstrating extensive, multiple antimicrobial resistance is increasing in England, leaving few treatment choices. Cefiderocol is a novel siderophore cephalosporin approved in Europe for the treatment of aerobic GNB infections in adults with limited treatment options. We report pooled data for a clinical isolate set collected in England between 2014-2018. Methods: MICs were determined by broth microdilution according to International Organization for Standardization guidelines. Cefiderocol susceptibility was tested using iron-depleted cation-adjusted Muller-Hinton broth. Susceptibility rates were based on EUCAST breakpoints. In the absence of a species-specific breakpoint, pharmacokinetic/pharmacodynamic breakpoints were used. Results: Of 1886 isolates from England [74.1% Enterobacterales (18.7% Escherichia coli, 17.2% Klebsiella pneumoniae), 25.9% non-fermenters (18.4% Pseudomonas aeruginosa, 3.7% Acinetobacter baumannii)], 98.7% were cefiderocol-susceptible. Cefiderocol susceptibility in Enterobacterales (99.0%) was significantly (P < 0.01) greater than ceftolozane/tazobactam (94.3%), but similar to meropenem (99.3%) and ceftazidime/avibactam (99.4%). Overall, cefiderocol susceptibility (98.0%) in non-fermenters was significantly (P < 0.01) higher than comparators (range, 84.5-92.4%). Susceptibility to cefiderocol was 98.3-99.6% by infection source and was significantly (P < 0.01) greater than comparators for isolates from patients with nosocomial pneumonia (cefiderocol, 98.3%; comparators range, 79.8-93.8%). Excluding intrinsically meropenem-resistant Stenotrophomonas maltophilia, 47/1846 isolates (2.5%) were meropenem-resistant. A high proportion of meropenem-resistant P. aeruginosa were susceptible to cefiderocol (95.0%). All S. maltophilia isolates (40/40) were cefiderocol-susceptible. Conclusion: A substantial proportion of clinical isolates from England, representing a wide range of pathogens across multiple infection sources, was cefiderocol-susceptible. Cefiderocol retained activity against meropenem-resistant strains.
  • Incidents in molecular pathology: frequency and causes during routine testing.

    Keppens, Cleo; Van Royen, Yann; Brysse, Anne; Cotteret, Sophie; Høgdall, Estrid; Kuhlmann, Tine Plato; O'Sullivan, Brendan; Pauwels, Patrick; Pauwels, Siegrid; Rot, Mitja; et al. (College of American Pathologists, 2021-10-01)
    Context.—: Errors in laboratory medicine could compromise patient safety. Good laboratory practice includes identifying and managing nonconformities in the total test process. Varying error percentages have been described in other fields but are lacking for molecular oncology. Objectives.—: To gain insight into incident causes and frequency in the total test process from 8 European institutes routinely performing biomarker tests in non-small cell lung cancer and colorectal cancer. Design.—: All incidents documented in 2018 were collected from all hospital services for pre-preanalytical entries before the biomarker test, as well as specific incidents for biomarker tests. Results.—: There were 5185 incidents collected, of which 4363 (84.1%) occurred in the pre-preanalytical phase (all hospital services), 2796 of 4363 (64.1%) related to missing or incorrect request form information. From the other 822 specific incidents, 166 (20.2%) were recorded in the preanalytical phase, 275 (33.5%) in the analytical phase, and 194 (23.6%) in the postanalytical phase, mainly due to incorrect report content. Only 47 of 822 (5.7%) incidents were recorded in the post-postanalytical phase, and 123 (15.0%) in the complete total test process. For 17 of 822 (2.1%) incidents the time point was unknown. Pre-preanalytical incidents were resolved sooner than incidents on the complete process (mean 6 versus 60 days). For 1215 of 5168 (23.5%) incidents with known causes a specific action was undertaken besides documenting them, not limited to accredited institutes. Conclusions.—: There was a large variety in the number and extent of documented incidents. Correct and complete information on the request forms and final reports are highly error prone and require additional focus.
  • Interpreting EQA-understanding why commutability of materials matters.

    Badrick, Tony; Miller, W Greg; Panteghini, Mauro; Delatour, Vincent; Berghall, Heidi; MacKenzie, Finlay; Jones, Graham; MacKenzie, Finlay; Healthcare Scientists (Oxford University Press, 2022-03-31)
    No abstract available
  • Interobserver variability in the assessment of stromal tumor-infiltrating lymphocytes (sTILs) in triple-negative invasive breast carcinoma influences the association with pathological complete response: the IVITA study.

    Van Bockstal, Mieke R; François, Aline; Altinay, Serdar; Arnould, Laurent; Balkenhol, Maschenka; Broeckx, Glenn; Burguès, Octavio; Colpaert, Cecile; Dedeurwaerdere, Franceska; Dessauvagie, Benjamin; et al. (Elsevier, 2021-07-03)
    High stromal tumor-infiltrating lymphocytes (sTILs) in triple-negative breast cancer (TNBC) are associated with pathological complete response (pCR) after neoadjuvant chemotherapy (NAC). Histopathological assessment of sTILs in TNBC biopsies is characterized by substantial interobserver variability, but it is unknown whether this affects its association with pCR. Here, we aimed to investigate the degree of interobserver variability in an international study, and its impact on the relationship between sTILs and pCR. Forty pathologists assessed sTILs as a percentage in digitalized biopsy slides, originating from 41 TNBC patients who were treated with NAC followed by surgery. Pathological response was quantified by the MD Anderson Residual Cancer Burden (RCB) score. Intraclass correlation coefficients (ICCs) were calculated per pathologist duo and Bland-Altman plots were constructed. The relation between sTILs and pCR or RCB class was investigated. The ICCs ranged from -0.376 to 0.947 (mean: 0.659), indicating substantial interobserver variability. Nevertheless, high sTILs scores were significantly associated with pCR for 36 participants (90%), and with RCB class for eight participants (20%). Post hoc sTILs cutoffs at 20% and 40% resulted in variable associations with pCR. The sTILs in TNBC with RCB-II and RCB-III were intermediate to those of RCB-0 and RCB-I, with lowest sTILs observed in RCB-I. However, the limited number of RCB-I cases precludes any definite conclusions due to lack of power, and this observation therefore requires further investigation. In conclusion, sTILs are a robust marker for pCR at the group level. However, if sTILs are to be used to guide the NAC scheme for individual patients, the observed interobserver variability might substantially affect the chance of obtaining a pCR. Future studies should determine the 'ideal' sTILs threshold, and attempt to fine-tune the patient selection for sTILs-based de-escalation of NAC regimens. At present, there is insufficient evidence for robust and reproducible sTILs-guided therapeutic decisions.
  • Simultaneous detection of five one-carbon metabolites in plasma using stable isotope dilution liquid chromatography tandem mass spectrometry

    Adaikalakoteswari, Antonysunil; Webster, Craig; Goljan, Ilona; Saravanan, Ponnusamy; Goljan, Ilona; Saravanan, Ponnusamy; Webster, Craig; Diabetes and Metabolism; Medical and Dental; Pathology; et al. (Elsevier, 2016-02-15)
    Disturbance in one-carbon (1-C) cycle occurs due to nutritional deficiencies (vitamin B12/folate) or specific genetic polymorphisms. This leads to altered levels of key 1-C metabolites such as SAM (s-adenosyl methionine), SAH (s-adenosyl homocysteine), methionine, homocysteine and MMA (methyl malonic acid). These 1-C metabolites are determinants of cellular methylation potential and epigenetic modifications of DNA which impairs metabolic pathways in several pathological diseases and developmental programming. Though methods were able to measure these analytes only independently, none of the methods detect simultaneously. Therefore we developed a method to measure these five 1-C metabolites in a single run using liquid chromatography tandem mass spectrometry (LC-MS/MS). We used stable isotopes dilution LC-MS/MS to measure the 1-C metabolites in human plasma. Blood samples were collected from pregnant women (n=30) at early gestation in the ongoing, multicentre, prospective PRiDE study. Linearity exhibited across the calibration range for all the analytes with the limit of detection (LOD) of 1.005nmol/l for SAM, 0.081nmol/l for SAH, 0.002μmol/l for methionine, 0.046μmol/l for homocysteine and 3.920nmol/l for MMA. The average recovery for SAM was 108%, SAH-110%, methionine-97%, homocysteine-91% and MMA-102%. The inter-assay CV for SAM was 7.3, SAH-5.6%, methionine-3.5%, homocysteine-7.0% and MMA-4.0%. The intra-assay CV for SAM was 8.7%, SAH-4.7%, methionine-5.4%, homocysteine-8.1% and MMA-6.1%. Pregnant women at early gestation with low B12 levels had significantly higher homocysteine, MMA, lower levels of methionine, SAM and SAM:SAH ratio and higher triglycerides. We developed a simple and rapid method to simultaneously quantify 1-C metabolites such as SAM, SAH, methionine, homocysteine and MMA in plasma by stable isotope dilution LC-MS/MS which would be useful to elucidate the epigenetic mechanisms related in the gene-nutrient interactions.
  • Guidelines for cellular and molecular pathology content in clinical trial protocols: the SPIRIT-Path extension.

    Kendall, Timothy J; Robinson, Max; Brierley, Daniel J; Lim, Shujing Jane; O'Connor, Daniel J; Shaaban, Abeer M; Lewis, Ian; Chan, An-Wen; Harrison, David J; Shaaban, Abeer M; et al. (Lancet Publishing Group, 2021-10)
    The 2013 SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) Statement provides evidence-based recommendations for the minimum content to be included in a clinical trial protocol. Assessment of biospecimens is often required for trial eligibility or as part of an outcome evaluation, and precision molecular approaches are increasingly used in trial design. However, cellular and molecular pathology practices within trials have not been codified or formalised. We developed international consensus reporting guidelines for cellular and molecular pathology content in clinical trial protocols (the SPIRIT-Path extension) using an international Delphi process, which assesses candidate items generated from a previous systematic review, followed by an expert consensus meeting. 74 individuals from five continents responded, including clinicians, statisticians, laboratory scientists, patient advocates, funders, industry representatives, journal editors, and regulators. The SPIRIT-Path guidelines recommend 14 additional items (seven extensions to the SPIRIT checklist and seven elaborations) that should be addressed in trial protocols containing pathology content, alongside the SPIRIT 2013 Statement items. SPIRIT-Path recommends that protocols should document the individuals, processes, and standards for all cellular and molecular pathology components of the trial, including all stages of the specimen pathway and any digital pathology methods, with specific consideration of the value of trial data and biological tissues for additional translational studies.
  • Understanding the limitations of your assay using EQA data with serum creatinine as an example.

    Marrington, Rachel; MacKenzie, Finlay; Marrington, Rachel; MacKenzie, Finlay; NEQAS; Additional Professional Scientific and Technical Field; University Hospitals Birmingham (De Gruyter, 2024-04-04)
    Objectives: Laboratories need to take into consideration the specificity and imprecision of assays not only in verification, but also of quality assessment. This study investigates the composition of serum used in EQA materials by comparing material from a single and multiple donors (pooled material), across multiple methods, using creatinine as an example. Methods: Sixteen different serum matrices were distributed as 36 specimens through the UK NEQAS for Acute and Chronic Kidney Disease Scheme from March 2022 to March 2023. Male-only and female-only serum was used as single donations, pooled donations, unmanipulated or with added exogenous creatinine. Specimens were distributed to primarily UK participants (approximately n=500) for creatinine analysis. Data has been reviewed by method compared to the enzymatic creatinine method principle mean. Results: From the 16 different matrices, only the enzymatic creatinine assay systems from Roche Cobas and Siemens Atellica met the minimum acceptable bias goal, from biological data, of 5.6 %, in all specimens. Pooled material showed less variation in bias across all methods. Conclusions: Since Laboratories invest a lot of time and money in quality management, they need to know the limitations of their assays so that they are not investigating 'apparent' EQA/IQC problems which are purely due to non-specific, imprecise assay, rather than an analytical issue in their laboratory. When large numbers of individual donations are combined, interferents are essentially diluted out. Therefore, if EQA material is of this type it will be very difficult to determine the actual assay's bias and variability.
  • Inhibition of the glucocorticoid-activating enzyme 11β-hydroxysteroid dehydrogenase type 1 drives concurrent 11-oxygenated androgen excess.

    Schiffer, Lina; Oestlund, Imken; Snoep, Jacky L; Gilligan, Lorna C; Taylor, Angela E; Sinclair, Alexandra J; Singhal, Rishi; Freeman, Adrian; Ajjan, Ramzi; Tiganescu, Ana; et al. (Federation of American Societies for Experimental Biology ; Wiley, 2024-04-15)
    Aldo-keto reductase 1C3 (AKR1C3) is a key enzyme in the activation of both classic and 11-oxygenated androgens. In adipose tissue, AKR1C3 is co-expressed with 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1), which catalyzes not only the local activation of glucocorticoids but also the inactivation of 11-oxygenated androgens, and thus has the potential to counteract AKR1C3. Using a combination of in vitro assays and in silico modeling we show that HSD11B1 attenuates the biosynthesis of the potent 11-oxygenated androgen, 11-ketotestosterone (11KT), by AKR1C3. Employing ex vivo incubations of human female adipose tissue samples we show that inhibition of HSD11B1 results in the increased peripheral biosynthesis of 11KT. Moreover, circulating 11KT increased 2-3 fold in individuals with type 2 diabetes after receiving the selective oral HSD11B1 inhibitor AZD4017 for 35 days, thus confirming that HSD11B1 inhibition results in systemic increases in 11KT concentrations. Our findings show that HSD11B1 protects against excess 11KT production by adipose tissue, a finding of particular significance when considering the evidence for adverse metabolic effects of androgens in women. Therefore, when targeting glucocorticoid activation by HSD11B1 inhibitor treatment in women, the consequently increased generation of 11KT may offset beneficial effects of decreased glucocorticoid activation.
  • Testing for t(3;8) in MYC/BCL6 re-arranged large B cell lymphoma identifies a high risk subgroup with inferior survival

    Maybury, Bernard Douglas; James, Lisa Jane; Phillips, Neil; Venkatadasari, Indrani; Qureshi, Iman; Riley, James William Elliot; Talbot, Georgina; Moosai, Shivir; Giles, Hannah Victoria; Chadderton, Nicola; et al. (American Society of Hematology, 2024-04-22)
    A reciprocal t(3;8) BCL6::MYC fusion is common in large B cell lymphoma (LBCL) with MYC and BCL6 disruption. These pseudo-double hit cases are not adverse, whereas t(3;8) negative MYC/BCL6 lymphoma has an inferior prognosis relative to other MYC-rearranged LBCL.
  • A practical approach to screening for carbapenemase-producing Enterobacterales- views of a group of multidisciplinary experts from English hospitals.

    Jenkins, D R; Auckland, C; Chadwick, C; Dodgson, A R; Enoch, D A; Goldenberg, S D; Hussain, A; Martin, J; Spooner, E; Whalley, T; et al. (BioMed Central, 2024-04-26)
    Introduction: Carbapenemase-producing Enterobacterales (CPE) are an important public health threat, with costly operational and economic consequences for NHS Integrated Care Systems and NHS Trusts. UK Health Security Agency guidelines recommend that Trusts use locally developed risk assessments to accurately identify high-risk individuals for screening, and implement the most appropriate method of testing, but this presents many challenges. Methods: A convenience sample of cross-specialty experts from across England met to discuss the barriers and practical solutions to implementing UK Health Security Agency framework into operational and clinical workflows. The group derived responses to six key questions that are frequently asked about screening for CPE. Key findings: Four patient groups were identified for CPE screening: high-risk unplanned admissions, high-risk elective admissions, patients in high-risk units, and known positive contacts. Rapid molecular testing is a preferred screening method for some of these settings, offering faster turnaround times and more accurate results than culture-based testing. It is important to stimulate action now, as several lessons can be learnt from screening during the COVID-19 pandemic, as well as from CPE outbreaks. Conclusion: Further decisive and instructive information is needed to establish CPE screening protocols based on local epidemiology and risk factors. Local management should continually evaluate local epidemiology, analysing data and undertaking frequent prevalence studies to understand risks, and prepare resources- such as upscaled screening- to prevent increasing prevalence, clusters or outbreaks. Rapid molecular-based methods will be a crucial part of these considerations, as they can reduce unnecessary isolation and opportunity costs. Keywords: Antimicrobial resistance; Carbapenemase-producing enterobacterales; Guidance; Healthcare legislation; Public health; Roundtable meeting.
  • Cross-tissue, single-cell stromal atlas identifies shared pathological fibroblast phenotypes in four chronic inflammatory diseases

    Korsunsky, Ilya; Wei, Kevin; Pohin, Mathilde; Kim, Edy Y; Barone, Francesca; Major, Triin; Taylor, Emily; Ravindran, Rahul; Kemble, Samuel; Watts, Gerald F M; et al. (Cell Press, 2022-05-31)
    Background: Pro-inflammatory fibroblasts are critical for pathogenesis in rheumatoid arthritis, inflammatory bowel disease, interstitial lung disease, and Sjögren's syndrome and represent a novel therapeutic target for chronic inflammatory disease. However, the heterogeneity of fibroblast phenotypes, exacerbated by the lack of a common cross-tissue taxonomy, has limited our understanding of which pathways are shared by multiple diseases. Methods: We profiled fibroblasts derived from inflamed and non-inflamed synovium, intestine, lungs, and salivary glands from affected individuals with single-cell RNA sequencing. We integrated all fibroblasts into a multi-tissue atlas to characterize shared and tissue-specific phenotypes. Findings: Two shared clusters, CXCL10+CCL19+ immune-interacting and SPARC+COL3A1+ vascular-interacting fibroblasts, were expanded in all inflamed tissues and mapped to dermal analogs in a public atopic dermatitis atlas. We confirmed these human pro-inflammatory fibroblasts in animal models of lung, joint, and intestinal inflammation. Conclusions: This work represents a thorough investigation into fibroblasts across organ systems, individual donors, and disease states that reveals shared pathogenic activation states across four chronic inflammatory diseases.
  • Outbreak of diarrhea caused by a novel cryptosporidium hominis subtype during british military training in Kenya

    Toriro, Romeo; Pallett, Scott; Woolley, Stephen; Bennett, Charlie; Hale, Isra; Heylings, Jennifer; Wilkins, Daniel; Connelly, Thomas; Muia, Kennedy; Avery, Patrick; et al. (Oxford University Press, 2024-01-03)
    Background: We report clinical, epidemiological, and laboratory features of a large diarrhea outbreak caused by a novel Cryptosporidium hominis subtype during British military training in Kenya between February and April 2022. Methods: Data were collated from diarrhea cases, and fecal samples were analyzed on site using the multiplex polymerase chain reaction (PCR) BioFire FilmArray. Water was tested using Colilert kits (IDEXX, UK). DNA was extracted from feces for molecular characterization of Cryptosporidium A135, Lib13, ssu rRNA, and gp60 genes. Results: One hundred seventy-two of 1200 (14.3%) personnel at risk developed diarrhea over 69 days. One hundred six primary fecal samples were tested, and 63/106 (59.4%; 95% CI, 0.49%-0.69%) were positive for Cryptosporidium spp. Thirty-eight had Cryptosporidium spp. alone, and 25 had Cryptosporidium spp. with ≥1 other pathogen. A further 27/106 (25.5%; 95% CI, 0.18%-0.35%) had non-Cryptosporidium pathogens only, and 16/106 (15.1%; 95% CI, 0.09%-0.23%) were negative. C. hominis was detected in 58/63 (92.1%) Cryptosporidium spp.-positive primary samples, but the others were not genotypable. Twenty-seven C. hominis specimens were subtypable; 1 was gp60 subtype IeA11G3T3, and 26 were an unusual subtype, ImA13G1 (GenBank accession OP699729), supporting epidemiological evidence suggesting a point source outbreak from contaminated swimming water. Diarrhea persisted for a mean (SD) of 7.6 (4.6) days in Cryptosporidium spp. cases compared with 2.3 (0.9) days in non-Cryptosporidium cases (P = .001). Conclusions: Real-time multiplex PCR fecal testing was vital in managing this large cryptosporidiosis outbreak. The etiology of a rare C. hominis gp60 subtype emphasizes the need for more genotypic surveillance to identify widening host and geographic ranges of novel C. hominis subtypes.
  • Clinicopathological features and androgen receptor expression in triple negative breast cancer at Lagos, Nigeria

    Haruna, Muibat; Daramola, Adetola Olubunmi; Awolola, Nicholas Awodele; Badr, Nahla Mustafa; Banjo, Adekunbiola Aina Fehintola; Shaaban, Abeer; Shaaban, Abeer; Histopathology; Medical and Dental (ecancer, 2022-10-03)
    Introduction: Androgen receptor (AR) is one of the predominant nuclear hormone receptors in invasive breast cancer and can be explored as a biomarker of response for targeted anti-androgen therapy, especially in the setting of triple negative breast cancer (TNBC). Luminal AR is a distinct subtype amongst TNBC cases following gene expression studies. TNBC is higher in Africans (23%-82%) and African-Americans (29.8%) compared to Caucasian (10%-15%) breast cancer patients; however, there is a paucity of data on AR expression in this population. The aim of this study is to determine the expression of AR and the proportion of AR positive cancers in TNBCs at the Lagos University Teaching Hospital, Lagos, Nigeria. Methodology: Out of 99 reviewed cases, 78 formalin fixed, paraffin embedded TNBC cases were assembled into a tissue microarray, stained and analysed for AR expression using immunohistochemistry. Results: The mean age of the TNBC patients was 49.3 years (range: 20-80 years). The histologic types in this study were invasive carcinoma (no special type) 75.4%; metaplastic carcinoma 21.4%; lobular carcinoma and mucinous carcinoma 1.6% each. Of 61 TNBC cases analysed, 37.7% were AR positive and 62.3% were AR negative, making the latter to become quadruple negative breast cancers. There was a significant association between age and AR expression (p = 0.02). In the subjects that expressed AR positivity, patients below 50 years accounted for 34.8% (8 of 23) while 65.2% (15 of 23) were above 50 years. There was no significant association between AR expression and histologic type or tumour grade. Conclusion: Over a third of this Nigerian TNBC cohort study is AR+. This warrants further exploration of the predictive and prognostic significance of its expression amongst TNBC and the potential for targeted therapy, specifically androgen antagonists to improve the outcome of this disease with limited therapeutic options.
  • The frequency and clinical significance of centromere enumeration probe 17 alterations in human epidermal growth factor receptor 2 immunohistochemistry-equivocal invasive breast cancer.

    Katayama, Ayaka; Starczynski, Jane; Toss, Michael S; Shaaban, Abeer M; Provenzano, Elena; Quinn, Cecily M; Callagy, Grace; Purdie, Colin A; Millican-Slater, Rebecca; Purnell, David; et al. (Wiley, 2022-08-08)
    Background and aims: Chromosome 17 alterations affect the assessment of HER2 gene amplification in breast cancer (BC), but its clinical significance remains unclear. This study aimed to identify the prevalence of centromere enumeration probe 17 (CEP17) alterations, and its correlation with response to neoadjuvant therapy (NAT) in BC patients with human epidermal growth factor receptor 2 (HER2) immunohistochemistry-equivocal score. Methods and results: A large BC cohort (n = 6049) with HER2 immunohistochemistry score 2+ and florescent in-situ hybridisation (FISH) results was included to assess the prevalence of CEP17 alterations. Another cohort (n = 885) with available clinicopathological data was used to evaluate the effect of CEP17 in the setting of NAT. HER2-amplified tumours with monosomy 17 (CEP17 copy number < 1.5 per nucleus), normal 17 (CEP17 1.5-< 3.0) and polysomy 17 (CEP17 ≥ 3.0) were observed in 16, 59 and 25%, respectively, compared with 3, 74 and 23%, respectively, in HER2-non-amplified tumours. There was no significant relationship between CEP17 alterations and pathological complete response (pCR) rate in both HER2-amplified and HER2-non-amplified tumours. The independent predictors of pCR were oestrogen (ER) negativity in HER2-amplified tumours [ER negative versus positive; odds ratio (OR) = 11.80; 95% confidence interval (CI) = 1.37-102.00; P = 0.02], and histological grade 3 in HER2 non-amplified tumours (3 versus 1, 2; OR = 5.54; 95% CI = 1.61-19.00; P = 0.007). Conclusion: The impacts of CEP17 alterations are not as strong as those of HER2/CEP17 ratio and HER2 copy number. The hormonal receptors status and tumour histological grade are more useful to identify BC patients with a HER2 immunohistochemistry-equivocal score who would benefit from NAT.
  • Multiparametric MRI and T2/FLAIR mismatch complements the World Health Organization 2021 classification for the diagnosis of IDH-mutant 1p/19q non-co-deleted/ATRX-mutant astrocytoma.

    Sawlani, V; Jen, J P; Patel, M; Jain, M; Haq, H; Ughratdar, I; Wykes, V; Nagaraju, S; Watts, C; Pohl, U; et al. (Wiley, 2023-12-05)
    Aim: To investigate whether T2-weighted imaging-fluid-attenuated inversion recovery (T2/FLAIR) mismatch, T2∗ dynamic susceptibility contrast (DSC) perfusion, and magnetic resonance spectroscopy (MRS) correlated with the histological diagnosis and grading of IDH (isocitrate dehydrogenase)-mutant, 1p/19q non-co-deleted/ATRX (alpha-thalassemia mental retardation X-linked)-mutant astrocytoma. Materials: Imaging of 101 IDH-mutant diffuse glioma cases of histological grades 2-3 (2019-2021) were analysed retrospectively by two neuroradiologists blinded to the molecular diagnosis. T2/FLAIR mismatch sign is used for radio-phenotyping, and pre-biopsy multiparametric MRI images were assessed for grading purposes. Cut-off values pre-determined for radiologically high-grade lesions were relative cerebral blood volume (rCBV) ≥2, choline/creatine ratio (Cho/Cr) ≥1.5 (30 ms echo time [TE]), Cho/Cr ≥1.8 (135 ms TE). Results: Sixteen of the 101 cases showed T2/FLAIR mismatch, all of which were histogenetically confirmed IDH-mutant 1p/19q non-co-deleted/ATRX mutant astrocytomas; 50% were grade 3 (8/16) and 50% grade 2 (8/16). None showed contrast enhancement. Nine of the 16 had adequate multiparametric MRI for analysis. Any positive value by combining rCBV ≥2 with Cho/Cr ≥1.5 (30 ms TE) or Cho/Cr ≥1.8 (135 ms TE) predicted grade 3 histology with sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 100%. Conclusion: The T2/FLAIR mismatch sign detected diffuse astrocytomas with 100% specificity. When combined with high Cho/Cr and raised rCBV, this predicted histological grading with high accuracy. The future direction for imaging should explore a similar integrated layered approach of 2021 classification of central nervous system (CNS) tumours combining radio-phenotyping and grading from structural and multiparametric imaging.
  • Vitamin B12 deficiency and altered one-carbon metabolites in early pregnancy is associated with maternal obesity and dyslipidaemia

    Adaikalakoteswari, Antonysunil; Wood, Catherine; Mina, Theresia H.; Webster, Craig; Goljan, Ilona; Weldeselassie, Yonas; Reynolds, Rebecca M.; Saravanan, Ponnusamy; Wood, Catherine; Goljan, Ilona; et al. (Nature Research, 2020-07-06)
    Vitamin B12 (B12) is a micronutrient essential for one-carbon (1C) metabolism. B12 deficiency disturbs the 1C cycle and alters DNA methylation which is vital for most metabolic processes. Studies show that B12 deficiency may be associated with obesity, insulin resistance and gestational diabetes; and with obesity in child-bearing women. We therefore hypothesised that the associations between B12 deficiency, BMI and the metabolic risk could be mediated through altered 1C metabolites in early pregnancy. We explored these associations in two different early pregnancy cohorts in the UK (cohort 1; n = 244 and cohort 2; n = 60) with anthropometric data at 10-12 weeks and plasma/serum sampling at 16-18 weeks. B12, folate, total homocysteine (tHcy), methionine, MMA, metabolites of 1C metabolism (SAM, SAH) and anthropometry were measured. B12 deficiency (< 150 pmol/l) in early pregnancy was 23% in cohort 1 and 18% in cohort 2. Regression analysis after adjusting for likely confounders showed that B12 was independently and negatively associated with BMI (Cohort 1: β = - 0.260, 95% CI (- 0.440, - 0.079), p = 0.005, Cohort 2: (β = - 0.220, 95% CI (- 0.424, - 0.016), p = 0.036) and positively with HDL cholesterol (HDL-C) (β = 0.442, 95% CI (0.011,0.873), p = 0.045). We found that methionine (β = - 0.656, 95% CI (- 0.900, - 0.412), p < 0.0001) and SAH (β = 0.371, 95% CI (0.071, 0.672), p = 0.017) were independently associated with triglycerides. Low B12 status and alteration in metabolites in 1C metabolism are common in UK women in early pregnancy and are independently associated with maternal obesity and dyslipidaemia. Therefore, we suggest B12 monitoring in women during peri-conceptional period and future studies on the pathophysiological relationship between changes in 1C metabolites and its association with maternal and fetal outcomes on larger cohorts. This in turn may offer potential to reduce the metabolic risk in pregnant women and their offspring.
  • UK recommendations for HER2 assessment in breast cancer: an update.

    Rakha, Emad A; Tan, Puay Hoon; Quinn, Cecily; Provenzano, Elena; Shaaban, Abeer M; Deb, Rahul; Callagy, Grace; Starczynski, Jane; Lee, Andrew H S; Ellis, Ian O; et al. (BMJ Publishing Group, 2022-12-23)
    The last UK breast cancer (BC) human epidermal growth factor receptor 2 (HER2) testing guideline recommendations were published in 2015. Since then, new data and therapeutic strategies have emerged. The American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) published a focused update in 2018 that reclassified in situ hybridisation (ISH) Group 2 (immunohistochemistry (IHC) score 2+and HER2/chromosome enumeration probe 17 (CEP17) ratio ≥2.0 and HER2 copy number <4.0 signals/cell), as well as addressed other concerns raised by previous guidelines. The present article further refines UK guidelines, with specific attention to definitions of HER2 status focusing on eight key areas: (1) HER2 equivocal (IHC 2+) and assignment of the ASCO/CAP ISH group 2 tumours; (2) the definition of the group of BCs with low IHC scores for HER2 with emphasis on the distinction between IHC score 1+ (HER2-Low) from HER2 IHC score 0 (HER2 negative); (3) reporting cases showing HER2 heterogeneity; (4) HER2 testing in specific settings, including on cytological material; (5) repeat HER2 testing, (6) HER2 testing turnaround time targets; (7) the potential role of next generation sequencing and other diagnostic molecular assays for routine testing of HER2 status in BC and (8) use of image analysis to score HER2 IHC. The two tiered system of HER2 assessment remains unchanged, with first line IHC and then ISH limited to IHC equivocal cases (IHC score 2+) but emerging data on the relationship between IHC scores and levels of response to anti-HER2 therapy are considered. Here, we present the latest UK recommendations for HER2 status evaluation in BC, and where relevant, the differences from other published guidelines.
  • Damage-associated cellular markers in the clinical and pathogenic profile of vaccine-induced immune thrombotic thrombocytopenia

    Abrams, Simon T; Du, Min; Shaw, Rebecca J; Johnson, Carla; McGuinness, Dagmara; Schofield, Jeremy; Yong, Jun; Turtle, Lance; Nicolson, Phillip L R; Moxon, Christopher; et al. (Elsevier, 2023-12-15)
    Background: Adenoviral vector-based COVID-19 vaccine-induced immune thrombotic thrombocytopenia (VITT) is rare but carries significant risks of mortality and long-term morbidity. The underlying pathophysiology of severe disease is still not fully understood. The objectives were to explore the pathophysiological profile and examine for clinically informative biomarkers in patients with severe VITT. Methods: Twenty-two hospitalized patients with VITT, 9 pre- and 21 post-ChAdOx1 vaccine controls, were recruited across England, United Kingdom. Admission blood samples were analyzed for cytokine profiles, cell death markers (lactate dehydrogenase and circulating histones), neutrophil extracellular traps, and coagulation parameters. Tissue specimens from deceased patients were analyzed. Results: There were strong immune responses characterized by significant elevations in proinflammatory cytokines and T helper 1 and 2 cell activation in patients with VITT. Markers of systemic endothelial activation and coagulation activation in both circulation and organ sections were also significantly elevated. About 70% (n = 15/22) of patients met the International Society for Thrombosis and Haemostasis criteria for disseminated intravascular coagulation despite negligible changes in the prothrombin time. The increased neutrophil extracellular trap formation, in conjunction with marked lymphopenia, elevated lactate dehydrogenase, and circulating histone levels, indicates systemic immune cell injury or death. Both lymphopenia and circulating histone levels independently predicted 28-day mortality in patients with VITT. Conclusion: The coupling of systemic cell damage and death with strong immune-inflammatory and coagulant responses are pathophysiologically dominant and clinically relevant in severe VITT.

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