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In partnership with NHS England, Genomics England’s ambitious plans to embed genomic medicine into routine patient care are well underway. Clare Turnbull and colleagues discuss its progress

T-cell non-Hodgkin’s lymphomas develop following transformation of tissue resident T-cells. We performed a meta-analysis of whole exome sequencing data from 403 patients with eight subtypes of T-cell non-Hodgkin’s lymphoma to identify mutational signatures and associated recurrent gene mutations. Signature 1, indicative of age-related deamination, was prevalent across all T-cell lymphomas, reflecting the derivation of these malignancies from memory T-cells. Adult T-cell leukemia-lymphoma was specifically associated with signature 17, which was found to correlate with the IRF4 K59R mutation that is exclusive to Adult T-cell leukemia-lymphoma. Signature 7, implicating UV exposure was uniquely identified in cutaneous T-cell lymphoma (CTCL), contributing 52% of the mutational burden in mycosis fungoides and 23% in Sezary syndrome. Importantly this UV signature was observed in CD4 + T-cells isolated from the blood of Sezary syndrome patients suggesting extensive re-circulation of these T-cells through skin and blood. Analysis of non-Hodgkin’s T-cell lymphoma cases submitted to the national 100,000 WGS project confirmed that signature 7 was only identified in CTCL strongly implicating UV radiation in the pathogenesis of cutaneous T-cell lymphoma.

While pathologists have always played a pivotal role in clinical trials ensuring accurate diagnosis and staging, pathology data from prognostic and predictive tests are increasingly being used to enrol, stratify and randomise patients to experimental treatments. The use of pathological parameters as primary and secondary outcome measures, either as standalone classifiers or in combination with clinical data, is also becoming more common. Moreover, reporting of estimates of residual disease, termed ‘pathological complete response’, have been incorporated into neoadjuvant clinical trials. Pathologists have the expertise to deliver this essential information and they also understand the requirements and limitations of laboratory testing. Quality assurance of pathology‐derived data builds confidence around trial‐specific findings and is necessarily focused on the reproducibility of pathological data, including ‘estimates of uncertainty of measurement’, emphasising the importance of pathologist education, training, calibration and demonstration of satisfactory inter‐observer agreement. There are also opportunities to validate objective image analysis tools alongside conventional histological assessments. The ever‐expanding portfolio of clinical trials will demand more pathologist engagement to deliver the reliable evidence‐base required for new treatments. We provide guidance for quality assurance of pathology scoring and reporting in clinical trials.

ObjectiveChlamydia trachomatis (Ct) is the most commonly reported sexually transmitted infection in the USA and causes important reproductive morbidity in women. The Centers for Disease Control and Prevention recommend routine screening of sexually active women under age 25 but not among men. Despite three decades of screening women, chlamydia prevalence in women remains high. Untested and untreated men can serve as a reservoir of infection in women, and male-screening based intervention can be an effective strategy to reduce infection in women. We assessed the impact of screening men on the Ct prevalence in women.DesignWe created an individual-based network model to simulate a realistic chlamydia epidemic on sexual contact networks for a synthetic population (n=5000). The model is calibrated to the ongoing routine screening among African American (AA) women in the USA and detailed a male-screening programme, Check It, that bundles best practices for Ct control. We used sensitivity analysis to quantify the relative importance of each intervention component.SettingCommunity-based venues in New Orleans, Louisiana, USA.ParticipantsHeterosexual AA men, aged 15 to 24, who had sex with women in the past 2 months.InterventionVenue-based screening, expedited index treatment, expedited partner treatment and rescreening.ResultsWe estimate that by annually screening 7.5% of the AA male population in the age-range, the chlamydia prevalence would be reduced relatively by 8.1% (95% CI 5.9% to 10.4%) in AA women and 8.8% (95% CI 6.9% to 10.8%) in AA men. Each man screened could prevent 0.062 (95% CI 0.030 to 0.094) cases in men and 0.204 (95% CI 0.143 to 0.267) cases in women. The model suggested the importance of intervention components ranked from high to low as venue-based screening, expedited index treatment, expedited partner treatment and rescreening.ConclusionThe findings indicated that male-screening has the potential to substantially reduce the prevalence among women in high-prevalence communities.

It has been asserted that there was an erosion of medical ethics during the Covid-19 pandemic and a departure from the principle of obtaining fully informed consent from patients before treatment. In light of these assertions, this article reviews the historical development of medical ethics and the approach to obtaining informed consent and critiques the consent practices before and during the pandemic. It then describes a new tool for displaying key statistics on the benefits and risks of interventions to help explain them to patients and suggests a more rigorous process for seeking fully informed consent in the future.

AimsWhole-genome sequencing (WGS) is beginning to be applied to cancer samples in the clinical setting. This ideally requires high-quality, minimally degraded DNA of high tumour cell content, while retaining sufficient tissue with excellent morphology for histopathological diagnosis and immunohistochemistry. The aim of this study was to investigate alternative ways of handling cancer samples to fulfil both diagnostic and molecular requirements.MethodsEx vivo biopsies were taken to investigate the feasibility of using cancer cells ‘shaken’ from the surface of a biopsy for WGS, while maintaining the tissue biopsy for histological diagnosis. WGS from the shaken cells was compared with the gold standard of a fresh-frozen (FF) biopsy. The procedure was piloted in the real-world setting for breast cancer samples.ResultsCells shaken from ex vivo biopsies can yield DNA of sufficient quantity and quality for WGS, while having no discernible impact on quality of tissue morphology. WGS data showed good coverage, comparable variant calls and generally higher tumour content in shaken cell samples compared with the control FF samples. For real-world biopsies, DNA yields were lower, but WGS data were of excellent quality for the cases analysed.ConclusionsShaken biopsy sampling allows genomic sequencing from patients with cancer who may otherwise not receive a genome sequence due to limited sample availability. It represents a way of overcoming the logistics of obtaining and storing FF tissue making it a suitable technique for wider scale implementation in the clinical setting.

Digital pathology and image analysis potentially provide greater accuracy, reproducibility and standardisation of pathology‐based trial entry criteria and endpoints, alongside extracting new insights from both existing and novel features. Image analysis has great potential to identify, extract and quantify features in greater detail in comparison to pathologist assessment, which may produce improved prediction models or perform tasks beyond manual capability. In this article, we provide an overview of the utility of such technologies in clinical trials and provide a discussion of the potential applications, current challenges, limitations and remaining unanswered questions that require addressing prior to routine adoption in such studies. We reiterate the value of central review of pathology in clinical trials, and discuss inherent logistical, cost and performance advantages of using a digital approach. The current and emerging regulatory landscape is outlined. The role of digital platforms and remote learning to improve the training and performance of clinical trial pathologists is discussed. The impact of image analysis on quantitative tissue morphometrics in key areas such as standardisation of immunohistochemical stain interpretation, assessment of tumour cellularity prior to molecular analytical applications and the assessment of novel histological features is described. The standardisation of digital image production, establishment of criteria for digital pathology use in pre‐clinical and clinical studies, establishment of performance criteria for image analysis algorithms and liaison with regulatory bodies to facilitate incorporation of image analysis applications into clinical practice are key issues to be addressed to improve digital pathology incorporation into clinical trials.

Mutational signatures are imprints of pathophysiological processes arising through tumorigenesis. We generated isogenic CRISPR-Cas9 knockouts (Δ) of 43 genes in human induced pluripotent stem cells, cultured them in the absence of added DNA damage, and performed whole-genome sequencing of 173 subclones. Δ Δ Δ Δ Δ Δ Δ Δ and Δ produced marked mutational signatures indicative of being critical mitigators of endogenous DNA modifications. Detailed analyses revealed mutational mechanistic insights, including how 8-oxo-dG elimination is sequence-context-specific while uracil clearance is sequence-context-independent. Mismatch repair (MMR) deficiency signatures are engendered by oxidative damage (C>A transversions), differential misincorporation by replicative polymerases (T>C and C>T transitions), and we propose a 'reverse template slippage' model for T>A transversions. Δ Δ and Δ signatures were similar to each other but distinct from Δ . Finally, we developed a classifier, MMRDetect, where application to 7,695 WGS cancers showed enhanced detection of MMR-deficient tumors, with implications for responsiveness to immunotherapies.

Abstract Rationale The Xpert (GeneXpert) MTB/RIF, an integrated polymerase chain reaction assay, has not been systematically studied in extrapulmonary and in particular mediastinal tuberculosis (TB). Objectives To investigate the performance of Xpert MTB/RIF in the diagnosis of intrathoracic nodal TB in a large tertiary urban medical center in the UK. Methods We collected clinical, cytological, and microbiological data from two cohorts: 116 consecutive patients referred with mediastinal lymphadenopathy with detailed diagnostic information obtained, and an immediately subsequent second cohort of 52 consecutive patients with microbiologically confirmed mediastinal TB lymphadenopathy. All data were derived between January 2010 and October 2012. All patients underwent endobronchial ultrasound and transbronchial needle aspiration (TBNA). The performance of a single Xpert MTB/RIF assay alongside standard investigations, cytology, and microscopy/culture was evaluated against culture-confirmed TB. Measurements and Main Results Microbiologically confirmed TB mediastinal lymphadenopathy was diagnosed in a total of 88 patients from both cohorts. Three culture-negative cases with associated caseating granulomatous inflammation on TBNA were given a probable diagnosis. A single Xpert MTB/RIF assay demonstrated overall sensitivity for culture-positive TB of 72.6% (62.3–81.0%). Xpert specificity from cohort 1 was 96.3% (89.1–99.1%). The positive predictive value was 88.9% (69.7–97.1%), negative predictive value was 86.5% (76.9–92.1%), and odds ratio was 51.3 (24.0–98.0) for correctly identifying culture-positive disease. Xpert captured all microscopy-positive cases (14 of 14) and the majority of microscopy-negative cases (48 of 71, 67.6%). Among the cases that were culture positive by TBNA, Xpert identified two-thirds of the multiple drug–resistant TB cases, leading to immediate regimen change up to 5 weeks ahead of positive cultures. The use of Xpert combined with cytology increased the sensitivity to 96.6%. Conclusions Xpert MTB/RIF provides a rapid, useful, and accurate test to diagnose mediastinal nodal TB in intermediate-incidence settings. The additional use of TBNA cytology further enhances the sensitivity of Xpert. This combination can facilitate rapid risk assessment and prompt TB treatment.