Showing papers by "Adrian C Bateman published in 2021"

Human Intestinal Macrophages Are Involved in the Pathology of Both Ulcerative Colitis and Crohn Disease.

Abstract: Background Intestinal macrophages are key immune cells in the maintenance of intestinal immune homeostasis and have a role in the pathogenesis of inflammatory bowel disease (IBD) However, the mechanisms by which macrophages exert a pathological influence in both ulcerative colitis (UC) and Crohn disease (CD) are not yet well understood Methods We purified intestinal macrophages from gastrointestinal mucosal biopsies (patients with UC, patients with CD, and healthy donors) and analyzed their transcriptome by RNA sequencing and bioinformatics, confirming results with quantitative polymerase chain reaction and immunohistochemistry Results Compared with those of healthy donors, intestinal macrophages in patients with UC and with CD showed cellular reprograming of 1287 and 840 dysregulated genes, respectively (false discovery rate ≤ 01) The UC and CD intestinal macrophages showed an activated M1 inflammatory phenotype and the downregulation of genes engaged in drug/xenobiotic metabolism Only macrophages from CD showed, concomitant to an M1 phenotype, a significant enrichment in the expression of M2 and fibrotic and granuloma-related genes For the first time, we showed (and validated by quantitative polymerase chain reaction and immunohistochemistry) that intestinal macrophages in patients with IBD present both M1 and M2 features, as recently described for tumor-associated macrophages, that affect key pathways for IBD pathology, represented by key markers such as MMP12 (fibrosis), CXCL9 (T-cell attraction), and CD40 (T-cell activation) Conclusions Our data support the therapeutic targeting of macrophages to maintain remission in IBD but also indicate that a shift toward an M2 program-as proposed by some reports-may not limit the recruitment and activation of T cells because M2 features do not preclude M1 activation in patients with UC or CD and could exacerbate M2-related CD-specific features such as fibrosis and the formation of granulomas

DNA mismatch repair proteins: scientific update and practical guide

Abstract: DNA mismatch repair (MMR) proteins are essential for the recognition and correction of sporadic genetic mutations that occur during DNA replication. Deficient MMR function (dMMR) leads to an increased risk of development of neoplasia. Identification of dMMR within tumours can suggest a high chance of the inherited cancer condition Lynch syndrome and predicts poor clinical response to certain conventional chemotherapies but an increased likelihood of response to immunotherapy. This review provides an update on the biology of MMR proteins, their encoding genes and mechanisms for the development of dMMR. This is followed by a discussion of the identification and significance of dMMR in routine clinical practice.

Histopathological diagnosis of tumour deposits in colorectal cancer: a Delphi consensus study

Abstract: Aims Tumour deposits (TDs) are an important prognostic marker in colorectal cancer. However, the classification, and inclusion in staging, of TDs has changed significantly in each tumour-node-metastasis (TNM) edition since their initial description in TNM-5, and terminology remains controversial. Expert consensus is needed to guide the future direction of precision staging. Methods and results A modified Delphi consensus process was used. Statements were formulated and sent to participants as an online survey. Participants were asked to rate their agreement with each statement on a five-point Likert scale and also to suggest additional statements for discussion. These responses were circulated together with anonymised comments, and statements were modified prior to carrying out a second online round. Consensus was set at 70%. Overall, 32 statements reached consensus. There were concerns that TDs were currently incorrectly placed in the TNM system and that their prognostic importance was being underestimated. There were concerns regarding interobserver variation and it was felt that a clearer, more reproducible definition of TDs was needed. Conclusions Our main recommendations are that the number of TDs should be recorded even if lymph node metastases (LNMs) are also present and that nodules with evidence of origin [extramural venous invasion (EMVI), perineural invasion (PNI), lymphatic invasion (LI)] should still be categorised as TDs and not excluded, as TNM-8 specifies. Whether TDs should continue to be included in the N category at all is controversial, and did not achieve consensus; however, participants agreed that TDs are prognostically worse than LNMs and the N1c category is suboptimal, as it does not reflect this.

DNA mismatch repair protein immunohistochemistry - an illustrated guide.

Abstract: DNA mismatch repair (MMR) is an essential physiological process for correcting mutations occurring during DNA replication. Deficient MMR (dMMR) leads to increased tumour mutational burden, with a heightened risk of neoplasia. Demonstration of dMMR via the immunohistochemical assessment of MMR proteins is useful when screening for inherited cancer syndromes (especially Lynch syndrome) and for the prediction of clinical cancer response to conventional chemotherapy and novel immunotherapies. Identification of dMMR may also be helpful in other situations e.g. when considering a diagnosis of conventional dysplasia in sessile serrated lesions of the large intestine. This article provides a practical illustrated guide to DNA MMR interpretation, using a series of clinical examples.

The spectrum of serrated colorectal lesions-new entities and unanswered questions.

Abstract: Hyperplastic polyps (HPs) of the colon and rectum were historically thought not to be associated with an increased risk of development of colorectal cancer (CRC). The recognition of variants of serrated colorectal lesions that possessed relatively subtle but significant morphological differences from those of HPs and that could be associated with epithelial dysplasia and CRC led to the characterisation of sessile serrated lesions (SSLs) and traditional serrated adenomas (TSAs). These links were supported by the identification of genetic alterations that are commonly found in HPs, SSLs, TSAs, and CRC, e.g. BRAF and KRAS mutations. The 'serrated pathway' to CRC may progress faster than the traditional 'adenoma-carcinoma sequence', underlining the importance of identifying these lesions. The diagnostic histological criteria for SSLs have since been more clearly defined, in parallel with a drive to increase the recognition of these lesions at endoscopy. The existence of lesions showing overlapping morphological and molecular features with those of HPs, SSLs and TSAs has most recently been highlighted-including mucin-rich TSA, serrated tubulovillous adenoma, and those showing mixed histological features, e.g. comprising differing combinations of HP, SSL, and TSA. Morphological and molecular studies of this range of lesions are providing insights into the relationships of serrated colorectal lesions with each other and with CRC. This article provides an overview of the current understanding of serrated colorectal lesions, including a discussion of those with overlapping and mixed features.

Interobserver variation in the classification of tumor deposits in rectal cancer – is the use of histopathological characteristics the way to go?

Abstract: The focus on lymph node metastases (LNM) as the most important prognostic marker in colorectal cancer (CRC) has been challenged by the finding that other types of locoregional spread, including tumor deposits (TDs), extramural venous invasion (EMVI), and perineural invasion (PNI), also have significant impact. However, there are concerns about interobserver variation when differentiating between these features. Therefore, this study analyzed interobserver agreement between pathologists when assessing routine tumor nodules based on TNM 8. Electronic slides of 50 tumor nodules that were not treated with neoadjuvant therapy were reviewed by 8 gastrointestinal pathologists. They were asked to classify each nodule as TD, LNM, EMVI, or PNI, and to list which histological discriminatory features were present. There was overall agreement of 73.5% (κ 0.38, 95%-CI 0.33–0.43) if a nodal versus non-nodal classification was used, and 52.2% (κ 0.27, 95%-CI 0.23–0.31) if EMVI and PNI were classified separately. The interobserver agreement varied significantly between discriminatory features from κ 0.64 (95%-CI 0.58–0.70) for roundness to κ 0.26 (95%-CI 0.12–0.41) for a lone arteriole sign, and the presence of discriminatory features did not always correlate with the final classification. Since extranodal pathways of spread are prognostically relevant, classification of tumor nodules is important. There is currently no evidence for the prognostic relevance of the origin of TD, and although some histopathological characteristics showed good interobserver agreement, these are often non-specific. To optimize interobserver agreement, we recommend a binary classification of nodal versus extranodal tumor nodules which is based on prognostic evidence and yields good overall agreement.

Variation in histopathological assessment and association with surgical quality indicators following oesophagectomy.

Abstract: Background Histopathological outcomes, such as lymph node yield and margin positivity, are used to benchmark and assess surgical centre quality, and are reported annually by the National Oesophago-Gastric Cancer Audit (NOGCA) in England and Wales. The variation in pathological specimen assessment and how this affects these outcomes is not known. Methods A survey of practice was circulated to all tertiary oesophagogastric cancer centres across England and Wales. Questions captured demographic data, and information on how specimens were prepared and analysed. National performance data were retrieved from the NOGCA. Survey results were compared for tertiles of lymph node yield, and circumferential and longitudinal margins. Results Survey responses were received from 32 of 37 units (86 per cent response rate), accounting for 93.1 per cent of the total oesophagectomy volume in England and Wales. Only 5 of 32 units met or exceeded current guidelines on specimen preparation according to the Royal College of Pathologists guidelines. There was wide variation in how centres defined positive (R1) margins, and how margins and lymph nodes were assessed. Centres with the highest nodal yield were more likely to use systematic fat blocking, and to re-examine specimens when the initial load was low. Systematic blocking of lesser curve fat resulted in significantly higher rates of patients with at least 15 lymph nodes examined (91.4 versus 86.5 per cent; P = 0.027). Conclusion Preparation and histopathological assessment of specimens varies significantly across institutions. This challenges the validity of currently used surgical quality metrics for oesophageal and other tumours.

Consensus recommendations for the standardized histopathological evaluation and reporting after radical oesophago-gastrectomy (HERO consensus).

Abstract: Background Variation in the approach, radicality, and quality of gastroesophageal surgery impacts patient outcomes. Pathological outcomes such as lymph node yield are routinely used as surrogate markers of surgical quality, but are subject to significant variations in histopathological evaluation and reporting. A multi-society consensus group was convened to develop evidence-based recommendations for the standardized assessment of gastroesophageal cancer specimens. Methods A consensus group comprised of surgeons, pathologists, and oncologists was convened on behalf of the Association of Upper Gastrointestinal Surgery of Great Britain & Ireland. Literature was reviewed for 17 key questions. Draft recommendations were voted upon via an anonymous Delphi process. Consensus was considered achieved where >70% of participants were in agreement. Results Consensus was achieved on 18 statements for all 17 questions. Twelve strong recommendations regarding preparation and assessment of lymph nodes, margins, and reporting methods were made. Importantly, there was 100% agreement that the all specimens should be reported using the Royal College of Pathologists Guidelines as the minimum acceptable dataset. In addition, two weak recommendations regarding method and duration of specimen fixation were made. Four topics lacked sufficient evidence and no recommendation was made. Conclusions These consensus recommendations provide explicit guidance for gastroesophageal cancer specimen preparation and assessment, to provide maximum benefit for patient care and standardize reporting to allow benchmarking and improvement of surgical quality.

Current dilemmas in the pathological staging of colorectal cancer: the results of a national survey.

Abstract: 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.

New life for old cellular pathology: a transformational approach to the upcycling of historic e-pathology records for contemporary clinical uses.

Abstract: Aims Cellular pathology (‘e-pathology’) record sets are a rich data resource with which to populate the electronic patient record (EPR). Accessible reports, even decades old, can be of great value in contemporary clinical decision making and as a resource for longitudinal clinical research. The aim of this short paper is to describe a solution in a major UK University Hospital which gives immediate visibility and clinical utility to 30 years of e-pathology records Methods Over the past decade, we have created a timeline structured and iconographic data framework for the ‘whole-of-life’ visualisation of the entirety of an EPR. We have enhanced this interface with the sequential extraction of 373 342 e-pathology reports from legacy Ferranti (1990–1997) and Masterlab (1997–2004) files. They have been uploaded into our SQL file servers, following appropriate data quality and patient identity reconciliation checks. Results We have restored a large repository of previously inaccessible e-pathology records to clinical use and to immediacy of access as a foundation element of our timeline structured EPR. This process has also allowed us to populate and validate an EPR-integral breast cancer data system of 20 000 cases with e-pathology records dating back to 1990. Conclusions The revitalisation of old e-pathology reports into a timeline structured EPR creates preserves and upcycles the investment in pathology reporting which is otherwise progressively lost to clinical use. E-pathology records provide reliable, life-long evidence of critical transition points in individual lives and disease progression for clinical and research use, when they can be instantly accessed.

Minimally invasive versus open distal pancreatectomy for pancreatic ductal adenocarcinoma (DIPLOMA): study protocol for a randomized controlled trial

Abstract: Background Recently, the first randomized trials comparing minimally invasive distal pancreatectomy (MIDP) with open distal pancreatectomy (ODP) for non-malignant and malignant disease showed a 2-day reduction in time to functional recovery after MIDP. However, for pancreatic ductal adenocarcinoma (PDAC), concerns have been raised regarding the oncologic safety (i.e., radical resection, lymph node retrieval, and survival) of MIDP, as compared to ODP. Therefore, a randomized controlled trial comparing MIDP and ODP in PDAC regarding oncological safety is warranted. We hypothesize that the microscopically radical resection (R0) rate is non-inferior for MIDP, as compared to ODP. Methods/design DIPLOMA is an international randomized controlled, patient- and pathologist-blinded, non-inferiority trial performed in 38 pancreatic centers in Europe and the USA. A total of 258 patients with an indication for elective distal pancreatectomy with splenectomy because of proven or highly suspected PDAC of the pancreatic body or tail will be randomly allocated to MIDP (laparoscopic or robot-assisted) or ODP in a 1:1 ratio. The primary outcome is the microscopically radical resection margin (R0, distance tumor to pancreatic transection and posterior margin ≥ 1 mm), which is assessed using a standardized histopathology assessment protocol. The sample size is calculated with the following assumptions: 5% one-sided significance level (α), 80% power (1-β), expected R0 rate in the open group of 58%, expected R0 resection rate in the minimally invasive group of 67%, and a non-inferiority margin of 7%. Secondary outcomes include time to functional recovery, operative outcomes (e.g., blood loss, operative time, and conversion to open surgery), other histopathology findings (e.g., lymph node retrieval, perineural- and lymphovascular invasion), postoperative outcomes (e.g., clinically relevant complications, hospital stay, and administration of adjuvant treatment), time and site of disease recurrence, survival, quality of life, and costs. Follow-up will be performed at the outpatient clinic after 6, 12, 18, 24, and 36 months postoperatively. Discussion The DIPLOMA trial is designed to investigate the non-inferiority of MIDP versus ODP regarding the microscopically radical resection rate of PDAC in an international setting. Trial registration ISRCTN registry ISRCTN44897265 . Prospectively registered on 16 April 2018.