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The article presents a case study of a 48-year-old woman who underwent a restorative proctocolectomy in 1987 with dukes A adenocarcinoma of the ascending colon and went into a gluten-free diet due to coeliac disease, which was diagnosed in 2000. It says that she was diagnosed with pouchitis refractory to antibiotics symptoms in late 2009, wherein pouchoscopy showed a five centimeter by five centimeter inflamed area. The patient underwent pouch excision with abdominal hysterectomy.

Understanding the evolutionary pathways to metastasis and resistance to immune-checkpoint inhibitors (ICI) in melanoma is critical for improving outcomes. Here, we present the most comprehensive intrapatient metastatic melanoma dataset assembled to date as part of the Posthumous Evaluation of Advanced Cancer Environment (PEACE) research autopsy program, including 222 exome sequencing, 493 panel-sequenced, 161 RNA sequencing, and 22 single-cell whole-genome sequencing samples from 14 ICI-treated patients. We observed frequent whole-genome doubling and widespread loss of heterozygosity, often involving antigen-presentation machinery. We found KIT extrachromosomal DNA may have contributed to the lack of response to KIT inhibitors of a KIT-driven melanoma. At the lesion-level, MYC amplifications were enriched in ICI nonresponders. Single-cell sequencing revealed polyclonal seeding of metastases originating from clones with different ploidy in one patient. Finally, we observed that brain metastases that diverged early in molecular evolution emerge late in disease. Overall, our study illustrates the diverse evolutionary landscape of advanced melanoma., Significance: Despite treatment advances, melanoma remains a deadly disease at stage IV. Through research autopsy and dense sampling of metastases combined with extensive multiomic profiling, our study elucidates the many mechanisms that melanomas use to evade treatment and the immune system, whether through mutations, widespread copy-number alterations, or extrachromosomal DNA. See related commentary by Shain, p. 1294. This article is highlighted in the In This Issue feature, p. 1275., (©2023 The Authors; Published by the American Association for Cancer Research.)

Background: Clinical metagenomics (CMg) has the potential to be translated from a research tool into routine service to improve antimicrobial treatment and infection control decisions. The SARS-CoV-2 pandemic provides added impetus to realise these benefits, given the increased risk of secondary infection and nosocomial transmission of multi-drug-resistant (MDR) pathogens linked with the expansion of critical care capacity., Methods: CMg using nanopore sequencing was evaluated in a proof-of-concept study on 43 respiratory samples from 34 intubated patients across seven intensive care units (ICUs) over a 9-week period during the first COVID-19 pandemic wave., Results: An 8-h CMg workflow was 92% sensitive (95% CI, 75-99%) and 82% specific (95% CI, 57-96%) for bacterial identification based on culture-positive and culture-negative samples, respectively. CMg sequencing reported the presence or absence of β-lactam-resistant genes carried by Enterobacterales that would modify the initial guideline-recommended antibiotics in every case. CMg was also 100% concordant with quantitative PCR for detecting Aspergillus fumigatus from 4 positive and 39 negative samples. Molecular typing using 24-h sequencing data identified an MDR-K. pneumoniae ST307 outbreak involving 4 patients and an MDR-C. striatum outbreak involving 14 patients across three ICUs., Conclusion: CMg testing provides accurate pathogen detection and antibiotic resistance prediction in a same-day laboratory workflow, with assembled genomes available the next day for genomic surveillance. The provision of this technology in a service setting could fundamentally change the multi-disciplinary team approach to managing ICU infections. The potential to improve the initial targeted treatment and rapidly detect unsuspected outbreaks of MDR-pathogens justifies further expedited clinical assessment of CMg., (© 2021. The Author(s).)

ADAPTeR is a prospective, phase II study of nivolumab (anti-PD-1) in 15 treatment-naive patients (115 multiregion tumor samples) with metastatic clear cell renal cell carcinoma (ccRCC) aiming to understand the mechanism underpinning therapeutic response. Genomic analyses show no correlation between tumor molecular features and response, whereas ccRCC-specific human endogenous retrovirus expression indirectly correlates with clinical response. T cell receptor (TCR) analysis reveals a significantly higher number of expanded TCR clones pre-treatment in responders suggesting pre-existing immunity. Maintenance of highly similar clusters of TCRs post-treatment predict response, suggesting ongoing antigen engagement and survival of families of T cells likely recognizing the same antigens. In responders, nivolumab-bound CD8 + T cells are expanded and express GZMK/B. Our data suggest nivolumab drives both maintenance and replacement of previously expanded T cell clones, but only maintenance correlates with response. We hypothesize that maintenance and boosting of a pre-existing response is a key element of anti-PD-1 mode of action., Competing Interests: Declaration of interests L.A. is funded by the Royal Marsden Cancer Charity. E.H. and M.M. are funded by Cancer Research UK (CRUK). F.B. is funded by the Rosetrees Trust (M829). J.A. is a full-time employee of Hoffmann-La Roche AG (Basel, Switzerland). D.A.M has received consultancy fees from AstraZeneca, Thermo Fisher, and Eli Lilly. A.F. has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No. 892360. L.P. has received research funding from Pierre Fabre, and honoraria from Pfizer, Ipsen, Bristol-Myers Squibb, and EUSA Pharma. R.S. has received non-financial support from Merck and Bristol Myers Squibb; research support from Merck, Puma Biotechnology, and Roche; and advisory board fees for Bristol Myers Squibb; and personal fees from Roche for an advisory board related to a trial-research project; all related to breast cancer research projects. R.S. reports no conflict of interests related to this project. M.J.H. is a Cancer Research UK (CRUK) Clinician Scientist (RCCFEL\100099) and has received funding from CRUK, National Institute for Health Research, Rosetrees Trust, UKI NETs and NIHR University College London Hospitals Biomedical Research Center. M.J.H. is a member of the Scientific Advisory Board and Steering Committee for Achilles Therapeutics. G.K. is a scientific co-founder of and consulting for Enara Bio and a member of its scientific advisory board. G.K. receives core funding from the Francis Crick Institute (FC0010099). B.C. is supported by a CRUK Project Grant. J.L. has received research funding from Bristol-Myers Squibb, Merck, Novartis, Pfizer, Achilles Therapeutics, Roche, Nektar Therapeutics, Covance, Immunocore, Pharmacyclics, and Aveo, and served as a consultant to Achilles, AstraZeneca, Boston Biomedical, Bristol-Myers Squibb, Eisai, EUSA Pharma, GlaxoSmithKline, Ipsen, Imugene, Incyte, iOnctura, Kymab, Merck Serono, Nektar, Novartis, Pierre Fabre, Pfizer, Roche Genentech, Secarna, and Vitaccess. C.S. acknowledges grant support from Pfizer, AstraZeneca, Bristol-Myers Squibb, Roche-Ventana, Boehringer-Ingelheim, Archer Dx Inc (collaboration in minimal residual disease sequencing technologies), and Ono Pharmaceutical, is an AstraZeneca Advisory Board member and Chief Investigator for the MeRmaiD1 clinical trial, has consulted for Pfizer, Novartis, GlaxoSmithKline, MSD, Bristol-Myers Squibb, Celgene, AstraZeneca, Illumina, Genentech, Roche-Ventana, GRAIL, Medicxi, Bicycle Therapeutics, and the Sarah Cannon Research Institute, has stock options in Apogen Biotechnologies, Epic Bioscience, GRAIL, and has stock options and is co-founder of Achilles Therapeutics. Patents: C.S. holds European patents relating to assay technology to detect tumor recurrence (PCT/GB2017/053289); to targeting neoantigens (PCT/EP2016/059401), identifying patent response to immune checkpoint blockade (PCT/EP2016/071471), determining HLA LOH (PCT/GB2018/052004), predicting survival rates of patients with cancer (PCT/GB2020/050221), identifying patients who respond to cancer treatment (PCT/GB2018/051912), a US patent relating to detecting tumor mutations (PCT/US2017/28013) and both a European and US patent related to identifying insertion/deletion mutation targets (PCT/GB2018/051892). C.S. is Royal Society Napier Research Professor (RP150154). His work is supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001169), the UK Medical Research Council (FC001169), and the Wellcome Trust (FC001169). C.S. is funded by Cancer Research UK (TRACERx, PEACE and CRUK Cancer Immunotherapy Catalyst Network), Cancer Research UK Lung Cancer Center of Excellence, the Rosetrees Trust, Butterfield and Stoneygate Trusts, NovoNordisk Foundation (ID16584), Royal Society Research Professorship Enhancement Award (RP/EA/180007), the NIHR BRC at University College London Hospitals, the CRUK-UCL Center, Experimental Cancer Medicine Center and the Breast Cancer Research Foundation, USA (BCRF). His research is supported by a Stand Up To Cancer-LUNGevity-American Lung Association Lung Cancer Interception Dream Team Translational Research Grant (SU2C-AACR-DT23-17). Stand Up To Cancer is a program of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the Scientific Partner of SU2C. C.S. also receives funding from the European Research Council (ERC) under the European Union’s Seventh Framework Program (FP7/2007-2013) Consolidator Grant (FP7-THESEUS-617844), European Commission ITN (FP7-PloidyNet 607722), an ERC Advanced Grant (PROTEUS) from the European Research Council under the European Union’s Horizon 2020 research and innovation program (835297), and Chromavision from the European Union’s Horizon 2020 research and innovation program (665233). S.A.Q. is a CRUK Senior Cancer Research Fellowship (C36463/A22246) and is funded by a CRUK Biotherapeutic Program Grant (C36463/A20764) and the Rosetrees and Stonygate Trusts (A1388) and a donation from the Khoo Teck Puat UK Foundation via the UCL Cancer Institute Research Trust (539288). S.T. is funded by Cancer Research UK (grant reference number C50947/A18176), the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC0010988), the UK Medical Research Council (FC0010988), and the Wellcome Trust (FC0010988), the National Institute for Health Research (NIHR) Biomedical Research Center at the Royal Marsden Hospital and Institute of Cancer Research (grant reference number A109), the Royal Marsden Cancer Charity, The Rosetrees Trust (grant reference number A2204), Ventana Medical Systems Inc (grant reference numbers 10467 and 10530), the National Institutes of Health (Bethesda, MD) and Melanoma Research Alliance. ST has received speaking fees from Roche, Astra Zeneca, Novartis, and Ipsen. S.T. has the following patents filed: Indel mutations as a therapeutic target and predictive biomarker PCTGB2018/051892 and PCTGB2018/051893 and Clear Cell Renal Cell Carcinoma Biomarkers P113326GB., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Competing interests: RPL has received educational grants from Ferring, Pfizer and Vifor Pharma. MAS served as a speaker, a consultant and/or an advisory board member for Sandoz, Janssen, Takeda, MSD, Falk, Samsung Bioepis, Galapagos and Bristol-Myers Squibb. DHJ has received educational grants from Janssen, Bayer, BMS and EUSA Pharma and has served as a speaker/an advisory board member for Janssen, AstraZeneca, MSD and Pfizer.

The rapid pace at which COVID-19 studies are being published is surpassed only by the spread of the virus and the destruction wreaked by the pandemic globally. Therefore, it is likely that, even in the few months prior to this article reaching print, the COVID-19 literature would have moved on. The authors of this article work at a centre for COVID autopsies in London, and the aim of the article is, using their first-hand experience of COVID-19 autopsies, to distil what in their judgement are the most valid and important findings of internationally published COVID-19 autopsy studies. The intention is to provide an illustrated summary of the pathology of the organ systems most often affected by COVID-19, which will be particularly useful to trainee histopathologists and to busy consultant surgical histopathologists who may not have encountered COVID-19 first hand. For the reader who wishes to probe further the question of pathogenesis, a few pertinent references are provided., (© 2020 Published by Elsevier Ltd.)

Background: Prognostication in oesophageal cancer on the basis of preoperative variables is challenging. Many of the accepted predictors of survival are only derived after surgical treatment and may be influenced by neoadjuvant therapy. This study aims to explore the relationship between pre-treatment endoscopic tumour morphology and postoperative survival., Methods: Patients with endoscopic descriptions of tumours were identified from the prospectively managed databases including the OCCAMS database. Tumours were classified as exophytic, ulcerating or stenosing. Kaplan Meier survival analysis and multivariable Cox regression analyses were performed to determine hazard ratios (HR) with 95% confidence intervals., Results: 262 patients with oesophageal adenocarcinoma undergoing potentially curative resection were pooled from St Thomas' Hospital (161) and the OCCAMS database (101). There were 70 ulcerating, 114 exophytic and 78 stenosing oesophageal adenocarcinomas. Initial tumour staging was similar across all groups (T3/4 tumours 71.4%, 70.2%, 74.4%). Median survival was 55 months, 51 months and 36 months respectively (p < 0.001). Rates of lymphovascular invasion (P = 0.0176), pathological nodal status (P = 0.0195) and pathological T stage (P = 0.0007) increased from ulcerating to exophytic to stenosing lesions. Resection margin positivity was 21.4% in ulcerating tumours compared to 54% in stenosing tumours (p < 0.001). When compared to stenosing lesions, exophytic and ulcerating lesions demonstrated a significant survival advantage on multivariable analysis (HR 0.56 95% CI 0.31-0.93, HR 0.42 95% CI 0.21-0.82)., Conclusion: This study demonstrates that endoscopic morphology may be an important pre-treatment prognostic factor in oesophageal cancer. Ulcerating, exophytic and stenosing tumours may represent different pathological processes and tumour biology., Competing Interests: Declaration of competing interest We have no conflicts of interest to disclose., (Copyright © 2020 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Aim: To assess the utility of a London-based infectious and tropical disease histopathology diagnostic review service., Methods: The original and specialist review histopathology reports of 457 samples from over 3 years of referrals were compared retrospectively., Results: Overall 329 (72.0%) showed no significant difference; 34 (7.4%) showed a non-clinically significant difference; and 94 (20.6%) showed a clinically significant difference. Of the 94 clinically significant discrepancies, 46 (48.9%) were incorrectly suspected infections; 19 (20.2%) were missed infections; 8 (8.5%) were different infections; and in 20 (21.3%), the specialist review yielded more specific identification of an organism or a more correct assessment of its viability., Conclusions: A review of histopathology cases by an infectious disease (ID) histopathology referral centre has yielded a 20.6% clinically significant error rate. Measures to improve training in ID histopathology in the UK are discussed., Competing Interests: Competing interests: UM has 1.0 Programmed Activity funded by the Hospital for Tropical Diseases., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: A positive circumferential resection margin (CRM) has been associated with higher rates of locoregional recurrence and worse survival in oesophageal cancer. The aim of this study was to establish if clinicopathological and radiological variables might predict CRM positivity in patients who received neoadjuvant chemotherapy before surgery for oesophageal adenocarcinoma., Methods: Multivariable analysis of clinicopathological and CT imaging characteristics considered potentially predictive of CRM was performed at initial staging and following neoadjuvant chemotherapy. Prediction models were constructed. The area under the curve (AUC) with 95% confidence intervals (c.i.) from 1000 bootstrapping was assessed., Results: A total of 223 patients were included in the study . Poor differentiation (odds ratio (OR) 2·84, 95 per cent c.i. 1·39 to 6·01) and advanced clinical tumour status (T3-4) (OR 2·93, 1·03 to 9·48) were independently associated with an increased CRM risk at diagnosis. CT-assessed lack of response (stable or progressive disease) following chemotherapy independently corresponded with an increased risk of CRM positivity (OR 3·38, 1·43 to 8·50). Additional CT evidence of local invasion and higher CT tumour volume (14 cm 3 ) improved the performance of a prediction model, including all the above parameters, with an AUC (c-index) of 0·76 (0·67 to 0·83). Variables associated with significantly higher rates of locoregional recurrence were pN status ( P  = 0·020), lymphovascular invasion ( P  = 0·007) and poor response to chemotherapy (Mandard score 4-5) ( P  = 0·006). CRM positivity was associated with a higher locoregional recurrence rate, but this was not statistically significant ( P  = 0·092)., Conclusion: The presence of advanced cT status, poor tumour differentiation, and CT-assessed lack of response to chemotherapy, higher tumour volume and local invasion can be used to identify patients at risk of a positive CRM following neoadjuvant chemotherapy., (© 2019 The Authors. BJS Open published by John Wiley & Sons Ltd on behalf of BJS Society Ltd.)

Introduction: Patients with suspected pancreaticobiliary cancers frequently undergo endoscopic retrograde cholangiopancreatography (ERCP) to obtain brush cytology for confirmatory diagnosis. The outcome of this often leads to the management of the patient and can avoid more invasive investigations. There is a wide range of sensitivities and specificities reported in the literature., Aims: To determine the accuracy of the brush cytology obtained at ERCP by performing a retrospective audit of all patients admitted to Guy's and St. Thomas' Hospital for ERCP during 2008-2013. Also, to evaluate the impact of cytology results on patient care following ERCP., Method: Data were collected from 4 January 2008 to 27 December 2013. This involved analysing EndoSoft (the in-house software for endoscopic data entry), Pathnet (the pathology database) and Electronic Patient Records., Results: 162 patients underwent brush cytology during ERCP. 58 patients had positive cytology. With intention-to-treat analysis, sensitivity was 54.7%, specificity was 100.0% and negative predictive value was 53.9% with a positive predictive value of 100%. Patients with a positive brush cytology result required fewer investigations compared with patients with a negative cytology result., Conclusions: Our results compare favourably with previous studies in the field. Brush cytology has been ignored in recent times due to perceived poor results and efficacy. Our audit shows that it can reduce the number of investigations required to reach a diagnosis of malignancy and so is a valuable tool in the diagnosis of pancreaticobiliary malignancies. However, better guidance on preparation of samples for cytology is needed to reduce the number of insufficient samples.

Aims: Because of the clinical difficulty in identifying the early stages of human immunodeficiency virus (HIV) infection, the histopathologist often has to consider the diagnosis of HIV in tissue samples from patients with no previous suspicion of HIV infection. The aim was to investigate the practicality and utility of routine HIV-1 p24 immunohistochemistry on tissue samples received at a London histopathology laboratory., Methods and Results: Over a 3-year period, HIV-1 p24 was evaluated immunohistochemically on 123 cases. Of these, 37 (30%) showed positive expression of p24 in lesional follicular dendritic cells (FDCs). Of these 37 cases, 11 were not clinically suspected to be HIV+ and had no prior serological evidence of HIV infection. These cases represented lymph node biopsies, tonsillar and nasopharyngeal biopsies and a parotid excision. In addition to expression on FDCs, in 22 cases (60%), p24 also highlighted mononuclear cells and macrophages. p24 was also useful in confirming the presence of HIV in lymphoid tissue in non-lymphoid organs such as the lung, anus, salivary gland and brain. Immunonegativity occurred in occasional known HIV+ cases, probably related to treatment or tissue processing., Conclusions: This study confirms the usefulness of this technique in detecting unsuspected HIV infection in lymphoid and non-lymphoid organs on histopathological material and should be part of routine evaluation of lymph nodes and lymphoid tissue in other organs if morphological or clinical features suggest HIV infection.

Neoadjuvant chemoradiotherapy is being increasingly offered to patients with invasive esophageal carcinoma in an effort to downstage the tumor and consequently increase the rate of curative resection. A substantial amount of data has suggested that pathologic tumor regression following neoadjuvant therapy is an important predictor of local recurrence and long-term survival in esophageal cancer. Therefore, it is important that these posttreatment resection specimens are handled in a standardized manner and a reproducible method of tumor regression grading is used. Pathologic examination of such specimens is not straightforward, and, in fact, it presents a particular challenge to pathologists, especially when a good response to neoadjuvant therapy has been achieved and little or no residual tumor remains. We provide some guidelines for handling and reporting such specimens and outline the commonly used tumor regression grading systems for posttreatment esophagectomy specimens.

Precise localization and diagnosis of pancreatic endocrine tumors (PETs) is important, because pancreatic PETs have different clinical and biological behavior and treatment modalities than do exocrine pancreatic tumors. In contrast to the much more common exocrine adenocarcinomas, cytologic studies of PET are relatively rare and many cytopathologists lack experience with the cytomorphologic features of these tumors.During the last 10 yr, endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) has matured into an accurate, highly sensitive, and cost-effective modality for the preoperative localization of pancreatic PETs. This has resulted in an increased number of PETs first sampled as cytology specimens. This manuscript focuses on the cytomorphologic features most suggestive of pancreatic PETs, differential diagnosis, and diagnostic pitfalls of PETs. The technical development of EUS-guided FNA and the ancillary studies for pancreatic PETs are also reviewed. The data summarized in this review indicate that EUS-FNA is a valuable method in the recognition of pancreatic PETs and in most cases cytopathologists could reach a correct diagnosis of these tumors, including their hormone producing capability on aspirated cytologic material., ((c) 2006 Wiley-Liss, Inc.)

Intestinal intraepithelial lymphocytes (IELs) belong to a unique T-cell population interspersed between epithelial cells of both the small and large intestine. It is becoming increasingly recognised that an increased number of IELs with a normal villous architecture is within the wide spectrum of histological abnormalities observed in coeliac disease. An increased number of IELs is the earliest pathological change following gluten challenge and a high IEL count may be the only sign of gluten sensitivity. Therefore, the finding of a raised IEL count with normal villous architecture is of sufficient clinical importance to be reported in routine small bowel biopsies. However, it is evident that not all small intestinal biopsy specimens showing increased IELs are explained by gluten sensitivity. Increased IELs in small bowel mucosa have also been associated with autoimmune disorders, tropical sprue, food protein intolerance, Helicobacter pylori-associated gastritis, peptic duodenitis, parasitic and viral infections, as well as the development of intestinal lymphoma. Histological examination of a biopsy specimen of the small bowel remains the diagnostic gold standard for coeliac disease. There will be an ever increasing demand for histological confirmation of gluten sensitivity in patients in whom the classic microscopic appearance of flattened villi may not have fully developed. The more widespread recognition by histopathologists of the pattern of injury manifested by increased numbers of IELs in intestinal biopsy specimens will certainly help in early diagnosis of coeliac disease, lessen diagnostic confusion and influence the modern practice of gastrointestinal tract medicine. This review discusses some of the recent developments in clinical pathology pertaining to increased IELs in small bowel mucosal biopsies.

The SmN protein is a component of small nuclear ribonucleoprotein particles and closely related to the ubiquitously expressed SmB and B' splicing proteins. However, SmN is only expressed in a limited range of tissues and cell types such as brain, heart and early embryonic cells. The isolation of cDNA clones derived from the mRNA encoding SmN in different cell types has indicated that the brain and embryonic forms of the protein are identical and are encoded by a distinct gene to that encoding SmB and B'. It has been suggested however, that the cardiac form of SmN is encoded by a distinct mRNA which is derived from a different gene from that encoding the brain and embryonic forms of SmN. By using the polymerase chain reaction as well as cDNA cloning we have shown that this is not the case and that the cardiac, brain and embryonic forms of the protein are identical and are translated from the same mRNA encoded by a single gene. The significance of this finding is discussed in terms of the complex expression pattern of this gene and the possible functional role of SmN.