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Aberrant expression of viral-like repeat elements is a common feature of epithelial cancers, and the substantial diversity of repeat species provides a distinct view of the cancer transcriptome. Repeatome profiling across ovarian, pancreatic, and colorectal cell lines identifies distinct clustering independent of tissue origin that is seen with coding gene analysis. Deeper analysis of ovarian cancer cell lines demonstrated that human satellite II (HSATII) satellite repeat expression was highly associated with epithelial-mesenchymal transition (EMT) and anticorrelated with IFN-response genes indicative of a more aggressive phenotype. SATII expression--and its correlation with EMT and anticorrelation with IFN-response genes-- was also found in ovarian cancer RNA-Seq data and was associated with significantly shorter survival in a second independent cohort of patients with ovarian cancer. Repeat RNAs were enriched in tumor-derived extracellular vesicles capable of stimulating monocyte-derived macrophages, demonstrating a mechanism that alters the tumor microenvironment with these viral-like sequences. Targeting of HSATII with antisense locked nucleic acids stimulated IFN response and induced MHC I expression in ovarian cancer cell lines, highlighting a potential strategy of modulating the repeatome to reestablish antitumor cell immune surveillance., Introduction Repetitive elements make up approximately 50% of the human genome (1, 2), and their aberrant expression has been described across a wide range ofcancers (3-5). Repeat suppression is achieved [...]

Background: Lymph node (LN) harvesting is associated with outcomes in colonic cancer. We sought to interrogate whether a distinctive immune milieu of the primary tumour is associated with LN yield. Methods: A total of 926 treatment-naive patients with colorectal adenocarcinoma with more than 12 LNs (LN-high) were compared with patients with 12 or fewer LNs (LN-low). We performed immunohistochemistry and quantification on tissue microarrays for HLA class I/II proteins, beta-2-microglobulin (B2MG), CD8, CD163, LAG3, PD-L1, FoxP3, and BRAF V600E. Results: The LN-high group was comprised of younger patients, longer resections, larger tumours, right-sided location, and tumours with deficient mismatch repair (dMMR). The tumour microenvironment showed higher CD8+ cells infiltration and B2MG expression on tumour cells in the LN-high group compared to the LN-low group. The estimated mean disease-specific survival was higher in the LN-high group than LN-low group. On multivariate analysis for prognosis, LN yield, CD8+ cells, extramural venous invasion, perineural invasion, and AJCC stage were independent prognostic factors. Conclusion: Our findings corroborate that higher LN yield is associated with a survival benefit. LN yield is associated with an immune high microenvironment, suggesting that tumour immune milieu influences the LN yield. [ABSTRACT FROM AUTHOR]

Background: While many pancreatic neuroendocrine tumours (PanNET) show indolent behaviour, predicting the biological behaviour of small nonfunctional PanNETs remains a challenge. Nonfunctional PanNETs with an epigenome and transcriptome that resemble islet alpha cells (ARX‐positive) are more aggressive than neoplasms that resemble islet beta cells (PDX1‐positive). In this study, we explore the ability of immunohistochemistry for ARX and PDX1 and telomere‐specific fluorescence in situ hybridisation (FISH) for alternative lengthening of telomeres (ALT) to predict recurrence. Methods: Two hundred fifty‐six patients with PanNETs were identified, and immunohistochemistry for ARX and PDX1 was performed. Positive staining was defined as strong nuclear staining in >5% of tumour cells. FISH for ALT was performed in a subset of cases. Results: ARX reactivity correlated with worse disease‐free survival (DFS) (P = 0.011), while there was no correlation between PDX1 reactivity and DFS (P = 0.52). ALT‐positive tumours (n = 63, 31.8%) showed a significantly lower DFS (P < 0.0001) than ALT‐negative tumours (n = 135, 68.2%). ARX reactivity correlated with ALT positivity (P < 0.0001). Among nonfunctional tumours, recurrence was noted in 18.5% (30/162) of ARX‐positive tumours and 7.5% (5/67) of ARX‐negative tumours. Among WHO grade 1 and 2 PanNETs with ≤2 cm tumour size, 14% (6/43) of ARX‐positive tumours recurred compared to 0 of 33 ARX‐negative tumours and 33.3% (3/9) ALT‐positive tumours showed recurrence versus 4.4% (2/45) ALT‐negative tumours. Conclusion: Immunohistochemistry for ARX and ALT FISH status may aid in distinguishing biologically indolent cases from aggressive small low‐grade PanNETs, and help to identify patients who may preferentially benefit from surgical intervention. [ABSTRACT FROM AUTHOR]

Background: Diagnosing paediatric Crohn's disease (CD) based on histology can present challenges. We evaluate the histological spectrum of treatment-naïve biopsies from children with CD and assess these findings' diagnostic and predictive value., Methods: Three cohorts were identified: (1) 137 patients with CD, (2) 116 patients with ulcerative colitis (UC) and (3) 50 patients without inflammatory bowel disease. Biopsies from the gastrointestinal (GI) tract were re-examined for signs of active and chronic inflammation, including lymphocyte-pattern oesophagitis, focal enhancing gastritis and indicators of chronicity. Additionally, granulomas and microgranulomas (defined as clusters of 4-9 epithelioid histiocytes) were evaluated., Results: Lymphocyte-pattern oesophagitis was observed in 15% of patients (n=20). Moderate-to-severe diffuse gastritis was noted in 50.4% of patients (n=68), while focal enhancing gastritis was identified in 11.1% (n=15). In terminal ileal biopsies, 46.1% exhibited activity and 5.3% showed features of chronicity. Active colitis was present in 73% of patients (n=100), with chronic colitis seen in 11.7% (n=16). Granulomas and microgranulomas were observed in 31.4% (43/137) and 48.9% (67/137) of patients, respectively. Notably, 30.7% (42/137) of patients with microgranulomas were without granulomas. Previously undetected microgranulomas were found in 20 of 27 cases. 2.5% of patients with UC and none of the control cohort showed microgranulomas. Lymphocyte-pattern oesophagitis was associated with an increased need for anti-tumor necrosis factor (TNF) therapy (p=0.007)., Conclusions: GI microgranulomas, often overlooked, are specific to CD in the proper clinical context. Oesophageal lymphocytosis may predict a need for more aggressive treatment. The study brings to light under-recognised aspects of CD's histological diagnosis, including the oversight of microgranulomas, the high prevalence of diffuse gastritis and low prevalence of focal enhancing gastritis, the frequent absence of terminal ileitis and the infrequent occurrence of chronic colitis., Competing Interests: Competing interests: VD is the editor-in-chief of the Journal of Clinical Pathology. However, he was not involved in the adjudication process., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: We sought to assess the expression of human leukocyte antigen (HLA) proteins and β2-microglobulin (B2M) in tumor cells and the relationship with immune microenvironment and outcome in colorectal cancer (CRC)., Methods: A total of 953 CRC cases were evaluated by immunohistochemistry for HLA class I, HLA class II, and B2M. The expression level of these biomarkers was correlated with clinicopathologic information, BRAF V600E and mismatch repair (MMR) proteins, and the quantitated expression levels of immune cells (CD8 and CD163) and immune regulatory proteins (FoxP3, programmed cell death 1 ligand 1 [PD-L1], and LAG3)., Results: We found that B2M-low tumors were statistically correlated with aggressive histologic features, including higher stage, higher grade, extramural venous invasion, perineural invasion, and distant metastasis. Expression of B2M was positively correlated (R2 = 0.3) and significantly associated with MMR-deficient tumors (P < .001); B2M-low tumors were also associated with an "immune cold"' microenvironment, including a reduced number of immune cells (CD8 and CD163), reduced expression of immune regulatory proteins by immune cells (PD-L1, FoxP3, and LAG3), and reduced tumor cell expression of PD-L1. These B2M-low tumors correlated with lower disease-specific survival (P = .018), a finding that maintained significance only for the proficient MMR cohort (P = .037)., Conclusions: Our findings suggest that B2M expression may support predictive models for both outcome and checkpoint inhibitor therapy treatment response for colorectal adenocarcinoma., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)