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Mismatch repair‐deficient (MMRd) colorectal cancers (CRCs) have high mutation burdens, which make these tumours immunogenic and many respond to immune checkpoint inhibitors. The MMRd hypermutator phenotype may also promote intratumour heterogeneity (ITH) and cancer evolution. We applied multiregion sequencing and CD8 and programmed death ligand 1 (PD‐L1) immunostaining to systematically investigate ITH and how genetic and immune landscapes coevolve. All cases had high truncal mutation burdens. Despite pervasive ITH, driver aberrations showed a clear hierarchy. Those in WNT/β‐catenin, mitogen‐activated protein kinase, and TGF‐β receptor family genes were almost always truncal. Immune evasion (IE) drivers, such as inactivation of genes involved in antigen presentation or IFN‐γ signalling, were predominantly subclonal and showed parallel evolution. These IE drivers have been implicated in immune checkpoint inhibitor resistance or sensitivity. Clonality assessments are therefore important for the development of predictive immunotherapy biomarkers in MMRd CRCs. Phylogenetic analysis identified three distinct patterns of IE driver evolution: pan‐tumour evolution, subclonal evolution, and evolutionary stasis. These, but neither mutation burdens nor heterogeneity metrics, significantly correlated with T‐cell densities, which were used as a surrogate marker of tumour immunogenicity. Furthermore, this revealed that genetic and T‐cell infiltrates coevolve in MMRd CRCs. Low T‐cell densities in the subgroup without any known IE drivers may indicate an, as yet unknown, IE mechanism. PD‐L1 was expressed in the tumour microenvironment in most samples and correlated with T‐cell densities. However, PD‐L1 expression in cancer cells was independent of T‐cell densities but strongly associated with loss of the intestinal homeobox transcription factor CDX2. This explains infrequent PD‐L1 expression by cancer cells and may contribute to a higher recurrence risk of MMRd CRCs with impaired CDX2 expression. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Background: Gastric and gastro-esophageal junction cancers (GCs) frequently recur after resection, but markers to predict recurrence risk are missing. T-cell infiltrates have been validated as prognostic markers in other cancer types, but not in GC because of methodological limitations of past studies. We aimed to define and validate the prognostic role of major T-cell subtypes in GC by objective computational quantification.Methods: Surgically resected chemotherapy-naïve GCs were split into discovery (n = 327) and validation (n = 147) cohorts. CD8 (cytotoxic), CD45RO (memory), and FOXP3 (regulatory) T-cell densities were measured through multicolor immunofluorescence and computational image analysis. Cancer-specific survival (CSS) was assessed. All statistical tests were two-sided.Results: CD45RO-cell and FOXP3-cell densities statistically significantly predicted CSS in both cohorts. Stage, CD45RO-cell, and FOXP3-cell densities were independent predictors of CSS in multivariable analysis; mismatch repair (MMR) and Epstein-Barr virus (EBV) status were not statistically significant. Combining CD45RO-cell and FOXP3-cell densities into the Stomach Cancer Immune Score showed highly statistically significant (all P ≤ .002) CSS differences (0.9 years median CSS to not reached). T-cell infiltrates were highest in EBV-positive GCs and similar in MMR-deficient and MMR-proficient GCs.Conclusion: The validation of CD45RO-cell and FOXP3-cell densities as prognostic markers in GC may guide personalized follow-up or (neo)adjuvant treatment strategies. Only those 20% of GCs with the highest T-cell infiltrates showed particularly good CSS, suggesting that a small subgroup of GCs is highly immunogenic. The potential for T-cell densities to predict immunotherapy responses should be assessed. The association of high FOXP3-cell densities with longer CSS warrants studies into the biology of regulatory T cells in GC. [ABSTRACT FROM AUTHOR]

McGowan R, Challoner BR, Ross S, Holloway S, Joss S, Wilcox D, Holden ST, Tolmie J, Longman C. Results of Duchenne muscular dystrophy family screening in practice: leaks rather than cascades? Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disease caused by mutations in the gene that encodes the protein dystrophin. Approximately 2 of 3 affected boys inherit their mutation from their carrier mother whereupon other female relatives are at risk of carrying the mutation. Female carriers are also at risk of developing cardiomyopathy and regular cardiac screening is recommended. Clinical genetics services offer genetic counselling and carrier tests for consenting relatives of DMD patients known as 'cascade screening'. We retrospectively analysed data from two genetics centres, West of Scotland and South East Thames where the latter centre operated a computer-held DMD register. Over the period, 1971-2008, a total of 843 potential carriers, in 195 West of Scotland families, were tested: 16% of 1st degree relatives and 48% of 2nd degree and more distant relatives were not tested. In South East Thames, a total of 1223 potential carriers in 349 families were tested: 49% of 1st degree and 65% of 2nd degree and more distant relatives were not tested. These data are similar to Becker muscular dystrophy/DMD carrier screening results recently reported from the Netherlands. Retrospective results from three countries indicate that despite efforts to offer extended cascade screening, significant numbers of potential carriers of DMD remain unaware of their reproductive and health risks. [ABSTRACT FROM AUTHOR]

Background: From 1980 to 2003 Liberia entered into a period of conflict and civil wars. During this time Liberia's health and educational services were severely disrupted. Equipment and supplies were stolen from the Medical School and the buildings damaged severely. A majority of health care workers, university faculty, and hospital and medical school administrators fled the country. Objective: The objective of this study was to evaluate the impact of civil war on the training of medical students and physicians, and to identify a feasible intervention. Methods: The authors compiled data from three sources at an Emergency Medicine symposium held at the A.M. Dogliotti School of Medicine, in Monrovia, Liberia, in September 2007. These were (1) data from 13 anonymous surveys completed by symposium participants who were physicians or physicians in training, and (2) answers from six open discussion groups at the symposium concerning perceived barriers to medical training. (3) Supporting documents volunteered by the Dean from interviews in 2002, 2007 and 2009 or published on line in 2002 and 2006 were incorporated, and a focused literature review was performed. Results: The 12 medical students and 1 physician who returned completed surveys and attended the symposium all reported a delay in their training, with 75% of respondents citing a past and current lack of Clinical and Basic Science faculty as a major delaying factor. The six open discussion groups at the symposium and the information provided by the Dean substantiated these findings. Conclusions: Volunteer Basic Science and Clinical faculty for the medical school and teaching hospitals from a coalition of concerned partnering institutions would be a targeted intervention to assist in re-building the medical educational capacity of Liberia. [ABSTRACT FROM AUTHOR]