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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]

The National Institutes of Health is giving more research grants to medical schools that have the most active research programs. Between 1986 and 1997, the percentage of research grants awarded to the top 10 medical schools ranked by research activity increased from 24.6% to 27%. The percentage of research grants awarded to the 75 medical schools with the least active research programs decreased from 24.3% to 21.8%. Clinical departments received a greater share of research grants than basic science departments.

Diphenoxylate/atropine (DPX/ATR) is commonly used to treat diarrhea, and consists of the opioid diphenoxylate hydrochloride and atropine sulfate. Only 40 of the 101 reported cases of DPX/ATR overdose in children have been described in detail. DPX/ATR poisoning consists of two phases: (1) the first phase is from the atropine, and is characterized by high fever, a red flushed appearance, and rapid breathing; and (2) the second phase (opioid phase) is due to diphenoxylate, and is characterized by central nervous system and respiratory depression and constriction of the pupils. DPX/ATR intoxication is dangerous because respiratory depression may recur up to 24 hours after ingestion. Eight cases of accidental DPX/ATR intoxication in children are described, and 28 previous cases are also reviewed. The overdose was related mainly to intoxication with opioid. Six of the 36 cases of DPX/ATR poisoning involved symptoms of atropine intoxication, including central nervous system excitement, high blood pressure, fever, and flushed dry skin. The effects of atropine occurred before, during, and after opioid effects. Thirty-three children showed symptoms of opioid overdose without signs of atropine toxicity. DPX-induced hypoxia (low levels of oxygen) was associated with abnormalities in breathing and muscle tone, and heart attack. In three cases, hypoxia was associated with the accumulation of fluid (edema) in the brain and with death. Depression of breathing recurred in seven cases 13 to 24 hours after ingestion of the drug, and was probably due to accumulation of difenoxine, an active metabolic product of DPX. The opioid antagonist, naloxone, which counteracts opioid effects, can be used to treat depressed or inadequate breathing, and should be followed by washing out of the stomach, repeated administration of activated charcoal, and close monitoring for 24 hours. (Consumer Summary produced by Reliance Medical Information, Inc.)

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]

Inmates are a unique patient population. When emergencies arise or their medical problems exceed the capabilities of the prison infirmary, inmates are frequently referred to the local hospital emergency department. There are many unique aspects of the prison environment that must be considered when managing these patients. These patients are high risk from a medicolegal standpoint, and their medical care and chart should reflect this reality. Correctional medicine is an emerging subspecialty area focusing on the issues related to the care of this patient population. [ABSTRACT FROM AUTHOR]

Patients in police custody are brought to emergency departments primarily for the treatment of drug overdose or withdrawal, smuggling of contraband, and trauma. Excited delirium from methamphetamine, cocaine, or phencyclidine intoxication may be a harbinger of death. Use of physical restraints and less-than-lethal deterrents during the arrest may increase morbidity and may require prompt aggressive treatment. Forensic issues arise when police request blood for alcohol assays, body searches for contraband, and retrieval of bullets for evidence. It is estimated that medical evidence plays a role in one-fourth of all criminal trials. Emergency department personnel must protect the patient's rights and respond to police requests. The medical record should be accurate, impartial, and suitable for testifying in court. A clear medical record may obviate the need for future subpoenas. [ABSTRACT FROM AUTHOR]