TCF-1 limits intraepithelial lymphocyte antitumor immunity in colorectal carcinoma.

Intraepithelial lymphocytes (IELs), including αß and γδ T cells (T-IELs), constantly survey and play a critical role in maintaining the gastrointestinal epithelium. We show that cytotoxic molecules important for defense against cancer were highly expressed by T-IELs in the small intestine. In contrast, abundance of colonic T-IELs was dependent on the microbiome and displayed higher expression of TCF-1/TCF7 and a reduced effector and cytotoxic profile, including low expression of granzymes. Targeted deletion of TCF-1 in γδ T-IELs induced a distinct effector profile and reduced colon tumor formation in mice. In addition, TCF-1 expression was significantly reduced in γδ T-IELs present in human colorectal cancers (CRCs) compared with normal healthy colon, which strongly correlated with an enhanced γδ T-IEL effector phenotype and improved patient survival. Our work identifies TCF-1 as a colon-specific T-IEL transcriptional regulator that could inform new immunotherapy strategies to treat CRC.

Post-mortem magnetic resonance imaging with computed tomography-guided biopsy for foetuses and infants: a prospective, multicentre, cross-sectional study.

BACKGROUND: Post-mortem imaging has been suggested as an alternative to conventional autopsy in the prenatal and postnatal periods. Noninvasive autopsies do not provide tissue for histological examination, which may limit their clinical value, especially when infection-related morbidity and mortality are suspected. METHODS: We performed a prospective, multicentre, cross-sectional study to compare the diagnostic performance of post-mortem magnetic resonance imaging with computed tomography-guided biopsy (Virtopsy®) with that of conventional autopsy in foetuses and infants. Cases referred for conventional autopsy were eligible for enrolment. After post-mortem imaging using a computed tomography scanner and a magnetic resonance imaging unit, computed tomography-guided tissue sampling was performed. Virtopsy results were compared with conventional autopsy in determining the likely final cause of death and major pathologies. The primary outcome was the proportion of cases for which the same cause of death was determined by both methods. Secondary outcomes included the proportion of false positive and false negative major pathological lesions detected by virtopsy and the proportion of computed tomography-guided biopsies that were adequate for histological examination. RESULTS: Overall, 101 cases (84 fetuses, 17 infants) were included. Virtopsy and autopsy identified the same cause of death in 91 cases (90.1%, 95% CI 82.7 to 94.5). The sensitivity and specificity of virtopsy for determining the cause of death were 96.6% (95% CI 90.6 to 98.8) and 41.7% (95% CI 19.3 to 68.0), respectively. In 32 cases (31.7%, 95% CI 23.4 to 41.3), major pathological findings remained undetected by virtopsy, and in 45 cases (44.6%, 95% CI 35.2 to 54.3), abnormalities were diagnosed by virtopsy but not confirmed by autopsy. Computed tomography-guided tissue sampling was adequate for pathological comments in 506 of 956 biopsies (52.7%) and added important diagnostic value in five of 30 cases (16.1%) with an unclear cause of death before autopsy compared with postmortem imaging alone. In 19 of 20 infective deaths (95%), biopsies revealed infection-related tissue changes. Infection was confirmed by placental examination in all fetal cases. CONCLUSIONS: Virtopsy demonstrated a high concordance with conventional autopsy for the detection of cause of death but was less accurate for the evaluation of major pathologies. Computed tomography-guided biopsy had limited additional diagnostic value. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01888380).

Copeptin Release in Arterial Hypotension and Its Association with Severity of Disease in Critically Ill Children.

Low copeptin levels may indicate inadequate arginine-vasopressin release promoting arterial hypotension, whereas high copeptin concentrations may reflect disease severity. This single-center prospective non-randomized clinical trial analyzed the course of blood copeptin in critically ill normo- and hypotensive children and its association with disease severity. In 164 patients (median age 0.5 years (interquartile range 0.1, 2.9)), the mean copeptin concentration at baseline was 43.5 pmol/L. Though not significantly different after 61 h (primary outcome, mean individual change: −12%, p = 0.36, paired t-test), we detected 1.47-fold higher copeptin concentrations during arterial hypotension when compared to normotension (mixed-effect ANOVA, p = 0.01). In total, 8 out of 34 patients (23.5%) with low copeptin concentrations <10 pmol/L were hypotensive. Copeptin was highest in the adjusted mixed-effect regression analysis within the first day (+20% at 14 h) and decreased significantly at 108 h (−27%) compared to baseline (p = 0.002). Moreover, we found a significant association with vasopressor-inotrope treatment intensity, infancy (1−12 months) and cardiopulmonary bypass (all p ≤ 0.001). In conclusion, high copeptin values were associated with arterial hypotension and severity of disease in critically ill children. This study does not support the hypothesis that low copeptin values might be indicative of arginine-vasopressin deficiency.

X-Linked Lymphoproliferative Disease Mimicking Multisystem Inflammatory Syndrome in Children-A Case Report.

Most children with a SARS-CoV-2 infection are asymptomatic or exhibit mild symptoms. However, a small number of children develop features of substantial inflammation temporarily related to the COVID-19 also called multisystem inflammatory syndrome in children (MIS-C) or pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS), clinically similar to Kawasaki disease, toxic shock syndrome and hemophagocytic lymphohistiocytosis (HLH). It is well-known that genetic pre-disposition plays an important role in virally-triggered diseases such as Epstein-Barr virus (EBV)-associated HLH, while this has not yet been established for patients with MIS-C. Here we describe a male patient fulfilling the diagnostic criteria of MIS-C, who was initially treated according to current consensus guidelines. Presence of hypofibrinogenemia, normal lymphocyte counts and C-reactive protein, but substantial hyperferritinemia distinguish this patient from others with MIS-C. The clinical course following initial presentation with acute respiratory distress syndrome was marked by fatal liver failure in the context of EBV-associated HLH despite treatment with steroids, intravenous immunoglobulins, interleukin (IL)-1 receptor blockade and eventually HLH-directed treatment. X-linked lymphoproliferative disease type 1 (XLP1), a subtype of primary HLH was diagnosed in this patient post-mortem. This case report highlights the importance of including HLH in the differential diagnosis in MIS-C with severe disease course to allow specific, risk-adapted treatment and genetic counseling.