ICOS-Positive Regulatory T Cells in Hepatocellular Carcinoma: The Perspective from Digital Pathology Analysis.

INTRODUCTION: Inducible co-stimulator (ICOS), an important co-stimulatory receptor on effector T cells (Teffs), may also contribute to tumor growth due to its high expression on regulatory T cells (Tregs). This study explored the clinical significance of ICOS-expressing Tregs in hepatocellular carcinoma (HCC). METHODS: Tumor tissues from HCC patients who received curative hepatectomy were obtained at a referral center. Dual immunohistochemistry was performed to evaluate the expression of ICOS and Foxp3. The cell densities and proximities between stained cells in regions of interest were measured by digital pathology and the associations with clinical outcome were analyzed. RESULTS: A total of 142 patients (male:female = 112: 30, median age of 61.0 years) were enrolled. Among them, 87 (61.3%) had chronic hepatitis B virus infection and 33 (23.2%) had chronic hepatitis C infection. Low α-fetoprotein level (<20 ng/mL) and early-stage were significantly associated with improved overall survival (OS). The density of ICOS+Foxp3+ cells and the ratio of ICOS+Foxp3+/total Foxp3+ cells were significantly higher (p < 0.001) in the tumor center than in the peritumor area. Patients with a high density of ICOS+Foxp3+ cells or a high ratio of ICOS+Foxp3+/total Foxp3+ cells in the tumor center trended to have a shorter OS. A shorter distance between ICOS+Foxp3+ cells and ICOS+Foxp3- cells (likely Teffs) in the tumor center was significantly associated with a shorter OS (p = 0.030), suggesting active immunosuppression of ICOS+ Tregs on ICOS+ Teffs. CONCLUSION: An increased abundance of ICOS+ Tregs in the tumor center in comparison to the peritumor area indicates a strong immunosuppressive tumor microenvironment of HCC. A high proportion of ICOS+Foxp3+ cells and a shorter distance between ICOS+ Tregs and other ICOS+ cells were associated with a poor OS, suggesting that depleting ICOS+ Tregs might provide clinical benefit for patients with HCC.

How to interpret skin prick tests and serum-specific IgE in children and young people with food allergy.

Food allergy is common, it can lead to significant morbidity andnegatively impacts on quality of life; therefore, it is vitally important we get the diagnosis right. However, making the diagnosis can be complex. Clinical history is the most important diagnostic tool and subsequent investigation may help confirm the diagnosis. The investigations available to most paediatric departments are skin prick testing and specific IgE so we will focus on these. Within this article we explore the evidence related to targeted testing and how to interpret these within the clinical context.

The Thr224Asn mutation in the VPS45 gene is associated with the congenital neutropenia and primary myelofibrosis of infancy.

Severe congenital neutropenia as well as primary myelofibrosis are rare in infancy. Elucidation of the underlying mechanism is important because it extends our understanding of the more common adult forms of these disorders. Using homozygosity mapping followed by exome sequencing, we identified a Thr224Asn mutation in the VPS45 gene in infants from consanguineous families who suffered from life-threatening neutropenia, which was refractory to granulocyte CSF, from defective platelet aggregation and myelofibrosis. The mutation segregated in the families, was not present in controls, affected a highly conserved codon, and apparently destabilized the Vps45 protein, which was reduced in the patients' leukocytes. Introduction of the corresponding mutation into yeast resulted in reduced cellular levels of Vps45 and also of the cognate syntaxin Tlg2, which is required for membrane traffic through the endosomal system. A defect in the endosomal-lysosomal pathway, the homologous system in humans, was suggested by the absence of lysosomes in the patients' fibroblasts and by the depletion of α granules in their platelets. Importantly, accelerated apoptosis was observed in the patients' neutrophils and bone marrow. This is the first report of a Vps45-related disease in humans, manifesting by neutropenia, thrombasthenia, myelofibrosis, and progressive bone marrow failure.