Intrinsic activation of ß-catenin signaling by CRISPR/Cas9-mediated exon skipping contributes to immune evasion in hepatocellular carcinoma.

Comprehensive analysis of clinical samples has recently identified molecular and immunological classification of hepatocellular carcinoma (HCC), and the CTNNB1 (ß-catenin)-mutated subtype exhibits distinctive characteristics of immunosuppressive tumor microenvironment. For clarifying the molecular mechanisms, we first established human and mouse HCC cells with exon 3 skipping of ß-catenin, which promoted nuclear translocation and activated the Wnt/ß-catenin signaling pathway, by using newly developed multiplex CRISPR/Cas9-based genome engineering system. Gene set enrichment analysis indicated downregulation of immune-associated gene sets in the HCC cells with activated ß-catenin signaling. Comparative analysis of gene expression profiles between HCC cells harboring wild-type and exon 3 skipping ß-catenin elucidated that the expression levels of four cytokines were commonly decreased in human and mouse ß-catenin-mutated HCC cells. Public exome and transcriptome data of 373 human HCC samples showed significant downregulation of two candidate cytokine genes, CCL20 and CXCL2, in HCC tumors with ß-catenin hotspot mutations. T cell killing assays and immunohistochemical analysis of grafted tumor tissues demonstrated that the mouse Ctnnb1Δex3 HCC cells evaded immunosurveillance. Taken together, this study discovered that cytokine controlled by ß-catenin signaling activation could contribute to immune evasion, and provided novel insights into cancer immunotherapy for the ß-catenin-mutated HCC subtype.

A case of tracheal obstruction caused by reflux and aspiration of semi-solid nutrients via the nasogastric tube.

INTRODUCTION: Semi-solid nutrients have several advantages, including reduced cases of diarrhea and aspiration pneumonia, and are usually administered via percutaneous endoscopic gastrostomy owing to its high viscosity. Administering semi-solid nutrients via a nasogastric tube was recently introduced in clinical practice; however, its safety has not been well confirmed. PRESENTATION OF CASE: An 82-year-old man with a right occipital hemorrhage and severe diarrhea consulted the nutritional support team. Administrations of semi-solid nutrients (HINE E-GEL®) via the nasogastric tube was initiated, which gradually alleviated his symptoms. Fourteen days after initiation, he suddenly had pulmonary failure owing to a tracheal obstruction caused by the reflux and aspiration of semi-solid nutrients. Intubation and subsequent reflex cough expectorated sputum with gel-form particles, which quickly stabilized his pulmonary condition. After this, his hospital course was stable, and he was referred to another hospital for further rehabilitation. DISCUSSION: Semi-solid nutrients administered via the nasogastric tube have different ingredients compared with those administered via percutaneous endoscopic gastrostomy. HINE E-GEL®, for example, contains pectin and calcium phosphate that changes from liquid to semi-solid inside the stomach via chemical reactions under acidic conditions. Data on the viscosity of HINE E-GEL® in vivo are insufficient. Uncertainty regarding the form and viscosity of HINE E-GEL® inside the stomach complicates clinical practice. CONCLUSIONS: Although semi-solid nutrients have several advantages, including reduced diarrhea and gastroesophageal reflux, evidence on semi-solid nutrients via the nasogastric tube is insufficient. It should be noted that semi-solid nutrient reflux can be more fatal than liquid nutrients.

Rapid growth speed of cysts can predict malignant intraductal mucinous papillary neoplasms.

BACKGROUND: Branch duct intraductal papillary mucinous neoplasm (BD-IPMN) has the potential for malignant transformation. Current risk factors used to predict malignant transformation, such as mural nodules and cyst size > 30 mm, are insufficient. Therefore, we aimed to investigate the predictive significance of cyst growth speed. MATERIALS AND METHODS: Between 2006 and 2017, 102 patients underwent pancreatectomy for IPMN. Of these, 50 patients with pathologically diagnosed BD-IPMN were selected for cyst growth analysis. Cyst growth speed, total cyst growth, and cyst growth rate were calculated retrospectively using the maximum diameter of the cyst at the first diagnosis and images taken preoperatively. RESULTS: Of the 50 BD-IPMN cases, 33 were diagnosed as benign (low to intermediate dysplasia) and 17 were malignant (10 high-grade dysplasias and seven invasive carcinomas). While no significant differences were observed in the presence of enhancing mural nodules or cyst size, malignant IPMN grew at a significantly faster speed (5.7 versus 1.6 mm/y; P < 0.001), greater amount of cyst diameter (10.1 versus 3.1 mm; P = 0.015), and greater percentage of cyst diameter (28.5% versus 9.5%; P = 0.006) than those of benign IPMN. Receiver operator characteristic curve analysis indicated that cyst growth speed had the greatest predictive performance among these three factors. Cyst growth speed > 3.5 mm/y was demonstrated to predict malignant IPMN with a sensitivity of 88% and specificity of 91%. CONCLUSIONS: Cyst growth speed > 3.5 mm/y may be a good predictor for malignant IPMN. It can improve the diagnostic accuracy and optimize surgery for BD-IPMN.