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Cholesterol sulfate, produced by hydroxysteroid sulfotransferase 2B1 (SULT2B1), is highly abundant in the intestine. Herein, we study the functional role and underlying intestinal epithelial repair mechanisms of cholesterol sulfate in ulcerative colitis. The levels of cholesterol and cholesterol sulfate, as well as the expression of Sult2b1 and genes involved in cholesterol biosynthesis, are significantly higher in inflamed tissues from patients with ulcerative colitis than in intestinal mucosa from healthy controls. Cholesterol sulfate in the gut and circulation is mainly catalyzed by intestinal epithelial SULT2B1. Specific deletion of the Sult2b1 gene in the intestinal epithelial cells aggravates dextran sulfate sodium-induced colitis; however, dietary supplementation with cholesterol sulfate ameliorates this effect in acute and chronic ulcerative colitis in mice. Cholesterol sulfate promotes cholesterol biosynthesis by binding to Niemann-Pick type C2 protein and activating sterol regulatory element binding protein 2 in colonic epithelial cells, thereby alleviates ulcerative colitis. In conclusion, cholesterol sulfate contributes to the healing of the mucosal barrier and exhibits therapeutic efficacy against ulcerative colitis in mice. New treatment strategies are required for ulcerative colitis. Here the authors show in mouse models that cholesterol sulfate, an endogenous active cholesterol derivative, contributes to the healing of the mucosal barrier by promoting cholesterol biosynthesis in colonic epithelial cells and exhibits therapeutic efficacy against ulcerative colitis.

PurposeTo identify triple-negative (TN) breast cancer imaging biomarkers in comparison to other molecular subtypes using multiparametric MR imaging maps and whole-tumor histogram analysis.Materials and methodsThis retrospective study included 134 patients with invasive ductal carcinoma. Whole-tumor histogram-based texture features were extracted from a quantitative ADC map and DCE semi-quantitative maps (washin and washout). Univariate analysis using the Student’s t test or Mann–Whitney U test was performed to identify significant variables for differentiating TN cancer from other subtypes. The ROC curves were generated based on the significant variables identified from the univariate analysis. The AUC, sensitivity, and specificity for subtype differentiation were reported.ResultsThe significant parameters on the univariate analysis achieved an AUC of 0.710 (95% confidence interval [CI] 0.562, 0.858) with a sensitivity of 63.6% and a specificity of 73.1% at the best cutoff point for differentiating TN cancers from Luminal A cancers. An AUC of 0.763 (95% CI 0.608, 0.917) with a sensitivity of 86.4% and a specificity of 72.2% was achieved for differentiating TN cancers from human epidermal growth factor receptor 2 (HER2) positive cancers. Also, an AUC of 0.683 (95% CI 0.556, 0.809) with a sensitivity of 54.5% and a specificity of 83.9% was achieved for differentiating TN cancers from non-TN cancers. There was no significant feature on the univariate analysis for TN cancers versus Luminal B cancers.ConclusionsWhole-tumor histogram-based imaging features derived from ADC, along with washin and washout maps, provide a non-invasive analytical approach for discriminating TN cancers from other subtypes.Key Points• Whole-tumor histogram-based features on MR multiparametric maps can help to assess biological characterization of breast cancer.• Histogram-based texture analysis may predict the molecular subtypes of breast cancer.• Combined DWI and DCE evaluation helps to identify triple-negative breast cancer.

We report 10 additional cases of GLI1-altered mesenchymal tumor to further delineate its clinicopathological and molecular spectrum. There were seven males and three females with a median age of 31 years (range 1.3 ~ 75 years). Five tumors arose in the oral cavity, one each in the stomach, uterine cervix, elbow, groin, and thigh. Histologically, all cases except one were composed of monomorphic round to epithelioid cells showing an infiltrative multinodular growth pattern. The neoplastic cells were surrounded by a rich network of capillary vessels. Vessel invasion or subendothelial protrusion into the vascular space was commonly present. One tumor developed regional lymph node metastasis. The remaining case showed a predominantly spindle cell tumor. By immunohistochemistry, most tumors showed diffuse staining of CD56 (8/8) with variable expression of S100 protein (7/8). In three tumors harboring amplified genes, strong and diffuse nuclear staining of MDM2 (2/3) and CDK4 (3/3) were noted. Next-generation sequencing (NGS) studies revealed GLI1 fusions in 7 cases and GLI1 amplification in 2 cases, which were validated by fluorescence in situ hybridization (FISH) analysis in the majority of cases. One case did not show fusion gene by RNA-seq, but FISH revealed both amplification and break-apart of GLI1 gene. Follow-up information showed local recurrences in two patients. All other patients remained disease-free at the last follow-up. Our study further demonstrates that mesenchymal tumors with GLI1 alterations represent a distinctive clinicopathological entity. Although the tumor has a propensity for the tongue, it can also arise in somatic soft tissues as well as in visceral organs. Based on the characteristic morphological features and genomic profiles, we propose the term “GLI1-altered mesenchymal tumor” to describe this emerging entity.

Gene fusions are one of the most important molecular biomarkers for tumor diagnosis, classification and targeted therapy. How to accurately detect them is a key issue in clinical work. In this study, a custom-designed integration of DNA and RNA-based next generation sequencing (NGS) assay including 16 targeted therapy related genes was developed and validated to identify gene fusions in solid tumors. This assay accurately identified all 10 different types of fusion in 8 commercial fusion spiked-in reference standards and 29 fusions including 16 different fusion forms in 60 clinical solid tumor samples previously identified by clinical testing methods. In addition, a TPM3 :: NTRK1 fusion was additionally identified and validated by Sanger sequencing, which showed a false-negative result for the previous result. Mutational abundance limit of detection for the assay was assessed with a series of dilution experiments. These fusions can be stably detected when the mutational abundance is down to 5% for DNA and 250–400 copies/100 ng for RNA. The intra-assay and inter-assay reproducibility was observed in three samples and three replicates. This integration of DNA and RNA-based NGS assay shows excellent performance on formalin-fixed, paraffin-embedded samples, results at different levels can complement each other, thereby facilitating precise diagnosis and treatment.

Mesenchymal epithelial transition (MET) factor alteration in non-small cell lung cancer (NSCLC) includes MET exon 14 skipping alteration (METex14 skipping), MET gene amplification, MET gene mutation (mainly kinase domain mutation), MET gene fusion, and MET protein overexpression. The incidence of METex14 skipping in patients with NSCLC is 0.9–4.0%. At present, drugs targeting METex14 skipping have been approved in China and other countries like Japan and USA. Patients with advanced NSCLC should undergo testing, including METex14 skipping, to screen the population with benefit from targeted therapy with MET inhibitors. The incidence of de novo MET gene amplification in NSCLC patients is 1–5%, the incidence of acquired MET gene amplification in epidermal growth factor receptor tyrosine kinase inhibitor (TKI)-resistant patients is 5–50%, and the incidence in anaplastic lymphoma kinase (ALK) TKI-resistant patients is about 13%; the incidence of MET protein overexpression in NSCLC patients is 13.7–63.7%. Several clinical trials on MET gene amplification and MET protein overexpression are ongoing, which have demonstrated their important guiding significance as biomarkers in the clinical treatment with MET inhibitors. Accurate detection of MET alterations is a prerequisite for MET inhibitor therapy. Since there are many types of MET alterations and related testing methods, as well as many problems and challenges during clinical testing, further sorting and standardization are required. Combined with clinical practice experience, literature review, and expert discussion, the writing group developed this consensus on the three main types of MET alterations (METex14 skipping, MET gene amplification, and MET protein overexpression) in order to guide the practical applications of clinical MET testing.

Background Previous studies on cancer of unknown primary (CUP) mainly focus on treatment and prognosis in western populations and lacked clinical evaluation of different IHC markers, so this study aimed to evaluate characteristics of CUP and recommend a diagnostic strategy from a single center in China. Methods and results Data of 625 patients with CUP were retrospectively collected and reviewed. The patients ranged in age from 20 to 91 years, with a female-to-male ratio of 1.3:1. The predominant histological type was poor or undifferentiated adenocarcinomas (308; 49.3%). The results of Canhelp-Origin molecular testing for the identification of the tissue of origin in 262 of 369 patients (71.0%) were considered predictable (similarity score > 45), with the most common predicted primary tumor site being the breast (57, 21.8%). Unpredictable molecular results correlated with more aggressive clinical parameters and poor survival. Thee positivity rates of several targeted antibodies (GATA3, GCDFP15, TTF1, Napsin A, and PAX8), based on the clinically predicted site, were lower than those reported for the corresponding primary tumors. Nonetheless, TRPS1 and INSM1 were reliable markers of predicted breast carcinoma (75.0%) and neuroendocrine tumors (83.3%), respectively. P16 expression, as well as HPV and EBER testing contributed significantly to the diagnosis of squamous cell carcinomas. Survival analysis revealed that older ages (> 57), ≥ 3 metastatic sites, non-squamous cell carcinomas, bone/liver/lung metastases, unpredictable molecular results, and palliative treatment correlated with poor overall survival. Conclusions We recommend a CUP diagnostic strategy involving the use of targeted antibody panels as per histological findings that is potentially applicable in clinical practice. The markers TRPS1, INSM1, and P16 expression, as well as HPV and EBER testing are particularly valuable in this aspect. Molecular testing is also predictive of survival rates.

Human epidermal growth factor receptor 2 (HER2) gene amplification helps identify breast cancer patients who may respond to targeted anti-HER2 therapy. This study aims to develop an automated method for quantifying HER2 fluorescence in situ hybridization (FISH) signals and improve the working efficiency of pathologists. An Aitrox artificial intelligence (AI) model based on deep learning was constructed, and a comparison between the AI model and traditional manual counting was performed. In total, 918 FISH images from 320 consecutive invasive breast cancers were analysed and automatically classified into 5 groups according to the 2018 ASCO/CAP guidelines. The overall classification accuracy was 85.33% (157/184) with a mean average precision of 0.735. In Group 5, the most common group, the consistency was as high as 95.90% (117/122), while the consistency was low in the other groups due to the limited number of cases. The causes of this inconsistency, including clustered HER2 signals, coarse CEP17 signals and some section quality problems, were analysed. The developed AI model is a reliable tool for evaluating HER2 amplification statuses, especially for breast cancer in Group 5; additional cases from multiple centres could further improve the accuracy achieved for other groups.

Background Uterine tumors resembling ovarian sex-cord tumors (UTROSCTs) are rare mesenchymal neoplasms predominantly arising in perimenopausal and postmenopausal women. UTROSCTs with growth regulation by estrogen in breast cancer 1 ( GREB1 )-rearrangement or GREB1 -rearranged uterine tumors are exceptionally rare, with only 12 previously reported cases. Here, we report a case of UTROSCT with the GREB1 -nuclear receptor coactivator 2 ( NCOA2 ) fusion gene. Case presentation A 57-year-old woman presented with a 10.0 cm uterine mass. The tumor was composed of short spindle or epithelioid cells, arranged in diffused sheets, nested, and trabecular/cordlike. The tumor harbored the GREB1-NCOA2 fusion gene, as confirmed by RNA sequencing. The tumor recurred in the pelvis at 30 months after the initial diagnosis. We also compared the clinical and pathologic features of this case with those of the 12 previously published uterine GREB1 -rearranged tumors. Of the combined 13 cases (present case and 12 previous cases), the mean age of patients was 64.8 years (range, 51–74 years). Of the nine reported cases of GREB1 -rearranged tumor with follow up, four cases recurred or metastasized (44.4%). Microscopically, most tumors (10/12, 83.3%) showed infiltrative growth, and two were well demarcated. Mitotic figures ranged from 0 to 14 per 10 high-power fields (2 mm 2 ; mean: 3.6). Lymphovascular invasion and necrosis were each present in two cases (2/12, 16.7% and 2/7, 28.6%, respectively). Conclusions This case provided further evidence that UTROSCTs with GREB1 -rearrangement may have a high risk of recurrence/metastasis. Further studies are necessary to clarify the clinical features of this type of tumor, particularly the prognosis, potential treatment, and range of possible molecular events.

Background According to 2018 ASCO/CAP guideline, HER2 FISH-equivocal breast cancers will be categorized as HER2 negative except those with IHC 3+. However, whether or not HER2 FISH-equivocal breast cancers was a heterogeneous group has not been well illustrated. Methods 195 HER2 FISH-equivocal breast cancer samples were collected from 2014 to 2018. The molecular subtype was identified according to 2013 St Gallen consensus, and HER2 status was also re-determined following 2018 ASCO/CAP guideline. All samples were classified into 4 groups according to the average HER2 copy number (4.0–4.4, 4.5–4.9, 5.0–5.4, 5.5–5.9 signals/cell). The relationship between HER2 copy number and clinicopathological parameters was analyzed. Results 183 (93.8%) of 195 FISH-equivocal cases were classified as luminal-like subtype, while the other 12 (6.2%) were undetermined. Following 2018 ASCO/CAP guideline, all FISH-equivocal cases were recategorized as HER2 negative. Therefore, 31(15.9%) cases were luminal A-like, 152 (77.9%) were luminal B-like (HER2 negative) and 12 (6.2%) were triple negative. The average HER2 copy number showed a positive correlation with chromosome 17 polysomy, but had no significant association with other clinicopathological parameters as well as prognosis. 17 (8.7%) patients were treated with trastuzumab, but showed no difference in prognosis with those who didn’t receive targeted therapy. Conclusions In this study, all HER2 FISH-equivocal breast cancers were recategorized as HER2 negative according to 2018 ASCO/CAP guideline. Most of these patients were luminal B-like (HER2 negative). The average HER2 copy number had no significant association with clinicopathological parameters, as well as prognosis.

The contribution of CXCL12/CXCR4/CXCR7 axis to cancer progression has been increasingly recognized. However, its role in thyroid cancer development remains unclear. The present study aimed to examine the expression and function of CXCL12 and its receptors in thyroid cancer. The expression of CXCL12/CXCR4/CXCR7 in human tissue specimens of papillary, follicular, medullary, and anaplastic thyroid carcinoma, follicular adenoma, Hashimoto's thyroiditis and nodular goiter were examined by immunohistochemistry using a tissue microarray. CXCR4 and CXCR7 were over-expressed in human thyroid cancer cells K1 by transduction of recombinant lentivirus. The effect of overexpression of CXCR4 and CXCR7 on K1 cell proliferation and invasion and the molecular mechanism underlying the effect were investigated. CXCL12 was exclusively expressed in papillary thyroid carcinoma tissue but absent in other types of thyroid malignancies and benign lesions. CXCR7 was widely expressed in the endothelial cells of all types of malignancy but only occasionally detected in benign lesions. CXCR4 was expressed in 62.5% of papillary thyroid carcinoma tissue specimens and in 30-40% of other types of malignancy, and it was either absent or weakly expressed in benign lesions. CXCL12 stimulated the invasion and migration of K1 cells overexpressing CXCR4, but did not affect K1 cells overexpressing CXCR7. K1 cell proliferation was not affected by overexpression of CXCR4 or CXCR7. Overexpression of CXCR4 in K1 cells significantly increased AKT and ERK phosphorylation and markedly induced the expression and activity of matrix metalloproteinase-2 (MMP-2). Thus, CXCL12 may be an effective diagnostic marker for papillary thyroid carcinoma, and CXCL12/CXCR4/CXCR7 axis may contribute to thyroid cancer development by regulating cancer cell migration and invasion via AKT and ERK signaling and MMP-2 activation.