RNA-Seq-Based Molecular Classification Analyses in Colorectal Cancer and Synchronous Adenoma.

Colorectal cancers (CRC) are classified into consensus molecular subtypes (CMS) based on gene expression profiles. The revised classification system iCMS was proposed by considering intrinsic epithelial status, microsatellite instability (MSI), and fibrosis. This study aimed to provide molecular evidence for the adenoma-carcinoma sequence concept by examining CRC and synchronous adenomas using iCMS. Epithelial CMS cell proportion was estimated using CiberSortx, an in silico cell fractionation method that included CMS cell types among the reference cell types. A random forest (RF) model estimated the posterior probabilities of CMS classes, which were compared with the CiberSortx results. Gene expression profiles of the published iCMS signature panel were retrieved from our dataset and subjected to heatmap clustering for classification. Bulk RNA sequencing data were collected from 29 adenocarcinomas and 11 adenoma samples. CiberSortx showed all CRC contained either CMS2 or CMS3 as the major epithelial cancer cell type. The RF model classified approximately half of the CRC as CMS4, whereas CMS4 was hardly detected by CiberSortx. Because they were enriched with myofibroblasts as per the CiberSortx classification, we tentatively designated them as iCMS2-F/iCMS3-F. iCMS coupled with the application of an in silico cell fractionation method can provide the molecular dissection of CRC and adenoma.

Gemigliptin, a DPP4 inhibitor, ameliorates nonalcoholic steatohepatitis through AMP-activated protein kinase-independent and ULK1-mediated autophagy.

OBJECTIVE: Abnormal autophagic function and activated inflammasomes are typical features in the liver of patients with non-alcoholic steatohepatitis (NASH). Here, we explored whether gemigliptin, a dipeptidyl peptidase 4 (DPP4) inhibitor for treatment of type 2 diabetes, can induce autophagy and regulate inflammasome activation as a potential NASH treatment independent of its anti-diabetic effect. METHODS: Expression analysis was performed using human liver samples obtained from 18 subjects who underwent hepatectomy. We explored the function and mechanism of gemigliptin using a methionine- and choline-deficient diet (MCD)-induced NASH mouse model and HepG2 cells cultured in MCD-mimicking medium. RESULTS: Autophagy was suppressed by marked decreases in the expression of ULK1 and LC3II/LC3I ratio in human NAFLD/NASH patients, a NASH mouse model, and HepG2 cells cultured with MCD-mimicking media. Surprisingly, we found that the expression of p-AMPK decreased in liver tissues from patients with steatosis but was restored in NASH patients. The expression of p-AMPK in the NASH mouse model was similar to that of the control group. Hence, these results indicate that autophagy was reduced in NASH via an AMPK-independent pathway. However, gemigliptin treatment attenuated lipid accumulation, inflammation, and fibrosis in the liver of MCD diet-fed mice with restoration of ULK1 expression and autophagy induction. In vitro, gemigliptin alleviated inflammasome activation through induction of ULK1-dependent autophagy. Furthermore, gemigliptin treatment upregulated ULK1 expression and activated AMPK even after siRNA-mediated knockdown of AMPKα1/2 and ULK1, respectively. CONCLUSIONS: Collectively, these results suggest that gemigliptin ameliorated NASH via AMPK-independent, ULK1-mediated effects on autophagy.

Diagnostic performance of a novel ultrasound-based quantitative method to assess liver steatosis in histologically identified nonalcoholic fatty liver disease.

AIMS: To investigate the diagnostic performance of ultrasound-guided attenuation parameter (UGAP) for the detection of hepatic steatosis in nonalcoholic fatty liver disease (NAFLD) cohorts using histopathology as the reference standard andcomparing it with that of various imaging modalities. MATERIALS AND METHODS: A total of 87 subjects who underwent UGAP, controlled attenuation parameter (CAP), and magnetic resonance imaging-based proton density fat fraction (MRI-PDFF) between December, 2020 and January, 2022 were enrolled. Of these patients, 38 patients had NAFLD. The association between UGAP and clinical and imaging parameters was assessed using Pearson's or Spearman's correlations. The area under the receiver operating characteristic curve (AUROC) was used to evaluate the diagnostic performance. RESULTS: The UGAP and MRI-logPDFF demonstrated strong positive correlations (correlation coefficient= 0.704, P <0.0001). UGAP showed excellent diagnostic performance for distinguishing steatosis grade ≥1 with an AUROC of 0.821 (95% confidence interval [CI], 0.729-0.913), which was comparable to that of MRI-PDFF (0.829, 95%CI, 0.723-0.936). The AUROCs of BUSG (B-mode ultrasonography) (0.766, 95% CI, 0.767-0.856) and CAP (0.788, 95% CI, 0.684-0.891) were slightly lower than those of UGAP. The AUROCs of UGAP, MRI-PDFF, CAP, and BUSG for detecting steatosis grade ≥2 were 0.796 (95% CI, 0.616-0.975), 0.971 (95% CI, 0.936-1.000), 0.726 (95% CI, 0.561-0.891) and 0.774 (95% CI, 0.612-0.936), respectively. CONCLUSION: UGAP may be a valuable potential screening tool as a first-line assessment of liver steatosis in patients with NAFLD.

Dual Oxidase 2 (DUOX2) as a Proteomic Biomarker for Predicting Treatment Response to Chemoradiation Therapy for Locally Advanced Rectal Cancer: Using High-Throughput Proteomic Analysis and Machine Learning Algorithm.

High-throughput mass-spectrometry-based quantitative proteomic analysis was performed using formalin-fixed, paraffin-embedded (FFPE) biopsy samples obtained before treatment from 13 patients with locally advanced rectal cancer (LARC), who were treated with concurrent chemoradiation therapy (CCRT) followed by surgery. Patients were divided into complete responder (CR) and non-complete responder (nCR) groups. Immunohistochemical (IHC) staining of 79 independent FFPE tissue samples was performed to validate the predictive ability of proteomic biomarker candidates. A total of 3637 proteins were identified, and the expression of 498 proteins was confirmed at significantly different levels (differentially expressed proteins-DEPs) between two groups. In Gene Ontology enrichment analyses, DEPs enriched in biological processes in the CR group included proteins linked to cytoskeletal organization, immune response processes, and vesicle-associated protein transport processes, whereas DEPs in the nCR group were associated with biosynthesis, transcription, and translation processes. Dual oxidase 2 (DUOX2) was selected as the most predictive biomarker in machine learning algorithm analysis. Further IHC validation ultimately confirmed DUOX2 as a potential biomarker for predicting the response of nCR to CCRT. In conclusion, this study suggests that the treatment response to RT may be affected by the pre-treatment tumor microenvironment. DUOX2 is a potential biomarker for the early prediction of nCR after CCRT.

Aspergillus appendicitis complicating chemotherapy of leukemia: A case report and review of the literature.

INTRODUCTION: The diagnosis of primary Aspergillus appendicitis can be missed or delayed because of its rarity. We report our experience of a case of Aspergillus appendicitis complicating chemotherapy of leukemia. PRESENTATION OF CASE: A 48-year-old man who was diagnosed with acute myeloid leukemia developed high fever and epigastric pain two weeks after administration of his fourth consolidation chemotherapy. Right lower quadrant tenderness and rebound tenderness were noticed on physical examination, and the abdomen and pelvis computed tomography suggested acute perforated appendicitis with localized peritonitis. Emergency laparoscopy showed an inflamed appendix, which was resected. Pathology reports revealed invasive aspergillosis in the appendix. The patient recovered after high-dose antifungal therapy, although he required prolonged hospitalization. DISCUSSION: Acute appendicitis is very rarely caused by fungi infection with an overall incidence of up to 1.15 %. Differential diagnosis of fungal appendicitis without pathology report is challenging due to low incidence. CONCLUSION: Isolated Aspergillus appendicitis is a rare disease that can progress without appropriate antifungal therapy even after surgical resection of the appendix. Surgeons should pay attention to pathology reports after appendectomy to avoid missing unusual cases, especially in immunocompromised patients.

Venous Invasion and Perineural Invasion as Upstaging and Poor Prognostic Factors in N0 Gastric Cancers.

BACKGROUND/AIM: Lymph node metastasis is an important prognostic factor in gastric cancer patients. In node-negative (N0) gastric cancer patients, additional prognostic factors are needed to reinforce TNM staging. PATIENTS AND METHODS: We semi-quantitatively recorded the presence of lymphatic, venous, and perineural invasion and evaluated the possibility that they could be used as upstaging factors in N0 gastric cancer by comparing N0 gastric cancer cases with N1 cases. RESULTS: Venous (p<0.001) and perineural (p<0.001) invasion were important factors in the relapse-free survival of N0 patients, but lymphatic invasion was not. N0 cases with venous or perineural invasion had survival curves similar to those of N1 patients. In addition, the number of invasive features (lymphatic, venous, or perineural) was an important factor in predicting poor patient survival. CONCLUSION: Venous and perineural invasion were significant prognostic factors in N0 gastric cancer cases. It is necessary to record lymphatic, venous, and perineural invasion separately in the pathology report, especially in cases of N0 gastric cancer.

Proto-oncogene Pokemon in thyroid cancer: a potential promoter of tumorigenesis in papillary thyroid carcinoma.

BACKGROUND: Pokemon is an oncogenic transcription regulator that plays a critical role in cellular differentiation. Although it has been found to be overexpressed in several types of cancer involving different organs, its role in thyroid gland has yet to be reported. The objective of this study was to evaluate the expression of Pokemon in papillary thyroid carcinoma (PTC) based on clinicopathological parameters. METHODS: Tissue microarray samples derived from patients with PTC or benign thyroid disease were used to evaluate Pokemon expression based on immunohistochemical analysis. Correlations of its expression with various clinicopathological parameters were then analyzed. RESULTS: Pokemon expression was observed in 22.0% of thyroid follicular cells from the normal group, 44.0% from the group with benign thyroid diseases, and 92.1% from the group with PTC (p < .001). The intensity of Pokemon expression was markedly higher in the PTC group. Pokemon expression level and PTC tumor size showed an inverse correlation. T1a tumors showed strong expression levels of Pokemon. However, larger tumors showed weak expression (p = .006). CONCLUSIONS: Pokemon expression is associated with tumorigenesis of PTC, with expression showing an inverse correlation with PTC tumor size. This might be related to the negative regulation of aerobic glycolysis by Pokemon.

High-sensitivity C-reactive Protein and Regression of Low-grade Squamous Intraepithelial Lesion: The Role of Low-grade Inflammation in Cervical Carcinogenesis.

BACKGROUND: Inflammation is emerging as a potential mechanism of cervical carcinogenesis. However, few studies have investigated the association between host inflammatory status and the natural course of cervical precursor lesion. The aim of this study was to assess the probability of LSIL regression, associated with an inflammatory biomarker, high-sensitivity C-reactive protein (hs-CRP). METHODS: In a longitudinal cohort study, female participants were examined annually or biannually using cervical cytology between 2006 and 2015. Incident LSIL cases were included in the analysis, with regression defined as at least one consecutive normal cytologic result. A total of 520 women aged 22-64 years were followed up for LSIL regression. The multivariable-adjusted hazard ratios (HRs) for LSIL regression were estimated using a parametric proportional hazards model. RESULTS: During 827.5 person-years of follow-up, 486 out of 520 subjects (93.5%) showed LSIL regression. After adjusting several important potential confounders, a higher quartile of hs-CRP levels was significantly associated with a lower rate of regression (for quartile 4 vs quartile 1, inverse HR 1.33; 95% CI, 1.04-1.69; P for trend = 0.028). CONCLUSIONS: The low rate of spontaneous regression recorded in women with higher hs-CRP lends support to the role of the perturbated host inflammatory status in cervical carcinogenesis, and suggests that hs-CRP level could help monitor LSIL.

Clinicopathological characteristics and outcomes of gastrointestinal stromal tumors with high progranulin expression.

BACKGROUND & AIMS: Progranulin (PGRN) is known to promote tumorigenesis and proliferation of several types of cancer cells. However, little is known about the clinicopathological features of patients with gastrointestinal stromal tumors (GISTs) with regard to PGRN expression. METHODS: A retrospective analysis was performed on patients with GISTs who underwent curative surgical resection between 2007 and 2017. PGRN expression was evaluated by immunohistochemical (IHC) analysis and semi-quantitatively categorized (no expression, 0; weak, 1+; moderate, 2+; strong, 3+). Tumors with a staining intensity of 2+ or 3+ were considered high PGRN expression. RESULTS: Fifty-four patients were analyzed; 31 patients (57%) were male. The median age at surgery was 60 years (range, 33-79), and the most common primary site was the stomach (67%). Thirty-five patients (65%) had spindle histology; 42 patients (78%) were separated as a high-risk group according to the modified National Institutes of Health (NIH) classification. High PGRN-expressing tumors were observed in 27 patients (50%), had more epithelioid/mixed histology (68% vs. 32%; p = 0.046), and KIT exon 11 mutations (76% vs. 24%; p = 0.037). Patients with high PGRN-expressing tumors had a worse recurrence-free survival (RFS) (36% of 5-year RFS) compared to those with low PGRN-expressing tumors (96%; p<0.001). Multivariate analysis showed that high PGRN expression and old age (>60 years) were independent prognostic factors for poor RFS. CONCLUSIONS: High PGRN-expressing GISTs showed more epithelioid/mixed histology and KIT exon 11 mutations. PGRN overexpression was significantly associated with poor RFS in patients with GISTs who underwent curative resection.

Total length of positive resection margins can predict remnant gastric cancer following endoscopic submucosal dissection.

BACKGROUND: Prediction of remnant tumor is important in determining subsequent treatment options for gastric cancer patients with positive resection margin (RM) after endoscopic submucosal dissection (ESD). METHODS: Based on the assumption that pathologic factors, including the length and type of involved RM, could potentially predict residual tumor, we evaluated 451 ESD specimens in patients with early gastric cancer. RESULTS: Of 408 cases, 37 (9.1 %) showed positive RMs. RM involvement in gastric cancer ESD specimens was associated with extended or beyond ESD criteria, greater tumor size, poor differentiation, submucosal invasion, lymphovascular invasion, and upper third location. Among the 37 positive RM cases, residual tumor was present in seven (18.9 %). The presence of residual tumor was not significantly associated with any clinicopathologic parameters except for tumor size and RM status. The total length of the involved RM was the most significant factor associated with the presence of residual tumor (P < 0.008). A total length cut-off value of 6 mm yielded a sensitivity of 85.7 % and negative predictive value of 94.7 % for predicting remnant tumor at gastrectomy following ESD. CONCLUSIONS: In conclusion, when the ESD specimen exhibits positive RM, a quantitative assessment of the involved RM should be included in the pathology report, as this can help the clinician predict remnant tumor and determine appropriate future treatment.

Prognostic Value of Progranulin in Patients with Colorectal Cancer Treated with Curative Resection.

Progranulin (PGRN) has been characterized as an autocrine growth and survival factor and is known to stimulate tumorigenesis and proliferation of several types of cancer cell. However, little is known about the prognostic role of PGRN in colorectal cancer (CRC). A retrospective analysis was performed for patients with colorectal cancer who underwent curative resection between May 2013 and June 2015. PGRN expression in tumor cells was semi-quantitatively categorized (no expression, 0; weak/focal, 1+; moderate/focal or diffuse, 2+; strong/diffuse, 3+), and high expression was considered for tumors graded ≥2+ staining intensity. A total of 109 patients (28 stage I, 32 stage II, and 49 stage III) were analyzed. Thirty-eight patients (35%) had tumors with high PGRN expression, and there was a trend of elevated pre-operative CEA and CA19-9 levels in patients with high PGRN-expressing tumors compared to those with low PGRN-expressing tumors (CEA, 49% vs. 21%; CA19-9, 21% vs. 7%). The 3-year recurrence-free survival (3Y-RFS) and overall survival rates were 83.7% (95% CI, 76.8-90.6) and 96.0% (95% CI, 92.3-99.7), respectively. Patients with high PGRN-expressing tumors had a worse rate of 3Y-RFS (66.8%) compared to those with low PGRN-expressing tumors (92.4%; p = 0.010). Multivariate analysis showed that high PGRN expression, age (>66 years), stage (III), and perineural invasion (+) were independent prognostic factors associated with poor RFS after adjusting for confounding factors including sex, MSI, tumor location, KRAS, and lympho-vascular invasion. PGRN overexpression was significantly associated with poor RFS in patients with CRC who have undergone curative resection.

Standardized Pathology Report for Colorectal Cancer, 2nd Edition.

The first edition of the 'Standardized Pathology Report for Colorectal Cancer,' which was developed by the Gastrointestinal Pathology Study Group (GIP) of the Korean Society of Pathologists, was published 13 years ago. Meanwhile, there have been many changes in the pathologic diagnosis of colorectal cancer (CRC), pathologic findings included in the pathology report, and immunohistochemical and molecular pathology required for the diagnosis and treatment of colorectal cancer. In order to reflect these changes, we (GIP) decided to make the second edition of the report. The purpose of this standardized pathology report is to provide a practical protocol for Korean pathologists, which could help diagnose and treat CRC patients. This report consists of "standard data elements" and "conditional data elements." Basic pathologic findings and parts necessary for prognostication of CRC patients are classified as "standard data elements," while other prognostic factors and factors related to adjuvant therapy are classified as "conditional data elements" so that each institution could select the contents according to the characteristics of the institution. The Korean version is also provided separately so that Korean pathologists can easily understand and use this report. We hope that this report will be helpful in the daily practice of CRC diagnosis.

BioPATH: A Biomarker Study in Asian Patients with HER2+ Advanced Breast Cancer Treated with Lapatinib and Other Anti-HER2 Therapy.

PURPOSE: BioPATH is a non-interventional study evaluating the relationship of molecular biomarkers (PTEN deletion/downregulation, PIK3CA mutation, truncated HER2 receptor [p95HER2], and tumor HER2 mRNA levels) to treatment responses in Asian patients with HER2+ advanced breast cancer treated with lapatinib and other HER2-targeted agents. MATERIALS AND METHODS: Female Asian HER2+ breast cancer patients (n=154) who were candidates for lapatinib-based treatment following metastasis and having an available primary tumor biopsy specimen were included. The primary endpoint was progression-free survival (PFS). Secondary endpoints were response rate, overall survival on lapatinib, correlation between biomarker status and PFS for any previous trastuzumab-based treatment, and conversion/conservation rates of the biomarker status between tissue samples collected at primary diagnosis and at recurrence/metastasis. Potential relationships between tumor mRNA levels of HER2 and response to lapatinib-based therapy were also explored. RESULTS: p95HER2, PTEN deletion/downregulation, and PIK3CA mutation did not demonstrate any significant co-occurrence pattern and were not predictive of clinical outcomes on either lapatinib-based treatment or any previous trastuzumab-based therapy in the metastatic setting. Proportions of tumors positive for p95HER2 expression, PIK3CA mutation, and PTEN deletion/down-regulation at primary diagnosis were 32%, 31.2%, and 56.2%, respectively. Despite limited availability of paired samples, biomarker status patterns were conserved in most samples. HER2 mRNA levels were not predictive of PFS on lapatinib. CONCLUSION: The prevalence of p95HER2 expression, PIK3CA mutation, and PTEN deletion/downregulation at primary diagnosis were similar to previous reports. Importantly, no difference was observed in clinical outcome based on the status of these biomarkers, consistent with reports from other studies.

Factors affecting KRAS mutation detection in colorectal cancer tissue.

BACKGROUND: With the recent development of molecular tests for various biomarkers, it has become even more important to prepare adequate tissue samples. However, little is known about how the effect of cold ischemia time or formalin fixation time can affect KRAS mutation detection in colorectal cancer. METHODS: This study included the results of KRAS mutation tests for colorectal cancer in 401 specimens. We investigated clinicopathologic factors that may affect DNA quality of formalin-fixed, paraffin-embedded (FFPE) tissue including specimen type, cold ischemia time, and formalin fixation time and assessed the detection rate of the KRAS mutation in samples with varying DNA quality. RESULTS: Sample DNA quality for KRAS mutation test was better in biopsy specimens, which showed markedly shorter cold ischemia time and shorter formalin fixation time compared to resection specimens. A cold ischemia time of one hour or less was associated with better sample DNA quality. But the formalin fixation time was not a significant factor when it fell within the range performed in routine pathology diagnosis. When prolonged formalin fixation was tested, we confirmed that the specimen DNA quality gradually got worse from one month to three months. CONCLUSIONS: The biopsy specimens showed better sample DNA quality for KRAS mutation test compared to resection specimens. In a routine diagnostic pathology setting, the cold ischemia time was an important factor affecting DNA quality and the formalin fixation had a wide time range for optimal DNA quality.

Clinicopathologic characteristics of early gastric cancer according to specific intragastric location.

BACKGROUND: Although the incidence of early gastric cancer (EGC) continues to rise, there have been few studies on the intra-gastric distribution and locational characteristics of EGCs. In addition, there has been no attempt to visualize the intra-gastric distribution of EGCs using a merged tumor map. METHODS: We investigated the anatomic distribution of 644 cases of EGCs and analyzed the correlation between clinicopathologic findings and location by dividing areas of the stomach vertically and transversely. Merged tumor maps were generated using 310 surgically resected cases. RESULTS: Early gastric cancer was most commonly located in the antrum (57.5%) along the lesser curvature (37.8%). The intra-gastric distributions were similar in the merged tumor maps. Vertically, cancers of the middle third were associated with younger patient age, larger tumor size, and more frequent poorly differentiated (PD) or signet ring cell histology than cancers in other sites. Submucosal invasion was most frequently observed in the upper third. When divided transversely, tumors in the anterior or posterior wall showed more frequent PD or signet ring cell histology than those along the lesser or greater curvatures. CONCLUSIONS: EGC is the most prevalent in the antrum along the lesser curvature and has characteristic locational features, including histologic type, invasion depth, patient age, and tumor size. These results will improve the endoscopic detection rate of EGC and help to determine endoscopic resectability.

Ultrasonic versus monopolar energy-based surgical devices in terms of surgical smoke and lateral thermal damage (ULMOST): a randomized controlled trial.

BACKGROUND: The purpose of this study was to compare the degree of surgical smoke or vapor and lateral thermal damage caused by two different energy-based surgical devices (ESDs) used in colpotomy during total laparoscopic hysterectomy. METHODS: Patients undergoing laparoscopic hysterectomy were randomly assigned to an ultrasonic ESD group (n = 20) or monopolar ESD group (n = 20). Colpotomy was performed using the assigned ESD. The degree of surgical smoke or vapor obstructing the laparoscopic view was assessed by two independent reviewers using a 5-point Likert scale, in which a higher score indicates worse visibility. The degree of the lateral thermal damage was measured as the width from the point of instrument application to the margins of the unchanged nearby tissue using a light microscope. RESULTS: The baseline characteristics did not statistically differ between the two groups. The degree of surgical smoke or vapor obstructing vision was 1.2 ± 0.8 points in the ultrasonic group and 3.9 ± 0.7 points in the monopolar groups (p < 0.001). The lateral thermal damage was significantly increased in the monopolar group compared to in the ultrasound group (1500 µm [1200-2500 µm] vs. 950 µm [650-1725 µm], p = 0.037). CONCLUSION: Ultrasonic ESD had better laparoscopic visibility and caused less lateral thermal damage during colpotomy compared to monopolar device.

The prognostic significance of protein arginine methyltransferase 6 expression in colon cancer.

Protein arginine methylation is involved in cellular differentiation and proliferation. Recently, aberrant expression of protein arginine methyltransferases, which are responsible for the methylation reaction, has been reported in various types of cancer. However, there is no clear evidence regarding the prognostic value of abnormal PRMT6 expression in colorectal cancer or the effect of PRMT6 regulation on CRC cells. We investigated the expression patterns of PRMT6 in patients with stage II and III CRC. We detected nuclear expression of PRMT6 in 23.7% of carcinoma samples by immunohistochemistry. Among the clinicopathological parameters, the ratio of poorly differentiated cancer cells was approximately two-fold higher in patients with PRMT6-positive disease than in those with PRMT6-negative disease (p = 0.002). Patients with PRMT6-positive CRC had a shorter disease-free survival than those with PRMT6-negative CRC in both univariate and multivariate analyses (p = 0.018 and p = 0.035, respectively). siRNA-mediated inhibition of PRMT6 expression in CRC cells induced p21WAF1/CIP1 overexpression and suppressed cell growth and colony-forming ability. Concomitantly, apoptosis was induced in PRMT6-suppressed CRC cells. These data suggest that PRMT6 can serve as a biomarker for unfavorable prognosis and as a therapeutic target in CRC.

Diagnostic performance and useful findings of ultrasound re-evaluation for patients with equivocal CT features of acute appendicitis.

OBJECTIVE: To evaluate the diagnostic performance of ultrasound and to determine which ultrasound findings are useful to differentiate appendicitis from non-appendicitis in patients who underwent ultrasound re-evaluation owing to equivocal CT features of acute appendicitis. METHODS: 62 patients who underwent CT examinations for suspected appendicitis followed by ultrasound re-evaluation owing to equivocal CT findings were included. Equivocal CT findings were considered based on the presence of only one or two findings among the CT criteria, and ultrasound re-evaluation was done based on a predefined structured report form. The diagnostic performance of ultrasound and independent variables to discriminate appendicitis from non-appendicitis were assessed. RESULTS: There were 27 patients in the appendicitis group. The overall diagnostic performance of ultrasound re-evaluation was sensitivity of 96.3%, specificity of 91.2% and accuracy of 91.9%. In terms of the performance of individual ultrasound findings, probe-induced tenderness showed the highest accuracy (86.7%) with sensitivity of 74% and specificity of 97%, followed by non-compressibility (accuracy 71.7%, sensitivity 85.2% and specificity 60.6%). The independent ultrasound findings for discriminating appendicitis were non-compressibility (p = 0.002) and increased flow on the appendiceal wall (p = 0.001). CONCLUSION: Ultrasound re-evaluation can be used to improve diagnostic accuracy in cases with equivocal CT features for diagnosing appendicitis. The presence of non-compressibility and increased vascular flow on the appendix wall are useful ultrasound findings to discriminate appendicitis from non-appendicitis. Advances in knowledge: Ultrasound re-evaluation is useful to discriminate appendicitis from non-appendicitis when CT features are inconclusive.

MerTK is a novel therapeutic target in gastric cancer.

INTRODUCTION: The role of MerTK has not been assessed in gastric cancer (GC). The aim of this study was to identify a subgroup of GC patients with MerTK tumor overexpression, and to evaluate MerTK as a potential therapeutic target in this disease. METHODS: Protein and mRNA expression of MerTK were evaluated, and other various in vitro analyses including shRNA transfection, cell cycle anslysis, MTS assay and colony forming assay were carried out with GC cell lines and GC patient-derived cells (PDCs). RESULTS: shRNA-mediated knockdown of MerTK resulted in inhibition of cell growth, as well as increased cellular apoptosis in MerTK positive GC cells. Out of 192 GC patients, 16 (8.3%) patients showed strong protein expression and they had a significantly shorter overall survival compared to those with no MerTK expression. In 54 cases of GC PDCs, 4 cases (7.4%) showed mRNA overexpression, which was comparable to the protein expression rate. When we administered UNC1062, a novel MerTK-selective small molecular tyrosine kinase inhibitor, proliferation of MerTK overexpressing GC cells and PDCs were considerably inhibited. CONCLUSION: MerTK may be involved in GC carcinogenesis, and it could be a potential novel therapeutic target in GC patients.

Predictive Value of Sphingosine Kinase 1 Expression in Papillary Thyroid Carcinoma.

BACKGROUND/AIM: Sphingolipid metabolites are emerging as key signaling molecules in cancer. Sphingosine kinase 1 is up-regulated in many different types of human malignancies and plays a crucial role in cancer development and progression. The utility of sphingosine kinase 1 to act as a predictive biomarker in thyroid cancer remains unclear. MATERIALS AND METHODS: Sphingosine kinase 1 expression was evaluated using immunohistochemical staining in 110 formalin-fixed, paraffin-embedded papillary thyroid carcinoma tissue samples. RESULTS: Sphingosine kinase 1 expression in papillary thyroid carcinoma tissue was significantly higher than in nodular goiter (p<0.001) or normal thyroid (p<0.001) tissue. Sphingosine kinase 1 was observed in the cytoplasm of tumor cells. Thirty-four (30.9%) of 110 papillary thyroid carcinomas exhibited high sphingosine kinase 1 expression, that was significantly associated with tumor multiplicity (p=0.004), extrathyroidal extension (p=0.013), presence of lymph node metastasis (p<0.001), and number of metastatic lymph nodes (p=0.042). In addition, high sphingosine kinase 1 expression was the only independent predictor of lymph node metastasis (p<0.001). CONCLUSION: Sphingosine kinase 1 is involved in papillary thyroid carcinoma development and progression and can serve as a potential biomarker predictive of lymph node metastasis.