Prognostic Value of Metastatic Tumoral Caveolin-1 Expression in Patients with Resected Gastric Cancer

Objective. Caveolin-1 (Cav-1), as the main component of caveolae, has complex roles in tumourigenesis in human malignancies. We investigated Cav-1 in primary and metastatic tumor cells of gastric cancer (GC) and its association with clinical outcomes. Methods. We retrieved 145 cases of GC who had undergone curative gastrectomy. The expression levels of Cav-1 was evaluated by immunohistochemistry, and its association with clinicopathological parameters and patient survival was analyzed. Results. High expression of Cav-1 protein of the GC in the stomach and metastatic lymph node was 12.4% (18/145) and 16.5% (15/91). In the multivariate analysis, tumoral Cav-1 protein in metastatic lymph node showed prognostic significance for relapse-free survival (RFS, HR, 3.934; 95% CI, 1.882–8.224; P=0.001) and cancer-specific survival outcome (CSS, HR, 2.681; 95% CI, 1.613–8.623; P=0.002). Among the GCs with metastatic lymph node, it remained as a strong indicator of poor prognosis for RFS (HR, 3.136; 95% CI, 1.444–6.810; P=0.004) and CSS (HR, 2.509; 95% CI, 1.078–5.837; P=0.032). Conclusion. High expression of tumoral Cav-1 protein in metastatic lymph node is associated with unfavorable prognosis of curative resected GC, indicating the potential of novel prognostic markers

Diagnostic proficiency test using digital cytopathology and comparative assessment of whole slide images of cytologic samples for quality assurance program in Korea

Background The Korean Society for Cytopathology introduced a digital proficiency test (PT) in 2021. However, many doubtful opinions remain on whether digitally scanned images can satisfactorily present subtle differences in the nuclear features and chromatin patterns of cytological samples. Methods We prepared 30 whole-slide images (WSIs) from the conventional PT archive by a selection process for digital PT. Digital and conventional PT were performed in parallel for volunteer institutes, and the results were compared using feedback. To assess the quality of cytological assessment WSIs, 12 slides were collected and scanned using five different scanners, with four cytopathologists evaluating image quality through a questionnaire. Results Among the 215 institutes, 108 and 107 participated in glass and digital PT, respectively. No significant difference was noted in category C (major discordance), although the number of discordant cases was slightly higher in the digital PT group. Leica, 3DHistech Pannoramic 250 Flash, and Hamamatsu NanoZoomer 360 systems showed comparable results in terms of image quality, feature presentation, and error rates for most cytological samples. Overall satisfaction was observed with the general convenience and image quality of digital PT. Conclusions As three-dimensional clusters are common and nuclear/chromatin features are critical for cytological interpretation, careful selection of scanners and optimal conditions are mandatory for the successful establishment of digital quality assurance programs in cytology

Atherosclerotic Progression Attenuates the Expression of Nogo-B in Autopsied Coronary Artery: Pathology and Virtual Histology Intravascular Ultrasound Analysis

The relation of Nogo-B to atherosclerotic plaque progression is not well understood. Thus, the purpose of this study was to assess the expression of Nogo-B in fibroatheromas (FA) of different stages, classified using virtual histology intravascular ultrasound (VH-IVUS) analysis in 19 autopsied cases of non-sudden cardiac death. VH-IVUS imaging analysis was performed 30 mm from the ostium of each coronary artery. VH-IVUS revealed 11 early FAs (34.5±8.3 yr), 12 late FAs (42.6±16.6 yr), 8 thick-cap FAs (TkCFAs) (46.4±11.1 yr), and 6 thin-cap FAs (TCFAs) (51.8±6.8 yr). TkCFAs and TCFAs were defined as advanced FA. FA progression advanced with age (P=0.04). VH-IVUS analysis of small, early FAs showed smaller necrotic cores and relatively less calcium compared to more advanced FAs with large necrotic cores (P<0.001). Histopathology and immunohistochemical stains demonstrated that early or late FAs had smaller necrotic cores, less empty space of decalcification, and greater Nogo-B expression compared to advanced FAs (vs. early FA, P=0.013; vs. late FA, P=0.008, respectively). These findings suggest that FA progression is inversely associated with Nogo-B expression. Local reduction of Nogo-B may contribute to plaque formation and/or instability

High Endothelial Venule with Concomitant High CD8+ Tumor-Infiltrating Lymphocytes Is Associated with a Favorable Prognosis in Resected Gastric Cancer

CD8+ tumor-infiltrating lymphocytes (TILs) play a major role in antitumor immunity. High endothelial venules (HEVs) are related to diverse immune cells in solid tumors. We analyzed CD8+ and Foxp3+ TILs in combination with HEVs to determine their prognostic role in advanced gastric cancer (AGC). We enrolled 157 patients with AGC in this study. The densities of CD8+ TILs and Foxp3+ TILs were calculated using immunohistochemical staining. HEVs were evaluated by MECA-79 expression. HEVs were identified in 60 (38.2%) cases and was significantly associated with an increased number of CD8+ TILs (p = 0.027) but not of Foxp3+ TILs (p = 0.455) and CD20+ TILs (p = 0.163). A high CD8+/HEV+ level was significantly associated with nodal metastasis (p = 0.048). In survival analysis, patients with high CD8+/HEV+ levels demonstrated the longest overall survival (OS) (p = 0.015). Furthermore, a high CD8+/HEV+ level was an independent prognostic factor in AGC (p = 0.011; hazard ratio (HR) = 0.435; 95% confidence interval (CI) = 0.245&ndash;0.837). HEVs were found to play an important role in antitumor immunity associated with CD8+ TILs in AGC. This analysis of HEVs and CD8+ TILs helps stratify patients with AGC and sheds light on tumor immunity

Transcriptional Profiling Reveals Mesenchymal Subtypes of Small Cell Lung Cancer with Activation of the Epithelial-to-Mesenchymal Transition and Worse Clinical Outcomes

While molecular subtypes of small cell lung cancers (SCLC) based on neuroendocrine (NE) and non-NE transcriptional regulators have been established, the association between these molecular subtypes and recently recognized SCLC-inflamed (SCLC-I) tumors is less understood. In this study, we used gene expression profiles of SCLC primary tumors and cell lines to discover and characterize SCLC-M (mesenchymal) tumors distinct from SCLC-I tumors for molecular features, clinical outcomes, and cross-species developmental trajectories. SCLC-M tumors show elevated epithelial-to-mesenchymal transformation (EMT) and YAP1 activity but a low level of anticancer immune activity and worse clinical outcomes than SCLC-I tumors. The prevalence of SCLC-M tumors was 3.2&ndash;7.4% in primary SCLC cohorts, which was further confirmed by immunohistochemistry in an independent cohort. Deconvoluted gene expression of tumor epithelial cells showed that EMT and increased immune function are tumor-intrinsic characteristics of SCLC-M and SCLC-I subtypes, respectively. Cross-species analysis revealed that human primary SCLC tumors recapitulate the NE-to-non-NE progression murine model providing insight into the developmental relationships among SCLC subtypes, e.g., early NE (SCLC-A and -N)- vs. late non-NE tumors (SCLC-M and -P). Newly identified SCLC-M tumors are biologically and clinically distinct from SCLC-I tumors which should be taken into account for the diagnosis and treatment of the disease

EGFR-Tyrosine Kinase Inhibitors Induced Activation of the Autocrine CXCL10/CXCR3 Pathway through Crosstalk between the Tumor and the Microenvironment in EGFR-Mutant Lung Cancer

CXCL10 is a cytokine that is elevated during EGFR-TKI treatment in the tumor microenvironment of lung cancer. Here, we report an original study that the impact of the CXCL10/CXCR3 pathway on EGFR-TKI resistance in EGFR-mutant lung cancer through a cytokine array analysis during in vitro coculture with tumor cells and activated PBMCs treated with EGFR-TKI, as well as the serial analysis of CXCL10 in EGFR-mutant lung cancer transgenic mice during EGFR-TKI treatment. In EGFR-mutant tumor cells cocultured with activated PBMCs, EGFR-TKI treatment increased CXCL10 in the supernatant; this activated CXCR3 in the tumor cells to induce the phosphorylation of Src and the NF-κB subunit, p65, and the expression of HIF-1α. CXCL10 siRNA treatment of EGFR-mutant tumor cells also decreased CXCL10 in the supernatant from coculturing with activated PBMCs, suggesting that the effects of CXCL10 occur via autocrine and paracrine pathways. Importantly, elevated CXCL10/CXCR3 signaling was recapitulated in a transgenic lung cancer mouse model. Our results show that increased CXCL10 levels during early EGFR-TKI treatment stimulate oncogenic signaling of persistent tumor cells to contribute to EGFR-TKI resistance via autocrine and paracrine pathways

Prognostic value of Dickkopf-1 and ß-catenin expression in advanced gastric cancer

Abstract Background Dickkopf-1 (DKK1) is a Wnt/ß-catenin pathway antagonist related to gastric cancer (GC) carcinogenesis. However, the prognostic role of combined DKK1 and ß-catenin expression in advanced GC (AGC) is not clear. Methods In total, 158 patients with AGC who underwent gastric resection were enrolled in this study. DKK1 and ß-catenin expression was evaluated in whole tumor sections by immunohistochemistry. Results DKK1 expression was high in 73 (46.2%) patients, while ß-catenin expression was positive in 51 (32.3%) patients. The expression of DKK1 was positively correlated with that of ß-catenin (P < 0.001). The combined expression of DKK1 and ß-catenin was significantly associated with high N stage (N2 and N3) (P = 0.042). In addition, patients with high DKK expression demonstrated poorer overall (OS) (P < 0.001) and disease-free survival (DFS) (P = 0.001). However, there were no differences between high DKK1 expression with ß-catenin positivity and high DKK1 expression with ß-catenin negativity (OS, P = 0.379: DFS, P = 0.255). Multivariate analysis revealed that high DKK1 alone or high DKK1 with ß-catenin positivity were independent prognostic factors for both OS (high DKK1: hazard ratio [HR], 2.130; 95% confidence interval [CI]; 1.370–3.312, P = 0.001; high DKK1 with ß-catenin positivity: HR, 2.140; 95% CI, 1.343–3.409: P = 0.001) and DFS (high DKK1: HR, 2.092; 95% CI, 1.180–3.708; P = 0.012; high DKK1 with ß-catenin positivity: HR, 2.357; 95% CI, 1.291–4.306; P = 0.005). Conclusion Our results indicate that high DKK1 expression regardless of ß-catenin positivity is a crucial prognostic factor for predicting tumor recurrence and survival in patients with resected AGC

DNA Methylation-Mediated Downregulation of <i>DEFB1</i> in Prostate Cancer Cells

<div><p>Epigenetic aberrations play crucial roles in prostate cancer (PCa) development and progression. The <i>DEFB1</i> gene, which encodes human ß-defensin-1 (HBD-1), contributes to innate immune responses and functions as a potential tumor suppressor in urological cancers. We investigated whether differential DNA methylation at the low CpG-content promoter (LCP) of <i>DEFB1</i> was associated with transcriptional regulation of <i>DEFB1</i> in PCa cells. To identify distinct CpG loci within the <i>DEFB1</i> LCP related to the epigenetic regulation of <i>DEFB1</i>, we performed an <i>in vitro</i> methylated reporter assay followed by bisulfite sequencing of the <i>DEFB1</i> promoter fragment. The methylation status of two adjacent CpG loci in the <i>DEFB1</i> LCP was found to be important for <i>DEFB1</i> expression in PCa cells. Paired epithelial specimens of PCa patients (<i>n</i> = 60), which were distinguished as non-tumor and tumor tissues by microdissection, were analyzed by bisulfite pyrosequencing of site-specific CpG dinucleotide units in the <i>DEFB1</i> LCP. CpG methylation frequencies in the <i>DEFB1</i> LCP were significantly higher in malignant tissues than in adjacent benign tissues across almost all PCa patients. These results suggested that methylation status of each CpG site in the <i>DEFB1</i> promoter could mediate downregulation of <i>DEFB1</i> in PCa cells.</p></div

Association of the methylation frequencies of the (A) CpG 3 and (B) CpG 4 sites in the <i>DEFB1</i> LCP with the corresponding Gleason scores and T stages of PCa tissues.

<p>Data shown in the blue box plots represent the methylation levels in non-tumor tissue samples, and data shown in the red box plots represent the methylation levels in tumor tissue samples. NT, non-tumor; T, tumor. **<i>P</i> < 0.01 and ***<i>P</i> < 0.001.</p

A case of hypopigmented mycosis fungoides successfully treated with 311 nm narrowband ultraviolet B phototherapy

Hypopigmented mycosis fungoides (HMF) is a rare clinical variant of mycosis fungoides (MF) characterized by hypopigmented lesions involving most commonly trunk and proximal extremities. We report here a case of HMF in 22-year-old Korean woman successfully treated with 311 nm narrow-band ultraviolet B (NB-UVB) phototherapy. She presented with progressive asymptomatic hypopigmented patches on wholebody 1-year ago and diagnosed as HMF based on clinicopathologic findings. She was treated with NB-UVB phototherapy and showed almost complete clearance after 8-month without any side effects. Keywords: Lymphoma, T-cell, Cutaneous, Mycosis fungoides, Phototherapy, PUVA therapy, Ultraviolet therap