Association of Cyclooxygenase-2 Expression With Endoplasmic Reticulum Stress and Autophagy in Triple-Negative Breast Cancer

Cyclooxygenase-2 plays a role in oncogenesis and its overexpression is associated with triple-negative breast cancer. However, the mechanisms whereby cyclooxygenase-2 contribute to breast cancer are complex and not well understood. Cyclooxygenase-2 overexpression causes hypoxia, oxidative stress, and endoplasmic reticulum stress. The aim of this study is to investigate the correlations among cyclooxygenase-2 expression, endoplasmic reticulum stress-associated molecules, and autophagy-associated molecules in triple-negative breast cancer. Surgical specimens from two cohorts of triple-negative breast cancer patients without neoadjuvant systemic therapy were analyzed: cohorts 1 and 2 consisted of 218 cases from 2004 to 2006 and 221 cases from 2007 to 2009, respectively. Specimens were evaluated by immunohistochemical examination of cyclooxygenase-2, endoplasmic reticulum stress markers, and autophagy markers expression using tissue microarrays. Cyclooxygenase-2 was overexpressed in 29.8% and 23.9% of cases in cohorts 1 and 2, respectively; and it was positively correlated with two out of three endoplasmic reticulum stress-associated molecules (XBP1, p = 0.025 and p = 0.003 in cohort 1 and cohort 2, respectively; PERK, p \u3c 0.001 in both cohorts). Cyclooxygenase-2 was also positively correlated with two out of three autophagy markers (p62, p = 0.002 and p = 0.003 in cohort 1 and cohort 2, respectively; beclin1, p \u3c 0.001 in both cohorts). Although cyclooxygenase-2 was not an independent prognostic factor for distant metastasis free survival and overall survival, its expression was associated with the expression of endoplasmic reticulum stress and autophagy molecules in triple-negative breast cancer

Thymic Metastasis in Breast Cancer: A Case Report

A malignant tumor is generally believed to be very unlikely to metastasize to the thymus. Only three cases of thymic metastases have been reported so far in the medical literature. We report here a rare case of metastatic breast cancer to the thymus, which was detected by CT and PET scanning, and the metastasis was also confirmed by video-assisted thoracic surgery biopsy. Recognition of an unusual breast cancer metastasis, such as to the thymus, as well as the usual patterns of breast cancer metastasis will facilitate an accurate, prompt diagnosis and its appropriate treatment

Association between p53 Expression and Amount of Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancer

Background Most triple-negative breast cancers (TNBCs) have a high histologic grade, are associated with high endoplasmic stress, and possess a high frequency of TP53 mutations. TP53 missense mutations lead to the production of mutant p53 protein and usually show high levels of p53 protein expression. Tumor-infiltrating lymphocytes (TILs) accumulate as part of the anti-tumor immune response and have a strong prognostic and predictive significance in TNBC. We aimed to elucidate the association between p53 expression and the amount of TILs in TNBC. Methods In 678 TNBC patients, we evaluated TIL levels and expression of endoplasmic stress molecules. Immunohistochemical examination of p53 protein expression was categorized into three groups: no, low, and high expression. Results No, low, and high p53 expression was identified in 44.1% (n = 299), 20.1% (n = 136), and 35.8% (n = 243) of patients, respectively. Patients with high p53 expression showed high histologic grade (p < .001), high TIL levels (p = .009), and high expression of endoplasmic reticulum stress-associated molecules (p-eIF2a, p = .013; XBP1, p = .007), compared to patients with low p53 expression. There was no significant difference in disease-free (p = .406) or overall survival rates (p = .444) among the three p53 expression groups. Conclusions High p53 expression is associated with increased expression of endoplasmic reticulum stress molecules and TIL influx

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

Prognostic parameters for recurrence of papillary thyroid microcarcinoma

<p>Abstract</p> <p>Background</p> <p>Papillary thyroid microcarcinoma (PTMC) is defined as a papillary thyroid carcinoma less than or equal to 1.0 cm in size. Independent prognostic factors for clinical recurrence of PTMC have not been clearly delineated.</p> <p>Methods</p> <p>Clinicopathological parameters predicting PTMC recurrence were determined by retrospective analysis of 307 patients.</p> <p>Results</p> <p>Of the 293 patients eligible for analysis, 14 (5%) had recurrence during a median follow-up time of 65 months. Recurrence was observed in 8 of 166 patients (0.5%) treated with total or near-total thyroidectomy; gender (P = 0.02) and presence of lateral cervical node metastases at initial surgery (P = 0.01) were associated with recurrence. Six of the 127 patients (0.5%) treated with hemi- or subtotal thyroidectomy experience recurrences, but no significant prognostic factor for recurrence was identified. Multivariate Cox-regression analysis showed that gender and cervical lymph node metastasis were significant variables</p> <p>Conclusion</p> <p>PTMC showed very diverse disease extent and could not be regarded as indolent, relatively benign disease based on the primary tumor size. The extent of surgery should be based on prognostic parameters, such as gender and lateral neck node metastasis, in patients with PTMC.</p

Preoperative serum HER2 extracellular domain levels in primary invasive breast cancer

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.Abstract Background Despite the preclinical outcomes and biologic significance of the presence of the human epidermal growth factor receptor-2 (HER2) extracellular domain (ECD), there is little evidence supporting the measurement of ECD levels in any clinical setting. The aim of this study was to determine the prevalence of elevated serum HER2 ECD levels, the association between these levels and tissue HER2 overexpression, and the potential clinical prognostic value of HER2 ECD in primary invasive breast cancer. Methods Serum HER2 ECD levels were examined preoperatively in 2,862 consecutive stage I–III primary breast cancer patients between 2007 and 2009. Serum HER2 ECD levels were measured by chemiluminescence immunoassay (ADVIA Centaur), and the tissue HER2 status was assessed by immunohistochemistry and fluorescence in situ hybridization. The cutoff value for the serum level of HER2 ECD was set at 15.2 ng/ml. Results Among the 2,862 patients, 126 (4.4%) had elevated serum HER2 ECD levels, and HER2 was overexpressed in the tumor tissue of 692 patients (24.2%), with a concordance of 78.7%. Multivariate analysis revealed that elevated serum HER2 ECD was a significant independent prognostic factor for worse distant-metastasis-free survival [DMFS; hazard ratio (HR) = 2.50, 95% confidence interval (CI) = 1.5–4.3, P = 0.001] and breast-cancer-specific survival (BCSS; HR = 2.0, 95% CI = 1.1–3.8, P = 0.036), which were much stronger in patients with tissue HER2-positive tumors (DMFS: HR = 3.8, 95% CI = 2.0–7.0, P < 0.001; BCSS: HR = 2.6, 95% CI = 1.2-5.3, P = 0.012). Conclusions Given the prevalence of HER2 expression, its measurement as an independent prognostic factor can be clinically useful, particularly in patients with tissue HER2-positive tumors

Expression of Aquaporin 5 (AQP5) Promotes Tumor Invasion in Human Non Small Cell Lung Cancer

The aquaporins (AQP) are water channel proteins playing a major role in transcellular and transepithelial water movement. Recently, the role of AQPs in human carcinogenesis has become an area of great interest. Here, by immunohistochemistry (IHC), we have found an expression of AQP5 protein in 35.3% (IHC-score: ≥1, 144/408) of the resected NSCLC tissue samples. Cases with AQP5-positive status (IHC-score: ≥2) displayed a higher rate of tumor recurrence than negative ones in NSCLC (54.7% vs. 35.1%, p = 0.005) and worse disease-free survival (p = 0.033; OR = 1.52; 95%CI:1.04−2.23). Further in vitro invasion assay using BEAS-2B and NIH3T3 cells stably transfected with overexpression constructs for full length wild-type AQP5 (AQP5) and its two mutants, N185D which blocks membrane trafficking and S156A which blocks phosphorylation on Ser156, showed that AQP5 induced cell invasions while both mutants did not. In BEAS-2B cells, the expression of AQP5 caused a spindle-like and fibroblastic morphologic change and losses of cell-cell contacts and cell polarity. Only cells with AQP5, not either of two mutants, exhibited a loss of epithelial cell markers and a gain of mesenchymal cell markers. In a human SH3-domains protein array, cellular extracts from BEAS-2B with AQP5 showed a robust binding activity to SH3-domains of the c-Src, Lyn, and Grap2 C-terminal. Furthermore, in immunoprecipitation assay, activated c-Src, phosphorylated on Tyr416, showed a stronger binding activity to cellular extracts from BEAS-2B with AQP5 compared with N185D or S156A mutant. Fluorescence in situ hybridization (FISH) analysis failed to show evidence of genomic amplification, suggesting AQP5 expression as a secondary event. Based on these clinical and molecular observations, we conclude that AQP5, through its phosphorylation on Ser156 and subsequent interaction with c-Src, plays an important role in NSCLC invasion and, therefore, may provide a unique opportunity for developing a novel therapeutic target as well as a prognostic marker in NSCLC