Decreased Expression of Cell Adhesion Molecule 4 in Gastric Adenocarcinoma and Its Prognostic Implications

Cell adhesion molecule 4 (CADM4) is a novel tumor suppressor candidate. The prognostic implications of CADM4 in gastric cancer have not been conclusively elucidated. Therefore, we evaluated the clinicopathological significance and prognostic value of CADM4 expression in a large series of patients with gastric adenocarcinoma. Immunohistochemical staining for CADM4 was performed on 534 gastric adenocarcinomas. We evaluated the associations between CADM4 expression and the clinicopathological and molecular characteristics of the adenocarcinomas. The prognostic effect of CADM4 expression was evaluated by survival analyses. Low CADM4 expression was significantly associated with young age (p = 0.046), aggressive histological type (p < 0.001), high pT category (p < 0.001), nodal metastasis (p < 0.001), high stage (p = 0.002), lymphovascular invasion (p = 0.001), and perineural invasion (p = 0.001). Low CADM4 expression was more frequently observed in tumors without human epidermal growth factor receptor 2 (HER2) amplification (p = 0.002). Low CADM4 expression was associated with worse overall survival (p = 0.007) and recurrence-free survival (p = 0.005) in the survival analyses. Low CADM4 expression was associated with aggressive clinicopathological features and poor clinical outcomes. CADM4 can act as a tumor suppressor in gastric adenocarcinoma and can be considered a prognostic biomarker.ope

Nuclear Expression Loss of SSBP2 Is Associated with Poor Prognostic Factors in Colorectal Adenocarcinoma

Single-stranded DNA binding protein 2 (SSBP2) is involved in DNA damage response and may induce growth arrest in cancer cells, having a potent tumor suppressor role. SSBP2 is ubiquitously expressed and the loss of its expression has been reported in various tumor types. However, the correlation between SSBP2 expression and colorectal cancer (CRC) prognosis remains unclear. SSBP2 nuclear expression was evaluated immunohistochemically in 48 normal colonic mucosae, 47 adenomas, 391 primary adenocarcinomas, and 131 metastatic carcinoma tissue samples. The clinicopathological factors, overall survival (OS), and recurrence-free survival were evaluated, and associations with the clinicopathological parameters were analyzed in 391 colorectal adenocarcinoma patients. A diffuse nuclear SSBP2 expression was detected in all normal colonic mucosa and adenoma samples. SSBP2 expression loss was observed in 131 (34.3%) primary adenocarcinoma and 100 (76.3%) metastatic carcinoma samples. SSBP2 expression was significantly associated with poor prognostic factors, such as vascular invasion (p = 0.005), high pT category (p = 0.045), and shorter OS (p = 0.038), using univariate survival analysis. Nuclear SSBP2 expression loss was significantly observed in colorectal carcinoma and metastatic carcinoma tissues, being associated with poor prognostic factors. SSBP2 acts as a tumor suppressor and may be used as a CRC prognostic biomarker.ope

Low DUSP4 Expression Is Associated With Aggressive Phenotypes and Poor Prognosis in Gastric Cancer

Background/aim: Dual-specificity protein phosphatase 4 (DUSP4) negatively regulates MAPK signaling and is involved in various cellular processes. We herein evaluated the relationship between DUSP4 expression and clinicopathological characteristics in a large series of gastric cancer samples. Materials and methods: DUSP4 expression was examined by immunohistochemistry in 508 gastric cancer samples. Cases were classified according to the TCGA molecular classification and HER2 amplification. Kaplan-Meier plots were used to predict the relationship between mRNA expression of DUSP4 and survival. Results: Low expression of DUSP4 was significantly correlated with larger tumor size, higher pT category, positive nodal status, higher stage, lymphovascular invasion, perineural invasion, worse overall survival, and worse recurrence-free survival. No correlation was observed between DUSP4 expression and molecular characteristics. Bioinformatics analysis showed that low mRNA expression was associated with a poor prognosis. Conclusion: Low expression of DUSP4 is associated with aggressive phenotypes of gastric cancer and a poor prognosis.ope

Loss of DUSP4 Expression as a Prognostic Biomarker in Clear Cell Renal Cell Carcinoma

Dual-specificity protein phosphatase 4 (DUSP4) is a negative regulator of mitogen-activated protein kinases. The prognostic impact of DUSP4 expression in renal cell carcinoma is not well studied. Therefore, we evaluated the clinicopathological implications of DUSP4 expression in clear cell renal cell carcinoma by performing immunohistochemistry (IHC). The clinical outcome according to DUSP4 expression was evaluated through survival analyses, and the association between mRNA expression and prognosis was confirmed by online analysis (Kaplan-Meier plotter). Loss of DUSP4 expression was noted in most histological subtypes of renal cell carcinoma. Loss of DUSP4 expression in clear cell renal cell carcinoma was significantly correlated with old age (p = 0.033), high histologic grade (p < 0.001), tumor necrosis (p < 0.001), and high pT category (p < 0.001). In survival analysis, loss of DUSP4 expression was associated with poor clinical outcomes in cancer-specific survival and recurrence-free survival (p = 0.010 and p = 0.007, respectively). Upon TCGA data analysis, patients with low DUSP4 mRNA expression showed a shorter overall survival (p = 0.023). These results suggest that loss of DUSP4 expression can be used as a potential biomarker for predicting clinical outcomes in clear cell renal cell carcinoma patients.ope

Carbon monoxide-releasing molecule-3: Amelioration of renal ischemia reperfusion injury in a rat model

Purpose: Despite the role of carbon monoxide in ameliorating ischemia-reperfusion injury (IRI), its use in the clinical setting is restricted owing to its toxicity. Herein, we investigated the in vivo effects of carbon monoxide-releasing molecule-3 (CORM-3) on IRI. Materials and methods: Fifteen rats were equally and randomly divided into three groups: sham (right nephrectomy), control (right nephrectomy and left renal ischemia), and CORM-3 (right nephrectomy and CORM-3 injection before left renal ischemia). Kidney tissues and blood samples collected from sacrificed rats were evaluated to determine the renoprotective effect and mechanism of CORM-3. Results: Concentrations of serum creatinine and kidney injury molecule-1 in the CORM-3 group were significantly lower than in the control group after 75 minutes of IRI (1.2 vs. 2.4 mg/dL, p=0.01, and 292 vs. 550 pg/mL, p<0.001, respectively). Furthermore, the CORM-3 group exhibited a higher portion of normal tubules and glomeruli. TUNEL staining revealed fewer apoptotic renal tubular cells in the CORM-3 group than in the control group. The expression of 960 genes in the CORM-3 group was also altered. Pretreatment with CORM-3 before renal IRI produced a significant renoprotective effect. Fifteen of the altered genes were found to be involved in the peroxisome proliferator-activated receptors signaling pathway, and the difference in the expression of these genes between the CORM-3 and control groups was statistically significant (p<0.001). Conclusions: CORM-3 ameliorates IRI by decreasing apoptosis and may be a novel strategy for protection against renal warm IRI.ope

Automated Gleason Scoring and Tumor Quantification in Prostate Core Needle Biopsy Images Using Deep Neural Networks and Its Comparison with Pathologist-Based Assessment

The Gleason grading system, currently the most powerful prognostic predictor of prostate cancer, is based solely on the tumor's histological architecture and has high inter-observer variability. We propose an automated Gleason scoring system based on deep neural networks for diagnosis of prostate core needle biopsy samples. To verify its efficacy, the system was trained using 1133 cases of prostate core needle biopsy samples and validated on 700 cases. Further, system-based diagnosis results were compared with reference standards derived from three certified pathologists. In addition, the system's ability to quantify cancer in terms of tumor length was also evaluated via comparison with pathologist-based measurements. The results showed a substantial diagnostic concordance between the system-grade group classification and the reference standard (0.907 quadratic-weighted Cohen's kappa coefficient). The system tumor length measurements were also notably closer to the reference standard (correlation coefficient, R = 0.97) than the original hospital diagnoses (R = 0.90). We expect this system to assist pathologists to reduce the probability of over- or under-diagnosis by providing pathologist-level second opinions on the Gleason score when diagnosing prostate biopsy, and to support research on prostate cancer treatment and prognosis by providing reproducible diagnosis based on the consistent standards.ope

Utilization potential of intraluminal optical coherence tomography for the Eustachian tube

Imaging the Eustachian tube is challenging because of its complex anatomy and limited accessibility. This study fabricated a fiber-based optical coherence tomography (OCT) catheter and investigated its potential for assessing the Eustachian tube anatomy. A customized OCT system and an imaging catheter, termed the Eustachian OCT, were developed for visualizing the Eustachian tube. Three male swine cadaver heads were used to study OCT image acquisition and for subsequent histologic correlation. The imaging catheter was introduced through the nasopharyngeal opening and reached toward the middle ear. The OCT images were acquired from the superior to the nasopharyngeal opening before and after Eustachian tube balloon dilatation. The histological anatomy of the Eustachian tube was compared with corresponding OCT images, The new, Eustachian OCT catheter was successfully inserted in the tubal lumen without damage. Cross-sectional images of the tube were successfully obtained, and the margins of the anatomical structures including cartilage, mucosa lining, and fat could be successfully delineated. After balloon dilatation, the expansion of the cross-sectional area could be identified from the OCT images. Using the OCT technique to assess the Eustachian tube anatomy was shown to be feasible, and the fabricated OCT image catheter was determined to be suitable for Eustachian tube assessment.ope

PD-L1 Upregulation by the mTOR Pathway in VEGFR-TKI-Resistant Metastatic Clear Cell Renal Cell Carcinoma

Purpose: Tyrosine kinase inhibitors (TKI) targeting vascular endothelial growth factor receptor (VEGFR) signaling pathways have been used for metastatic clear cell renal cell carcinoma (mCCRCC), but resistance to the drug develops in most patients. We aimed to explore the underlying mechanism of the TKI resistance with regard to programmed death-ligand 1 (PD-L1) and to investigate signaling pathway associated with the resistant mechanism. Materials and methods: To determine the mechanism of resistance, 10 mCCRCC patients from whom tumor tissues were harvested at both the pretreatment and the TKI-resistant post-treatment period were included as the discovery cohort, and their global gene expression profiles were compared. A TKI-resistant renal cancer cell line was established by long-term treatment with sunitinib. Results: Among differentially expressed genes in the discovery cohort, increased PD-L1 expression in post-treatment tissues was noted in four patients. Pathway analysis showed that PD-L1 expression was positively correlated with the mammalian target of rapamycin (mTOR) signaling pathway. The TKI-resistant renal cancer cells showed increased expression of PD-L1 and mTOR signaling proteins and demonstrated aggressive tumoral behaviour. Treatment with mTOR inhibitors down-regulated PD-L1 expression and suppressed aggressive tumoral behaviour, which was reversed with stimulation of the mTOR pathway. Conclusion: These results showed that PD-L1 expression may be increased in a subset of VEGFR-TKI-resistant mCCRCC patients via the mTOR pathway.ope

Loss of Single-Stranded DNA Binding Protein 2 Expression Is Associated with Aggressiveness and Poor Overall Survival in Patients with Invasive Breast Carcinoma

Background: Single-stranded DNA binding protein 2 (SSBP2) is involved in the DNA damage response and the maintenance of genome stability. Previous studies have suggested that SSBP2 has a tumor suppressor function or oncogenic function. Loss of SSBP2 expression has been reported in various tumors. However, the role of SSBP2 expression in invasive breast carcinoma has not been reported. Methods: Immunohistochemical staining for SSBP2 was performed on tissue microarrays consisting of 491 invasive breast carcinoma cases. The result of nuclear SSBP2 staining was stratified as either negative or positive. Then, we investigated the correlations between SSBP2 expression and various clinicopathological parameters and patient outcomes. Results: Loss of nuclear SSBP2 expression was observed in 61 cases (12.4%) of 491 invasive breast carcinomas. Loss of nuclear SSBP2 expression was significantly correlated with larger tumor size (p < 0.001, chi-squared test), higher histological grade (p = 0.016, Cochran-Armitage trend test), higher pathological T stage (p < 0.001, Cochran-Armitage trend test), estrogen receptor status (p < 0.001, chi-squared test), and molecular subtype (p < 0.001, chi-squared test). Kaplan-Meier survival analysis revealed that patients with loss of nuclear SSBP2 expression had worse overall survival (p = 0.013, log-rank test). However, loss of nuclear SSBP2 expression was not correlated with recurrence-free survival (p = 0.175, log-rank test). Conclusions: Loss of nuclear SSBP2 expression was associated with adverse clinicopathological characteristics and poor patient outcomes. SSBP2 acts as a tumor suppressor in invasive breast carcinoma and may be used as a prognostic biomarker.ope

Yet Another Automated Gleason Grading System (YAAGGS) by weakly supervised deep learning

The Gleason score contributes significantly in predicting prostate cancer outcomes and selecting the appropriate treatment option, which is affected by well-known inter-observer variations. We present a novel deep learning-based automated Gleason grading system that does not require extensive region-level manual annotations by experts and/or complex algorithms for the automatic generation of region-level annotations. A total of 6664 and 936 prostate needle biopsy single-core slides (689 and 99 cases) from two institutions were used for system discovery and validation, respectively. Pathological diagnoses were converted into grade groups and used as the reference standard. The grade group prediction accuracy of the system was 77.5% (95% confidence interval (CI): 72.3-82.7%), the Cohen's kappa score (κ) was 0.650 (95% CI: 0.570-0.730), and the quadratic-weighted kappa score (κquad) was 0.897 (95% CI: 0.815-0.979). When trained on 621 cases from one institution and validated on 167 cases from the other institution, the system's accuracy reached 67.4% (95% CI: 63.2-71.6%), κ 0.553 (95% CI: 0.495-0.610), and the κquad 0.880 (95% CI: 0.822-0.938). In order to evaluate the impact of the proposed method, performance comparison with several baseline methods was also performed. While limited by case volume and a few more factors, the results of this study can contribute to the potential development of an artificial intelligence system to diagnose other cancers without extensive region-level annotations.ope