A robust model training strategy using hard negative mining in a weakly labeled dataset for lymphatic invasion in gastric cancer.

Gastric cancer is a significant public health concern, emphasizing the need for accurate evaluation of lymphatic invasion (LI) for determining prognosis and treatment options. However, this task is time-consuming, labor-intensive, and prone to intra- and interobserver variability. Furthermore, the scarcity of annotated data presents a challenge, particularly in the field of digital pathology. Therefore, there is a demand for an accurate and objective method to detect LI using a small dataset, benefiting pathologists. In this study, we trained convolutional neural networks to classify LI using a four-step training process: (1) weak model training, (2) identification of false positives, (3) hard negative mining in a weakly labeled dataset, and (4) strong model training. To overcome the lack of annotated datasets, we applied a hard negative mining approach in a weakly labeled dataset, which contained only final diagnostic information, resembling the typical data found in hospital databases, and improved classification performance. Ablation studies were performed to simulate the lack of datasets and severely unbalanced datasets, further confirming the effectiveness of our proposed approach. Notably, our results demonstrated that, despite the small number of annotated datasets, efficient training was achievable, with the potential to extend to other image classification approaches used in medicine.

Assessment of thyroid cartilage ossification pattern in cancer patients: A suggestion of active ossification by tumor progression.

BACKGROUND: Ossified cartilage is much more susceptible to cancer infiltration, but the reason remains unknown, and the relationship between the ossification pattern and cancer infiltration has not been studied. METHODS: The presence of thyroid cartilage ossification, cancer infiltration, ossification pattern (usual: direction from inferior to superior; unusual: other than the usual pattern), and distance between cancer and ossified cartilage were evaluated in laryngectomy specimens. RESULTS: There were 28 and 27 cases of usual and unusual patterns, respectively. There was no association between ossification pattern and cancer infiltration. However, the distance between the ossified area and cancer cells was greater in the usual pattern than in the unusual pattern (p = 0.006). And the usual pattern was more frequently observed in cases with a distance >1 mm than in cases with cancer infiltration or a distance ≤1 mm (p = 0.004). CONCLUSION: These results suggest the possibility of an active ossification due to tumor progression.

CD47 Expression Predicts Unfavorable Prognosis in Clear Cell Renal Cell Carcinoma after Curative Resection.

The role of CD47 expression as a 'do not eat me' signal that inhibits phagocytosis of tumor cells by macrophages is well established. Immune checkpoint therapy that targets CD47 has been successful in preclinical trials and is currently undergoing clinical investigation for various human malignancies. Here, the clinicopathological correlation with CD47 expression in clear cell renal cell carcinoma (ccRCC) was explored. CD47 expression was evaluated by immunohistochemical staining in tissue microarray sections of 235 ccRCC tissues. CD47 expression was observed in 28 (11.9%) of 235 ccRCC tissues and was significantly associated with higher WHO/ISUP grade (p = 0.001), frequent lymphovascular invasion (p = 0.036), frequent renal vein thrombus (p = 0.018), frequent sinus fat invasion (p = 0.004), frequent sarcomatous change (p = 0.001), higher pT stage (p = 0.002), higher pN stage (p = 0.002), higher pM stage (p < 0.001), and advanced American Joint Committee on Cancer stage (p = 0.002). In the survival analyses, positive CD47 expression was associated with cancer-specific survival (p = 0.003). However, positive CD47 expression was not associated with recurrence-free survival. In conclusion, CD47 expression was associated with adverse clinicopathological parameters and cancer-specific survival in patients with ccRCC.

Low expression of DUSP4 expression predicts unfavorable prognosis in gallbladder adenocarcinoma.

Background: Dual specificity phosphatase 4 (DUSP4), which regulates the mitogen activated protein kinases, has emerged as a tumor suppressor gene in several human malignancies. Aims and Objectives: In this study, we investigated the clinicopathologic significance and the prognostic role of DUSP4 in gallbladder adenocarcinoma. Materials and methods: DUSP4 expression was evaluated immunohistochemically in tissue microarray from 110 gallbladder adenocarcinoma samples and scored by H score system. The cut off (H score <170) was determined by ROC curve analysis. Results: Low expression of DUSP4 expression was observed in 57 (51.8%) out of 110 gallbladder adenocarcinoma samples. Low expression of DUSP4 expression was significantly associated with high histologic grade (P = 0.017), high pT stage (P = 0.002) and high AJCC stage (P = 0.007). Kaplan Meier survival curves revealed that patients with low expression of DUSP4 expression had significantly worse cancer specific survival (P = 0.024, log rank test). However, there was no significant association between DUSP4 expression and recurrence free survival. Conclusions: In conclusion, gallbladder adenocarcinoma with low expression of DUSP4 expression was associated with adverse clinicopathologic characteristics and poor patient outcome.patient outcome.

Recoverability of Diabetic Nephropathy of Donor Kidney After Kidney Transplantation.

Some kidney donors have diabetes, and little of their natural course of diabetic nephropathy (DN) is known. The aim of this study was to analyze the changes in pathologic lesions in the diabetic donor kidney after KT by performing protocol biopsy two weeks and one year after KT. This retrospective study included 103 patients who underwent KT, with kidneys from donors with a history of diabetes mellitus (DM). Among them, data of 34 patients who underwent biopsy two weeks and one year after KT were reviewed. Biopsy specimens were reviewed using light microscopy and electron microscopy. Glomerular basement membrane (GBM) thickness at 2 weeks and 1 year was compared. Biopsy showed that DN occurred in 29 of the 34 patients. Only trivial histological changes were observed in 22 patients (64.7%), including 5 patients who did not show DN. At one year after transplantation, there was no change in the DN histologic class in 26 patients (76.5%), and there was no statistically significant difference in the change in GBM thickness. This pattern was observed regardless of the recipient's DM or glycemic control. With this understanding, clinicians can use kidneys from DM donors with more comfort, thereby reducing the kidney discard rate.

Clinicopathological Implications of ASAP1 Expression in Hepatocellular Carcinoma.

Background: The expression of ArfGAP with SH3 domain ankyrin repeat and PH domain 1 (ASAP1) is increased in various types of cancer, showing potential as a prognostic marker. The clinicopathological implications of ASAP1 expression in patients with hepatocellular carcinoma (HCC) remain unclear. We thus investigated the clinicopathological significance and prognostic effect of ASAP1 expression in HCC patients. Materials and Methods: ASAP1 expression was assessed in 149 HCC tissue samples using immunohistochemistry (IHC). The associations between ASAP1 expression and clinicopathological characteristics were analyzed. The prognostic effect of ASAP1 expression in patients with HCC was evaluated based on survival analyses and confirmed using a web-based tool. Results: ASAP1 expression was observed in the cytoplasm of tumor cells. High ASAP1 expression was observed in 89 (59.7%) of 149 cases. High ASAP1 expression was significantly associated with male patients (p = 0.018), higher histological grade (p = 0.013), vessel invasion (p = 0.021), and higher stage (p = 0.020). High ASAP1 expression was associated with shorter overall survival (OS; p = 0.041) and recurrence-free survival (RFS; p = 0.008) based on Kaplan-Meier survival analyses. Web-based analysis using Kaplan-Meier (KM) plotter showed high mRNA ASAP1 expression to be associated with short OS (p = 0.001). Conclusion: High ASAP1 expression was associated with aggressive clinicopathological characteristics and poor clinical outcomes in patients with HCC. ASAP1 can be considered a prognostic biomarker in HCC patients.

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.

Omission of chemotherapy for hormone receptor-positive and human epidermal growth factor receptor 2-negative breast cancer: patterns of treatment and outcomes from the Korean Breast Cancer Society Registry.

Purpose: Although adjuvant chemotherapy (CTx) is still recommended for high-risk patients with hormone receptor-positive and human epidermal receptor (HER)-2-negative breast cancer, recent studies found that selected patients with low disease burden may be spared from CTx and receive hormonal treatment (HT) alone. This study aims to evaluate the trends of treatment (CTx + HT vs. HT alone) in Korea and to assess the impact on overall survival (OS) according to treatment pattern. Methods: The Korean Breast Cancer Society Registry was queried (2000 to 2018) for women with pT1-2N0-1 hormone receptor-positive and HER2-negative disease who underwent surgery and adjuvant systemic treatment (CTx and HT). Clinicopathologic factors, change in pattern of treatment over time, and OS for each treatment option were analyzed. Results: A total of 40,938 women were included in the study; 20,880 (51.0%) received CTx + HT, while 20,058 (49.0%) received HT only. In recent years, there has been a steady increase in the use of HT alone, from 21.0% (2000) to 64.6% (2018). In Cox regression analysis, age, type of breast and axillary operations, T and N stages, body mass index, histologic grade, and presence of lymphovascular invasion were prognostic indicators for OS. There was no significant difference between CTx + HT and HT alone in terms of OS (P = 0.126). Conclusion: Over the years, there has been a shift from CTx + HT to HT alone without a significant difference in OS. Therefore, HT alone could be a safe treatment option in selected patients, even those with T2N1 disease.

Eculizumab as rescue therapy in a kidney transplant recipient with atypical hemolytic uremic syndrome: a case report.

A 61-year-old female patient with chronic kidney disease due to diabetes mellitus and hypertension-induced nephropathy received a deceased donor kidney transplant in March 2020. In July 2020, she was transferred from a local hospital due to the exacerbation of general weakness and diarrhea. Upon her arrival, we noticed a high level of serum creatinine (sCr) of 1.5 mg/dL and a decrease in urine output. Her laboratory results indicated significant hemolysis, with a hemoglobin level of 7.0 g/dL, platelet count of 20 ×103/µL, and a lactate dehydrogenase level of 3,207 IU/L. Kidney biopsy showed severe thrombotic microangiopathy without any evidence of acute rejection. Under the impression of atypical hemolytic uremic syndrome (aHUS), we immediately started plasmapheresis and hemodialysis for anuria. Eculizumab was considered as a kidney graft rescue therapy since her sCr level was not effectively decreased, and her anuria continued despite hemodialysis and plasmapheresis. Eculizumab (900 mg) was administered weekly for 4 weeks. An additional 600 mg of eculizumab was administered on the day of plasmapheresis. Since the patient's laboratory data gradually improved, hemodialysis and plasmapheresis were ceased on admission day 37. After that, eculizumab was administered biweekly (1,200 mg) two more times. The patient's sCr and platelet count normalized after 2 months of eculizumab treatment. Based on our experience, a shorter interval between the clinical diagnosis of aHUS and administration of eculizumab increases the likelihood of rescuing the kidney.

Low-Level Expression of MTUS1 Is Associated with Poor Survival in Patients with Lung Adenocarcinoma.

Microtubule-associated tumor suppressor 1 (MTUS1) is thought to be downregulated in arious human cancers, which suggests its role as a tumor suppressor. This study investigated the clinicopathological significance of MTUS1 expression in lung adenocarcinoma. Tissue microarray blocks consisting of 161 cases were constructed, and immunohistochemical staining was used to assess MTUS1 expression. Correlations of MTUS1 expression and clinicopathological parameters were analyzed. In addition, we used public databases and performed bioinformatics analysis. Low level of MTUS1 was significantly associated with higher clinical stage (p = 0.006), higher tumor stage (p = 0.044), lymph node metastasis (p = 0.01), worse histologic grade (p = 0.007), lymphovascular invasion (p = 0.014), and higher Ki-67 proliferation index (p < 0.001). Patients with low MTUS1 expression also showed shorter disease-free survival (p = 0.002) and cancer-specific survival (p = 0.006). Analysis of data from the Cancer Genome Atlas confirmed that the mRNA expression of MTUS1 in lung adenocarcinoma was significantly lower than that of normal lung tissue (p = 0.02), and patients with decreased MTUS1 expression showed significantly shorter overall survival (p = 0.008). These results suggest that MTUS1 may be a potential biomarker for predicting clinical outcomes in lung adenocarcinoma patients.

Correlation of CD47 Expression with Adverse Clinicopathologic Features and an Unfavorable Prognosis in Colorectal Adenocarcinoma.

CD47, a transmembrane protein, is widely overexpressed on the tumor cell surface. However, the prognostic significance of CD47 expression in colorectal adenocarcinoma (CRA) has not yet been clarified. Here, we investigated the clinicopathologic significance of CD47 expression in CRA. CD47 expression was evaluated via immunohistochemical analysis of microarray sections of 328 CRA tissues. CD47 expression was observed in 53 (16.2%) of the 328 CRA tissues, and positive expression was associated with lymphatic invasion (p = 0.018), perineural invasion (p = 0.024), tumor budding (p = 0.009), the pathologic N stage (p = 0.022), and the American Joint Committee on Cancer (AJCC) stage (p = 0.027). In survival analyses of 329 patients, a positive CD47 expression was associated with a poor recurrence-free survival (RFS) (p = 0.032). In multivariate analysis, however, it was not an independent prognostic factor. In patients who underwent surgical resection without adjuvant treatment, a positive CD47 expression was associated with a shorter RFS (p = 0.001) but not with cancer-specific survival (CSS). In patients who received postoperative adjuvant treatment, no significant differences were found in both RFS and CSS. In conclusion, we investigated CD47 expression in 328 CRA tissues. A positive CD47 expression was observed in a minority (16.2%) of the tissues and was significantly associated with adverse clinicopathologic features and a poor patient outcome.

Clinicopathological Significance of MTUS1 Expression in Patients With Renal Cell Carcinoma.

BACKGROUND/AIM: Microtubule-associated tumor suppressor 1 (MTUS1) is a novel tumor suppressor involved in proliferation and migration, and down-regulation of MTUS1 is associated with the poor prognosis of several cancers. We evaluated the clinicopathological significance of MTUS1 expression in renal cell carcinoma (RCC). PATIENTS AND METHODS: We assessed MTUS1 expression by immunohistochemical staining of tissue microarrays from 249 cases of RCC. We analyzed the correlation of MTUS1 expression and clinicopathological characteristics. Additionally, we used public databases and performed bioinformatics analysis. RESULTS: We investigated The Cancer Genome Atlas databases and identified that MTUS1 mRNA expression was significantly lower in RCC tissues than in normal tissues. Loss of MTUS1 expression was correlated with high WHO/ISUP nuclear grade, lymphovascular invasion, renal vein thrombus, and high pT stage in patients with RCC. Although there was no statistically significant correlation between MTUS1 expression and patients' prognosis in our cohort, MTUS1 overexpression was significantly correlated with a favorable prognosis in public data. CONCLUSION: Loss of MTUS1 expression in RCC might be a potential biomarker for predicting clinical outcome.

Comparison of the Lymph2Cx Assay and Hans Algorithm in Determining the Cell-of-Origin of Diffuse Large B-Cell Lymphomas, Not Otherwise Specified.

In the era of precision medicine, accurate and reproducible assignment of cell-of-origin (COO) in diffuse large B-cell lymphoma patients has become important. The Lymph2Cx assay is accurately determining COO by analyzing RNA expression of 20 selected genes while the Hans algorithm based on immunohistochemistry is the most popular method for routine daily diagnosis. However, there are discrepancies between the 2 methods, which need to be evaluated for better correlation. We prospectively analyzed 156 cases of diffuse large B-cell lymphoma, not otherwise specified to analyze the characteristics of discrepancy groups of COO determined by Lymph2Cx and Hans algorithm. We investigated the pattern and cause of discrepancy of COO assigned by the 2 methods. Hans algorithm classified 50 cases (32%) as germinal-center B-cell-like (GCB) type and 106 cases (68%) as non-GCB type. Lymph2Cx assay assigned 43 cases (28%) as GCB type, 94 cases (60%) as activated B-cell-like type, and 19 cases (12%) as intermediate/unclassified type. The agreement rate was 86% after exclusion of unclassified type. With regard to the clinicopathologic factors related with discrepancy between Hans algorithm and Lymph2Cx assay, endoscopic biopsy of the gastrointestinal tract (4/11, 36%) showed higher discrepancy rate (P=0.052). Immunophenotypically, CD10/BCL6/MUM1 GCB type and CD10/BCL6//MUM1 (=30%, low level expression) non-GCB type exhibited a significantly higher discrepancy rate (6/13, 46%; 4/13, 31%) (P=0.0001). Activated B-cell-like subgroup via Lymph2Cx assay predicted poor progression-free survival (mean survival duration 28.6 mo, P=0.049) compared with the GCB and unclassified type. Hans algorithm revealed no significant difference in progression-free survival and overall survival (P=0.122 and 0.121). These results suggest that when assigning COO via Hans algorithm, CD10/BCL6/MUM1 GCB type and CD10/BCL6/MUM1 (=30%, low level) non-GCB type require careful interpretation, especially if the MUM1 staining is weak and heterogeneous in the biopsied specimen.

Low Expression of Single-stranded DNA Binding Protein 2 (SSBP2) Predicts Unfavourable Postoperative Outcomes in Patients With Clear Cell Renal Cell Carcinoma.

BACKGROUND: Single-stranded DNA binding protein 2 (SSBP2) is a subunit of a single-stranded DNA binding complex, which is involved in the maintenance of hematopoietic stem cells and stress responses. Numerous studies have suggested that SSBP2 functions as a tumor suppressor and is silenced through a pathway mediated by promoter hypermethylation. However, the role of SSBP2 in human renal cell carcinoma has not been reported, to date. Herein, we investigated the clinicopathological significance of SSBP2 expression in clear cell renal cell carcinoma (ccRCC). MATERIALS AND METHODS: We constructed tissue micro arrays consisting of 173 ccRCC tissues, and SSBP2 expression was evaluated semi-quantitatively based on the staining intensity and the proportion of stained cells. Regarding statistical analysis, the tissues were divided into two groups according to SSBP2 expression, and correlation of SSBP2 expression with various clinicopathological characteristics and patient outcomes was evaluated. RESULTS: Low SSBP2 expression was observed in 114 of 175 (65.9%) of ccRCC cases, and low SSBP2 expression was significantly correlated with larger tumor size (p=0.005, Chi-square test), higher WHO/ISUP histological grade (p<0.001, Chi-square test), tumor necrosis (p=0.008, Chi-square test), sarcomatoid change (p=0.021, Chi-square test), and higher pT AJCC stage (p=0.002, Chi-square test). Kaplan-Meier survival curves revealed that patients with low SSBP2 expression had worse recurrence-free survival (p=0.041, log-rank test). CONCLUSION: ccRCC with low SSBP2 expression was associated with adverse clinicopathological characteristics and poor patient outcomes.

Loss of MTUS1 Expression Is Associated With Poor Prognosis in Patients With Gallbladder Carcinoma.

BACKGROUND/AIM: Microtubule-associated scaffold protein 1 (MTUS1) acts as tumor suppressor in several cancer types. This study assessed the relationship between clinicopathological characteristics and expression of microRNA candidates based on MTUS1 expression in gallbladder cancer (GBC). MATERIALS AND METHODS: MTUS1 expression was evaluated by immunohistochemical staining of tissue microarrays from 109 cases of GBC. The association of MTUS1 expression with clinicopathological factors was explored. Two microRNA candidates (miR-19a-3p, and miR-19b-3p), which were identified by a literature review and computational analysis, were assessed in GBC tissue samples by quantitative real-time polymerase chain reaction. RESULTS: Low MTUS1 expression in GBC was associated with high histological grade, perineural invasion, lymphovascular invasion, high T-stage, advanced TNM stage, poorer disease-free survival, and poorer cancer-specific survival. No statistical association between MTUS1 expression and expression of microRNA candidates was observed. CONCLUSION: MTUS1 may act as tumor suppressor and might be a potential biomarker for predicting prognosis in GBC.

Changing trends in lymphoid neoplasm distribution in South Korea: analysis of 8615 cases from a single institute, 1997-2016: An observational study.

The purpose of this study was to evaluate changes in the proportion of lymphoid neoplasm subtypes in South Korea. A total of 8615 cases of lymphoid neoplasms diagnosed in 1997-2016 at Samsung Medical Center in South Korea were classified according to the 2008 World Health Organization system. The total number and proportion of lymphoid neoplasms were compared between these two decades, with data from nationwide studies, and with other countries. To evaluate changes in the proportion of subtypes, crude rate of each subtype per 100 lymphoma patients during each decade and age adjusted rate were calculated. There were 3024 patients with lymphoid neoplasm in 1997-2006, and 5591 in 2007-2016, which represents an average increase of 1.85 times over the 20-year study period. Crude rate and age adjusted rate were increased in Hodgkin's lymphoma and mature B cell lymphoma while precursor lymphoid neoplasms and mature T cell lymphoma were decreased. Among B cell neoplasms, age adjusted rate of plasma cell neoplasm, follicular lymphoma, mantle cell lymphoma increased while there was no significant change in extranodal marginal zone lymphoma and Burkitt lymphoma. The increase in follicular lymphoma was due to the increases in nodal follicular lymphoma of low grade and duodenal-type follicular lymphoma. These results are consistent with the dynamics of causative factors, including socioeconomic factors, in Korea.

MicroRNA-374a Expression as a Prognostic Biomarker in Lung Adenocarcinoma.

BACKGROUND: Lung cancer is the most common cause of cancer-related death, and adenocarcinoma is the most common histologic subtype. MicroRNA is a small non-coding RNA that inhibits multiple target gene expression at the post-transcriptional level and is commonly dysregulated in malignant tumors. The purpose of this study was to analyze the expression of microRNA-374a (miR-374a) in lung adenocarcinoma and correlate its expression with various clinicopathological characteristics. METHODS: The expression level of miR-374a was measured in 111 formalin-fixed paraffin-embedded lung adenocarcinoma tissues using reverse transcription-quantitative polymerase chain reaction assays. The correlation between miR-374a expression and clinicopathological parameters, including clinical outcome, was further analyzed. RESULTS: High miR-374 expression was correlated with advanced pT category (chi-square test, p=.004) and pleural invasion (chi-square test, p=.034). Survival analysis revealed that patients with high miR-374a expression had significantly shorter disease-free survival relative to those with low miR-374a expression (log-rank test, p=.032). CONCLUSIONS: miR-374a expression may serve as a potential prognostic biomarker for predicting recurrence in early stage lung adenocarcinoma after curative surgery.

The clinicopathologic significance of extranodal tumor extension in locally advanced (pT3) colorectal adenocarcinoma and its association with the loss of E-cadherin expression.

We investigated the clinicopathologic significance of extranodal tumor extension (ENTE) in locally advanced and prognostically inhomogeneous pT3 (pathologic T3) colorectal adenocarcinomas with regional lymph node metastasis. ENTE is defined as an interruption of the nodal capsule by tumor cells with extranodal growth. ENTE was observed in 46.3% of pT3 colorectal adenocarcinomas and was significantly associated with vascular invasion (P = 0.037, chi-square test), tumor deposit (P = 0.004, chi-square test) and high pN (pathologic N) stage (P = 0.002, chi-square test). An immunohistochemical study revealed that the loss of E-cadherin was significantly associated with ENTE (OR, 2.265; 95% CI, 1.008-5.086; P = 0.048). Kaplan-Meier survival analyses showed a significant difference between ENTE (+) and ENTE (-) groups for both cancer-specific survival (CSS) and recurrence-free survival (RFS) (P = 0.004 and P = 0.020, respectively, log-rank test). In the pN1a (single lymph node metastasis) subgroup, CSS and RFS were significantly shorter in patients with ENTE (P = 0.001 and P < 0.001, respectively, log-rank test). Comparing CSS and RFS according to pN stages and ENTE status, the survival curves of the pN1 group with ENTE were similar to those of the pN2 group without ENTE. ENTE is a useful prognostic factor for pT3 colorectal adenocarcinomas with regional lymph node metastasis, especially depending on the pN stages. The loss of E-cadherin expression may be an indicator of ENTE. Therefore, ENTE in colorectal adenocarcinoma should be considered in pN staging systems in the future.

MET is overexpressed in microsatellite instability-high gastric carcinoma.

BACKGROUND: MET is a tyrosine kinase receptor for the hepatocyte growth factor, and its overexpression is a poor prognostic factor in gastric carcinomas. Programmed death-ligand 1 (PD-L1) is an important biomarker of immunotherapy and is frequently positive in microsatellite instability-high (MSI-H) gastric carcinomas. In lung cancers, MET activation up-regulates PD-L1 expression. In this study, we investigated expression of MET and PD-L1 in MSI-H gastric carcinoma and the effects on prognosis. METHODS: MET and PD-L1 (SP142) immunohistochemistry was performed in 73 gastric carcinomas with MSI-H. In cases with MET overexpression, we performed fluorescent in situ hybridization (FISH). PD-L1 expression was calculated from both tumor cells (2+ and 3+ in > 10% of tumor cells was defined as PD-L1TC+) and immune cells (positive in >5% immune cells was PD-L1IC+), and also used a combined positive score (CPS; number of PD-L1 staining cells relative to all viable tumor cells; > 1 was PD-L1+). RESULTS: In 73 MSI-H gastric carcinomas, MET overexpression was observed in 11 cases (15.1%). In all 11 cases with MET overexpression,MET amplification was not found. MET overexpression was not related to any of clinico-pathological variables and PD-L1 expression. However, the PD-L1 CPS tended to be higher in tumors that were MET positive. Although MET overexpression alone was not a prognostic indicator, combined MET overexpression/PD-L1 predictive models showed that patients with MET+/PD-L1+ showed the best prognosis for overall survival as compared to other groups. CONCLUSION: MET overexpression was observed in 15% of MSI-H gastric carcinomas and was associated with high level expression of PD-L1.

Single-stranded DNA binding protein 2 expression is associated with patient survival in hepatocellular carcinoma.

BACKGROUND: SSBP2, single-stranded DNA binding protein 2, is a subunit of the ssDNA-binding complex that is involved in the maintenance of genome stability. The majority of previous studies have suggested a tumor-suppressive role of SSBP2, which is silenced by promoter hypermethylation in several human malignancies, such as hematologic malignancies, prostate cancer, esophageal squamous cell carcinoma, ovarian cancer, and gallbladder cancer. However, an oncogenic role of SSBP2 has been suggested in glioblastoma patients. We investigated the clinicopathologic significance of SSBP2 expression in hepatocellular carcinoma. METHODS: We constructed tissue microarrays consisting of 21 normal liver parenchyma and 213 hepatocellular carcinoma tissues with corresponding adjacent non-neoplastic tissues. SSBP2 expression was investigated by immunohistochemistry, and positive expression was defined as more than 10% of the tumor cells to show nuclear staining. We then analyzed the correlations between SSBP2 expression and various clinicopathologic characteristics, and further studied the role of SSBP2 in cell growth and migration. RESULTS: Hepatocytes were negative for SSBP2 immunohistochemistry in all normal liver samples, whereas the nuclei of normal bile duct epithelium and sinusoidal endothelium were immunoreactive. Positive immunoreactivity was found in one (0.6%) out of 180 non-neoplastic liver tissue samples adjacent to the tumor and in 16 (8.5%) out of 189 hepatocellular carcinomas. Positive SSBP2 expression was significantly correlated with tumor multifocality (P = 0.027, chi-square test), high histologic grade (P = 0.003, chi-square test), and frequent vascular invasion (P = 0.001, chi-square test). Kaplan-Meier survival curves revealed that patients with SSBP2 expression had poor prognosis in both disease-free and overall survival (P = 0.004 and P = 0.026, respectively, log-rank test). SSBP2-positive tumors also had a higher Ki-67 proliferation index (P <  0.001, t-test). Furthermore, downregulation of SSBP2 in the Huh7 cell line inhibited cell migration (P = 0.022, t-test) with altered expression of epithelial-mesenchymal transition markers. CONCLUSIONS: The minority of hepatocellular carcinomas expressed SSBP2 by immunohistochemistry, whereas normal hepatocytes were negative. SSBP2-positive hepatocellular carcinomas were significantly associated with aggressive phenotypes and poor clinical outcome.