Implications of NOVA1 suppression within the microenvironment of gastric cancer: association with immune cell dysregulation.

BACKGROUND: The neuronal splicing factor neuro-oncological ventral antigen 1 (NOVA1) is enriched in normal fibroblasts. Stromal spindle cells such as fibroblasts are major components of tissue inflammation and tertiary lymphoid structures within the microenvironment that contribute to the survival and growth of cancer cells. In the present study, we investigated changes of NOVA1 expression in tertiary lymphoid structures in early and advanced gastric cancer microenvironments in terms of tumor progression and immune regulation. METHODS: Using immunohistochemistry, we analyzed NOVA1 expression in tumor cells, T cells, and stromal spindle cells as well as infiltrating densities of CD3+ T cells, forkhead box P3 positive (FOXP3+) regulatory T cells, CD68+ macrophages, CD163+ M2 macrophages, and myeloperoxidase-positive neutrophils in 396 surgically resected gastric cancer tissues. RESULTS: Suppressed NOVA1 expression in tumor cells, T cells, and stromal spindle cells was closely related to decreased infiltration of FOXP3+ regulatory T cells, increased infiltration of CD68+ macrophages and CD163+ M2 macrophages, more advanced tumor stage, and inferior overall survival rate. In addition, low infiltration of CD3+ T cells and FOXP3+ regulatory T cells and high infiltration of CD68+ macrophages were associated with inferior overall survival. Specifically, weak NOVA1 expression in tumor cells was independently related to more advanced tumor stage and inferior overall survival. CONCLUSIONS: NOVA1 suppression was frequently noted in the gastric cancer microenvironment, and attenuated NOVA1 expression in tumor cells was associated with tumor progression and poor prognosis. This finding seems to be related to immune dysfunction through changes in the immune cell composition of T cells and macrophages.

Programmed death-ligand 1 expression in gastric adenocarcinoma is a poor prognostic factor in a high CD8+ tumor infiltrating lymphocytes group.

Gastric adenocarcinoma is one of the most common causes of cancer-related death. In this study, we conducted immunohistochemical studies for PD-L1, PD-1, CTLA-4, and CD8 using tissue microarrays from 464 gastric cancer samples and evaluated the correlations between their expression, clinicopathologic factors, and five-year overall survival. PD-L1 and PD-1 expression was significantly correlated with several adverse prognostic pathologic factors, including higher T-stage, diffuse Lauren histologic type, and lymphatic invasion. Conversely, CTLA-4 expression was correlated with factors of favorable clinical outcomes. A complete case analysis revealed that high PD-L1 and PD-1 expression had an adverse effect on five-year overall survival in univariate analyses. Subgroup analyses wherein patients were divided into two groups according to CD8+ tumor infiltrating lymphocyte levels (high and low) showed that high PD-L1 expression was a significant adverse prognostic factor only in the high CD8+ tumor-infiltrating lymphocytes group. Further research and clinical trials are needed to determine the clinical usefulness of these findings.

NOVA1 inhibition by miR-146b-5p in the remnant tissue microenvironment defines occult residual disease after gastric cancer removal.

Occult residual disease in remnant tissues could be the cause of tumor relapse. To identify signal molecules and target cells that may be indicative of occult residual disease within a remnant microenvironment, proximal resection margin tissues of gastric cancers were used, as these correspond to the nearest remnant tissues after gastrectomy. Increased miR-146b-5p in the remnant microenvironment was determined to be a strong risk factor for tumor relapse and poor survival rate. NOVA1, a target gene of miR-146b-5p, was decreased in remnant tissues of patients with a poor prognosis. NOVA1 was enriched in stromal spindle cells such as fibroblasts within normal tissues. In non-neoplastic inflammation, such as gastritis, NOVA1 was highly enriched in T lymphocytes and stromal spindle cells, while expression of this protein was frequently decreased in those types of cells within gastric cancer tissues. Particularly, decreased NOVA1 in T cells within the gastric cancer tissues was correlated with decreased FOXP3-positive regulatory T cells and was associated with poor patient prognosis. In vitro analysis showed that the NOVA1 gene was inhibited by miR-146b-5p. In immune cells as well as stromal spindle cells, decreased NOVA1, possibly inhibited by miR-146b-5p, is a candidate biomarker predicting poor prognosis of gastric cancer patients and is also a biomarker of occult residual disease in remnant tissues after gastric cancer removal.

Expression of ROR1, pAkt, and pCREB in gastric adenocarcinoma.

The receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a transmembrane protein of receptor tyrosine kinase family. High expression of ROR1 is reported in many types of malignancies and is thought to be involved in tumor growth, apoptosis, and epithelial-mesenchymal transition. In this study, we examined the expression of ROR1, pAkt, and pCREB in gastric adenocarcinoma and analyzed with clinicopathologic factors and tumor proliferation. Tissue microarray blocks containing 424 gastric adenocarcinomas were used for immunohistochemical staining. Ki-67 labeling index was used for tumor proliferation activity. High expression of ROR1 (63%), pAkt (36%), and pCREB (20%) was observed in gastric adenocarcinomas, and expression of these proteins was well intercorrelated. ROR1 and pCREB expression was associated with Ki-67 labeling index (P < .001). Expression of pAkt and pCREB group showed longer survival in univariate analysis (P = .007 and P < .001, respectively). This is the first study that analyzed ROR1 expression in gastric adenocarcinoma tissue samples. We revealed that gastric adenocarcinomas highly express ROR1 and related proteins and its prognostic significance. ROR1 in gastric adenocarcinoma could be possible candidate of therapeutic target, and more comprehensive study is required.

Lysyl-tRNA synthetase (KRS) expression in gastric carcinoma and tumor-associated inflammation.

BACKGROUND: Lysyl-tRNA synthetase (KRS) is an aminoacyl-tRNA synthetase (ARS) that is essential for protein synthesis during ligation of specific amino acids to their cognate tRNAs. Aberrant expression of ARSs is associated with various human cancers. METHODS: Using immunohistochemical detection, the present study analyzed the clinical relevance of KRS expression in tumor cells and tumor-associated inflammatory cells (TAI) in 457 patients who underwent curative radical surgery and standard adjuvant therapy and who were observed on long-term follow-up. RESULTS: High expression of KRS in tumor cells (tumor-KRS(+)) was noted in 43.3 % (198 of 457) of cases. High expression of KRS in tumor-associated inflammatory cells (TAI-KRS(+)) including macrophages/monocytes, CD4-positive T cells, and/or neutrophils was observed in 37.2 % (170 of 457) of cases. Status of KRS in the tumor and TAI revealed an association with the known clinicopathological parameters for prognosis of gastric cancer. Tumor-KRS(+) status correlated to shorter overall survival, especially in stage III to IV cancers (P = 0.003), while TAI-KRS(+) status correlated significantly to longer overall survival in gastric cancer (P = 0.049). Cases with tumor-KRS(+) and TAI-KRS(-) status showed significantly reduced survival rates compared to those of other cases (P = 0.010), and status of tumor-KRS(+) and TAI-KRS(-) was revealed as an independently poor prognostic factor of overall survival (P = 0.001). CONCLUSIONS: KRS-related inflammation can be identified in a subset of gastric cancer. This may be a possible mechanism of immune surveillance against tumor progression. In addition, expression status of KRS in tumor and TAI may be an independent prognostic marker for gastric cancer patients.

Prognostic significance of heat shock protein 70 expression in early gastric carcinoma.

BACKGROUND: Overexpression of heat shock protein 70 (HSP70) has been observed in many types of cancer including gastric adenocarcinomas, although the exact role of HSP70 in carcinogenesis remains unclear. METHODS: The study analyzed a total of 458 radical gastrectomy specimens which were immunohistochemically stained with HSP70, p53, and Ki-67 antibodies. RESULTS: The study determined that the expression of HSP70 was significantly increased in early gastric cancer (EGC) compared to advanced gastric cancer (p<0.001). The HSP70 expression was correlated with well-differentiated tumor type, intestinal type of Lauren classification and the lower pT and pN stage. Negative expression of Ki-67 and p53 expression was associated with poor prognosis. The study did not find any correlation between HSP70 and p53 expression. The study determined that HSP70 expression in the EGC subgroup was associated with a poor prognosis (p=0.009), as well as negative Ki-67 expression (p=0.006), but was not associated with p53. Based on multivariate analysis, HSP70 expression (p=0.024), negative expression of Ki-67, invasion depth and lymph node metastasis were determined to be independent prognostic markers. CONCLUSIONS: HSP70 is expressed in the early stages of gastric adenocarcinoma. In EGC, HSP70 is a poor independent prognostic marker and is correlated with a low proliferation index.

Expression of moesin and CD44 is associated with poor prognosis in gastric adenocarcinoma.

AIMS: CD44 has been reported as a negative prognostic marker in gastric cancer. It interacts with moesin in epithelial-mesenchymal transition. To date, to our knowledge, there has been no clinical study dealing with the relationship between moesin and gastric adenocarcinoma. We analysed the expression of moesin and CD44 in gastric adenocarcinoma tissue, and correlations with clinicopathological factors. METHODS AND RESULTS: A retrospective analysis was made of 430 patients who had undergone gastrectomy at the Korea University Guro Hospital between 2002 and 2005 for gastric adenocarcinoma. Using tissue microarray and immunohistochemical staining, moesin expression was observed in 192 (44.7%) cases; it was associated significantly with poorly differentiated histology, invasion depth, lymph node metastasis, lymphatic invasion and advanced pathological TNM stage. CD44 expression was not correlated with clinicopathological features or moesin expression. Moesin expression was a strong predictor of lymph node metastasis in logistic regression analysis. Both moesin expression and CD44 expression were associated significantly with poor overall survival in univariate analysis. Furthermore, in multivariate analysis, moesin and CD44 were independent markers of poor prognosis, along with pathological TNM stage and older patient age. CONCLUSION: Moesin expression and CD44 expression might be useful markers of poor prognosis in gastric adenocarcinoma.

Pigmented perivascular epithelioid cell tumor (PEComa) of the kidney: a case report and review of the literature.

Heavily pigmented perivascular epithelioid cell tumors (PEComa) are rare, only eight cases of which have been reported. Unlike typical epithelioid angiomyolipoma, most of these tumors have been encountered in female patients without tuberous sclerosis. The long-term prognosis thereof is undetermined. Cytological similarity and heavy melanin pigment make it difficult for pigmented PEComa to be differentiated from pigmented clear cell renal cell carcinoma or malignant melanoma. The immunoprofile of tumor cells, such as human melanoma black-45 expression, as well as the absence or presence of other melanocytic or epithelial markers, are helpful in determining a differential diagnosis. Here we report a case of heavily pigmented PEComa of the right kidney and review the literature describing this tumor. In this case, the immunoprofile and clinical features corresponded well to those described in the literature. Since the prognosis of such disease has not yet been established, close follow-up of this patient was recommended.

Plexiform angiomyxoid myofibroblastic tumor of the stomach: report of two cases and review of the literature.

Plexiform angiomyxoid myofibroblastic tumor (PAMT) of the stomach is a recently recognized entity. Because of its rarity, only 22 cases have been reported in the English-language literature and most of these are single case reports. We report two cases of gastric PAMT. The tumor cells were bland and plexiform arranged in a myxoid stroma, which was positive for alcian blue. Immunohistochemically, the tumor cells were positive for smooth muscle actin, but negative for c-kit, CD34, desmin, S-100 protein, epithelial membrane antigen, neurofilament, and protein kinase C-theta. Mutation analyses for exon 9, 11, 13, and 17 of KIT genes and 12, 14, and 18 of the platelet-derived growth factor receptor alpha (PDGFRA) genes were performed and the tumors were wild-type for mutation.

A pharmacodynamic analysis of factors affecting recovery from anesthesia with propofol-remifentanil target controlled infusion.

AIM: To examine individual patient's demographic parameters and clinical variables related to return of consciousness (ROC) and the pharmacodynamic relationship between propofol effect-site concentration (C(e)) and ROC from propofol-remifentanil anesthesia. METHODS: Ninety-four patients received propofol-remifentanil anesthesia using the effect-site target-controlled infusion (TCI) system. All clinical events were noted, and variables possibly related to propofol C(e) at ROC were examined using linear correlation analyses. Pharmacodynamic modeling incorporating covariates was performed using NONMEM (Nonlinear Mixed Effects Modeling) VII software. RESULTS: The C(e) values of propofol at loss of consciousness (LOC) and ROC were 4.4±1.1 µg/mL and 1.1±0.3 µg/mL, respectively. Age was negatively correlated with propofol C(e) at ROC (r=-0.48, P<0.01). Including age as a covariate in C(e50) (the effect-site concentration associated with 50% probability of return of consciousness) and λ (the steepness of the concentration-versus-response relationship) significantly improved the performance of the basic model based on the likelihood ratio test, with a significant decrease in the minimum value of the objective function. The C(e50) in 25-, 50-, and 75-year-old patients was predicted to be 1.38, 1.06, and 0.74 µg/mL, respectively. The λ in 25-, 50-, and 75-year-old patients was predicted to be 12.23, 8.70, and 5.18, respectively. CONCLUSION: Age significantly affects the relationship between propofol C(e) and ROC, and pharmacodynamic modeling including age could lead to better predictions of ROC during emergence from propofol-remifentanil anesthesia.

Expression of SIRT1 and DBC1 in Gastric Adenocarcinoma.

BACKGROUND: Sirtuin 1 (SIRT1) and deleted in breast cancer 1 (DBC1) are known as tumor suppressor or promoter genes. This may be due to their diverse functions and interaction with other proteins. Gastric adenocarcinoma is one of the most common malignancies, but little is known about its carcinogenesis. Therefore, we investigated the association of immunohistochemical expression of SIRT1, DBC1, p53, and ß-catenin and their variable clinicopathological characteristics. METHODS: We obtained samples from 452 patients who underwent gastrectomy. Tissue microarray blocks were constructed and immonohistochemical staining was performed. RESULTS: Expression of DBC1 and SIRT1 was associated with lower histologic grade, intestinal type of Lauren classification, and lower pT (p<0.001) and pN stage (DBC1, p=0.002; SIRT1, p<0.001). Association between absence of lymphatic invasion, and SIRT1 (p=0.001) and DBC1 (p=0.004) was observed. Cytoplasmic ß-catenin expression was associated with lower histologic grade, pT, pN, tumor-node-metastasis (TNM) stage, DBC1 (p<0.001), and SIRT1 (p=0.001). Expression of SIRT1 and DBC1 was not associated with p53 (p=0.063 and p=0.060). DBC1 was an independent good prognostic factor in multivariate analysis (p=0.012). CONCLUSIONS: SIRC1 and DBC1 can be considered to be good prognostic factors in gastric adenocarcinoma.

A head-to-head comparison between 64-slice multidetector computed tomographic and conventional coronary angiographies in measurement of myocardial bridge.

BACKGROUND: It has been suggested that multidetector computed tomographic coronary angiography (MDCT-CA) may be a reliable modality for the diagnosis and assessment of myocardial bridge (MB). However, the correlation between MB measurements of MDCT-CA and conventional coronary angiography (CCA) has not been determined. METHODS: We assessed the correlation between MDCT-CA and CCA in MB measurements. One hundred twenty consecutive patients (77 men, 61±12 yrs) underwent MDCT-CA and CCA simultaneously from suspected coronary artery disease. MB measurements on MDCT-CA included location, length, depth, within-MB diameter, reference luminal diameters of segment proximal and distal MB, and luminal narrowing. MB measurements on CCA included length, within-MB diameter, reference lumen diameters of segment proximal and distal to MB, and luminal narrowing. RESULTS: We observed 38 MB segments in 30 patients (25%), with 6 patients having ≥2 MB segments. The within-MB diameters on MDCT-CA and CCA showed a significant correlation during systolic (1.3±0.3 mm vs. 1.2±0.5 mm: r=0.394, P=0.028) and diastolic phases (1.4±0.4 mm vs. 1.6±0.6 mm: r=0.524, P=0.001). Systolic luminal narrowing (SLN) on CCA ranged from 8% to 75% (38±16%), and a definite milking effect (defined as SLN>50%) was observed in only 7 segments (18.4% of 38 MBs, or 5.8% of all cohorts). In case of MB segments with a definite milking effect, length of MBs on MDCT-CA and CCA correlated significantly (systolic phase: r=0.794, P=0.033 and diastolic phase: r=0.766, P=0.045). SLN on CCA was not related with any MB measurement on MDCT-CA. CONCLUSIONS: In case of MBs with sufficient systolic compression, diameter and length of MBs correlates significantly between MDCT-CA and CCA analysis. The detection rate of MB on CCA may be associated with the degree of systolic compression, and systolic compression on CCA cannot be predicted by any measurement on MDCT-CA.