Clinicopathological Significance of DUB3 Expression in Non-small Cell Lung Cancer and Relationship Between DUB3 Expression and LATS1 Expression.

BACKGROUND/AIM: Deubiquitinating enzyme 3 (DUB3) is a member of the ubiquitin-specific proteases family involved in regulating cell proliferation, invasion, and apoptosis. However, the biological role and clinicopathological significance of DUB3 expression have not been elucidated in non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: We evaluated the expression of DUB3 by immunohistochemistry using tissue microarrays and assessed the clinicopathologic significance of DUB3 expression levels in 187 patients with NSCLC, including its two major subtypes (93 cases of adenocarcinoma and 72 cases of squamous cell carcinoma). RESULTS: In adenocarcinoma, we observed that DUB3 expression had an effect on tumor size (p=0.030), vessel invasion (p=0.038), T stage (p=0.014), and tumor recurrence (p=0.002). Kaplan-Meier curves with log-rank test showed that high DUB3 expression was correlated with significantly more favorable clinical outcomes compared to those of the low expression group in adenocarcinoma (p=0.013). Multivariate analysis of disease-free survival also demonstrated that DUB3 expression is an independent prognostic factor in lung adenocarcinoma (p=0.017). Additionally, we identified the correlation between DUB3 and the expression of large tumor suppressor kinase 1 expression, a core protein of the Hippo pathway. CONCLUSION: DUB3 could function as a tumor suppressor by regulating the Hippo pathway in lung adenocarcinoma and can be considered a powerful predictive factor and therapeutic target.

A novel class of antimicrobial drugs selectively targets a Mycobacterium tuberculosis PE-PGRS protein.

The continued spread of drug-resistant tuberculosis is one of the most pressing and complex challenges facing tuberculosis management worldwide. Therefore, developing a new class of drugs is necessary and urgently needed to cope with the increasing threat of drug-resistant tuberculosis. This study aims to discover a potential new class of tuberculosis drug candidates different from existing tuberculosis drugs. By screening a library of compounds, methyl (S)-1-((3-alkoxy-6,7-dimethoxyphenanthren-9-yl)methyl)-5-oxopyrrolidine-2-carboxylate (PP) derivatives with antitubercular activity were discovered. MIC ranges for PP1S, PP2S, and PP3S against clinically isolated drug-resistant Mycobacterium tuberculosis strains were 0.78 to 3.13, 0.19 to 1.56, and 0.78 to 6.25 µg/ml, respectively. PPs demonstrated antitubercular activities in macrophage and tuberculosis mouse models, showing no detectable toxicity in all assays tested. PPs specifically inhibited M. tuberculosis without significantly changing the intestinal microbiome in mice. Mutants selected in vitro suggest that the drug targets the PE-PGRS57, which has been found only in the genomes of the M. tuberculosis complex, highlighting the specificity and safety potency of this compound. As PPs show an excellent safety profile and highly selective toxicity specific to M. tuberculosis, PPs are considered a promising new candidate for the treatment of drug-resistant tuberculosis while maintaining microbiome homeostasis.

Clinical utility of methionyl-tRNA synthetase 1 immunostaining in cytologic brushings of indeterminate biliary strictures: a multicenter prospective study.

BACKGROUND AND AIMS: Endobiliary brushings are routinely used in the diagnosis, treatment, and prognostication of biliary strictures. However, standard Papanicolaou (Pap) staining has a low sensitivity in this setting, and the accuracy of brush cytology has not been established for indeterminate strictures. We therefore evaluated the diagnostic merit of methionyl-transfer RNA synthetase 1 (MARS1) immunofluorescence (IF) staining in such cytologic specimens. METHODS: During ERCP, endobiliary brushings were obtained from patients with extrahepatic biliary strictures prospectively enrolled at 6 tertiary hospitals. Using liquid-based cytologic preparations of these samples, we performed Pap and MARS1 IF staining. RESULTS: In total, 240 patients were eligible; of these, we compared the Pap and MARS1 IF staining results of 218 (malignant, 157; benign, 61). By conventional Pap staining, the diagnoses were distributed as follows: malignant, 55; suspicious of malignancy, 60; atypical, 45; negative for malignancy, 58. MARS1 IF staining was strongly positive in malignant biliary stricture but not so in specimens negative for malignancy. The diagnostic parameters (sensitivity, specificity, positive predictive value, negative predictive value, and accuracy) of the MARS1 IF (93.6%, 96.7%, 98.7%, 85.5%, and 94.5%, respectively) and conventional Pap (73.2%, 100%, 100%, 59.2%, and 80.7%, respectively) staining methods differed significantly (P < .0001). CONCLUSIONS: The high sensitivity and accuracy of MARS1 IF staining enabled the detection of malignancy in patients with biliary strictures. Further prospective studies are needed to validate our findings. (Clinical trial registration number: NCT03708445.).

Ovarian yolk sac tumor with epithelial tumor component in a postmenopausal woman - case report and literature review.

Ovarian yolk sac tumors are common germ cell tumors usually arising in young women. Yolk sac tumors in elderly women are infrequently encountered and most of them are combined with other epithelial tumor components including endometrioid carcinoma or serous carcinoma. Here, we report an extremely rare case of a yolk sac tumor with mucinous tumor and large cell neuroendocrine carcinoma components in a postmenopausal woman, which is the third yolk sac tumor case with a neuroendocrine tumor element in an elderly woman. An 82-year-old female visited our hospital due to abdominal distention. Abdominal computed tomography (CT) demonstrated a solid and cystic mass, measuring about 9.0 cm in the largest diameter. A total hysterectomy with bilateral salpingo-oophorectomy and excisional biopsy of the peritoneal metastatic lesions was performed. Histologic evaluation revealed a malignant ovarian tumor composed of a variety of tumor components, including a yolk sac tumor, a mucinous tumor with multifocal mucinous carcinomatous areas, and a large-cell neuroendocrine carcinoma. After surgery, the patient refused further treatment and the disease recurred in the pelvic peritoneum and a left supraclavicular lymph node nine months later.

Clinicopathological correlation of PD-L1 and TET1 expression with tumor-infiltrating lymphocytes in non-small cell lung cancer.

The immunohistochemical analysis of PD-L1 expression is still important in cancer immunotherapy. PD-L1 expression is affected by various tumor microenvironmental factors including tumor infiltrating lymphocytes (TILs) and DNA methylation biomarkers. Given the complex communication between tumor cells and immune cells, we analyzed the expression of PD-L1 and TET1 with TILs in human NSCLC and the correlation with various clinicopathological characteristics and patient prognosis. A total of 96 cases of NSCLC were enrolled in this study. Using tissue microarray, we performed immunohistochemical staining to analyze PD-L1 and TET1 expression. Image-Pro Plus was used as an automated imaging analysis software program to analyze the density of CD3+, CD4+ and CD8 + TILs. PD-L1 expression was positively correlated with the density of CD3+, CD4+ and CD8 + TILs (p = 0.038, p = 0.020, and p = 0.009, respectively); however, no significant relationship existed between TET1 expression and any TILs. The survival analysis revealed that a high PD-L1 expression was associated with favorable prognosis for OS (p = 0.049) and DFS (p = 0.029) in advanced-stage II-IV patients, but not in early stage I. Density of CD8+ TILs was an independent and favorable prognostic factor for DFS (p = 0.008) and OS (p = 0.002) in early-stage I patients. However, high TET-1 expression was associated with poor prognosis for OS (p = 0.029) in total NSCLC patients. These findings suggest the correlation and favorable prognostic impact of PD-L1 and TILs in NSCLC. In addition, DNA demethylase TET1 has oncogenic effects, showing association with poor prognosis.

Vulvar epithelioid leiomyoma with myxoid change: A case report and literature review.

RATIONALE: Smooth muscle tumors of the vulva are infrequent neoplasms with diverse histologic features and unclear biologic behavior. Herein, we report a very rare case of vulvar epithelioid leiomyoma and review of previous reported cases of these tumors. In addition, we have discussed the representative diagnostic criteria of vulvar smooth muscle tumors and prognostic significance of epithelioid morphology. PATIENT CONCERNS: We recently met a 45-year-old woman with complaint of painful vulvar mass. INTERVENTIONS: Excisional biopsy was performed. DIAGNOSES: Pathologic examination revealed a vulvar epithelioid leiomyoma with multinodular growth pattern. Mitotic activity was rare and cellular atypia was not identified. Based on histology and immunohistochemical staining results, the case was diagnosed as vulvar epithelioid leiomyoma. OUTCOMES: After mass excision, the patient was discharged with no complication and there was no evidence recurrence for 6 months. LESSONS: After reviewing previous papers and diagnostic criterion, we thought that vulvar smooth muscle tumors with predominant epithelioid morphology may be associated with unfavorable prognosis, Therefore, pathologists should examine the epithelioid component in vulvar smooth muscle tumors carefully.

Efficacy of 3 fine-needle biopsy techniques for suspected pancreatic malignancies in the absence of an on-site cytopathologist.

BACKGROUND AND AIMS: EUS-guided fine-needle aspiration/biopsy (EUS-FNA/B) has a high diagnostic accuracy for pancreatic tumors. Most reports have focused on the diagnostic yield of cytology or histology; the ability of various FNA/B techniques to obtain an adequate mass of cells or tissue has rarely been investigated. METHODS: Patients with suspected pancreatic malignancy underwent EUS-FNB using a 22-gauge ProCore needle by either the stylet slow-pull-back technique (group A), conventional negative suction after stylet removal (group B), or non-suction after stylet removal (group C) in the absence of an on-site cytopathologist. The adequacy of the 3 techniques based on the diagnostic yield, cellularity, blood contamination, and core-tissue acquisition was evaluated. RESULTS: A total of 50 patients (27 males) were analyzed. The mean tumor size was 21 to 40 mm in 54%. The rate of a good or excellent proportion of cellularity was highest in group A compared with groups B and C (72% vs 60% vs 50%, P = .049). A >25% rate of blood contamination was more prevalent in group B (30% vs 42% vs 10%, P = .009). The rate of adequate core-tissue acquisition was not different (52% vs 34% vs 50%, P = .140). Based on the multivariate generalized estimation equation, the stylet slow-pull-back technique and a tumor size >40 mm were favorable factors for diagnostic adequacy. CONCLUSIONS: The stylet slow-pull-back technique might enable acquisition of tissue and assessment of cellularity for the diagnosis of pancreatic tumors suspected to be malignant. (Clinical trial registration number: KCT0002190.).

Bone regeneration strategy by different sized multichanneled biphasic calcium phosphate granules: In vivo evaluation in rabbit model.

A variety of synthetic materials are currently in use as bone substitutes, among them a new calcium phosphate-based multichannel, cylindrical, granular bone substitute that is showing satisfactory biocompatibility and osteoconductivity in clinical applications. These cylindrical granules differ in their mechanical and morphological characteristics such as size, diameter, surface area, pore size, and porosity. The aim of this study is to investigate whether the sizes of these synthetic granules and the resultant inter-granular spaces formed by their filling critical-sized bone defects affect new bone formation characteristics and to determine the best formulations from these individual types by combining the granules in different proportions to optimize the bone tissue regeneration. We evaluated two types of multichanneled cylindrical granules, 1 mm and 3 mm in diameter, combined the granules in two different proportions (wt%), and compared their different mechanical, morphological, and in vitro and in vivo biocompatibility characteristics. We assessed in vitro biocompatibility and cytotoxicity using MC3T3-E1 osteoblast-like cells using MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay and confocal imaging. In vivo investigation in a rabbit model indicated that all four samples formed significantly better bone than the control after four weeks and eight weeks of implantation. Micro-computed tomography analysis showed more bone formation by the 1 mm cylindrical granules with 160 ± 10 µm channeled pore and 50% porosity than the other three samples ( p<.05), which we confirmed by histological analysis.

Prognostic value of fibrosis ratio in metastatic lymph nodes of node-positive advanced gastric cancer.

Lymph node metastasis plays a crucial role in predicting prognosis in advanced gastric cancer (AGC). In the present study, we formulated a fibrosis ratio (FR), defined as the number of metastatic lymph nodes with fibrosis divided by the total number of lymph nodes, and sought to determine whether it can be used to predict the prognosis of patients with AGC and improve on existing node staging. We retrospectively analyzed 161 patients who underwent curative resection for node-positive AGC between 2001 and 2010, evaluating the association between FR, lymph node ratio (LNR), and micrometastasis, and the relationship between FR and clinicopathologic findings, overall survival (OS) and disease-free survival (DFS). A high FR was significantly related to T stage (P < .001), N stage (P < .001), tumor stage (P < .001), lymphatic invasion (P < .001), and venous invasion (P = .007). FR was significantly correlated with an increased number of metastatic lymph nodes (P = .001, R = 0.869) and LNR (P = .001, R = 0.943), but not with total harvested lymph nodes. Patients with micrometastases had a lower FR, compared with those without micrometastases (P < .001). A survival analysis showed poor OS for patients in the entire cohort (P < .001); N1 (P = .002), N2 (P = .004), N3a (P = .010), and N3b (P = .003) stages; and groups with high LNR (P = .013) and low LNR (P = .001). DFS was also poor for the entire cohort (P < .001) and the N2 (P = .013), N3b (P = .002), high-LNR (P = .036), and low-LNR (P = .001) groups, but not the N1 or N3a group. Univariate and multivariate analyses revealed that high FR was an independent prognostic factor for OS (hazard ratio [HR], 2.780; CI, 1.655-4.670; P < .001) and DFS (HR, 2.051; CI, 1.199-3.508; P = .009) in AGC. Collectively, our findings indicate that high FR is associated with adverse clinicopathologic parameters in AGC, clearly establishing nodal fibrosis as a pathological finding with value in predicting poor prognosis of patients with AGC. Thus, combining current N stage and LNR diagnostics with FR could improve prognostic prediction in AGC.

Clinical Effectiveness of Submucosal Injection with Indigo Carmine Mixed Solution for Colon Endoscopic Mucosal Resection.

BACKGROUND/AIMS: Submucosal injection with indigo carmine mixed solution can improve the delineation of colorectal neoplasia during endoscopic mucosal resection (EMR). Thus, the aim of this study was to evaluate the efficacy of submucosal injection with indigo carmine mixed solution during EMR of colorectal neoplasia. METHODS: This was a prospective, randomized, controlled study of a total of 212 neoplastic colon polyps (5-20 mm) subjected to EMR in a single tertiary university hospital. The patients were randomized into two groups according to whether or not indigo carmine mixed solution was used, and the complete resection rate (CRR) after EMR was evaluated. RESULTS: A total of 212 neoplastic polyps (normal saline group, 115; indigo carmine group, 97) were successfully removed by EMR. There was no significant difference in the CRR (92.8 vs. 89.6%, p = 0.414) or macroscopic delineation (86.0 vs. 93.8%, p = 0.118) between the two groups. In a separate analysis of sessile serrated adenomas/polyps (SSAs/Ps), macroscopic delineation was better in the indigo carmine group than the normal saline group (87.5 vs. 53.8%), albeit not significantly (p = 0.103). In univariate analyses, the CRR was significantly related to polyp location, polyp morphology, macroscopic delineation, and pathologic findings. In a multiple logistic regression analysis, macroscopic delineation (odds ratio (OR), 7.616, p = 0.001) and polyp pathology (OR, 8.621; p < 0.001) were significantly associated with the CRR. CONCLUSIONS: Submucosal injection with indigo carmine mixed solution did not improve the CRR or macroscopic delineation of EMR of colorectal neoplasias.

The relationship between local recurrence and positive lateral margin after en bloc resection of colorectal neoplasm.

BACKGROUND: The factors associated with recurrence of colonic neoplasm after endoscopic resection with a positive lateral margin are not well known. Thus, we evaluate the relationship between recurrence and positive lateral margin after endoscopic en bloc resection of colorectal neoplasm. METHODS: A retrospective review of 9302 patients who underwent colonic endoscopic resection from January 2008 to January 2015. Of these, a total of 76 patients with positive lateral margins with clear evidence of the its location on endoscopic picture after endoscopic en bloc resection of colorectal neoplasm (>10 mm) were included. RESULTS: Ten of 76 (13.2%) patients experienced recurrence during the follow-up period (mean f/u month, 21.7 ± 15.6). In cases with positive lateral margins, the 3- and 5-year local recurrence rate of colorectal neoplasm was 28.1% and 40.1%, respectively. The histological features of the recurrence group were as follows: one case of adenocarcinoma [from low-grade adenoma (LGA)]; two cases of high-grade adenoma (HGA) (one from HGA and one from LGA); and seven cases of LGA (four from adenocarcinoma, two from LGA, and one from HGA). The mean age of patients, locations of the lesions, and histologic type were not significantly associated with local recurrence. In multivariate Poisson regression analyses, total length of lateral margin involvement ≥8 mm (relative risk 12.51; 95% CI 1.11-140.34, p = .040) was a significant predictor of local recurrence. CONCLUSIONS: Positive lateral margins ≥8 mm may be a reliable predictor of local recurrence after endoscopic en bloc resection of colorectal neoplasm.

Composite trichoblastoma and inverted follicular keratosis: a case report.

Composite trichoblastoma and inverted follicular keratosis is extremely rare and the histogenesis is unclear. To date, only four cases have been described in a report. We report a case of 62-year-old woman patient with a palpable cutaneous nodule on the buttock. The patient had a history of squamous cell carcinoma on the lower lip 13 months ago. Excisional biopsy was done, and the microscopic examination revealed composite tumor of trichoblastoma and inverted follicular keratosis. The patient has not been experienced recurrence after surgery.

Low angiomotin-p130 with concomitant high Yes-associated protein 1 expression is associated with adverse prognosis of advanced gastric cancer.

Angiomotin (AMOT) promotes angiogenesis and plays a role in neovascularization during tumorigenesis. Recently, the AMOT isoform, AMOT-p130, was shown to exert a regulatory effect on Yes-associated protein 1 (YAP1), a major downstream effector of the Hippo pathway. The specific roles of AMOT-p130 and YAP1 in advanced gastric cancer (AGC) are yet to be established. In this study, a total of 166 patients with AGC were enrolled, and AMOT-p130 and YAP1 levels were analyzed by immunohistochemistry using tissue microarrays. Low AMOT-p130 together with high YAP1 expression (n = 30, 18.1%) was associated with high T stage (p = 0.042), high TNM stage (p = 0.025), and venous invasion (p = 0.048). A Kaplan-Meier survival analysis with log-rank test revealed a significant correlation with decreased AMOT-p130 coupled with high nuclear YAP1 expression with shorter overall survival (p = 0.0045) and disease-free survival (p = 0.0028). Furthermore, multivariate analyses showed that the low AMOT-p130/high YAP1 expression profile was an independent prognostic factor for disease-free survival (p = 0.008, HR = 1.874, CI, 1.177-2.986) and overall survival (p = 0.012, HR = 1.903, CI, 1.152-3.143). Our findings collectively demonstrate that low AMOT-p130 combined with high YAP1 expression is correlated with an unfavorable AGC prognosis.

Karyopherin α-2 is a reliable marker for identification of patients with high-risk stage II colorectal cancer.

PURPOSE: Adjuvant chemotherapy (AC) is frequently considered in patients with high-risk stage II colorectal cancer (CRC). Among patients with stage II CRC who do not receive AC because they are not considered to be at high risk, 20-25% will develop recurrence and die from the disease. Elevated levels of KPNA2 have been observed in various cancers, and overexpression of KPNA2 is related to CRC progression. METHODS: We examined the expression of KPNA2 using 293 CRC tissues, including 118 with stage II CRC, and investigated the applicability of KPNA2 as a biomarker to predict high-risk stage II CRC. Moreover, we further investigated the role of KPNA2 as an oncogene in CRC carcinogenesis using in vitro functional studies. RESULTS: High KPNA2 expression was associated with vascular (p = 0.027) and lymphatic invasion (p = 0.009) in patients with stage II CRC. On multivariate analysis, high KPNA2 expression (HR 3.174, 95% CI 2.060-4.889; p < 0.001) was independently associated with survival in patients with CRC. The overall survival rate in patients with high KPNA2 expression was higher than that in patients with low KPNA2 expression in CRC (p < 0.001), even in patients with stage II CRC (p = 0.001). Additionally, KPNA2 was associated with tumorigenesis and cancer progression in CRC cells; high KPNA2 expression was associated with increased cell proliferation (p < 0.05), migration (p = 0.03), invasion (p = 0.001), and semisolid agar colony formation (p < 0.001). CONCLUSION: KPNA2 expression is useful for identification of patients with high-risk stage II CRC who could benefit from AC and that KPNA2 may also be a promising therapeutic target.

Examination of In vitro and In vivo biocompatibility of alginate-hyaluronic acid microbeads As a promising method in cell delivery for kidney regeneration.

In this study, alginate (ALG) and alginate-hyaluronic acid (ALG-HA) injectable microbeads, with the purpose of delivering stem cells for tissue engineering, were prepared by a spraying method into a CaCl2 solution that shows high porosity for the exchange of nutrition and waste. In addition, the size distribution and surface morphology was investigated using optical and scanning electron microscopy, respectively. The chemical structural properties of the ALG-HA microbeads were examined by Fourier transform infrared spectroscopy. The biocompatibility of ALG and ALG-HA microbeads was examined in vitro. Rat bone marrow stem cells were encapsulated in microbeads to investigate cell release, cell viability, proliferation, and secretion of growth factors such as VEGF and PDGF. Growth factors were released for the 21day experimental period. Cells were found to be released from the microbeads after 7days. Furthermore, the in vivo biocompatibility of ALG-HA microbeads was examined using microbeads without cell encapsulation in the kidney capsule, in order to assess the foreign body reaction and inflammatory response, for 14days. The desired in vivo response to ALG-HA microbeads hydrogel makes it an exquisite candidate for subcapsular cell and drug delivery to kidney tissue.

Thymoquinone (TQ) inhibits the replication of intracellular Mycobacterium tuberculosis in macrophages and modulates nitric oxide production.

BACKGROUND: Human tuberculosis, which is caused by the pathogen Mycobacterium tuberculosis, remains a major public health concern. Increasing drug resistance poses a threat of disease resurgence and continues to cause considerable mortality worldwide, which necessitates the development of new drugs with improved efficacy. Thymoquinone (TQ), an essential compound of Nigella sativa, was previously reported as an active anti-tuberculosis agent. METHODS: In this study, the effects of TQ on intracellular mycobacterial replication are examined in macrophages. In addition, its effect on mycobacteria-induced NO production and pro-inflammatory responses were investigated in Mycobacterium tuberculosis (MTB)-infected Type II human alveolar and human myeloid cell lines. RESULTS: TQ at concentrations ranging from 12.5 to 25 µg/mL and 6.25 to 12.5 µg/mL reduced intracellular M. tuberculosis H37Rv and extensively drug-resistant tuberculosis (XDR-TB) 72 h post-infection in RAW 264.7 cells. TQ treatment also produced a concentration-dependent reduction in nitric oxide production in both H37Rv and XDR-TB infected RAW 264.7 cells. Furthermore, TQ reduced the expression of inducible nitric oxide synthase (iNOS) and pro-inflammatory molecules such as tumor necrosis factor-alpha (TNF-α) and interlukin-6 (IL-6) in H37Rv-infected cells and eventually reduced pathogen-derived stress in host cells. CONCLUSIONS: TQ inhibits intracellular H37Rv and XDR-TB replication and MTB-induced production of NO and pro-inflammatory molecules. Therefore, along with its anti-inflammatory effects, TQ represents a prospective treatment option to combat Mycobacterium tuberculosis infection.

Clinicopathologic and Prognostic Significance of Transducin-Like Enhancer of Split 1 Protein Expression in Invasive Breast Cancer.

PURPOSE: Transducin-like enhancer of split 1 (TLE1) is a member of the TLE family of transcriptional co-repressors that control the transcription of a wide range of genes. We investigated the prognostic significance of TLE1 protein expression in breast cancers by using immunohistochemistry and explored the relationship of TLE1 with clinicopathological parameters. METHODS: Immunohistochemistry was performed on 456 cases of breast cancer tiled on tissue microarrays. The relationship between TLE1 expression in normal breast specimens and ductal carcinoma in situ (DCIS) was also analyzed. RESULTS: TLE1 was highly expressed in 57 of 456 (12.5%) carcinoma samples. TLE1 was more frequently expressed in DCIS and invasive breast cancers than in normal breast tissue (p=0.002). High expression of TLE1 significantly correlated with negative lymph node (LN) metastasis (p=0.007), high histologic grade (p<0.001), estrogen receptor negativity (p<0.001), progesterone receptor negativity (p<0.001), human epidermal growth factor receptor 2 (HER2) positivity (p<0.001), and high Ki-67 proliferation index (p<0.001). Based on intrinsic subtypes, high TLE1 expression was strongly associated with HER2+ and triple-negative breast cancers (TNBC) (p<0.001). Survival analysis demonstrated no significant association between TLE1 expression and disease-free survival (DFS) (p=0.167) or overall survival (OS) (p=0.286). In subgroup analyses, no correlation was found between TLE1 expression and DFS or OS according to LN status or intrinsic subtype. CONCLUSION: High TLE1 expression is significantly associated with the HER2+ and TNBC subtypes. This is the first study documenting immunohistochemical expression of TLE1 in invasive breast cancer and its association with clinicopathological parameters, prognosis, and intrinsic subtype.

Reduced angiomotin p130 expression correlates with poor prognosis in lung adenocarcinoma.

AIMS: Lung cancer is the leading cause of cancer-related deaths worldwide, and it still results in a poor prognosis despite research and development of a treatment modality. Angiomotin (AMOT) was first described as a protein involved in angiogenesis, and although the oncogenic and tumour-suppressive roles of AMOT were recently reported, the biological function of AMOT has not yet been clarified. The aim of this study was thus to evaluate the relationship between reduced AMOT p130 expression and clinicopathological parameters, including patients' survival. METHODS: We enrolled 67 patients with lung adenocarcinoma in this study and measured the immunoreactivity of AMOT p130 in a tissue microarray. The data were analysed using a χ2 test, Cox regression hazards model and log-rank test with Kaplan-Meier curves. RESULTS: Reduced AMOT p130 expression is related to lung adenocarcinoma developed at a young age with statistical significance, but there is no statistical significance for the other clinicopathological parameters. Kaplan-Meier curves with log-rank test showed that reduced AMOT p130 expression had significantly better survival rate compared with the retained group (p=0.002). Univariable and multivariable analyses of the disease free survival revealed that the decreased AMOT expression was an independent prognostic factor (p=0.004, p=0.008, respectively). CONCLUSIONS: Decreased AMOT p130 could be an independent indicator of poor survival in patients with lung adenocarcinoma.

Expression of Programmed Death Receptor Ligand 1 with High Tumor-Infiltrating Lymphocytes Is Associated with Better Prognosis in Breast Cancer.

PURPOSE: The interaction of programmed death receptor 1 (PD-1) and its ligand, programmed death receptor ligand 1 (PD-L1), negatively regulates immune responses. This study aimed to clarify PD-L1 expression levels in breast cancer through immunohistochemistry (IHC) and to evaluate associations between these findings and clinicopathologic variables, including prognosis. METHODS: PD-L1 expression was analyzed using IHC on tissue microarrays of 465 invasive breast carcinomas. RESULTS: High PD-L1 expression was demonstrated in 63 of 465 tumors (13.5%). High PD-L1 expression was significantly associated with high histologic grade (p<0.001), negative lymph nodes (p=0.011), early pathologic stage (p=0.025), high tumor-infiltrating lymphocyte (TIL) (p<0.001) counts, negative estrogen receptor (p<0.001) and progesterone receptor (p=0.002) expression, positive human epidermal growth factor receptor 2 (HER2) (p=0.003), cytokeratin 5/6 (p=0.011), epidermal growth factor receptor (p<0.001), and p53 (p<0.001) expression, and high Ki-67 proliferating index (p<0.001). Based on intrinsic subtypes, high PD-L1 expression and high TIL counts were significantly associated with the HER2 and triple-negative basal type (p<0.001). PD-L1 expression was significantly associated with better disease-free survival (DFS) (p=0.041) and overall survival (OS) (p=0.026) in the univariate analysis, but not in the multivariate analysis. Higher TIL levels was an independent prognostic factor for decreased disease progression (hazard ratio [HR], 2.389; 95% confidence interval [CI], 1.284-4.445; p=0.006) and overall death (HR, 3.666; 95% CI, 1.561-8.607; p=0.003). CONCLUSION: PD-L1 protein expression in breast cancer is associated with better DFS and OS, but is not an independent prognostic factor. High PD-L1 expression was significantly associated with high TIL levels. This finding has important implications for antibody therapies targeting the PD-1/PD-L1 signaling mechanism in breast cancer.

Clinicopathological Significance of Elevated PIK3CA Expression in Gastric Cancer.

PURPOSE: PIK3CA is often mutated in a variety of malignancies, including colon, gastric, ovary, breast, and brain tumors. We investigated PIK3CA expression in gastric cancer and explored the relationships between the PIK3CA expression level and clinicopathological features as well as survival of the patients. MATERIALS AND METHODS: We examined PIK3CA expression in a tissue microarray of 178 gastric adenocarcinomas by immunohisto-chemistry and reviewed patients' medical records. RESULTS: In our study, 112 of the 178 gastric cancer patients displayed positive PIK3CA expression. Overexpression of PIK3CA was correlated with low grade differentiation (P=0.001), frequent lymphatic invasion (P=0.032), and high T stage (P=0.040). Patients with positive PIK3CA staining were more likely to display worse overall survival rate than those with negative PIK3CA staining, as determined by Kaplan-Meier survival analysis with log-rank test (P=0.047) and a univariate analysis using the Cox proportional hazard model (hazard ratio=1.832, P=0.051). CONCLUSIONS: Elevated PIK3CA expression was significantly correlated with tumor invasiveness, tumor phenotypes, and poor patient survival.