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Background: It is still difficult to detect and diagnose early adenocarcinoma of the esophagogastric junction (EGJ) using conventional endoscopy or image-enhanced endoscopy. A glutamylprolyl hydroxymethyl rhodamine green (EP-HMRG) fluorescent probe that can be enzymatically activated to become fluorescent after the cleavage of a dipeptidyl peptidase (DPP)-IV-specific sequence has been developed and is reported to be useful for the detection of squamous cell carcinoma of the head and neck, and esophagus; however, there is a lack of studies that focuses on detecting EGJ adenocarcinoma by fluorescence molecular imaging. Therefore, we investigated the visualization of early EGJ adenocarcinoma by applying EP-HMRG and using clinical samples resected by endoscopic submucosal dissection (ESD)., Methods: Fluorescence imaging with EP-HMRG was performed in 21 clinical samples resected by ESD, and the fluorescence intensity of the tumor and non-tumor regions of interest was prospectively measured. Immunohistochemistry was also performed to determine the expression of DPP-IV., Results: Fluorescence imaging of the clinical samples showed that the tumor lesions were visualized within a few minutes after the application of EP-HMRG, with a sensitivity, specificity, and accuracy of 85.7, 85.7, and 85.7%, respectively. However, tumors with a background of intestinal metaplasia did not have a sufficient contrast-to-background ratio since complete intestinal metaplasia also expresses DPP-IV. Immunohistochemistry measurements revealed that all fluorescent tumor lesions expressed DPP-IV., Conclusions: Fluorescence imaging with EP-HMRG could be useful for the detection of early EGJ adenocarcinoma lesions that do not have a background of intestinal metaplasia.

Background: Although asbestos acts as a potent carcinogen in pleural mesothelial and pulmonary epithelial cells, it still remains unclear whether asbestos causes specific and characteristic gene alterations in these different kinds of target cells, because direct comparison in an identical patient is not feasible. We experienced a rare synchronous collision tumor composed of malignant pleural mesothelioma (MPM) and primary pulmonary adenocarcinoma (PAC) in a 77-year-old man with a history of long-term smoking and asbestos exposure, and compared the DNA copy number alteration (CNA) and somatic mutation in these two independent tumors., Methods: Formalin-fixed paraffin-embedded (FFPE) tissues of MPM and PAC lesions from the surgically resected specimen were used. Each of these MPM and PAC lesions exhibited a typical histology and immunophenotype. CNA analysis using SNP array was performed using the Illumina Human Omni Express-12_FFPE (Illumina, San Diego, CA, USA) with DNA extracts from each lesion. Somatic mutation analysis using next-generation sequencing was performed using the TruSeq Amplicon Cancer Panel (Illumina)., Results: The CNA analysis demonstrated a marked difference in the frequency of gain and loss between MPM and PAC. In PAC, copy number (CN) gain was detected more frequently and widely than CN loss, whereas in MPM there was no such obvious difference. PAC did not harbor CNAs that have been identified in asbestos-associated lung cancer, but did harbor some of the CNAs associated with smoking. MPM exhibited CN loss at 9p21.2-3, which is the most common genetic alteration in mesothelioma., Conclusion: In this particular case, asbestos exposure may not have played a primary role in PAC carcinogenesis, but cigarette smoking may have contributed more to the occurrence of CN gains in PAC. This comparative genetic analysis of two different lesions with same amount of asbestos exposure and cigarette smoke exposure has provided information on differences in the cancer genome related to carcinogenesis.

It has been clear that cancer-associated fibroblasts (CAFs) in the tumor microenvironment play an important role in pancreatic ductal adenocarcinoma (PDAC) progression. However, how CAFs relate to the patients' prognosis and the effects of chemoradiation therapy (CRT) has not been fully investigated. Tissue microarrays (TMAs) representing 167 resected PDACs without preoperative treatment were used for immunohistochemical studies (IHC) of palladin, α-smooth muscle actin (SMA), and podoplanin. Correlations between the expression levels of these markers and clinicopathological findings were analyzed statistically. Whole sections of surgical specimens from PDACs with and without preoperative CRT, designated as the chemotherapy-first group (CF, n = 19) and the surgery-first group (SF, n = 21), respectively, were also analyzed by IHC. In TMAs, the disease-specific survival rate (DSS) at 5 years for all 167 cases was 23.1%. Seventy cases (41.9%) were positive for palladin and had significantly lower DSS (p = 0.0430). α-SMA and podoplanin were positive in 167 cases (100%) and 131 cases (78.4%), respectively, and they were not significantly associated with DSS. On multivariable analysis, palladin expression was an independent poor prognostic factor (p = 0.0243, risk ratio 1.60). In the whole section study, palladin positivity was significantly lower (p = 0.0037) in the CF group (5/19) with a significantly better DSS (p = 0.0144) than in the SF group (16/22), suggesting that stromal palladin expression is a surrogate indicator of the treatment effect after chemoradiation therapy.

The host immune system plays a significant role in tumor control, although most cancers escape immune surveillance through a variety of mechanisms. The aim of the present study was to evaluate the clinicopathological significance of a novel co-inhibitory receptor, B and T lymphocyte attenuator (BTLA), the anergy cell marker Casitas-B-lineage lymphoma protein-b (Cbl-b), and clinical implications of tumor-infiltrating immune cells in gallbladder cancer (GBC) tissues. We investigated 211 cases of GBC, 21 cases of chronic cholecystitis (CC), and 11 cases of xanthogranulomatous cholecystitis (XGC) using immunohistochemistry to detect tissue-infiltrating immune cells and their expression of BTLA and Cbl-b, and carried out correlation and survival analyses. The density of infiltrating T cells was significantly higher in CC and XGC than in GBC. The density ratio of BTLA(+) cells to CD8(+) T cells (BTLA/CD8) and that of Cbl-b(+) cells to CD8(+) T cells (Cbl-b/CD8) were significantly higher in GBC than in CC and XGC. The FOXP3/CD4, BTLA/CD8, and Cbl-b/CD8 ratios were significantly correlated with each other, and also with malignant phenotypes. Survival analyses revealed that a lower density of tumor-infiltrating CD8(+) cells, and higher Foxp3/CD4, BTLA/CD8, and Cbl-b/CD8 ratios were significantly associated with shorter overall survival and disease-free survival in GBC patients. Multivariate analyses showed that M factor, perineural invasion, BTLA/CD8, and Cbl-b/CD8 were closely associated with shorter overall survival. These findings suggest that higher ratios of BTLA/CD8 and Cbl-b/CD8 are independent indicators of unfavorable outcome in GBC patients, and that upregulation of BTLA in cancer tissues is involved in inhibition of antitumor immunity., (© 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.)

Background: Cancer stem cells (CSCs) have been reported to play an important role in chemoradiation resistance. Although the association of CSC markers with clinicopathological outcomes after neoadjuvant chemoradiotherapy (NACRT) has been reported in various types of cancers, there have been no such reports for pancreatic cancer. Here we examined the sequential changes in CSC marker expressions after NACRT in patients with pancreatic adenocarcinoma (PA) and the impact of these changes on the prognosis., Methods: We used immunohistochemistry to evaluate the expressions of the CSC markers epithelial cell adhesion molecule (EpCAM), CD24, CD44, CD133, CXCR4 and Aldehyde dehydrogenase 1 (ALDH1) in resected specimens obtained from 28 PA patients, and we compared these expressions with the patients' clinicopathological parameters and survival data., Results: The expression frequencies of CD44 and ALDH1 were significantly higher in the NACRT group (n = 17) compared to the non-NACRT group (n = 11), but the CD133 expression was significantly lower in the NACRT group. In the NACRT group, the expression of CD133 was inversely correlated with that of ALDH1, and CD133+/ALDH1- expression was associated with an unfavorable patient outcome., Conclusion: This is the first report showing that NACRT may influence the expression frequencies of CD44, CD133 and ALDH1 in PA patients. Moreover, CD133 and ALDH1 expressions may be useful predictors of prognosis in PA patients who have received NACRT.

Alterations in the epidermal growth factor receptor (EGFR) gene are associated with carcinogenesis in non-small cell lung cancer. However, the intratumoral distribution of these abnormalities has not been elucidated. This study included patients with surgically resected lung adenocarcinoma. The predominant histological growth pattern was determined. Chromogenic in situ hybridization (CISH) and EGFR-mutation specific-antibodies were used for analysis of changes in gene copy number and EGFR mutations, respectively. EGFR mutation detected immunohistochemistry (IHC) and amplification were identified in 31 (53%) and 30 (52%) cases, respectively. The predominant growth patterns in the 58 tumors evaluated were papillary (28, 48%), lepidic (8, 14%), acinar (15, 26%), and solid (7, 12%). EGFR mutations were the least common in cases with a solid predominant pattern. The incidence of EGFR amplification did not differ among predominant patterns. Analyzing each histological subtype, no differences were noted between the prevalence of EGFR-IHC positive and CISH-positive rates. In the analysis of EGFR amplification, CISH-positive status was more prevalent in IHC-positive cases than in IHC-negative cases. All 19 cases that were both IHC and CISH positive were analyzed. In 17 cases (90%), the IHC-positive area was equal to or larger than the CISH-positive area. Among the histological subtypes of lung adenocarcinoma, the solid predominant subtype was distinguishable by its infrequent EGFR mutations. EGFR gene mutations preceded changes in oncogenic drive, more so than did EGFR gene number alterations during the developmental process of lung adenocarcinoma., (Copyright © 2013 Elsevier GmbH. All rights reserved.)

Background: Fluorine-18-fluorodeoxyglucose uptake on positron emission tomography is reported to have prognostic significance in patients after resection of lung adenocarcinoma. However, its relationship with histopathologic features remains unknown., Methods: We conducted a retrospective analysis of 205 patients who had undergone surgical resection of primary lung adenocarcinoma (> 1.0 cm) after preoperative fluorine-18-fluorodeoxyglucose-positron emission tomography between January 1999 and December 2008 at Hokkaido University Hospital. Fluorine-18-fluorodeoxyglucose uptake was measured by the maximum standardized uptake value. A histopathologic review was performed according to the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification, and various histopathologic factors were evaluated semi-quantitatively. Correlations between these clinicopathologic factors and the maximum standardized uptake value (high ≥ 2.0 vs low < 2.0) were analyzed., Results: Univariate analysis of clinicopathologic factors demonstrated that the following were significantly correlated with a high maximum standardized uptake value: an elevated carcinoembryonic antigen level, larger tumor size, upgraded pT, pN, pStage, non-lepidic histology, abundant fibroblastic/hyalinized stroma, necrosis, presence of pleural involvement, lymphatic and vascular invasion and more intra- and extracellular mucin. Multivariate analysis demonstrated that a tumor size of > 2.0 cm, non-lepidic histology and abundant fibroblastic/hyalinized stroma were significantly correlated with the high maximum standardized uptake value., Conclusion: More histopathologic factors are known to correlate with poor prognosis in lung adenocarcinomas showing high maximum standardized uptake values than in those showing low maximum standardized uptake values. Therefore, prognostication of patients with a resectable lung adenocarcinoma on the basis of preoperative fluorine-18-fluorodeoxyglucose uptake is histopathologically valid. Such observations may also help us to clarify the pathobiological mechanism responsible for the increased fluorine-18-fluorodeoxyglucose uptake in lung adenocarcinomas with a poor prognosis.

Previously, we used the reverse transcription-polymerase chain reaction (RT-PCR) to show that mammaglobin (MGB1) can serve as a differential marker of breast cancer metastasis from primary lung cancer. However, mRNA-based methods are not appropriate for use in clinical practices. In this study, we examined MGB1 protein expression in 480 tumors from various organs using immunohistochemical detection and a tissue microarray technique. Breast cancers expressing MGB1 were also analyzed clinicopathologically to determine whether these cancers constitute a characteristic subset. Immunohistochemically, MGB1 was expressed specifically in breast cancers. Of the other cancers examined, including 29 of the head and neck, eight of the thyroid, 106 of the lung, 35 of the gastrointestinal tract, three of the pancreas, 14 of the uterine cervix and 13 of the ovary, none were positive for MGB1 except a proportion of salivary gland tumors (6/11, 55%) and endometrial cancers (3/23, 13%). Among the 238 breast cancers, MGB1 was expressed in 114 (48%), most of which were classified histologically as invasive duct or lobular carcinomas. Clinicopathologically, MGB1 expression was associated with positive expression of estrogen receptors and negative expression of CK5, but not with pathological stage, HER2 gene amplification or p53 immunoreactivity. Kaplan-Meier analysis revealed prolonged disease-free survival in patients with MGB1-positive breast cancers (log rank test, P=0.016), but the Cox proportional hazard model failed to confirm that MGB1 was an independent prognostic factor (hazard ratio 1.77, P=0.1755). In terms of practical diagnosis, MGB1 immunohistochemistry can serve as a differential marker of breast cancer metastasis from primary lung cancer for two reasons. Firstly, HER2-positive breast cancer frequently lacks estrogen receptor expression, but MGB1 is expressed in about half of this subtype. Secondly, as primary lung adenocarcinomas may express estrogen receptors, MGB1 expression provides further discrimination of the origin of breast cancers.

Simple Summary: Pancreatic ductal adenocarcinoma is one of the most lethal malignancies, and there are vast unmet medical needs. In this study, we hypothesized that chimeric antigen receptor engineered T cell (CAR-T) targeting carcinoembryonic antigen (CEA) would be effective in the treatment of pancreatic ductal adenocarcinoma. In vivo experiments in a more clinically similar environment were considered necessary; we examined the antitumor effects of adoptive anti-CEA-CAR-T, using orthotopic xenograft mouse models of pancreatic ductal adenocarcinoma. As result, the therapeutic effect of anti-CEA-CAR-T therapy was related to the CEA expression level. Furthermore, the retrospective analysis of pathological findings from pancreatic ductal adenocarcinoma patients showed a correlation between the intensity of CEA immunostaining and tumor heterogeneity. These findings show that anti-CEA-CAR-T therapy can be useful for pancreatic ductal adenocarcinoma; furthermore, the pathological findings of CEA can be clinically used as biomarkers to select cases for anti-CEA-CAR-T therapy. Chimeric antigen receptor engineered T cell (CAR-T) therapy has high therapeutic efficacy against blood cancers, but it has not shown satisfactory results in solid tumors. Therefore, we examined the therapeutic effect of CAR-T therapy targeting carcinoembryonic antigen (CEA) in pancreatic adenocarcinoma (PDAC). CEA expression levels on the cell membranes of various PDAC cell lines were evaluated using flow cytometry and the cells were divided into high, medium, and low expression groups. The relationship between CEA expression level and the antitumor effect of anti-CEA-CAR-T was evaluated using a functional assay for various PDAC cell lines; a significant correlation was observed between CEA expression level and the antitumor effect. We created orthotopic PDAC xenograft mouse models and injected with anti-CEA-CAR-T; only the cell line with high CEA expression exhibited a significant therapeutic effect. Thus, the therapeutic effect of CAR-T therapy was related to the target antigen expression level, and the further retrospective analysis of pathological findings from PDAC patients showed a correlation between the intensity of CEA immunostaining and tumor heterogeneity. Therefore, CEA expression levels in biopsies or surgical specimens can be clinically used as biomarkers to select PDAC patients for anti-CAR-T therapy. [ABSTRACT FROM AUTHOR]