Solid Adenocarcinoma Research Articles

P3.02a-003 ALK and ROS1 Rearrangements, Coexistence and Treatment in EGFR-Wild Type Lung Adenocarcinoma - A Multicenter Study of 732 Cases: Topic: ALK

Anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) rearrangements represent two of the most frequency fusion targets in lung adenocarcinoma. The aim of this study was to investigate the clinicopathological characteristics, coexistence and treatment of ALK and ROS1- rearrangement patients in lung adenocarcinoma without EGFR mutations. Patients who harbored EGFR wild-type gene were screened for ALK and ROS1 gene in four Hospitals in China. ALK and ROS1 rearrangements were detected using RT-PCR. Progression free survival curves were plotted using the Kaplane-Meier method. Seven hundred and thirty-two patients enrolled in current study. Of the 732 patients, the median age was 59 years (range: 28–81). ALK and ROS1 rearrangements were detected in 89 (12.2%) and 32 (4.4%) patients, respectively. One patient was identified with ALK/ROS1 coexistence. Both of ALK and ROS1 positive were predominantly found in younger and non-smokers. More patients with ALK/ROS1 rearrangements were associated with TTF1 expression，napsin A expression and solid predominant adenocarcinoma subtype (Figure 1 ). ALK and ROS1 rearrangements frequency was enriched in EGFR wild-type patients and ALK/ROS1 coexistence was rare. The ALK and ROS1 arrangements were associated with age, smoking status, TTF1 expression, napsin A expression and solid predominant adnocarcinoma subtype.

P3.02c-064 Higher PD-L1 Expression Correlates with Solid and High Grade Lung Adenocarcinomas: Implications for Immunotherapy Selection: Topic: IT Biomarkers

Evidence of likely response to immunotherapy, including programmed death ligand-1 (PD-L1) expression, assumes more importance in selecting immunotherapy as a first line therapy over conventional therapy. However, PD-L1 expression is heterogeneous and known to be underestimated on small biopsies. Correlation of PD-L1 expression with clinicopathologic features may provide additional useful information in this setting. In phase II clinical trials (POPLAR study) survival benefit from atezolizumab correlated PD-L1 expression in either tumor cells or tumor-infiltrating immune cells assessed by immunohistochemistry with clone SP142 for patients with previously treated non-small cell lung carcinoma (NSCLC). To our knowledge the clinicopathologic features of NSCLC have not been reported for subsets defined by PD-L1 expression in either tumor cells or tumor-infiltrating immune cells. A total of 125 adenocarcinomas and 38 squamous cell carcinomas were included in the study. PD-L1 immunohistochemistry with the SP142 clone was performed on whole tissue sections and scored according to percent of PD-L1-positive tumor cells (TC0 for <1%, TC1 for 1-4%, TC2 for 5-49%, and TC3 for ≥50%) and percent tumor area with PD-L1-positive tumor-infiltrating immune cells (IC0 for <1%, IC1 for 1-4%, IC2 for 5-9%, IC3 for ≥10%). Adenocarcinoma cases which scored either TC1/2/3 or IC1/2/3 include the majority (22 of 34; 65%) with high histologic grade, a minority (15 of 46; 33%) with low histologic grade, the majority (25 of 36; 69%) with solid subtype, and a minority for most other subtypes. Compared to the adenocarcinoma TC0 and IC0 subset, the TC1/2/3 or IC1/2/3 subset correlated with higher histologic grade (p = .0051, χ2 test for trend) and solid subtype (p = .0006, Fisher’s exact test). Compared to the adenocarcinoma TC0/1 or IC0/1 subset, the TC2/3 or IC2/3 subset correlated with higher histologic grade (p = .0021, χ2 test for trend), solid subtype (p = .0001, Fisher’s exact test), and higher smoking pack-years (p = .012, Mann-Whitney test). No other clinicopathologic variable, including survival, correlated with subsets for either adenocarcinoma or squamous cell carcinoma. Lung adenocarcinoma subsets defined by PD-L1 expression in either tumor cells or tumor-immune cells correlated with high histologic grade, solid subtype, and high smoking pack-years. Our results suggest that high histologic grade and solid subtype may provide useful supplementary information for the decision to treat with atezolizumab, particularly for first line therapy, when PD-L1 mmunohistochemistry is negative on small biopsies or samples are insufficient for testing.

Lung Adenocarcinoma With MUC4 Expression Is Associated With Smoking Status, HER2 Protein Expression, and Poor Prognosis: Clinicopathologic Analysis of 338 Cases

BackgroundMUC4 is a transmembrane glycoprotein that plays a role in the cell growth signaling pathway and has been studied in various organ malignancies. This study aimed to analyze MUC4 expression in resected lung adenocarcinomas (ADCs) to define the clinicopathologic characteristics of MUC4-positive cancers. Patients and MethodsImmunohistochemical MUC4 analysis was performed using tissue microarray slides containing 338 lung ADCs. Associations between MUC4 expression and the following clinicopathologic parameters were evaluated: sex; age; smoking status; tumor stage; tumor grade; lymphovascular invasion; pleural invasion; TTF-1 and HNF4α expression; EGFR, KRAS, BRAF, and HER2 mutation status; and ALK and ROS1 fusion status. ResultsNinety-four tumors (27.8%) were MUC4 positive. Most patients with MUC4-positive tumors were male (P < .001) and smokers (P = .006). Moreover, MUC4 expression was significantly associated with solid ADCs (P < .001) and vascular invasion (P = .001). MUC4 expression inversely correlated with TTF-1 expression (P = .020) and EGFR mutations (P = .004). Interestingly, MUC4 expression correlated with HER2 protein expression (P = .042), although MUC4 expression did not correlate with HER2 DNA amplification or HER2 gene mutations. Patients with MUC4-positive tumors had significantly worse prognoses compared to patients with MUC4-negative tumors (P = .025). ConclusionThe present study showed that MUC4-positive lung ADCs correlated with male smokers, solid ADCs, negative TTF-1 expression, the EGFR wild-type gene, HER2 protein expression, and poorer prognoses. These results suggest that MUC4-positive lung ADC may be a distinct subtype found in patients with smoking-related poor outcomes, mediated by HER2 signaling pathway.

Clinicopathological significance of caveolin-1 expression by cancer-associated fibroblasts in lung adenocarcinoma.

Caveolin is an essential constituent of caveolae and has many biological functions. Expression of caveolin-1 in cancer cells was reported to be a prognostic marker in several types of cancers, the prognostic significance of its expression in cancer-associated fibroblasts (CAFs) has not been investigated. This study aimed to evaluate the clinicopathological significance of expression by CAFs in lung adenocarcinoma. We examined caveolin-1 expression in both CAFs and cancer cells in stage I invasive lung adenocarcinoma (n=412) and analyzed the relationship between the expression and clinicopathological factors. Caveolin-1 expression by CAFs and cancer cells was observed in 12.1% and 7.8% of adenocarcinomas, respectively. Tumors with caveolin-1-positive CAFs had vascular and pleural invasion significantly more frequently than those with caveolin-1-negative CAF (p<0.05). This was also the cases with tumors with caveolin-1-positive cancer cells (p<0.01). Caveolin-1 expression by CAFs and that by cancer cells were significant predictors of shorter recurrence-free survival (p<0.001). Caveolin-1 expression by CAFs and cancer cells was found in 25% and 30% of solid predominant subtype, respectively, but only 9.2% and 2.7% of non-solid predominant subtype, respectively. The frequency of cases with caveolin-1-positive CAFs or cancer cells was significantly higher in the solid predominant subtype than in non-solid predominant subtype (p<0.001). Our current results highlight the prognostic importance of caveolin-1 expression by CAFs in stage I lung adenocarcinoma and provide new insights into the biological significance of caveolin-1 in the tumor microenvironment, especially in microenvironment of solid predominant adenocarcinoma.

Predictive Value of Preoperative Serum Tumor Marker Levels for Pathological Characteristics of Resected Lung Adenocarcinoma

SESSION TITLE: Lung Cancer I SESSION TYPE: Original Investigation Poster PRESENTED ON: Wednesday, October 26, 2016 at 01:30 PM - 02:30 PM PURPOSE: The aim of this study was to investigate the association between preoperative serum tumor marker levels and pathological characteristics of resected lung adenocarcinoma. METHODS: We retrospectively reviewed patients with lung adenocarcinoma who had undergone macroscopic complete resection from 2013 to 2015. Patients with multiple lung cancer other than adenocarcinoma, previous treatment history of lung cancer, or active other malignancies were excluded. Preoperative serum tumor marker levels (CEA, SCC, SLX, CYFRA, ProGRP, and NSE) and preoperative clinical factors (age, sex, smoking index, and tumor size) were analyzed with univariate analysis (Fisher’s exact test or the chi-square test) and multivariate logistic regression analysis to identify predictors for the pathological involvement (positive pleural effusion or lavage cytology, pleural involvement, pulmonary metastasis, lymph node involvement, lymphovascular involvement, and/or upstaging) or the poor prognostic subtypes (solid or micropapillary predominant adenocarcinoma). For the significant factors, optimal cutoff points were determined with a receiver operating characteristic (ROC) analysis. RESULTS: Of a total of consecutive 183 patients, 100 were male and 83 were female, and the median age was 70 years. On pathologic diagnosis, 4 (2%) patients had positive pleural effusion or lavage cytology, 36 (20%) had pleural involvement, 6 (3%) had pulmonary metastasis, 20 (11%) had lymph node involvement, 39 (21%) had lymphovascular involvement, and 43 (23%) showed upstaging. In total, 72 patients (39%) had the pathological involvement. In the subtypes of adenocarcinoma, 17 (9%) patients had solid or micropapillary predominant adenocarcinoma, 129 (71%) had invasive adenocarcinoma other than these 2 subtypes, and 37 (20%) had AIS or MIA. Both univariate and multivariate analysis identified CEA and tumor size for the pathological involvement and smoking index and SLX for the poor prognostic subtypes as significant predictors. Of patients with CEA ≥5.3 ng/ml or SLX ≥34 U/ml which were determined by the ROC analysis, 33 of 57 (58%) and 9 of 39 (23%) patients had the pathological involvement or the poor prognostic subtypes, respectively. CONCLUSIONS: Preoperative higher CEA and SLX may predict pathological characteristics of lung adenocarcinoma, such as presence of pathological involvement and poor prognostic subtypes. CLINICAL IMPLICATIONS: Preoperative serum tumor marker levels should be considered for deciding surgical treatment strategy of lung adenocarcinoma. DISCLOSURE: The following authors have nothing to disclose: Terumoto Koike, Akihiko Kitahara, Seijiro Sato, Takehisa Hashimoto, Shin-ichi Toyabe, Masanori Tsuchida No Product/Research Disclosure Information

The ultrastructural features of the reaction of protein - synthesizing apparatus of follicular cells of the thyroid gland at distant interaction with the tumor.

Background. Long-standing observations among the patients with primary cancer of the thyroid gland show the high risk of primary cancer appearance in other organs. Simultaneously the high risk of the appearance of thyroid gland cancer is observed after the malignant non-thyroid neoplasms. Objective. The purpose of the present investigation was to study the condition and dynamics of changes in the protein-synthesizing apparatus of follicular cell of the thyroid gland during the process of distant interaction with the tumor in the experiment. Methods. As the experimental model of cancer we have used a model of the slightly differentiated solid adenocarcinoma of Guerin. Experiment was carried out on the male Wistar. Rats were divided into 2 groups. First group - control. To the second group - transplanted cells of Guerin's carcinoma by hypodermic injection beside the region of thighs. Results. After 2 weeks of transplanted tumor growth in follicular cells the increase in the free ribosome number is observed, they are localized in the apical and central part of cells. Granular endoplasmic reticulum is represented by cisterns with ribosomes unevenly distributed on their surface. The mutual parallel alignment of the membranes of endoplasmic reticulum is disrupted. These changes could evidence the violations of the direct way of protein synthesis and activation of the intracellular system of thyrocyte restitution. Conclusion. Distant interaction is manifested on the early stage of tumor progression based on changes in the relationship between the free and connected ribosomes in cell cytoplasm with the subsequent development of diffuse changes of the granular endoplasmic reticulum and the disturbance of the synthetic, transport and secretory functions of the cell.

Visceral Pleural Invasion Is a Significant Prognostic Factor in Patients with Partly Solid Lung Adenocarcinoma Sized 30 mm or Smaller

This study analyzed the impact of visceral pleural invasion (VPI) on the disease-free survival (DFS) of patients with partly solid pulmonary adenocarcinoma sized 30 mm or smaller. This is a retrospective study of 147 patients with surgically resected pathologic N0 pulmonary adenocarcinoma that had a partly solid appearance on preoperative computed tomography. All patients presented with tumors of size 30 mm or smaller. The DFS rate was estimated using Kaplan-Meier method. A multivariate analysis for prognostic factors was performed using the Cox proportional hazards regression model. VPI was found in 36 patients. The 5-year DFS in 111 patients without VPI (97.6%) was significantly higher than that in 36 patients with VPI (63%) (p < 0.0001). Univariate analysis revealed three significant poor prognostic predictors: the presence of VPI, the presence of lymphovascular invasion, and the size of the solid component on computed tomography (>20, ≤30 mm). According to the multivariate analysis, VPI was found to be a significant poor prognostic predictor (hazard ratio for DFS = 7.31, 95% confidence interval = 1.444-37.014, p = 0.016). VPI is a significant predictor of poor prognosis for small-sized (≤30 mm) partly solid lung adenocarcinoma. Therefore, upstaging of the T factor from T1 to T2 on the basis of VPI as described by the TNM staging system is mandatory regardless of ground-glass opacity in small lung adenocarcinoma.

Mucin-1 correlates with survival, smoking status, and growth patterns in lung adenocarcinoma.

Mucin-1 (MUC1) affects cancer progression in lung adenocarcinoma, and its aberrant expression pattern has been correlated with poor tumor differentiation and impaired prognosis. In this study, the immunohistochemical expression of MUC1 and Mucin-4 (MUC4) was analyzed in a series of 106 surgically operated stage I-IV pulmonary adenocarcinomas. MUC1 immunohistochemistry was evaluated according to the Nagai classification, and the immunohistochemical profile of the tumors was correlated with detailed clinical and histological data. The effect of cigarette smoke on MUC1 expression in lung cancer cell lines was examined using real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) and immunoelectron microscopy (IEM). In contrast to the normal apical localization of MUC1, a basolateral and cytoplasmic (depolarized) MUC1 expression pattern was frequently encountered in the high-grade subtypes, i.e., solid predominant adenocarcinoma and the cribriform variant of acinar predominant adenocarcinoma (p<0.001), and was rarely observed in tumors containing a non-predominant lepidic component (p<0.001). Furthermore, the altered staining pattern of MUC1 correlated with stage (p=0.002), reduced overall survival (p=0.031), and was associated with smoking (p<0.001). When H1650 adenocarcinoma cells were exposed to cigarette smoke and analyzed by RT-qPCR and IEM, the levels of the MUC1 transcript and protein were elevated (p=0.042). In conclusion, MUC1 participates in the pathogenesis of lung adenocarcinoma and associates with smoking both in vitro and in vivo. In lung adenocarcinoma, depolarized MUC1 protein expression correlated with histological growth patterns, stage, and patient outcome.

Prognostic Role of Subtype Classification in Small-Sized Pathologic N0 Invasive Lung Adenocarcinoma

The prognosis of patients with small, node-negative lung cancers, which the current indication for adjuvant chemotherapy never includes, is sometimes poor despite complete tumor resection. The present study aimed to identify independent prognostic factors and to clarify possible candidates for adjuvant chemotherapy among patients with small, node-negative invasive adenocarcinoma. This study involved 153 patients with completely resected small (≤20 mm) pathologic N0 invasive adenocarcinomas. Invasive adenocarcinoma was classified as lepidic predominant (LPA), papillary or acinar predominant (PA), or solid or micropapillary predominant (SM), according to the International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society classification. Overall survival and recurrence-free survival were estimated from Kaplan-Meier curves. Prognostic factors for recurrence-free survival were determined using univariate and multivariate Cox proportional hazards models. Three-year overall survival and recurrence-free survival rates were 98% and 98%, 97% and 88%, and 85% and 64% for LPA, PA, and SM tumors, respectively. Prognosis was the worst for patients with SM tumors (overall survival LPA versus PA, p= 0.099; LPA versus SM, p < 0.001; and PA versus SM, p= 0.032; recurrence-free survival LPA versus PA, p= 0.014; LPA versus SM, p < 0.001; and PA versus SM, p < 0.001). Subtype was a significantly independent prognostic factor for recurrence-free survival in multivariate analysis (SM versus LPA hazard ratio 22, 95% confidence interval: 2.5 to 190, p= 0.0054). Patients with small (≤20 mm) pathologic N0 solid or micropapillary predominant invasive adenocarcinoma might be possible candidates for adjuvant chemotherapy.

Large-cell lung carcinoma by the 2015 WHO classification: a clinicopathologic analysis of 93 cases

To analyze the clinicopathologic characteristics of large-cell lung carcinoma (LCC) subtypes according to the 2015 WHO classification. A total of 93 cases of LCC were identified among 1 634 cases of morphologically undifferentiated non-small cell lung carcinoma. Clinicopathologic and immunohistochemical characteristics were retrospectively reviewed. Among 93 cases of LCC, 50 cases were solid adenocarcinoma (53.8%), 21 cases were non-keratinzing squamous cell carcinoma (22.6%), 3 cases were adenosquamous carcinoma (3.2%), 8 cases were large cell carcinoma with unclear immunohistochemical features (8.6%), and 11 cases were large cell carcinoma with null immunohistochemical features (11.8%). No significant differences in clinical features were found among various immunophenotypes. The overall survival of 1, 3 and 5 years of all cases was 51.0%, 5.4% and 1.1%, respectively and the mean survival was (15.2±1.2)months. Notably the null type had the lowest survival rate of 18% in one year, significantly worse than those of solid adenocarcinoma and non-keratinzing squamous cell carcinoma. The 2015 WHO classification based on immunohistochemical phenotype replaces the morphological approach in separating poorly differentiated non-small cell lung carcinoma from the former large cell lung carcinoma. The null immunohistochemical subtype may represent a distinct subtype of undifferentiated carcinoma with the worst prognosis.

The WHO 2015 classification of lung tumours: Evolution of tumour classification in lung cancer

There are many important changes in the 2015 WHO classification of lung tumours, reflecting the numerous advances in tumour genetics and therapy over the past decade.1 A classification system for small biopsies and cytology is provided for the first time, with emphasis on integration of molecular testing and usage of a limited panel of immunohistochemistry when needed. Adenocarcinoma classification has changed significantly with definitions for adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA), and discontinuation of the term bronchioloalveolar carcinoma. Invasive adenocarcinomas are classified according to the predominant pattern, shown to have prognostic significance and also to predict response to adjuvant chemotherapy. These changes will also likely impact on the next TNM staging system in terms of multiple primary tumours and measurement of tumour invasive size. Large cell carcinoma is now restricted to resected tumours that lack clear morphological and immunohistochemical differentiation, with reclassification of those that do to solid adenocarcinoma and non-keratinising squamous cell carcinoma. Squamous cell carcinoma classification is simplified to keratinising, non-keratinising and basaloid subtypes, with the non-keratinising tumours ideally requiring immunohistochemical confirmation. Criteria for diagnosing neuroendocrine tumours remain essentially unchanged but these tumours are now grouped in one category. There are many important changes in the 2015 WHO classification of lung tumours, reflecting the numerous advances in tumour genetics and therapy over the past decade.1 A classification system for small biopsies and cytology is provided for the first time, with emphasis on integration of molecular testing and usage of a limited panel of immunohistochemistry when needed. Adenocarcinoma classification has changed significantly with definitions for adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA), and discontinuation of the term bronchioloalveolar carcinoma. Invasive adenocarcinomas are classified according to the predominant pattern, shown to have prognostic significance and also to predict response to adjuvant chemotherapy. These changes will also likely impact on the next TNM staging system in terms of multiple primary tumours and measurement of tumour invasive size. Large cell carcinoma is now restricted to resected tumours that lack clear morphological and immunohistochemical differentiation, with reclassification of those that do to solid adenocarcinoma and non-keratinising squamous cell carcinoma. Squamous cell carcinoma classification is simplified to keratinising, non-keratinising and basaloid subtypes, with the non-keratinising tumours ideally requiring immunohistochemical confirmation. Criteria for diagnosing neuroendocrine tumours remain essentially unchanged but these tumours are now grouped in one category.

Relationship of epidermal growth factor receptor activating mutations with histologic subtyping according to International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society 2011 adenocarcinoma classification and their impact on overall survival.

Background:There is limited Indian data on epidermal growth factor receptor (EGFR) gene activating mutations (AMs) prevalence and their clinicopathologic associations. The current study aimed to assess the relationship between EGFR AM and histologic subtypes and their impact on overall survival (OS) in a North Indian cohort.Patients and Methods:Retrospective analysis of nonsmall cell lung cancer patients who underwent EGFR mutation testing (n = 186) over 3 years period (2012–2014). EGFR mutations were tested using polymerase chain reaction amplification and direct sequencing. Patients were classified as EGFR AM, EGFR wild type (WT) or EGFR unknown (UKN). Histologically adenocarcinomas (ADC) were further categorized as per the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society-2011 classification.Results:Overall EGFR AM prevalence was 16.6%. The ratio of exon 19 deletions to exon 21 L858R mutations was 3.17:1. Female sex (P = 0.002), never smoking status (P = 0.002), metastatic disease (P = 0.032), and nonsolid subtype of ADC (P = 0.001) were associated with EGFR AM on univariate logistic regression analysis (LRA). On multivariate LRA, solid ADC was negatively associated with EGFR AM. Median OS was higher in patients with EGFR AM (750 days) as compared to EGFR-WT (459 days) or EGFR-UKN (291 days) for the overall population and in patients with Stage IV disease (750 days vs. 278 days for EGFR-WT, P = 0.024). On univariate Cox proportional hazard (CPH) analysis, smoking, poor performance status (Eastern Cooperative Oncology Group ≥ 2), EGFR-UKN status, and solid ADC were associated with worse OS while female sex and lepidic ADC had better OS. On multivariate CPH analysis, lepidic ADC (hazard ratio [HR] =0.12) and EGFR-WT/EGFR-UKN (HR = 2.39 and HR = 3.30 respectively) were independently associated with OS in separate analyses.Conclusions:Histologic subtyping of ADC performed on small biopsies is independently associated with EGFR AM and with better OS. EGFR AM presence is a positive prognostic factor for OS.

β-Tubulin-III Is an Immunohistochemical Marker for the Early Invasive Foci of Nonmucinous Lung Adenocarcinoma

Objective: The present study is to investigate the expression of CD34, β-Tubulin-III and Collagen IV-Laminin in adenocarcinoma in situ (AIS), the AIS component of minimally invasive adenocarcinoma (MIA), and early invasive foci, in order to find a valuable immunohistochemical marker for discriminating AIS and its early invasive foci. Methods: A total of 51 AIS patients and 88 MIA patients were included in the present study. In addition, 40 atypical adenomatous hyperplasia (AAH) patients and 54 invasive adenocarcinoma (IA) patients were included as control. Immunohisto-chemical staining of β-Tubulin-III, CD34, CD31, F8 and Collagen IV-Laminin was performed by serial sectioning. β-Tubulin-III was used to show invasive adenocarcinoma foci, CD34 was used to indicate interstitial cells in AIS, CD31 and F8 were used to identify capillary endothelial cells in tumor tissues, and Collagen IV-Laminin was used to visualize the basement membrane component of AIS. Results: The basement membranes and interstitial cells of AAH, AIS and the AIS component of MIA had positive expression of CD34, while mucinous AIS and various invasive adenocarcinomas had no CD34-positive basement membranes or interstitial cells. Invasive cancers such as alveolar adenocarcinoma, papillary adenocarcinoma, micropapillary adenocarcinoma and solid adenocarcinoma had strong positive expression of β-Tubulin-III, while AAH, AIS and the AIS component of MIA, and invasive mucinous adenocarcinoma had negative expression of β-Tubulin-III. AAH, AIS and the AIS component of MIA were surrounded by basement membranes with positive expression of Collagen IV-Laminin, AIS and the AIS component of MIA had significantly thickened basement membranes, and none of invasive adenocarcinomas was surrounded by basement membranes. Conclusions: The present study demonstrates that immunohistochemical staining of CD34, β-Tubulin-III, and Collagen IV-Laminin discriminates AIS component of lung adenocarcinoma from early invasive foci, with the efficacy of β-Tubulin-III being the best. Staining of β-Tubulin-III precisely identifies the early invasive foci of MIA, and can be used as a marker for the identification of the early invasive foci of nonmucinous lung adenocarcinoma.

Antitumor effect of the curaxin CBL0137 on the models of colon cancer

Curaxins represent low molecular weight carbazole derivatives, which simultaneously activate p53-dependent apoptosis and inhibit NF-kBdependent signal transduction pathways. Antitumor activity of curaxin CBL0137 was demonstrated in vivo on the model of solid transplantable mouse colon adenocarcinoma Akatol. Significant tumor growth inhibition caused by CBL0137 treatment was observed. On the 37th day after tumor transplantation for CBL0137 oral doses 5, 10, 15 and 20 mg/kg the tumor growth inhibition indexes were 53, 50, 56 and 74 %, respectively. CBL0137 treatment extended life span of mice in all study groups receiving this test article. Maximum lifespan increase (81,7 %) was observed in the group of mice treated with 20 mg/kg dose of CBL0137. The cytotoxicity of CBL0137 was assessed on human colon cancer cells in vitro. We demonstrated that CBL0137 inhibits the expression COX2, which in its turn is known to exhibit antiapoptotic, pro-angiogenic and pro- metastatic properties. Thus, we demonstrated antitumor effect of CBL0137 against colon cancer in vitro and in vivo.

Detection of ALK translocation in non-small cell lung carcinoma (NSCLC) and its clinicopathological significance using the Ventana immunohistochemical staining method: a single-center large-scale investigation of 1, 504 Chinese Han patients.

ObjectiveThe novel fully automated immunohistochemistry (IHC) assay-Ventana anaplastic lymphoma kinase (ALK)-D5F3 for screening ALK rearrangements has been approved by China’s Food and Drug Administration in 2013, our previous study disclosed a highly specificity and sensitivity nearly 100%, and its efficacy needs to be evaluated in a large cohort of primary lung adenocarcinoma patients, and to compare clinicopathological features with ALK (+) and ALK (-) lung adenocarcinoma.MethodsA total of 1,504 consecutive surgical lung adenocarcinoma cases of Chinese Han population were collected and re-diagnosed according to the 2011 multidisciplinary classification of lung adenocarcinoma. Fully automated Ventana ALK-D5F3 IHC staining with a binary scoring was adopted to evaluate staining and correlated with clinicopathological characters, including age, sex, differentiation degree, histological subtype, lymph node metastasis, and clinical staging. ALK (+) patients were followed-up, and targeted therapy of ALK-inhibitors was adopted and observed in patients with stage IV according to the NCCN guideline. ResultsALK positive adenocarcinomas were identified in 6.6% of the surgically resected 1,504 NSCLCs, and significantly younger than the negative group (P<0.05).Mucinous adenocarcinoma (28.2%) was determined to be predominant in ALK (+) cases, followed by the solid type (11.7%), specific type (6.8%), papillary type (5.6%), acinar type (5.5%), and lepidic type (3.1%), and the differences were statistically significant (χ2=42.011, P<0.05). ALK (+) adenocarcinoma with lymph node metastasis (10.8%) were significantly higher than that without lymph node metastasis (4.5%) (χ2=19.809, P<0.05); and ALK (+) in phase IV (20%) was significantly higher than phase III (12.9%), phase II (4.2%), phase I (4.5%), and phase 0 (0) (χ2=36.068, P<0.05). Multivariate logistic regression disclosed that patient age, AJCC staging, and histological mucinous subtype were correlated with ALK positive staining (OR=0.959, 1.578, 5.036, respectively). Sixty eight patients had followed-up results, five patients out of which primarily diagnosed or progressed into Stage IV benefited well from targeted therapy with Crizotinib. ConclusionsThe ALK fusion protein was seen in 6.6% Chinese NSCLC patients, and mostly seen in younger, clinically higher staging, mucinous and solid predominant adenocarcinoma. Clinical trials in patients of Stage IV confirmed that ALK-D5F3 Ventana IHC is serviceable in screening ALK-positive candidates for molecular targeted therapy.

MicroRNA Expression Profile on Solid Subtype of Invasive Lung Adenocarcinoma Reveals a Panel of Four miRNAs to Be Associated with Poor Prognosis in Chinese Patients.

According to the reclassification of lung adenocarcinoma (LAC) proposed in 2011, solid predominant lung adenocarcinoma (SPA) has been associated with poor outcomes for LAC patients. However, the prognostic value of the presence of solid subtype remains unclear. Besides, there is little data about the roles of microRNA (miRNA) in solid subtype of LAC. In this study, 243 LAC patients were classified into solid subtype positive and negative groups (S+ LAC, n=134 and S- LAC, n=109) according to whether the solid subtype was more than 5% of the tumor component or not. We analyzed the relationship between solid subtype and patients' outcome by univariate and multivariate analyses. Solid subtype was proved to be significantly associated with the 5-year overall survival and played as an independent prognostic factor for stage I-III invasive LAC patients. Then miRNA microarray was used to identify differentially expressed miRNAs in solid subtype, resulting in 31 differential miRNAs. Quantitative reverse transcription-PCR (QRT-PCR) was used to validate 4 key miRNAs (miR-133b, miR-155-5p, miR-124-3p, miR-145-5p). Further, CCK-8 and transwell assays were performed to validate the impact of one dysregulated miRNA (miR-133b) on LAC cell function. Interestingly, while miR-133b could significantly inhibit the proliferation of A549 and SPC-A1, it showed no effect on the migration or invasion of LAC cell lines. These results suggest that solid subtype can exert independent prognostic impact on LAC patients, and 4 important dysregulated miRNAs in solid subtype of LAC may be involved in the malignancy of S+LAC, thus may further have clinical perspective for S+ LAC in the future.

Clinicopathological features and relation between anaplastic lymphoma kinase (ALK) mutation and histological subtype of lung adenocarcinoma in Eastern European Caucasian population.

Introduction: The incidence of echinoderm microtubule-associated protein-like4-anaplastic lymphoma kinase (EML4-ALK) mutation among surgically treated patients with adenocarcinoma of the lung of the Eastern European ethnicity is underreported. The aim of this trial was the determination of EML4-ALK mutation frequency in investigated population, and the evaluation of correlations between lung adenocarcinoma subtype and clinical characteristics with mutation status.Patients and methods: This was a prospective trial which included 195 patients with adenocarcinoma of the lung who underwent surgical treatment. ALK mutation screening was performed by immunohistochemistry (IHC). IHC scores of 2+ and 3+ were regarded as positive. Confirmatory FISH was performed in all IHC positive and in 2:1 ratio in negative patients.Results: Overall ALK mutation rate established by IHC was 6.2%, while FISH confirmed rate of 5.1%. The FISH confirmed ALK positivity in 7.6% Hungarians, 5.5% Serbians, and 6.6% Slovakians. Acinar subtype of adenocarcinoma of the lung was significantly (p=0.02) related to EML4-ALK positive mutation status. Most of the patients were males (56.9%), smokers (50.8%), or former smokers (28.7%) with acinar (55.4%) or solid (35.9%) adenocarcinoma of the lung. Sensitivity and specificity of IHC were 100% and 98.9% respectively.Conclusions: ALK mutation rate in surgically treated patients with adenocarcinoma of the lung was found to be 6.2% by IHC and 5.1% by FISH. Acinar subtype of the adenocarcinoma of the lung was significantly related to ALK positive mutation.

長期生存したhuman immunodeficiency virus感染症を合併した肺原発充実型腺癌の1例

長期生存したhuman immunodeficiency virus感染症を合併した肺原発充実型腺癌の1例

Solid adenocarcinoma of the bile duct: a report of three patients

Solid adenocarcinoma of the bile duct: a report of three patients

Associations between serum carcinoembryonic antigen levels and adenocarcinoma subtypes of the lung

Abstract Background Increased serum carcinoembryonic antigen (CEA) levels have been associated with a poor outcome in lung cancer. The aim of this study was to further clarify the associations between CEA levels and adenocarcinoma subtypes. Patients and methods We retrospectively assessed preoperative serum CEA levels and clinicopathological factors in 307 consecutive patients who underwent resection for primary lung adenocarcinoma with curative intent. Results Subtypes included adenocarcinoma in situ (AIS) in 20 cases, minimally invasive adenocarcinoma (MIA) in 20, invasive mucinous adenocarcinoma (IMA) in three, lepidic predominant adenocarcinoma ( LPA ) in 41, papillary predominant adenocarcinoma (PPA) in 106, acinar predominant adenocarcinoma (APA) in 90, solid predominant adenocarcinoma (SPA) in 23, and micropapillary predominant adenocarcinoma (MPA) in four. Serum CEA levels varied according to gender, age, smoking status, clinical stage, lymph node metastasis, pathological stage, and adenocarcinoma subtype. Serum CEA levels were higher in the APA, MPA, IMA, and SA subtypes than in the AIS, MIA, PPA, and LPA subtypes. Multiple regression analysis revealed that the clinical stage and adenocarcinoma subtype were significantly associated with serum CEA levels. Univariate analysis demonstrated that preoperative CEA levels were significantly associated with both the postoperative disease-free survival (DFS) and overall survival. Cox regression analysis revealed that the clinical stage and adenocarcinoma subtype were significantly associated with the postoperative DFS. Conclusion The serum CEA level was elevated in advanced disease stages and certain adenocarcinoma subtypes, suggesting the usefulness of CEA as a marker reflecting the malignant behavior of lung adenocarcinomas.