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Background: Pathological response is an important marker for tumor aggressiveness in patients with esophageal squamous cell carcinoma (ESCC) who receive preoperative chemoradiation followed by esophagectomy. We aim to evaluate the prognostic value of histological factors after trimodality treatments.Methods: 91 patients who received preoperative chemoradiation followed by transthoracic esophagectomy between 2009 and 2014 were included. The pathological examination was reviewed. Overall survival and disease free survival were recorded. Survival analysis was performed using the Cox regression model, and the survival curves were compared by the log-rank test.Results: Survival analysis showed lymphovascular invasion (LVI, hazard ratio [HR]: 2.009, p = 0.029), perineural invasion (PNI, HR: 2.226, p = 0.019), ypN stage (HR: 2.041, p = 0.019), extracapsular invasion (ECI, HR: 2.804, p = 0.003), and incomplete resection (HR: 1.897, p = 0.039) as unfavorable prognostic factors affecting overall survival (OS). Moreover, tumor regression grade (TRG, HR: 1.834, p = 0.038), LVI (HR: 1.975, p = 0.038), ECI (HR: 2.836, p = 0.003), and incomplete resection (HR: 2.254, p = 0.007) adversely affected disease-free survival (DFS). Prognostic classification based on poor primary tumor (TRG2/3, LVI(+), and PNI (+)), lymph node (ypN(+) and ECI(+)), and surgical (incomplete resection) factors significantly predicts OS (p = 0.013) and DFS (p = 0.017). However, the use of postoperative adjuvant therapy was not a significant prognostic factor even in medium- and high-risk ESCC patients who underwent trimodality treatments.Conclusions: Histological factors, including primary tumor, lymph node, and surgical factors has high prognostic value for predicting outcomes in ESCC patients receiving preoperative chemoradiation followed by surgery. [ABSTRACT FROM AUTHOR]

OBJECTIVES: The aim of the study is to demonstrate the relationship between clinicopathological variables and occult lymph node metastasis in resected lung adenocarcinoma. METHODS: The clinicopathological characteristics of 471 patients with clinical N2-negative status undergoing resection for lung adenocarcinoma of 3 cm or smaller at Taipei Veterans General Hospital between 2004 and 2012 were retrospectively reviewed. The association between clinicopathological variables and lymph node metastasis was analysed by univariate and multivariate logistic regression. RESULTS: Among the 471 patients, there were 386 (82.0%) patients with pathological N0 status, 35 (7.4%) with pathological N1 status and 50 (10.6%) with pathological N2 status. Greater tumour size (P = 0.002), presence of a micropapillary pattern (P < 0.001), presence of a solid pattern (P < 0.001) and predominant pattern group (micropapillary/solid predominant) (P = 0.001) were significantly associated with higher percentage of occult N2 lymph node metastasis. In multivariate analysis, greater tumour size (P = 0.008), presence of micropapillary pattern (P < 0.001) and presence of solid pattern (P = 0.001) were significant predictors of occult N2 lymph node metastasis in tumours of 3 cm or smaller. When histological pattern was entered as the predominant pattern in multivariate analysis, micropapillary/solid predominant pattern (P = 0.005) was also a significant predictor of occult N2 lymph node metastasis. CONCLUSIONS: The presence of micropapillary or solid pattern, as well as micropapillary/solid predominant pattern, is significantly associated with occult N2 lymph node metastasis in lung adenocarcinoma. Radical mediastinal lymph node dissection may help to identify occult lymph node metastasis in these patients. [ABSTRACT FROM AUTHOR]

Background: Few studies have investigated prognostic biomarkers of distant metastases of lung cancer. One of the central difficulties in identifying biomarkers from microarray data is the availability of only a small number of samples, which results overtraining. Recently obtained evidence reveals that epithelial-mesenchymal transition (EMT) of tumor cells causes metastasis, which is detrimental to patients' survival. Results: This work proposes a novel optimization approach to discovering EMT-related prognostic biomarkers to predict the distant metastasis of lung cancer using both microarray and survival data. This weighted objective function maximizes both the accuracy of prediction of distant metastasis and the area between the disease-free survival curves of the non-distant and distant metastases. Seventy-eight patients with lung cancer and a follow-up time of 120 months are used to identify a set of gene markers and an independent cohort of 26 patients is used to evaluate the identified biomarkers. The medical records of the 78 patients show a significant difference between the disease-free survival times of the 37 non-distant- and the 41 distant-metastasis patients. The experimental results thus obtained are as follows. 1) The use of disease-free survival curves can compensate for the shortcoming of insufficient samples and greatly increase the test accuracy by 11.10%; and 2) the support vector machine with a set of 17 transcripts, such as CCL16 and CDKN2AIP, can yield a leave-one-out cross-validation accuracy of 93.59%, a test accuracy of 76.92%, a large disease-free survival area of 74.81%, and a mean survival prediction error of 3.99 months. The identified putative biomarkers are examined using related studies and signaling pathways to reveal the potential effectiveness of the biomarkers in prospective confirmatory studies. Conclusions: The proposed new optimization approach to identifying prognostic biomarkers by combining multiple sources of data (microarray and survival) can facilitate the accurate selection of biomarkers that are most relevant to the disease while solving the problem of insufficient samples. [ABSTRACT FROM AUTHOR]

Background: Few studies have investigated prognostic biomarkers of distant metastases of lung cancer. One of the central difficulties in identifying biomarkers from microarray data is the availability of only a small number of samples, which results overtraining. Recently obtained evidence reveals that epithelial-mesenchymal transition (EMT) of tumor cells causes metastasis, which is detrimental to patients' survival. Results: This work proposes a novel optimization approach to discovering EMT-related prognostic biomarkers to predict the distant metastasis of lung cancer using both microarray and survival data. This weighted objective function maximizes both the accuracy of prediction of distant metastasis and the area between the disease-free survival curves of the non-distant and distant metastases. Seventy-eight patients with lung cancer and a follow-up time of 120 months are used to identify a set of gene markers and an independent cohort of 26 patients is used to evaluate the identified biomarkers. The medical records of the 78 patients show a significant difference between the disease-free survival times of the 37 non-distant- and the 41 distant-metastasis patients. The experimental results thus obtained are as follows. 1) The use of disease-free survival curves can compensate for the shortcoming of insufficient samples and greatly increase the test accuracy by 11.10%; and 2) the support vector machine with a set of 17 transcripts, such as CCL16 and CDKN2AIP, can yield a leave-one-out cross-validation accuracy of 93.59%, a test accuracy of 76.92%, a large disease-free survival area of 74.81%, and a mean survival prediction error of 3.99 months. The identified putative biomarkers are examined using related studies and signaling pathways to reveal the potential effectiveness of the biomarkers in prospective confirmatory studies. Conclusions: The proposed new optimization approach to identifying prognostic biomarkers by combining multiple sources of data (microarray and survival) can facilitate the accurate selection of biomarkers that are most relevant to the disease while solving the problem of insufficient samples. [ABSTRACT FROM AUTHOR]

Background Thoracoscopic lobectomy is a safe and effective procedure; however, the ways by which to incorporate this technically demanding procedure into residency training is still unknown. We reported on the outcomes of thoracoscopic lobectomies performed by a single thoracic resident, who was simultaneously undergoing training for both open and thoracoscopic lobectomies. Patients and Methods Between January 2010, and May 2011, data from 87 consecutive thoracoscopic lobectomies that were performed by a trainee surgeon (B.-Y.W.) were prospectively obtained. Data were grouped into the first 30 and subsequent 57 cases. Patient characteristics, operative data, complications, and surgical pathology were analyzed. Results The mean operating time in group 2 was significantly lower compared with group 1 (264.0 ± 45.9 min in group 1 vs. 197.5 ± 57.7 min in group 2; p < 0.001). There were no mortalities in both the groups and no significant differences in postoperative complications. Conclusions Thoracoscopic lobectomy can be taught to a nonexperienced thoracic resident during an open procedure without compromising the safety of patients. It appears that surgical performance reaches a plateau after the completion of 30 cases. [ABSTRACT FROM AUTHOR]

Background and Aim It is of importance to search for prognostic indicators supplementing the tumour-node- metastasis stage for surgically resected early-stage lung adenocarcinomas. The roles of stromal invasion and micropapillary pattern in categorising histopathology and predicting the prognosis of stage I lung adenocarcinomas are explored. Methods We retrospectively examined 212 consecutive surgically resected stage I lung adenocarcinomas to propose a new histopathology-based categorical classification. Category A tumours have pure lepidic growth pattern without stromal invasion (ie, adenocarcinoma in situ). Stromal invasion in the form of central fibrotic focus is absent in category B tumours and present in category C tumours. Category B is subclassified into B1, which has areas of lepidic growth, and B2, which does not. Category C is subclassified into C1, which has invasive tumour cells in the periphery of central fibrotic focus, and C2, which has invasive tumour cells in the centre of central fibrotic focus. Based on the absence or presence of micropapillary pattern, the C2 tumours are further subclassified into C2a and C2b, respectively. Results The 5-year recurrence-free probabilities for categories B1 (17 cases), B2 (10 cases), C1 (nine cases), C2a (114 cases) and C2b (62 cases) are 100%, 78.8%, 100%, 67.5% and 53.1%, respectively (p<0.001). Conclusions Based on stromal invasion and micropapillary pattern, the histopathological categorical classification proposed here provides a concise and precise scheme for outcome prediction in early-stage lung adenocarcinomas. [ABSTRACT FROM AUTHOR]

The article highlights a study which investigated prognostic factors and recurrence of completely resected node-negative non-small cell lung cancer (NSCLC) with visceral pleural invasion (VPI). Results of the study revealed that patients with invasion to the visceral pleural surface (PL2) have worse survival, in comparison to patients with invasion beyond the elastic layer (PL1). PL2 was found to be a significant prognostic factor for recurrence of NSCLC with VPI.

Background: We aimed to study whether positron emission tomography/computed tomography (PET/CT) findings are associated with lymph node staging, as outlined by the 7th edition American Joint Committee on Cancer (AJCC) TNM staging system in patients with esophageal squamous cell carcinoma (ESCC). Methods: A series of 76 ESCC patients undergoing esophagectomy were included in this study. The relation between PET/CT findings [maximum standardized uptake value (SUVmax)] and pathologic lymph node status (N stage) was studied. Results: The SUVmax of extra-tumor uptake, but not that of the main tumor, was significantly associated with the N classification. N2/N3 disease was observed in 61.1% of patients with an SUVmax for extra-tumor uptake of >4.9, whereas only 17.2% of patients with an SUVmax of extra-tumor uptake of <4.9 were classified as N2/N3 The number of PET abnormalities (NPAs) was also significantly associated with the N classification. Patients with three or more NPAs had a 65% chance of being classified as N2/N3, whereas patients with one or two NPAs had less than a 20% chance of being classified as N2/N3. Conclusions: The SUVmax of extra-tumor uptake and the NPAs were significantly associated with the N classification outlined by the 7th edition of the AJCC TNM staging system. PET/CT does help identify patients with advanced lymph node metastasis (N2/N3 stage) instead of simply indicating nodal involvement. [ABSTRACT FROM AUTHOR]

The p53 tumor suppressor exerts its function mainly as a transcriptional activator. Here we show that the Ras-related small GTPase Rad, an inhibitor of Rho kinase, is a direct transcriptional target of p53. Expression of Rad messenger RNA (mRNA) and protein was induced by DNA damage in a p53-dependent manner. The −2934/−2905-bp Rad promoter region, to which p53 bound, was required for p53-mediated Rad gene activation. Treatment by DNA damaging agents increased p53 occupancy and histone acetylation in the region of Rad promoter containing the p53-binding site. Expression of Rad diminished the inhibitory phosphorylation at Ser3 of cofilin, a regulator of actin dynamics, and suppressed migration and invasiveness of cancer cells. Knockdown of Rad promoted cell migration and alleviated the p53-mediated migration suppression. Frequent loss of Rad mRNA and protein expression was observed in non-small cell lung carcinoma tissues. Together our results reveal a mechanism that p53 may inhibit cell migration by disrupting actin dynamics via Rad activation and implicate a tumor suppressor role of Rad in lung cancer. [ABSTRACT FROM AUTHOR]

Objective: The current American Joint Committee on Cancer staging system for esophageal cancer is based on lymph node location, irrespective of the number of involved and examined lymph nodes.Methods: We enrolled 488 patients receiving primary curative resection without neoadjuvant therapy for esophageal cancer between 1995 and 2006. The importance of total resected lymph node number (TLN) and metastatic lymph node number (MLN) and ratio (MLR) on patient survival was investigated.Results: The overall 3-year survival rate was 35.4%. The 3-year survival rate was equivalent among patients in N1 (23.3%), M1a (22.0%), and nonregional lymph node metastasis-related M1b (18.5%, p = 0.321). No survival difference was noted between patients with TLN < 15 or > or =15 (p = 0.249). Both MLN and MLR significantly predicted patient survival. The 3-year survival rate was 52.3%, 29.2%, and 8.0% for patients with MLN = 0, 1-3, and > or =4, respectively (p < 0.001). For patients with MLR = 0-0.2 or >0.2, the 3-year survival rate was 28.7% and 9.8%, respectively (p < 0.001). However, survival rate differences were more evident when TLN was more than 15.Conclusions: We recommend designating both regional and nonregional lymph nodes as N nodes. MLN and MLR, but not TLN, are prognostic factors in esophageal cancer. [ABSTRACT FROM AUTHOR]

Sclerosing haemangioma is an uncommon lung tumour that typically presents as a solitary, peripheral pulmonary nodule in the lower lobe. Little is known of the appearance of these tumours on FDG-PET scan. We report two patients with sclerosing haemangioma with increased uptake on FDG-PET scan, which complicated the preoperative work-up. Although the CT scan features of these two masses were compatible with the differential diagnosis of sclerosing haemangioma, the central location and increased uptake on FDG-PET scan raised the suspicion of malignancy. We conclude that centrally located large sclerosing haemangiomas may be avid on FDG-PET scan, and that familiarity with this false positive finding helps in the diagnosis of a solitary pulmonary nodule. [ABSTRACT FROM AUTHOR]

The article focuses on the findings of a study concerning the measurement of the levels of bile acids in patients with suspected ventilator-associated pneumonia (VAP) and provide a possible pathway for neutrophilic inflammation to explain its proinflammatory effect. Moreover, the study shows that early intervention to prevent bile acid aspiration may reduce the intensity of neutrophilic inflammation in intubated and ventilated patients in the intensive care units (ICU).

Background: Lung adenocarcinoma is the leading cause of cancer-related deaths among both men and women in the world. Despite recent advances in diagnosis and treatment, the mortality rates with an overall 5-year survival of only 15%. This high mortality is probably attributable to early metastasis. Although several well-known markers correlated with poor/ metastasis prognosis in lung adenocarcinoma patients by immunohistochemistry was reported, the molecular mechanisms of lung adenocarcinoma development are still not clear. To explore novel molecular markers and their signaling pathways will be crucial for aiding in treatment of lung adenocarcinoma patients. Methodology/Principal Findings: To identify novel lung adenocarcinoma-associated /metastasis genes and to clarify the underlying molecular mechanisms of these targets in lung cancer progression, we created a bioinformatics scheme consisting of integrating three gene expression profile datasets, including pairwise lung adenocarcinoma, secondary metastatic tumors vs. benign tumors, and a series of invasive cell lines. Among the novel targets identified, FLJ10540 was overexpressed in lung cancer tissues and is associated with cell migration and invasion. Furthermore, we employed two coexpression strategies to identify in which pathway FLJ10540 was involved. Lung adenocarcinoma array profiles and tissue microarray IHC staining data showed that FLJ10540 and VEGF-A, as well as FLJ10540 and phospho-AKT exhibit positive correlations, respectively. Stimulation of lung cancer cells with VEGF-A results in an increase in FLJ10540 protein expression and enhances complex formation with PI3K. Treatment with VEGFR2 and PI3K inhibitors affects cell migration and invasion by activating the PI3K/AKT pathway. Moreover, knockdown of FLJ10540 destabilizes formation of the P110-α/P85-α-(PI3K) complex, further supporting the participation of FLJ10540 in the VEGF-A/PI3K/AKT pathway. Conclusions/Significance: This finding set the stage for further testing of FLJ10540 as a new therapeutic target for treating lung cancer and may contribute to the development of new therapeutic strategies that are able to block the PI3K/AKT pathway in lung cancer cells. [ABSTRACT FROM AUTHOR]

The article reports on the results of a study designed to determine how bile acids interact with airway epithelium and whether transforming growth factor-beta1 (TGF-B1) secretion and fibroblast proliferation are affected. A description of study methods is presented. The study concluded that aspiration of bile acids may induce airway fibrosis through the production of TGF-B1 and fibroblast proliferation.

Background: The development of microarrays permits us to monitor transcriptomes on a genome-wide scale. To validate microarray measurements, quantitative-real time-reverse transcription PCR (Q-RT-PCR) is one of the most robust and commonly used approaches. The new challenge in gene quantification analysis is how to explicitly incorporate statistical estimation in such studies. In the realm of statistical analysis, the various available methods of the probe level normalization for microarray analysis may result in distinctly different target selections and variation in the scores for the correlation between microarray and Q-RT-PCR. Moreover, it remains a major challenge to identify a proper internal control for Q-RT-PCR when confirming microarray measurements. Results: Sixty-six Affymetrix microarray slides using lung adenocarcinoma tissue RNAs were analyzed by a statistical re-sampling method in order to detect genes with minimal variation in gene expression. By this approach, we identified DDX5 as a novel internal control for Q-RT-PCR. Twenty-three genes, which were differentially expressed between adjacent normal and tumor samples, were selected and analyzed using 24 paired lung adenocarcinoma samples by Q-RT-PCR using two internal controls, DDX5 and GAPDH. The percentage correlation between Q-RT-PCR and microarray were 70% and 48% by using DDX5 and GAPDH as internal controls, respectively. Conclusion: Together, these quantification strategies for Q-RT-PCR data processing procedure, which focused on minimal variation, ought to significantly facilitate internal control evaluation and selection for Q-RT-PCR when corroborating microarray data. [ABSTRACT FROM AUTHOR]

The responses of airway epithelium following exposure to neutrophil elastase NE were investigated. Human bronchial epithelial cells were explanted on insert surfaces of a modified air-liquid interface culture system to which NE was added to stimulate epithelial cells. PGE[sub 2] release significantly increased within 10 min of incubation with NE and peaked 3 h after NE (20 µg/ml) stimulation. This action required proteolytic activity as α[sub 1]-antitrypsin blocked NE-induced PGE[sub 2] release. The production of PGE[sub 2] was also inhibited by indomethacin: a selective cyclooxygenase (COX)-2 inhibitor, celecoxib; and dexamethasone. Moreover, the mRNA expression for COX-2 relative to that for a housekeeping gene was approximately eightfold that of the unstimulated cells. Dexamethasone inhibited COX-2 gene transcription, We further observed that NE-induced PGE[sub 2] release involved activation of p44/42, but not p38, MAP kinases. Such p44/42 MAP kinases were rapidly phosphorylated, with the concentration of phosphorylated p44/42 MAP kinases peaking at 10 min after stimulation and declining in culture at 90 min. The specific p44/42 MAP kinase inhibitor UO126 completely blocked p44/42 phosphorylation and, subsequently, PGE[sub 2] production. The airway epithelium may play important bronchoprotective and immunomodulatory roles in chronic neutrophilic inflammation. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Recently, an association between viral infection and the development of esophageal carcinoma has been reported, particularly the human papilloma virus (HPV) and Esptein-Bar virus (EBV). However, geographic variation in carcinogenesis is realized. In this study, we investigate the viral carcinogenesis and the biologic effect of viral infection on esophageal squamous cell carcinoma (ESCC) in Taiwan. METHODS: To determine the association of viral infection (EBV and HPV) with ESCC, we applied polymerase chain reaction (PCR), immunohistochemistry, and in situ hybridization (ISH) to examine 119 surgical specimens from different sites of esophagus in 31 ESCC patients. Additionally, an immunoperoxidase method was used to detect EBV latent membrane protein-1 (LMP-1), p53, CD45RO (UCHL-1), Fas ligand (Fas L), and RNA ISH with oligo-nucleotide sequences was used to detected interleukin-6 (IL-6) mRNA. RESULTS: By PCR, EBV DNA was detected in 11 cases (35.5%). Expression of EBERs in ESCC was further confirmed with ISH. Nonetheless, no LMP-1 expression was detected. On the other hand, human papillomavirus (HPV) was identified in only one case (3.2%) of ESCC. Furthermore, HPV was located by ISH in the distant normal region rather than in tumor cells. In EBV-positive cases, accumulation of p53 protein was detected in 10 lesions (91%); CD45RO+ lymphocytes together with expressions of FasL and IL-6 were respectively identified in 100%, 63.6%, and 54.5% of 11 EBV-positive lesions. Interestingly, in the EBV-negative cases (n = 20), p53 protein was detected in 40% of lesions; CD45RO 30%; FasL 50%, and IL-6 10%. CONCLUSIONS: In this study, no correlation was found between the presence of EBV in ESCC and the patients' age, sex, as well as survival. Although our results indicate that EBV could be associated with ESCC, the clinical role of EBV in ESCC remains to be determined. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Enucleation of an Advanced Esophageal Gastrointestinal Stromal Tumor With Liver Metastasis" in the February 12, 2006 issue.

Several letters to the editor are presented in response to the article "Prognostic Significance of the Non-Size Based AJCC T2 Descriptors: Visceral Pleura Invasion, Hilar Atelectasis, or Obstructive Pneumonitis in Stage IB Non-Small Cell Lung Cancer Is Dependent on Tumor Size," by S. H. Ou and colleagues in the March 2008 issue.