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Whether the survival outcome of patients with non-metastatic esophageal squamous cell carcinoma (NM-ESCC) receiving definitive concurrent chemoradiotherapy (CCRT) is better with intensity-modulated radiotherapy (IMRT) or with 3-dimensional conformal radiotherapy (3DCRT) has been debated in the literature. We designed this population-based propensity-score (PS)-matched analysis to address this question. We identified eligible patients diagnosed between 2008 and 2015 from the Taiwan Cancer Registry and constructed a PS-matched cohort (1:1 for IMRT vs 3DCRT) to balance observable potential confounders. We compared the hazard ratio (HR) of death between IMRT and 3DCRT during the entire follow-up period. We also evaluated freedom from local regional recurrence (FFLRR) and esophageal cancer-specific survival (ECSS). Sensitivity analyses (SA) were performed to examine the robustness of our findings. Our study population constituted 558 patients who were well balanced with regard to the measured covariables. The HR of death with IMRT compared to 3DCRT was 0.43 (95% confidence interval 0.35-0.52, P < .001). The results remained significant for FFLRR and ECSS. In SA, our results remained significant when additional covariables were taken into consideration. The survival outcome of patients with NM-ESCC receiving CCRT might be better with IMRT vs 3DCRT. These study results should be interpreted with caution given some possible covariates lacking in the registry. Further studies are needed to clarify this issue.

Background: Although concurrent chemoradiotherapy (CCRT) coupled with image-guided radiotherapy (IGRT) is associated with a theoretical benefit in non-operated localized esophageal squamous cell carcinoma (NOL-ESCC) patients, there is currently no clinical evidence to support this., Results: The study population in the primary analysis comprised 866 patients who were well balanced in terms of their co-variables. The HR for mortality when group A was compared with group B was 0.82 (95% confidence interval, 0.7-0.95). SA revealed that the result was moderately sensitive., Materials and Methods: Eligible patients diagnosed between 2008 and 2013 were identified in the Taiwan Cancer Registry. A propensity score-matched cohort was constructed [1:1 in groups A (with IGRT) and B (without IGRT)] to balance any observable potential confounders. The hazard ratio (HR) for mortality was compared between groups A and B during the follow-up period. Sensitivity analyses (SA) were performed to evaluate the robustness of the findings regarding the selection of confounders and a potential unobserved confounder., Conclusions: The current results provide the first clinical evidence that CCRT coupled with IGRT is associated with better overall survival when compared with CCRT without IGRT in NOL-ESCC patients. However, this study should be interpreted with caution given its non-randomized nature and the moderate sensitivity of the data. Further studies are needed to clarify this finding.

Background: The optimal radiotherapy dose for non-operated localized esophageal squamous cell carcinoma (NOL-ESCC) patients undergoing concurrent chemoradiotherapy (CCRT) is hotly debated., Methods: We identified eligible patients diagnosed within 2008-2013 from Taiwan Cancer Registry and constructed a propensity score matched cohort (1:1 for high dose (⩾60Gy) vs standard dose (50-50.4Gy)) to balance observable potential confounders. We compared the hazard ratio (HR) of death between standard and high radiotherapy dose groups during the entire follow-up period. We performed sensitivity analysis (SA) to evaluate the robustness of our finding regarding potential unobserved confounders & index date definition., Results: Our study population constituted 648 patients with well balance in observed co-variables. The HR of death when high dose was compared to standard dose was 0.75 (95% confidence interval 0.64-0.88). Our result was sensitive to potential unobserved confounders but robust to alternative index date definition in SA., Conclusions: We found that higher than standard radiotherapy dose may lead to better survival for NOL-ESCC patients undergoing CCRT., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

SOX2 is a transcription factor essential for self-renewal and pluripotency of embryonic stem cells. Recently, SOX2 was found overexpressed in the majority of the lung squamous cell carcinoma (SQC), in which it acts as a lineage-survival oncogene. However, downstream targets/pathways of SOX2 in lung SQC cells remain to be identified. Here, we show that BMP4 is a downstream target of SOX2 in lung SQC. We found that SOX2-silencing-mediated inhibition of cell growth was accompanied by upregulation of BMP4 mRNA and its protein expression. Meta-analysis with 293 samples and qRT-PCR validation with 73 clinical samples revealed an inversely correlated relationship between levels of SOX2 and BMP4 mRNA, and significantly lower mRNA levels in tumor than in adjacent normal tissues. This was corroborated by immunohistochemistry analysis of 35 lung SQC samples showing lower BMP4 protein expression in tumor tissues. Cell-based experiments including siRNA transfection, growth assay and flow cytometry assay, further combined with a xenograft tumor model in mice, revealed that reactivation of BMP4 signaling could partially account for growth inhibition and cell cycle arrest in lung SQC cells upon silencing SOX2. Finally, chromatin immunoprecipitation analysis and luciferase reporter assay revealed that SOX2 could negatively regulate BMP4 promoter activity, possibly through binding to the promoter located in the first intron region of BMP4. Collectively, our findings suggest that BMP4 could act as a tumor suppressor and its downregulation by elevated SOX2 resulting in enhanced growth of lung SQC cells., (© 2014 UICC.)

Background: Polymorphisms (1082A>G, - 819C>T, and -592G>A) in the interleukin-10 (IL10) promoter are associated with its transcriptional activity. IL10 induction by cigarette smoking plays a role in smoking-related lung tumor progression. We therefore expected to find a difference in impact of IL10 haplotypes on overall survival (OS) and relapse-free survival (RFS) between squamous cell carcinomas (SCC) and adenocarcinomas (ADC) of lung., Materials and Methods: Normal lung tissues adjacent to resected tumors from 439 lung cancer patients were collected to determine IL10 haplotypes (ATA and non-ATA) by direct sequencing and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Kaplan-Meier and multivariate Cox regression models were used to assess the impact of IL10 haplotype on OS and RFS. Resluts: The non-ATA haplotype was more prevalent in patients with nodal metastatic tumors (N1 and N2) than in those with non-nodal metastatic tumors (N0). This observation was only made for patients with SCC and not ADC. Patients with SCC with the non-ATA haplotype had poorer OS and RFS when compared to those with the ATA haplotype, whereas IL10 haplotype was not associated with the clinical outcome of patients with ADC., Conclusion: The IL10 haplotype may independently predict survival and relapse in patients with surgically resected SCC, but not ADC.

To identify common genetic variants that contribute to lung cancer susceptibility, we conducted a multistage genome-wide association study of lung cancer in Asian women who never smoked. We scanned 5,510 never-smoking female lung cancer cases and 4,544 controls drawn from 14 studies from mainland China, South Korea, Japan, Singapore, Taiwan and Hong Kong. We genotyped the most promising variants (associated at P < 5 × 10(-6)) in an additional 1,099 cases and 2,913 controls. We identified three new susceptibility loci at 10q25.2 (rs7086803, P = 3.54 × 10(-18)), 6q22.2 (rs9387478, P = 4.14 × 10(-10)) and 6p21.32 (rs2395185, P = 9.51 × 10(-9)). We also confirmed associations reported for loci at 5p15.33 and 3q28 and a recently reported finding at 17q24.3. We observed no evidence of association for lung cancer at 15q25 in never-smoking women in Asia, providing strong evidence that this locus is not associated with lung cancer independent of smoking.

A recent genome-wide association study (GWAS) of subjects from Japan and South Korea reported a novel association between the TP63 locus on chromosome 3q28 and risk of lung adenocarcinoma (p = 7.3 × 10(-12)); however, this association did not achieve genome-wide significance (p ≤ 10(-7)) among never-smoking males or females. To determine if this association with lung cancer risk is independent of tobacco use, we genotyped the TP63 SNPs reported by the previous GWAS (rs10937405 and rs4488809) in 3,467 never-smoking female lung cancer cases and 3,787 never-smoking female controls from 10 studies conducted in Taiwan, Mainland China, South Korea, and Singapore. Genetic variation in rs10937405 was associated with risk of lung adenocarcinoma [n = 2,529 cases; p = 7.1 × 10(-8); allelic risk = 0.80, 95% confidence interval (CI) = 0.74-0.87]. There was also evidence of association with squamous cell carcinoma of the lung (n = 302 cases; p = 0.037; allelic risk = 0.82, 95% CI = 0.67-0.99). Our findings provide strong evidence that genetic variation in TP63 is associated with the risk of lung adenocarcinoma among Asian females in the absence of tobacco smoking.

Introduction: To investigate the feasibility and clinical impact of the 7th edition of the "Tumor, Node, Metastasis" (TNM) classification scheme in lung cancer as proposed by the International Association for the Study of Lung Cancer (IASLC) for non-small cell lung cancer., Methods: We evaluated the feasibility of the new staging system in our routine biweekly multidisciplinary lung cancer staging conference compared with the 6th TNM staging in a prospective manner from April 2008 to June 2009. The impact of IASLC staging versus the 6th TNM staging was observed at three levels: change in substaging, staging, and clinical management (based on the discussion within the staging conference)., Results: From 348 patients discussed during these conferences, 226 eligible non-small cell lung cancer patients newly diagnosed within the study period were reviewed and clinically staged. The majority were elderly (median age, 67 years) and men (58%). Of these, 23 patients had different staging, and four patients had different substaging in the IASLC staging compared with the 6th TNM staging. An impact on clinical management was seen in 2.7% (6 of 226) of these patients because of coding ipsilateral different-lobe metastasis as T4 instead of M1., Conclusions: The new staging system was clinically feasible and resulted in some (27 of 226, 12%) differences in staging. An impact on clinical decision making was occasionally seen within our institutional practice. Further studies are needed to investigate the comprehensive and long-term impact of the new staging system.

Aim: To observe the interaction between the expression of telomerase activity (TA) and its associate genes in regulation of the terminal restriction fragment length (TRFL) in esophageal squamous cell carcinoma (SCC)., Methods: Seventy-four specimens of esophageal SCC were examined. The TA was measured by telomeric repeat amplification protocol (TRAP) assay, and the associated genes [human telomerase-specific reverse transcriptase (hTERT), hTERC, TP1, c-Myc, TRF1, and TRF2] were detected using RT-PCR method. The TRFL was measured by Telomere Length Assay Kit and Southern blotting. The correlations between the expression of telomerase and its associated genes with the TRFL and survivals were examined., Results: Expressions of the TA, hTERT, hTERC, TP1, c-Myc, TRF1, and TRF2 genes were observed in 85.1%, 64.9%, 79.7%, 100.0%, 94.6%, 82.4%, and 91.9% of the tumor tissues, respectively. The TRFL of the tumor and normal esophageal tissues were 2.70+/-1.42 and 4.93+/-1.74 kb, respectively (P<0.0001). The TRFL of the telomerase positive and telomerase negative tumor tissues were 2.72+/-1.44 and 2.58+/-1.32 kb, respectively (P = 0.767). The TRFL ratios (TRFLR) of the telomerase positive and telomerase negative tumor tissues were 0.55+/-0.22 and 0.59+/-0.41, respectively (P = 0.742). The expression rates of h-TERT (P = 0.0002), hTERC (P<0.0001), and TRF1 (P = 0.002) in the tumor tissues are higher than those of the normal paired tissues. Though TA is markedly activated in tumor tissues (P<0.0001), its expression is not related to clinicopathological parameters including gender, tumor differentiation, and TNM stages. The cumulative 4-year survival rates of telomerase positive and telomerase negative cases were 35.86% and 31.2%, respectively (P = 0.8442). The cumulative 4-year survival rates of patients with their TRFLR 85% were 38.7% and 15.7%, respectively (P = 0.1307)., Conclusion: Though telomerase expression is not related to tumor stages and prognosis, our data support that the TA increased as the TRFL decreased, probably under the control of hTERT, hTERC, and TRF1. When telomerase expression was activated, only TRF2 overexpression persisted to stabilize T-loop formation. Furthermore, as the TRFLR decreased to 85%, a trend of better prognosis was observed. Cox model analysis indicates a higher t/n TRFLR and distant metastasis are independent poorer prognostic factors (P = 0.035 and P = 0.042, respectively).

Background: Natural killer (NK) cells are important effector cells in the defense against tumors. The present study retrospectively examines the intratumoral NK cells in primary resected esophageal squamous cell carcinoma (ESCC) and the correlation between the patient' outcome and the intratumoral NK cells infiltration., Methods: Immunohistochemistry was used to analyze the intratumoral NK cell infiltration in 38 archival specimens from patients with primary resected ESCC., Results: According to the cut-off point of the staining for intratumoral NK cell infiltration, 14 (37%) cases had high level infiltration and 24 (63%) low. The 5-year survival of patients with high level NK infiltration was significantly better than that of patients with a low level of NK infiltration (p < 0.01). Multivariate analysis did not show NK cell infiltration to be a significant prognostic factor., Conclusions: Intratumoral NK cell infiltration is associated with a favorable outcome in ESCC. Intratumoral NK cell infiltration might be used as a variable with prognostic value in primary resected ESCC.

We assessed the association of three genetic polymorphisms, NAD(P)H quinone oxidoreductase (NQO1), Glutathione-S-transferase P1 (GSTP1), and manganese superoxide dismutase (MnSOD), with lung cancer risk in 198 cases and 332 controls in Taiwan. Overall, NQO1 and MnSOD polymorphisms were not associated with an increased risk of lung cancer. Individuals carrying variant alleles of GSTP1 were at higher risk of squamous cell lung carcinoma (odds ratio, 1.63; 95% confidence interval, 0.96-2.74). When the groups were further stratified by smoking status following gender and histological type, the wild-type NQO1 was associated with lung adenocarcinoma among smokers but not among nonsmokers (odds ratio, 2.49; 95% confidence interval, 1.17-5.32). These results suggest that NQO1 plays a role in the development of cigarette smoking-associated lung adenocarcinoma. In addition, GSTP1 polymorphism was associated with the risk of squamous cell lung carcinoma in Taiwan.

Aims: The present study retrospectively examines the expression of caspase-3 in primary resected esophageal squamous cell carcinoma (ESCC) and the correlation between the outcome of patients and the expression of proteins., Methods: Immunohistochemistry and Western blot analyses were used to analyse the expression of caspase-3 in 40 archival specimens of patients with primary resected ESCC., Results: According to our cut-off point of the staining for caspase-3, 24 (60%) cases were positive and 16 (40%) negative. Caspase-3 expression correlated with a significant favorable prognosis in primary resected ESCC (P=0.02). A multivariate analysis of clinical and biological factors indicated that stage, tumor differentiation, and caspase-3 expression were independent prognostic factors., Conclusions: Caspase-3 expression might be a good and new prognostic indicator for primary resected ESCC.