Yu Jin Lim

Survival Impact of Adjuvant Radiation Therapy in Masaoka Stage II to IV Thymomas: A Systematic Review and Meta-analysis

PURPOSE To evaluate the survival impact of postoperative radiation therapy (PORT) in stage II to IV thymomas, using systematic review and meta-analysis. METHODS AND MATERIALS A database search was conducted with EMBASE, PubMed, Web of Science, Cochrane Library, and Ovid from inception to August 2015. Thymic carcinomas were excluded, and studies comparing overall survival (OS) with and without PORT in thymomas were included. The hazard ratios (HRs) of OS were extracted, and a random-effects model was used in the pooled analysis. RESULTS Seven retrospective series with a total of 1724 patients were included and analyzed. Almost all of the patients underwent macroscopically complete resection, and thymoma histology was confirmed by the World Health Organization criteria. In the overall analysis of stage II to IV thymomas, OS was not altered with the receipt of PORT (HR 0.79, 95% confidence interval [CI] 0.58-1.08). Although PORT was not associated with survival difference in Masaoka stage II disease (HR 1.45, 95% CI 0.83-2.55), improved OS was observed with the addition of PORT in the discrete pooled analysis of stage III to IV (HR 0.63, 95% CI 0.40-0.99). Significant heterogeneity and publication bias were not found in the analyses. CONCLUSIONS From the present meta-analysis of sole primary thymomas, we suggest the potential OS benefit of PORT in locally advanced tumors with macroscopically complete resection, but not in stage II disease. Further investigations with sufficient survival data are needed to establish detailed treatment indications.

Role of Postoperative Radiotherapy in Nonlocalized Thymoma Propensity-Matched Analysis of Surveillance, Epidemiology, and End Results Database

Introduction: Because of a lack of randomized trials, the role of postoperative radiotherapy (PORT) in thymomas has not been established. This study evaluated the prognostic impact of the adjuvant treatment in surgically resected nonlocalized thymomas. Methods: Patients diagnosed between 2000 and 2010 were identified from the Surveillance, Epidemiology, and End Results database (1973–2011 registry). Cases with localized or organ-confined tumors were not included. Propensity-matched analysis was conducted considering baseline characteristics. Results: A total of 529 patients were identified. The median age was 57 years (range, 18–86), and 345 (65%) patients received PORT. Before and after propensity score matching, overall survival (OS; p = 0.018 and 0.008, respectively) and disease-specific survival (DSS; p = 0.007 and 0.008, respectively) were better in the PORT group. In multivariate analyses of the matched population, no receipt of PORT induced poorer OS (hazard ratio [HR], 1.98; 95% confidence interval [CI], 1.27–3.09) and DSS (HR, 2.64; 95% CI, 1.32–5.29). Primary tumor extensions of adjacent organs or structures and further contiguous extensions also resulted in worse outcomes (p < 0.001 and equal to 0.039 for OS; p = 0.006 and 0.009 for DSS, respectively). In the subgroup analyses, PORT was associated with favorable OS in stages III and IV (p = 0.049 and 0.012, respectively) and DSS in stage III (p = 0.005). Conclusion: Regarding the independent prognostic significance of PORT, this population-based analysis demonstrates the survival benefits of PORT in relation to nonlocalized thymomas. We recommend consideration of PORT in the poor prognostic subset of stages III to IV in the contemporary era.

Clinical InvestigationSurvival Impact of Adjuvant Radiation Therapy in Masaoka Stage II to IV Thymomas: A Systematic Review and Meta-analysis

PURPOSE To evaluate the survival impact of postoperative radiation therapy (PORT) in stage II to IV thymomas, using systematic review and meta-analysis. METHODS AND MATERIALS A database search was conducted with EMBASE, PubMed, Web of Science, Cochrane Library, and Ovid from inception to August 2015. Thymic carcinomas were excluded, and studies comparing overall survival (OS) with and without PORT in thymomas were included. The hazard ratios (HRs) of OS were extracted, and a random-effects model was used in the pooled analysis. RESULTS Seven retrospective series with a total of 1724 patients were included and analyzed. Almost all of the patients underwent macroscopically complete resection, and thymoma histology was confirmed by the World Health Organization criteria. In the overall analysis of stage II to IV thymomas, OS was not altered with the receipt of PORT (HR 0.79, 95% confidence interval [CI] 0.58-1.08). Although PORT was not associated with survival difference in Masaoka stage II disease (HR 1.45, 95% CI 0.83-2.55), improved OS was observed with the addition of PORT in the discrete pooled analysis of stage III to IV (HR 0.63, 95% CI 0.40-0.99). Significant heterogeneity and publication bias were not found in the analyses. CONCLUSIONS From the present meta-analysis of sole primary thymomas, we suggest the potential OS benefit of PORT in locally advanced tumors with macroscopically complete resection, but not in stage II disease. Further investigations with sufficient survival data are needed to establish detailed treatment indications.

High ratio of programmed cell death protein 1 (PD-1)+/CD8+ tumor-infiltrating lymphocytes identifies a poor prognostic subset of extrahepatic bile duct cancer undergoing surgery plus adjuvant chemoradiotherapy

BACKGROUND AND PURPOSE This study investigated the prognostic role of PD-L1 expression, PD-1(+) tumor-infiltrating lymphocytes (TILs), and the ratio of PD-1(+)/CD8(+) TILs in extrahepatic bile duct (EHBD) cancer. MATERIALS AND METHODS We analyzed 83 patients with EHBD cancer who underwent curative surgery plus fluoropyrimidine-based chemoradiotherapy (CRT). Expressions of PD-L1, PD-1, and CD8 were assessed by immunohistochemistry. RESULTS Fifty-six (68%) patients were PD-L1-positive, and its lower expression level was associated with hilar tumor location (P=0.044). A higher ratio of PD-1(+)/CD8(+) TILs was associated with poorer overall survival (OS) (P=0.032), relapse-free survival (RFS) (P=0.024), and distant metastasis-free survival (DMFS) (P=0.039) in Kaplan-Meier analyses, but survival differences were not observed according to the PD-L1 expression level. With Cox proportional hazards models, the ratio of PD-1(+)/CD8(+) TILs was the independent prognostic factor in OS (HR 2.47, 95% CI 1.04-5.86), RFS (HR 2.41, 95% CI 1.08-5.41), and DMFS (HR 2.67, 95% CI 1.00-7.11) after adjusting for other significant clinicopathologic variables. CONCLUSION A strong survival impact of the ratio of PD-1(+)/CD8(+) TILs was observed in EHBD cancer. In the poor prognostic subgroup, the blockade of the immune checkpoint in combination with conventional multimodality treatment needs to be considered.

Tumor Growth Suppression and Enhanced Radioresponse by an Exogenous Epidermal Growth Factor in Mouse Xenograft Models with A431 Cells

Purpose The purpose of this study was to evaluate whether an exogenous epidermal growth factor (EGF) could induce anti-tumor and radiosensitizing effects in vivo. Materials and Methods BALB/c-nu mice that were inoculated with A431 (human squamous cell carcinoma) cells in the right hind legs were divided into five groups: I (no treatment), II (EGF for 6 days), III (EGF for 20 days), IV (radiotherapy [RT]), and V (RT plus concomitant EGF). EGF was administered intraperitoneally (5 mg/kg) once a day and the RT dose was 30 Gy in six fractions. Hematoxylin and eosin (H&E) stained sections of tumor, liver, lung, and kidney tissues were investigated. Additionally, tumors were subjected to immunohistochemistry staining with caspase-3. Results EGF for 6 days decreased tumor volume, but it approached the level of the control group at the end of follow-up (p=0.550). The duration of tumor shrinkage was prolonged in group V while the slope of tumor re-growth phase was steeper in group IV (p=0.034). EGF for 20 days decreased tumor volume until the end of the observation period (p < 0.001). Immunohistochemistry revealed that mice in group V showed stronger intensity than those in group IV. There were no abnormal histological findings upon H&E staining of the normal organs. Conclusion EGF-induced anti-tumor effect was ascertained in the xenograft mouse models with A431 cells. Concomitant use of EGF has the potential role as a radiosensitizer in the design of fractionated irradiation.

Treatment outcome of ductal carcinoma in situ patients treated with postoperative radiation therapy.

Purpose To evaluate the outcome of ductal carcinoma in situ (DCIS) patients who underwent surgery followed by radiation therapy (RT). Materials and Methods We retrospectively reviewed 106 DCIS patients who underwent surgery followed by postoperative RT between 1994 and 2006. Ninety-four patients underwent breast-conserving surgery, and mastectomy was performed in 12 patients due to extensive DCIS. Postoperative RT was delivered to whole breast with 50.4 Gy/28 fx. Tumor bed boost was offered to 7 patients (6.6%). Patients with hormonal receptor-positive tumors were treated with hormonal therapy. Results The median follow-up duration was 83.4 months (range, 33.4 to 191.5 months) and the median age was 47.8 years. Ten patients (9.4%) had resection margin <1 mm and high-grade and estrogen receptor-negative tumors were observed in 39 (36.8%) and 20 (18.9%) patients, respectively. The 7-year ipsilateral breast tumor recurrence (IBTR)-free survival rate was 95.3%. Resection margin (<1 or ≥1 mm) was the significant prognostic factor for IBTR in univariate and multivariate analyses (p < 0.001 and p = 0.016, respectively). Conclusion Postoperative RT for DCIS can achieve favorable treatment outcome. Resection margin was the important prognostic factor for IBTR in the DCIS patients who underwent postoperative RT.

Clinical Implications of Cytotoxic T Lymphocyte Antigen-4 Expression on Tumor Cells and Tumor-Infiltrating Lymphocytes in Extrahepatic Bile Duct Cancer Patients Undergoing Surgery Plus Adjuvant Chemoradiotherapy

BackgroundThere currently is only limited knowledge on the role of tumor-specific immunity in cholangiocarcinoma.ObjectiveThis study evaluated the clinical implications of cytotoxic T lymphocyte antigen-4 (CTLA-4) expression levels and CD4+ and CD8+ tumor-infiltrating lymphocytes (TILs) in extrahepatic bile duct (EHBD) cancer.Patients and MethodsImmunohistochemistry of CTLA-4, CD4, and CD8 was performed for 77 EHBD cancer patients undergoing surgery plus adjuvant chemoradiotherapy. CTLA-4 expression on tumor cells and TILs were assessed by using H-scores and the proportion of CTLA-4+ lymphocytes, respectively.ResultsWith optimal cutoff values determined by a maximal chi-square method with overall survival (OS) data, patients with CTLA-4 H-score >70 and a proportion of CTLA-4+ TILs >0.15 showed higher mean density of CD8+ and CD4+ TILs, respectively (P = 0.025 for CD8+ and P = 0.055 for CD4+ TILs). The high CTLA-4 H-score level was associated with prolonged OS and disease-free interval (DFI) (P = 0.025 and 0.004, respectively). With differential levels of CTLA-4 H-score according to hilar and non-hilar locations (high rate 32 vs. 68%, respectively; P = 0.013), an exploratory subgroup analysis demonstrated that the associations between the CTLA-4 expression and OS and DFI were confined to hilar tumors (P = 0.003 and <0.001, respectively), but not to non-hilar ones (P = 0.613 and 0.888, respectively).ConclusionsThis study demonstrates a potential prognostic relevance of CTLA-4 expression in EHBD cancer. We suggest a differential survival impact of the CTLA-4 expression level according to different tumor locations.

Superior Treatment Response and In-field Tumor Control in Epidermal Growth Factor Receptor-mutant Genotype of Stage III Nonsquamous Non–Small cell Lung Cancer Undergoing Definitive Concurrent Chemoradiotherapy

Micro‐Abstract We conducted a comparative outcome analysis to evaluate the differential radioresponse and survival outcomes in epidermal growth factor receptor (EGFR)‐mutant and wild‐type nonsquamous non–small cell lung cancer undergoing definitive chemoradiotherapy. With more favorable metabolic activity, the EGFR‐mutant group showed significantly better post‐chemoradiation response and superior tumor control inside the radiation field. Our results underline the need of precise therapeutic strategy based on the EGFR mutational status. Background: Although previous in vitro data have suggested a more radio‐sensitive nature of epidermal growth factor receptor (EGFR)‐mutant non–small cell lung cancer (NSCLC) cell lines, the clinical behavior according to the EGFR mutational status has not been well‐established. In this study, we performed a comparative outcome analysis of EGFR‐mutant and wild‐type locally advanced NSCLC with chemoradiotherapy (CRT). Patients and Methods: A total of 102 patients with stage III nonsquamous NSCLC undergoing primary CRT were identified. Clinicopathologic characteristics, including the degree of glucose uptake, were evaluated. Failure patterns considering the radiation field and survival outcomes were compared according to the EGFR mutational status. Results: Pre‐ and post‐CRT maximum standardized uptake values were significantly lower in EGFR‐mutant tumors (P = .010 and .018, respectively). The overall response rate was higher in the EGFR‐mutant group compared with the wild‐type (89% vs. 64%, respectively; P = .023). The 3‐year overall survival rate was better with the genetic alteration (68.0% vs. 47.4%, P = .046), but the statistical significance did not remain in multivariate analysis (hazard ratio, 0.68; 95% confidence interval, 0.30‐1.55). Considering the tumor progression inside or outside the radiation field, the EGFR‐mutant group showed longer in‐field time to progression (P = .002), even after adjusting for other related baseline variables (hazard ratio, 0.27; 95% confidence interval, 0.11‐0.71). Conclusion: The differential metabolic activity, failure patterns, and prognosis suggest the distinct nature of the EGFR‐mutant tumors. EGFR mutational status needs to be considered for more precise curative‐intent treatment strategies of locally advanced nonsquamous NSCLC.