The emerging outcome of postoperative radiotherapy for stage IIIA(N2) non-small cell lung cancer patients: based on the three-dimensional conformal radiotherapy technique and institutional standard clinical target volume.

BACKGROUND: The aim of this study was to evaluate the clinical efficacy of postoperative radiotherapy (PORT), administered using three-dimensional conformal radiotherapy (3D-CRT) and our institutional standard clinical target volume (CTV) delineation, for completely resected stage IIIA(N2) non-small cell lung cancer (NSCLC). METHODS: From 2005 to 2012, consecutive patients with pT1-3N2 NSCLC who were treated with PORT employing our institutional CTV delineation after complete surgery or who underwent complete resection in our hospital but without PORT were identified. We excluded patients who had received neoadjuvant chemotherapy or radiation therapy (RT). Kaplan-Meier estimates for locoregional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS) and overall survival (OS) were performed. In the OS estimation, patients who received epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) during follow-up were censored at the time of TKI initiation. RESULTS: Data from 70 patients in the PORT group and 287 in the non-PORT group were analysed. All 70 cases received 3D-CRT following our institutional CTV guideline, with a median total dose of 50.4 Gy at 1.8 Gy/fraction. At a median follow-up of 34.3 months for the PORT group and 31.2 months for the non-PORT group, PORT significantly improved local control (5-yr LRFS 91.9% for PORT vs 66.4% for non-PORT, P < 0.001) and OS (5-yr OS 57.5% for PORT vs 35.1% for non-PORT, P = 0.003), whereas no differences in DMFS were noted (P = 0.18). In multivariable analyses, PORT was independently associated with an improved LRFS (HR 0.2, P = 0.001) and OS (HR 0.4, P = 0.001). All patients completed the planned RT dose without interruption of RT due to treatment-related complications. CONCLUSIONS: Our data suggested that PORT administered using the 3D-CRT technique following our institutional CTV delineation guideline resulted in a promising outcome with favourable survival for completely resected IIIA(N2) NSCLC, after controlling for subsequent EGFR-TKI confounding in the OS analysis. Prospective trials are needed to further corroborate these results.

Safety and efficacy of nimotuzumab in combination with radiotherapy for patients with squamous cell carcinoma of the esophagus.

BACKGROUND: We investigated nimotuzumab (h-R3), a humanized monoclonal antibody against epidermal growth factor receptor, when combined with irradiation or chemoradiation for squamous cell carcinoma (SCC) of the esophagus. The aim of this study was to evaluate its safety and efficacy. METHODS: We retrospectively analyzed 66 patients with esophageal SCC treated with a combination of h-R3 and radiation or chemoradiation between December 2008 and September 2011 at Fudan University Shanghai Cancer Center. Fifty-two of the 66 patients received h-R3 combined with chemoradiation and 14 received h-R3 plus radiation. The median total irradiation dose was 61 Gy given by conventional fractionation. The h-R3 weekly dosage was 100 mg (6/66), 200 mg (54/66), or 400 mg (6/66) given concurrently during the irradiation period. RESULTS: Patients tolerated the treatment well. Grade 3-4 adverse events and toxicities occurred in 50 % of the patients. h-R3-related toxicities manifested as Grade 1 skin rash in 1 case and Grade 2 infusion-related reaction in 2 cases. The median overall survival (OS) and progression-free survival (PFS) were 26.0 months and 16.7 months, respectively. OS, PFS and locoregional control (LC) at 2 years were 54, 37 and 80 %, respectively. CONCLUSIONS: h-R3 in combination with irradiation or chemoradiation was safe and tolerable, and yielded encouraging OS, PFS and LC.

[Expression of Six1 and Six4 in esophageal squamous cell carcinoma and their correlation with clinical prognosis].

OBJECTIVE: Six1 and Six4 are expressed in several tumors, and associated with tumor progress and poor prognosis. The aim of this study was to investigate the expression of Six1 and Six4 in esophageal squamous cell carcinoma (ESCC), and to evaluate their correlation with the clinicopathological factors and prognosis. METHODS: Tissue microarray technology and immunohistochemical method (EnVision) were used to detect the expression of Six1 and Six4 in the tumor tissues and corresponding adjacent normal epithelium of esophagus from 292 ESCC patients. RESULTS: Among the 292 ESCC patients, the positive rates of Six1 and Six4 protein expression in tumor tissues were 72.9% (213/292) and 56.2% (164/292), respectively, significantly higher than the expression rate of 33.2% (97/292) and 32.5% (95/292) in adjacent normal epithelium of esophagus (P < 0.05). Chi square test showed that the expression of Six1 protein was related to tumor size, depth of tumor invasion and patient survival status; higher Six4 protein expression level was related to poor differentiation and increased depth of invasion. Single factor Log-rank analysis revealed that gender, TNM stage, Six1 protein expression level were related to the overall survival of ESCC patients (P < 0.05), while the five-year survival rate was significantly higher in the Six1-negative group than the Six1-positive group [51.9% (41/79) vs. 43.7% (93/213)]. Multi-factor Cox proportional risk model analysis showed that TNM stage and positive expression of Six1 were independent prognostic factors for ESCC patients (P < 0.05). CONCLUSIONS: Six1 and Six4 are highly expressed in ESCC. Their expression levels are closely related to the progress and prognosis of ESCC. Over-expression of Six1 is related to poor prognosis in ESCC patients. Thus, Six1 could be used as an important prognostic indicator for ESCC patients.

[Value of cytopathology in endobronchial ultrasound-guided transbronchial needle aspiration].

OBJECTIVE: To evaluate the role of cytopathology in endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) for lung tumor diagnosis and staging. METHODS: Two-hundred consecutive cases of lung tumor with EBUS-TBNA performed during the period from April, 2009 to September, 2010 in Shanghai Cancer Hospital were retrospectively reviewed. The cytologic diagnoses were categorized as non-diagnostic, negative, suspicious and malignant. When available, cell block preparation and immunohistochemistry were performed. On the 22 positive cases diagnosed by on-site evaluation, epidermal growth factor receptor (EGFR) mutation study was carried out. RESULTS: In the 200 cases of cytology specimens, 122 cases (69.3%) were diagnosed as malignant, 42 cases (23.9%) as benign and 12 cases (6.8%) as suspicious for malignancy. The non-diagnostic rate was 12.0% (24/200). Amongst the 200 cases studied, 140 cases (70.0%) had histologic correlation available (via core biopsy, mediastinoscopic biopsy or surgical excision). The sensitivity and specificity of EBUS-TBNA cytologic diagnoses were 94.4% and 100%, when using histopathologic findings and clinical follow-up data as gold standard. The cell block preparation and immunohistochemistry were useful in subtyping and diagnosis of extrathoracic malignancy. EGFR mutations were detected in 8 cytology samples (36.4%). CONCLUSIONS: EBUS-TBNA is a sensitive and specific tool for diagnosis and staging of lung cancer. The cytology samples can be used for further ancillary investigations including cell block preparation, immunohistochemistry and molecular studies.

Establishment and characterization of primary lung cancer cell lines from Chinese population.

AIM: To establish and characterize primary lung cancer cell lines from Chinese population. METHODS: Lung cancer specimens or pleural effusions were collected from Chinese lung cancer patients and cultured in vitro with ACL4 medium (for non-small cell lung carcinomas (NSCLC)) or HITES medium (for small cell lung carcinomas (SCLC)) supplemented with 5% FBS. All cell lines were maintained in culture for more than 25 passages. Most of these cell lines were further analyzed for oncogenic mutations, karyotype, cell growth kinetics, and tumorigenicity in nude mice. RESULTS: Eight primary cell lines from Chinese lung cancer patients were established and characterized, including seven NSCLC cell lines and one SCLC cell line. Five NSCLC cell lines were found to harbor epidermal growth factor receptor (EGFR) kinase domain mutations. CONCLUSION: These well-characterized primary lung cancer cell lines from Chinese population provide a unique platform for future studies of the ethnic differences in lung cancer biology and drug response.

[Evaluation of the value of EBUS-TBNA in diagnosis of mediastinal lesions].

OBJECTIVE: To evaluate the value of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in diagnosis of mediastinal lesions and to discuss its optimal indication. METHODS: One hundred and twenty three patients with mediastinal lesions who underwent EBUS-TBNA were included in this study. The accuracy, sensitivity, specificity, positive and negative predictive value of EBUS-TBNA in diagnosis of mediastinal lesions were analyzed according to the final diagnosis and evaluate its value and the optimal indication. RESULTS: In the 123 patients, EBUS-TBNA was successfully performed to obtain samples from 286 stations of lymph nodes (2.33 stations/per patient). The puncture success rate was 100%. The procedure was uneventful without complications. Final diagnosis indicated that there were 83 positive and 40 negative patients. EBUS-TBNA had a sensitivity of 95.2%, specificity of 100%, positive predictive value of 100%, negative predictive value of 90.0%, and overall accuracy of 96.8%. For diagnosis of the epithelial cancer, EBUS-TBNA had an accuracy of 98.8%, sensitivity of 98.8%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 100%. EBUS-TBNA failed to reveal three lymphomas. For diagnosis of benign mediastinal diseases, EBUS-TBNA had a diagnosis rate of 47.2% which had a confirmed clinical application value. CONCLUSIONS: EBUS-TBNA may be expected to replace the mediastinoscopy as a superior choice for diagnosis of mediastinal epithelial cancers. EBUS-TBNA can not replace mediastinoscopy but being a promising tool for diagnosis of benign mediastinal lesions including granulomas. For certain special diseases such as lymphoma, mediastinoscopy cannot be replaced. However, EBUS-TBNA can be a potentially favorite choice for early stage screening.

Clinical impact of the tumor immune microenvironment in completely resected stage IIIA(N2) non-small cell lung cancer based on an immunoscore approach.

BACKGROUND: Completely resected stage IIIA(N2) non-small cell lung cancer (NSCLC) comprises a heterogeneous population according to discrepancies in survival prognosis. Accumulating evidence suggests that tumor-infiltrating lymphocytes (TILs) are clinically significant, despite a lack of consensus regarding the immunoscore (IS) in NSCLC. Here, we determined the prognostic value of the immune microenvironment as an IS in a uniform cohort of patients with completely resected stage IIIA(N2) NSCLC. METHODS: Consecutive patients with pathologically confirmed stage IIIA(N2) NSCLC and who underwent complete resection (2005-2012) were retrospectively reviewed. Tissue microarrays (TMAs) were constructed from surgical paraffin-embedded primary lung tumor specimen. For each case, two representative regions from the tumor center (CT) and two from the invasive margin (IM) containing the highest density of lymphocytes were selected. Densities of CD3+, CD45RO+, and CD8+ lymphocytes were assessed using immunohistochemistry (IHC) by specialized pathologists according to predefined scoring scales. Patients were classified according to IS definition based on TIL type, density, and distribution, and relationships between IS and prognosis were evaluated. RESULTS: Patients (N = 288) with complete IHC-based TMA spots were included. Univariate analyses showed that CD3+ T cell density was associated with neither overall survival (OS) nor distant metastasis-free survival (DMFS), whereas CD45RO+ T cell density in the IM was a significant prognostic factor for DMFS (p = 0.02) and was predictive of OS (p = 0.05). Combined CD45RO+ and CD8+ cell infiltration in tumor regions (CT and IM) significantly improved IS prognostic impact. Multivariate analyses revealed IS as an independent prognostic predictor for both DMFS (p = 0.001) and OS (p = 0.002). CONCLUSION: The proposed IS might provide valuable prognostic information, including prediction of DMFS and OS in stage IIIA(N2) NSCLC patients. Larger patient cohorts are needed to validate this IS classification, which might assist with accurate risk stratification and treatment decisions.

Intensity Modulated Radiation Therapy Plus Etoposide/Cisplatin for Patients With Limited Advanced Unresectable Thymic Epithelial Tumors: A Prospective Phase 2 Study.

PURPOSE: This prospective phase 2 study evaluated the efficacy and safety of intensity modulated radiation therapy plus etoposide/cisplatin (EP) for patients with unresectable thymic epithelial tumors (TETs). METHODS AND MATERIALS: Patients with limited advanced unresectable TETs whose lesions could be encompassed within radiation fields were enrolled in this study. Two cycles of EP (75 mg/m2 etoposide and 25 mg/m2 cisplatin on days 1-3 and days 29-31) were administered concurrently with radiation therapy, followed by 2 cycles after radiation therapy. The primary endpoint was the objective response rate. The secondary endpoints were the progression-free survival rate, overall survival rate, and incidence of adverse events. RESULTS: Fifty-six patients were enrolled between June 2011 and May 2018. Twenty-two and 34 patients had thymomas and thymic carcinomas, respectively. The median age was 52 (range, 21-76) years, and 30 patients (53.6%) were men. Eight patients (14.3%) had stage III tumors, 6 (10.7%) had stage IVA tumors, and 42 (75.0%) had stage IVB tumors. The objective response rate was 85.7% (95% confidence interval, 76.3%-95.2%). With a median follow-up of 46 (range, 7-101) months, the 1-, 2-, and 5-year progression-free survival rates were 66.1%, 48.0%, and 29.5%, and the 1-, 2-, and 5-year overall survival rates were 91.0%, 76.2%, and 56.2%, respectively. The most common grade 3 to 4 adverse event was leukopenia (42.9%). Pulmonary fibrosis was also observed (5.3%). CONCLUSIONS: Because intensity modulated radiation therapy with EP is effective and safe for limited advanced unresectable TETs, it could be a suitable treatment option for such patients.

[CT-guided hookwire localization of small solitary pulmonary nodules in video-assisted thoracoscopic surgery].

OBJECTIVE: Video-assisted thoracoscopic surgery (VATS) provides a minimally invasive approach to resect small solitary pulmonary nodules (SSPN). The aim of this study is to evaluate the efficacy and safety of preoperative CT-guided hookwire localization for SSPN in VATS. METHODS: Hookwire was used to localize 26 SSPN under CT guidance in 24 patients (14 male, 10 female, age range 21-61 years, mean 52.3 years), preoperatively, and wedge resection was performed through VATS. The lesion size, distance from the lesion to parietal pleura, the time of localization and complications were evaluated. RESULTS: All the 26 pulmonary nodules were preoperatively detected and localized with hookwire under CT-guidance. The mean lesion size was 10.05 +/- 3.08 mm in diameter, and the mean distance from lesion to parietal pleura was 10.09 +/- 2.62 mm. The mean localization time was 20.18 +/- 7.16 min, and then the nodules were removed by VATS within 18 +/- 6.65 min. The major complication of CT-guided hookwire localization was mild pneumothorax in 6 patients (25.0%), but no one needed chest tube drainage. The dislodgment of hookwire was found in only one patient (4.2%) during the operation, but the lesion was still successfully resected under VATS. Of those patients, 8 were confirmed to have a primary NSCLC by rapid pathologic diagnosis during VATS wedge resection, and then VATS lobectomies were performed. CONCLUSION: The preoperative CT-guided hookwire localization for small solitary pulmonary nodules is an effective and safe technique to assist VATS resection of the nodules.

Synergistic inhibitory activity of zoledronate and paclitaxel on bone metastasis in nude mice.

Zoledronic acid (Zometa, ZOL) and cytotoxic chemotherapy agents have been reported to have synergistic antitumor activities. However, there is limited data on the effects of combination therapies on the development of bone metastasis in animal models of lung cancer. The purpose of this study was to establish a human lung adenocarcinoma cell line with high bone metastatic potential in an immunodeficient mouse model and to evaluate the synergistic inhibitory activity of zoledronate and paclitaxel (P) on bone metastasis in nude mice. A human lung adenocarcinoma cell line with high bone metastatic potential (SPC-A1-BM) was established by 10 rounds of in vivo selection. Cells were inoculated into the cardiac ventricle of NIH-BNX mice, which were treated 8 days later with: ZOL (0.2 mg/kg s.c. twice weekly) alone, P (6.0 mg/kg every week, i.p.) alone, P + ZOL, or vehicle (10 mice per group). Tumor growth was evaluated with bone scans, X-rays and in situ immunohistochemistry. Serum n-telopeptide of type I collagen (NTX) was measured by ELISA. Survival was assessed using the Kaplan-Meier method. Bone scan, radiographic and histological assessments revealed fewer bone metastases in all treatment groups vs. vehicle, with P + ZOL significantly reducing the incidence of bone metastases detected by bone scans (P=0.020) and X-rays (P=0.036). A histological analysis revealed marginal differences in the number of bone metastases between P + ZOL and vehicle (P=0.058). There was a trend towards differences in survival between the groups (P=0.1511) and survival was significantly longer for the P + ZOL group vs. vehicle (P=0.022). Compared with vehicle and ZOL alone, cancerous cells in the bone of mice treated with P + ZOL expressed higher levels of Bax and lower levels of Bcl-2 and Bcl-xl. ZOL produced a trend towards reduced NTX levels vs. vehicle and P + ZOL produced a profound reduction in NTX vs. vehicle (P=0.022). The results of this study indicated that zoledronate enhanced the efficacy of paclitaxel synergistically, by reducing the incidence of bone metastasis from lung cancer and prolonging survival in a mouse model of non-small cell lung cancer with a high potential for metastasis to bone.

[Serum proteomic patterns may assist the diagnosis of solitary pulmonary nodules].

OBJECTIVE: To screen relatively specific biomarkers in serum from lung adenocarcinoma patients by surface-enhanced laser desorption and ionization time of flight mass spectrometry (SELDI-TOFMS), and to investigate the clinical value of SELDI-TOF-MS in differentiation of benign from malignant solitary pulmonary nodules (SPN). METHODS: Serum samples from 71 lung adenocarcinoma patients and 71 healthy volunteers with matched gender, age and history of smoking were analyzed using WCX2 ProteinChip to screen potential biomarkers. 28 patients received surgical treatment among total 53 patients with SPN. The clinical value of SELDI-TOF-MS in differentiation of benign from malignant solitary pulmonary nodules was evaluated by pathological diagnosis. RESULTS: Five highly expressed potential biomarkers were identified with the relative molecular weights of 4047.79 Da, 4203.99 Da, 4959. 81 Da, 5329. 30 Da and 7760.12 Da. The postoperative pathologic diagnosis was lung adenocarcinoma in 24 patients with SPN, validating the clinical value of the 5 potential biomarkers. CONCLUSION: SELDI-TOF-MS technology is a quick, easy, convenient, and high-throughput analyzing method capable of screening several relatively specific potential biomarkers from the serum of lung adenocarcinoma patients and may have attractive clinic value in differentiation of solitary pulmonary nodules.

Prognostic value of tumor-infiltrating lymphocytes for patients with completely resected stage IIIA(N2) non-small cell lung cancer.

BACKGROUND: The patient prognosis after complete resection for pathologic stage IIIA(N2) non-small cell lung cancer (NSCLC) remains a significant concern. The clinical relevance of the host immune response to NSCLC has yet to be established. We aimed to investigate the prognostic value of tumor-infiltrating lymphocytes (TILs) in a uniform cohort of patients with completely resected stage IIIA(N2) NSCLC. METHODS: From 2005 to 2012, consecutive patients with pathologic stage IIIA(N2) NSCLC who underwent complete resection at our institution were reviewed. For each case, full-face hematoxylin and eosin-stained sections from surgical specimens were evaluated for the TIL density. A published, recommended TIL scoring scale was followed. The patients were stratified into the TIL- or TIL+ group based on pathologic evaluation. RESULTS: Data from 320 patients were included in the analysis. Based on a median follow-up duration of 30.8 months, a higher density of TILs was associated with an improved postoperative survival time (P = 0.06). Subgroup analyses indicated that this positive effect was the greatest for patients with squamous cell carcinoma (SCC; P = 0.03). Among those with SCC, the TIL+ patients experienced a significantly increased 3-year distant metastasis-free survival (DMFS) compared to the TIL- patients (60.6% versus 42.7%, P = 0.02). Multivariate analyses of the 93 patients with SCC tumors confirmed that TIL+ was an independent prognostic factor for an increased DMFS (HR = 0.39, 95%CI 0.17-0.87, P = 0.02) and a prolonged overall survival (OS; HR = 0.47, 95%CI 0.22-1.00, P = 0.05). CONCLUSIONS: Our data suggest a potential role of TILs in predicting the survival of patients with completely resected stage IIIA(N2) NSCLC. The beneficial effects of TILs were more pronounced in the prediction of the DMFS and the OS in patients with SCC. This parameter should be considered for prospective inclusion in clinical trials.

High EGFR and low p-Akt expression is associated with better outcome after nimotuzumab-containing treatment in esophageal cancer patients: preliminary clinical result and testable hypothesis.

The epidermal growth factor receptor (EGFR) is widely overexpressed in esophageal squamous cell carcinoma (ESCC) and it results is associated with a poor prognosis. Identifying the subgroup of ESCC patients who are sensitive to EGFR-targeted therapy is a key point to facilitate its medical use.We retrospectively analyzed 32 ESCC patients treated with the combination of nimotuzumab (h-R3) and radiotherapy (RT) or chemoradiotherapy (CRT). Expression of EGFR and phosphorylated proteins associated with EGFR signaling pathway, i.e. p-Akt and p-Erk, were assessed with immunohistochemistry (IHC) for all patients. Correlations between these proteins' expression levels and overall survival (OS) were assessed.High expression of EGFR, p-Akt and p-Erk was detected in 53.1% (17/32), 54.8% (17/31) and 59.4% (19/32) of tumors respectively. No significant differences in OS were found between high EGFR, p-Akt and p-Erk expression groups and their respective counterparts. Of note, significantly better overall survival was observed in patients with coexistence of high EGFR expression and low p-Akt expression (p = 0.030).Our data allowed us to put forward a hypothesis that high EGFR and low p-Akt expression may predict a clinical benefit of EGFR antagonists such as nimotuzumab combined with RT or CRT. This can be discussed in the terms of oncogene addiction and synthetic lethality concepts. This hypothesis can be further tested in larger groups of patients.

Patterns of failure after radical surgery among patients with thoracic esophageal squamous cell carcinoma: implications for the clinical target volume design of postoperative radiotherapy.

BACKGROUND: This study evaluated patterns of treatment failure (especially locoregional failure; LRF) after radical esophagectomy and proposes a clinical target volume (CTV) for postoperative radiotherapy (PORT) among patients with thoracic esophageal squamous cell carcinoma (SCC). METHODS: All patients who were followed up in our center after radical esophagectomy between 2007 and 2011 were retrospectively enrolled. The patterns of first discovered failure were assessed, and LRFs (including anastomotic and regional lymph node recurrences) were evaluated to determine whether our proposed PORT CTV encompassed these areas. The clinicopathologic factors predictive of lymphatic recurrence type were analyzed. RESULTS: Of the 414 patients who underwent surgery and were followed up over the study, 207 experienced recurrent or metastatic diseases. The median time to progression was 11.0 months. Of the 173 patients with locoregional recurrence, nodal failure recurred in 160; supraclavicular and superior mediastinal lymph nodes had the highest metastasis rates. All 233 recurrent sites across the 160 patients were located in a standard CTV area, including the bilateral supraclavicular areas, the entire mediastinum, and the left gastric lymphatic drainage region. A total of 203 sites (87.2%) were located in either the bilateral supraclavicular areas or the entire mediastinum, and 185 sites (79.4%) were located in either the bilateral supraclavicular areas or the upper mediastinum. A multivariate analysis revealed the lymph node metastatic ratio (LNMR) and tumor differentiation were risk factors for nodal failure. CONCLUSIONS: Locoregional recurrence (especially lymph node recurrence) was the most common and potentially preventable type of initial treatment failure after curative surgery among patients with thoracic esophageal SCC. The proposed PORT CTV covered most LRF sites. The lymphatic drainage regions for PORT are selective, and the supraclavicular and superior mediastinal areas should be considered. However, the value of PORT and the extent of CTV should be investigated in further prospective studies.

Patterns of local-regional failure in completely resected stage IIIA(N2) non-small cell lung cancer cases: implications for postoperative radiation therapy clinical target volume design.

PURPOSE: To analyze patterns of local-regional failure (LRF) for completely resected stage IIIA(N2) non-small cell lung cancer (NSCLC) patients treated in our hospital and to propose a clinical target volume (CTV) for postoperative radiation therapy (PORT) in these patients. METHODS AND MATERIALS: From 2005 to 2011, consecutive patients with pT1-3N2 NSCLC who underwent complete resection in our hospital but who did not receive PORT were identified. The patterns of first LRF were assessed and evaluated as to whether these areas would be encompassed by our proposed PORT CTV. RESULTS: With a median follow-up of 24 months, 173 of 250 patients (69.2%) experienced disease recurrence. Of the 54 patients with LRF as the first event, 48 (89%) had recurrence within the proposed PORT CTV, and 6 (11%) had failures occurring both within and outside the proposed CTV (all of which occurred in patients with right-lung cancer). Ninety-three percent of failure sites (104 of 112) would have been contained within the proposed PORT CTV. For left-sided lung cancer, the most common lymph node station failure site was 4R, followed by 7, 4L, 6, 10L, and 5. For right-sided lung cancer, the most common site was station 2R, followed by 10R, 4R, and 7. CONCLUSIONS: LRF following complete surgery was an important and potentially preventable pattern of failure in stage IIIA(N2) patients. Ipsilateral superior mediastinal recurrences dominated for right-sided tumors, whereas left-sided tumors frequently involved the bilateral superior mediastinum. Most of the LRF sites would have been covered by the proposed PORT CTV. A prospective investigation of patterns of failure after PORT (following our proposed CTV delineation guideline) is presently underway and will be reported in a separate analysis.

CYP19A1 gene polymorphisms and risk of lung cancer.

OBJECTIVES: To investigate the association between polymorphisms of aromatase (encoded by the CYP19A1 gene and a key enzyme in biosynthesis of oestradiol) and the risk of lung cancer, and whether there were differences stratified by sex and smoking history. METHODS: This case-control study included consecutive, nonselected and pathologically-confirmed lung cancer patients and healthy people. Participants were classed as nonsmokers or smokers by questionnaire. Peripheral blood samples from all participants were genotyped for three single-nucleotide polymorphism (SNPs; rs727479, rs730154 and rs10046); allelic frequencies were compared across genotype and clinical records. RESULTS: A total of 529 patients with lung cancer and 567 age- and sex-matched controls were included. After adjustment for age, sex and smoking history, rs727479 was significantly associated with the incidence of lung cancer (for alleles AC vs AA). There was also a significant difference between patients and controls in haplotype CCA, while haplotype ACA was only significantly associated with nonsmokers and female nonsmokers. CONCLUSIONS: Polymorphisms of CYP19A1 may be related to the increased risk of lung cancer; in particular, haplotype ACA may contribute to lung-cancer progression in nonsmokers. Further validation with larger populations is required.

Polymorphisms in the ERCC5 gene and risk of esophageal squamous cell carcinoma (ESCC) in Eastern Chinese populations.

BACKGROUND: Excision repair cross complementing group 5 (ERCC5 or XPG) plays an important role in regulating DNA excision repair; its functional single nucleotide polymorphisms (SNPs) may alter DNA repair capacity and thus contribute to cancer risk. METHODOLOGY/PRINCIPAL FINDINGS: In a hospital-based case-control study of 1115 esophageal squamous cell carcinoma (ESCC) cases and 1117 cancer-free controls, we genotyped three potentially functional SNPs of ERCC5 (SNPs, rs2296147T>C, rs2094258C>T and rs873601G>A) and estimated crude and adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for their associations with risk of ESCC using unconditional logistic regression models. We also calculated false-positive report probabilities (FPRPs) for significant findings. We found that compared with the TT genotype, ERCC5 rs2296147 C variant genotypes were associated with a significantly lower ESCC risk (CT: adjusted OR = 0.76, 95% CI = 0.63-0.93, CT/CC: adjusted OR = 0.80, 95% CI = 0.67-0.96); however, this risk was not observed for the other two SNPs (rs2094258C>T and rs873601 G>A), nor in further stratification and haplotype analysis. CONCLUSIONS/SIGNIFICANCES: These findings suggested that ERCC5 polymorphisms may contribute to risk of ESCC in Eastern Chinese populations, but the effect was weak and needs further validation by larger population-based case-control studies.

Association between gene polymorphism of CD14-159 (C/T) and allergic asthma.

The objective of this study was to evaluate the possible association between the CD14-159 polymorphism and adult asthma in the Chinese population. A total of 188 asthmatic patients and 60 healthy adults were enrolled in the present study, and the CD14-159 polymorphism was genotyped using the polymerase chain reaction-restriction fragment length polymorphism (PCR­RFLP) analysis. The results showed that the frequencies of CC, CT and TT genotypes were 12.2, 47.9, and 39.9%, respectively, in the asthma group, and 8.3, 50.0, and 41.7%, respectively, in healthy adults, with no statistical difference between the two groups (P>0.05). The frequencies of C and T allele were 36.2 and 63.8%, respectively, in the asthma group, 33.3 and 66.7%, respectively, in the healthy group, and no statistical difference was observed in the allele frequencies between the two groups (P>0.05). Our data suggest that the CD14-159 polymorphism is not associated with adult asthma in Chinese population.