Jianxing He

A practical molecular assay to predict survival in resected non-squamous, non-small-cell lung cancer: development and international validation studies.

BACKGROUND The frequent recurrence of early-stage non-small-cell lung cancer (NSCLC) is generally attributable to metastatic disease undetected at complete resection. Management of such patients depends on prognostic staging to identify the individuals most likely to have occult disease. We aimed to develop and validate a practical, reliable assay that improves risk stratification compared with conventional staging. METHODS A 14-gene expression assay that uses quantitative PCR, runs on formalin-fixed paraffin-embedded tissue samples, and differentiates patients with heterogeneous statistical prognoses was developed in a cohort of 361 patients with non-squamous NSCLC resected at the University of California, San Francisco. The assay was then independently validated by the Kaiser Permanente Division of Research in a masked cohort of 433 patients with stage I non-squamous NSCLC resected at Kaiser Permanente Northern California hospitals, and on a cohort of 1006 patients with stage I-III non-squamous NSCLC resected in several leading Chinese cancer centres that are part of the China Clinical Trials Consortium (CCTC). FINDINGS Kaplan-Meier analysis of the Kaiser validation cohort showed 5 year overall survival of 71·4% (95% CI 60·5-80·0) in low-risk, 58·3% (48·9-66·6) in intermediate-risk, and 49·2% (42·2-55·8) in high-risk patients (p(trend)=0·0003). Similar analysis of the CCTC cohort indicated 5 year overall survivals of 74·1% (66·0-80·6) in low-risk, 57·4% (48·3-65·5) in intermediate-risk, and 44·6% (40·2-48·9) in high-risk patients (p(trend)<0·0001). Multivariate analysis in both cohorts indicated that no standard clinical risk factors could account for, or provide, the prognostic information derived from tumour gene expression. The assay improved prognostic accuracy beyond National Comprehensive Cancer Network criteria for stage I high-risk tumours (p<0·0001), and differentiated low-risk, intermediate-risk, and high-risk patients within all disease stages. INTERPRETATION Our practical, quantitative-PCR-based assay reliably identified patients with early-stage non-squamous NSCLC at high risk for mortality after surgical resection. FUNDING UCSF Thoracic Oncology Laboratory and Pinpoint Genomics.

Development and validation of a nomogram for predicting survival in patients with resected non-small-cell lung cancer.

PURPOSE A nomogram is a useful and convenient tool for individualized cancer prognoses. We sought to develop a clinical nomogram for predicting survival of patients with resected non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS On the basis of data from a multi-institutional registry of 6,111 patients with resected NSCLC in China, we identified and integrated significant prognostic factors for survival to build a nomogram. The model was subjected to bootstrap internal validation and to external validation with a separate cohort of 2,148 patients from the International Association for the Study of Lung Cancer (IASLC) database. The predictive accuracy and discriminative ability were measured by concordance index (C-index) and risk group stratification. RESULTS A total of 5,261 patients were included for analysis. Six independent prognostic factors were identified and entered into the nomogram. The calibration curves for probability of 1-, 3-, and 5-year overall survival (OS) showed optimal agreement between nomogram prediction and actual observation. The C-index of the nomogram was higher than that of the seventh edition American Joint Committee on Cancer TNM staging system for predicting OS (primary cohort, 0.71 v 0.68, respectively; P < .01; IASLC cohort, 0.67 v 0.64, respectively; P = .06). The stratification into different risk groups allowed significant distinction between survival curves within respective TNM categories. CONCLUSION We established and validated a novel nomogram that can provide individual prediction of OS for patients with resected NSCLC. This practical prognostic model may help clinicians in decision making and design of clinical studies.

BEYOND: A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Phase III Study of First-Line Carboplatin/Paclitaxel Plus Bevacizumab or Placebo in Chinese Patients With Advanced or Recurrent Nonsquamous Non–Small-Cell Lung Cancer

PURPOSE The phase III BEYOND trial was undertaken to confirm in a Chinese patient population the efficacy seen with first-line bevacizumab plus platinum doublet chemotherapy in globally conducted studies. PATIENTS AND METHODS Patients age ≥ 18 years with locally advanced, metastatic, or recurrent advanced nonsquamous non-small-cell lung cancer (NSCLC) were randomly assigned to receive carboplatin (area under the curve, 6) intravenously and paclitaxel (175 mg/m(2)) intravenously (CP) on day 1 of each 3-week cycle, for ≤ six cycles, plus placebo (Pl+CP) or bevacizumab (B+CP) 15 mg/kg intravenously, on day 1 of each cycle, until progression, unacceptable toxicity, or death. The primary end point was progression-free survival (PFS); secondary end points were objective response rate, overall survival, exploratory biomarkers, safety. RESULTS A total of 276 patients were randomly assigned, 138 to each arm. PFS was prolonged with B+CP versus Pl+CP (median, 9.2 v 6.5 months, respectively; hazard ratio [HR], 0.40; 95% CI, 0.29 to 0.54; P < .001). Objective response rate was improved with B+CP compared with Pl+CP (54% v 26%, respectively). Overall survival was also prolonged with B+CP compared with Pl+CP (median, 24.3 v 17.7 months, respectively; HR, 0.68; 95% CI, 0.50 to 0.93; P = .0154). Median PFS was 12.4 months with B+CP and 7.9 months with Pl+CP (HR, 0.27; 95% CI, 0.12 to 0.63) in EGFR mutation-positive tumors and 8.3 and 5.6 months, respectively (HR, 0.33; 95% CI, 0.21 to 0.53), in wild-type tumors. Safety was similar to previous studies of B+CP in NSCLC; no new safety signals were observed. CONCLUSION The addition to bevacizumab to carboplatin/paclitaxel was well tolerated and resulted in a clinically meaningful treatment benefit in Chinese patients with advanced nonsquamous NSCLC.

Prognostic Significance of Programmed Cell Death 1 (PD-1) or PD-1 Ligand 1 (PD-L1) Expression in Epithelial-Originated Cancer: A Meta-Analysis

AbstractThe expression of programmed cell death 1 (PD-1) and its ligand (PD-L1) has been observed in various epithelial-originated malignancies. However, whether the expression of PD-L1 on tumor cells or the expression of PD-1 on tumor-infiltrating lymphocytes (TILs) is associated with patients’ survival remains controversial.Electronic databases were searched for eligible literatures. Data of hazard ratio (HR) for overall survival (OS) with 95% confidence interval (CI) according to the expression status of PD-L1 or PD-1 evaluated by immunohistochemistry were extracted. The outcomes were synthesized based on random-effects model. Subgroup analyses were proposed.Twenty-nine studies covering 12 types of epithelial-originated malignancies involving 7319 patients (2030/3641 cases for PD-L1 positive/negative, 505/1143 cases for PD-1 positive/negative) with available data of the outcome stratified by PD-L1/PD-1 status were enrolled. Epithelial-originated cancer patients with positive expression of PD-L1 on tumor tissues were associated with significantly poorer OS when compared to those with negative expression of PD-L1 (HR 1.81, 95% CI 1.33–2.46, P < 0.001). Similarly, patients with PD-1 positive expression on TILs had significantly shorter OS than the PD-1 negative group (HR 2.53, 95% CI 1.22–5.21, P = 0.012). In analyses of PD-L1, all subgroups showed consistent trends toward unfavorable prognoses of patients with positive PD-L1 expression, regardless of antibodies and evaluation cutoffs. Subgroup analyses on PD-1 were not available due to limited data.PD-L1 or PD-1 expression status is a significant prognostic factor in epithelial-originated malignancies.

Nonintubated Video-Assisted Thoracoscopic Surgery Under Epidural Anesthesia Compared With Conventional Anesthetic Option A Randomized Control Study

Objective. The purposes of this study were to evaluate the feasibility, safety, and advantages of nonintubated video-assisted thoracoscopic surgery (VATS) under epidural anesthesia, by comparing with the performance of conventional approaches. Patients and methods. A total of 354 patients (245 men and 109 women) were recruited in this study. The surgical procedures included bullae resection, pulmonary wedge resection, and lobectomy. The anesthetic technique (epidural vs general) was selected randomly. Patients who underwent nonintubated VATS under epidural anesthesia comprised the intervention group, and patients who received VATS under general anesthesia with double lumen tube comprised the control group. Results. In total, 167 patients were included in the intervention group, and 180 patients were included in the control group. The 2 treatment groups of bullae resection showed significant differences in postoperative fasting time, duration of postoperative antibiotic use depending on the time when the white blood cells decreased to normal levels, and duration of postoperative hospital stay (P < .05). Nonintubated VATS is associated with a decreased level of inflammatory cytokines (P < .05). Conclusion. VATS under anesthesia with nontracheal intubation is safe and feasible, and has demonstrated advantages, including shorter postoperative fasting time, shorter duration of antibiotic use, and shorter hospital stay, compared with VATS under general anesthesia with double lumen tube.

Choice of Surgical Procedure for Patients With Non-Small-Cell Lung Cancer ≤ 1 cm or > 1 to 2 cm Among Lobectomy, Segmentectomy, and Wedge Resection: A Population-Based Study.

PURPOSE According to the lung cancer staging project, T1a (≤ 2 cm) non-small-cell lung cancer (NSCLC) should be additionally classified into ≤ 1 cm and > 1 to 2 cm groups. This study aimed to investigate the surgical procedure for NSCLC ≤ 1 cm and > 1 to 2 cm. METHODS We identified 15,760 patients with T1aN0M0 NSCLC after surgery from the Surveillance, Epidemiology, and End Results database. Overall survival (OS) and lung cancer-specific survival (LCSS) were compared among patients after lobectomy, segmentectomy, or wedge resection. The proportional hazards model was applied to evaluate multiple prognostic factors. RESULTS OS and LCSS favored lobectomy compared with segmentectomy or wedge resection in patients with NSCLC ≤ 1 cm and > 1 to 2 cm. Multivariable analysis showed that segmentectomy and wedge resection were independently associated with poorer OS and LCSS than lobectomy for NSCLC ≤ 1 cm and > 1 to 2 cm. With sublobar resection, lower OS and LCSS emerged for NSCLC > 1 to 2 cm after wedge resection, whereas similar survivals were observed for NSCLC ≤ 1 cm. Multivariable analyses showed that wedge resection is an independent risk factor of survival for NSCLC > 1 to 2 cm but not for NSCLC ≤ 1 cm. CONCLUSION Lobectomy showed better survival than sublobar resection for patients with NSCLC ≤ 1 cm and > 1 to 2 cm. For patients in whom lobectomy is unsuitable, segmentectomy should be recommended for NSCLC > 1 to 2 cm, whereas surgeons could rely on surgical skills and the patient profile to decide between segmentectomy and wedge resection for NSCLC ≤ 1 cm.

Video-assisted thoracic surgery versus open thoracotomy for non-small-cell lung cancer: a propensity score analysis based on a multi-institutional registry

OBJECTIVES Comparative long-term survival and oncological outcomes for patients with non-small-cell lung cancer (NSCLC) who undergo video-assisted thoracic surgery (VATS) or conventional open lobectomy remain uncertain. We conducted a multi-institutional propensity-matched study to stratify potential differences in these outcomes. METHODS We established a multi-institutional registry for 4312 patients with NSCLC who underwent lobectomy between 2001 and 2008 from eight institutions in the Peoples Republic of China. Age, gender, histological type and tumour staging were entered into a non-parsimonious multivariable logistic regression model to assess long-term survival outcomes. The predicted probability derived from the logistic equation was used as the propensity score for each individual. Based on similar propensity scores, we matched 1458 of the 1700 patients who underwent VATS lobectomy with 1458 of the 2612 patients who underwent open lobectomy and compared their long-term survival outcomes. RESULTS The mean age of the 2916 matched patients was 59 (standard deviation = 11) years. After propensity-matching, VATS and open lobectomy patients were similar in regards to important prognostic variables. Three prognostic factors were independently associated with improved survival in the multivariate analysis: age < 60 (P < 0.001), female gender (P = 0.013) and pathological staging (P < 0.001). Patients who underwent VATS vs open lobectomy had similar long-term survival (P = 0.07). CONCLUSIONS The current propensity score analysis suggests that well-matched patients with NSCLC who underwent standardized VATS lobectomy had similar long-term survival outcomes when compared with those who underwent open lobectomy.

MethylPurify: tumor purity deconvolution and differential methylation detection from single tumor DNA methylomes

We propose a statistical algorithm MethylPurify that uses regions with bisulfite reads showing discordant methylation levels to infer tumor purity from tumor samples alone. MethylPurify can identify differentially methylated regions (DMRs) from individual tumor methylome samples, without genomic variation information or prior knowledge from other datasets. In simulations with mixed bisulfite reads from cancer and normal cell lines, MethylPurify correctly inferred tumor purity and identified over 96% of the DMRs. From patient data, MethylPurify gave satisfactory DMR calls from tumor methylome samples alone, and revealed potential missed DMRs by tumor to normal comparison due to tumor heterogeneity.

STV11 encodes a sulphotransferase and confers durable resistance to rice stripe virus

Rice stripe virus (RSV) causes one of the most serious viral diseases of rice (Oryza sativa L.), but the molecular basis of RSV resistance has remained elusive. Here we show that the resistant allele of rice STV11 (STV11-R) encodes a sulfotransferase (OsSOT1) catalysing the conversion of salicylic acid (SA) into sulphonated SA (SSA), whereas the gene product encoded by the susceptible allele STV11-S loses this activity. Sequence analyses suggest that the STV11-R and STV11-S alleles were predifferentiated in different geographic populations of wild rice, Oryza rufipogon, and remained prevalent in cultivated indica and japonica rice varieties, respectively. Introgression of the STV11-R allele into susceptible cultivars or heterologous transfer of STV11-R into tobacco plants confers effective resistance against RSV. Our results shed new insights into plant viral defense mechanisms and suggest effective means of breeding RSV-resistant crops using molecular marker-assisted selection or genetic engineering.

Anesthesia with nontracheal intubation in thoracic surgery

OBJECTIVE To study one-lung respiration during VATS wedge resection of bullae and pulmonary nodules with nontracheal intubation, and to explore the changes of vital signs when patients return to two-lung ventilation. METHODS Twenty-two patients with normal cardiopulmonary function and absence of contraindications to epidural anesthesia were included in this study. VATS wedge resection of bullae or pulmonary nodules was performed. 0.5% Ropivacain was administrated for epidural anesthesia (T8-9), and 2 mL of 2% lidocaine was used for local anesthetic block of the intrathoracic vagus nerves. The BIS value was maintained between 50 and 70 by target-controlled infusion of propofol and remifentanil. Electrocardiogram (ECG), heart rate (HR), blood pressure (Bp), pulse oxygen saturation (SpO(2)), respiratory rate (RR), bispectral index (BIS) and urine volume were monitored. RESULTS None patients were converted to endotracheal intubation during anesthesia. MAP and SpO(2) after wound disclosure were stable (P>0.05), level of CVP significantly elevated, HR and RR increased (P<0.05), PaCO(2) increased gradually while PaO(2) remained stable. Fifteen minutes after wound closure, MAP, RR and SpO(2) returned to their pre-anesthesia levels, PH value gradually recovered, PaCO(2) tended to decrease and returned to normal one hour after wound closure. Physical agitation occurred in one case due to inadequate epidural anesthesia during skin incision. Cough before intrathoracic vagal blockade was noted in two cases (9.1%) because of lobe traction. CONCLUSIONS Nontracheal intubation is feasible in VATS wedge resection of bullae and pulmonary nodules. The patients are with stable intraoperative vital signs and none experiences hypoxemia; intraoperative hypercapnia is tolerable and transient, which can be improved quickly when bilateral lungs resume spontaneous respiration.