Mutation Profile of Resected EGFR-Mutated Lung Adenocarcinoma by Next-Generation Sequencing.

BACKGROUND: The efficacy of adjuvant targeted therapy for operable lung cancer is still under debate. Comprehensive genetic profiling is needed for detecting co-mutations in resected epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma (ADC), which may interfere the efficacy of adjuvant tyrosine kinase inhibitor (TKI) treatment. MATERIALS AND METHODS: Mutation profiling of 416 cancer-relevant genes was conducted for 139 resected stage I-IIIa lung ADCs with EGFR mutations using targeted next-generation sequencing. Co-mutation profiles were systematically analyzed. RESULTS: Rare EGFR alterations other than exon 19 deletion and L858R, such as L861Q (∼3%) and G719A (∼2%), were identified at low frequencies. Approximately 10% of patients had mutations in EGFR exon 20 that could confer resistance to first-generation TKIs. Ninety-one percent of patients harbored at least one co-mutation in addition to the major EGFR mutation. TP53 was the top mutated gene and was found more frequently mutated at later stage. Markedly, NF1 mutations were found only in stage II-III ADCs. Conversely, RB1 mutations were more frequent in stage I ADCs, whereas APC mutations were observed exclusively in this group. Thirty-four percent of patients with EGFR TKI-sensitizing mutations had genetic alterations involving EGFR downstream effectors or bypass pathways that could affect the response to EGFR TKIs, such as PIK3CA, BRCA1, and NOTCH1. CONCLUSION: Operable lung ADCs with EGFR TKI-sensitizing mutations are associated with a high proportion of co-mutations. Mutation profiling of these resected tumors could facilitate in determining the applicability and efficacy of adjuvant EGFR TKI therapeutic strategy. IMPLICATIONS FOR PRACTICE: The efficacy of adjuvant epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy for lung cancer harboring EGFR mutation after surgical resection is still under debate. Next-generation sequencing of 416 cancer-relevant genes in 139 resected lung cancers revealed the co-mutational landscape with background EGFR mutation. Notably, the study identified potential EGFR TKI-resistant mutations in 34.71% of patients with a drug-sensitizing EGFR mutation and who were naive in terms of targeted therapy. A comprehensive mutation profiling of these resected tumors could facilitate in determining the applicability and efficacy of adjuvant EGFR TKI therapeutic strategy for these patients.

[Design, synthesis of novel N, N'-bis-(halogenophenyl)-4- methoxybenzene-1, 3-disulfonamides and evaluation of their anti-platelet aggregation activity].

Combining the structural features of picotamide and linotroban, a series of N,N'-bis-(halogenophenyl)-4-methoxybenzene-1, 3-disulfonamides were designed and synthesized on the basic principles of drug design. The structures of target compounds were confirmed by IR, 1H NMR and HR-MS, and the in vitro antiplatelet aggregation activity was evaluated by Born turbidimetric method with adenosine diphosphate (ADP) as the platelet aggregation inducers. The assay results showed that twelve compounds (4b, 4f, 4l, 5b, 5d-5g, 5j, 5k, 5m and 5n) were found to have superior anti-platelet aggregation activities than the positive drug picotamide. The preliminary structure-activity relationship (SAR) has been explored.

Effects of CXCR4 gene silencing by lentivirus shRNA on proliferation of the EC9706 human esophageal carcinoma cell line.

CXCL12/CXCR4 has been studied as an important biomarker for many human malignancies, but studies are limited for esophageal squamous cell carcinoma (ESCC). In this study, an effective RNAi sequence targeting the CXCR4 gene was selected, a lentiviral shRNA vector was constructed to specifically silence CXCR4 expression in the EC9706 ESCC cell line, and the effects of CXCR4 silencing on cell growth in vitro and tumour growth in nude mice were then evaluated. The expression of CXCR4 in EC9706 was significantly downregulated after transfection with a lentiviral shRNA vector. The expression of the apoptosis-related gene Bcl-2 was decreased. In addition, after CXCR4 inhibition, cell growth was considerably inhibited, increased apoptosis in the EC9706 cells was found, the G0/G1 percentage was significantly increased, and the number of cells in S phase was reduced. Moreover, tumour growth in nude mice was inhibited. In conclusion, the downregulation of CXCR4 expression by transfection with a lentiviral shRNA vector in ESCC cells could inhibit tumour proliferation. Our data may provide an avenue for finding new ESCC treatments.

Complete mediastinal lymph node dissection in video-assisted thoracoscopic lobectomy versus lobectomy by thoracotomy.

BACKGROUND: Although video-assisted thoracic surgery (VATS) lobectomy has been used more and more frequently for the treatment of patients with early-stage lung cancer, controversies are mainly focused on whether the complete mediastinal lymph node dissection (MLND) can be achieved by VATS. This retrospective study aimed to compare the validity of MLND between VATS and open thoracotomy. METHODS: Patients with lung cancer were matched from a pool of pulmonary lobectomies performed by one surgeon. Patients undergoing VATS were matched with those undergoing thoracotomy in terms of gender, age, clinical tumor stage, tumor location, and surgical procedure. RESULTS: After matching, 31 patients in VATS group and 31 patients in open group were eligible for analysis. In the VATS and open groups, the mean total number of dissected lymph nodes was 28.2 ± 8.4 and 29.8 ± 11.6 (p = 0.517), respectively. In the VATS and open groups, the number of N1 nodes was 9.5 ± 4.1 and 8.4 ± 4.7 (p = 0.333), respectively. And the number of N2 nodes was also similar between the VATS and open group (18.6 ± 7.0 vs 21.4 ± 10.0, p = 0.211). No significant differences were observed between the two groups in the operating time, the blood loss, the length of chest tube drainage, the length of hospital stay, and the rate of specific complications. CONCLUSION: Our early experience suggests that, with regard to the number of the dissected lymph nodes, VATS lobectomy can achieve complete MLND, compared with the traditional approach. MLND by VATS is technically feasible and safe for early-stage lung cancer.

"Capsule drape wrap"-a new technology for iridoschisis management during phacoemulsification.

AIM: To introduce a new technique for iridoschisis management during phacoemulsification: "capsule drape wrap". METHODS: "Capsule drape wrap" technique was used for an 80-year-old man with idiopathic iridoschisis in the right eye during phacoemulsification. The inserted flexible nylon iris hooks to hold anterior capsule in place, the margin of the anterior capsule could act as drape wrap, tracking the fibrillary iris strands firmly from free floating and stabilizing the capsular bags simultaneously. RESULTS: The eye with iridoschisis was successfully treated. Iris fibrils remained immobile during the procedure, and despite the severity of iridoschisis, there were no intraoperative complications such as tear of the iris, hyphema, iris prolapse, loss of mydriasis, or rupture of the posterior lens capsule during phacoemulsification. The best-corrected visual acuity was increased by 0.1 (logMAR) 6mo after the surgery. CONCLUSION: "Capsule drape wrap" for iridoschisis is easily manageable, prevents further disruption to the loose iris fibers and ensures the stability of capsule-iris complex simultaneously, consequently minimizing the risk of surgical complications in phacoemulsification.

Efficacy and safety of gemcitabine and capecitabine combination for patients with previously treated advanced primary pulmonary lymphoepithelioma-like carcinoma: a retrospective single-arm cohort study.

Background: Primary pulmonary lymphoepithelioma-like carcinoma (PLELC) is a rare and unique subtype of non-small cell lung cancer (NSCLC). Studies reporting on salvage treatment for pretreated PLELC are limited. Positive interactions between gemcitabine (GEM) and capecitabine (CAP) have been demonstrated in preclinical studies. In addition, the clinical benefit of the combination has been reported for other malignancies. However, the efficacy and safety of the combination for pretreated PLELC remain unclear. Therefore, we conducted this retrospective study to examine the activity and safety of gemcitabine plus capecitabine (GEM/CAP) combination for previously treated PLELC. Methods: Patients with PLELC at Sun Yat-sen University Cancer Center who received GEM combined with CAP between May 2013 and January 2021 as the second-line therapy or beyond were retrospectively enrolled. Treatment consisted of intravenous GEM (1,000 mg/m2 on days 1 and 8) and oral CAP (1,000 mg/m2 twice daily on days 1-14) every 3 weeks. Evaluation of response was performed every 2 cycles in accordance with Response Evaluation Criteria in Solid Tumors version 1.1. Safety was assessed in accordance with Common Terminology Criteria for Adverse Events version 5.0. Clinical characteristics were collected from medical records. The survival data were obtained by medical records or telephone. Follow-ups were performed until February 3rd, 2021. Results: A total of 16 patients were enrolled in this study. There were 5, 4, 4, and 3 patients treated with GEM/CAP combination as the second-, third-, fourth-, and fifth-line settings, respectively. There were 8 patients with partial response (PR) (50.00%), 6 with stable disease (SD) (37.50%), 2 with progressive disease (PD) (12.50%), and none with complete response (CR). The objective response rate and disease control rate (DCR) were 50.00% and 87.50%, respectively. The most common hematological and nonhematological adverse events (AEs) at any grade were neutropenia (31.25%) and hand-foot syndrome (43.75%). At a median follow-up of 29.3 months with 95% confidence interval (CI) of 20.3 to 38.3 months, the median progression-free survival (PFS) was 9.3 months (95% CI: 6.5-12.1 months). The median overall survival (OS) was 41.5 months (95% CI: 3.1-79.8 months). Conclusions: This retrospective study demonstrated the potential clinical benefit of GEM in combination with CAP for pretreated PLELC. Future multicenter large-scale, prospective studies are warranted.

Invasiveness assessment by artificial intelligence against intraoperative frozen section for pulmonary nodules ≤ 3 cm.

PURPOSE: To investigate the performance of an artificial intelligence (AI) algorithm for assessing the malignancy and invasiveness of pulmonary nodules in a multicenter cohort. METHODS: A previously developed deep learning system based on a 3D convolutional neural network was used to predict tumor malignancy and invasiveness. Dataset of pulmonary nodules no more than 3 cm was integrated with CT images and pathologic information. Receiver operating characteristic curve analysis was used to evaluate the performance of the system. RESULTS: A total of 466 resected pulmonary nodules were included in this study. The areas under the curves (AUCs) of the deep learning system in the prediction of malignancy as compared with pathological reports were 0.80, 0.80, and 0.75 for all, subcentimeter, and solid nodules, respectively. Additionally, the AUC in the AI-assisted prediction of invasive adenocarcinoma (IA) among subsolid lesions (n = 184) was 0.88. Most malignancies that were misdiagnosed by the AI system as benign diseases with a diameter measuring greater than 1 cm (26/250, 10.4%) presented as solid nodules (19/26, 73.1%) on CT. In an exploratory analysis involving nodules underwent intraoperative pathologic examination, the concordance rate in identifying IA between the AI model and frozen section examination was 0.69, with a sensitivity of 0.50 and specificity of 0.97. CONCLUSION: The deep learning system can discriminate malignant diseases for pulmonary nodules measuring no more than 3 cm. The AI model has a high positive predictive value for invasive adenocarcinoma with respect to intraoperative frozen section examination, which might help determine the individualized surgical strategy.

Pan-Immune-Inflammatory Value in Patients with Non-Small-Cell Lung Cancer Undergoing Neoadjuvant Immunochemotherapy.

Background: We aimed to investigate the predictive value of a systematic serum inflammation index, pan-immune-inflammatory value (PIV), in pathological complete response (pCR) of patients treated with neoadjuvant immunotherapy to further promote ideal patients' selection. Methods: The clinicopathological and baseline laboratory information of 128 NSCLC patients receiving neoadjuvant immunochemotherapy between October 2019 and April 2022 were retrospectively reviewed. We performed least absolute shrinkage and selection operator (LASSO) algorithm to screen candidate serum biomarkers for predicting pCR, which further entered the multivariate logistic regression model to determine final biomarkers. Accordingly, a diagnostic model for predicting individual pCR was established. Kaplan-Meier method was utilized to estimate curves of disease-free survival (DFS), and the Log rank test was analyzed to compare DFS differences between patients with and without pCR. Results: Patients with NSCLC heterogeneously responded to neoadjuvant immunotherapy, and those with pCR had a significant longer DFS than patients without pCR. Through LASSO and the multivariate logistic regression model, PIV was identified as a predictor for predicting pCR of patients. Subsequently, a diagnostic model integrating with PIV, differentiated degree and histological type was constructed to predict pCR, which presented a satisfactory predictive power (AUC, 0.736), significant agreement between actual and our nomogram-predicted pathological response. Conclusion: Baseline PIV was an independent predictor of pCR for NSCLC patients receiving neoadjuvant immunochemotherapy. A significantly longer DFS was achieved in patients with pCR rather than those without pCR; thus, the PIV-based diagnostic model might serve as a practical tool to identify ideal patients for neoadjuvant immunotherapeutic guidance.

Prognostic value of L4 lymph node dissection during video-assisted thoracoscopic surgery in patients with left-sided non-small cell lung cancer: a single-center, retrospective cohort study.

Background: Lymph node dissection (LND) is crucial procedure during radical resection of non-small cell lung cancer (NSCLC), but the prognostic value of L4 LND remains elusive. To investigate the prognostic value of L4 LND in patients with left-side NSCLC who underwent video-assisted thoracoscopic surgery (VATS). Methods: Three hundred twelve patients who underwent VATS between Jan. 2007 and Dec. 2016 were reviewed. Of those, 119 underwent L4 LND (L4D+), whereas the other 193 patients did not (L4D-). The inclusion criteria were as follows: patients diagnosed with primary left-sided NSCLC who underwent VATS lobectomy combined with LND; patients subjected to R0 resection and tumor pathological stage T1-4N0-2M0. The primary endpoint was overall survival (OS). OS was calculated from the operation date to the date of death. The chi-square test was used for categorical variables, and a t test was used for continuous variables. Results: A total of 119 patients underwent L4 LND, and the procedure was more likely to be performed on upper lobe tumors (P=0.019). Patient distributions with respect to age, gender, smoking history, clinical stage, adjuvant therapy, tumor differentiation and tumor size were well balanced between two groups. More lymph nodes (LNs) were dissected in the L4D+ group than in the L4D- group (P<0.001). The rate of metastasis to L4 lymph nodes was 9.2%, which was comparable between patients with upper and lower lobe tumors (8.9% vs. 10.0%, P=1.000). The L4D+ group exhibited a significantly better OS than the L4D- group (median OS: undefined vs. 130 months, HR 0.47; 95% CI: 0.31-0.72; P=0.002). Multivariate analysis showed that L4 LND was an independent factor for OS. However, OS did not significantly differ between the two groups of cT1aN0 and cT1bN0 patients (OS: HR 0.44; 95% CI: 0.18-1.06; P=0.12). Conclusions: L4 LND is recommended for patients with left-sided NSCLC as an essential component of radical resection. The role of L4 LND in cT1a-bN0 disease warrants further study.

Phase 2 trial of neoadjuvant toripalimab with chemotherapy for resectable stage III non-small-cell lung cancer.

Multimodality treatment provides modest survival benefits for patients with locally advanced (stage III) non-small-cell lung cancer (NSCLC). Nevertheless, preoperative immunotherapy has continuously been shown to be promising in treating resectable NSCLC.This phase 2 trial enrolled patients with AJCC-defined stage IIIA or T3-4N2 IIIB NSCLC deemed surgically resectable. Patients received three cycles of neoadjuvant treatment with intravenous PD-1 inhibitor toripalimab (240 mg), carboplatin (area under the curve 5), and pemetrexed (500 mg/m2 for adenocarcinoma) or nab-paclitaxel (260 mg/m2 for other subtypes) on day 1 of each 21-day cycle. Surgical resection was performed 4-5 weeks afterward. The primary endpoint was major pathological response (MPR), defined as less than 10% residual tumor remaining at the time of surgery.Thirty-three patients were enrolled, of whom 13 (39.4%) had T3-4N2 stage IIIB disease. Thirty (90.9%) patients underwent resection and all except one (96.7%) achieved R0 resection. Twenty patients (60.6%) in the intention-to-treat population achieved an MPR, including 15 patients (45.5%) who achieved a pathological complete response (pCR). The MPR and pCR rates in the per-protocol population were 66.7% and 50.0%, respectively. The surgical complications included three cases of arrhythmias, one case of a prolonged air leak, and one case of chylothorax. The most common grade 3 treatment-related adverse event (TRAE) was anemia (2, [6.1%]). Severe TRAEs included one (3.0%) case of grade 3 peripheral neuropathy that resulted in surgical cancellation.Toripalimab plus platinum-based doublet chemotherapy yields a high MPR rate, manageable toxicity, and feasible resection in stage III NSCLC.Trial ClinicalTrials.gov (NCT04304248).

[Short and long-term outcomes of neoadjuvant chemotherapy for locally advanced esophageal carcinoma].

OBJECTIVE: This study was to compare the 5-year survival rate, the surgical resection rate, the post-operative complications and mortality of patients who underwent surgical resection for carcinoma of esophagus with or without neoadjuvant chemotherapy. To evaluate neoadjuvant chemotherapy in the treatment of esophageal carcinoma. METHODS: Forty-two patients with locally advanced esophageal carcinoma undergoing neoadjuvant chemotherapy and surgical resection (CS group), and 75 patients with the same phase undergoing surgical resection alone (S group) from August 2003 to March 2009 in Sun Yat-sen University Cancer Center were reviewed. The 5-year survival rate, the surgical resection rate, the post-operative complications and mortality between the two groups were analyzed. RESULTS: Forty-two patients after neoadjuvant chemotherapy, the complete response rate was 11.9%, the partial response was 47.6%, the total clinical response rate was 59.5%. The surgical resection rate of CS group and S group were 100% and 89.5% (P = 0.029). There was no statistically difference in the post-operative complications and mortality between two groups. The overall 5-year survival for CS group and S group were 31.7% and 26.4%, respectively (P = 0.266). In the subgroup analysis, the 5-year survival of patients with clinical response was significant higher than S group (P = 0.010). CONCLUSIONS: The neoadjuvant chemotherapy can improve surgical resection rate and long-term survival of esophageal carcinoma patients with clinical response without increasing the post-operative complications and mortality.

Correlation and prognostic significance of PD-L1 and P53 expression in resected primary pulmonary lymphoepithelioma-like carcinoma.

BACKGROUND: Aberrant expression of programmed cell death-ligand 1 (PD-L1) and protein 53 (P53) has been observed in various malignancies, and recently, the mechanism of PD-L1 regulation by P53 has been elucidated. We aimed to explore possible correlations between PD-L1 and P53 expression and the prognosis of patients with resected pulmonary lymphoepithelioma-like carcinoma (LELC). METHODS: A total of 67 consecutive patients with primary pulmonary LELC who underwent radical resection from January 2003 to December 2014 were enrolled in our study. Membranous PD-L1 and nuclear P53 expression were detected by immunohistochemical staining (IHC). RESULTS: Positive expression of PD-L1 in tumor cells (TCs), PD-L1 in tumor-infiltrating lymphocytes (TILs) and P53 was investigated in 44 patients (65.7%), 37 patients (55.2%), and 34 patients (50.7%), respectively. Using univariate and multivariable analysis, both PD-L1 (+) in TCs and P53 (+) were observed to be significantly independent prognostic factors associated with longer disease-free survival (DFS, P=0.037 and 0.039, respectively), along with early stage LELC (P=0.037), but had no association with overall survival (OS) (P>0.05). In the P53 (+) group, the rate of patients with PD-L1 (+) in TCs was significantly higher than in the P53 (-) group (85.3% vs. 45.5%, P=0.001). In addition, among the 45 patients who underwent adjuvant chemotherapy, DFS was significantly longer in patients with either PD-L1 (+) in TCs or P53 (+) (P=0.036 and 0.044, respectively). CONCLUSIONS: PD-L1 and P53 may be potential therapeutic targets for primary pulmonary LELC. PD-L1 (+) in TCs and P53 (+) were reliable predictors for longer DFS and benefits from adjuvant therapy in resected cases. Routine detection of these two indices in lung LELC may be warranted.

Tumor-stroma ratio (TSR) in non-small cell lung cancer (NSCLC) patients after lung resection is a prognostic factor for survival.

BACKGROUND: In recent years, the tumor-stroma ratio (TSR) has been considered to a new and independent predictive variable for the prognosis of some kinds of neoplasms. The objective of this study was to assess the prognostic significance of the TSR in non-small cell lung cancer (NSCLC). METHODS: A cohort of 261 NSCLC patients who underwent radical surgery of lung cancer were included in the present study. Two independent observers visually estimated the TSR on hematoxylin-eosin (H&E) stained tissue pathological slices. According to the proportion of stroma ≥50% or <50%, We separate the patients into two groups: those with stroma-poor and those with stroma-rich tumors. RESULTS: Both univariate and multivariate analyses disclosed that the TSR was associated with overall survival (OS) [hazard ratio (HR), 1.741; 95% confidence intervals (CI), 1.040-2.913 and HR, 1.904; 95% CI, 1.132-3.202, respectively]. The HR values for disease-free survival (DFS) were 1.795 (95% CI, 1.073-3.005) and 2.034 (95% CI, 1.210-3.420). The OS and DFS of patients with stroma-poor tumors were better than those with stroma-rich tumors. CONCLUSIONS: These results demonstrated that the TSR is a new prognostic factor for NSCLC. Stroma-poor tumors were associated with longer disease-free period and better prognosis than were stroma-rich tumors in NSCLC patients. The TSR may contribute to the development of individualized treatment for NSCLC in the future.

[Preoperative induction chemotherapy for unresectable stage IIIA non-small-cell lung cancer].

OBJECTIVE: To evaluate the potential reconsideration of curative operative treatment for patients with unresectable stage IIIA (N2) non-small-cell lung cancer (NSCLC). METHODS: From Jan. 1999 to Dec. 2002, 76 patients with unresectable stage IIIA (N2) NSCLC were entered in this study. They had all been proved by chest CT, chest film and fiberobronchoscopy. Twenty-one (27.6%) patients were examined by mediastinoscopy. All the patients received two cycles of chemotherapy with NVB (25 mg/m(2), D1, D5) and carboplatin (300 mg/m(2), D1). All the patients were staged again three weeks after induction chemotherapy. Sixty-four patients who achieved partial response (PR) or complete response (CR) were allowed to undergo surgery. Twelve patients who did not responde to chemotherapy received radiotherapy instead. Of the 64 surgically treated patients, 56 (84.7%) had a complete resection and then received 2 cycles of chemotherapy using the same regime, 8 patients had an incomplete resection and then received radiotherapy for the residual tumor. RESULTS: The median survival for these 76 patients with unresectable stage IIIA (N2) NSCLC treated by either surgery or radiation after induction chemotherapy was 18.6 months with 1-, 2-, 3-year survival rate of 64.2%, 39.4% and 25.6%, respectively. The median survival for the 56 patients with a complete resection was 28.2 months with 1-, 2-, 3-year survival rate of 70.4%, 52.5% and 38.6%, respectively. CONCLUSION: Preoperative induction chemotherapy with NVB plus carboplatin should be seriously considered for the patients with unresectable stage IIIA (N2) NSCLC, It is suggested that, whenever possible, surgery should be taken as the first choice for the patients who show down-staged benefits that complete resection can be attempted.

An Elevated Peripheral Blood Monocyte-to-Lymphocyte Ratio Predicts Poor Prognosis in Patients with Primary Pulmonary Lymphoepithelioma-Like Carcinoma.

Primary pulmonary lymphoepithelioma-like carcinoma (LELC) is a rare type of non-small cell lung cancer. In this study, we retrospectively reviewed the data from 74 consecutive patients with pulmonary LELC and investigated the prognostic value of pretreatment monocyte-to-lymphocyte ratio (MLR). The cut-off value determined by ROC curve for MLR was 0.262. According to this cut-off value, 36 (48.6%) patients had lower MLR value (<0.262) at diagnosis. There was no significant correlation between MLR level and gender, age, smoking history, stage, and lactate dehydrogenase (LDH) level. The 2-year, 5-year, and 10-year OS rate were 86%, 72%, and 61%, respectively; the 2-year, 5-year, and 10-year PFS rate were 71%, 63%, and 49%, respectively. In univariate analysis, advanced stage, elevated LDH level, and higher MLR value (> = 0.262) were significantly associated with poor OS and PFS. In a multivariate Cox regression model that included stage, LDH and MLR level, all of these three factors were found to be independent prognostic factors for both PFS and OS. In patients who received radical surgery, MLR level remained significantly correlated with OS and PFS. In conclusion, we firstly demonstrated that pretreatment MLR can be used as a useful independent prognostic marker in patients with pulmonary LELC, and might guide us to optimize the treatment strategies. However, due to the relatively rarity of this disease and the limitation of a retrospective study, further prospective studies performed in multicenter are necessary to validate the prognostic value of MLR in pulmonary LELC.

Prognostic impact of pattern-based grading system by the new IASLC/ATS/ERS classification in Asian patients with stage I lung adenocarcinoma.

OBJECTIVES: We examined the prognostic effect of the grading system based on the new IASLC/ATS/ERS classification in an Asian cohort of patients with early-stage lung adenocarcinoma. MATERIALS AND METHODS: Patients with a lung adenocarcinoma less than 3cm in diameter that had undergone complete anatomic resection, diagnosed with pT1a-2aN0M0 consecutively from 2004 to 2013, were enrolled. All specimens were reviewed according to the new IASLC/ATS/ERS classification. The growth patterns were divided into three major categories: grade 1 for lepidic growth, grade 2 for acinar and papillary patterns, and grade 3 for solid and micropapillary patterns. Each tumor was then graded according to the modified grading system, the final score being the sum of the two most predominant grades. The correlations of clinical and pathological factors with disease-free survival (DFS) and overall survival (OS) were evaluated. RESULTS: In total, 201 adenocarcinomas were eligible for score grading. Only 37 (18.4%) patients had a pure pathological growth pattern. Higher stage, greater tumor diameter, positive lymphovascular invasion, and a higher score were associated with shorter DFS. In contrast, stage no longer had a significant impact on OS in a multivariable analysis. Acinar/papillary-predominant tumors with a score of 3 or 4 were associated with better survival than those with a score of 5 (5-year DFS rate: 64.68 vs. 44.18%, HR=2.19, 95% CI: 1.24-3.87; 5-year OS rate: 85.61 vs. 68.59%, HR=3.03, 95% CI: 1.25-7.32). CONCLUSION: The architectural scores may help to stratify survival differences among certain predominant growth subtypes of adenocarcinoma.

The Frequency and Clinical Implication of ROS1 and RET Rearrangements in Resected Stage IIIA-N2 Non-Small Cell Lung Cancer Patients.

To evaluate the frequency and clinicopathological features of ROS1 and RET rearrangements in N2 node positive stage IIIA (IIIA-N2) non-small cell lung cancer (NSCLC) patients, we retrospectively screened 204 cases with a tissue microarray (TMA) panel by fluorescent in situ hybridization (FISH), and confirmed by direct sequencing and immunohistochemistry (IHC). The relationship between ROS1 or RET rearrangements, clinicopathological features, and prognostic factors were analyzed in resected stage IIIA-N2 NSCLC. Of the 204 cases, 4 cases were confirmed with ROS1 rearrangement, but no RET rearrangement was detected. All 4 ROS1-rearranged cases were adenocarcinomas. The predominant pathological type was acinar pattern in ROS1-rearranged tumors, except for 1 case harboring a mixture acinar and mucous tumor cells. Variants of ROS1 rearrangement were SDC4-ROS1 (E2:E32), SDC4-ROS1 (E4:E32) and SDC4-ROS1 (E4:E34). There was no significant association between ROS1 rearrangement and clinicopathological characteristics. In this cohort, multivariate analysis for overall survival (OS) indicated that squamous cell carcinoma and lobectomy were independent predictors of poor prognosis; R0 surgical resection and non-pleural invasion were independent predictors of good prognosis. In resected stage IIIA-N2 NSCLC patients, ROS1-rearranged cases tended to occur in younger patients with adenocarcinomas. The prognosis of resected stage IIIA-N2 is generally considered poor, but patients with ROS1 rearrangement will benefit from the targeted therapy.

Mutation abundance affects the efficacy of EGFR tyrosine kinase inhibitor readministration in non-small-cell lung cancer with acquired resistance.

There is no consensus in the salvage treatment for non-small-cell lung cancer (NSCLC) with acquired resistance to primary epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). Fifty-one consecutive EGFR-mutated NSCLC patients with TKI retreatment after acquired resistance were enrolled in this study. The quantitation of mutation abundance was performed by real-time fluorescent quantitative PCR. The correlation between mutation abundance and outcomes of readministrated TKI was analyzed by survival analysis. Patients with high (H) mutation abundance (24/51) had a significantly (log-rank, P < 0.05) longer (5.27-2.53 months) median progression-free survival (PFS), compared with the low (L) abundance group (27/51), whereas the median overall survival showed no difference (21.00-18.20 months, log-rank P = .403) between the two groups. Objective response and disease control rates in group H and group L regarding the second round TKI treatment were 8.3, 70.8 and 0, 48.1 %, respectively. Groupings with different mutation abundances were significantly associated with PFS under multivariate Cox proportional hazards regression model [hazard ratio (HR) for group H vs. L, 0.527; P = .036]. Mutation abundance affects the efficacy of EGFR-TKIs readministration in NSCLC with acquired resistance. The quantitative mutation abundance of EGFR may be a potential predictor for selecting optimal patients to readministrate EGFR-TKIs after acquired resistance to primary TKI.

Risk of cerebral metastases for postoperative locally advanced non-small-cell lung cancer.

BACKGROUND: Cerebral metastases are the main determining factor in the failure of locally advanced non-small-cell lung cancer (NSCLC) management. Our study assessed the risk factors of brain metastases in patients with postoperative, locally advanced NSCLC. Implications for PCI treatment are discussed. METHODS: Two hundred twenty-three patients treated with surgical resection for stage III-N2 NSCLC were retrospective analyzed to elucidate risk factors for development of brain metastases, and to establish a mathematical model. RESULTS: Median survival time for this patient population was 29.5 months. Frequency of brain metastases in the entire patient population was 38.1% (85/223). Frequency of brain metastases in patients with single mediastinal lymph-node region with metastases at 1, 2, and 3 years was 5.6%, 14.0%, and 19.0%, respectively. The frequency of brain metastases in patients with multiple mediastinal lymph-node regions with metastases was 31.8%, 60.3%, 68.0%, respectively (P<0.001). The frequency of brain metastases among patients with mediastinal metastasis number less than 4, 4-6, and more than 6 was significantly different (P<0.001). There were also significant differences in brain metastases frequency between patients with complete versus incomplete resection (P=0.001), and patients with non-squmous versus squamous (P=0.029), and patients administered adjuvant chemotherapy versus none (P=0.032). CONCLUSION: A mathematical model to predict brain metastases risk was developed. It can aid in selection of patients with locally advanced NSCLC for PCI in clinical trails.

[Quality of life after lobectomy for early stage non-small cell lung cancer--video-assisted thoracoscopic surgery versus minimal incision thoracotomy].

BACKGROUND & OBJECTIVE: Quality of life (QOL) after video-assisted thoracoscopic surgery (VATS) lobectomy for clinical early stage non-small cell lung cancer (NSCLC) has seldom been systematically studied. This study was to compare the QOL in patients with clinical early stage NSCLC after VATS or minimal incision thoracotomy (MIT) lobectomy, and to explore the characteristic of QOL after VATS lobectomy. METHODS: A prospective randomized controlled trial was conducted. From Mar. 2004 to Mar. 2005, 32 consecutive patients with early stage NSCLC and tumor size of < or =6 cm diagnosed by CT scan were recruited and randomized to VATS group (17 patients) and MIT group(15 patients). Two patients in VAYS group were excluded for conversion to posterolateral thoracotomy because of uncontrolled bleeding and dense pleural adhesion. QOL was assessed using Lung Cancer Symptom Scale (LCSS) before operation and at 1, 3 and 6 months after operation. RESULTS: There were no significant differences between the 2 groups in age, sex, tumor pathologic stage, tumor size, and postoperative complications. One month after operation, the scores of dyspnea and pain were significantly lower in VATS group than in MIT group (10.9+/-7.4 vs. 17.4+/-9.6, P=0.047; 13.7+/-9.5 vs. 23.0+/-12.2, P=0.028). The score of overall symptom was slightly lower in VATS group than in MIT group (9.7+/-7.2 vs. 16.2+/-10.9, P=0.066). Five major symptoms (appetite, fatigue, cough, dyspnea, and pain) at the VATS group were deteriorated after operation. Appetite, fatigue and cough were deteriorated significantly at 1 month after operation (P<0.05), but returned to nearly preoperative levels at 3 months after operation (P>0.05) except appetite, and all returned to baseline levels at 6 months after operation (P>0.05). CONCLUSIONS: Compared with MIT lobectomy, VATS will lead to better QOL for the patients with early stage NSCLC. It takes 6 months for the patients to return to preoperative QOL levels after VATS lobectomy.