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The clinical efficacy of neoadjuvant immunotherapy plus chemotherapy remains elusive in localized epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). Here, we report interim results of a Simon's two-stage design, phase 2 trial using neoadjuvant sintilimab with carboplatin and nab-paclitaxel in resectable EGFR-mutant NSCLC. All 18 patients undergo radical surgery, with one patient experiencing surgery delay. Fourteen patients exhibit confirmed radiological response, with 44% achieving major pathological response (MPR) and no pathological complete response (pCR). Similar genomic alterations are observed before and after treatment without influencing the efficacy of subsequent EGFR-tyrosine kinase inhibitors (TKIs) in vitro. Infiltration and T cell receptor (TCR) clonal expansion of CCR8 + regulatory T (Treg) hi /CXCL13 + exhausted T (Tex) lo cells define a subtype of EGFR-mutant NSCLC highly resistant to immunotherapy, with the phenotype potentially serving as a promising signature to predict immunotherapy efficacy. Informed circulating tumor DNA (ctDNA) detection in EGFR-mutant NSCLC could help identify patients nonresponsive to neoadjuvant immunochemotherapy. These findings provide supportive data for the utilization of neoadjuvant immunochemotherapy and insight into immune resistance in EGFR-mutant NSCLC., Competing Interests: Declaration of interests W.-Z.Z.. received speech honoraria from AstraZeneca, Roche, Eli Lilly, and Pfizer outside the submitted work. Z.-M.Z. is a founder of Analytical BioSciences. Y.-L.W. received research funding from Roche and speech honoraria from AstraZeneca, Roche, Eli Lilly, Pfizer, and Sanofi, and he was a research consultant for AstraZeneca. Q.Z. reports honoraria from AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, MSD, Pfizer, Roche, and Sanofi outside the submitted work., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Importance: Uninterrupted targeted therapy until disease progression or intolerable toxic effects is currently the routine therapy for advanced non-small cell lung cancer (NSCLC) involving driver gene variations. However, drug resistance is inevitable., Objective: To assess the clinical feasibility of adaptive de-escalation tyrosine kinase inhibitor (TKI) treatment guided by circulating tumor DNA (ctDNA) for achieving complete remission after local consolidative therapy (LCT) in patients with advanced NSCLC., Design, Setting, and Participants: This prospective nonrandomized controlled trial was conducted at a single center from June 3, 2020, to July 19, 2022, and included 60 patients with advanced NSCLC with driver variations without radiologically detectable disease after TKI and LCT. The median (range) follow-up time was 19.2 (3.8-29.7) months. Data analysis was conducted from December 15, 2022, to May 10, 2023., Intervention: Cessation of TKI treatment and follow-up every 3 months. Treatment was restarted in patients with progressive disease (defined by the Response Evaluation Criteria in Solid Tumors 1.1 criteria), detectable ctDNA, or elevated carcinoembryonic antigen (CEA) levels, whichever manifested first, and treatment ceased if all indicators were negative during follow-up surveillance., Main Outcomes and Measures: Progression-free survival (PFS). Secondary end points were objective response rate, time to next treatment, and overall survival., Results: Among the total study sample of 60 participants (median [range] age, 55 [21-75] years; 33 [55%] were female), the median PFS was 18.4 (95% CI, 12.6-24.2) months and the median (range) total treatment break duration was 9.1 (1.5-28.1) months. Fourteen patients (group A) remained in TKI cessation with a median (range) treatment break duration of 20.3 (6.8-28.1) months; 31 patients (group B) received retreatment owing to detectable ctDNA and/or CEA and had a median PFS of 20.2 (95% CI, 12.9-27.4) months with a median (range) total treatment break duration of 8.8 (1.5-20.6) months; and 15 patients (group C) who underwent retreatment with TKIs due to progressive disease had a median PFS of 5.5 (95% CI, 1.5-7.2) months. For all participants, the TKI retreatment response rate was 96%, the median time to next treatment was 29.3 (95% CI, 25.3-35.2) months, and the data for overall survival were immature., Conclusions and Relevance: The findings of this nonrandomized controlled trial suggest that this adaptive de-escalation TKI strategy for patients with NSCLC is feasible in those with no lesions after LCT and a negative ctDNA test result. This might provide a de-escalation treatment strategy guided by ctDNA for the subset of patients with advanced NSCLC., Trial Registration: ClinicalTrials.gov Identifier: NCT03046316.

Objectives: To elucidate the impact of [ 18 F]FDG positron emission tomography/computed tomography (PET/CT) vs. CT workup on staging and prognostic evaluation of clinical stage (c) I-II NSCLC., Methods: We retrospectively identified 659 cI-II NSCLC who underwent CT (267 patients) or preoperative CT followed by PET/CT (392 patients), followed by curative-intended complete resection in our hospital from January 2008 to December 2013. Differences were assessed between preoperative and postoperative stage. Five-year disease-free survival (DFS) and overall survival (OS) rates were calculated using the Kaplan-Meier approach and compared with log-rank test. Impact of preoperative PET/CT on survival was assessed by Cox regression analysis., Results: The study included 659 patients [mean age, 59.5 years ± 10.8 (standard deviation); 379 men]. The PET/CT group was superior over CT group in DFS [12.6 vs. 6.9 years, HR 0.67 (95% CI 0.53-0.84), p < 0.001] and OS [13.9 vs. 10.5 years, HR 0.64 (95% CI 0.50-0.81), p < 0.001]. In CT group, more patients thought to have cN0 migrated to pN1/2 disease as compared with PET/CT group [26.4% (66/250) vs. 19.2% (67/349), p < 0.001], resulting in more stage cI cases being upstaged to pII-IV [24.7% (49/198) vs. 16.1% (47/292), p = 0.02], yet this was not found in cII NSCLC [27.5% (19/69) vs. 27.0% (27/100), p = 0.94]. Cox regression analysis identified preoperative PET/CT as an independent prognostic factor of OS and DFS (p = 0.002, HR = 0.69, 95% CI 0.54-0.88; p = 0.004, HR = 0.72, 95% CI 0.58-0.90)., Conclusion: Addition of preoperative [ 18 F]FDG PET/CT was associated with superior DFS and OS in resectable cI-II NSCLC, which may result from accurate staging and stage-appropriate therapy., (© 2023. The Author(s) under exclusive licence to The Japanese Society of Nuclear Medicine.)

This prospective multicenter phase II study evaluated the clinical efficacy of neoadjuvant nivolumab-exclusive (N) and nivolumab-chemotherapy (N/C) combinations based on PD-L1 expression. Eligible patients exhibited resectable clinical stage IIA-IIIB (AJCC 8th edition) NSCLC without EGFR/ALK alterations. Patients received either mono-nivolumab (N) or nivolumab + nab-paclitaxel+ carboplatin (N/C) for three cycles based on PD-L1 expression. The primary endpoint was the major pathological response (MPR). Key secondary endpoints included the pathologic complete response (pCR), objective response rate (ORR), and event-free survival (EFS). Baseline PD-L1 expression and perioperative circulating tumor DNA (ctDNA) status were correlated with pCR and EFS. Fifty-two patients were enrolled, with 46 undergoing surgeries. The MPR was 50.0% (26/52), with 25.0% (13/52) achieving pCR, and 16.7% and 66.7% for patients with PD-L1 ≥ 50% in N and N/C groups, respectively. Thirteen (25.0%) patients experienced grade 3 or higher immune-related adverse events during neoadjuvant treatment. Patients with post-neoadjuvant ctDNA negativity was more likely to have pCR (39.1%) compared with those remained positive (6.7%, odds ratio = 6.14, 95% CI 0.84-Inf, p = 0.077). With a median follow-up of 25.1 months, the 18-month EFS rate was 64.8% (95% CI 51.9-81.0%). For patients with ctDNA- vs. ctDNA + , the 18m-EFS rate was 93.8% vs 47.3% (HR, 0.15; 95% CI 0.04, 0.94; p = 0.005). Immunochemotherapy may serve as an optimal neoadjuvant treatment even for patients with PD-L1 expression ≥ 50%. ctDNA negativity following neoadjuvant treatment and surgery could help identify superior pathological and survival benefits, which requires further confirmation in a prospective clinical trial (NCT04015778)., (© 2023. The Author(s).)

EMERGING-CTONG 1103 showed improved progression-free survival (PFS) with neoadjuvant erlotinib vs. chemotherapy for patients harbouring EGFR sensibility mutations and R0 resected stage IIIA-N2 non-small cell lung cancer (NSCLC) (NCT01407822). Herein, we report the final results. Recruited patients were randomly allocated 1:1 to the erlotinib group (150 mg/day orally; neoadjuvant phase for 42 days and adjuvant phase to 12 months) or to the GC group (gemcitabine 1250 mg/m 2 plus cisplatin 75 mg/m 2 intravenously; 2 cycles in neoadjuvant phase and 2 cycles in adjuvant phase). Objective response rate (ORR), complete pathologic response (pCR), PFS, and overall survival (OS) were assessed along with safety. Post hoc analysis was performed for subsequent treatments after disease recurrence. Among investigated 72 patients (erlotinib, n = 37; GC, n = 35), the median follow-up was 62.5 months. The median OS was 42.2 months (erlotinib) and 36.9 months (GC) (hazard ratio [HR], 0.83; 95% confidence interval [CI], 0.47-1.47; p = 0.513). The 3- and 5-year OS rates were 58.6% and 40.8% with erlotinib and 55.9% and 27.6% with GC (p 3-y  = 0.819, p 5-y  = 0.252). Subsequent treatment was administered in 71.9% and 81.8% of patients receiving erlotinib and GC, respectively; targeted therapy contributed mostly to OS (HR, 0.35; 95% CI, 0.18-0.70). After disease progression, the ORR was 53.3%, and the median PFS was 10.9 months during the EGFR-TKI rechallenge. During postoperative therapy, grade 3 or 4 adverse events (AEs) were 13.5% in the erlotinib group and 29.4% in the GC group. No serious adverse events were observed. Erlotinib exhibited clinical feasibility for resectable IIIA-N2 NSCLC over chemotherapy in the neoadjuvant setting., (© 2022. The Author(s).)

Objective To investigate the expression of androgen receptor(AR)and its correlations with different molecular subtypes and clinicopathological features of breast invasive carcinoma of no special type(IBC-NST)in females of Tibetan ethnic minority in Tibet.Methods This study enrolled 54 female patients of Tibetan ethnic minority with IBC-NST surgically removed in the Tibet Autonomous Region People's Hospital from December 2015 to March 2021 for retrospective analysis.The clinical and pathological data of all the enrolled patients were collected.The immunohistochemical method was employed to determine the expression of AR,cell proliferation marker antigen (Ki-67),estrogen receptor(ER),human epidermal growth factor receptor 2(HER-2),and progesterone receptor(PR).For those with unclear HER-2 results,fluorescence in situ hybridization was employed for the determination.The relationship of AR expression with molecular subtypes and clinicopathological features was then analyzed.Results The expression of AR in Tibetan female patients with IBC-NST was correlated with ER( χ 2 =8.200, P =0.004),PR( χ 2 =9.900, P =0.003),and molecular subtype( χ 2 =11.690, P =0.009)and not correlated with tumor location,age,size,histological grade,lymph node metastasis,vascular invasion,clinical stage,or expression of HER-2 and Ki-67(all P >0.05).Molecular subtype was correlated with histological grade( χ 2 =24.970, P =0.001),clinical stage( χ 2 =9.035, P =0.029),and lymph node metastasis( χ 2 =9.691, P =0.021).Conclusions The positive expression rate of AR in the triple-negative IBC-NST patients of Tibetan ethnic minority was significantly lower than that in ER-or PR-positive patients in Tibet.Molecular subtype was correlated with histological grade,clinical stage,and lymph node metastasis.

Background: Estimating the growth of pulmonary sub-solid nodules (SSNs) is crucial to the successful management of them during follow-up periods. The purpose of this study is to (1) investigate the measurement sensitivity of diameter, volume, and mass of SSNs for identifying growth and (2) seek to establish a deep learning-based model to predict the growth of SSNs., Methods: A total of 2,523 patients underwent at least 2-year examination records retrospectively collected with sub-solid nodules. A total of 2,358 patients with 3,120 SSNs from the NLST dataset were randomly divided into training and validation sets. Patients from the Yibicom Health Management Center and Guangdong Provincial People's Hospital were collected as an external test set (165 patients with 213 SSN). Trained models based on LUNA16 and Lndb19 datasets were employed to automatically obtain the diameter, volume, and mass of SSNs. Then, the increase rate in measurements between cancer and non-cancer groups was studied to evaluate the most appropriate way to identify growth-associated lung cancer. Further, according to the selected measurement, all SSNs were classified into two groups: growth and non-growth. Based on the data, the deep learning-based model (SiamModel) and radiomics model were developed and verified., Results: The double time of diameter, volume, and mass were 711 vs. 963 days (P = 0.20), 552 vs. 621 days (P = 0.04) and 488 vs. 623 days (P< 0.001) in the cancer and non-cancer groups, respectively. Our proposed SiamModel performed better than the radiomics model in both the NLST validation set and external test set, with an AUC of 0.858 (95% CI 0.786-0.921) and 0.760 (95% CI 0.646-0.857) in the validation set and 0.862 (95% CI 0.789-0.927) and 0.681 (95% CI 0.506-0.841) in the external test set, respectively. Furthermore, our SiamModel could use the data from first-time CT to predict the growth of SSNs, with an AUC of 0.855 (95% CI 0.793-0.908) in the NLST validation set and 0.821 (95% CI 0.725-0.904) in the external test set., Conclusion: Mass increase rate can reflect more sensitively the growth of SSNs associated with lung cancer than diameter and volume increase rates. A deep learning-based model has a great potential to predict the growth of SSNs., Competing Interests: XY, YW, RL, HHY, JL, SL, BJ, SD, QN, WZ are employed by Guangdong Provincial People’s Hospital. BL is employed by South China University of Technology. Authors AL, JW, JF and HL are employed by Guangzhou Shiyuan Electronics Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Liao, Li, Yan, Lin, Liu, Wang, Fang, Liu, Hou, Song, Yang, Li, Jiang, Dong, Nie, Zhong, Wu and Yang.)

Primary pulmonary lymphoepithelioma-like carcinoma (PLELC) is an Epstein-Barr virus (EBV)-related, rare subtype of non-small-cell lung cancer (NSCLC). Immune checkpoint inhibitors (ICI) show durable responses in advanced NSCLC. However, their effects and predictive biomarkers in PLELC remain poorly understood. We retrospectively analyzed the data of 48 metastatic PLELC patients treated with ICI. Pretreated paraffin-embedded specimens (n = 19) were stained for PD-1, PD-L1, LAG3, TIM3, CD3, CD4, CD8, CD68, FOXP3, and cytokeratin (CK) by multiple immunohistochemistry (mIHC). Next-generation sequencing was performed for 33 PLELC samples. Among patients treated with ICI monotherapy (n = 30), the objective response rate (ORR), disease control rate (DCR), median progression-free survival (mPFS), and overall survival (mOS) were 13.3%, 80.0%, 7.7 months, and 24.9 months, respectively. Patients with PD-L1 ≥1% showed a longer PFS (8.4 vs . 2.1 months, p = 0.015) relative to those with PD-L1 <1%. Among patients treated with ICI combination therapy (n = 18), ORR, DCR, mPFS, and mOS were 27.8%, 100.0%, 10.1 months, and 19.7 months, respectively. Patients with PD-L1 ≥1% showed a significantly superior OS than those with PD-L1 <1% (NA versus 11.7 months, p = 0.001). Among the 19 mIHC patients, those with high PD-1/PD-L1 and LAG3 expression showed a longer PFS (19.0 vs . 3.9 months, p = 0.003). ICI also showed promising efficacy for treating metastatic PLELC. PD-L1 may be both predictive of ICI treatment efficacy and prognostic for survival in PLELC. PD-1/PD-L1 combined with LAG3 may serve as a predictor of ICI treatment effectiveness in PLELC. Larger and prospective trials are warranted to validate both ICI activity and predictive biomarkers in PLELC. This study was partly presented as a poster at the IASLC 20th World Conference on Lung Cancer 2019, 7-10 September 2019, Barcelona, Spain., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhong, Yin, Chen, Xie, Lv, Yang, Yang, Zhou, Wang, Zhong, Gao, Zhou, Chen, Tu, Liao, Zhang, Zhang, Lu, Zheng, Zhang, Wu and Zhang.)

Objective To analyze the clinicopathological features and immunohistochemical expression of meningiomas in the Tibetan population in Tibet,and improve the understanding of meningiomas. Methods The clinical and pathological data of all the meningiomas diagnosed by pathology in Tibet Autonomous Region People's Hospital from April 2013 to March 2021 were analyzed retrospectively.All the cases underwent immunohistochemical staining of trimethylation of lysine 27 on histone H3 (H3K27me3),mucin 4 (MUC4),somatostatin receptor 2 (SSTR2),progesterone receptor,epithelial membrane antigen,glial fibrillary acidic protein,vimentin,S-100,P53,and Ki-67.The histopathological features and the staining results were observed under a light microscope. Results A total of 116 cases of meningiomas were included in this study,with the male-to-female ratio of 1.0∶2.6 and the age of 4-73 years.The main clinical symptom was headache.The imaging examination showed that 114 cases had single lesions and 2 cases had multiple lesions.The tumors were located in the cranium (108 cases) and spinal canal (8 cases).The maximum diameter of the tumors ranged from 0.3 cm to 10.0 cm,with a mean of (5.7±2.2) cm.In terms of microscopic grading and histological types,the 116 cases included 111 cases of WHO grade Ⅰ (including 53 cases of fibrous type,20 cases of meningothelial type,24 cases of transitional type,10 cases of psammomatous type,etc.),4 cases of WHO grade Ⅱ (3 cases of atypical type and 1 case of clear cell type),and 1 case of WHO grade Ⅲ (papillary type).The immunohistochemical staining showed H3K27me3 expression absent in 9 cases (9/116,7.8%),MUC4 positive in 64 cases (64/116,55.2%),SSTR2 positive in 101 cases (101/116,87.1%).Eighty cases had follow-up results,among which 71 cases had no recurrence,while 9 cases recurred. Conclusions Meningioma is the most common tumor in the central nervous system in the pathological file of Tibet.It mainly attacks the middle-aged female patients,occupying the parasagittal sinus,falx,and convex surface of the brain.Fibrous meningioma of WHO grade Ⅰ is common,while the meningiomas of WHO grades Ⅱ and Ⅲ are rare.The expression degree of MUC4 is higher in meningothelial and transitional meningiomas but lower in fibrous meningiomas.There may be no correlation between the absence of H3K27me3 expression and prognosis.

The efficacy and potential limitations of molecular residual disease (MRD) detection urgently need to be fully elucidated in a larger population of non-small cell lung cancer (NSCLC). We enrolled 261 patients with stages I to III NSCLC who underwent definitive surgery, and 913 peripheral blood samples were successfully detected by MRD assay. Within the population, only six patients (3.2%) with longitudinal undetectable MRD recurred, resulting in a negative predictive value of 96.8%. Longitudinal undetectable MRD may define the patients who were cured. The peak risk of developing detectable MRD was approximately 18 months after landmark detection. Correspondingly, the positive predictive value of longitudinal detectable MRD was 89.1%, with a median lead time of 3.4 months. However, brain-only recurrence was less commonly detected by MRD (n = 1/5, 20%). Further subgroup analyses revealed that patients with undetectable MRD might not benefit from adjuvant therapy. Together, these results expound the value of MRD in NSCLC., Significance: This study confirms the prognostic value of MRD detection in patients with NSCLC after definitive surgery, especially in those with longitudinal undetectable MRD, which might represent the potentially cured population regardless of stage and adjuvant therapy. Moreover, the risk of developing detectable MRD decreased stepwise after 18 months since landmark detection. This article is highlighted in the In This Issue feature, p. 1599., (©2022 The Authors; Published by the American Association for Cancer Research.)

Background: Pleural effusion (PE) has been one of the promising sources of liquid biopsy in advanced lung cancer patients. However, its clinical utility is not widely accepted due to the lack of full estimation of its potential versus routine clinical samples., Method: A total of 164 advanced lung cancer patients were enrolled with 164 matched tumor tissue and PE-cfDNA, 153 accompanied plasma and 63 1 PE-sDNA., Result: PE-cfDNA displayed significantly higher median mutant allele frequency and an overall mutation concordance rate of 65% to tissue, which was higher than PE-sDNA (43%) and plasma-cfDNA (43%). The discrepancies between PE-cfDNA and tumor tissue were high in several genes, including SMARCA4, PIK3CA, ERBB2, KM T2A, ALK and NF1. For clinically actionable mutations, the concordance rate between PE-cfDNA and tumor tissue is 87%. Eleven patients were identified with actionable mutations in PE-cfDNA and four patients benefited from PE-cfDNA-guided targeted. Meanwhile, PE-cfDNA recapitulated mutations of diverse tissue origins and provided more mutational information under the circumstance that tumor tissue or tumor tissue of different origins were unavailable. The combination of tumor tissue and PE-cfDNA profiling increased positive detection rates of patients compared to tumor tissue alone. Our finding highlighted the importance of PE-cfDNA in the optimal selection of patients for targeted therapy., Conclusion: The PE-cfDNA-based liquid biopsy displays better performance in the characterization of gene alterations than PE-sDNA and plasma-cfDNA. PE-cfDNA together with tumor tissue profiling optimizes comprehensively genomic profiling of lung cancer patients, which might be important for selecting patients for better treatment management., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective To investigate the clinicopathological features and immunohistochemical phenotypes of brain metastatic carcinoma in Tibetan patients. Methods The clinical and pathological data of all patients with brain metastases from 2014 to 2020 in Tibet Autonomous Region People's Hospital were retrospectively analyzed,including 13 cases of brain metastatic carcinoma.All cases were diagnosed and classified by immunohistochemical staining. Results 13 cases(9 males and 4 females)of brain metastatic carcinoma,aged 26-62 years old,present with headache,dizziness,nausea and vomiting clinically.Four patients had a medical history of tumor,and among the 9 patients with no history of tumor,7 present space occupying lesions in both the brain and other organs.Imaging data could be found in 10 cases,including 4 cases of single lesion and 6 cases of multiple lesions.Primary tumors were identified in 11 cases(8 located in the lung,including 4 cases of adenocarcinoma,3 cases of small cell carcinoma,and 1 case of squamous cell carcinoma;1 case of urothelial carcinoma of the renal pelvis;1 case of thyroid papillary carcinoma;1 case of uterine choriocarcinoma),whereas the primary tumor was unknown for the other 2 cases(1 case of small cell carcinoma and 1 case of adenocarcinoma). Conclusions Brain metastatic carcinoma are more common among middle-aged and elderly people in Tibet.Most of the cases have no history of tumor,with the initial site at the brain metastatic lesions.The most common primary site is the lung,and the primary site of some cases is unknown.Multiple lesions are common in brain metastatic carcinoma,especially in the cerebral hemisphere.For older patients with multiple brain space occupying lesions,the possibility of brain metastatic carcinoma increases.

Objective: To investigate the short-term efficacy and safety of generic bortezomib in the treatment of Chinese patients with multiple myeloma (MM)., Methods: Clinical data of 62 MM patients (median age of 62 years) who had accepted at least 2 cycles of chemotherapy based on generic bortezomib in our center from December 2017 to July 2019 were retrospectively analyzed, including 47 newly diagnosed patients and 15 with disease recurrence or progression., Results: Anemia, renal dysfunction, hypoproteinemia and high level of β 2 -microglobulin were all improved rapidly after induction treatment. In 56 patients who had completed at least 4 cycles of chemotherapy, the overall response rate (ORR) was 85.7%, and 64.3% of the patients achieved very good partial response (VGPR) or better, and 28.6% achieved complete remission (CR) or better. In the 19 patients who had already completed all planned induction and consolidation treatment (9 cycles of chemotherapy or 4-6 cycles of chemotherapy plus autologous hematopoietic stem cell transplantation), 84.2% achieved VGPR or better, and 57.9% achieved CR or stringent complete remission (sCR). Median follow-up time was 300 days with data cut-off date of September 20, 2019, and the progression-free survival (PFS) rate and overall survival (OS) rate were 62.1% and 85.3%, respectively. The possible adverse reactions associated with bortezomib were grade 1-2, the most common hematologic adverse reaction was thrombocytopenia (27.4%), and the most common non-hematologic adverse reaction was peripheral neuropathy (43.5%), followed by asthenia (37.1%)., Conclusion: The disease severity can be rapidly alleviated after generic bortezomib-based chemotherapy, and a favorable short-term efficacy and survival have been observed with a generally acceptable toxicity profile. However, the long-term outcomes will be examined through further follow-up.

Background: Small peripheral pulmonary nodules, which are usually deep-seated with no visual markers on the pleural surface, are often difficult to locate during surgery. At present, CT-guided percutaneous techniques are used to locate pulmonary nodules, but this method has many limitations. Thus, we aimed to evaluate the accuracy and feasibility of electromagnetic navigational bronchoscopy (ENB) with pleural dye to locate small peripheral pulmonary nodules before video-associated thoracic surgery (VATS)., Methods: The ENB localisation procedure was performed under general anaesthesia in an operating room. Once the locatable guide wire, covered with a sheath, reached the ideal location, it was withdrawn and 0.2-1.0 mL of methylene blue/indocyanine green was injected through the guide sheath. Thereafter, 20-60 mL of air was instilled to disperse the dye to the pleura near the nodules. VATS was then performed immediately., Results: Study subjects included 25 patients with 28 nodules. The mean largest diameter of the pulmonary nodules was 11.8 mm (range, 6.0-24.0 mm), and the mean distance from the nearest pleural surface was 13.4 mm (range, 2.5-34.9 mm). After the ENB-guided localisation procedure was completed, the dye was visualised in 23 nodules (82.1%) using VATS. The average duration of the ENB-guided pleural dye marking procedure was 12.6 min (range, 4-30 min). The resection margins were negative in all malignant nodules. Complications unrelated to the ENB-guided localisation procedure occurred in two patients, including one case of haemorrhage and one case of slow intraoperative heart rate., Conclusion: ENB can be used to safely and accurately locate small peripheral pulmonary nodules and guide surgical resection., Trial Registration Number: ChiCTR1900021963., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Patients undergoing thoracic lung wedge resection could benefit from tubeless strategies. However, postoperative pneumothorax is a primary limiting factor for such strategies. Accordingly, we evaluated the safety and efficacy of the prophylactic use of an air-extraction catheter as an improved drainage strategy and compared the findings with those for chest tube drainage in patients undergoing thoracic wedge resection., Methods: Patients undergoing thoracic wedge resection between August 2017 and October 2018 were enrolled in this single-center, randomized, open-label, noninferiority trial. Patients who received an improved drainage strategy involving the use of a prophylactic air-extraction catheter were randomized to the intervention group, whereas those who underwent routine chest tube drainage were assigned to the control group. Analysis was based on the per-protocol population. The primary outcome was the incidence of pneumothorax on postoperative day 1. Secondary outcomes included patient recovery and related complications, including pleural effusion, lung infection, numeric rating scale score for pain, postoperative chest tube or catheter removal, postoperative hospitalization, and chest tube reinsertion., Results: A total of 96 patients were randomized. Baseline demographic and clinical characteristics were similar between groups. The incidence of pneumothorax in the intervention and control groups was 10.0% and 9.1%, respectively (noninferiority, P = 1.00). In addition, there were no significant between-group differences in secondary outcomes. A significantly lower pain score was observed in the intervention group (P = .001)., Conclusions: The improved drainage strategy is not inferior to standard chest tube drainage after thoracic wedge resection and should be popularized., (Copyright © 2020 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

In this study, we evaluated the diagnostic value and molecular characteristics of plasma extracellular vesicles (EVs)-derived miRNAs for patients with solitary pulmonary nodules (SPNs), particularly ground-glass nodules (GGNs). This study was registered at www.clinicaltrials.gov under registration number NCT03230019. Small RNA sequencing was performed to assess plasma EVs miRNAs in 59 patients, including 12 patients with benign nodules (2017, training set). MiRNA profiles of 40 an additional individuals were sequenced (2018, validation set). Overall, 16 pure GGNs, 21 mixed GGNs, and 42 solid nodules were included, with paired post-operative plasma samples available for 20 patients. The target miRNA/reference miRNA ratio was used to construct a support vector machine (SVM) model. The SVM model with the best specificity showed 100% specificity in both the training and validation sets independently. The model with the best sensitivity showed 100% and 96.9% sensitivity in the training and validation sets, respectively. Principal component analysis revealed that pure GGN distributions were distinct from those of solid nodules, and mixed GGNs had a diffuse distribution. Among differentially expressed miRNAs, miR-500a-3p, miR-501-3p , and miR-502-3p were upregulated in tumor tissues and enhanced overall survival. The SVM classifier accurately distinguished malignant GGNs and benign nodules. The distinct profile characteristics of miRNAs provided insights into the feasibility of EVs miRNAs as prognostic factors in lung cancer., (© 2019 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group on behalf of The International Society for Extracellular Vesicles.)

Purpose: To assess the benefits of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors as neoadjuvant/adjuvant therapies in locally advanced EGFR mutation-positive non-small-cell lung cancer., Patients and Methods: This was a multicenter (17 centers in China), open-label, phase II, randomized controlled trial of erlotinib versus gemcitabine plus cisplatin (GC chemotherapy) as neoadjuvant/adjuvant therapy in patients with stage IIIA-N2 non-small-cell lung cancer with EGFR mutations in exon 19 or 21 (EMERGING). Patients received erlotinib 150 mg/d (neoadjuvant therapy, 42 days; adjuvant therapy, up to 12 months) or gemcitabine 1,250 mg/m 2 plus cisplatin 75 mg/m 2 (neoadjuvant therapy, two cycles; adjuvant therapy, up to two cycles). Assessments were performed at 6 weeks and every 3 months postsurgery. The primary end point was objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1; secondary end points were pathologic complete response, progression-free survival (PFS), overall survival, safety, and tolerability., Results: Of 386 patients screened, 72 were randomly assigned to treatment (intention-to-treat population), and 71 were included in the safety analysis (one patient withdrew before treatment). The ORR for neoadjuvant erlotinib versus GC chemotherapy was 54.1% versus 34.3% (odds ratio, 2.26; 95% CI, 0.87 to 5.84; P = .092). No pathologic complete response was identified in either arm. Three (9.7%) of 31 patients and zero of 23 patients in the erlotinib and GC chemotherapy arms, respectively, had a major pathologic response. Median PFS was significantly longer with erlotinib (21.5 months) versus GC chemotherapy (11.4 months; hazard ratio, 0.39; 95% CI, 0.23 to 0.67; P < .001). Observed adverse events reflected those most commonly seen with the two treatments., Conclusion: The primary end point of ORR with 42 days of neoadjuvant erlotinib was not met, but the secondary end point PFS was significantly improved.

Introduction: Inhibition of programmed cell death-1 (PD-1) and its ligand programmed death ligand 1 (PD-L1) by using an immune checkpoint inhibitor has emerged as a promising immunotherapy for NSCLC. The correlation of PD-L1 expression in tumor cells with treatment outcomes has been reported in many pivotal trials; however, the relationship remains unclear. Here, we demonstrate that those patients with both high density of PD-1-positive CD8 and PD-L1-positive CD4-positive CD25-positive (PD-1 hi PD-L1 hi ) regulatory T cells (Tregs) have a better response to PD1/PD-L1 blockade., Methods: In our study between April 1, 2014, and May 30, 2017, a total of 73 NSCLC peripheral blood samples and fresh tumor specimens were collected for study. Of these, 42 large (10-mm 3 ) fresh tumor specimens were obtained from surgical procedures and checked for expression of immunology biomarkers, including PD-L1, PD-1, CD8, CD4, and CD25, in tumor cells and tumor-infiltrating lymphocytes (TILs) by flow cytometry, immunohistochemistry, and immunofluorescence (IF). Moreover, 31 small biopsy specimens from patients who received immunotherapy (pembrolizumab or nivolumab) were analyzed by immunohistochemistry and IF. The correlation between flow cytometry and IF detected for TILs' density was evaluated by Spearman's rank correlation test; the primary end point was progression-free survival. For the PD-1/PD-L1 blockade assay, the TILs and peripheral blood mononuclear CD8 T cells were cultured (1×10 5 per well) with anti-PD-1 (clone MIH4), anti-PD-L1 (clone MIH1). The cytotoxic activity of TILs in killing NSCLC cells after stimulation by anti-PD-1 and anti-PD-L1 was measured by a conventional 51 Cr release assay., Results: We first identified a population of high-PD-L1-expressing CD25-positive CD4-positive T cells (PD-L1 hi Tregs) in the tumor microenvironment. The frequency of PD-L1 hi Tregs was higher in tumor tissue (mean 48.6 ± 14.3% in CD25-positive CD3-positive CD4-positive T cells) than in blood (mean 35.4 ± 10.2% in CD25-positive CD3-positive CD4-positive T cells) and normal tissue (mean 38.6 ± 9.7% in CD25-positive CD3-positive CD4-positive T cells) (p < 0.05), as determined by flow cytometry. The frequency of PD-L1 hi Tregs was positively correlated with PD-1-positive CD8 in Tregs. In addition, the TILs from these patients (PD-1 hi PD-L1 hi ) showed PD-1/PD-L1 pathway dependence and could induce a greater killing effect of TILs by PD-1/PD-L1 blockade treatment. The patients with PD-L1-positive NSCLC with PD-1 hi PD-L1 hi TILs showed a better clinical outcome than those with a low frequency of PD-1 hi CD8 or PD-L1 hi Tregs (median progression-free survival not reached versus 2 months)., Conclusions: Our findings suggested that the density of PD-L1-positive CD4-positive CD25-positive Tregs in the tumor microenvironment can serve as a diagnostic factor to supplement PD-L1 expression in tumor cells and predict the response to PD-1/PD-L1 blockade immunotherapy in NSCLC., (Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

This paper focuses on the collective dynamics of multisynchronization among heterogeneous genetic oscillators under a partial impulsive control strategy. The coupled nonidentical genetic oscillators are modeled by differential equations with uncertainties. The definition of multisynchronization is proposed to describe some more general synchronization behaviors in the real. Considering that each genetic oscillator consists of a large number of biochemical molecules, we design a more manageable impulsive strategy for dynamic networks to achieve multisynchronization. Not all the molecules but only a small fraction of them in each genetic oscillator are controlled at each impulsive instant. Theoretical analysis of multisynchronization is carried out by the control theory approach, and a sufficient condition of partial impulsive controller for multisynchronization with given error bounds is established. At last, numerical simulations are exploited to demonstrate the effectiveness of our results.

Chlorinated polycyclic aromatic hydrocarbons (ClPAHs) with three to five aromatic rings have been documented to ubiquitously occur in environmental matrices. In this study, residual concentrations and profiles of 20 individual ClPAHs were determined in 35 surface sediment samples from Maowei Sea, a semi-enclosed shallow inland bay located in the northwestern part of South China Sea. The concentrations of ΣClPAHs in sediment ranged from 313 to 9650 pg/g dw with a detection rate of 43-100%. Of the individual ClPAH congeners, 9-ClPhe was the most abundant in Maowei Sea with the concentrations that ranged from 99.9 to 3610 pg/g dw (mean 1120 pg/g dw). High-molecular-weight ClPAH congeners (four to five rings) were predominant in sediments from sampling locations near a petrochemical industrial complex, whereas low-molecular-weight ClPAH congeners (three rings) were predominant in sediments from estuarine and mangrove locations. A positive matrix factorization (PMF) model in combination with dioxin-like toxic equivalency quotient (TEQ) results was used to apportion sources of ClPAHs. Vehicular emission, combustion/chemical industrial processes, and two other unknown sources accounted for 40.1, 25.5, 20.8, and 13.6%, respectively, of ClPAH sources in sediment; their contribution to TEQs in sediments were 24.2, 40.5, 19.3, and 16.0%, respectively. Further investigations are needed to elucidate potential sources and ecological risks of ClPAHs in sediments.

Background: Right upper lobectomy (RUL) for lung cancer with different dissecting orders involves the most variable anatomical structures, but no studies have analyzed its effects on postoperative recovery. This study compared the conventional surgical approach, VAB (dissecting pulmonary vessels first, followed by the bronchus), and the alternative surgical approach, aBVA (dissecting the posterior ascending arterial branch first, followed by the bronchus and vessels) on improving surgical feasibility and postoperative recovery for lung cancer patients., Methods: According to the surgical approach, consecutive lung cancer patients undergoing RUL were grouped into aBVA and VAB cohorts. Their clinical, pathologic, and perioperative characteristics were collected to compare perioperative outcomes., Results: Three hundred one patients were selected (109 in the aBVA cohort and 192 in the VAB cohort). The mean operation time was shorter in the aBVA cohort than in the VAB cohort (164 vs. 221 min, P < 0.001), and less blood loss occurred in the aBVA cohort (92 vs. 141 mL, P < 0.001). The rate of conversion to thoracotomy was lower in the aBVA cohort than in the VAB cohort (0% vs. 11.5%, P < 0.001). The mean duration of postoperative chest drainage was shorter in the aBVA cohort than in the VAB cohort (3.6 vs. 4.5 days, P = 0.001). The rates of postoperative complications were comparable (P = 0.629). The median overall survival was not arrived in both cohorts (P > 0.05). The median disease-free survival was comparable for all patients in the two cohorts (not arrived vs. 41.97 months) and for patients with disease recurrences (13.25 vs. 9.44 months) (both P > 0.05). The recurrence models in two cohorts were also comparable for patients with local recurrences (6.4% vs. 7.8%), distant metastases (10.1% vs. 8.3%), and both (1.8% vs. 1.6%) (all P > 0.05)., Conclusions: Dissecting the right upper bronchus before turning over the lobe repeatedly and dissecting veins via the aBVA approach during RUL would promote surgical feasibility and achieve comparable postoperative recovery for lung cancer patients.

Purpose: Although clinical studies have shown promise for targeting programmed cell death protein-1 (PD-1) and ligand (PD-L1) signaling in non-small cell lung cancer (NSCLC), the factors that predict which subtype patients will be responsive to checkpoint blockade are not fully understood. Experimental Design: We performed an integrated analysis on the multiple-dimensional data types including genomic, transcriptomic, proteomic, and clinical data from cohorts of lung adenocarcinoma public (discovery set) and internal (validation set) database and immunotherapeutic patients. Gene set enrichment analysis (GSEA) was used to determine potentially relevant gene expression signatures between specific subgroups. Results: We observed that TP53 mutation significantly increased expression of immune checkpoints and activated T-effector and interferon-γ signature. More importantly, the TP53/KRAS comutated subgroup manifested exclusive increased expression of PD-L1 and a highest proportion of PD-L1 + /CD8A + Meanwhile, TP53- or KRAS -mutated tumors showed prominently increased mutation burden and specifically enriched in the transversion-high (TH) cohort. Further analysis focused on the potential molecular mechanism revealed that TP53 or KRAS mutation altered a group of genes involved in cell-cycle regulating, DNA replication and damage repair. Finally, immunotherapeutic analysis from public clinical trial and prospective observation in our center were further confirmed that TP53 or KRAS mutation patients, especially those with co-occurring TP53/KRAS mutations, showed remarkable clinical benefit to PD-1 inhibitors. Conclusions: This work provides evidence that TP53 and KRAS mutation in lung adenocarcinoma may be served as a pair of potential predictive factors in guiding anti-PD-1/PD-L1 immunotherapy. Clin Cancer Res; 23(12); 3012-24. ©2016 AACR ., (©2016 American Association for Cancer Research.)

Background: Supraclavicular lymph node (SCLN) biopsies play an important role in diagnosing and staging lung cancer. However, not all patients with SCLN metastasis can have a complete resection. It is still unknown whether SCLN incisional biopsies affect the prognosis of non-small cell lung cancer (NSCLC) patients., Methods: Patients who were histologically confirmed to have NSCLC with SCLN metastasis were enrolled in the study from January 2007 to December 2012 at Guangdong Lung Cancer Institute. The primary endpoint was OS, and the secondary endpoints were complications and local recurrence/progression., Results: Two hundred two consecutive patients who had histologically confirmed NSCLC with SCLN metastasis were identified, 163 with excisional and 39 with incisional biopsies. The median OS was not significantly different between the excisional (10.9 months, 95% CI 8.7-13.2) and incisional biopsy groups (10.1 months, 95% CI 6.3-13.9), P = 0.569. Multivariable analysis showed that an Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥2 (HR = 2.75, 95% CI 1.71-4.38, P < 0.001) indicated a worse prognosis. Having an epidermal growth factor receptor (EGFR) mutation (HR = 0.58, 95% CI 0.40-0.84, P = 0.004) and receiving systemic treatment (HR = 0.36, 95% CI 0.25-0.53, P < 0.001) were associated with a favorable OS. Neither the number (multiple vs. single) nor site (bilateral vs. unilateral) of SCLNs was associated with an unfavorable OS, and SCLN size or fixed SCLNs did not affect OS., Conclusions: SCLN incisional biopsies did not negatively influence the prognosis of NSCLC patients. It was safe and feasible to partly remove a metastatic SCLN as a last resort in advanced NSCLC.

Objectives: The management of non-small cell lung cancer (NSCLC) relies on the tumour-node-metastasis (TNM) stage, and the treatment regimen differs based on the N status. Positron emission tomography-computed tomography (PET-CT) has emerged as a powerful imaging tool for the detection of various cancers with a relatively low false-negative rate. We explored predictors to identify false-negative N2 disease in PET-CT., Methods: A total of 284 consecutive cN0 patients with peripheral NSCLC who underwent PET-CT scans followed by curative intent resections were enrolled as a training set to identify predictors of occult N2 metastases by multivariable analysis. The accuracy and cut-off values for the predictors were calculated using a receiver operating characteristic curve. Clinical and pathological data were analysed retrospectively. An additional 151 patients were collected as a test set to validate the results, including the occult N2 rate and accuracy., Results: In total, 8.5% (24/284) PET-CT-diagnosed N0 NSCLC cases had pathologically diagnosed N2 metastases. The SUV max of the primary tumour was a unique independent risk factor for occult N2 NSCLC [P = 0.003, 95% confidence interval = 0.81-0.96, odds ratio (OR) = 0.88]. Occult N2 metastases occurred more frequently in the subcarinal (16/24) and right lower paratracheal lymph nodes (12/24). Accordingly, we divided the patients into two groups by SUV max : the occult N2 rates in the SUV max of <2.6 and SUV max of ≥2.6 groups were 1.0% (1/100) and 12.5% (23/184), respectively (P = 0.001). In the test set, the occult N2 incidence rate was 9.3% (14/151), with the highest rates occurring in the subcarinal (9/14) and right lower paratracheal lymph nodes (6/14). In the two groups defined by SUV max , the occult N2 rates were 4% (2/50) and 11.9% (12/101), respectively., Conclusions: The SUV max of the primary tumour was an independent risk factor for occult N2 metastases in NSCLC patients diagnosed as clinical N0 by PET-CT. SUV max of ≥2.6 of the primary tumour may indicate the risk of N2 metastases, and invasive mediastinal staging techniques or comprehensive therapy should not be ignored in these patients., (© The Author 2016. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: Video-assisted thoracoscopic surgery (VATS) lobectomy has emerged as a safe and effective technique for treating early-stage lung cancer. Novel three-dimensional, high-definition (3D HD) imaging has removed this technical obstacle and is increasingly used in laparoscopic surgery. We compared our initial experience of 3D HD VATS with standard two-dimensional (2D) HD VATS to identify the advantages and disadvantages of 3D HD visualization in VATS., Methods: The data of consecutive patients diagnosed with lung cancer who underwent 2D or 3D thoracoscopic lobectomy or bilobectomy at the Guangdong Lung Cancer Institute from July 2013 to October 2014 were retrospectively analyzed. Operation duration, estimated blood loss, length of postoperative stay, major complications, and mortality were recorded for each patient., Results: In total, 359 patients were enrolled in the study. Lobectomy was performed in 339 patients and bilobectomy in 20; the 3D HD system was used for 178 of the 359 patients, and the 2D HD system for 181. Tumor size, distribution of the resected lobes, and the demographic characteristics of the patients were matched between the two groups. The mean operative time for 3D VATS was 163 minutes (range 60-330), whereas 2D VATS required 184 minutes (range 75-360; P < 0.001). The volume of blood loss was 109 and 144 mL in the 3D and 2D VATS groups, respectively (P = 0.064)., Conclusions: The new-generation 3D HD imaging system is feasible and safe for thoracic lobectomy. The 3D system required a shorter operative duration., (© 2016 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background: Individualization of pulmonary parenchymal resection and lymphadenectomy in lung cancer patients will likely become more important as surgical innovation. This study explored the utility of intraoperative pathological frozen sections of regional lymph nodes in non-small cell lung cancer (NSCLC) patients., Methods: Patients with NSCLC underwent intraoperative sampling of N1 station lymph nodes depending on the location of the tumor, any other suspicious lymph nodes were also biopsied. The contribution of frozen-section analysis to surgical decision-making was evaluated., Results: Of 74 lung cancer patients who underwent intraoperative frozen section analysis of lymph nodes, the positive rate was 18/74 (24.3%). The extents of agreement between preoperative N staging (cN) and intraoperative N staging (sN), cN staging and postoperative N staging (pN), and sN staging and pN staging were 62.2% (46/74), 63.5% (47/74), and 71.6% (53/74), respectively. When frozen section was combined with evaluation of pulmonary function and intrathoracic adhesions, surgical strategies were modified during operations in 18 cases (5 sN-positive, 13 sN-negative). Of these patients, five underwent extensive pulmonary parenchymal resection, and four had conservative lung parenchymal resection. In nine patients, the extent of lymph node dissection (LND) was changed., Conclusions: Intraoperative frozen section of regional lymph nodes led to 24.3% operative strategies modification in lung cancer. Frozen section analysis may make an important contribution to surgical decision-making in terms of pulmonary parenchymal resection and LND., Competing Interests: The authors have no conflicts of interest to declare.

Programmed cell death protein-1 (PD-1) and ligand (PD-L1) provide an important escape mechanism from immune attack, and blockade therapy of these proteins show promising clinical benefits in many types of cancer. PD-L1 can be induced by interferon-gamma (IFN-γ), hypoxia, or toll-like receptor (TLR)-mediated pathways that confer adaptive immune resistance, or upregulated by oncogenic signals leading to constitutive expression and resulting in intrinsic immune resistance. The PD-1/PD-L1 checkpoint blockade, which targets regulatory pathways in T cells to overcome immune resistance, is correlated to PD-L1 expression pattern and the presence of tumor-infiltrating lymphocytes (TILs). Meanwhile, immunogenic mutation loads show significant response to checkpoint blockade, which is probably due to PD-1/L1 status and TIL content. Finally, the clinical strategies to design effective checkpoint-targeting immunotherapies are based on the classification of inducible/constitutive expression of PD-L1 and the presence of TILs.

Background: We want to establish a lobe-specific mediastinal lymphadenectomy protocol for solitary pulmonary nodules (SPNs) in non-small cell lung cancer (NSCLC)., Methods: We retrospectively analyzed 401 patients with pathological diagnoses of NSCLC who underwent lobectomy, bilobectomy, or pneumonectomy with systematic lymphadenectomy from March 2004 to June 2011 in our hospital. All of the patients enrolled had a SPN preoperatively. Information about the primary tumor location, lymph node metastasis, and other baseline data were collected. Stepwise logistic regression was used to identify the key factors indicating non-regional mediastinal lymph node metastases (NRM)., Results: Of the primary tumors, 117, 39, 74, 104, and 67 were in the right upper lung (RUL), right middle lung (RML), right lower lung (RLL), left upper lung (LUL), and left lower lung (LLL), respectively. Stepwise regression showed that #2,4, #10,11, and #10,11 as well as #7 was the key lymph node station for RUL, LUL, and lower lobes: #2,4 [odds ratio (OR)=28.000, 95% confidence interval (CI): 2.917-268.790, P=0.004] for RUL, #10,11 (OR=31.667, 95% CI: 2.502-400.833, P=0.008) for LUL, #10,11 (OR=19.540, 95% CI: 4.217-90.541, P<0.001) and #7 (OR=7.395, 95% CI: 1.586-34.484, P=0.011) for lower lobes, respectively. Patients with tumors >2 cm rarely had NRM without primary regional mediastinal involvement., Conclusions: With rigid consideration, a lobe-specific lymphadenectomy is feasible in practice. This protocol can be used when the lobe-specific key nodes are negative in intraoperative frozen sections, especially for NSCLC diagnosed as SPN <2 cm preoperatively.

Objective: In the 7(th) edition of the TNM classification of malignant tumors, the prognosis for pT4-M1a stage IV lung cancer is better than for stage pIIIB. Subgroups of lung cancer patients who underwent incomplete resection (R1/R2) have a favorable prognosis. This study compares the prognosis between cases of invisible local residual disease and intrathoracic disseminated pT4-M1aIV., Methods: Patient characteristics and histological and molecular profiles were retrospectively collected for lung cancer patients who underwent resection intended to be curative but were accidentally incomplete. All patients were divided into either a local residual group or an intrathoracic disseminated pT4M1a group. Progression-free survival (PFS) and overall survival (OS) were evaluated by Kaplan-Meier and Cox regression models., Results: In total, 1,483 consecutive lung cancer patients receiving thoracotomies at Guangdong Lung Cancer Institute were retrospectively analyzed. Fifty-eight patients receiving incomplete resections (R1/R2) were enrolled, including 38 patients with local residual cancer (2.6% of all patients) and 20 patients with disseminated pM1a (1.3%). Patient characteristics, and histological and molecular profiles of the two groups were different. Compared to the local residual group, the disseminated pT4-M1a group contained more females (P=0.002), more patients younger than 60 years of age (P=0.028), more non-smokers (P=0.037), more adenocarcinomas (20/20 vs. 20/38, P<0.001), more adenocarcinomas with lepidic pattern (11/20 vs. 4/38, P<0.001), higher carcinoembryonic antigen (CEA) levels (P=0.06), higher epidermal growth factor receptor (EGFR) mutation rates (16/20 vs. 7/38, P<0.001), a higher R2/R1 resection ratio (P=0.013), a higher advanced stage IV/IIIB ratio (P<0.001), but fewer lymph node metastases (P=0.013). Median PFS for the local residual and disseminated pT4-M1a groups was 9.0 and 18.0 months, respectively [95% confidence interval (CI), 5.285-16.715; P =0.099]. Median OS was 15.0 and 45.0 months, respectively (95% CI, 18.972-39.028; P=0.001). Cox regression analysis revealed that group (local residual vs. disseminated pT4-M1a) was the only independent prognostic factor (P=0.044) for OS., Conclusions: Accidental invisible intrathoracic disseminated pT4-M1a may be a distinct lung cancer subtype with a favorable prognosis. The prolonged PFS and OS might reflect the natural history of this distinct subtype, together with a favorable response to EGFR tyrosine kinase inhibitors (EGFR-TKI). For asymptomatic and slow-growing accidental pT4-M1a disease, the role of a wait-and-see strategy and the appropriate timing of systemic treatment require further investigation.

Background: Available study revealed advanced tumors have a higher expression rate of MAGE-A3 gene which has a lot of single nucleotide polymorphism (SNP) loci with polymorphisms. This study aimed to analyze the allele frequency of SNP loci in MAGE-A3 gene and investigate the relationship between MAGE-A3 gene polymorphisms and clinical factors., Methods: Tumor samples of a cohort of 191 NSCLC patients were collected. EGFR mRNA expression were detected by qRT-PCR. SNPs in whole length of MAGE-A3 gene were detected by direct sequencing. Frequencies of the SNPs were correlated to gene expression, mutation status of EGFR and clinical factors., Results: Sequencing analysis confirmed that allele frequencies of genotypes on SNP loci rs5970360, rs5925210, rs5970361, rs5925211 and rs35123853 were CC (0.681)/CT (0.319), CC (0.660)/CG (0.340), CC (0.681)/CA (0.319), AA (0.984)/AT (0.016) and GG (1.000)/GA (0.000), respectively, which were different from the frequencies and genotypes of MAGE-A3 in SNP database. Chi-square tests showed the EGFR mRNA expression level had significant correlation with the genotypes of SNP loci rs5970360 and rs5925210. But all frequencies of each MAGE-A3 SNPs were not found significantly different between EGFR mutant and wild type patients. MAGE-A3 gene polymorphisms had no significant effects on survival of NSCLC patients., Conclusions: Chinese patients with NSCLC had different SNP patterns of MAGE-A3 in comparison with those in international SNP database. These MAGE-A3 SNP loci might have not prognostic significance. MAGE-A3 SNP loci rs5970360 and rs5925210 might be predictive for EGFR mRNA expression levels and helpful to the selection of patients for epidermal growth factor receptor (EGFR) targeted immunotherapy.

The genetic regulatory networks are complex dynamic systems which reflect various kinetic behaviors of living things. In this paper, a new structure of coupled repressilators is introduced to exploit the underlying functions. The new coupled repressilator model consists of two identical repressilators inhibiting each other directly. The coupling delays are taken into account. The existence of a unique equilibrium for this system is verified firstly, then the stability criteria for equilibrium are analyzed without and with coupling delays. The different functions on equilibrium and its stability played by related biochemical parameters in the structure including maximal transcription rate, coupling strength, the decay rate ratio between proteins and mRNAs, and coupling delays are discussed. At last, several numerical simulations are made to demonstrate our results., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Purpose: We investigated the incidence of concomitant epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements in Chinese patients with non-small cell lung cancer (NSCLC), and assessed responses to EGFR tyrosine kinase inhibitors (EGFR-TKIs) and crizotinib in such tumors., Experimental Design: We screened 977 consecutive patients with NSCLC for the presence of concomitant EGFR mutations and ALK rearrangements by rapid amplification of cDNA ends-coupled PCR sequencing and FISH. Immunohistochemistry (IHC) and Western blotting were used to correlate the activation of EGFR, ALK, and downstream proteins with responses to EGFR-TKIs and crizotinib., Results: The overall frequency of concomitant EGFR mutations and ALK rearrangements was 1.3% (13/977). EGFR/ALK co-alterations were found in 3.9% (13/336) EGFR-mutant and 18.6% (13/70) ALK-rearranged patients. Ten tumors were treated with first-line EGFR-TKIs, with a response rate of 80% (8/10). Two tumors with high phospho-ALK levels and low phospho-EGFR levels achieved stable and progressive disease, respectively. Median progression-free survival was 11.2 months. Coexpression of mutant EGFR and ALK fusion proteins in the same tumor cell populations was detected by IHC. Two cases with high phospho-ALK levels treated with crizotinib achieved partial responses; two cases with low phospho-ALK levels had progressive or stable disease., Conclusion: ALK rearrangements and EGFR mutations could coexist in a small subgroup of NSCLC. Advanced pulmonary adenocarcinomas with such co-alterations could have diverse responses to EGFR-TKIs and crizotinib. Relative phospho-ALK and phospho-EGFR levels could predict the efficacy of EGFR-TKI and crizotinib., (©2014 AACR)

Background: There is no published overview of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) failure modes in advanced non-small-cell lung cancer (NSCLC). This study aimed to classify the diversity of EGFR-TKI failure, and to investigate the usefulness of clinical modes in subsequent management and prognosis., Methods: One-hundred and twenty consecutive clinical trial patients with EGFR-TKI failure were enrolled as the training set to establish a clinical model based on clinical factors. Another 107 routine patients were enrolled as the validating set according to a Bayes discriminant analysis. EGFR mutations and c-MET amplification were analyzed. Kaplan-Meier survival analysis was used to test the differences among three clinical modes and subsequent management., Results: The duration of disease control, evolution of tumor burden, and clinical symptom were verified as feasible grouping variables. A correct grouping rate achieved 87.9%. The cohort was classified into three groups, as follows: 130 patients with dramatic progression, 42 with gradual progression, and 55 with local progression. Progression-free survivals (PFSs) for the dramatic progression, gradual progression, and local progression groups were 9.3, 12.9, and 9.2 months, respectively (P = 0.007). Overall survivals for the groups (OSs) were 17.1, 39.4, and 23.1 months, respectively (P < 0.001). TKI continuation was superior to switching chemotherapy in a subsequent setting for gradual progression (39.4 months vs. 17.8 months; P = 0.02). The difference of EGFR or c-MET among the three groups was not significant., Conclusions: Clinical modes of EGFR-TKI failure could favor strategies for subsequent treatment and predicting a survival benefit in advanced NSCLC., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Objective: To evaluate the efficacy and safety of nedaplatin/gemcitabine (NG) and carboplatin/gemcitabine (CG) in the management of untreated advanced non-small cell lung cancer (NSCLC)., Methods: Sixty-two patients with previously untreated advanced NSCLC were recruited between June 2006 and November 2007. Subjects were randomly assigned to the NG arm (n=30) and the CG arm (n=32). Only patients (24 and 25 in the NG and CG arms, respectively) who completed ≥2 chemotherapy cycles were included in the data analysis. The primary outcome measure was the objective response rate (ORR). The secondary outcome measures included progression-free survival (PFS), overall survival (OS) and adverse events., Results: There were no statistically significant differences in the efficacy measures (ORR, P=0.305; median PFS, P=0.198; median OS, P=0.961) or in the major adverse events (grade 3/4 neutropenia, P=0.666; grade 3/4 anemia, P=0.263; grade 3/4 thrombocytopenia, P=0.212) between the two treatment arms. However, there was a trend towards higher ORR (37.5% vs. 24.0%), longer PFS (6.0 vs. 5.0 months), and less adverse events in the NG arm., Conclusion: NG regimen seems to be superior over CG regimen for advance NSCLS, but further investigation is needed to validate this superiority.

Background: Mutations in the epidermal growth factor receptor (EGFR) have been confirmed as predictors of efficacy for EGFR-tyrosine kinase inhibitors (TKIs). We investigated whether polymorphisms of the EGFR and cytochrome P450, family 1, member A1 (CYP1A1) genes were associated with clinical outcome in NSCLC patients treated with EGFR-TKI., Methods: Genotypes for the intron 1 (CA)n repeat and R497K polymorphisms in the EGFR gene and the *2A (3801 T→C) and *2C (2455 A→G) polymorphisms in CYP1A1 gene were evaluated in 115 NSCLC patients by PCR-RFLP and DNA sequencing. Genetic polymorphisms were correlated with clinical outcomes of EGFR-TKIs. From a subgroup of patients whose tumour tissues were available, associations between somatic EGFR mutations, EGFR expression, and genomic polymorphisms were also analysed., Results: EGFR intron 1 (CA)n and CYP1A1*2A polymorphisms were independent predictive factors (p=0.046, p=0.011, respectively) and the latter was also a prognostic factor (p=0.001) for patients treated with EGFR-TKIs. We also observed a strong synergistic effect from two genotypes. Specifically, patients with both the T/T allele of the CYP1A1 gene and shorter intron 1 CA repeats (≤ 16 CA) of the EGFR gene showed an improved response (p=0.002) compared with patients with the T/C or C/C allele and longer intron 1 CA repeats (both alleles >16 CA). In contrast, for R497K and CYP1A1*2C, no relationship was observed with clinical outcome for patients treated with EGFR-TKIs (p=0.573; p=0.629, respectively). Both SNPs in the CYP1A1 gene showed a correlation with EGFR somatic mutations., Conclusions: The findings of this study suggest that the CYP1A1*2A polymorphism is a predictor for clinical outcome in NSCLC patients treated with EGFR-TKI therapy, and combining analysis of both CYP1A1*2A and EGFR intron 1 (CA)n polymorphisms may be useful for predicting treatment outcome in NSCLC patients treated with EGFR-TKIs., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: Epidermal growth factor receptor (EGFR) mutations may accumulate during the multistage progression of bronchioloalveolar carcinoma (BAC), leading to heterogeneity within the tumor. This study sought to determine whether metachronous adenocarcinomas with a BAC component emerging in the lung field arise from a single or multiple clones in the same individual., Materials and Methods: Samples of adenocarcinomas exhibiting various degrees of BAC were obtained by thoracotomy. Sequential specimens were obtained upon detection of metachronous lesions in the lung field. Genomic DNA was extracted from specimens, and the presence of activating mutations in EGFR was determined via direct sequencing. Our pathologic findings, sequential image information, and genetic data were compared to track evidence of cancer evolution., Results: Based on EGFR gene analyses of tumor specimens from 431 patients, 17 cases of sequential BAC-related adenocarcinomas, obtained by thoracotomy, were noteworthy. Upon alteration of the BAC/adenocarcinoma components, the EGFR tyrosine kinase inhibitor-untreated series, which had at least one episode of an EGFR-activating mutation, represented 3 potential hypotheses: no significant EGFR evolution for a single clone, genetic alterations from mutant to wild-type EGFR for multifocal lesions, or a switch from wild-type to mutant EGFR, leading to indeterminable cancer progression., Conclusion: Genetic analysis, in conjunction with pathologic and radiologic diagnoses, can be used to explore the origin of multifocal BAC. The single-clone model indicates subsequent disease progression, whereas genetic alterations from mutations to wild-type EGFR are suggestive of second primary carcinoma. In cases when additional lesions emerge after the radical resection of BAC-related lung cancer, sequential tumor samples should be obtained for further evaluation.

Objective: Further investigation on the incidence and clinicopathologic features of bronchioloalveolar carcinomas (BAC) including: (1) BAC of strictly defined, (2) adenocarcinoma with bronchioloalveolar features, (3) other different histologic subtypes of lung adenocarcinomas., Methods: Surgical specimens from 348 lung adenocarcinoma patients admitted in that hospital between 1998 - 2005 were included. And clinical data were collected at the same time. Patients of strictly defined BAC, BAC with focal invasion (BWFI), and adenomas with bronchioloalveolar features (AWBF) were followed-up. Data were analyzed using SPSS statistics software and Kaplan-Meier survival curves were constructed., Results: The resected lung adenocarcinomas consisted of different histologic subtypes. The most frequent one was adenocarcinoma of mixed subtypes (78.2%, 272/348), followed by the acinar type (8.1%, 28/348), the papillary type (4.0%, 14/348), the BAC (3.7%, 13/348), the mucinous (colloid) type (3.4%, 12/348) and the solid types (2.3%, 8/348). The fetal adenocarcinoma was the least component detected. There was no significant difference on the survival curves between groups BAC and BWFI. The survival rate of patients with AWBF was poorer than that of BAC and BWFI., Conclusions: Since patients with strictly defined (simple) BAC, BWFI, and AWBF have their own distinct clinicopathologic features and prognosis respectively, they should be strictly distinguished from other types of pulmonary adenocarcinomas.

Aims: It has been shown that the introduction of a second mutation into the already mutated epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC) will alter the sensitivity to tyrosine kinase inhibitors (TKIs). EGFR double activating mutations involving both exons 19 and 21 were previously detected in Asian patients, but the sensitivity to TKIs had not yet been characterised. Our objective was to profile the status of EGFR double mutations in Chinese NSCLC patients and to further ascertain the biological properties., Materials and Methods: In total, 145 NSCLC tumour samples from unselected Chinese NSCLC patients were sequenced to screen mutations in exons 18, 19 and 21 of EGFR. Five patients were detected to harbour the delE746-A750+L858R double activating mutations. Subcloning experiments were carried out, expression vectors inserted with corresponding full-length EGFR were constructed, and in vitro transient transfections were performed in 293T cells. Whole cell lysates were collected to assess the sensitivity to TKIs using immunoblotting., Results: All five patients had adenocarcinoma. The frequency of double mutations was 3.4% (5/145). Three patients received and responded to gefitinib treatment. Subcloning experiments showed that all the subclones were either wild type or double mutated. At a concentration of TKIs of 0.1 microM, the autophosphorylation of the double mutant was inhibited greater than that of either single mutated EGFR. However, the difference disappeared when the concentration increased to 1 microM., Conclusions: delE746-A750+L858R double activating EGFR mutations exist in Chinese NSCLC patients and both locate on the same allele. These patients tend to respond well to TKIs and the sensitivity to TKIs of this double mutated EGFR is enhanced compared with either single mutant. Nonetheless, the alteration in downstream signal transduction of the double mutant remains to be determined.

Background: Conventional treatment for non-small cell lung cancer (NSCLC) brain metastases (BM) is whole-brain radiotherapy (WBRT). The efficacy is limited. It might be increased by a potent radiosensitizer such as gemcitabine, which is believed to cross the disrupted blood-brain barrier. The primary objective of this study was to determine the maximum tolerated dose (MTD) of weekly gemcitabine given concurrently with WBRT., Methods: Patients with BM from NSCLC were included. The dose of WBRT was 3750 cGy (total 15 times, 3 weeks). Gemcitabine was given concurrently with WBRT on days 1, 8 and 15. The starting dose was 400 mg/m(2), escalated by 100 mg/m(2) increments. At least three patients were included per level. Dose limiting toxicity (DLT) was defined as grade 4 hematological or grade 2 neurological toxicity. When two or more patients experience DLT, the MTD was reached., Results: A total of 16 patients were included; 69% had a performance status (PS) 1 (Eastern Cooperative Oncology Group, ECOG). A total of 69% had concurrent active extra cranial diseases. All had more than 3 BM. Up to 600 mg/m(2) (level 3) no neurology toxicity was observed. At 600 mg/m(2) two out of 9 patients developed grade 4 thrombocytopenia. One of the two patients' thrombocytopenia was confused with disseminated intravascular coagulation (DIC). At 700 mg/m(2) two out of 4 patients developed neurotoxicities. One developed grade 3 seizure and cognitive disorder. Another patient developed suspected grade 2 muscle weakness., Conclusions: The MTD was reached at a dose of 700 mg/m(2). The dose of 600 mg/m(2) would be considered for further study.

Objective: To evaluate the efficacy, target population and influencing factors of Gefitinib in patients with non-small-cell lung cancer (NSCLC) pretreated with platinum., Methods: Patients with NSCLC who had been previously treated with at least one course of platinum based chemotherapy received 250 mg oral doses of Gefitinib once daily till disease progression. Response rate, progression free survival, overall survival and toxicity profile were analyzed. Kaplan-Meier method was used to analyze the survival rate. Cox regression was used to define the predictive factors., Results: A hundred and fifteen patients were enrolled into the study from July 2001 to May 2005. The follow-up was ended on Sep. 30, 2006. Median follow up time was 30 months. The compliance rate was 100%. The median symptom improving time was 8 days. Complete response rate was 4.3% (5/115), partial response 39.1% (45/115), stable disease 27.0% (31/115) and progressive disease 29.6% (34/115). Response rate was 43.5% (50/115). Disease control rate was 70.4% (81/115). The median progression-free survival and median overall survival were 8 and 11 months, respectively. One and two-year progression-free survival rates and overall survival rates were 32.2% (events 78), 5.6% (events 103) and 41.7% (death 67), 21.5% (death 87) respectively; 3-year overall survival 12.3% (death 93). Adenocarcinoma was the only predictor for therapeutic effect in the Cox model (P = 0.004). The primary failure to gefitinib was due to brain metastasis (39.4%, 28/71). Grade III skin toxicity was found in 5.2% (6/115) patients., Conclusion: Gefitinib is the drug of choice for patients with heavily pretreated stage III(B) and IV adenocarcinoma of NSCLC with safe and accepted toxicity profile.

Objective: To investigate the mutation of epithelial growth factor receptor (EGFR) gene in the non-small cell lung carcinoma (LSCLG) patients with different genders and the relationship between the gender of LSCLG patients and the curative effects of gefitinib, an specific tyrosine kinase., Methods: Tumor specimens were obtained from 135 NSCLC patients, 94 males (78.7% smoking) and 41 females (17.1% smoking), of which 20 received gefitinib treatment after the failure of chemotherapy, during operation and stored at -80 degrees C. The genomic DNA of the cancer tissues was extracted by using Trizol reagent. Nest-PCR was used to amplify the exons 18, 19, and 21 of the EGFR gene and the PCR products were purified by agarose electrophoresis and then sequenced., Results: EGFR mutation was found in 29 of the 135 NSCLC patients (21.5%), with a mutation rate of 19.1% in the males and a mutation rate of 26.8% in the females (P = 0.344). The mutation types included G719C and G719V in exon 16, delE746 - 750, and delE746 - 751 in exon 19, and L858R and L861Qin exon 21. Among the 20 patients who received gefitinib treatment the disease control rate was 85% (17/20), being 76.9% in the male patients (10/13) and being 100% in the female patients (7/7) (P = 0.521). There were not significant differences in the mean time-to-progression (TTP) between the male and female patients (9 months vs. 14 months, P = 1), and between the patients with the wild type of EGFR gene and those with the mutated type of gene (9 months vs. 14 months, P = 1)., Conclusion: There is no significant relationship between the curative effect of gefitinib on NSCLC and gender and EFGR status.

Objective: To explore the effects of lead on the thyroid function of occupationally exposed workers., Method: 157 workers occupationally exposed to lead in a smelting factory were investigated. The concentration of lead in air at workshop was measured by flame atomic absorption spectrophotometry (FAAS) and the levels of blood lead (PbB) by atomic absorption spectrophotometry (AAS), zinc protoporphyrin (ZPP) by ZnPP meter, as well as the indexes of thyroid function, thyroid-stimulating hormone (TSH), triiodothyronine (T(3)), thyroxin (T(4)), free T(3) (FT(3)), and free T(4) (FT(4)) in serum by radioimmunoassay., Results: The workers with higher level of blood lead (> 2.88 micro mol/L) showed lower levels of T(3) [(1.54 +/- 0.39) nmol/L] and FT(3) [(5.50 +/- 1.26) pmol/L] than those with lower blood lead level [PbB: (1.92 approximately 2.88) micro mol/L group, T(3): (1.71 +/- 0.45) nmol/L, FT(3): (6.12 +/- 1.64) pmol/L, P < 0.05]. There was no obvious effect of length of service on thyroid hormone of exposed workers., Conclusion: Higher level of blood lead may cause certain damage to thyroid function by inhibiting deiodination of T(4). No obvious relation between length of service and thyroid function was found.