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Chylothorax is an uncommon and serious clinical condition, typically induced by trauma, either postsurgical or accidental injury, but the mechanism of chylothorax caused by nephrotic syndrome is still unclear. Here, we report a case of primary nephrotic syndrome with membranous nephropathy (MN) in a 66-year-old man who presented with severe chylothorax. The chylothorax was managed by intercostal chest tube drainage, subcutaneous injection of enoxaparin, and treatment with anti-inflammatory agents and diuretics. After treatment, the patient's pleural effusion decreased, and the chyle gradually became clear. We discuss the causes of MN with chylothorax. We considered that the hypoproteinemia changed the permeability of mucous membranes and lymphatic vessels, leading to leakage of chylous particles and chylous pleural effusion formation. Chylothorax may also have been caused by severe tissue edema, edema of the lymphatic walls, and increased pressure, resulting in increased permeability or rupture of the lymphatic wall, and leakage of chylous fluid into the thoracic cavity. Because of its rarity, we hope this case report will improve clinicians' understanding of MN complications in primary nephrotic syndrome and provide suitable treatment options for future clinical reference.

Background Resistance is almost inevitable and is still a major obstacle in epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) therapy. Only limited relevant clinical studies evaluated the therapeutic effects by combing metformin and EGFR-TKIs in non-small cell lung cancer (NSCLC) patients. Therefore, we evaluated the efficacy of concurrent use of metformin with EGFR-TKIs, and assessed whether the addition of metformin may improve clinical outcomes and delay the occurrence of EGFR-TKI resistance. Methods We conducted cell proliferation and apoptosis assay for investigation of metformin in combination with EGFR-TKIs to overcome EGFR-TKI resistance in vitro. Furthermore, we retrospectively reviewed clinicopathological characteristics and therapeutic outcomes of EGFR-mutant advanced NSCLC diabetic patients who received EGFR-TKIs with or without concurrent use of metformin. Results In vitro experiment, metformin showed synergistic interaction both with gefitinib in PC9R (CI =0.77) and with osimertinib in PC9R/OR (CI =0.77) in proliferation inhibition assay. Metformin can also augment apoptosis effect of these TKI-resistant cells to EGFR-TKIs. In retrospective cohort, a total of 85 patients were identified (cohort A), in which 28 patients had concurrent use of metformin. The objective response rate in metformin use group was significantly higher (85.7% vs. 47.4%, P=0.001). The median progression-free survival (PFS) and overall survival (OS) in metformin use group were significantly longer (21.6 vs. 9.2 months, P=0.000; 48.4 vs. 36.6 months, P=0.049). Further analysis revealed that metformin obviously prolonged the median PFS2 of osimertinib treatment among patients who progressed to prior line EGFR-TKIs due to secondary EGFR T790M mutation (cohort B). Conclusions Our study suggest that concurrent use of metformin could be beneficial to EGFR-mutant NSCLC patients treated with either first-line EGFR-TKIs or second-line osimertinib.

Cancer immune function and tumor microenvironment are governed by long noncoding RNAs (lncRNAs). Nevertheless, it has yet to be established whether lncRNAs play a role in tumor-associated neutrophils (TANs). Here, a computing framework based on machine learning was used to identify neutrophil-specific lncRNA with prognostic significance in squamous cell carcinoma and lung adenocarcinoma using univariate Cox regression to comprehensively analyze immune, lncRNA, and clinical characteristics. The risk score was determined using LASSO Cox regression analysis. Meanwhile, we named this risk score as “TANlncSig”. TANlncSig was able to distinguish between better and worse survival outcomes in various patient datasets independently of other clinical variables. Functional assessment of TANlncSig showed it is a marker of myeloid cell infiltration into tumor infiltration and myeloid cells directly or indirectly inhibit the anti-tumor immune response by secreting cytokines, expressing immunosuppressive receptors, and altering metabolic processes. Our findings highlighted the value of TANlncSig in TME as a marker of immune cell infiltration and showed the values of lncRNAs as indicators of immunotherapy.

A low-cost and high-precision CW radar system is proposed for non-contact detection of the target’s tiny vibration. The radar system can obtain the vibration frequency and amplitude of the target by extracting the phase change of the reflected signal caused by the target’s vibrations. The proposed radar system uses a combination of the phase shifter and the hardware-based phase comparator, which has the advantages of high detection accuracy and low system complexity. Besides, the combination establishes a linear relationship between the phase change caused by vibration and the output signal of the phase comparator, providing the system with the ability to detect the vibration amplitude. Experimental validations show that the radar system can accurately detect the vibration frequency and amplitude of the loudspeaker and monitor human respiration in real-time at a distance of 2 m. For the amplitude experimental, the absolute error of the vibration amplitude measured by the radar system within 30 cm is less than 0.1 mm.

BACKGROUND: Anti-programmed cell death 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) immunotherapy has boosted the prognosis in advanced lung cancer. Meanwhile, accumulating cases showed the correlation between tuberculosis (TB) reactivation and anti-PD-1/PD-L1 immunotherapy. However, the safety and efficacy of anti-PD-1/PD-L1 immunotherapy for lung cancer complicated with TB infection could only be learned from real-world data. METHODS: We retrospectively analyzed 562 patients with advanced lung cancer who received anti-PD-1/PD-L1 immunotherapy at Shanghai Pulmonary Hospital from 2015 to 2019, including 13 patients with TB infection. Besides, relevant literature reviews were performed online to analyze the safety and efficacy of immunotherapy and to explore the appropriate treatment strategies in this specific population. RESULTS: In our cohort, the initiation of anti-PD-1/PD-L1 immunotherapy was from June 2015 to December 2019. Among them, 13 patients had TB infection prior to immunotherapy including 11 latent TB and 2 active TB, and all of them were treated with anti-PD-1 immunotherapy. Patients with active TB infection were treated with concurrent anti-TB and anti-PD-1 treatments, and the remaining received either mono-immunotherapy or combined immunotherapy. Neither reactivation of latent TB nor progression of active TB was monitored in our cohort during immunotherapy. Severe immune-related adverse events (irAEs) were diagnosed in two patients. Treatment strategies such as discontinuation of immunotherapy and administration of corticosteroids were provided timely, and one with latent TB infection got gradually improved, but the other one with active TB died quickly. The median progression-free survival (PFS) was 5.5 months for tumor immunotherapy in our cohort. However, the PFS of immunotherapy was merely 2.1 and 2.2 months in lung cancer patients with active TB infection. CONCLUSIONS: Immunotherapy is relatively safe for lung cancer patients complicated with previously treated latent TB, and the efficacy of immunotherapy in this specified population is not inferior to that in lung cancer patients without TB infection. TB screening before anti-PD-1/PD-L1 immunotherapy is strongly recommended, and irAEs should be monitored more cautiously in lung cancer patients with active TB infection.

Purpose Our previous study demonstrated that cytological specimens can be used as alternative samples for detecting anaplastic lymphoma kinase (ALK) fusion with the method of reverse transcriptase PCR (RT-PCR) in patients with advanced non-small-cell lung cancer (NSCLC). The current study aimed to investigate the feasibility of cytological specimens for ROS proto-oncogene 1, receptor tyrosine kinase (ROS1) fusion detection by RT-PCR in advanced NSCLC patients. Patients and methods A total of 2,538 patients with advanced NSCLC, including 2,101 patients with cytological specimens and 437 patients with tumor tissues, were included in this study. All patients were screened for ROS1 fusion status by RT-PCR. The efficacy of crizotinib treatment was evaluated in ROS1 fusion-positive NSCLC patients. Results Among 2,101 patients with cytological specimens, the average concentration of RNA acquired from cytological specimens was 47.68 ng/μL (95% CI, 43.24-52.62), which was lower than the average of 66.54 ng/μL (95% CI, 57.18-76.60, P=0.001) obtained from 437 tumor tissues. Fifty-five patients harbored ROS1 fusion gene that was detected by RT-PCR, and 14 of them were treated with crizotinib. The incidence of ROS1 fusion was 1.95% (41/2,101) in 2,101 patients with cytological specimens, similar to the rate of 3.20% (14/437, P=0.102) for the 437 patients with tumor tissue. Regarding crizotinib treatment, no statistically significant differences were observed in the objective response rate (ORR) (81.8% vs 100%, P=0.604) between the cytological and tissue subgroups of ROS1-positive patients. Conclusion This study shows that cytological specimens can be utilized as alternative samples for ROS1 fusion detection by RT-PCR in advanced NSCLC patients.

Background Single-port inflatable mediastinoscopy with simultaneous laparoscopic-assisted surgery for radical esophagectomy is a promising surgical method with high technical requirements and needs team cooperation. Therefore, it is necessary to define a learning curve to guide personnel training and improve the safety of these surgical techniques.Method This study prospectively analyzed the data of 79 consecutive patients, who underwent the surgery in the Fifth Affiliated Hospital of Sun Yat-sen University from October 2016 to May 2018. All of these patients were treated by the same surgical team with extensive experience in thoracotomy, laparotomy, thoracoscopic surgery and laparoscopic surgery. The learning curve was analyzed by cumulative summation (CUSUM) analysis, with the assessment of operative time, estimated blood loss, and postoperative complications.Result By analyzing these data, The scatter diagram of every measure showing a declining situation. The learning curve decreased beginning at 25th operation. All patients were chronologically divided into two groups, the group 1(the first 25 patients) and the group 2 (the last 54 patients). The median estimated blood loss of group 2 was lower than group 1(200 vs 100ml, pConclusion For a surgical team with extensive experience in thoracotomy, laparotomy, thoracoscopic surgery and laparoscopic surgery, 25 cases are needed before becoming proficient in this surgery.

Immune checkpoint inhibitors targeting the programmed cell death receptor/ligand 1 (PD-1/PD-L1) pathway have profoundly improved the clinical management of non-small-cell lung cancer (NSCLC). Nevertheless, the superiority of single-agent PD-1/PD-L1 inhibitors in pretreated EGFR mutant patients has turned out to be moderate. One proposed mechanism for poor response to immune checkpoint inhibitors is an immunosuppressive tumor microenvironment. Therefore, we utilized two autochthonous EGFR-driven lung tumor models to investigate dynamic microenvironmental responses to EGFR-TKI treatment. We observed that at an early stage, sensitive EGFR-TKIs caused obvious tumor shrinkage accompanied by increased cytotoxic CD8+ T cells and dendritic cells, eradication of Foxp3+ Tregs, and inhibition of M2-like polarization of macrophages. However, the tumor microenvironmental changes that may be most beneficial for combination treatment with immune-mediated anticancer approaches were only temporary and disappeared as treatment continued. Meanwhile, the level of myeloid-derived suppressor cells (MDSCs), particularly mononuclear MDSCs, was consistently elevated throughout the treatment. Analysis of inflammatory factors in serum showed that EGFR-TKIs increased the levels of IL-10 and CCL-2. Our study systematically analyzed dynamic changes in tumor microenvironments responding to EGFR-TKIs in vivo. The results have implications for combination therapy using EGFR-TKIs. The optimal sequence of the treatment and strategies that modulate the tumor microenvironment to a state that may favor antitumor immune responses need to be considered when designing clinical trials.

Objectives Small-cell lung cancer (SCLC) has been viewed as a smoking-related disease, with only 2% to 5% patients being never-smokers. This study aimed to investigate the clinical characteristics of never-smoking and its association with treatment outcomes in Chinese SCLC patients in real world. Methods We performed a retrospective study of 303 patients with SCLC and grouped into smokers and never-smokers. The clinical characteristics and treatment outcomes of two groups were collected and compared. Results In total, 113 patients with limited-stage (LS) SCLC and 190 patients with extensive-stage (ES) SCLC were enrolled. Sixty-nine (22.8%) patients were never-smokers. Both the median progression-free survival (PFS) and overall survival (OS) were significantly longer in never-smokers than in smokers (PFS, 8.37 vs. 7.10 months, P = 0.036; OS, 19.73 vs. 14.40 months, P = 0.044) in all populations. Multivariate analysis suggested that never-smoking was a significant favorable prognostic factor for PFS (HR = 0.753; P = 0.047) instead of OS (HR = 0.780; P = 0.236) in patients with SCLC. The objective response rate (ORR) to first-line therapy were similar between two group (52.6% vs. 59.4%, P = 0.315). Moreover, prophylactic cranial irradiation (PCI) resulted in marginally significantly longer PFS than observation in patients with ES-SCLC who obtained objective response after first-line therapy (10.57 vs. 7.73 months, P = 0.075). Conclusion The current study indicated that never-smokers are increasingly prevalent in Chinese patients with SCLC. Never-smokers with SCLC had significantly longer PFS and OS compared with smokers, and smoking was an independent poor prognostic factor for PFS in patients with SCLC.

To investigate the prognostic value of PD-L1 expression combined with CD8+ TILs density in patients with resected NSCLC and correlations with clinicopathological features. We retrospectively enrolled 178 patients with resected NSCLC from 2011 to 2015. All surgical primary and 58 matched metastatic lymph node specimens were tested for PD-L1, CD8+ TILs, and oncogenic alterations. PD-L1+ was detected in 71 (39.9%) and CD8high TILs in 74 (41.6%) cases. Smoking, SqCC, and EGFR- were associated with both PD-L1+ and CD8high TILs. Patients with CD8high TILs had longer OS (P = 0.012). PD-L1- was significantly associated with longer OS in patients with oncogenic alterations (P = 0.047). By multivariate analysis, CD8high TILs (HR = 0.411; 95% CI, 0.177-0.954; P = 0.038), rather than PD-L1, was the independent predictive factor for OS. The longest and shortest OS were achieved in patients with PD-L1+ /CD8high and PD-L1+ /CD8low , respectively (P = 0.025). Inconsistent PD-L1 expression levels were observed in 23 of 58 (39.7%) patients with primary and matched metastatic lymph node specimens. Of them, CD8high TILs was significantly associated with longer OS in patients with metastatic lymph nodes and/or consistent PD-L1 expression (P = 0.017 and 0.049, respectively). The combination of PD-L1 and CD8+ TILs density, instead of PD-L1 alone, suggested impressive prognostic values in NSCLC patients. Less than half of patients with resected NSCLC experienced inconsistent PD-L1 expression between primary and metastatic lesions. The level of PD-L1 expression in advanced NSCLC needs to be evaluated more comprehensively.

BACKGROUND The authors' previous study demonstrated that the B-cell chronic lymphocytic leukemia/lymphoma (Bcl-2)-like 11 (BCL2L11) (Bim) deletion polymorphism was associated with poor clinical response to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in patients with non–small cell lung cancer (NSCLC) with EGFR mutations. The objective of the current study was to investigate the impact of the Bim deletion polymorphism among patients with anaplastic lymphoma kinase (ALK)-positive or ROS proto-oncogene 1, receptor tyrosine kinase (ROS1)-positive NSCLC who were treated with crizotinib. METHODS A total of 55 patients with ALK-positive NSCLC and 14 patients with ROS1-positive NSCLC who were treated with crizotinib were enrolled into the current study. The Bim deletion polymorphism was analyzed by polymerase chain reaction. The clinical features of the Bim deletion polymorphism and its impact on the effect of crizotinib were investigated. RESULTS The Bim deletion polymorphism was present in 9 of 69 patients with ALK-positive or ROS1-positive NSCLC (13.0%). There were no differences noted with regard to clinicopathological features between patients with and without the Bim deletion polymorphism. Patients with the Bim deletion polymorphism had a significantly shorter progression-free survival (PFS) and lower objective response rate compared with those without (median PFS, 182 days vs 377 days [P = .008]) (objective response rate, 44.4% vs 81.7% [P =.041]) in all populations. The significant difference in PFS was observed in patients with ALK-positive NSCLC (83 days vs 305 days [P =.0304]) compared with those with ROS1-positive NSCLC (218 days vs not reached [P =.082]). Multivariate analysis indicated that the Bim deletion polymorphism was an independent predictive factor for patients with ALK-positive NSCLC who were treated with crizotinib (hazard ratio, 4.786 [P =.006]). CONCLUSIONS The Bim deletion polymorphism was found to be associated with poor clinical response to crizotinib in patients with ALK fusion-positive NSCLC. Cancer 2017;123:2927–35. © 2017 American Cancer Society.

Introduction To depict the genomic landscape of Chinese early-stage lung squamous cell carcinoma (LUSC) and investigate its correlation with tumor mutation burden (TMB), PD-L1 expression, and immune infiltrates. Methods Whole-exome sequencing was performed on 189 surgically resected LUSC. TMB was defined as the sum of nonsynonymous single nucleotide and indel variants. CD8+ tumor-infiltrating lymphocyte (TIL) density and PD-L1 expression were evaluated by immunohistochemistry. Six immune infiltrates were estimated using an online database. Results The median TMB was 9.43 mutations per megabase. Positive PD-L1 expression and CD8+ TILs density were identified in 24.3% and 78.8%. PIK3CA amplification was associated with significantly higher TMB (P = 0.036). Frequent genetic alterations had no impact on PD-L1 expression but PIK3CA amplification and KEAP1 mutation were independently associated with significantly lower CD8+ TIL density (P

Purpose Our previous study demonstrated that cytological specimens can be used as alternative samples for detecting anaplastic lymphoma kinase (ALK) fusion with the method of reverse transcriptase PCR (RT-PCR) in patients with advanced non-small-cell lung cancer (NSCLC). The current study aimed to investigate the feasibility of cytological specimens for ROS proto-oncogene 1, receptor tyrosine kinase (ROS1) fusion detection by RT-PCR in advanced NSCLC patients. Patients and methods A total of 2,538 patients with advanced NSCLC, including 2,101 patients with cytological specimens and 437 patients with tumor tissues, were included in this study. All patients were screened for ROS1 fusion status by RT-PCR. The efficacy of crizotinib treatment was evaluated in ROS1 fusion-positive NSCLC patients. Results Among 2,101 patients with cytological specimens, the average concentration of RNA acquired from cytological specimens was 47.68 ng/μL (95% CI, 43.24–52.62), which was lower than the average of 66.54 ng/μL (95% CI, 57.18–76.60, P=0.001) obtained from 437 tumor tissues. Fifty-five patients harbored ROS1 fusion gene that was detected by RT-PCR, and 14 of them were treated with crizotinib. The incidence of ROS1 fusion was 1.95% (41/2,101) in 2,101 patients with cytological specimens, similar to the rate of 3.20% (14/437, P=0.102) for the 437 patients with tumor tissue. Regarding crizotinib treatment, no statistically significant differences were observed in the objective response rate (ORR) (81.8% vs 100%, P=0.604) between the cytological and tissue subgroups of ROS1-positive patients. Conclusion This study shows that cytological specimens can be utilized as alternative samples for ROS1 fusion detection by RT-PCR in advanced NSCLC patients.

Emerging evidence has shown that exosomes derived from drug‐resistant tumour cells are able to horizontally transmit drug‐resistant phenotype to sensitive cells. However, whether exosomes shed by EGFR T790M‐mutant–resistant NSCLC cells could transfer drug resistance to sensitive cells has not been investigated. We isolated exosomes from the conditioned medium (CM) of T790M‐mutant NSCLC cell line H1975 and sensitive cell line PC9. The role and mechanism of exosomes in regulating gefitinib resistance was investigated both in vitro and in vivo. Exosome‐derived miRNA expression profiles from PC9 and H1975 were analysed by small RNA sequencing and confirmed by qRT‐PCR. We found that exosomes shed by H1975 could transfer gefitinib resistance to PC9 both in vitro and in vivo through activating PI3K/AKT signalling pathway. Small RNA sequencing and RT‐PCR confirmed that miR‐3648 and miR‐522‐3p were the two most differentially expressed miRNAs and functional study showed that up‐regulation of miR‐522‐3p could induce gefitinib resistance in PC9 cell. The findings of our study reveal an important mechanism of acquired resistance to EGFR‐TKIs in NSCLC.

Objective Data on the clinical activity of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in patients with non-small-cell lung cancer (NSCLC) and uncommon EGFR mutations remain insufficient. This study aimed to investigate the effect of first-line EGFR-TKIs or platinum-based chemotherapy in NSCLC patients with uncommon EGFR mutations. Methods We retrospectively enrolled 504 patients with EGFR-mutant NSCLC. The clinical characteristics and treatment outcomes were collected and compared between patients with common and uncommon EGFR-mutant NSCLC. Results Seventy patients (13.9%) harboring uncommon EGFR mutations were included. Thirty of these patients received EGFR-TKIs and 40 received platinum-based chemotherapy as first-line therapy. The objective response rate (ORR) and median progression-free survival (mPFS) of patients treated with TKIs in the uncommon mutation group was significantly inferior to that in the common mutation group (ORR: 23.3% vs. 51.8%, P=0.003; mPFS: 7.1 vs. 10.9 months, P

Figure S1. (A) the distribution of TMB; (Bâ D) the comparison of TMB (B), PD-L1 expression (C), and CD8+ TIL density (D) between patients with CNVs and those without CNVs. Figure S2. (A) The representative immunohistochemical images of PD-L1 expression, (B) the correlations of PD-L1 expression score between SP142 and E1L3N, and (C) the distribution of PD-L1 expression score in each antibody assay. Figure S3. The representative immunohistochemical images of CD8+ TIL expression. Figure S4. The distribution of different PD-L1 expression (A) and CD8+ TIL density (B); (C) correlation between TMB and PD-L1 expression, (F) TMB and CD8+ TIL density, and (E) PD-L1 expression and CD8+ TIL density. Figure S5. Association between frequent somatic mutations and six immune cells infiltration. Figure S6. Association between frequent CNVs and six immune cells infiltration. Figure S7. DFS at PD-L1 expression cutoff of 5% (A) and 50% (B); CD8+ TIL expression cutoff of 5% (C) and 50% (D); TMB cutoff of 25th (E), 50th (F), 75th (G) and 90th (H) percentile; TMB plus PD-L1 at TMB cutoff of 25th (I), 50th (J), 75th (K) and 90th (L) percentile; TMB plus CD8+ TIL expression at TMB cutoff of 25th (M), 50th (N), 75th (O) and 90th (P) percentile. Figure S8. OS at PD-L1 cutoff of 5% (A) and 50% (B); CD8+ TIL expression cutoff of 5% (C) and 50% (D); TMB cutoff of 25th (E), 50th (F), 75th (G) and 90th (H) percentile; TMB plus PD-L1 at TMB cutoff of 25th (I), 50th (J), 75th (K) and 90th (L) percentile; TMB plus CD8+ TIL expression at TMB cutoff of 25th (M), 50th (N), 75th (O) and 90th (P) percentile. Table S1. The relationship between EGFR amplification/EML4-ALK fusion and clinicopathological features. Table S2. Baseline characteristics of included patients according to smoking status. (DOCX 3849 kb)

Background Osimertinib demonstrates superior efficacy in patients with non-small cell lung cancer (NSCLC) who acquired EGFR T790M mutation as resistant mechanism to upfront EGFR tyrosine kinase inhibitors (TKIs). Not all the T790M-positive tumors are homogeneously sensitive to osimertinib, however, and the duration of response often varies. Previous studies suggest that loss of T790 M at osimertinib resistance is correlated with shortened survival benefit of osimertinib. The aim of this study is to investigate the prevalence of T790 M loss after progression to osimertinib in Chinese patients with NSCLC harboring EGFR T790 M mutation and to compare their clinical outcomes and characteristics when stratified by T790 M mutational status at osimertinib resistance. Patients and methods All patients with a secondary T790 M mutation after progression to prior-line EGFR TKIs and received single-agent osimertinib were reviewed. The patients who were reassessed for T790 M mutation post-osimertinib resistance were included in final analysis. Detailed clinicopathologic characteristics and response data were collected. Results Of the patients with confirmed T790 M mutation as acquired resistance to early-generation EGFR TKIs and subsequently received single-agent osimertinib, 84 patients experienced clinical progression after osimertinib treatment and were eligible for analysis. Among them, 31 patients underwent repeated T790 M mutation testing on osimertinib resistance. Sixteen patients had maintained T790 M mutation, whereas 15 patients lost T790 M at resistance. Loss of T790 M at resistance was remarkably correlated with shorter duration of response to osimertinib (P = 0.0005). Furthermore, the overall survival after osimertinib treatment was also decreased in T790M-loss group (P=0.021). The objective response rates were comparable between T790M-maintain and T790M-loss group (31.3% and 26.7%, respectively). In multivariate analysis, loss of T790M remained statistically associated with early progression to osimertinib. Conclusion Loss of T790 M mutation at resistance was correlated with early progression and overall survival in response to osimertinib treatment in Chinese patients with NSCLC harboring acquired T790 M mutation.

Background Although EGFR-tyrosine kinase inhibitors (EGFR-TKIs) are the standard treatment for patients with EGFR-mutant non-small-cell lung cancer (NSCLC), responses vary within individuals. The current study aimed to investigate whether serum levels of several cytokines and their dynamic changes during TKI treatment could be used to predict the efficacy of EGFR-TKIs. Materials and methods Pre-treatment and one-month post-treatment serum levels of hepatocyte growth factor (HGF), interleukin-10 (IL-10), interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), interferon gamma (IFN-γ) and monocyte chemotactic protein-1 (MCP-1) were measured using enzyme-linked immunosorbent assay and U-plex biomarker group assays in patients with EGFR-mutant NSCLC received first-line EGFR-TKIs. Results Patients who had lower baseline serum levels of IL-6 had better object response rate (ORR) than those with high levels (74.2% vs 42.9%, p = 0.014). PFS was significantly longer in patients with low baseline level of IL-6 (19.57 vs. 13.73 months, p = 0.003) and in those with reduced serum VEGF and HGF levels after treatment (20.30 vs. 14.33 months, p = 0.009; 22.77 vs. 14.33 months, p = 0.002; respectively). Multivariate analyses showed that lower baseline serum IL-6 level was significantly associated with longer PFS (HR = 0.469, p = 0.022) and OS (HR = 0.181, p = 0.004). Reduction of serum VEGF and HGF levels after treatment was associated with significantly longer PFS (HR = 0.447, p = 0.017; HR = 0.365, p = 0.003; respectively). Lower pre-treatment serum VEGF level was associated with dramatically longer OS (HR = 0.277, p = 0.018). Conclusions Our study suggested that serum levels of HGF, IL-6 and VEGF and its dynamic change during TKI treatment could be used to predict the efficacy of EGFR-TKIs treatment in patients with EGFR-mutant NSCLC.

Programmed death-ligand 1 (PD-L1) expression might serve as a predictive biomarker for immune checkpoint inhibitors in lung cancer. However, the relationship between PD-L1 expression and imaging features of lung cancer has not been fully understood.A total of 350 patients with pathologically confirmed adenocarcinoma who received surgical treatment and had preoperative thin section computed tomography (CT) examination were included. Quantitative CT features including the mean CT value and tumor mass were measured on multiplanar reconstructed images. PD-L1-positive tumor was defined as the tumor proportion score 5%.Seventy-four of 350 (21.1%) specimens were detected as PD-L1-positive tumors. PD-L1 expression was adversely associated with epidermal growth factor receptor mutation status (P .001) and was significantly associated with invasive adenocarcinomas rather than preinvasive lesions and minimally invasive adenocarcinomas (P .001). Multivariate analysis identified absence of surrounding ground glass opacity (P = .022), shape (P = .008), pleural indentation (P = .007), tumor mean CT value (P = .004), and the ratio of consolidation mass to tumor mass (P = .003) as being significantly associated with the expression of PD-L1. To improve the diagnostic accuracy, a joint model that combined 5 imaging traits was conducted. The area under the curve of the joint model was 0.783, with a sensitivity of 81.1% and specificity of 64.1%, respectively.PD-L1 expression was associated with pathologic invasiveness of adenocarcinomas and CT features, which suggested the possibility of predicting PD-L1 expression status via imaging features.

The lack of response to treatment in most lung cancer patients suggests the value of broadening the benefit of anti–PD-1/PD-L1 monotherapy. Judicious dosing of antiangiogenic agents such as apatinib (VEGFR2-TKI) can modulate the tumor immunosuppressive microenvironment, which contributes to resistance to anti–PD-1/PD-L1 treatment. We therefore hypothesized that inhibiting angiogenesis could enhance the therapeutic efficacy of PD-1/PD-L1 blockade. Here, using a syngeneic lung cancer mouse model, we demonstrated that low-dose apatinib alleviated hypoxia, increased infiltration of CD8+ T cells, reduced recruitment of tumor-associated macrophages in tumor and decreased TGFβ amounts in both tumor and serum. Combining low-dose apatinib with anti–PD-L1 significantly retarded tumor growth, reduced the number of metastases, and prolonged survival in mouse models. Anticancer activity was evident after coadministration of low-dose apatinib and anti–PD-1 in a small cohort of patients with pretreated advanced non–small cell lung cancer. Overall, our work shows the rationale for the treatment of lung cancer with a combination of PD-1/PD-L1 blockade and low-dose apatinib.

We performed this retrospective study to investigate whether the KRAS mutation status and its subtypes could predict the effect of first-line platinum-based chemotherapy in Chinese patients with non-small cell lung cancer (NSCLC). Patients received who had KRAS mutations were enrolled. Correlations between KRAS mutations, specific mutant subtypes and responses to chemotherapy were analyzed using Kaplan-Meier and Cox proportional hazard methods. A total of 2,183 cases who received KRAS mutation detection were included. A total of 218 of these cases were indicated to have KRAS mutations. KRAS mutations were identified more commonly in males compared with females (P=0.035). The most common subtypes were G12C, G12D and G12V. Among 73 KRAS mutant patients and 100 EGFR/ALK/KRAS wild-type patients with advanced NSCLC, KRAS-mutant NSCLC patients had a significantly shorter progression-free survival (P=0.007) compared with NSCLC patients with KRAS wild-type. In addition, there was a shorter but marginally statistically significant progression-free survival (PFS) in KRAS mutant patients with adenocarcinoma compared with those with non-adenocarcinoma (P=0.051). In the KRAS mutant group, patients with the KRAS G12V mutation had the poorest PFS compared with non-G12V mutant cases (P=0.045). In conclusion, KRAS mutation was a negative predictive factor of PFS in Chinese patients with advanced NSCLC who received first platinum-based chemotherapy. Patients with KRAS G12V mutations exhibited the poorest PFS compared with those with other KRAS mutant types.

To investigate the prognostic value of PD‐L1 expression combined with CD8+ TILs density in patients with resected NSCLC and correlations with clinicopathological features. We retrospectively enrolled 178 patients with resected NSCLC from 2011 to 2015. All surgical primary and 58 matched metastatic lymph node specimens were tested for PD‐L1, CD8+ TILs, and oncogenic alterations. PD‐L1+ was detected in 71 (39.9%) and CD8high TILs in 74 (41.6%) cases. Smoking, SqCC, and EGFR − were associated with both PD‐L1+ and CD8high TILs. Patients with CD8high TILs had longer OS (P = 0.012). PD‐L1− was significantly associated with longer OS in patients with oncogenic alterations (P = 0.047). By multivariate analysis, CD8high TILs (HR = 0.411; 95% CI, 0.177–0.954; P = 0.038), rather than PD‐L1, was the independent predictive factor for OS. The longest and shortest OS were achieved in patients with PD‐L1+/CD8high and PD‐L1+/CD8low, respectively (P = 0.025). Inconsistent PD‐L1 expression levels were observed in 23 of 58 (39.7%) patients with primary and matched metastatic lymph node specimens. Of them, CD8high TILs was significantly associated with longer OS in patients with metastatic lymph nodes and/or consistent PD‐L1 expression (P = 0.017 and 0.049, respectively). The combination of PD‐L1 and CD8+ TILs density, instead of PD‐L1 alone, suggested impressive prognostic values in NSCLC patients. Less than half of patients with resected NSCLC experienced inconsistent PD‐L1 expression between primary and metastatic lesions. The level of PD‐L1 expression in advanced NSCLC needs to be evaluated more comprehensively.

The authors' previous study demonstrated that the B-cell chronic lymphocytic leukemia/lymphoma (Bcl-2)-like 11 (BCL2L11) (Bim) deletion polymorphism was associated with poor clinical response to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in patients with non-small cell lung cancer (NSCLC) with EGFR mutations. The objective of the current study was to investigate the impact of the Bim deletion polymorphism among patients with anaplastic lymphoma kinase (ALK)-positive or ROS proto-oncogene 1, receptor tyrosine kinase (ROS1)-positive NSCLC who were treated with crizotinib.A total of 55 patients with ALK-positive NSCLC and 14 patients with ROS1-positive NSCLC who were treated with crizotinib were enrolled into the current study. The Bim deletion polymorphism was analyzed by polymerase chain reaction. The clinical features of the Bim deletion polymorphism and its impact on the effect of crizotinib were investigated.The Bim deletion polymorphism was present in 9 of 69 patients with ALK-positive or ROS1-positive NSCLC (13.0%). There were no differences noted with regard to clinicopathological features between patients with and without the Bim deletion polymorphism. Patients with the Bim deletion polymorphism had a significantly shorter progression-free survival (PFS) and lower objective response rate compared with those without (median PFS, 182 days vs 377 days [P = .008]) (objective response rate, 44.4% vs 81.7% [P =.041]) in all populations. The significant difference in PFS was observed in patients with ALK-positive NSCLC (83 days vs 305 days [P =.0304]) compared with those with ROS1-positive NSCLC (218 days vs not reached [P =.082]). Multivariate analysis indicated that the Bim deletion polymorphism was an independent predictive factor for patients with ALK-positive NSCLC who were treated with crizotinib (hazard ratio, 4.786 [P =.006]).The Bim deletion polymorphism was found to be associated with poor clinical response to crizotinib in patients with ALK fusion-positive NSCLC. Cancer 2017;123:2927-35. © 2017 American Cancer Society.