Nivolumab combined docetaxel versus nivolumab in patients with previously treated nonsmall cell lung cancer: a phase 2 study.

The current standard second-line treatment is immune checkpoint inhibitors monotherapy for nonsmall cell lung cancer (NSCLC) patients. The objective of this phase 2 study was to evaluate the efficacy and safety of nivolumab plus docetaxel compared with nivolumab monotherapy for second-line therapy in immunotherapy-naive patients with advanced NSCLC. Progression-free survival (PFS) was the primary endpoint of this phase 2 study. Patients were randomized to receive nivolumab plus docetaxel or nivolumab monotherapy. From July 2019 to June 2022, a total of 22 patients were recruited, with significantly longer median PFS observed in the nivolumab plus docetaxel group (4.0 months) compared to the nivolumab group (2.0 months), P  = 0.0019. The study was closed in June 2022 due to slow recruitment. The objective response rate was 10.0% [95% confidence interval (CI), 0-28.6] in the nivolumab group and 25% (95% CI, 0.5-49.5) in the nivolumab + docetaxel group ( P  = 0.346). Disease control was significantly higher in the nivolumab plus docetaxel arm (40.0% versus 83.3%, P  = 0.035). There was also an improvement in overall survival (OS) in the nivolumab + docetaxel arm, but this was not statistically significant (10.0 months versus 7.2 months, P  = 0.129). The addition of docetaxel to nivolumab was well-tolerated, with adverse events more common in the combination group. Despite the small sample size, the results suggest that the addition of docetaxel to nivolumab may be a promising treatment option for NSCLC patients progressing on platinum-based chemotherapy, with trends towards improved OS observed.

Construction of an endoplasmic reticulum stress-related signature in lung adenocarcinoma by comprehensive bioinformatics analysis.

BACKGROUND: Lung Adenocarcinoma (LUAD) is a major component of lung cancer. Endoplasmic reticulum stress (ERS) has emerged as a new target for some tumor treatments. METHODS: The expression and clinical data of LUAD samples were downloaded from The Cancer Genome Atlas (TCGA) and The Gene Expression Omnibus (GEO) database, followed by acquiring ERS-related genes (ERSGs) from the GeneCards database. Differentially expressed endoplasmic reticulum stress-related genes (DE-ERSGs) were screened and used to construct a risk model by Cox regression analysis. Kaplan-Meier (K-M) curves and receiver operating characteristic (ROC) curves were plotted to determine the risk validity of the model. Moreover, enrichment analysis of differentially expressed genes (DEGs) between the high- and low- risk groups was conducted to investigate the functions related to the risk model. Furthermore, the differences in ERS status, vascular-related genes, tumor mutation burden (TMB), immunotherapy response, chemotherapy drug sensitivity and other indicators between the high- and low- risk groups were studied. Finally, quantitative real-time polymerase chain reaction (qRT-PCR) was used to validate the mRNA expression levels of prognostic model genes. RESULTS: A total of 81 DE-ERSGs were identified in the TCGA-LUAD dataset, and a risk model, including HSPD1, PCSK9, GRIA1, MAOB, COL1A1, and CAV1, was constructed by Cox regression analysis. K-M and ROC analyses showed that the high-risk group had a low survival, and the Area Under Curve (AUC) of ROC curves of 1-, 3- and 5-years overall survival was all greater than 0.6. In addition, functional enrichment analysis suggested that the risk model was related to collagen and extracellular matrix. Furthermore, differential analysis showed vascular-related genes FLT1, TMB, neoantigen, PD-L1 protein (CD274), Tumor Immune Dysfunction and Exclusion (TIDE), and T cell exclusion score were significantly different between the high- and low-risk groups. Finally, qRT-PCR results showed that the mRNA expression levels of 6 prognostic genes were consistent with the analysis. CONCLUSION: A novel ERS-related risk model, including HSPD1, PCSK9, GRIA1, MAOB, COL1A1, and CAV1, was developed and validated, which provided a theoretical basis and reference value for ERS-related fields in the study and treatment of LUAD.

Evaluation of efficacy and toxicity of nivolumab combined with or without docetaxel in patients with advanced NSCLC.

BACKGROUND: The combination of PD-1/PD-L1 inhibitor and chemotherapy has been clinically confirmed to be beneficial as the first-line treatment of patients with advanced NSCLC. This study aimed to assess the effect of nivolumab + docetaxel versus nivolumab monotherapy in patients with NSCLC after the failure of platinum doublet chemotherapy. MATERIALS AND METHODS: The efficacy and toxicity of nivolumab + docetaxel combination therapy versus nivolumab monotherapy were compared in this retrospective study. Primary endpoint of the study was progression-free survival (PFS), and the secondary endpoints were objective response rate (ORR), overall survival (OS), and toxicity. RESULTS: Between November 2017 and December 2019, 77 patients were included in this study, with 58 patients in the nivolumab group and 19 in the nivolumab + docetaxel group. The median follow-up was 18 months, and the PFS was 8 months for patients receiving nivolumab + docetaxel and 2 months for those receiving nivolumab alone (p = 0.001), respectively. Nivolumab + docetaxel showed superior OS compared with nivolumab, with the median OS unreached versus 7 months (p = 0.011). Among patients without EGFR/ALK variation, compared to nivolumab monotherapy, nivolumab + docetaxel showed better PFS (p = 0.04) and OS (p = 0.05). There was no significant difference in grade 3-4 adverse events (AEs) between the two groups (p = 0.253). CONCLUSIONS: The combination of nivolumab and docetaxel demonstrated a meaningful improvement in progression-free survival and overall survival compared to nivolumab monotherapy, in patients with NSCLC after the failure of platinum doublet chemotherapy, irrespective of EGFR/ALK variation status.

A phase II study of anlotinib in 45 patients with relapsed small cell lung cancer.

The purpose of this prospective phase II clinical trial was to investigate the efficacy and safety of anlotinib in patients with relapsed small cell lung cancer (SCLC). Forty-five patients with relapsed SCLC were enrolled and treated with anlotinib (one cycle of 12 mg daily for 14 days, discontinued for 7 days, and repeated every 21 days) until disease progression or intolerance of treatment. The primary end point was progression-free survival (PFS). Secondary end points were overall survival (OS), disease control rate (DCR), objective control rate (ORR) and toxicity. The median PFS was 4.1 months (95% confidence interval [CI] 2.4-5.8) and the median OS was 6.1 months (95% CI 2.2-10.0). The OS for the limited-stage subgroup was significantly longer than that of the extensive-stage subgroup (P = .02). The DCR was 67%, and the ORR was 11%. The most common adverse event was hypertension (13%), which was controlled well with antihypertensive drugs. In conclusion, anlotinib has likely efficacy in patients with relapsed SCLC, and the side effects can be well tolerated. A longer OS was observed in limited-stage SCLC patients treated with anlotinib.

Clinical characteristics associated with non-small-cell lung cancer harboring ALK rearrangements in Chinese patients.

AIM: The ALK inhibitor, crizotinib, has demonstrated effectiveness in patients with non-small-cell lung cancer harboring ALK rearrangements. As few studies of the clinical characteristics of Chinese patients with ALK rearrangements have been reported, we conduct this study to gain more understanding in such area among Chinese patients. PATIENTS & METHODS: We undertook a retrospective study of 288 non-small-cell lung cancer patients admitted to our institution over a period of 4.5 years. RESULTS: Following testing, 14.9% of the patients (43/288) were found to be ALK fusion gene positive. Patient data including gender, age, smoking status, EGFR mutation status and medical imaging data were collected and analyzed. CONCLUSION: The findings suggested that patients with ALK rearrangements are more likely to be young, have EGFR wild-type, and more likely to exhibit mucus secretion, solid tumor growth, lymph node metastasis and pleural metastasis.

Real-world data on the first-line immune checkpoint inhibitors or in combination with chemotherapy in older patients (aged ≥ 75 years) with advanced non-small cell lung cancer.

Purpose: The purpose of this study is to investigate the efficacy and safety of immune checkpoint inhibitors (ICIs) or plus with chemotherapy in older patients. Methods: We enrolled 110 older patients with non-small cell lung cancer (NSCLC ≥75 years) who received either chemotherapy alone (chemo), ICI plus chemotherapy (ICI + chemo), or ICI alone and ICI plus other therapies, which included anti-angiogenesis drugs or other novel ICI (ICIs). Patient characteristics, treatment response, survival, and toxicity were evaluated. Results: In total population, the ICIs group has the highest disease control rate (DCR 75%). There were no significant differences in progression-free survival (PFS) and overall survival (OS) among older patients between ICI + chemo and ICIs groups (PFS: 5.3 months vs. 5.5 months, p = 0.70, OS: 10.7 months vs. 20.3 months, p = 0.995). Meanwhile, we observed ICIs had a longer PFS and OS than chemo group (PFS: 3.9 months vs. 5.5 months, p = 0.01, OS: 10.9 months vs. 20.3 months, p = 0.05). Subgroup analysis showed that patients with programmed death ligand-1 (PD-L1) ≥ 1% had a distinct longer trend toward OS in ICIs group compared to ICI + chemo group (22.4 months vs. 10.7 months, p = 0.605), even though there was no significant difference. In terms of safety, ICIs was more tolerable and had a lower discontinuation rate than ICI + chemo group. Conclusion: In the real world, ICI + chemo is more likely to be discontinued due to adverse effects and does not significantly improve patient survival compared with ICIs treatment in total population and subgroup. Therefore, ICI alone or ICIs plus other therapies, such as anti-angiogenesis drugs or other novel ICI (ICIs) could be recommended for older cases with PD-L1 positive NSCLC.

Aneuploid subtypes of circulating tumor cells and circulating tumor-derived endothelial cells predict the overall survival of advanced lung cancer.

Objective: This study aimed to detect circulating tumor cells (CTCs) and circulating tumor-derived endothelial cells (CTECs) in patients with advanced lung cancer, for describing the distribution characteristics of CTC and CTEC subtypes, exploring the correlation between CTC/CTEC subtypes and novel prognostic biomarkers. Methods: A total of 52 patients with advanced lung cancer were enrolled in this study. Using the subtraction enrichment-immunofluorescence in situ hybridization (SE-iFISH) system, CTCs and CTECs derived from these patients were identified. Results: Based on cell size, there were 49.3% small and 50.7% large CTCs, and 23.0% small and 77.0% large CTECs. Triploidy, tetraploidy, and multiploidy varied in the small and large CTCs/CTECs. Besides these three aneuploid subtypes, monoploidy was found in the small and large CTECs. Triploid and multiploid small CTCs and tetraploid large CTCs were associated with shorter overall survival (OS) in patients with advanced lung cancer. However, none of the CTECs subtypes showed a significant correlation with patient prognosis. In addition, we found strong positive correlations (P<0.0001) in the four groups including triploid small cell size CTCs and multiploid small cell size CTECs, and multiploid small cell size CTCs and monoploid small cell size CTECs. Furthermore, combined detection of the specific subtypes, including triploid small CTC and monoploid small CTEC, triploid small CTC and triploid small CTEC, and multiploid small CTC and monoploid small CTEC, were associated with poor prognosis in advanced lung cancer. Conclusions: Aneuploid small CTCs are associated with the outcome of patients with advanced lung cancer. In particular, the combined detection of triploid small CTCs and monoploid small CTECs, triploid small CTCs and triploid small CTECs, and multiploid small CTCs and monoploid small CTECs has clinical significance for predicting prognosis in patients with advanced lung cancer.

Second-line treatment options in advanced thymic carcinoma after failure of platinum-based chemotherapy: A multicenter retrospective study.

BACKGROUND: Currently there is no standard therapy recommended for second-line treatment for thymic carcinoma. Our study compared multidrug chemotherapy, single-agent chemotherapy, and PD-1 inhibitors in patients diagnosed with advanced thymic carcinoma who had previous platinum-based chemotherapy at the clinic. METHODS: The study included patients with thymic carcinoma who failed first-line platinum-based chemotherapy. Kaplan-Meier methods were applied in the study for estimating the progression-free survival (PFS) and overall survival (OS) curves. Pearson chi-square or Fisher's exact chi-square test was adopted to make comparisons of the objective response rate (ORR) between treatment groups. Cox regression was used for the multivariate analyses in PFS and OS. RESULTS: Among the 92 patients enrolled, multidrug chemotherapy was used in 51 (55.4%) patients for second-line therapy. Thirty-six patients (35.9%) received single-agent chemotherapy, and eight patients (8.7%) underwent PD-1 inhibitors. The multidrug chemotherapy group showed better efficacy than the other two groups, with an ORR of 35.3% (p = 0.006). The median PFS of multidrug chemotherapy, single-agent chemotherapy and PD-1 inhibitors were 5.0 months, 3.0 months, and 4.0 months, respectively (p = 0.008). Patients in the multidrug chemotherapy group also showed an advantage in OS in comparison with the other two treatment groups (p = 0.045), with a median OS of 30.4 months. Multivariate analysis showed that second-line treatment was independent factor for both PFS (p = 0.035) and OS (p = 0.037). Grade 3-4 AEs were mostly detected in patients receiving multidrug chemotherapy and were primarily hematologic. Treatment-related mortality was not found in any of the groups. CONCLUSIONS: Multidrug chemotherapy had a trend toward a more positive response rate and outcomes in longer survival time than single-agent chemotherapy and PD-1 inhibitors. Multidrug chemotherapy is a choice worth considering for second-line therapy in patients with thymic carcinoma if tolerable.

The overall survival benefit in Chinese ALK+ NSCLC patients received targeted therapies.

Background: Anaplastic lymphoma kinase (ALK) gene rearrangement is a series of mutations of non-small cell lung cancer (NSCLC) patients. Since 2011, multiple ALK inhibitors (ALKis) have been developed and launched for targeted therapy. In this study, we sought to investigate different strategies of sequential applying the ALKis and their clinical benefits to the overall survival (OS). Methods: A total of 176 patients with advanced NSCLC (stage IIIB-IV) harboring the ALK rearrangement were included in this cohort study. They were diagnosed between February 1, 2012 and November 19, 2019 at Peking University Cancer Hospital. Clinical characters were reviewed from patients' records. Strategies of drugs, progression-free survival (PFS) and OS were collected during the follow-ups. The Kaplan-Meier method and multivariate Cox proportional-hazard analysis were used to conduct the analyses survival and to examine the relationship between the variables and OS. Results: A significantly longer OS was observed either in patients treated with crizotinib [N=106, median OS (mOS): 32.9 months] or in patients treated with a next-generation ALKi [N=34, mOS: not reached (NR)] as the initial ALKi, compared with patients treated with conventional chemotherapy but no ALKi (N=36, mOS: 10.3 months, P<0.001). After disease progression with initial crizotinib, patients who received no ALKi had shorter OS than those who received only crizotinib beyond progressive disease (CBPD) (mOS: 9.7 vs. 20.3 months; P=0.015), only subsequent next-generation ALKis (mOS: 9.7 vs. 41.1 months; P<0.001), and CBPD followed with subsequent next-generation ALKis (mOS: 9.7 months vs. NR; P<0.001). Patients treated with 2 types of ALKi had better survival than those treated with 1 ALKi (mOS: 45.8 vs. 21.3 months, P=0.003), but no such survival benefit was observed in patients treated with ≥3 ALKis (P=0.366). Conclusions: ALKis have been shown to be clinically effective in treating NSCLC patients with ALK rearrangements. In the case of disease progression with crizotinib, either of CBPD or sequential other ALKis can extend patients' OS. The sequential application of multiple ALKis was found to be better than it of single ALKi in prolonging OS. However, the question of which inhibitor to select as the initial inhibitor needs to be examined further in future studies.

Prognostic factor analysis of patients with small cell lung cancer: Real-world data from 988 patients.

BACKGROUND: Small cell lung cancer (SCLC) is characterized by aggressive spread and poor prognosis, but has limited treatment options. Results of prognostic factors from randomized trials on treatment arrangement are conflicting and large-scale real-world analysis is lacking. METHODS: Patients diagnosed SCLC between 2008 and 2018 in Peking University Cancer Hospital were included in this study. Kaplan-Meier methods were adopted, and univariate analysis and multivariate Cox regression models were constructed to analyze prognostic factors. RESULTS: Among 1045 patients who presented to our center, 988 eligible patients were identified. Median overall survival (OS) was 16.0 months for the whole group, 24.0 months and 11.0 months for limited stage small cell lung cancer (LS-SCLC) and extensive stage small cell lung cancer (ES-SCLC), separately. Limited-stage, good performance status (PS) (ECOG 0-1), response to primary systemic treatment, and patients who received initiative irradiation and three or more lines of chemotherapy were predicted to have better OS in the whole group. Only response to first-line systemic therapy and prophylactic cranial irradiation (PCI) were independent prognostic factors of survival in LS-SCLC; while good PS (ECOG 0-1), without liver, bone, or subcutaneous metastases, response to first-line therapy, initial local irradiation, and three or more lines of systemic therapy predicted a favorable prognosis in ES-SCLC. CONCLUSIONS: The present study retrieved from large real-world data suggested that response to primary systemic therapy and aggressive radiotherapy are independent prognostic factors for SCLC. PCI and initiative irradiation for original or metastatic sites improved the OS in LS-SCLC and ES-SCLC, respectively.

Comparison of endostatin combined with PT-DC versus bevacizumab combined with PT-DC in the first-line treatment of advanced lung adenocarcinoma: a retrospective propensity score-matched cohort study.

BACKGROUND: Endostatin and bevacizumab have been approved for the first-line treatment of advanced non-small-cell lung cancer (NSCLC) patients in China; however, the clinical outcomes for each drug combined with platinum-based doublet chemotherapy (PT-DC) have not yet been directly compared. This study sought to assess the clinical outcomes of the 2 drugs combined with PT-DC in the first-line treatment of patients with advanced lung adenocarcinoma. METHODS: This retrospective cohort study examined the clinical data of patients with metastatic or recurrent lung adenocarcinoma (LUAD) treated with endostatin or bevacizumab combined with PT-DC as the first-line treatment from October 2010 to November 2019. Propensity score matching (PSM) was performed using a 1:1 ratio nearest neighbor algorithm. The effectiveness and safety outcomes for the 2 groups were evaluated. RESULTS: A total of 202 patients were enrolled in the study. Of these, the endostatin group comprised 124 patients and the bevacizumab group comprised 78 patients; 67 pairs of patients were identified after PSM. The progression-free survival (PFS) and overall survival (OS) of patients treated with PT-DC + endostatin and PT-DC + bevacizumab were compared [(PFS: before PSM 4.8 vs. 6.5 months, P=0.741; after PSM 6.5 vs. 6.1 months, P=0.402), (OS: before PSM 21.1 vs. 39.3 months, P=0.912; after PSM 23.6 vs. 39.3 months, P=0.579)]. The objective response rates (ORRs) and disease control rates (DCRs) of the 2 groups were comparable (37.7% vs. 50.7%, P=0.094; 89.6% vs. 92.5%, P=0.545). Adverse events (AEs) ≥ grade 3 were not observed in the PT-DC + endostatin group. Three (3.8%) cases of AEs ≥ grade 3 were observed the PT-DC + bevacizumab group, comprising hypertension (n=1), proteinuria (n=1), hemoptysis (n=1). CONCLUSIONS: This retrospective analysis showed that in first-line treatments, PT-DC + endostatin and PT-DC + bevacizumab appear to produce similar anti-tumor activities in patients with metastatic or recurrent lung adenocarcinoma. PT-DC + bevacizumab tended to result in worse adverse reactions than PT-DC + endostatin.

Pembrolizumab or Bevacizumab Plus Chemotherapy as First-Line Treatment of Advanced Nonsquamous Nonsmall Cell Lung Cancer: A Retrospective Cohort Study.

Objective: Pembrolizumab and bevacizumab both have antitumor activity. According to NCCN updated guideline the benefit of pembrolizumab or bevacizumab as a first line in management of advanced nonsmall cell lung cancer (NSCLC) is documented in randomized controlled studies. The study aimed to evaluate the response and complications of patients with advanced NSCLC treated with pembrolizumab or bevacizumab plus chemotherapy. Methods: This study was a retrospective cohort study of patients with advanced nonsquamous NSCLC who received cisplatin with pemetrexed combined with pembrolizumab (A group) or bevacizumab (B group) from 07/02/2018 to 07/03/2021 at Peking University Cancer Hospital. Progression-free survival (PFS) was the primary outcome. The secondary outcomes included overall survival (OS), objective response rate (ORR), disease control rate (DCR), duration of response (DoR), and adverse events (AEs). Results: This study included 66 patients, 34 in A group and 32 in B group. There were no differences in median PFS (7.6 vs 9.9 months, P = .601). There were no differences in median OS (23.1 vs 24.2 months, P = .782). There were no differences in ORR (57.6% vs 41.9%, P = .211) and DCR (93.9% vs 100.0%, P = .164) between 2 groups. The occurrence of AEs was similar. No new safety signals were observed. Grade 3 to 4 treatment-related AEs occurred in 17 (50.0%) patients of A group and in 12 (37.5%) of B group (P > .05). Conclusion: The addition of pembrolizumab or bevacizumab to pemetrexed plus cisplatin was well tolerated and resulted in a clinically meaningful treatment benefit in advanced nonsquamous NSCLC. When pembrolizumab is not suitable, bevacizumab plus chemotherapy may be an option.

Immune-Related Adverse Events and Their Association With the Effectiveness of PD-1/PD-L1 Inhibitors in Non-Small Cell Lung Cancer: A Real-World Study From China.

BACKGROUND: Programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) inhibitors are increasingly used in China, but no real-world data are available about the immune-related adverse events (irAEs). This real-world retrospective study aimed to assess the safety and effectiveness of PD-1/PD-L1 inhibitors in patients with non-small cell lung cancer (NSCLC) and to analyze the association between irAEs and effectiveness. METHODS: This was a retrospective study of the clinical data of patients with NSCLC treated with PD-1/PD-L1 inhibitors from August 2016 to November 2019 at Beijing Cancer Hospital. The patients were divided into the irAE or non-irAE groups. Overall adverse events, the impact of irAE on tumor response, and the association of irAEs with effectiveness were evaluated. RESULTS: One hundred and ninety-one patients were included, including 70 (36.6%) patients in the irAE group and 121 (63.4%) patients in the non-irAE group. AE, grades 3-5 AEs, and irAE occurred in 107 (56.0%), 24 (12.6%), and 70 (36.6%) of the patients, respectively. The objective response rate (ORR) and disease control rate (DCR) were higher in the irAE group compared with the non-irAE group (42.0% vs. 25.8%, P=0.038; 91.9% vs. 70.8%, P=0.002). Multivariable analyses identified that irAE were associated with progression-free survival (HR=0.62, 95%CI: 0.43-0.91; P=0.015), but not with overall survival (HR=0.76, 95%CI: 0.44-1.28; P=0.299). CONCLUSION: In NSCLC treated with PD-1/PD-L1 inhibitors, patients with irAEs showed improved effectiveness over patients without irAEs. Future studies of anti-PD-1/PD-L1 immunotherapy should explore this association and the underlying biological mechanisms of efficacy.

Efficacy and toxicities of gemcitabine and cisplatin combined with endostar in advanced thymoma and thymic carcinoma.

BACKGROUND: Thymoma and thymic carcinoma are rare thymic epithelial tumors. We investigated the efficacy of first-line gemcitabine and cisplatin (GP) chemotherapy versus gemcitabine and cisplatin chemotherapy combined with the anti-angiogenic drug endostar (GP + E) in advanced thymoma and thymic carcinoma. METHODS: The records of 45 patients with invasive metastatic thymomas or thymic carcinomas treated with GP as first-line therapy between August 2008 and July 2017 at the Department of Respiratory Medicine, Peking University Cancer Hospital and Institute were retrospectively reviewed. RESULTS: Eighteen patients (75%) in the GP + E group achieved a partial response and six (25%) had stable disease. In GP only group, nine (42.8%) patients achieved a partial response, 11 (52.4%) had stable disease, and one (4.8%) had progressive disease. The GP + E group had a significantly higher overall response rate (75% vs. 42.9%; P = 0.028), and median progression-free survival (PFS) and overall survival (OS) of 19 and 76 months, respectively. In the GP only group, median PFS and OS were 16 and 29 months, respectively. PFS and OS were not significantly different between the groups. CONCLUSIONS: GP has moderate efficacy and could represent a suitable first-line therapy for thymic carcinoma and thymoma. Chemotherapy combined with endostar could improve the overall response rate, but did not prolong PFS or OS.

Salvage treatment with anlotinib for advanced non-small cell lung cancer.

BACKGROUND: This real-world study assessed the efficacy and toxicity of anlotinib as salvage treatment in Chinese patients with advanced non-small cell lung cancer (NSCLC). METHODS: The medical records of 81 patients with advanced NSCLC who had failed at least two lines of chemotherapy were retrospectively collected. All patients were administered anlotinib treatment until disease progression or intolerance as a result of adverse events. Survival curves were created using the Kaplan-Meier method. The log-rank test was used for univariate analysis of progression-free survival (PFS) between groups. Cox regression was used to estimate the statistically significant factors based on univariate analysis. RESULTS: The median PFS was five months (95% confidence interval [CI] 3.5-6.5). The objective response rate (ORR) was 7% and the disease control rate (DCR) was 84%. The following subgroups of patients had longer PFS (P < 0.05): squamous cell carcinoma, no brain or liver metastases, Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1, and no previous VEGF-tyrosine kinase inhibitor treatment. The results of Cox regression indicated that an ECOG PS of 0-1 (hazard ratio 0.152, 95% CI 0.057-0.403; P = 0.00) and patients without brain metastases (hazard ratio 0.421, 95% CI 0.195-0.911; P = 0.028) had longer PFS following anlotinib treatment. CONCLUSION: Anlotinib, which is well tolerated, plays a significant role in the salvage treatment of advanced NSCLC. Patients with advanced NSCLC with an ECOG PS of 0-1 and no brain metastases achieved longer PFS following anlotinib salvage treatment.

[Impact of hepatitis B virus infected serum on the hepatic differentiation of human bone marrow mesenchymal stem cells].

OBJECTIVE: To study the effects of hepatitis B virus (HBV) infection in vitro on differentiation of mesenchymal stem cells (MSCs) to liver cells. METHODS: MSCs were isolated from human bone marrow by density gradient centrifugation, and expanded by adherent culture. MSCs were cultured under liver-stimulating condition, and different composition of serum was added to the induced medium: Group A: 5% fetal bovine serum (FBS); Group B: 2.5% FBS+2.5% HBV-containing serum; Group C: 2.5% FBS+2.5% serum from healthy volunteers; Group D: the undifferentiated MSCs cultured in LG-DMEM+10% FBS. The expressions of a variety of hepatic lineage markers were analyzed by immunocytochemistry and immunofluorescence. The functionality of differentiated cells was assessed by their ablility to store glycogen. After 2 weeks of exposure to HBV infected serum, HBV-specific protein was also detected by immunocytochemistry. RESULTS: As a result of our hepatic induction, the expressions of albumin (ALB) and alpha-fetoprotein (AFP) by MSCs were observed by immunocytochemical and immunofluorescence techniques. Moreover, MSCs had acquired the ability of glycogen storage which was characteristic of liver cells. Compared with the control group, the proliferation of MSCs was inhibited greatly by the virus-containing serum. After 2 weeks of exposure to HBV infected serum, the surface antigen (HBsAg) was detected in some induced MSCs. However, after immunocytochemical stain for ALB and AFP, there was not much difference between the Group B and C. The ability of glycogen storage of two groups were almost the same. Using confocal microscopy, we found the co-expressions of ALB and HBsAg in the same differentiated cells. CONCLUSION: The bone marrow MSCs have the ability to trans-differentiate into functional hepatocyte-like cells, hence may serve as a cell source for tissue engineering and cell therapy of hepatic diseases. HBV infected serum could inhibit the proliferation of MSCs in culture, but it seemed that the hepatic differentiation of the cell was unsuppressed.

Efficacy, safety and predictive indicators of apatinib after multilines treatment in advanced nonsquamous nonsmall cell lung cancer: Apatinib treatment in nonsquamous NSCLC.

AIM: Patients with advanced nonsquamous nonsmall cell lung cancer (NSCLC) who experienced progression with two or more lines chemotherapy have no treatment options that clearly confer a survival benefit. As a novel vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor, apatinib has a certain antitumor effect for various solid tumors. The present study evaluated the efficacy and safety of apatinib in advanced nonsquamous NSCLC as salvage treatment in Chinese real-world practice. METHODS: Twenty-eight patients were enrolled in this observational study from October 2015 to May 2017. Progression-free survival (PFS) and overall survival (OS) were graphed by Kaplan-Meier curve and intergroup comparisons were carried out by log-rank test. Objective response rate (ORR), disease control rate (DCR) and adverse effects (AEs) were also evaluated. RESULTS: Seven patients obtained partial response, and 18 obtained stable disease, representing an ORR of 26% and a DCR of 93%. Median PFS and OS were 3 (95% confidence interval [CI] 2.6-3.4) and 7.4 (95% CI 1.3-13.5) months, respectively. The efficacy analysis showed that Eastern Cooperative Oncology Group (ECOG) performance status 0-1 was correlated with prolonged OS and PFS (P < 0.05), and hypertension during apatinib treatment was correlated with prolonged OS (P < 0.05). Cox regression showed that ECOG performance status (P < 0.01) (RR = 0.231) (95% CI 0.083-0.642) and hypertension during apatinib treatment (P = 0.05) were predictive indicators for apatinib treatment. Grade 3-4 AEs with incidences of 10% or greater were hypertension (21%), hand-foot syndrome (14%) and proteinuria (11%) which could be relieved by dose reduction. CONCLUSION: In conclusion, apatinib has a certain therapeutic effect in patients with advanced nonsquamous NSCLC. ECOG performance status and hypertension during apatinib might be predictive indicators for treatment efficacy.

Efficacy and safety of extended use of platinum-based doublet chemotherapy plus endostatin in patients with advanced nonsmall cell lung cancer.

The aim of this study was to investigate the efficacy and safety of the extended use of platinum-based doublet chemotherapy (PT-DC) plus endostatin in patients with advanced nonsmall cell lung cancer (NSCLC).We performed a retrospective analysis of 200 newly diagnosed advanced NSCLC patients who had received at least 1 cycle of endostatin plus PT-DC between September 2009 and November 2014. Of these patients, 155 received 4 or more cycles of therapy (the extended therapy group), while 45 received less than 4 cycles of therapy (the control group). Clinical tumor responses, progression-free survival (PFS), overall survival (OS), and toxicity profiles were recorded and retrospectively analyzed.In the extended therapy group, 67 patients (43.2%) achieved a best overall response rate of partial response (PR), while in the control group, 13 patients (28.9%) had a best overall response rate of PR. After a median follow-up of 15.9 months, the median PFS and OS were 8.0 and 23.1 months in the extended arm and 5.8 and 14.0 months in the control arm, respectively. There were statistically significant differences in median PFS and OS between these 2 arms. Hematologic and gastrointestinal toxicities occurred more frequently in the extended therapy group, but no statistically significant difference was detected in grade 3 to 4 toxicities overall between these 2 groups.In conclusion, extended treatment using endostatin combined with PT-DC can provide additional survival benefits and satisfactory toxicity profiles in previously untreated patients with NSCLC, which merits further evaluation in a larger prospective study.

[Timing of Brain Radiation Therapy Impacts Outcomes in Patients with 
Non-small Cell Lung Cancer Who Develop Brain Metastases].

BACKGROUND: Radiotherapy combined with chemotherapy or molecular targeted therapy remains the standard of treatment for brain metastases from non-small cell lung cancer (NSCLC). The aim of this study is to determine if the deferral of brain radiotherapy impacts patient outcomes. METHODS: Between May 2003 and December 2015, a total of 198 patients with brain metastases from NSCLC who received both brain radiotherapy and systemic therapy (chemotherapy or targeted therapy) were identified. The rate of grade 3-4 adverse reactions related to chemotherapy and radiotherapy had no significant difference between two groups. 127 patients received concurrent brain radiotherapy and systemic therapy, and 71 patients received deferred brain radiotherapy after at least two cycles of chemotherapy or targeted therapy. Disease specific-graded prognostic assessment was similar in early radiotherapy group and deferred radiotherapy group. RESULTS: Median overall survival (OS) was longer in early radiotherapy group compared to deferred radiotherapy group (17.9 months vs 12.6 months; P=0.038). Progression free survival (PFS) was also improved in patients receiving early radiotherapy compared to those receiving deferred radiotherapy (4.0 months vs 3.0 months; P<0.01). Receiving tyrosine kinase inhibitor (TKI) therapy after the diagnosis of brain metastases as any line therapy improved the OS (20.0 months vs 10.7 months; P<0.01), whereas receiving TKI as first line therapy did not (17.9 months vs 15.2 months; P=0.289). CONCLUSIONS: Our study suggests that the use of deferred brain radiotherapy may resulted in inferior OS in patients with NSCLC who develop brain metastases. A prospective multi-central randomized study is imminently needed.

[Effects of Local Radiation Combined with Chemotherapy in the treatment of 
Patients with Extensive-stage Small Cell Lung Cancer].

BACKGROUND AND OBJECTIVE: Chemotherapy is a highly efficient primary treatment for extensive-stage small cell lung cancer (ES-SCLC). However, patients receiving such treatment are prone to develop drug resistance. Local treatment is palliative and thus can alleviate the local symptoms and improve quality of life, but limited evidence is available for prolonging survival. Hence, this study evaluated the role of local treatment in chemotherapy of patients with ES-SCLC. METHODS: A total of 302 ES-SCLC cases were enrolled in this retrospective study. Prognostic factors were analyzed by Kaplan-Meier and Cox multivariate proportional hazards model. RESULTS: Median progression-free survival (PFS) and median survival time (MST) of the patients were 4.4 and 10.4 months, respectively. 1-, 2-, and 3-year survival rates were 37.8%, 10.2% and 4.4%, correspondingly. The MST of the primary tumor radiotherapy plus chemotherapy group was 14.3 months, whereas that of the chemotherapy group was 8.2 months (P<0.01). The MSTs of multiple-site, single-site, and non-metastasis local treatments were 18.7, 12.3 and 8.9 months, respectively (P<0.01). The MSTs of initiative, passive, and non-metastasis local treatments were 16.0, 10.9 and 9.4 months, correspondingly (P<0.01). The MSTs of patients with prophylactic cranial irradiation (PCI) and those without PCI were 19.8 and 9.9 months, respectively (P<0.01). Primary tumor radiotherapy, metastasis local treatment, and PCI were independent prognostic factors for ES-SCLC. CONCLUSIONS: Primary tumor radiotherapy, metastasis local treatment, and PCI can significantly improve survival in patients with ES-SCLC.
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