Publications by authors named "Sujie Zhang"

33 Publications

Association of the Pretreatment Lung Immune Prognostic Index with Survival Outcomes in Advanced Gastric Cancer Patients Treated with Immune Checkpoint Inhibitors.

Clin Res Hepatol Gastroenterol 2021 Jun 25:101748. Epub 2021 Jun 25.

Department of Oncology, The First Medical Center, Chinese PLA General Hospital, Beijing, China. Electronic address:

Purpose: Recently, the lung immune prognostic index (LIPI) is considered to be associated with outcomes in multiple solid tumors treated with immune checkpoint inhibitors (ICIs). We sought to determine whether LIPI has the same predictive effect in advanced gastric cancer (AGC).

Methods: The clinical data of a real-world, retrospective cohort of AGC patients treated with ICIs were retrospectively analyzed. Based on pre-treatment dNLR>3 and LDH>250 U/L, patients were assigned to one of three groups: good (0 factors), intermediate (1 factor), and poor (2 factors). The subjects were divided into two groups: LIPI-good and LIPI-intermediate/poor groups. Then, the disease control rate (DCR), progression-free survival (PFS) and overall survival (OS) were compared between these two groups.

Results: Finally, 120 patients were enrolled in the study, for both the good group and intermediate/poor group, DCR was 69.5% vs. 42.1% (P=0.004). In a multivariate analysis, the LIPI-intermediate/poor group was associated with progressive disease, with an OR of 2.57 (95% CI, 1.05-6.30; P=0.039). Patients with a good LIPI score had a longer survival compared with those with intermediate/poor scores, with an estimated median OS of 10.4 vs. 3.9 months (HR=2.59, 95% CI: 1.69-3.98) and a median PFS of 7.7 vs. 2.1 months (HR=2.95, 95% CI:1.91-4.56). Multivariate analysis indicated that the intermediate/poor LIPI was independently associated with OS (HR: 2.32, 95% CI: 1.44-3.72) and PFS (HR: 2.48, 95% CI: 1.53-4.03).

Conclusions: These data are the first to suggest that the pretreatment LIPI was well correlated with the outcomes of patients with AGC treated with ICIs.
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http://dx.doi.org/10.1016/j.clinre.2021.101748DOI Listing
June 2021

HOXB5 promotes the progression of breast cancer through wnt/beta-catenin pathway.

Pathol Res Pract 2020 Jul 13;224:153117. Epub 2020 Jul 13.

National Clinical Research Center for Normal Aging and Geriatric & The Key Lab of Normal Aging and Geriatric, Institute of Geriatric, PLA General Hospital, Beijing, China. Electronic address:

Objective: The present study was designed to explore the function of HOXB5 in breast cancer and related signaling pathway.

Methods: Breast cancer tissues and non-cancerous tissues were collected from 82 cases who were pathologically diagnosed with breast cancer. The mRNA level of HOXB5 was detected via quantitative real-time polymerase chain reaction (qRT-PCR). Chi-square test was adopted to analyze the association of HOXB5 with clinical features. The viability, migration and invasion of breast cancer cells were detected through MTT and Transwell assays, respectively. Protein analysis was performed adopting western blot analysis.

Results: HOXB5 expression was increased in breast cancer tissues and cells, and showed positive correlation with tumor size (P = 0.028), TNM stage (P = 0.048), and lymph node metastasis (P = 0.002). Losing HOXB5 expression suppressed clone formation, proliferation, migration and invasion of breast cancer cells. The knockdown of HOXB5 significantly inactivated wnt/β-catenin pathway. Furthermore, wnt/β-catenin pathway had the potential to neutralize the oncogenic function of HOXB5 in breast cancer.

Conclusion: HOXB5 may be involved in the invasive progression of breast cancer. The function of HOXB5 in breast cancer was mediated by wnt/β-catenin pathway.
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http://dx.doi.org/10.1016/j.prp.2020.153117DOI Listing
July 2020

Response Efficacy of PD-1 and PD-L1 Inhibitors in Clinical Trials: A Systematic Review and Meta-Analysis.

Front Oncol 2021 16;11:562315. Epub 2021 Apr 16.

Department of Medical Oncology, Chinese People's Liberation Army (PLA) General Hospital, Beijing, China.

Background: Immune checkpoint inhibitors targeting the PD-1/PD-L1 pathway have demonstrated promise in treating a variety of advanced cancers; however, little is known regarding their efficacy under various clinical situations, including different cancer types, treatment lines, drug combinations, and therapeutic regimens.

Methods: Published articles and conference abstracts (in English) in PubMed, Embase, the Cochrane Central Register, and Web of Science were searched up to February 10, 2020. The data were analyzed by the meta-analysis program in Stata.

Results: A total of 16,400 patients from 91 clinical trials were included in this meta-analysis. PD-1/PD-L1 inhibitors had a mean ORR of 19.56% (95% CI: 15.09-24.03), a median TTR of 2.05 months (m) (95%CI: 1.85-2.26), and a median DOR of 10.65 m (95%CI: 7.78-13.52). First-line treatment had a higher ORR (36.57% vs. 13.18%) but a shorter DOR (9.00 m vs. 13.42 m) compared to the second-line or subsequent treatment. Immunotherapy combined with chemotherapy (I+C) (46.81% [95%CI: 36.02-57.60]) had a statistically significant higher ORR compared to immunotherapy (I) (17.75% [95%CI: 14.47-21.03]) or immunotherapy combined with immunotherapy (I+O) (12.25% [95%CI: 1.56-22.94]), while I+C (8.09 m [95%CI: 6.86-9.32]) appeared to reduce the DOR compared to I (12.39 m [95%CI: 7.60-17.18]). PD-1 inhibitors were associated with better ORR (21.65% vs. 17.60%) and DOR (11.26 m vs. 10.03 m) compared to PD-L1 inhibitors. There were no significant differences in TTR under different situations.

Conclusions: PD-1/PD-L1 inhibitors were promising immunotherapeutic agents to achieve satisfactory response efficacies with different cancer types, treatment lines, drug combinations, and therapeutic regimens. This comprehensive summary of the response efficacy of PD-1/PD-L1 inhibitors serves as a reference for clinicians to make evidence-based decisions.
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http://dx.doi.org/10.3389/fonc.2021.562315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085334PMC
April 2021

Prognostic value of baseline and change in neutrophil-to-lymphocyte ratio for survival in advanced non-small cell lung cancer patients with poor performance status receiving PD-1 inhibitors.

Transl Lung Cancer Res 2021 Mar;10(3):1397-1407

Department of Medical Oncology, Chinese PLA General Hospital, Beijing, China.

Background: Advanced non-small cell lung cancer (NSCLC) patients with poor performance status (PS) are likely to receive programmed cell death 1 (PD-1) inhibitors, despite limited evidence. The aim of the present study was to report the clinical outcomes and potential prognostic biomarkers in advanced NSCLC patients with poor PS receiving PD-1 inhibitors.

Methods: We conducted a retrospective study enrolling 101 advanced NSCLC patients from our hospital. Data of patients with poor PS 2-4 receiving PD-1 inhibitors were retrieved from medical records. Patients were stratified based on dichotomized baseline neutrophil-to-lymphocyte ratio (NLR), change in NLR (ΔNLR; 6 weeks post-treatment NLR minus baseline NLR), and their combination. The receiver-operating characteristic curve was used to assess the best cutoff for NLR. Multivariate Cox analysis was used to evaluate the prognostic value of NLR and ΔNLR for patients' survival.

Results: The optimal cutoff for NLR was 4.5. The median follow-up was 25.7 months, baseline NLR ≥4.5, and ΔNLR ≥0, which were independently and significantly associated with shorter overall survival (both P=0.002) and progression-free survival (P=0.004 for NLR and P<0.001 for ΔNLR). Furthermore, simultaneous elevation of the 2 factors was associated with worsened prognosis; patients with both NLR ≥4.5 and ΔNLR ≥0 had significantly increased risk of death [hazards ratio (HR): 10.79, 95% confidence interval (CI): 4.30-27.10] and disease progression (HR: 10.49, 95% CI: 4.39-25.09), compared with both low NLR and ΔNLR patients. Patients with either NLR ≥4.5 or ΔNLR ≥0 showed an intermediate risk for death (HR: 3.12, 95% CI: 1.35-7.21) and progression (HR: 3.45, 95% CI: 1.62-7.36).

Conclusions: High baseline NLR and increased post-treatment NLR might aid in the stratification of high progression and death risk groups in advanced NSCLC patients with poor PS receiving PD-1 inhibitors.
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http://dx.doi.org/10.21037/tlcr-21-43DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044483PMC
March 2021

Effects of Shenfu Qiangxin Drink on HO-induced oxidative stress, inflammation and apoptosis in neonatal rat cardiomyocytes and possible underlying mechanisms.

Exp Ther Med 2021 Jun 26;21(6):553. Epub 2021 Mar 26.

First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, P.R. China.

The aim of the present study was to investigate the effects of Shenfu Qiangxin Drink (SFQXD) on acute myocardial infarction (AMI) and identify the possible underlying mechanisms. Levels of reactive oxygen species (ROS) and inflammatory factors, including interleukin (IL)-6, IL-1β and tumor necrosis factor-α (TNF-α) in the blood samples of patients with AMI were measured using commercially available kits by visible spectrophotometry after SFQXD administration. The contents of phosphorylated (p-) forkhead box O3a (FOXO3a) was examined using an ELISA kit. In addition, a hydrogen peroxide (HO)-induced myocardial injury model was established using neonatal rat cardiomyocytes. Following treatment with SFQXD, the levels of intracellular ROS, cell apoptosis, oxidative stress- and inflammation-related markers were measured using commercially available kits by visible spectrophotometry. Additionally, western blot analysis was used to measure the expression of sirtuin-4 (SIRT4), p-FOXO3a, acetylated FOXO3a (ace-FOXO3a) and apoptosis-related genes (Bcl-2, Bax, BIM and cleaved caspase-3). Subsequently, to investigate the possible underlying regulatory mechanisms, SIRT4 expression was silenced by transfection with small hairpin RNA against SIRT4, following which changes in the extent of oxidative stress, inflammation and apoptosis were assessed. The levels of ROS and interleukin (IL)-1β were found to be significantly reduced, whilst FOXO3a phosphorylation was markedly increased following administration with SFQXD. , SFQXD dose-dependently inhibited HO-induced oxidative stress, inflammation and apoptosis in neonatal rat cardiomyocytes. In addition, FOXO3a phosphorylation was markedly upregulated whilst FOXO3a acetylation was downregulated following treatment of HO-induced primary neonatal cardiomyocytes with SFQXD. SIRT4 knockdown also markedly reversed the effects of SFQXD on oxidative stress, inflammation and apoptosis in neonatal rat cardiomyocytes. In conclusion, these findings demonstrated that SFQXD may alleviate oxidative stress-induced myocardial injury by potentially regulating SIRT4/FOXO3a signaling, suggesting that SFQXD may be of clinical value for the treatment of AMI.
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http://dx.doi.org/10.3892/etm.2021.9985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027745PMC
June 2021

Efficacy and safety of crizotinib plus bevacizumab in positive non-small cell lung cancer: an open-label, single-arm, prospective observational study.

Am J Transl Res 2021 15;13(3):1526-1534. Epub 2021 Mar 15.

School of Medicine, Nankai University Weijin Road 94#, Nankai District, Tianjin 300071, China.

Background: Crizotinib is a tyrosine kinase inhibitor (TKI) effective in positive non-small cell lung cancer (NSCLC) patients. Bevacizumab is an antiangiogenic monoclonal antibody, and improves clinical benefit of NSCLC in combination with EGFR-TKIs or chemotherapy. However, the efficacy and safety of crizotinib plus bevacizumab in treating naive positive NSCLC patients have not been studied.

Methods: In this open-label, single-arm, prospective observational study, locally advanced or metastatic rearrangement/ fusion/ amplification NSCLC patients were treated with crizotinib (250 mg orally twice daily) and bevacizumab (7.5 mg/kg intravenous every three weeks) until disease progression or intolerant toxicity or death. Primary end point was progressive free survival (PFS), secondary end points were duration of response (DOR), overall response rate (ORR), disease control rate (DCR) and safety. Patients receiving ≥1 cycle of treatment were evaluated.

Findings: Fourteen patients were eligible for analyzing between June 2016 and October 2017. There were 12 patients with rearrangement, 1 patient with fusion, and 1 patient with amplification. The median follow-up time was 42.8 months. The median PFS and DOR of the patients with rearrangement were 13.9 and 14.8 months respectively. Of the 12 patients, 7 gained partial response, 5 gained stable disease. The ORR and DCR were 58.3% and 100%. The PFS were 12.9 months and 1.9 months for patient with fusion or amplification. The most two common treatment-related adverse events were fatigue (28.6%) and rash (21.4%). 3 patients discontinued therapy because of liver damage or hemoptysis.

Interpretation: This study demonstrated that crizotinib plus bevacizumab showed benefit in treating naive rearrangement NSCLC patients, and the toxicity was relatively tolerant. Our results suggested that crizotinib plus bevacizumab might be a promising treatment strategy in positive NSCLC patients.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014364PMC
March 2021

Efficacy and safety of anti-PD-1-based therapy in combination with PARP inhibitors for patients with advanced solid tumors in a real-world setting.

Cancer Immunol Immunother 2021 Mar 19. Epub 2021 Mar 19.

Department of Medical Oncology, Chinese PLA General Hospital, Beijing, 100853, China.

Background: Rationale exists for combining immune checkpoint inhibitors and PARP inhibitors (PARPi), and results of clinical trials in ovarian cancer are promising, but data in other cancers are limited.

Method: Efficacy and safety of PARPi/anti-PD-1 in advanced solid tumors were retrospectively analyzed. The efficacy measures included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS).

Results: This retrospective study included data from 40 patients. The ORR was 27.5% (95% CI, 13.0-42.0%), with a DCR of 85.0% (95% CI, 73.4-96.6%). Except four patients in first-line treatment (three with PR and one with SD), the ORR of ≥second-line treatment, non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) was 22.2%, 23.1% and 28.6%, and the DCR was 83.3%, 84.6% and 71.4%, separately. The median PFS of all patients, ≥second-line treatment, NSCLC and SCLC was 4.6 m, 4.2 m, 4.5 m and 3.7 m. The median OS was 9.4 m, 11.4 m, 12.7 m and 5.4 m, respectively. Multivariable analysis revealed that BRCA1/2 mutation was positively correlated with ORR (P = 0.008), and LDH≥250U/L was negatively correlated with lowered DCR (P = 0.018), while lymphocyte number, ECOG and LDH significantly influenced both PFS and OS. We found that the possible resistant mechanisms were sarcomatous degeneration and secondary mutation, including BRCA2 truncation mutation, A2M, JAK1,T790M, KEAP1 and mTOR mutation. 37.5% patients had ≥grade 3 adverse events.

Conclusion: PARPi/anti-PD-1 is an effective and tolerable method for patients with advanced solid tumors, and BRCA1/2 is a potential biomarker.
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http://dx.doi.org/10.1007/s00262-021-02852-4DOI Listing
March 2021

The Synergistic Effect of PARP Inhibitors and Immune Checkpoint Inhibitors.

Clin Med Insights Oncol 2021 25;15:1179554921996288. Epub 2021 Feb 25.

Department of Medical Oncology, Chinese PLA General Hospital, Beijing, China.

Poly (ADP-ribose) polymerase (PARP) inhibitors have demonstrated great promise for treating cancers with homologous recombination (HR) defects, such as germline BRCA1/2 mutation. Further studies suggest that PARP inhibitors (PARPi) can also exhibit efficacy in HR-competent cancers, by amplifying the DNA damage and inducing immunogenic cell death, and PARPi lead to increasing tumor neoantigen, upregulation of interferons and PD-L1, and modulation of the tumor microenvironment, which may facilitate a more profound antitumor immune response. Immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 or CTLA-4 have achieved impressive success in the treatment of different malignancies. However, only a subset of populations derive clinical benefit, and the biomarkers and resistance mechanisms are not fully understood. Therefore, given that PARPi could potentiate the therapeutic effect of ICIs, PARPi combined with ICIs are becoming an alternative for patients who cannot benefit from ICI monotherapy. In this review, we focus on the mechanisms and immune role of PARPi and discuss the rationale and clinical studies of this combined regimen.
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http://dx.doi.org/10.1177/1179554921996288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934064PMC
February 2021

Relationship of ITPKA expression with the prognosis of breast cancer.

Mol Genet Genomic Med 2021 Apr 23;9(4):e1598. Epub 2021 Feb 23.

Nursing Department, Sixth Medical Center of Chinese PLA Hospital, Medical School of Chinese PLA, Beijing, China.

Background: Breast cancer (BC) represents a most common cancer among women worldwide. The outcomes of this disease remain dismal due to frequent recurrence and metastasis. Inositol-1,4,5-trisphosphate-3-kinase-A (ITPKA) plays an important role in regulating calcium signaling and actin dynamics. The dysregulation of ITPKA has been observed in several human cancers. The present study aimed to assess ITPKA expression and its prognostic value in BC.

Methods: ITPKA expression was examined via quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC) methods. In addition, Kaplan-Meier survival analysis and Cox regression analysis were performed to evaluate prognostic value of ITPKA in BC.

Results: Upregulated ITPKA expression was found in BC samples, according to both qRT-PCR and IHC analyses (all p < .05). ITPKA expression was positively correlated with lymph node metastasis (p = .021) and TNM stage (p = .009). Moreover, BC patients with high expression of ITPKA had poor overall survival compared with those with low expression (log-rank p < .05). Cox analysis verified that ITPKA expression was an independent prognostic factor for BC patients (HR = 4.239, 95%CI = 2.221-8.093 and p = .000).

Conclusion: BC cases show increased expression of ITPKA. ITPKA may act as an independent prognostic biomarker in BC.
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http://dx.doi.org/10.1002/mgg3.1598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8123748PMC
April 2021

Immunotherapy beyond progression in patients with advanced non-small cell lung cancer.

Transl Lung Cancer Res 2020 Dec;9(6):2391-2400

Department of Oncology, the Second Medical Center, Chinese PLA General Hospital, Beijing, China.

Background: Immune checkpoint inhibitors (ICIs) represent a great breakthrough in the treatment of advanced non-small cell lung cancer (aNSCLC). However, whether immunotherapy beyond progression (IBP) is effective for aNSCLC has yet to be established. Therefore, a retrospective clinical study was conducted to investigate the efficacy of IBP in patients with aNSCLC under real-world conditions.

Methods: A total of 125 Chinese patients with aNSCLC who experienced progressive disease (PD) after receiving monotherapy or combination therapy (combined with chemotherapy or/and antiangiogenic therapy) with programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) inhibitors between January 2015 and March 2019 were enrolled. Patients who were treated with ICIs for more than 6 weeks after PD were defined as IBP (n=39), while those who received ICI treatment for less than 6 weeks or discontinued it due to PD were defined as non-IBP (n=86). Patient clinical characteristics were evaluated. An optimization-based method was applied to balance the clinical baseline characteristics between the two groups.

Results: In total population, the IBP group had longer overall survival (median OS, 26.6 9.5 months; HR, 0.40; 95% CI: 0.23-0.69; P<0.001) and progression-free survival (median PFS, 8.9 4.1 months; HR, 0.41; 95% CI: 0.26-0.65; P<0.001), compared with the non-IBP group. Despite no significant difference in objective response rate (ORR, 15.4% 11.6%, P=0.560), disease control rate (DCR) was significantly higher in the IBP group (89.7% 61.6%, P<0.001). After balancing baseline covariates, the IBP group also had longer OS (median: 26.6 10.7 months; HR, 0.40; 95% CI: 0.19-0.84; P=0.015) and PFS (median: 9.7 4.3 months; HR, 0.28; 95% CI: 0.15-0.51; P<0.001), with a benefit in either of patients previously treated with ICI monotherapy or in combination therapy and with non-response to the previously ICI.

Conclusions: IBP is associated with longer OS and PFS in patients with aNSCLC. Our findings may suggest new therapeutic options for patients with aNSCLC who experienced disease progression after initial immunotherapy.
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http://dx.doi.org/10.21037/tlcr-20-1252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815351PMC
December 2020

A real-world study of the efficacy and safety of anti-programmed cell death-1 therapy combined with chemotherapy or targeted therapy in patients with advanced biliary tract cancer.

J Gastrointest Oncol 2020 Dec;11(6):1421-1430

Department of Medical Oncology, Chinese PLA General Hospital, Beijing, China.

Background: Immune checkpoint inhibitors (ICIs) represent a breakthrough in cancer treatment. However, they have rarely been used to treat biliary tract cancer (BTC). In the current study, we aimed to evaluate and compare the efficacy and safety of anti-programmed cell death-1 (PD-1) therapy used alone or in combination with chemotherapy or targeted therapy in the treatment of advanced BTC.

Methods: Patients with advanced BTC who were treated either with anti-PD-1 therapy alone or anti-PD-1 therapy plus chemotherapy or targeted therapy between December, 2015 and October, 2017 were retrospectively screened for eligibility. Patients who had previously received treatment with any agent targeting T-cell co-stimulation or immune checkpoints were excluded. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and safety were evaluated.

Results: A total of 37 patients were included in this study (15 cases in the monotherapy group and 22 cases in the combination group). Patients in the combination group had significantly longer OS [median, 8.2 3.6 months, HR 0.47 (0.20-1.10), P=0.011] and PFS (median, 3.9 2.0 months, HR 0.58 (0.28-1.19), P=0.034) than patients in the monotherapy group. The ORR was 18.2% (4/22) and 0% in the combination group and monotherapy group, respectively, and the difference was not significant (P=0.131). Furthermore, no significant difference was found between the two groups with respect to the incidence of grade 3-4 treatment-related adverse events (P=0.388).

Conclusions: Anti-PD-1 therapy plus chemotherapy or targeted therapy is an effective and tolerable treatment for patients with advanced BTC and is promising as a first-line treatment or beyond.
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http://dx.doi.org/10.21037/jgo-20-562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7807271PMC
December 2020

Pretreatment hemoglobin level as a predictor to evaluate the efficacy of immune checkpoint inhibitors in patients with advanced non-small cell lung cancer.

Ther Adv Med Oncol 2020 5;12:1758835920970049. Epub 2020 Nov 5.

Department of Oncology, The Second Medical Center of Chinese PLA General Hospital, 28 Fuxing Road, Haidian District, Beijing, China.

Background: Targeting immune checkpoints represents an immense breakthrough in cancer therapeutics. The prognostic value of hemoglobin (Hb) has been investigated in many malignancies including non-small cell lung cancer (NSCLC). However, the prognostic impact of pretreatment Hb count for immune checkpoint inhibitors (ICIs) in advanced NSCLC patients remains unclear.

Methods: A total of 310 late-stage NSCLC patients who received ICI therapies between January 2015 and March 2019 were prospectively enrolled. We used a propensity score-matched cohort analysis for this study. Patients' clinicopathological characteristics and pretreatment Hb concentration were assessed against the progression-free survival (PFS) and overall survival (OS) using the Kaplan-Meier method and Cox proportional hazards regression.

Results: A propensity score (PS)-matched cohort analysis was applied to adjust for potential bias and to create two comparable groups according to patients' clinicopathological characteristics. The patients with normal baseline Hb levels (⩾110 g/L) had significantly longer PFS [median: 10.0 4.0 months, hazard ratio (HR): 0.63, 95% confidence interval (CI): 0.46-0.86;  = 0.001] and OS [median: 17.6 10.5 months, HR (95% CI): 0.56 (0.40-0.79);  < 0.001] than those with decreased Hb count (<110 g/L) in a PS-matched cohort ( = 255). For patients with normal pretreatment Hb levels, ICI combination therapy was significantly associated with better PFS [median: 11.1 8.0 months, HR (95% CI): 0.74 (0.50-1.06);  = 0.09] and OS [median: 26.0 12.9 months, HR (95% CI): 0.56 (0.37-0.86);  = 0.008] than monotherapy, but there was no such trend for patients with decreased baseline Hb levels.

Conclusion: Our findings showed that normal pretreatment Hb count served as a favorable prognostic marker in advanced NSCLC patients treated with ICIs, representing an economical biomarker with readily measuring performance among all reported ones.
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http://dx.doi.org/10.1177/1758835920970049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7649885PMC
November 2020

Association of the Pretreatment Lung Immune Prognostic Index with Survival Outcomes in Advanced Hepatocellular Carcinoma Patients Treated with PD-1 Inhibitors.

J Hepatocell Carcinoma 2020 2;7:289-299. Epub 2020 Nov 2.

Department of Medical Oncology, Chinese PLA General Hospital, Beijing, People's Republic of China.

Purpose: At present, there are no validated biomarkers that can predict whether patients with advanced hepatocellular carcinoma (aHCC) are likely to benefit from anti-PD-1 therapy. We aimed to determine whether lung immune prognostic index (LIPI) is associated with outcomes in patients with aHCC treated with PD-1 inhibitors.

Patients And Methods: Patients undergoing initial treatment with PD-1 inhibitors for aHCC at a single center from January 1, 2015 to August 31, 2019 were included. The patients were stratified according to pretreatment LIPI based on a derived neutrophils/(leukocytes minus neutrophils) ratio (dNLR) ≥ 3 and a lactate dehydrogenase (LDH) level ≥ the upper limit of normal (ULN). Kaplan-Meier analysis and the Log rank test were used to calculate and compare survival between good LIPI and intermediate/poor LIPI scores. The prognostic values of LIPI for survival and disease control rate were evaluated using Cox proportional hazard and logistic regression models, respectively.

Results: Of the 108 study patients, 53 (49%) had a good LIPI (dNLR < 3 and LDH normal) and 55 (51%) had intermediate/poor LIPI (dNLR ≥ 3 or/and LDH ≥ ULN). With a median follow-up of 12.4 months, intermediate/poor LIPI was independently associated with shorter overall survival (OS) (hazard ratio [HR] 4.00; 95% CI, 2.00-8.03) and progression-free survival (PFS) (HR 2.65; 95% CI, 1.61-4.37). The median OS for good and intermediate/poor LIPI was not reached and was 13.7 (95% CI, 8.2-19.1) months, respectively, and the median PFS was 10.9 (95% CI, 8.9-12.9) and 4.0 (95% CI, 2.2-5.8) months (both P < 0.001), respectively.

Conclusion: Pretreatment LIPI combined with a dNLR ≥ 3 and/or LDH ≥ ULN is associated with poor outcomes in patients with aHCC treated with PD-1 inhibitors. Further validation in large, prospective studies are warranted.
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http://dx.doi.org/10.2147/JHC.S277453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7646485PMC
November 2020

Anti-PD-1/L1 plus anti-angiogenesis therapy as second-line or later treatment in advanced lung adenocarcinoma.

J Cancer Res Clin Oncol 2021 Mar 9;147(3):881-891. Epub 2020 Sep 9.

School of Medicine, Nankai University, 94 Weijin Road, Nankai, Tianjin, 300071, People's Republic of China.

Purpose: Anti-programmed cell death protein 1 or its ligand (anti-PD-1/L1) monotherapy has become the standard second-line treatment in advanced lung adenocarcinoma. However, the strategy treatment of anti-PD-1/L1 plus anti-angiogenesis therapy has not been evaluated. We conducted this retrospective study to assess the efficacy and safety of anti-PD-1/L1 plus anti-angiogenesis therapy in patients with advanced lung adenocarcinoma in the second-line or later setting.

Methods: Patients with advanced lung adenocarcinoma who received anti-PD-1/L1 plus anti-angiogenesis therapy or anti-PD-1/L1 monotherapy in the second-line or later treatment from March 2015 to May 2019 in PLA General Hospital were retrospectively analyzed. The progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety were assessed. Multivariate analyses of PFS and OS were performed with Cox proportional hazard regression models.

Results: Seventy-four patients were included in our study. Twenty-five patients were treated with anti-PD-1/L1 plus anti-angiogenesis therapy, and forty-nine patients were treated with anti-PD-1/L1 monotherapy. The disease control rate (DCR) was higher in the anti-PD-1/L1 plus anti-angiogenesis group than in the anti-PD-1/L1 monotherapy group (92.0% vs. 46.9%, P = 0.0004). The median progression-free survival (PFS) was 5.1 months vs. 2.0 months (HR 0.551 [95% confidence interval 0.337-0.902], P = 0.002) and median overall survival (OS) was 14.3 months vs. 8.4 months (HR 0.549 [95% CI 0.305-0.990], P = 0.046), respectively. Multivariate Cox proportional hazard regression models showed that anti-PD-1/L1 plus anti-angiogenesis group had prolonged PFS (HR 0.541 [95% CI 0.298-0.981], P = 0.033). The incidences of grade 3/4 adverse events were 12% (3/25) in anti-PD-1/L1 plus anti-angiogenesis group and 6% (3/49) in anti-PD-1/L1 monotherapy group.

Conclusion: Compared with anti-PD-1/L1 monotherapy, anti-PD-1/L1 plus anti-angiogenesis therapy could significantly improve the clinical response and bring longer PFS and OS in patients with advanced lung adenocarcinoma who had failed first-line or later treatment. Further prospective studies are needed to validate our findings.
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http://dx.doi.org/10.1007/s00432-020-03380-xDOI Listing
March 2021

Alveolar macrophages in patients with non-small cell lung cancer.

Int J Clin Exp Pathol 2020 1;13(7):1867-1872. Epub 2020 Jul 1.

Department of Oncology, First Department of Medical Oncology, Chinese PLA General Hospital Beijing, China.

Objective: To observe alveolar macrophages (AMs) in the microenvironment of patients with non-small cell lung cancer (NSCLC).

Materials And Methods: 20 NSCLC patients received bronchoalveolar lavage, and the bronchial alveolar lavage fluid (BALF) was collected. The phenotypes of AMs were detected by the opal multiplex immunofluorescence assay (mIF), flow cytometry, and western blot.

Results: AMs could easily be made into paraffin sections after agar pre-embedding. The mIF results showed that AMs highly expressed M1-type marker CD86, and M2-type marker CD163 under PerkinElmer Vectra microscope, while there was a significant difference between the expression of CD86 and CD163 (**<0.01), consistent with the flow cytometry results. Western blot revealed that the other markers of M1-type (CD16 and iNOS) expression in the AMs were compared with M2-type markers CD206 and ARG (*<0.05).

Conclusions: Our results showed that AMs simultaneously expressed M1-type markers and M2-type markers, while the M2 markers still dominated. This suggests agar pre-embedding is a very convenient method to embed cells to paraffin tissue, so that cell membrane or nuclear antigens are very easily detected by mIF.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414454PMC
July 2020

Comparative effectiveness of pembrolizumab vs. nivolumab in patients with recurrent or advanced NSCLC.

Sci Rep 2020 08 4;10(1):13160. Epub 2020 Aug 4.

Department of Graduate Administration, Chinese PLA General Hospital, Beijing, China.

The efficacies of pembrolizumab and nivolumab have never been directly compared in a real-world study. Therefore, we sought to retrospectively evaluate the objective response rate (ORR) and the progression-free survival (PFS) of patients with recurrent or advanced non-small cell lung cancer (NSCLC) in a real-world setting. This study included patients with recurrent or advanced NSCLC diagnosed between September 1, 2015 and August 31, 2019, who were treated with programmed cell death 1 (PD-1) inhibitors at the Cancer Center of the Chinese People's Liberation Army. PFS was estimated for each treatment group using Kaplan-Meier curves and log-rank tests. The multivariate analysis of PFS was performed with Cox proportional hazards regression models. A total of 255 patients with advanced or recurrent NSCLC treated with PD-1 inhibitors were identified. The ORR was significantly higher in the pembrolizumab group than in the nivolumab group, while PFS was not significantly different between the two groups. Subgroup analysis showed that the ORR was significantly higher for pembrolizumab than for nivolumab in patients in the first-line therapy subgroup and in those in the combination therapy as first-line therapy subgroup. Survival analysis of patients receiving combination therapy as second- or further-line therapy showed that nivolumab had better efficacy than pembrolizumab. However, the multivariate analysis revealed no significant difference in PFS between patients treated with pembrolizumab and those treated with nivolumab regardless of the subgroup. In our study, no significant difference in PFS was noted between patients treated with pembrolizumab and those treated with nivolumab in various clinical settings. This supports the current practice of choosing either pembrolizumab or nivolumab based on patient preferences.
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http://dx.doi.org/10.1038/s41598-020-70207-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403144PMC
August 2020

Efficacy and safety of PD-1/PD-L1 inhibitors plus nab-paclitaxel for patients with non-small cell lung cancer who have progressed after platinum-based chemotherapy.

Ther Adv Med Oncol 2020 6;12:1758835920936882. Epub 2020 Jul 6.

Department of Oncology, Chinese PLA General Hospital, 28 Fuxing Road, Haidian, Beijing 100853, People's Republic of China.

Background: Immunotherapy combined with platinum-based chemotherapy is now the standard first-line treatment for non-small cell lung cancer (NSCLC) patients. However, limited evidence exists to show the efficacy of immunotherapy plus taxanes for patients who have progressed after platinum-based chemotherapy.

Methods: The immunotherapy naïve patients with metastatic NSCLC who received anti-PD-1/PD-L1 monotherapy or combined with nab-paclitaxel after prior platinum-based chemotherapy from 2015 to 2018 in PLA General Hospital were identified. The progression-free survival, overall survival (OS), objective response rate (ORR), disease control rate (DCR) and safety were assessed.

Results: Of 57 patients, 40 were treated with anti-PD-1/PD-L1 monotherapy and 17 were treated with anti-PD-1/PD-L1 plus nab-paclitaxel. With a median OS follow-up of 16.3 months, the nab-paclitaxel group showed significantly longer OS compared with the immune monotherapy group (median, 28.6 months 15.9 months, log-rank  = 0.020). When adjusted by covariates in COX proportional regression model, both the treatment group [ = 0.009, hazard ratio (HR) 0.361; 95% confidence interval (CI) 0.168-0.773] and performance status ( = 0.003, HR 0.372; 95% CI 0.192-0.721) demonstrated independent association with the longer OS from combination therapy. In addition, ORR was 23.5% (4/17) in the immune checkpoints inhibitors (ICIs) plus nab-paclitaxel group 13.5% (5/37) in immune monotherapy group ( = 0.439), with a DCR of 88.2% (15/17) and 59.5% (22/37) ( = 0.034), respectively. The incidence of grade 3/4 adverse events was 23.5% (4/17) in the combination group and 2.5% (1/40) in the immune monotherapy group.

Conclusion: PD-1/PD-L1 inhibitor plus nab-paclitaxel resulted in significantly longer OS and higher response ICI single agent in metastatic NSCLC patients who have progressed after platinum-based chemotherapy. These findings need to be further explored by prospective studies.
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http://dx.doi.org/10.1177/1758835920936882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338650PMC
July 2020

Dynamics of Serum Tumor Markers Can Serve as a Prognostic Biomarker for Chinese Advanced Non-small Cell Lung Cancer Patients Treated With Immune Checkpoint Inhibitors.

Front Immunol 2020 10;11:1173. Epub 2020 Jun 10.

Department of Oncology, The First Medical Center of Chinese PLA General Hospital, Beijing, China.

Serum tumor markers carcinoembryonic antigen (CEA), cancer antigen 125 (CA125), cytokeratin 19 fragment (CYFRA21-1) and squamous-cell carcinoma-related antigen (SCC-Ag) are routinely used for monitoring the response to chemotherapy or targeted therapy in advanced-stage non-small cell lung cancer (NSCLC), however their role in immunotherapy remains unclear. The aim of this study was to investigate whether dynamics of these serum markers were associated with the efficacy and prognosis of Chinese late-stage NSCLC patients treated with programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) inhibitors. We initiated a longitudinal prospective study on advanced NSCLC patients treated with PD-1/PD-L1 inhibitors in Chinese PLA general hospital (Beijing, China). Blood samples of baseline and after 6 weeks' treatment were collected. CT scan were used by all patients to evaluate treatment efficacy according to RECIST 1.1. Serum tumor markers levels were measured with an electrochemical luminescence for SCC-Ag and with a chemiluminescent microparticle immunoassay for serum CEA, CA125, and CYFRA21-1. At least 20% decreases of the biomarkers from baseline were considered as meaningful improvements after 6 weeks of treatment with immune checkpoint inhibitors (ICIs). Optimization-based method was used to balance baseline covariates between different groups. Associations between serum tumor biomarker improvements and objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were analyzed. A total of 308 Chinese patients with advanced NSCLC were enrolled in the study. After balancing baseline covariates, patients with meaningful improvements in <2 out of 4 biomarkers (CEA, CA125, CYFRA21-1, and SCC-Ag) was ended up with lower ORR (0.08 vs. 0.35, < 0.001), shorten PFS (median: 5.4 vs. 12.5 months, < 0.001), and OS (median: 11.7 vs. 25.6 months, < 0.001) in the total population. Subgroup analysis of patients with adenocarcinoma revealed that patients with meaningful improvements in <2 out of 4 biomarkers had significant lower ORR (0.06 vs. 0.36, < 0.001), shorten PFS (median: 4.1 vs. 11.9 months, < 0.001), and OS (median: 11.9 vs. 24.2 months, < 0.001). So as in patients with squamous cell carcinoma, meaningful improvements in at least 2 out of 4 biomarkers were linked to better ORR (0.42 vs. 0.08, = 0.014), longer PFS (median: 13.1 vs. 5.6 months, = 0.001), and OS (median: 25.6 vs. 10.9 months, = 0.06). The dynamic change of CEA, CA125, CYFRA21-1, and SCC-Ag from baseline have prognostic value for late-stage NSCLC patients treated with PD-1/PD-L1 inhibitors. Decrease of associated biomarkers serum levels were associated with favorable clinical outcomes.
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http://dx.doi.org/10.3389/fimmu.2020.01173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7298878PMC
April 2021

The diagnostic and prognostic value of exosome-derived long non-coding RNAs in cancer patients: a meta-analysis.

Clin Exp Med 2020 Aug 5;20(3):339-348. Epub 2020 Jun 5.

School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.

Purpose: Exosome-derived long non-coding RNAs (lncRNAs) as novel biomarkers are widely investigated in various cancers, yet results remain controversial. The aim of this meta-analysis was to clarify the diagnostic and prognostic value of exosome-derived lncRNAs in cancer.

Methods: PubMed, Web of Science, EMBASE, CNKI, and WanFang online databases were comprehensively searched for eligible studies up to January, 2020. To evaluate the diagnostic effect, sensitivity, specificity, and area under the curve (AUC) were pooled. Threshold effect, subgroup analysis, and meta-regression were applied to explore heterogeneity. Deeks' funnel plot and sensitivity analysis were used to examine publication bias and stability of meta-analysis, respectively. The pooled hazard ratios (HRs) with 95% confidence intervals (CIs) for overall survival (OS) and recurrence free survival (RFS) were calculated to assess the prognostic value.

Results: A total of 29 eligible studies involving 3882 patients were enrolled in the meta-analysis, which included 26 on diagnosis and 11 on prognosis. For diagnosis analysis, the pooled sensitivity, specificity, and AUC were 0.83 (95% CI 0.78-0.87), 0.80 (95% CI 0.75-0.84), and 0.88 (95% CI 0.85-0.91), respectively. Meta-regression revealed that the cancer type acted as the potential source of heterogeneity. Sensitivity analysis and Deeks' funnel plot indicated that results were relatively robust and had no publication bias. For the prognosis analysis, results suggested that overexpression of exosome-derived lncRNAs which upregulated in cancer showed a significant association with poor OS (HR 2.21, 95% CI 1.79-2.71, p < 0.001). Conversely, overexpression of exosome-derived lncRNAs which downregulated in cancer was markedly related to better OS (HR 0.28, 95% CI 0.14-0.55, p < 0.001).

Conclusion: This meta-analysis reveals that exosome-derived lncRNAs might serve as promising diagnostic and prognostic biomarkers for cancer. However, the clinical value of exosome-derived lncRNAs needs to be further confirmed.
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http://dx.doi.org/10.1007/s10238-020-00638-zDOI Listing
August 2020

Association of immune-related pneumonitis with the efficacy of PD-1/PD-L1 inhibitors in non-small cell lung cancer.

Ther Adv Med Oncol 2020 9;12:1758835920922033. Epub 2020 May 9.

Department of Medical Oncology, Chinese PLA General Hospital, 28 Fuxing Road, Haidian, Beijing, 100853, China.

Background: Cutaneous adverse events (AEs) have been positively associated with immune checkpoint inhibitor (ICI) efficacy in patients with melanoma, but little is known regarding the association between checkpoint inhibitor pneumonitis (CIP) and programmed cell death protein 1/programmed death ligand 1 (PD-1/PD-L1) inhibitor efficacy in non-small cell lung cancer (NSCLC).

Methods: A single-institution, retrospective medical record review of patients with advanced or recurrent NSCLC who were treated with PD-1/PD-L1 inhibitors between 1 September 2015 and 1 June 2019 was conducted. A total of 276 NSCLC patients with or without immune-related pneumonitis who received at least one dose of ICIs and had at least one follow-up visit were identified. Kaplan-Meier curves of the progression-free survival (PFS) of patients stratified according to immune-related pneumonitis development were evaluated with the log-rank test as a preplanned primary objective. Multivariate analysis of PFS was performed with Cox proportional hazard regression models.

Results: In the cohort of 276 patients, 42 patients developed CIP attributed to PD-1/PD-L1 inhibitors. Survival analysis showed that the overall response rate was significantly higher in patients with CIP than in those without CIP (61.90% 29.91%, respectively, < 0.01), and that CIP development was significantly associated with increased PFS (45.80 weeks 21.15 weeks, respectively, < 0.01). Additionally, 16-week landmark analysis produced the same results. Similarly, subgroup analysis of PD-1 inhibitor-treated, nivolumab-treated, and pembrolizumab-treated groups also revealed that CIP increased survival in NSCLC patients. Additionally, grade 1-2 pneumonitis showed an association with increased ICI efficacy in NSCLC; however, grade 3-4 pneumonitis did not. In addition, only two of the four pneumonitis radiological subtypes showed associations with increased ICI efficacy in NSCLC.

Conclusion: CIP is associated with enhanced PD-1/PD-L1 inhibitor efficacy in NSCLC patients. Grade 1-2 pneumonitis and the radiological features of hypersensitivity and cryptogenic organizing pneumonia (COP) may be signs of enhanced ICI efficacy. However, further studies with larger numbers of patients and longer follow-up times are needed to validate our findings.
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http://dx.doi.org/10.1177/1758835920922033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7222233PMC
May 2020

Tumor Mutation Burden as a Potential Biomarker for PD-1/PD-L1 Inhibition in Advanced Non-small Cell Lung Cancer.

Target Oncol 2020 02;15(1):93-100

School of Medicine, Nankai University, 94 Weijin Road, Nankai, Tianjin, 300071, People's Republic of China.

Background: Immunotherapy based on programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors has revolutionized the treatment of non-small cell lung cancer (NSCLC). Patients with high PD-L1 expression or DNA mismatch repair deficiency (dMMR)/microsatellite instability-high (MSI-H) cancer are reported to benefit from PD-1/PD-L1 inhibitors. However, additional biomarkers are needed, and whether tumor mutation burden (TMB) can be a robust biomarker or not is still controversial.

Objective: We conducted this study to assess TMB as a biomarker for PD-1/PD-L1 inhibitor treatment in advanced NSCLC patients in a real-world setting.

Patients And Methods: Chinese NSCLC patients who received a PD-1/PD-L1 inhibitor at the People's Liberation Army General Hospital and who had pathological tissues available for TMB were retrospectively analyzed. Demographic and clinical information were evaluated. Targeted next-generation sequencing (NGS) of the tumor tissue was performed. The relationship between TMB and clinical benefit was assessed.

Results: Thirty-four patients treated with PD-1/PD-L1 inhibitors between March 2015 and January 2019 were analyzed. The TMB was greater in patients with complete response (CR)/partial response (PR) versus stable disease (SD) versus progressive disease (PD) (median 11 vs. 9.7 vs. 4.2 mutations/megabase [Mb]; p = 0.049). The median progression-free survival was 10.6 months in the TMB-high group versus 3.9 months in the TMB-low group (cut-off value = 10 mutations/Mb) (hazard ratio [HR] 0.26 [95% confidence interval 0.12-0.57], p = 0.0007). The median overall survival was 21.0 months and 11.6 months (HR 0.37 [0.17-0.81], p = 0.0126) in the TMB-high group and the TMB-low group, respectively. The disease control rate was higher in the TMB-high group than in the TMB-low group (100% vs. 70%, p = 0.024).

Conclusions: High TMB was associated with a better outcome in advanced NSCLC patients who received PD-1/PD-L1 inhibitors in China. Further studies are needed to confirm our findings.
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http://dx.doi.org/10.1007/s11523-020-00703-3DOI Listing
February 2020

Anti-PD-1 Therapy plus Chemotherapy and/or Bevacizumab as Second Line or later Treatment for Patients with Advanced Non-Small Cell Lung Cancer.

J Cancer 2020 1;11(3):741-749. Epub 2020 Jan 1.

Department of Oncology, Chinese PLA General Hospital, PLA School of Medicine, Beijing, People's Republic of China.

Immune checkpoint inhibitor combination therapy exhibited outstanding efficacy in first line setting for advanced non-small cell lung cancer (aNSCLC) patients. However, whether PD-1 inhibitor combined treatment is effective in second line or later setting remains unknown. Therefore, we retrospectively evaluated the efficacy of combined therapy of PD-1 inhibitor with chemotherapy and/or bevacizumab compared to PD-1 inhibitor alone for aNSCLC patients in second line or later setting. Patients with aNSCLC who have received anti-PD-1 based therapy between 2015 and 2017 were screened, and 55 patients were ultimately included and divided into the monotherapy group (N=33) and the combination group (N=22). Patients treated with combination therapy exhibited superior PFS versus those treated with monotherapy (median PFS, 7.5 months vs 3.3 months; hazard ratio 0.28; 95% CI, 0.14-0.56; <0.001). Objective response rate and disease control rate were 31.8% (7/22) and 95.5% (21/22) in the combination group and 10.0% (3/30) and 46.7% (14/30) in the monotherapy group, respectively (ORR, =0.075; DCR, <0.001). Five patients (22.7%) experienced grade 3-4 adverse events in the combination group and two patients (6.1%) in the monotherapy group. Taken together, our results indicated that for NSCLC patients who had failed on the first-line or later treatment, PD-1 inhibitor in combination with chemotherapy and/or bevacizumab might be a favorable treatment option. These findings warrant further validation in prospective studies.
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http://dx.doi.org/10.7150/jca.37966DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6959040PMC
January 2020

PTK2 promotes cancer stem cell traits in hepatocellular carcinoma by activating Wnt/β-catenin signaling.

Cancer Lett 2019 05 5;450:132-143. Epub 2019 Mar 5.

Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing, China. Electronic address:

Emerging evidence indicates that cancer stem cells (CSCs) are involved in tumorigenesis, tumor recurrence, and therapeutic resistance in hepatocellular carcinoma (HCC). However, the mechanisms underlying HCC CSC regulation remain largely unknown. Here we report our analysis of 97 paraffin-embedded HCC tumor specimens. We found that protein tyrosine kinase 2 (PTK2) expression correlated with liver CSC marker expression, overall survival, and recurrence-free survival in HCC patients. Our results further showed that PTK2 activated Wnt/β-catenin signaling by promoting nuclear accumulation of β-catenin in HCC cells. In this manner, PTK2 activates CSC traits and drives tumorigenicity in HCC cells, leading to HCC recurrence and sorafenib resistance. Moreover, PTK2 expression was negatively correlated with its level of promoter methylation. PTK2 apparently acts as an oncogene by increasing CSC traits and tumorigenicity in HCC. The present data suggest that PTK2 may be a novel prognostic biomarker for HCC recurrence, and a therapeutic target for HCC treatment.
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http://dx.doi.org/10.1016/j.canlet.2019.02.040DOI Listing
May 2019

Interaction between GDF5 gene polymorphisms and environment factors increased the risk of knee osteoarthritis: a case-control study.

Biosci Rep 2019 02 26;39(2). Epub 2019 Feb 26.

The First Clinical College, Henan University of Chinese Medicine, Zhengzhou 450046, Henan Province, China.

Using a case-control design, we assessed the association between single nucleotide polymorphisms (SNPs) of growth and differentiation factor 5 (GDF5)/rs143383 gene and interaction with environments and knee osteoarthritis (KOA). We recruited 288 KOA patients from the First Clinical College, Henan University of Chinese Medicine between June 2017 and May 2018. There was significant difference in genotype distribution between case group and control group (χ = 22.661, =0.000). The minor C allele was significantly higher in the case group than that in the control group (20.5 vs 8.1%, =0.000, odds ratio (OR) = 1.62, 95% confidence interval (CI): 1.29-2.03). Significant differences were also observed in other gene models. For age, all models show significant differences (<0.05) for those whose age was more than 60 years, and no significant difference was observed for those under 60 years. For non-smoking group, there were significant differences between case group and control group, and for smoker, significance level was found in TT compared with CC and allele gene models. Patients with drinking and Bbody mass index (MI )≥ 24 also showed significant relationship between rs143383 and osteoarthritis (OA) under the following models: TT vs CC (=0.000, =0.018), TT/CT vs CC (=0.043), TT vs CT/CC (=0.000, =0.009), and T vs C (=0.024, =0.000). Other gene models indicated no significance (>0.05). Our results revealed a possible genetic association between GDF5 and KOA, and the TT genotype of rs143383 increased the risk of KOA in Chinese Han population. The interaction between gene and drinking, smoking, and obesity further increased the risk of KOA.
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http://dx.doi.org/10.1042/BSR20182423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6390126PMC
February 2019

The risk variant rs884225 within EGFR impairs miR-103a-3p's anti-tumourigenic function in non-small cell lung cancer.

Oncogene 2019 03 23;38(13):2291-2304. Epub 2018 Nov 23.

Department of Oncology, PLA General Hospital, Beijing, China.

Epidermal growth factor receptor (EGFR) status is the major determinant of non-small cell lung cancer (NSCLC) therapy selection. Studies have hinted that EGFR antibodies or tyrosine kinase inhibitors were beneficial in patients with EGFR mutation-negative but EGFR-overexpressing of NSCLC. However, the mechanisms underlying EGFR amplification and overexpression in NSCLC remain largely unknown. Here, we report that rs884225, a single nucleotide polymorphism in the EGFR 3'-terminal untranslated region, was significantly associated with EGFR expression level and contributed to NSCLC susceptibility. Mechanistically, the rs884225 C allele enhanced EGFR expression by altering the miR-103a-3p binding site, thus impairing miR-103a-3p's anti-tumourigenic function. As a tumour suppressor gene, miR-103a-3p expression correlated with overall and recurrence-free survival in NSCLC patients. Furthermore, miR-103a-3p inhibited growth and metastasis via effects on the KRAS pathway and epithelial-to-mesenchymal transition in EGFR wild-type NSCLC cell lines, respectively, which substantially reduced EGFR expression and activity. Thus, rs884225 may be a biomarker for NSCLC susceptibility, and miR-103a-3p may be a potential therapeutic target in NSCLC.
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http://dx.doi.org/10.1038/s41388-018-0576-6DOI Listing
March 2019

Clinical observation of immune checkpoint inhibitors in the treatment of advanced pancreatic cancer: a real-world study in Chinese cohort.

Ther Clin Risk Manag 2018 11;14:1691-1700. Epub 2018 Sep 11.

Department of Oncology, Chinese PLA General Hospital, Beijing, China,

Background: In recent years, immune checkpoint inhibitors have been used with great success in the treatment of various cancers. However, when used in monotherapy, immune checkpoint inhibitors have a poor effect on pancreatic cancer. This study assessed the efficacy and safety of the use of immune checkpoint inhibitors for the treatment of advanced pancreatic cancer.

Patients And Methods: We evaluated patients with advanced pancreatic cancer who were treated with PD-1/PD-L1 inhibitors from 2015-2017. All the patients received PD-1/PD-L1 inhibitors as a monotherapy or in combination with other treatments, such as chemotherapy, targeted therapy, and CTLA-4 inhibitors at the recommended dosages.

Results: For the 43 patients enrolled, the objective response rate was 10.5%, the disease control rate was 50%, the median progression-free survival was 2.3 months, and the median overall survival (mOS) was 5.1 months. The mOS was longer for patients receiving combined therapy than for those receiving PD-1/PD-L1 inhibitor monotherapy (5.4 vs 2.0 months, = 0.020). Patients receiving immune therapy as a first-line treatment had prolonged survival compared with those receiving it as a second-line or multiple-line treatment, but the difference was not statistically significant (mOS: 7.0 vs 5.1 vs 2.8 months, = 0.161). There was a reduction in the serum level of CA19-9 associated with the response to treatment. Adverse events were tolerable and were mainly grade 1 and 2. The immune-related adverse events that occurred were hypothyroidism, diarrhea, and rash.

Conclusion: Immune checkpoint inhibitors showed a certain efficacy in the treatment of advanced pancreatic cancer and could confer long-term survival benefits. Combined therapy was more effective and may serve as an alternative option. Further studies should be performed.
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http://dx.doi.org/10.2147/TCRM.S173041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6140734PMC
September 2018

Decreased expression of RASSF10 correlates with poor prognosis in patients with colorectal cancer.

Medicine (Baltimore) 2017 Oct;96(42):e7011

Department of Oncology, Chinese PLA General Hospital, Beijing, China.

Ras association domain protein 10 (RASSF10) was reported to act as a prognostic indicator in various types of cancer and it was proved to be tumor suppressor gene in colorectal cancer (CRC). The purpose of this study was to evaluate the prognostic significance of RASSF10 in CRC.Quantitative real-time polymerase chain reaction was used to detect the messenger RNA (mRNA) expression while enzyme-linked immunosorbent assay was taken to measure the protein expression of RASSF10 in tumor tissues and adjacent normal tissues from 102 patients with CRC. The relationship between RASSF10 expression level and clinical characteristics of CRC patients was analyzed by chi-squared test. In addition, the association between overall survival of CRC patients and RASSF10 expression was estimated by Kaplan-Meier analysis. Cox regression analysis was used to evaluate the prognostic value of RASSF10.The expression level of RASSF10 in tumor tissues was significantly lower than that in the normal tissues both at mRNA and protein levels. Moreover, the expression level was correlated with lymph-node-metastasis and tumor-node-metastasis stage. Kaplan-Meier analysis suggested that patients with high expression level of RASSF10 had a longer overall survival than those with low level (log-rank test, P < .001). Besides, RASSF10 might be a potential biomarker in the prognosis of CRC according to cox regression analysis.The down regulated of RASSF10 is found in CRC and it may be an ideal prognostic marker.
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http://dx.doi.org/10.1097/MD.0000000000007011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5662333PMC
October 2017

Sp1-mediated transcriptional activation of miR-205 promotes radioresistance in esophageal squamous cell carcinoma.

Oncotarget 2017 Jan;8(4):5735-5752

State Key Laboratory of Antibody Medicine and Targeting Therapy, Shanghai, P.R. China.

Radiotherapy for esophageal squamous cell carcinoma (ESCC) patients is limited by resistance to ionizing radiation (IR). However, the roles and mechanisms of microRNAs in radioresistance are obscure. Here, we investigated that microRNA-205 (miR-205) was upregulated in radioresistant (RR) ESCC cells compared with the parental cells. Overexpression of miR-205 promoted colony survival post-IR, whereas depletion of miR-205 sensitized ESCC cells to IR in vitro and in vivo. Further, we demonstrated that miR-205 promoted radioresistance by enhancing DNA repair, inhibiting apoptosis and activating epithelial-mesenchymal transition (EMT). Mechanistically, miR-205, upregulated post-IR, was demonstrated to be activated by Sp1 in parallel with its host gene, miR-205HG, both of which showed a perfect correlation. We also identified and validated phosphatase and tensin homolog (PTEN), as a target of miR-205 that promoted radioresistance via PI3K/AKT pathway. Lastly, increased miR-205 expression was closely associated with decreased PTEN expression in ESCC tissues and miR-205 expression predicted poor prognosis in patients with ESCC. Taken together, these findings identify miR-205 as a critical determinant of radioresistance and a biomarker of prognosis. The Sp1-mediated transcriptional activation of miR-205 promotes radioresistance through PTEN via PI3K/AKT pathway in ESCC. Inhibition of miR-205 expression may be a new strategy for radiotherapy in ESCC.
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http://dx.doi.org/10.18632/oncotarget.13902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5351585PMC
January 2017

Bacillus as a potential diagnostic marker for yellow tongue coating.

Sci Rep 2016 08 31;6:32496. Epub 2016 Aug 31.

Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, China.

Observation of tongue coating, a foundation for clinical diagnosis and treatment in traditional Chinese medicine (TCM), is a major indicator of the occurrence, development, and prognosis of disease. The biological basis of tongue diagnosis and relationship between the types and microorganisms of tongue coating remain elusive. Thirteen chronic erosive gastritis (CEG) patients with typical yellow tongue coating (YTC) and ten healthy volunteers with thin white tongue coating (WTC) were included in this study. Patients were provided a 2-course targeted treatment of a herbal medicine Ban Xia Xie Xin decoction, traditionally prescribed for CEG patients with YTC, to evaluate the relationship between tongue coating microbiota and diagnosis of CEG with typical YTC. The tongue coating segregation structure was determined using Illumina Miseq sequencing of the V4-V5 region of the 16S ribosomal RNA gene. Bacillus was significantly observed only in CEG patients with YTC, but not in patients who received the decoction. YTC (n = 22) and WTC (n = 29) samples were collected for bacterial culturing to illustrate the relationship between Bacillus and YTC. The Bacillus positivity rate of YTC samples was 72.7%; Bacillus was not observed in WTC samples. In conclusion, Bacillus was strongly associated with YTC.
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http://dx.doi.org/10.1038/srep32496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5006162PMC
August 2016

ASPP2 suppresses stem cell-like characteristics and chemoresistance by inhibiting the Src/FAK/Snail axis in hepatocellular carcinoma.

Tumour Biol 2016 Oct 29;37(10):13669-13677. Epub 2016 Jul 29.

PLA General Hospital Cancer Center Key Lab, PLA Postgraduate School of Medicine, 28 Fuxing Road, Beijing, China.

Hepatocellular carcinoma (HCC) is the third leading cause of death in cancer patients worldwide. Understanding the molecular pathogenesis of HCC recurrence and chemoresistance is key to improving patients' prognosis. In this study, we report that downregulation of ASPP2, a member of the ankyrin-repeat-containing, SH3-domain-containing, and proline-rich-region-containing protein (ASPP) family, bestowed HCC cells with stem-like properties and resistance to chemotherapy, including the expansion of side population fractions, formation of hepatospheroids, expression of stem cell-associated genes, loss of chemosensitivity, and increased tumorigenicity in immunodeficient mice. An expression profiling assay revealed that ASPP2 specifically repressed focal adhesion kinase (FAK)/Src/extracellular signal regulated kinase (ERK) signaling. ASPP2 does this by physically interacting with C-terminal Src kinase (CSK) and stimulating its kinase activity, which eventually leads to activator protein 1 (AP1)-mediated downregulation of Snail expression. In addition, pharmacologic inhibition of Src attenuated the effects of ASPP2 deficiency. Our findings present functional and mechanistic insight into the critical role of ASPP2 in the inhibition of HCC stemness and drug resistance and may provide a new strategy for therapeutic combinations to treat HCC.
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http://dx.doi.org/10.1007/s13277-016-5246-0DOI Listing
October 2016
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