Publications by authors named "Xiuyu Cai"

37 Publications

Immune Cell Infiltration of the Primary Tumor Microenvironment Predicted the Treatment Outcome of Chemotherapy With or Without Bevacizumab in Metastatic Colorectal Cancer Patients.

Front Oncol 2020 27;10:581051. Epub 2021 Jan 27.

VIP Department, Sun Yat-sen University Cancer Center, Guangzhou, China.

Background: With the interest in cancer immunotherapy, it may be possible to combine immunotherapy with bevacizumab and chemotherapy. We evaluated whether tumor-infiltrating immune cells are associated with the efficacy of chemotherapy with or without bevacizumab for the treatment of metastatic colorectal cancer (mCRC).

Methods: This study enrolled mCRC patients on standard treatment with available detailed data and tumor tissue at Sun Yat-sen University Cancer Center between July 1, 2005, and October 1, 2017. CD3+ and CD8+ T cell densities examined by immunohistochemistry in both the tumor core (CT) and invasive margin (IM) were summed as the Immunoscore, and the CD8+/CD3+ T cell ratio was calculated. The predictive and prognostic efficacies of tumor-infiltrating immune cells for progression-free survival (PFS) and overall survival (OS) were analyzed with Kaplan-Meier and Cox analyses.

Results: The CD8+/CD3+ T cell ratio in the microenvironment was an independent prognostic factor for OS (28.12 mo vs. 16.56 mo, = 0.017) among the 108 studied patients. In the chemotherapy only group, patients with a high Immunoscore had a high overall response rate (ORR, 40.0% vs. 60.0%, = 0.022), those with a low CD8+/CD3+ T cell ratio in the microenvironment had a significantly longer PFS (8.64 mo vs. 6.01 mo, = 0.017), and those with a high CD3+ T cell density in the CT had a longer OS (16.56 mo vs. 25.66 mo, = 0.029). In the chemotherapy combined with bevacizumab group, patients with a higher CD8+ T cell density in the IM had a longer PFS (7.62 mo vs. 11.66 mo, = 0.034) and OS (14.55 mo vs. 23.72 mo, = 0.033).

Conclusion: Immune cells in primary tumors play an important role in predicting mCRC treatment efficacy. CD8 predicts the effect of bevacizumab plus chemotherapy, while CD3 and CD8/CD3 predict chemotherapy efficacy.
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http://dx.doi.org/10.3389/fonc.2020.581051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873592PMC
January 2021

Unique genomic features and prognostic value of COSMIC mutational signature 4 in lung adenocarcinoma and lung squamous cell carcinoma.

Ann Transl Med 2020 Sep;8(18):1176

Department of Neurosurgery, Tongji Hospital, Tongji University School of Medicine, Shanghai, China.

Background: Analysis of mutational signatures is becoming routine in cancer genomics, with implications for pathogenesis, classification, and prognosis. Among the signatures cataloged at COSMIC, mutational signature 4 has been linked to smoking. However, the distribution of signature 4 in Chinese lung cancer patients has not been evaluated, and its clinical value has not been evaluated. Here we survey mutational signatures in Chinese lung cancer patients and explore the relationship between signature 4 and other genomic features in the patients.

Methods: We extracted mutational signatures from whole-exome sequencing data of Chinese non-small cell lung cancer patients. The data included 401 lung adenocarcinoma (LUAD) and 92 squamous cell carcinoma (LUSC). We then performed statistical analysis to search for genomic and clinical features that can be linked to mutation signatures.

Results: We found signature 4 is the most frequent mutational signature in LUSC and the second most frequent in LUAD. Fifty-six LUAD and thirty-five LUSC patients were named with high signature 4 similarities (cosine similarity >0.7). These patients have shorter survival and higher tumor mutational burden comparing to those with low signature 4 similarities. Dozens of genes with single nucleotide variation, index mutations, and copy number variations were differentially enriched in the patients with high signature 4 similarities. Among these genes, , , , , , , and are common in both LUADs and LUSCs with high signature 4 similarities, showing that these genes are tightly associated with signature 4.

Conclusions: The present study is the first to report a comparison in Chinese NSCLC patients with or without COSMIC mutational signature 4. These results will help find the Signature 4 related mutational process in NSCLC.
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http://dx.doi.org/10.21037/atm-20-5952DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576056PMC
September 2020

Immune-related adverse events of a PD-L1 inhibitor plus chemotherapy versus a PD-L1 inhibitor alone in first-line treatment for advanced non-small cell lung cancer: A meta-analysis of randomized control trials.

Cancer 2021 Mar 29;127(5):777-786. Epub 2020 Oct 29.

Department of Thoracic Surgery and Oncology, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.

Background: The addition of chemotherapy to a programmed death 1/programmed death ligand 1 (PD-L1) inhibitor is a more effective option as a first-line treatment for advanced non-small cell lung cancer (NSCLC). It might also inhibit an overactive immune response and thereby reduce immune-related adverse events (irAEs). This meta-analysis assessed the rate of irAEs with a PD-(L)1 inhibitor plus chemotherapy (I+C) versus a PD-(L)1 inhibitor alone (I) and evaluated the indirect relative risk (RR) of I+C versus I.

Methods: The protocol of this study was registered with PROSPERO (CRD42020139923). The pooled rates of irAEs at different grades were calculated by a single-arm meta-analysis weighted by sample size, and RRs were determined by direct meta-analysis and indirect treatment comparison.

Results: Overall, I+C had a lower rate of grade 3 or higher irAEs than I (7.1% vs 10.6%; indirect RR, 0.516; 95% confidence interval [CI], 0.291-0.916), although irAEs of any grade were similar. The rate of pneumonitis with I+C was lower than the rate with I for any grade (5.9% vs 7.1%; indirect RR, 0.217; 95% CI, 0.080-0.588) and for grade 3 or higher. In the endocrine system, I+C was associated with a lower overall ratein comparison with I (16.1% vs 20.1%; indirect RR, 0.260; 95% CI, 0.120-0.564), whereas irAEs of the digestive system were similar with I+C and I. In other systems, I+C decreased the rate of skin reactions, including rash, in comparison with I (10.4% vs 12.9%; indirect RR, 0.474; 95% CI, 0.299-0.751). The rate of grade 3 or higher skin reactions (excluding rash) also decreased with I+C versus I (1.1% vs 2.0%) with an indirect RR of 0.158 (95% CI, 0.032-0.765), whereas other included irAEs were similar.

Conclusions: In comparison with a PD-(L)1 inhibitor alone, a combination with chemotherapy for the first-line treatment of NSCLC decreased the rates of most irAEs, such as pneumonitis and endocrine and skin reactions, and the overall rate.

Lay Summary: In the first-line treatment of advanced non-small cell lung cancer (NSCLC), the addition of chemotherapy to a programmed death 1/programmed death ligand 1 (PD-(L)1) inhibitor is a more effective option. Adding chemotherapy might reduce immune-related adverse events (irAEs). Thus, this article assesses the rate of irAEs with a PD-(L)1 inhibitor plus chemotherapy (I+C) in comparison with a PD-(L)1 inhibitor alone (I) and evaluates the indirect relative risk (RR) with I+C versus I. The key finding is that in comparison with a PD-(L)1 inhibitor alone, a combination with chemotherapy for the first-line treatment of NSCLC decreases the rates of most irAEs, such as pneumonitis and endocrine and skin reactions, and the overall rate.
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http://dx.doi.org/10.1002/cncr.33270DOI Listing
March 2021

Concomitant Mutations in EGFR 19Del/L858R Mutation and Their Association with Response to EGFR-TKIs in NSCLC Patients.

Cancer Manag Res 2020 18;12:8653-8662. Epub 2020 Sep 18.

Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, Guangzhou, People's Republic of China.

Objective: Differences in efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) have been observed between non-small cell lung cancer (NSCLC) patients with and mutation. We explored whether the total number or pattern of concomitant mutations of and may explain their different sensitivities.

Patients And Methods: This study contained the mutational profiles of EGFR-mutated NSCLC patients from two cohorts: Guangzhou (G1) and database (G2). Concomitant mutation status and EGFR-TKI response information were retrieved.

Results: A total of 403 patients covered 283 genes in the G1 and 803 patients with a different gene set in the G2 were included. Similar prevalence of total concomitant mutation number was observed in both G1 ( 32.48% vs 30.45%; =0.68) and G2 ( 74.9% vs 73.2%; =0.65) cohorts. Only pathway same more related to mutation. EGFR-TKI response information was recorded for 134 patients in the G2 cohort. showed a higher objective response (OR) rate compared with , regardless of concomitant mutations. Compared to patients with OR, non-OR patients had more concomitant mutations, both in (53.8% vs 83.3%; =0.021) and (51.4% vs 77.8%; =0.029). In particular, total concomitant mutations (OR=0.27; =0.03), sensitive mutations (OR=2.21; =0.04), and (OR=0.244; =0.02) significantly affected the TKI response.

Conclusion: Concomitant mutations were widespread in and and were associated with poorer OR to EGFR-TKIs. However, and had similar numbers and patterns of concomitant mutations, which might not explain the different sensitivity to EGFR-TKI.
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http://dx.doi.org/10.2147/CMAR.S255967DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509478PMC
September 2020

Apatinib plus Chemotherapy as a Second-Line Treatment in Unresectable Non-Small Cell Lung Carcinoma: A Randomized, Controlled, Multicenter Clinical Trial.

Oncologist 2020 11 25;25(11):e1640-e1649. Epub 2020 Jul 25.

Fujian Cancer Hospital and Fujian Medical University Cancer Hospital, Fuzhou, People' Republic of China.

Lessons Learned: The efficacy of second-line treatment for advanced non-small cell lung carcinoma (NSCLC) without a sensitizing driver gene mutation is still unsatisfactory. The combination of apatinib and chemotherapy improved progression-free survival in the second-line therapy of advanced NSCLC without a sensitizing mutation. This study offers a new treatment strategy for second-line treatment of such patients but requires confirmation in a larger multi-institutional trial.

Background: This study explored the efficacy and safety of apatinib combined with single-agent chemotherapy versus single-agent chemotherapy in the second-line treatment of advanced non-small-cell lung carcinoma (NSCLC) without driver mutations.

Methods: In this double-arm, open label, exploratory clinical study, we enrolled patients with unresectable locally advanced or advanced NSCLC without driver mutations that had progressed following first-line chemotherapy. The subjects were allocated into an experimental group and a control group by 2:1. The experimental group received apatinib combined with four cycles of docetaxel or pemetrexed until disease progression, intolerable toxicity, or discontinuation at the patient' request. The control group only received four cycles of docetaxel or pemetrexed. The primary endpoints were progression-free survival (PFS), and the secondary endpoints were overall survival (OS), disease control rate (DCR), and safety.

Results: Thirty-seven patients were enrolled. The efficacy of 33 patients was evaluated. The median PFS was 5.47 versus 2.97 months, the DCR was 95% versus 73%, and the objective response rate (ORR) was 27% versus 9% in the experimental versus control group. The OS was still under follow-up. The most common adverse effects included hypertension, hand-foot skin reaction (HFSR), and fatigue.

Conclusion: Apatinib combined with single-agent chemotherapy may be a novel option for second-line treatment of advanced NSCLC.
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http://dx.doi.org/10.1634/theoncologist.2020-0519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648327PMC
November 2020

Nivolumab plus ipilimumab versus pembrolizumab as chemotherapy-free, first-line treatment for PD-L1-positive non-small cell lung cancer.

Clin Transl Med 2020 Jan 7;10(1):107-115. Epub 2020 Apr 7.

State Key Laboratory of Oncology in South China, Guangzhou, China.

Background: Nivolumab plus ipilimumab (N-I) or pembrolizumab (PEM) is associated with survival improvement as chemotherapy-free, first-line treatment for patients with advanced non-small cell lung carcinoma (NSCLC) and positive programmed cell death ligand 1 (PD-L1). However, no direct comparison data exist between these two regimens to inform clinical decisions. Therefore, we performed indirect comparison for N-I versus PEM using frequentist methods.

Results: Three randomized trials (KEYNOTE-024, KEYNOTE-042, and CheckMate 227) involving 2372 patients were included. For patients with tumor PD-L1 level of ≥1%, pooled meta-analyses showed that both N-I and PEM improved overall survival (OS) relative to chemotherapy (N-I: hazard ratio [HR] 0.82, 95% CI 0.69-0.97; PEM: HR 0.81, 95% CI 0.71-0.93); whereas only N-I significantly improved progression-free survival (PFS) (N-I: HR 0.79, 95% CI 0.65-0.96; PEM: HR 1.07, 95% CI 0.94-1.21). Neither N-I nor PEM was associated with improved objective response rate (ORR) compared with chemotherapy (N-I: relative risk [RR] 1.20, 95% CI 0.98-1.46; PEM: RR 1.03, 95% CI 0.86-1.23). Indirect comparisons showed that N-I was associated with longer PFS than PEM (HR 0.77, 95% CI 0.62-0.95). However, N-I was not superior to PEM in terms of OS (HR 0.98, 95% CI 0.77-1.24) and ORR (RR 1.17, 95% CI 0.89-1.52). N-I showed a less favorable toxicity profile relative to PEM (all grade adverse events: RR 1.28, 95% CI 1.17-1.40).

Conclusions: N-I and PEM provide comparable OS benefit for PD-L1-positive NSCLC. N-I further improves PFS relative to PEM but at meaningful cost of toxicities.
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http://dx.doi.org/10.1002/ctm2.14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7240850PMC
January 2020

New first-line treatment strategies for advanced lung squamous cell carcinoma.

Transl Lung Cancer Res 2020 Apr;9(2):414-417

State Key Laboratory of Oncology in South China, Guangzhou 510060, China.

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http://dx.doi.org/10.21037/tlcr.2020.03.14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7225139PMC
April 2020

A Modified Algorithm Adjusting Both High and Minor Allele Frequency Mutation to Redefine Blood-Based Tumor Mutational Burden (bTMB) for Optimal Prediction of Clinical Benefits From Immune Checkpoint Inhibitor Therapy.

J Thorac Oncol 2020 05;15(5):e69-e72

Department of Thoracic Oncology, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease National Clinical Research Center for Respiratory Disease Guangzhou Institute of Respiratory Health, Guangzhou, People's Republic of China. Electronic address:

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http://dx.doi.org/10.1016/j.jtho.2019.12.120DOI Listing
May 2020

Cancer associated fibroblasts-derived exosomes contribute to radioresistance through promoting colorectal cancer stem cells phenotype.

Exp Cell Res 2020 06 10;391(2):111956. Epub 2020 Mar 10.

Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China. Electronic address:

Radioresistance observed in patients with colorectal cancer (CRC) may be related to the presence of cancer stem cells (CSCs), but the underlying mechanism(s) remain unclear. Cancer-associated fibroblasts (CAFs) can regulate the stemness of cancer cells and tumor radiosensitivity. In addition, exosomes have been reported to modify treatment response by mediating cell-cell communication. In this study, we aimed to investigate whether exosomes derived from CAFs (CAF-exosomes) are involved in mediating resistance to radiotherapy in colorectal cancer and to explore the underlying mechanism. We found that CSCs were inherently resistant to cell death induced by radiotherapy. CAF-derived CM promoted clonogenicity and radioresistance of CRC cells. Further investigations revealed that exosomes isolated from CM induced the above effects whereas exosome-depleted CM (solution) was not able to induce clonogenicity and radioresistance. Finally, exosomes could activate transforming growth factor-β (TGF-β) signaling pathway and TGFβ1-neutralizing antibody inhibit this effect and decrease clonogenicity and expression levels of stemness genes. In conclusion,our findings suggest CAFs promote stemness of CRC cells and thus increase radiation resistance. Exosomes derived from CAFs play a crucial role through activating TGF-β signaling pathway in this process.
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http://dx.doi.org/10.1016/j.yexcr.2020.111956DOI Listing
June 2020

Presence of allele frequency heterogeneity defined by ctDNA profiling predicts unfavorable overall survival of NSCLC.

Transl Lung Cancer Res 2019 Dec;8(6):1045-1050

Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, Guangzhou 510120, China.

Background: The generation of subclonal (low-frequency) mutations is driven by tumor mutations and the relationship between the heterogeneity of tumor mutation abundance and non-small cell lung cancer (NSCLC) remains unknown. We investigate the role of allele frequency heterogeneity (AFH) defined by circulating tumor DNA (ctDNA) profiling in predicting prognosis in advanced NSCLC patients.

Methods: Publicly available data set of POPLAR (N=211) and OAK (N=642) trials were used for analyzing. A low ratio of allele frequency (AF) of a mutation to the maximum-somatic-allele-frequency (MSAF) was used to define the presence of AFH. The prognostic value of AF/MSAF ratio that was below a defined cutoff point in overall survival (OS) was evaluated using Cox-proportional hazards regression; and the structural break point was determined by LOESS regression and Chow test. The derived AFH was also explored in an independent cohort (N=259) of advanced NSCLC receiving first-line EGFR-TKIs from the First Affiliated Hospital of Guangzhou Medical University.

Results: In the POPLAR and OAK cohort, low AF/MSAF ratio was found to be significantly associated with unfavorable OS in univariate and multivariate analysis. The structural break point analysis demonstrated that AF/MSAF <10% could yield the optimal value to stratify patients with poor OS, which was applied for defining the presence of AFH. The presence of AFH significantly correlated with unfavorable OS in advanced NSCLC regardless of treatment arms (overall: HR 1.52, immunotherapy: HR 1.81, chemotherapy: HR 1.32, all P<0.05). In the exploratory EGFR-TKIs cohort, the presence of AFH was also significantly associated with shorter OS (HR 1.72, P=0.039).

Conclusions: Our results demonstrate that the presence of AFH predict unfavorable prognosis in advanced NSCLC despite which drug the patients used. The presence of AFH defined by ctDNA might provide an easily-accessible biomarker for risk stratification in the current clinical practice.
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http://dx.doi.org/10.21037/tlcr.2019.12.10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6976377PMC
December 2019

The prognostic value of B7-H6 in esophageal squamous cell carcinoma.

Sci Rep 2019 12 2;9(1):18122. Epub 2019 Dec 2.

Department of Oncology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, Guangdong, China.

B7-H6, a member of the B7 family molecules, participates in the clearance of tumor cells by binding to NKp30 on NK cells. B7-H6 expression level in esophageal squamous cell carcinoma (ESCC) and the clinical value remain unknown. The goal of this study was to determine the expression of B7-H6 in ESCC and further explore its clinical significance. We retrospectively collected the clinical data of 145 patients diagnosed with ESCC between January 2007 and December 2008. The expression of B7-H6 of the pathological tissue samples was detected by immunohistochemistry. The chi-square (χ) test was used to analyse the relationships of B7-H6 and clinicopathological characteristics. Survival and hazard functions were estimated using the Kaplan-Meier method, and survival between groups was compared using the two-sided log-rank test. The Cox proportional hazards regression model was used to adjust for the risk factors related to overall survival (OS). 133/145 (91.72%) of the ESCC tissue samples exhibited B7-H6 expression. The expression level of B7-H6 was correlated with T stage (P = 0.036) and lymphatic metastasis status (P = 0.044). High B7-H6 expression (P = 0.003) was associated with a significantly worse OS than low B7-H6 expression. Multivariate Cox proportional hazards regression analysis demonstrated that tumour size (P = 0.021), B7-H6 expression (P = 0.025) and lymphatic metastasis status (P = 0.049) were independent prognostic factors of OS for ESCC. Collectively, our findings suggest that B7-H6 is widely expressed in ESCC samples. And B7-H6 may represent a predictor of poor prognosis for ESCC.
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http://dx.doi.org/10.1038/s41598-019-54731-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6889130PMC
December 2019

An exploratory study of CT-guided percutaneous radiofrequency ablation for stage I thymoma.

Cancer Imaging 2019 Dec 2;19(1):80. Epub 2019 Dec 2.

Department of Medical Imaging & Image Guided Therapy, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, People's Republic of China.

Background: Thymoma is a rare tumor that originates from thymic epithelial cells and is usually associated with myasthenia gravis. Radiofrequency ablation (RFA) is a minimally invasive and curative treatment for other tumors, but RFA has not been used for the early treatment of thymoma.

Methods: The current study included 13 patients with stage I thymoma who were not candidates for surgical resection or video-assisted thoracoscopic surgery (VATS). All patients underwent first-line CT-guided percutaneous RFA. The feasibility and therapeutic effects of the intervention were thoroughly documented.

Results: All tumors were completely ablated (13 / 13, 100%). During follow-up (median 80.5 months, range, 64.6-116.9 months), only 1 of the 13 patients had recurrence of thymoma (1 / 13, 7.7%) at 35.5 months after the initial ablation. There were no surgery-related deaths after RFA treatment. The most common complications were fever (13 / 13, 100%) and pain (13 / 13, 100%). There was only one patient who occurred severe puncture-related bleeding during the procedure that needed blood transfusion and intravascular embolization of the punctured-injured vessel.

Conclusion: CT-guided percutaneous RFA for treatment of stage I thymoma is associated with minor trauma, few complications and good treatment outcomes.
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http://dx.doi.org/10.1186/s40644-019-0267-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6889348PMC
December 2019

Hepatitis B virus reactivation in cancer patients with positive Hepatitis B surface antigen undergoing PD-1 inhibition.

J Immunother Cancer 2019 11 21;7(1):322. Epub 2019 Nov 21.

State Key Laboratory of Oncology in South China, Guangzhou, China.

Background: Hepatitis B virus (HBV) reactivation is a serious complication in patients with cancers and HBV infection undergoing immunosuppressant treatment or chemotherapy. However, the safety of anti-programmed cell death (PD) -1 and anti-programmed cell death-ligand 1 (PD-L1) therapy in these patients is unknown because they were excluded from clinical trials of immunotherapy.

Methods: This retrospective cohort study involved consecutive hepatitis B surface antigen (HBsAg) -positive cancer patients who were referred to Sun Yat-sen University Cancer Center and received an anti-PD-1/PD-L1 antibody between January 1, 2015 and July 31, 2018. The primary end point was the rate of the occurrence of HBV reactivation.

Results: In total, 114 eligible patients were included, among whom 90 (79%) were male, and the median (range) age was 46 (16-76) years. Six patients (5.3%) developed HBV reactivation, occurring at a median of 18 weeks (range, 3-35 weeks) from the commencement of immunotherapy. Among these patients, all of them had undetectable baseline HBV DNA; one had prophylactic antiviral therapy while five did not; four were positive for Hepatitis B e antigen while the other two were negative. At reactivation, the median HBV DNA level was 3.89 × 10 IU/mL (range, 1.80 × 10-6.00 × 10 IU/mL); five had HBV-related hepatitis and one exhibited increasing HBV DNA level without alanine transaminase elevation. No HBV-related fatal events occurred. The lack of antiviral prophylaxis was the only significant risk factor for HBV reactivation (odds ratio, 17.50 [95% CI, 1.95-157.07], P = .004).

Conclusions: HBV reactivation occurs in a subset of HBsAg-positive cancer patients undergoing anti-PD-1 or anti-PD-L1 immunotherapy. Regular monitoring of HBV DNA and antiviral prophylaxis are advised to prevent this potentially fatal complication.
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http://dx.doi.org/10.1186/s40425-019-0808-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6873745PMC
November 2019

Efficacy and safety of first line treatments for patients with advanced epidermal growth factor receptor mutated, non-small cell lung cancer: systematic review and network meta-analysis.

BMJ 2019 10 7;367:l5460. Epub 2019 Oct 7.

Department of Thoracic Surgery and Oncology, First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease and National Clinical Research Centre for Respiratory Disease, 151 Yanjiang Road, Guangzhou 510120, China

Objective: To compare the efficacy and safety of first line treatments for patients with advanced epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC).

Design: Systematic review and network meta-analysis.

Data Sources: PubMed, Embase, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and several international conference databases, from inception to 20 May 2019.

Eligibility Criteria For Selecting Studies: Published and unpublished randomised controlled trials comparing two or more treatments in the first line setting for patients with advanced EGFR mutated NSCLC were included in a bayesian network meta-analysis. Eligible studies reported at least one of the following clinical outcome measures: progression free survival, overall survival, objective response rate, and adverse events of grade 3 or higher.

Results: 18 eligible trials involved 4628 patients and 12 treatments: EGFR tyrosine kinase inhibitors (TKIs; osimertinib, dacomitinib, afatinib, erlotinib, gefitinib, and icotinib), pemetrexed based chemotherapy, pemetrexed free chemotherapy, and combination treatments (afatinib plus cetuximab, erlotinib plus bevacizumab, gefitinib plus pemetrexed based chemotherapy, and gefitinib plus pemetrexed). Consistent with gefitinib plus pemetrexed based chemotherapy (hazard ratio 0.95, 95% credible interval 0.72 to 1.24), osimertinib showed the most favourable progression free survival, with significant differences versus dacomitinib (0.74, 0.55 to 1.00), afatinib (0.52, 0.40 to 0.68), erlotinib (0.48, 0.40 to 0.57), gefitinib (0.44, 0.37 to 0.52), icotinib (0.39, 0.24 to 0.62), pemetrexed based chemotherapy (0.24, 0.17 to 0.33), pemetrexed free chemotherapy (0.16, 0.13 to 0.20), afatinib plus cetuximab (0.44, 0.28 to 0.71), and gefitinib plus pemetrexed (0.65, 0.46 to 0.92). Osimertinib and gefitinib plus pemetrexed based chemotherapy were also consistent (0.94, 0.66 to 1.35) in providing the best overall survival benefit. Combination treatments caused more toxicity in general, especially erlotinib plus bevacizumab, which caused the most adverse events of grade 3 or higher. Different toxicity spectrums were revealed for individual EGFR-TKIs. Subgroup analyses by the two most common EGFR mutation types indicated that osimertinib was associated with the best progression free survival in patients with the exon 19 deletion, and gefitinib plus pemetrexed based chemotherapy was associated with the best progression free survival in patients with the Leu858Arg mutation.

Conclusions: These results indicate that osimertinib and gefitinib plus pemetrexed based chemotherapy were associated with the best progression free survival and overall survival benefits for patients with advanced EGFR mutated NSCLC, compared with other first line treatments. The treatments resulting in the best progression free survival for patients with the exon 19 deletion and Leu858Arg mutations were osimertinib and gefitinib plus pemetrexed based chemotherapy, respectively.

Systematic Review Registration: PROSPERO CRD42018111954.
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http://dx.doi.org/10.1136/bmj.l5460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6778694PMC
October 2019

The prognostic value of major facilitator superfamily domain-containing protein 2A in patients with hepatocellular carcinoma.

Aging (Albany NY) 2019 10 4;11(19):8474-8483. Epub 2019 Oct 4.

Department of Integrated Therapy in Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, P. R. China.

Introduction: We aimed to characterize the expression of major facilitator superfamily domain-containing protein 2A (MFSD2A) in hepatocellular carcinoma (HCC) patients and analyze its prognostic value.

Results: Immunohistochemistry revealed that low expression of MFSD2A was present in 37 of 79 cases (46.84%), which was significantly correlated with poor histological differentiation ( = 0.012). The plasma MFSD2A level in HCC patients was significantly lower than in healthy controls ( = 0.0079) and controls with chronic hepatitis B virus (HBV) infection ( = 0.0430). Moreover, patients with lower MFSD2A expression had shorter survival than higher expression ( = 0.021). Multivariate analysis revealed that MFSD2A was an independent prognostic predictor for HCC patients ( = 0.027).

Conclusion: The current study indicate MFSD2A may be an optimal diagnostic and prognostic biomarker for HCC.

Methods: First, we examined MFSD2A expression in 24 paired HCC and nontumorous tissues by real-time quantitative PCR (RT-qPCR). Second, the protein levels of MFSD2A in 11 paired HCC and nontumorous tissues were investigated by western blotting (WB). Moreover, MFSD2A protein expression was evaluated by immunohistochemistry in 79 HCC patients. In addition, we detected the plasma level of MFSD2A in HCC patients and healthy individuals and investigated the relationship between MFSD2A expression and clinicopathological parameters or prognosis of HCC patients.
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http://dx.doi.org/10.18632/aging.102333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814593PMC
October 2019

Molecular and clinical analysis of Chinese patients with anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer.

Cancer Sci 2019 Oct 23;110(10):3382-3390. Epub 2019 Sep 23.

Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China.

Anaplastic lymphoma kinase (ALK) fusions have been recognized as a therapeutic target in non-small cell lung cancer (NSCLC). However, molecular signatures and clinical characteristics of the Chinese population with ALK-rearranged NSCLC are not well elucidated. In the present study, we carried out targeted next-generation sequencing on tissue and plasma ctDNA samples in 1688 patients with NSCLC. Overall, ALK fusions were detected in 70 patients (4.1%), and the frequencies of ALK fusions detected in tissue and plasma samples were 5.1% and 3.3%, respectively. Additionally, the prevalence of breakpoint locations for EML4-ALK fusions in ctDNA was significantly correlated with that in tumor tissues (R  = .91, P = .045). According to age, the incidence rates of ALK fusions among young (age <45 years), middle-aged (between 45 and 70 years) and elderly (>70 years) patients were significantly different (P < .001). In 70 ALK-rearranged cases, coexistence of epidermal growth factor receptor (EGFR) alterations and ALK fusions was detected in 12 cases (17.1%) and EGFR mutations tended to coexist with non-EML4-ALK rearrangements. Notably, novel ALK fusion partners, including TRIM66, SWAP70, WNK3, ERC1, TCF12 and FBN1 were identified in the present study. Among EML4-ALK fusion variants, patients with variant V1 were younger than patients with variant V3 (P = .023), and TP53 mutations were more frequently concurrent with variant V3 compared with variant V1 (P = .009). In conclusion, these findings provide new insights into the molecular-clinical profiles of patients with ALK-rearranged NSCLC that may improve the treatment strategy of this population.
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http://dx.doi.org/10.1111/cas.14177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6778633PMC
October 2019

Long-term outcomes of modified BFM-95 regimen in adults with newly diagnosed standard-risk acute lymphoblastic leukemia: a retrospective single-center study.

Int J Hematol 2019 Oct 18;110(4):458-465. Epub 2019 Jul 18.

Department of Hematological Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China.

The standard treatment for adult acute lymphoblastic leukemia (ALL) is undefined. Patients with newly diagnosed standard-risk ALL at a single institution were retrospectively analyzed. From 2010 to 2017, 46 patients were treated using the modified Berlin-Frankfurt-Münster (BFM)-ALL-95 regimen. Hematologic and molecular complete remission (CR) rates of 91.3% and 76.1% were achieved. The 5-year event-free survival (EFS) and overall survival (OS) rates for all patients in the cohort were 58.0% (95% confidence interval, 42.1-73.9%) and 66.7% (95% CI, 51.4-82.0%), respectively. No patient presented with central nervous system involvement after CR in this study. This condition could be related to four doses of high-dose methotrexate (MTX) every 3 months during the maintenance phase. Multivariate analysis revealed that minimal residual disease positive and time interval between induction IA and Protocol M of more than 70 days were independent adverse factors for EFS and OS. One or more instances of grade 4 myelosuppression occurred during induction therapy. Nonhematological side effects were mild. No toxicity-related deaths were observed in the entire cohort. The data indicated that the modified regimen is well tolerated and can produce the promising outcomes in Chinese adults with standard-risk ALL.
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http://dx.doi.org/10.1007/s12185-019-02703-0DOI Listing
October 2019

The incidence of lymph node metastasis in patients with different oncogenic driver mutations among T1 non-small-cell lung cancer.

Lung Cancer 2019 08 27;134:218-224. Epub 2019 Jun 27.

Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, Guangzhou, China. Electronic address:

Objective: To investigate the incidence and distribution of lymph node metastasis in patients with different gene mutations among pathological T1 non-small-cell lung cancers (NSCLC).

Methods: NSCLC cases resected in our institution between 2016 and 2018 were included. Driver mutation testing was performed in all resected tumor tissues. These patients were grouped by the type of gene mutations. On the basis of protein that mutant-genes encoded involved in the molecular pathway, the genotypes were further classified into four distinct groups: upstream receptor mutant protein (EGFR, HER2 and MET); downstream regulator mutant protein (KRAS and BRAF); fusion mutant protein (ROS1, ALK and RET) and the wild type group. The incidence of lymph node metastasis was compared among different groups.

Results: Of the 1052 patients enrolled, the frequency of positive mutations was 68.0%. The incidence of lymph node metastasis were as follows: wild type (19.3%), ROS1 (72.8%), BRAF (55.5%), ALK (44.7%), HER2 (40%), RET (23.1%), KRAS (15.3%), EGFR (15.3%) and MET mutation (0%) (P < 0.001). The incidence of lymph node metastasis was significantly higher in fusion mutant protein group (45.1%) compared with others (wild type 19.3%, downstream regulator mutant protein 19.1%, upstream receptor mutant protein 15.3%, all P < 0.001). Patients with fusion genes also showed higher proportion of vascular invasion and positive lymph node ratio of greater than 0.33 compared to others.

Conclusion: Different genotypes of NSCLC have different propensity to develop lymph node metastasis. Cases of fusion gene mutations had a higher risk and burden of lymph node metastasis than other genotypes, which may indicate that more intensive treatment or surveillance strategies should be applied for these patients.
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http://dx.doi.org/10.1016/j.lungcan.2019.06.026DOI Listing
August 2019

Expression and clinical significance of miRNA-145 and miRNA-218 in laryngeal cancer.

Oncol Lett 2019 Jul 13;18(1):764-770. Epub 2019 May 13.

Department of Radiation Oncology, Sun Yat-sen University Cancer Centre, Guangzhou, Guangdong 510060, P.R. China.

Expression of miRNA-145 and miRNA-218 in serum of patients with laryngeal cancer and the relationship between them and the clinicopathological parameters and prognosis were investigated. The clinical medical records of 132 patients with laryngeal cancer, who were admitted to Guangdong Second Provincial General Hospital from February 2009 to March 2014, were retrospectively analyzed and comprised the study group. The data of physical examinations of 56 healthy volunteers who took physical examinations in the same hospital comprised the control group. RT-qPCR was used to detect the expression levels of miRNA-145 and miRNA-218 in serum of the patients in the two groups. According to the relative expression levels of miRNA-145 and miRNA-218 in serum of the patients in the study group on the day when they left hospital, the study group was divided into the high expression group (n=73 patients) and the low expression group (n=59 patients). The patients received a 48-month follow-up visit and their survival condition was recorded and the Kaplan-Meier was used to carry out the survival analysis. The expression levels of miRNA-145 and miRNA-218 in serum of the patients in the study group were lower than those in the control group (P<0.05). The median survival time of the patients in the high expression group was 30 months while the median survival time of the patients in the low expression group was 26 months. The expression levels of miRNA-145 and miRNA-218 in serum of patients with laryngeal cancer decreased, the higher the expression levels of miRNA-145 and miRNA-218 in serum of patients with laryngeal cancer were, the better the prognosis was. miRNA-145 and miRNA-218 were used as indicators of assessing the prognosis of patients with laryngeal cancer.
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http://dx.doi.org/10.3892/ol.2019.10353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6540214PMC
July 2019

Thoracoscopic Treatment of Giant Pulmonary Bullae.

J Surg Res 2019 11 10;243:206-212. Epub 2019 Jun 10.

National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, Guangdong Province, China; Department of Thoracic Surgery, Peking University Shenzhen Hospital, Shenzhen, Guangdong Province, China. Electronic address:

Background: Giant pulmonary bullae (GPB) is rare. The aim of this study was to evaluate the functional results of video-assisted thoracic surgery (VATS) in the treatment of GPB and the factors associated with complications following VATS resection for GPB.

Materials And Methods: From January 2010 to January 2015, 44 GPB patients underwent surgery with VATS. Individual GPB patient characteristics and surgical outcomes were evaluated. The patients were separated into two groups (an emphysematous group and a nonemphysematous group), and differences between the respective groups were investigated.

Results: Although there were no mortalities within a 30-d postoperative period among the 44 GPB patients treated surgically with VATS, 28 experienced postoperative complications, of which the most common were air leaks. VATS for GPB resulted in obvious improvements in symptoms and lung function in the majority of cases. Among 26 patients with preoperative dyspnea, the symptoms of 22 patients (84.62%) improved after treatment with VATS resection for GPB, and the mean forced expiratory volume in 1 s increased from 2.24 L preoperatively to 2.5 L postoperatively (P = 0.02). The complication rate of patients aged >48 y, who smoked and had emphysema, was significantly higher than that of those who did not smoke and did not have emphysema (79.2% versus 45%, P = 0.019; 85.7% versus 25%, P < 0.05; 88% versus 31.6%, P < 0.05). These characteristics could be associated with complications.

Conclusions: VATS resection is a safe and effective treatment for GPB and leads to improvements in symptoms and lung function. Patients >48 y, who smoked and had emphysema, were more likely to experience postoperative complications. There could be a relationship between these characteristics and the patients' postoperative complications.
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http://dx.doi.org/10.1016/j.jss.2019.05.009DOI Listing
November 2019

Comparison of weekly and triweekly cisplatin regimens during concurrent chemoradiotherapy for nasopharyngeal carcinoma.

BMC Cancer 2019 May 22;19(1):482. Epub 2019 May 22.

Department of Oncology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangdong Pharmaceutical University, 19 Nonglinxia Road, Guangzhou, 510062, China.

Background: We compared the survival outcomes and acute toxicities of weekly and triweekly cisplatin regimens during concurrent chemoradiotherapy (CCRT) in nasopharyngeal carcinoma (NPC) patients.

Methods: Patients were treated with CCRT alone. CCRT was initiated on the first day of RT. Cisplatin 30-40 mg/m was infused on days 1, 8, 15, 22, 29, 36 and 43 in the Weekly Group, while cisplatin 80-100 mg/m was delivered on days 1, 22 and 43 in the Triweekly Group. The survival outcomes were revealed by the Kaplan-Meier method and Cox regression modelling to measure 5-year overall survival (OS), disease-free survival (DFS), locoregional relapse-free survival (LRFS) and distant metastasis-free survival (DMFS).

Results: Ninety-three (28.9%) patients received three to 7 cycles of cisplatin weekly (Weekly Group) and 229 (71.1%) patients received two to 3 cycles of cisplatin triweekly (Triweekly Group). Five-year OS (weekly vs. triweekly, 96.7% vs. 88.3%, P = 0.036) and DFS (weekly vs. triweekly, 90.7% vs. 80.5%, P = 0.028) were better in the Weekly Group than in the Triweekly Group. The weekly vs. triweekly 5-year DMFS and LRFS rates were: DMFS, 96.7% vs. 91.4%, χ = 2.694, P = 0.101; LRFS, 96.3% vs. 93.5%, χ = 1.317, P = 0.251. Cisplatin delivery regimen was not an independent prognostic factor. The incidence rate of acute toxicities was similar between the groups.

Conclusions: Compared with Triweekly cisplatin regimen, Weekly regimen may be a better choice during CCRT.
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http://dx.doi.org/10.1186/s12885-019-5688-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6532163PMC
May 2019

The impact of epidermal growth factor receptor mutations on the prognosis of resected non-small cell lung cancer: a meta-analysis of literatures.

Transl Lung Cancer Res 2019 Apr;8(2):124-134

Department of Thoracic Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510000, China.

Background: Epidermal growth factor receptor (EGFR) mutation represents a good response to EGFR-tyrosine kinase inhibitor and an advantageous prognostic factor in advanced-stage non-small cell lung cancer (NSCLC). However, the predictive value of EGFR mutation for prognosis in NSCLC patients after complete surgery, which more reflective of natural process, remains controversial. We sought to examine the predictive value of EGFR mutation in NSCLC. Several studies with small sample sizes have been reported but small studies bring bias especially in a postoperative setting. Therefore, we sought to pool all current evidence to show the true effects.

Methods: Electronic databases were used to search the relevant articles. Disease-free survival (DFS), which will be less effected by subsequent treatments after recurrence, was the primary endpoint. The DFS between EGFR mutated and wild-type patients were compared focus on stage I patients who are rarely received adjuvant therapy. Besides, the DFS of patients with 19 exon deletion (19del) and 21 exon L858R mutation (L858R) were compared. A random effects model was used.

Results: A total of 19 relevant studies which involved 4,872 cases were enrolled and 2,086 patients were EGFR-mutated. The majority of studies used PCR-based methods to detect EGFR mutations. Through meta-analysis, we observed the DFS of EGFR-mutated patients were similar to wild type patients in overall population (HR 0.93, 95% CI: 0.74 to 1.17). Similar results were observed in stage I subgroup (HR 0.82, 95% CI: 0.50 to 1.33). DFS of 19 del patients were potentially inferior to L858R patients but the difference was not significant (HR 1.38, 95% CI: 0.76 to 2.52).

Conclusions: There was no significant difference in postoperative DFS between EGFR-mutant patients and wild-type with resected NSCLC. In addition, there is still insufficient evidence to support different postoperative treatment strategies (especially for stage I) for both mutated and wild-type patients. However, 19 del may be a negative factor, which may require more strict management. Thus, we strongly encourage reporting specific prognostic impacts of different mutation types.
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http://dx.doi.org/10.21037/tlcr.2019.03.14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6504652PMC
April 2019

Association between certain non-small cell lung cancer driver mutations and predictive markers for chemotherapy or programmed death-ligand 1 inhibition.

Cancer Sci 2019 Jun 22;110(6):2014-2021. Epub 2019 May 22.

Department of Thoracic Surgery/Oncology, State Key Laboratory and National Clinical Research Center for Respiratory Disease, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.

This study aimed to analyze the association between driver mutations and predictive markers for some anti-tumor agents in non-small cell lung cancer (NSCLC). A cohort of 785 Chinese patients with NSCLC who underwent resection from March 2016 to November 2017 in the First Affiliated Hospital of Guangzhou Medical University was investigated. The specimens were subjected to hybridization capture and sequence of 8 important NSCLC-related driver genes. In addition, the slides were tested for PD-L1, excision repair cross-complementation group 1 (ERCC1), ribonucleotide reductase subunit M1 (RRM1), thymidylate synthase (TS) and β-tubulin III by immunohistochemical staining. A total of 498 (63.4%) patients had at least 1 driver gene alteration. Wild-type, EGFR rare mutation (mut), ALK fusion (fus), RAS mut, RET fus and MET mut had relatively higher proportions of lower ERCC1 expression. EGFR 19del, EGFR L858R, EGFR rare mut, ALK fus, HER2 mut, ROS1 fus and MET mut were more likely to have TS low expression. Wild-type, EGFR L858R, EGFR rare mut and BRAF mut were associated with lower β-tubulin III expression. In addition, wild-type, RAS mut, ROS1 fus, BRAF and MET mut had higher proportion of PD-L1 high expression. As a pilot validation, 21 wild-type patients with advanced NSCLC showed better depth of response and response rate to taxanes compared with pemetrexed/gemcitabine (31.2%/60.0% vs 26.6%/45.5%). Our study may aid in selecting the optimal salvage regimen after targeted therapy failure, or the chemo-regimen where targeted therapy has not been a routine option. Further validation is warranted.
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http://dx.doi.org/10.1111/cas.14032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6549909PMC
June 2019

PD-(L)1 inhibitors vs. chemotherapy vs. their combination in front-line treatment for NSCLC: An indirect comparison.

Int J Cancer 2019 12 10;145(11):3011-3021. Epub 2019 May 10.

Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, Guangzhou, China.

We comprehensively compared the therapeutic effects and safety of PD-1/L1 antibodies (I), chemotherapy (C) or their combination (I + C) as first-line treatments for advanced NSCLC. Online databases were searched to identify RCTs. Survival outcomes and safety events were pooled by indirect treatment comparison. Main subgroup analyses were conducted according to PD-L1 expression. A total of 11 RCTs involving 6,731 patients were included. Overall, PD-1/L1 inhibitors showed no difference to chemotherapy in PFS (HR 0.90, 0.65-1.24) and OS (HR 0.84, 0.64-1.09), while I + C was superior to chemotherapy both in PFS (HR 0.64, 0.58-0.71) and OS (HR 0.74, 0.62-0.89). I + C also showed advantages over PD-1/L1 in PFS (HR 0.71, 0.51-0.99) but not OS (HR 0.88, 0.64-1.22). In the PD-L1 < 1% subgroup, I + C was beneficial both in OS (HR 0.78, 0.67-0.90) and PFS (HR 0.72, 0.65-0.80) than chemotherapy. In PD-L1 ≥ 50% population, PD-1/L1 had longer OS than chemotherapy (HR 0.71, 0.60-0.84); I + C also had longer OS (HR 0.61, 0.49-0.77) and PFS (HR 0.41,0.34-0.49) than chemotherapy. In indirect analysis (PD-L1 ≥ 50%), I + C was superior to PD-1/L1 in terms of PFS (HR 0.54, 0.35-0.82), but not OS (HR 0.86, 0.65-1.14). Both treatment-related and immune-mediated adverse events occurred most frequently in the combination therapy group. We suggest that a combination regimen is preferable as first-line treatment for NSCLC patients with different PD-L1 expression, in the meanwhile, in cautious of side effects.
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http://dx.doi.org/10.1002/ijc.32366DOI Listing
December 2019

Erratum: The association between human papillomavirus presence and epidermal growth factor receptor mutations in Asian patients with non-small cell lung cancer.

Transl Lung Cancer Res 2018 09;7(Suppl 3):S302

Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China.

[This corrects the article DOI: 10.21037/tlcr.2018.03.16.].
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http://dx.doi.org/10.21037/tlcr.2018.07.14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6193910PMC
September 2018

The association between human papillomavirus presence and epidermal growth factor receptor mutations in Asian patients with non-small cell lung cancer.

Transl Lung Cancer Res 2018 Jun;7(3):397-403

Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China.

Background: The etiology of non-small cell lung cancer (NSCLC) in non-smoker patients remains largely unknown. It has been widely proved that human papillomavirus (HPV) participates in the development of various cancers. Epidermal growth factor receptor (EGFR) mutation patients represent a large portion of non-smokers with NSCLC. We performed this meta-analysis to determine whether HPV infection in NSCLC tissue is associated with EGFR mutations compared with HPV negative controls.

Methods: Online databases were searched up to June 30th 2017. We included studies in which HPV detection was based on polymerase chain reaction (PCR) methods. Random effects model was used in data synthesis and the relative effects were presented as odds ratio (OR) with 95% confidence intervals (CIs).

Results: Finally, four eligible studies with a total of 498 patients from Asian countries were identified and included. The general EFGR mutation positive rate was 38.2% among all patients, and the HPV DNA detection rate (HPV subtype being involved: 16, 18, 33 and 58) was 35.3%. The presence of EGFR mutation was significantly higher in HPV-positive patients compared with HPV-negative controls (52% 31%; OR =2.41, 95% CI: 1.21 to 4.77; P=0.012), with moderate heterogeneity among studies (I=59%; P=0.062).

Conclusions: Our results suggest that HPV infection is associated with EGFR mutations in NSCLC, at least in Asian populations. Further efforts should be made on exploring the potential mechanism and the prognostic character of HPV/EGFR positive NSCLC patient.
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http://dx.doi.org/10.21037/tlcr.2018.03.16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6037964PMC
June 2018

Dynamic imaging and pathological changes in pig liver after MR-guided microwave ablation.

BMC Cancer 2018 04 6;18(1):397. Epub 2018 Apr 6.

Department of Medical Imaging & Image Guided Therapy, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, East Dong Feng Road 651, Guangzhou, Guangdong, 510060, People's Republic of China.

Background: Magnetic resonance (MR)-guided microwave ablation is a well-developed technique for the treatment of tumors, especially hepatic carcinomas. However, there are no detailed reports on the changes in the MR images and histology observed after the ablation. This study aimed to dynamically map the pathological changes after ablation and the changes occurring on MR images.

Methods: We performed MR-guided microwave ablation in 10 Wuzhishan pigs and obtained an MR scan immediately after ablation (0 weeks) and at 1, 2, 3, and 4 weeks after ablation. We compared the ablation assessed on MR images to tissue specimens obtained during follow-up.

Results: We found no significant difference in the ablation size between MR images and tissue specimens; the mean length and width of the ablated zone were 4.27 cm and 2.42 cm, respectively, on MR images and 4.26 cm and 2.45 cm, respectively, on specimens (P > 0.05). Immediately after ablation, carbonization and cavities were observed in the center of the ablation zone. Surrounding layer cells were necrotic but maintained their original shapes. The outermost layer was inflamed, but gradually showed fibrotic characteristics. The MR images accurately reflected the exact histological tissue changes after the ablation procedure.

Conclusion: The dynamic imaging and pathological features of liver ablation outlined in this study will provide a useful reference for patient follow-up after MR-guided microwave ablation.
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http://dx.doi.org/10.1186/s12885-018-4157-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5889530PMC
April 2018

Hepatic arterial infusion of oxaliplatin plus fluorouracil/leucovorin vs. sorafenib for advanced hepatocellular carcinoma.

J Hepatol 2018 07 20;69(1):60-69. Epub 2018 Feb 20.

Minimally Invasive Interventional Division, Department of Medical Imaging and Interventional Radiology, Sun Yat-sen University Cancer Center, Guangzhou, China. Electronic address:

Background & Aims: To compare the overall survival (OS) and disease progression free survival (PFS) in patients with advanced hepatocellular carcinoma (Ad-HCC) who are undergoing hepatic arterial infusion (HAI) of oxaliplatin, fluorouracil/leucovorin (FOLFOX) treatment vs. sorafenib.

Methods: This retrospective study was approved by the ethical review committee, and informed consent was obtained from all patients before treatment. HAI of FOLFOX (HAIF) was recommended as an alternative treatment option for patients who refused sorafenib. Of the 412 patients with Ad-HCC (376 men and 36 women) between Jan 2012 to Dec 2015, 232 patients were treated with sorafenib; 180 patients were given HAIF therapy. The median age was 51 years (range, 16-82 years). Propensity-score matched estimates were used to reduce bias when evaluating survival. Survival curves were calculated by performing the Kaplan-Meier method and compared by using the log-rank test and Cox regression models.

Results: The median PFS and OS in the HAIF group were significantly longer than those in the sorafenib group (PFS 7.1 vs. 3.3 months [RECIST]/7.4 vs. 3.6 months [mRECIST], respectively; OS 14.5 vs. 7.0 months; p <0.001 for each). In the propensity-score matched cohorts (147 pairs), both PFS and OS in the HAIF group were longer than those in the sorafenib group (p <0.001). At multivariate analysis, HAIF treatment was an independent factor for PFS (hazard ratio [HR] 0.389 [RECIST]/0.402 [mRECIST]; p <0.001 for each) and OS (HR 0.129; p <0.001).

Conclusion: HAIF therapy may improve survival compared to sorafenib in patients with Ad-HCC. A prospective randomized trial is ongoing to confirm this finding.

Lay Summary: We compared the hepatic arterial infusion of FOLFOX (a combination chemotherapy) with sorafenib (a tyrosine kinase inhibitor) in patients with advanced hepatocellular carcinoma, retrospectively. It was found that hepatic arterial infusion of FOLFOX therapy may improve both progression free and overall survival in patients with advanced hepatocellular carcinoma.
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http://dx.doi.org/10.1016/j.jhep.2018.02.008DOI Listing
July 2018

Chloroquine exerts antitumor effects on NB4 acute promyelocytic leukemia cells and functions synergistically with arsenic trioxide.

Oncol Lett 2018 Feb 24;15(2):2024-2030. Epub 2017 Nov 24.

Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong 510060, P.R. China.

Chloroquine (CQ) has been confirmed to exhibit antitumor effects on different types of cancer cell, but whether it exerts the same effect on acute promyelocytic leukemia (APL) cells remains to be confirmed. In the present study, the effects of various concentrations of CQ on the growth, apoptosis and cell cycle distribution of NB4 cells, as well as the potential mechanisms underlying these effects, were examined. The combined effect of CQ and arsenic trioxide (ATO) on the growth of NB4 cells was also determined. The results of the present study demonstrated that CQ treatment inhibited cell proliferation, and induced mitochondrial pathway apoptosis and S phase arrest in a dose-dependent manner by regulating apoptosis- and cell cycle-related proteins. CQ and ATO had a synergistic effect on the growth inhibition of NB4 cells, which may have been induced through the inhibition of autophagy. In conclusion, the results of the present study indicated that CQ exhibits a cytotoxic effect on NB4 cells and has a synergistic effect when combined with ATO, which thereby improves the curative effect of ATO on APL.
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http://dx.doi.org/10.3892/ol.2017.7488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5774501PMC
February 2018

CAR-T cells targeting CLL-1 as an approach to treat acute myeloid leukemia.

J Hematol Oncol 2018 01 10;11(1). Epub 2018 Jan 10.

State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China.

Background: Acute myeloid leukemia (AML) is one of the most common types of adult acute leukemia. Standard chemotherapies can induce complete remission in selected patients; however, a majority of patients eventually relapse and succumb to the disease. Thus, the development of novel therapeutics for AML is urgently needed. Human C-type lectin-like molecule-1 (CLL-1) is a type II transmembrane glycoprotein, and its expression is restricted to myeloid cells and the majority of AML blasts. Moreover, CLL-1 is expressed in leukemia stem cells (LSCs), but absent in hematopoietic stem cells (HSCs), which may provide a potential therapeutic target for AML treatment.

Methods: We tested the expression of CLL-1 antigen on peripheral blood cells and bone marrow cells in healthy donor and AML patients. Then, we developed a chimeric antigen receptor (CAR) containing a CLL1-specific single-chain variable fragment, in combination with CD28, 4-1BB costimulatory domains, and CD3-ζ signaling domain. We further investigate the function of CLL-1 CAR-T cells.

Results: The CLL-1 CAR-T cells specifically lysed CLL-1 cell lines as well as primary AML patient samples in vitro. Strong anti-leukemic activity was observed in vivo by using a xenograft model of disseminated AML. Importantly, CLL-1 myeloid progenitor cells and mature myeloid cells were specifically eliminated by CLL-1 CAR-T cells, while normal HSCs were not targeted due to the lack of CLL-1 expression.

Conclusions: CLL-1 CAR-T represents a promising immunotherapy for the treatment of AML.
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http://dx.doi.org/10.1186/s13045-017-0553-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5761206PMC
January 2018