Publications by authors named "Meijuan Huang"

86 Publications

Case Report: Outcome of Osimertinib Treatment in Lung Adenocarcinoma Patients With Acquired KRAS Mutations.

Front Oncol 2021 22;11:630256. Epub 2021 Apr 22.

Department of Thoracic Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China.

Background: Osimertinib belongs to the third-generation epidermal growth factor receptor tyrosine kinase inhibitor that has shown positive effects in treating lung adenocarcinoma cancer. However, the subsequent resistance to Osimertinib has become a clinical challenge.

Case Presentation: We present two lung adenocarcinoma cases that developed a resistance to Osimertinib. Among them, one patient attained both KRAS exon 2 and exon 3 mutations and was given paclitaxel (albumin-bound) plus carboplatin. The other patient exhibited a KRAS exon 3 mutation, so the paclitaxel (albumin-bound) plus nivolumab was administered. Eventually, the second patient manifested a better clinical outcome than the first.

Conclusion: These results provide supporting evidence that KRAS exon 3 (R68S) mutations may be associated with Osimertinib resistance in lung adenocarcinoma patients. This further reveals the relationship between subtypes of acquired KRAS mutations and the effect of therapeutic approaches. Moreover, the combination of chemotherapy and immune checkpoint inhibitors may generate a satisfying disease control.
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http://dx.doi.org/10.3389/fonc.2021.630256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100222PMC
April 2021

The influence of STK11 mutation on acquired resistance to immunotherapy in advanced non-small cell lung cancer with Lynch syndrome: a case report and literature review.

Ann Palliat Med 2021 Mar 23. Epub 2021 Mar 23.

Department of Thoracic Oncology, Cancer Center, West China Hospital, Medical School, Sichuan University, Chengdu, China.

Immune checkpoint inhibitors (ICI) monotherapy or combination therapies have become increasingly popular in patients with advanced non-small cell lung cancer (NSCLC). However, there are still many unknowns concerning the predictive bio-markers and resistance mechanisms to immunotherapy. Patients with primary tumor STK11 mutation reportedly to have a lower response rate than the STK11 wildtype and possibly a primary resistance mechanism to ICIs. However, there is presently no data regarding the contribution of STK11 to acquired resistance to ICIs. Herein we report on a patient who was diagnosed with advanced lung squamous cell carcinoma accompanied by Lynch syndrome. The patient developed an STK11 mutation after receiving pembrolizumab as a first-line treatment. Programmed death ligand 1 (PD-L1) was highly expressed (50%) in the biopsy. HRAS Q61L and TP53 R158L were mainly detected. Unexpectedly, the patient carried an MSH6 heterozygous germline mutation, and was classified as proficient mismatch repair (pMMR). The patient subsequently received pembrolizumab (200 mg, ivgtt, q3w) as first line therapy and achieved stable disease (SD) as the best response. After eight treatment cycles, the patient suffered disease progression (PD), and an STK11 frameshift mutation was newly identified in his plasma circulating tumor deoxyribonucleic acid (ctDNA). This case study suggests that STK11 could contribute to pembrolizumab acquired resistance. Furthermore, the patient was also diagnosed with Lynch syndrome, which rarely occurs in lung cancer.
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http://dx.doi.org/10.21037/apm-20-1639DOI Listing
March 2021

Complete chloroplast genomes of Impatiens cyanantha and Impatiens monticola: Insights into genome structures, mutational hotspots, comparative and phylogenetic analysis with its congeneric species.

PLoS One 2021 2;16(4):e0248182. Epub 2021 Apr 2.

College of Landscape Architecture and Horticultural Science, Southwest Forestry University, Kunming, China.

Impatiens L., the largest genus in the family Balsaminaceae with approximately 1000 species, is a controversial and complex genus that includes many economically important species well known for medicinal and ornamental values. However, there is limited knowledge of molecular phylogeny and chloroplast genomics, and uncertainties still exist at a taxonomic level. In this study, we have assembled four chloroplast genomics specimens of Impatiens cyanantha and Impatiens monticola, which are found at the different altitudes of Guizhou and Yunnan in China, and compared them with previously published three wild Balsaminaceae species (Impatiens piufanensis, Impatiens glandlifera, and Hydrocera triflora). The complete chloroplast genome sequences ranged from 152,236 bp (I. piufanensis) to 154,189 bp (H. triflora) and encoded 115 total distinct genes, of which 81 were protein-coding, 30 were distinct transfer RNA genes(tRNA), and 4 were ribosomal RNA genes (rRNA). A comparative analysis of I. cyanantha (Guizhou) vs. I. cyanantha (Yunnan) and I. monticola (Guizhou) vs. I. monticola (Yunnan) revealed minor changes in lengths; however, similar gene contents, gene orders, and GC contents existed among them. Interestingly, highly coding and non-coding genes, and regions matK, psbK, atpH-atpI, trnC-trnT, petN, psbM, atpE, rbcL, accD, psaL, rps3-rps19, ndhG-ndhA,rpl16, rpoB, ndhB, ndhF, ycf1, and ndhH were found, which could be suitable for identification of species and phylogenetic studies. During the comparison between I. cyanantha (Guizhou) and I. cyanantha (Yunnan), we observed that the rps4, ycf2, ndhF, ycf1, and rpoC2 genes underwent positive selection. Meanwhile, in the comparative study of I. monticola (Guizhou) vs. I. monticola (Yunnan), The accD and ycf1 genes were positively selected. Additionally, phylogenetic relationships based on maximum likelihood (ML) and Bayesian inference (BI) among whole chloroplast genomes showed that a sister relationship with I. monticola (Guizhou) and I. monticola (Yunnan) formed a clade with I.piufanensis proving their close connection. Besides, I.cyanantha (Guizhou) and I. cyanantha (Yunnan) formed a clade with I. glandlifera. Along with the findings and the results, the current study might provide valuable significant genomic resources for systematics and evolution of the genus impatiens in different altitudes of regions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0248182PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018631PMC
April 2021

Docetaxel maintenance therapy versus best supportive care after first-line chemotherapy with different dose docetaxel plus cisplatin for advanced non-small cell lung cancer (TFINE study, CTONG-0904): an open-label, randomized, phase III trial.

Ann Transl Med 2021 Feb;9(4):338

Sanofi (China) Investment Co., Ltd. Shanghai Branch, Shanghai, China.

Background: Maintenance therapy is important in the management of advanced non-small cell lung cancer (NSCLC). The present TFINE study assessed the efficacy and safety of docetaxel continuation maintenance (DCM) therapy after first-line treatment with different doses of docetaxel plus cisplatin.

Methods: In this open-label, randomized, phase III study, newly diagnosed patients with advanced NSCLC were initially randomized (R1, 1:1) to receive first-line treatment with cisplatin 75 mg/m plus docetaxel 75 mg/m (DC75) or 60 mg/m (DC60) for up to 4 cycles. Patients without progression were further randomized (R2, 1:2) to best supportive care (BSC) or DCM (60 mg/m) for up to 6 cycles. The primary endpoint was progression-free survival (PFS) after R2, and the secondary endpoints included best response rate in first-line treatment, overall survival (OS), time to progression (TTP), and toxicities.

Results: A total of 375 patients were enrolled in R1 and 184 of these patients continued in R2. DCM significantly prolonged PFS compared to BSC (HR =0.57, median PFS =5.8 . 3.0 months, P=0.002). The response rates were 30.2% and 23.9% in the DC75 and DC60 groups, respectively (P=0.17). There was no significant difference in OS (12.3 . 13.7 months, P=0.77). Additionally, 47.8% and 45.7% of patients reported AEs in the DC75 and DC60 groups, respectively. Diarrhea was more frequent with DC75 than with DC60 (8.6% . 3.2%, P=0.029). Other toxicities were comparable between the 2 docetaxel dose groups.

Conclusions: Continuation maintenance treatment with docetaxel is well tolerated and improves PFS in patients with NSCLC. The docetaxel dose of 60 mg/m may be preferred due to similar efficacy and less diarrhea.

Trial Registration: NCT01038661.
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http://dx.doi.org/10.21037/atm-20-8078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944306PMC
February 2021

Prognostic significance of epigenetic regulatory gene expression in patients with non-small-cell lung cancer.

Aging (Albany NY) 2021 02 26;13(5):7397-7415. Epub 2021 Feb 26.

Department of Thoracic Oncology, West China Hospital of Sichuan University, Chengdu 610041, Sichuan, P.R. China.

In this study, we used public databases to investigate the prognostic significance of epigenetic regulatory gene expression in patients with non small-cell lung cancer (NSCLC). Oncomine database analysis showed that the mRNA levels of seven epigenetic regulatory genes, and , genes were significantly upregulated in NSCLC patients as compared to normal lung tissues. Functional enrichment analysis of these seven genes showed that the most enriched GO terms were DNA repair and rhythmic process, whereas, the most enriched KEGG pathway was lysine degradation pathway. The mRNA and protein expression levels of UHRF1, EZH2, TTF2, WHSC1 and RAD54L significantly correlated with tumor stage in NSCLC patients. Moreover, NSCLC patients exhibiting higher UHRF1, EZH2, WHSC1 and RAD54L mRNA and protein expression levels had poorer progression-free survival and overall survival. These findings demonstrate that UHRF1, EZH2, WHSC1 and RAD54L are potential prognostic biomarkers to distinguish high-risk from low-risk NSCLC patients.
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http://dx.doi.org/10.18632/aging.202600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993691PMC
February 2021

Changes of Brain Structure in Patients With Metastatic Non-Small Cell Lung Cancer After Long-Term Target Therapy With EGFR-TKI.

Front Oncol 2020 6;10:573512. Epub 2021 Jan 6.

Department of Thoracic Oncology and State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, China.

Purpose: Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy is the routine treatment for patients with metastatic non-small cell lung cancer (NSCLC) harboring positive EGFR mutations. Patients who undergo such treatment have reported cognitive decline during follow-up. This study, therefore, aimed to evaluate brain structural changes in patients receiving EGFR-TKI to increase understanding of this potential symptom.

Method: The medical records of 75 patients with metastatic NSCLC (without brain metastasis or other co-morbidities) who received EGFR-TKI therapy from 2010 to 2017 were reviewed. The modified Scheltens Visual Scale and voxel-based morphometry were used to evaluate changes in white matter lesions (WML) and gray matter volume (GMV), respectively.

Results: The WML scores were higher at the 12-month [8.65 ± 3.86; 95% confidence interval (CI), 1.60-2.35; p < 0.001] and 24-month follow-ups (10.11 ± 3.85; 95% CI, 2.98-3.87; p < 0.001) compared to baseline (6.68 ± 3.64). At the 24-month follow-up, the visual scores were also significantly higher in younger patients (3.89 ± 2.04) than in older patients (3.00 ± 1.78; p = 0.047) and higher in female patients (3.80 ± 2.04) than in male patients (2.73 ± 1.56; p = 0.023). Additionally, significant GMV loss was observed in sub-regions of the right occipital lobe (76.71 voxels; 95% CI, 40.740-112.69 voxels), left occipital lobe (93.48 voxels; 95% CI, 37.48-149.47 voxels), and left basal ganglia (37.57 voxels; 95% CI, 21.58-53.57 voxels) (all p < 0.005; cluster-level false discovery rate < 0.05).

Conclusions: An increase in WMLs and loss of GMV were observed in patients with metastatic NSCLC undergoing long-term EGFR-TKI treatment. This might reflect an unknown side-effect of EGFR-TKI treatment. Further prospective studies are necessary to confirm our findings.
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http://dx.doi.org/10.3389/fonc.2020.573512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815525PMC
January 2021

Distribution and therapeutic outcomes of intergenic sequence-ALK fusion and coexisting ALK fusions in lung adenocarcinoma patients.

Lung Cancer 2021 02 9;152:104-108. Epub 2021 Jan 9.

Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, PR China. Electronic address:

Introduction: Patients with ALK rearranged non-small-cell lung cancer (NSCLC) show survival benefits from tyrosine-kinase inhibitor (TKI). Widely application of DNA sequencing revealed various rearrangement pattern in addition to single EML4-ALK fusion. Here, we retrospectively analyzed the distribution and coexistence of ALK rearrangement and therapeutic outcome of patients with ALK rearranged NSCLC.

Method: ALK positive NSCLC patients were screened at West China Hospital. NGS was performed on pre-treatment samples. Clinical characteristics and therapeutic outcomes were collected to retrospectively analyzed.

Results: Among the 89 patients with 22 ALK rearrangements, fusions of intergenic sequences with ALK were found in 15 (16.85 %). Non-EML4-ALK fusions were present in 18 patients (20.22 %). Coexistence of rearrangements were present in 16 patients (17.98 %). Intergenic sequence-ALK and non-EML4-ALK fusions occurred at higher rates in patients with at least two fusions (62.5 % versus 6.85 % for intergenic sequence-ALK, 62.5 % versus 10.96 % for non-EML4-ALK). There were 40 ALK-rearranged NSCLC patients receiving the first-line crizotinib. The median progression-free survival (PFS) was 9.7 months when excluding three lost patients. In the seven patients who had at least two fusions, the median PFS was 11.9 months, compared with 9.0 months among those with single (p = 0.336). No significant difference in median PFS was found between patients with and without intergenic-ALK fusion (12.0 months versus 9.6 months, p = 0.989). The median PFS was 9.0 months in patients harboring a single EML4-ALK fusion versus 13.0 months in those with other ALK alterations (P = 0.890). The PFS of patients with single intergenic sequence-ALK fusion reached to 2.9 months, 27 months, and 28.9 months respectively.

Conclusion: Our study reports the distribution of intergenic sequence-ALK and coexisting fusions in ALK-rearranged NSCLC. Intergenic sequence-ALK and non-EML4-ALK are prone to coexist with other fusions. Neither intergenic sequence-ALK nor coexistence of fusions had a significant effect on the therapeutic benefit of treatment with crizotinib.
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http://dx.doi.org/10.1016/j.lungcan.2020.12.018DOI Listing
February 2021

Fueling chimeric antigen receptor T cells with cytokines.

Am J Cancer Res 2020 1;10(12):4038-4055. Epub 2020 Dec 1.

Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan, Hubei, China.

Chimeric antigen receptor (CAR)-T therapy started a new era of tumor treatment, especially for hematological malignancies. However, many challenges remain, including low-level proliferation and short-term persistence, insufficient CAR T-cell trafficking, suppressive tumor microenvironment (TME), frequent adverse events and the unaffordable manufacturing process. Cytokines are pleiotropic hormones involved in multiple processes of immunity, including activation, expansion, differentiation, and migration of immune cells. Both pre-clinical models and clinical trials showed that armoring CAR-T cells with cytokines strengthened the anti-tumor responses of CAR T cells. This review looked into the key role of cytokines as a promoter of anti-tumor activities of CAR-T cells and consequently a facilitator of clinical translation, mainly, from cytokines of the common γ-chains family, chemokines and chemokine receptors, immunosuppressive molecules and pro-inflammatory cytokines.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783740PMC
December 2020

The complete chloroplast genome sequence of horticultural plant, (Sect. Balsaminacea, Impatiens).

Mitochondrial DNA B Resour 2019 Dec 11;5(1):119-120. Epub 2019 Dec 11.

College of Landscape Architecture and Horticultural Science, Southwest Forestry University, Kunming, China.

The complete chloroplast genome sequence of , a widely cultivated horticultural species in the world is 151,692 bp, with a typical quadripartite structure including a pair of inverted repeat (IRs, 25,584 bp) regions separated by a small single copy (SSC, 17,494 bp) region and a large single copy (LSC, 83,029 bp) region. The overall GC content of plastid genome was 36.8%. The whole chloroplast genome contains 135 genes, including 89 protein-coding genes (PCGs), 38 transfer RNA genes(tRNAs), and 8 ribosomal RNA genes (rRNAs). Among these genes, 15 genes have one intron and 2 genes contain two introns. To investigate its evolution status, the phylogenetic tree based on APGIII reveal that there are close relationships to the same genus species and .
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http://dx.doi.org/10.1080/23802359.2019.1698339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721014PMC
December 2019

The complete chloroplast genome of Franch., an endemic species in Southwest China.

Mitochondrial DNA B Resour 2019 Nov 6;4(2):3846-3847. Epub 2019 Nov 6.

College of Landscape Architecture, Southwest Forestry University, Kunming, China.

The complete chloroplast genome sequence of Franch., an endemic species in Southwest China, we research genetic and phylogenetic relationship with other species in an effort to provide genomic resources useful for promoting its conservation and utilization. The total chloroplast genome size of is 152,609 bp, with a typical quadripartite structure including a pair of inverted repeat (IRs, 25,871 bp) regions separated by a small single copy (SSC, 17,502 bp) region and a large single copy (LSC, 83,365 bp) region. The overall GC content of plastid genome was 36.8%. The whole chloroplast genome contains 136 genes, including 89 protein-coding genes (PCGs), 38 transfer RNA genes (tRNAs), and 8 ribosomal RNA genes (rRNAs). Among these genes, 15 genes have one intron and 2 genes contain two introns. To investigate the evolution status, the phylogenetic tree based on APG III from 12 complete chloroplast plastomes of Ericales supports close relationships. According to the phylogenetic topologies, was closely related to
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http://dx.doi.org/10.1080/23802359.2019.1687024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7707457PMC
November 2019

Efficacy and Biomarker Analysis of Camrelizumab in Combination with Apatinib in Patients with Advanced Nonsquamous NSCLC Previously Treated with Chemotherapy.

Clin Cancer Res 2021 Mar 15;27(5):1296-1304. Epub 2020 Dec 15.

Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University, Shanghai, P.R. China.

Purpose: Our preclinical work suggests that appropriate angiogenesis inhibition could potentiate PD-1/PD-L1 blockade via alleviating hypoxia, increasing infiltration of CD8 T cells and reducing recruitment of tumor-associated macrophages. We hereby conducted a clinical trial to evaluate this combination in pretreated patients with advanced non-small cell lung cancer (NSCLC).

Patients And Methods: The study included phase Ib apatinib dose-escalation and phase II expansion cohorts. Patients received apatinib at doses of 250-500 mg orally once daily, in combination with camrelizumab 200 mg intravenously every 2 weeks.

Results: From March 2017 to October 2018, 105 chemotherapy-pretreated patients with nonsquamous NSCLC were enrolled and received apatinib 250 mg (recommended phase II dose) and camrelizumab. Among them, one (1.0%) complete response, 28 (26.7%) partial responses, and 48 (45.7%) stable diseases were observed. In the efficacy-evaluable population ( = 94), objective response rate (ORR) was 30.9% [95% confidence interval (CI), 21.7-41.2]. The median progression-free survival was 5.7 months (95% CI, 4.5-8.8) and overall survival was 15.5 months (95% CI, 10.9-24.5). Efficacy of combination therapy was evident across all PD-L1 and tumor mutation burden subgroups, and appeared to be improved in patients with STK11/KEAP1 mutation (mutant vs. wild-type, ORR: 42.9% vs. 28.1%; 1-year survival rate: 85.1% vs. 53.1%). No unexpected adverse events were observed.

Conclusions: Combined apatinib and camrelizumab showed encouraging antitumor activity and acceptable toxicity in chemotherapy-pretreated patients with advanced nonsquamous NSCLC. Patients with STK11/KEAP1 mutation might derive more benefits from this combination. We will validate these results in an ongoing phase III trial (NCT04203485).
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3136DOI Listing
March 2021

Efficacy and safety of eltrombopag in Chinese patients with chronic immune thrombocytopenia: stage 2 results from a multicenter phase III study.

Platelets 2020 Nov 29:1-7. Epub 2020 Nov 29.

Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences, Tianjin, China.

This phase III, randomized, placebo-controlled study conducted in three stages (6-week, randomized, placebo-controlled stage 1; 24-week, open-label stage 2; and continuous extension stage 3) assessed the long-term efficacy and safety of eltrombopag use in Chinese patients with chronic immune thrombocytopenia (ITP). This article presents the results from stage 2. Overall, 150 patients (placebo-eltrombopag [P-E], 50; eltrombopag-eltrombopag [E-E], 100) received open-label eltrombopag. The median platelet count was maintained between 41 × 10/L and 80 × 10/L. Most patients in both groups (P-E, 90.0%; E-E, 81.8%) achieved platelet counts ≥30 × 10/L and ≥2 times the baseline platelet count at least once with eltrombopag treatment. Overall, 32% of patients achieved platelet counts ≥50 × 10/L in ≥75% of platelet count assessments. Both groups showed a decreased tendency to infrequent bleeding and clinically significant bleeding events during stage 2 compared with baseline. Among patients who received ≥1 ITP medication at baseline, 70.4% in the P-E group and 40.8% in the E-E group reduced or permanently stopped ≥1 of their ITP medications. The stage 2 results further demonstrated a sustainable long-term efficacy and good tolerability of eltrombopag with a favorable benefit-risk ratio in Chinese chronic ITP patients.Trial registration: Clinicaltrials.gov NCT01762761. Registered 8 January 2013, https://clinicaltrials.gov/ct2/show/NCT01762761.
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http://dx.doi.org/10.1080/09537104.2020.1847267DOI Listing
November 2020

Applicability of the adjusted graded prognostic assessment for lung cancer with brain metastases using molecular markers (Lung-molGPA) in a Chinese cohort: A retrospective study of multiple institutions.

Cancer Med 2020 12 7;9(23):8772-8781. Epub 2020 Oct 7.

Department of Thoracic Oncology, Cancer Centre, Sichuan University West China Hospital, Chengdu, Sichuan, P.R. China.

Background: In this era of precision medicine, prognostic heterogeneity is an important feature of patients with non-small cell lung cancer (NSCLC) with brain metastases (BM). This multi-institutional study is aimed to verify the applicability of the adjusted Lung-molGPA model for NSCLC with BM in a Chinese cohort.

Methods: This retrospective study included 1903 patients at three hospitals in Southwest China. The performance of the Lung-molGPA model was compared with that of the adjusted DS-GPA model in terms of estimating the survival of NSCLC with BM.

Results: The median OS of this patient cohort was 27.0 months, and the adenocarcinoma survived longer than the non-adenocarcinoma (28.0 months vs 18.7 months, p < 0.001). The adjusted Lung-molGPA model was more accurate in predicting survival of adenocarcinoma patients than the adjusted DS-GPA model (C-index: 0.615 vs 0.571), and it was not suitable for predicting survival of non-adenocarcinoma patients (p = 0.286, 1.5-2.0 vs 2.5-3.0; p = 0.410, 2.5-3.0 vs 3.5-4.0).

Conclusions: The adjusted Lung-molGPA model is better than the DS-GPA model in predicting the prognosis of adenocarcinoma patients. However, it failed to estimate the prognosis for non-adenocarcinoma patients.
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http://dx.doi.org/10.1002/cam4.3485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724493PMC
December 2020

PD-L1 expression is a promising predictor of survival in patients with advanced lung adenocarcinoma undergoing pemetrexed maintenance therapy.

Sci Rep 2020 09 30;10(1):16150. Epub 2020 Sep 30.

Department of Thoracic Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China.

This study aimed to identify potential predictive factors for the survival of advanced lung adenocarcinoma patients undergoing pemetrexed maintenance therapy. 122 advanced lung adenocarcinoma patients who received pemetrexed maintenance therapy were retrospectively analyzed. Kaplan-Meier method with Log-rank test was used for survival analysis. Univariate and multivariate Cox regression were performed to evaluate prognostic factors for overall survival (OS) and progression-free survival (PFS). Bivariate correlation analysis was used for exploratory purpose. For the whole cohort of 122 patients, median PFS was 11.97 months (95% CI 10.611-13.329) and estimated median OS was 45.07 months (95% CI 31.690-58.450). The mPFS of ALK-positive patients was superior to negative patients (18.27 vs. 11.90 months; P  = 0.039). Patients with ECOG PS 0 (14.4 vs. 11.1 months; p = 0.040) and patients with single-organ metastasis (19.0 vs. 11.0 months; p = 0.014) had prolonged median PFS. Compared with the low PD-L1 expression group, PFS of high PD-L1 expression group were improved (13.6 vs. 11.1 months, p = 0.104, at 1% cut-off; 17.5 vs. 11.1 months, p = 0.009, at 10% cut-off; and 27.5 vs. 11.4 months, p = 0.005, at 50% cut-off). No differences were found between EGFR positive and negative patients. PD-L1 expression was an independent prognostic factor for both PFS and OS times (PFS: HR, 0.175; P  = 0.001; OS: HR, 0.107; P  = 0.036). Bivariate correlation showed a significant positive correlation between PD-L1 expression and PFS (correlation coefficient R = 0.485, P  < 0.001). High PD-L1 expression could be a potential effective predictor for favorable survival of advanced lung adenocarcinoma patients undergoing pemetrexed maintenance therapy.
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http://dx.doi.org/10.1038/s41598-020-73013-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527332PMC
September 2020

Coexisting of and Acquired in a Lung Adenocarcinoma with Rearrangements Loss During the Treatment of Crizotinib and Ceritinib: A Case Report.

Onco Targets Ther 2020 20;13:8313-8316. Epub 2020 Aug 20.

Department of Thoracic Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, People's Republic of China.

ALK rearrangements account for ~5% of non-small-cell lung cancer (NSCLC). Numerous rearrangement partners have been discovered. Here, we describe a 53-year-old nonsmoker with NSCLC, in whom we identified four novel rearrangements. The patient was diagnosed as adenocarcinoma in the right middle lobe of lung, with metastases in subcarinal lymph node, ipsilateral lung, pleura and contralateral rib (cT4N2M1, stage IV). Next-generation sequencing (NGS) identified three baseline fusions: (C[intragenic]:A20), (L[intergenic]:A20) and (A9:A19). The patient exhibited 12 months of progression-free survival (PFS) and a partial response (PR) to first-line crizotinib therapy. We then discovered a new fusion (S[intergenic]:A18) and a missense mutation C1156Y after resistance developed. Sequential ceritinib resulted in further 8 months of PFS, after which NGS results demonstrated the loss of and . This is the first description a NSCLC patient harbors four fusions and was sensitive to tyrosine kinase inhibitors (TKIs). Acquisition and loss of fusions after inhibitors may account for resistance.
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http://dx.doi.org/10.2147/OTT.S258067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7445493PMC
August 2020

[Safety and Preliminary Efficacy of Ceritinib 450 mg with Food in Chinese ALK-positive Non-small Cell Lung Cancer].

Zhongguo Fei Ai Za Zhi 2020 Aug;23(8):655-661

Department of Medical Oncology, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610041, China.

Background: Anaplastic lymphoma kinase (ALK) rearrangement is a common driver gene of non-small cell lung cancer (NSCLC). Ceritinib is a second-generation ALK inhibitor, which can bring survival benefits to ALK-positive metastatic NSCLC. However, few studies focus on the safety and efficacy of ceritinib in China. Therefore, this study intends to investigate the safety and preliminary efficacy of ceritinib 450 mg with meals in Chinese patients with ALK-positive NSCLC through a real world study.

Methods: From October 2018 to December 2019, patients with ALK-positive NSCLC from 8 medical centers in Sichuan province were recruited in this study. All of these participants received ceritinib 450 mg/d with food. The basic characteristics, adverse effects (AEs) and responses were collected and analyzed in order to evaluate the safety and efficacy of ceritinib.

Results: A total of 109 patients were included in this study. Data cutoff was January 23, 2020. The median duration of treatment exposure was 5.87 mon (range: 0.4 mon-15.7 mon). Total AEs were reported in 98 (89.9%) of 109 patients and grade 3 or 4 AEs were reported in 22.9% of patients. Most common AEs (mainly grade 1 or 2) were diarrhea (60.6%), elevated alanine aminotransferase (ALT)(38.5%) and aspartate aminotransferase (AST)(37.6%). As of data cutoff, 45 patients discontinued ceritinib. The overall response rate (ORR) was 37.6% (95%CI: 28.5%-47.4%) and disease control rate (DCR) was 86.2% (95%CI: 78.3%-92.1%).

Conclusions: The treatment of ceritinib 450 mg with food for Chinese ALK-positive NSCLC patients had a good safety profile and favorable DCR in real-world setting. However, this conclusion needs to be further verified by large sample, prospective trials.
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http://dx.doi.org/10.3779/j.issn.1009-3419.2020.102.33DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7467981PMC
August 2020

Innovative strategies to advance CAR T cell therapy for solid tumors.

Am J Cancer Res 2020 1;10(7):1979-1992. Epub 2020 Jul 1.

Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan, China.

Current cancer treatment strategies have been advanced by chimeric antigen receptor (CAR) cell therapy, a rapidly emerging cellular immunotherapy. The numerous revolutionary achievements of CAR T cells against hematological malignancies initiated an upsurge in research on translating this therapy into a treatment for solid tumors. Unfortunately, no equivalent success has yet been achieved in treating solid tumors. The main challenges posed by solid tumors have gradually been recognized and include a lack of unique antigen targets, antigen heterogeneity, limited infiltration into the tumor, and an immunosuppressive tumor microenvironment. Surmounting the limitations of solid tumors remains critical in popularizing CAR T cell applications. Various approaches to augmenting the efficiency of CAR T cells through directly optimizing CAR constructs or through innovative combination strategies such as vaccines, biomaterials, and oncolytic virus have arisen. In addition to describing the main obstacles that restrict the promotion of CAR T cells, this paper focuses on reviewing new ongoing strategies to circumvent these limitations.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7407347PMC
July 2020

Durable complete response after afatinib and crizotinib in an advanced non-small cell lung cancer patient with EGFR L861Q mutation and acquired MET amplification: a case report.

Ann Palliat Med 2020 Sep 29;9(5):3609-3613. Epub 2020 Jun 29.

Department of Thoracic Oncology, Cancer Center, West China Hospital, Medical School, Sichuan University, Chengdu, China.

Epidermal growth factor receptor (EGFR) L861Q mutation is a non-classical mutation, with a low incidence, poor response, and uncertain resistance mechanisms when treated by an EGFR tyrosine kinase inhibitor (EGFR-TKI). The liver is one of the most common distant organs to metastasize in nonsmall cell lung cancer (NSCLC), and achieving complete remission treatment for the liver is difficult. In this report, a patient was diagnosed with advanced lung adenocarcinoma harboring the EGFR L861Q mutation and responded well to afatinib for 16 months. Complete response and partial response (PR) appeared in the liver metastasis and primary lesion respectively. Following this, afatinib plus crizotinib overcame the acquired resistance of MET amplification and brought about the complete remission of the liver for 10 months. Interestingly, the liver remission endured for 22 months and persisted even when the disease progressed and the EGFR T790M mutation emerged. To our knowledge, this is the first time that afatinib induced longterm liver remission in a patient with an EGFR non-classical mutation, and in whom crizotinib with afatinib proved to be a reliable treatment for overcoming MET amplification resistance with an EGFR non-classical mutation. This precise and individualized gene-based treatment significantly prolonged the survival time of this stage IV case with brain metastases yielding 26 months of progression-free survival (PFS) time and more than 3 years of overall survival time.
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http://dx.doi.org/10.21037/apm-19-482DOI Listing
September 2020

Publisher Correction: Safety and feasibility of CRISPR-edited T cells in patients with refractory non-small-cell lung cancer.

Nat Med 2020 Jul;26(7):1149

Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41591-020-0973-6DOI Listing
July 2020

Circulating tumor DNA clearance predicts prognosis across treatment regimen in a large real-world longitudinally monitored advanced non-small cell lung cancer cohort.

Transl Lung Cancer Res 2020 Apr;9(2):269-279

Burning Rock Biotech, Guangzhou 510300, China.

Background: Although growth advantage of certain clones would ultimately translate into a clinically visible disease progression, radiological imaging does not reflect clonal evolution at molecular level. Circulating tumor DNA (ctDNA), validated as a tool for mutation detection in lung cancer, could reflect dynamic molecular changes. We evaluated the utility of ctDNA as a predictive and a prognostic marker in disease monitoring of advanced non-small cell lung cancer (NSCLC) patients.

Methods: This is a multicenter prospective cohort study. We performed capture-based ultra-deep sequencing on longitudinal plasma samples utilizing a panel consisting of 168 NSCLC-related genes on 949 advanced NSCLC patients with driver mutations to monitor treatment responses and disease progression. The correlations between ctDNA and progression-free survival (PFS)/overall survival (OS) were performed on 248 patients undergoing various treatments with the minimum of 2 ctDNA tests.

Results: The results of this study revealed that higher ctDNA abundance (P=0.012) and mutation count (P=8.5×10) at baseline are associated with shorter OS. We also found that patients with ctDNA clearance, not just driver mutation clearance, at any point during the course of treatment were associated with longer PFS (P=2.2×10, HR 0.28) and OS (P=4.5×10, HR 0.19) regardless of type of treatment and evaluation schedule.

Conclusions: This prospective real-world study shows that ctDNA clearance during treatment may serve as predictive and prognostic marker across a wide spectrum of treatment regimens.
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http://dx.doi.org/10.21037/tlcr.2020.03.17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7225135PMC
April 2020

Effect of Low-Dose Radiation Therapy on Abscopal Responses to Hypofractionated Radiation Therapy and Anti-PD1 in Mice and Patients With Non-Small Cell Lung Cancer.

Int J Radiat Oncol Biol Phys 2020 09 15;108(1):212-224. Epub 2020 May 15.

Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China. Electronic address:

Purpose: Hypofractionated radiation therapy (HFRT) can induce antitumor T cell responses, particularly in combination with immune checkpoint inhibitors (ICI), but abscopal effects are often precluded by insufficient T cell infiltration of distant, nonirradiated tumors. Additional noncytotoxic, low-dose radiation therapy (LDRT) of distant tumors may enhance the abscopal response, but clinical evidence and preclinical studies for this scenario are lacking.

Methods And Materials: We investigated whether triple treatment consisting of HFRT, ICI, and LDRT could achieve better systemic antitumor response in bilateral mouse tumor models and in patients with stage IV non-small cell lung cancer.

Results: Our analyses of bilateral mouse tumor models show that HFRT treatment of the primary tumor combined with LDRT treatment of the abscopal tumor and anti-PD1 therapy enhances the abscopal response compared with HFRT/anti-PD1, HFRT/LDRT, or LDRT/anti-PD1 double treatments; complete cure was observed in more than half of the mice treated with triple therapy. The enhanced abscopal effect was associated with increased infiltration of CD8+ effector T cells and upregulated expression of T cell-attracting chemokines. Of 9 patients with metastatic non-small cell lung cancer who were treated with this triple therapy, 3 and 2 patients showed partial responses and stable disease, respectively. Among 9 relatively large (175.7 ± 42.3 cm) LDRT lesions, 6 lesions decreased by 28% in size, on average.

Conclusions: Our study demonstrates preclinically that LDRT of established metastases significantly enhances the abscopal response to HFRT plus ICI. It also shows that additional LDRT was well tolerated by patients and that this treatment profile is effective and worth further study.
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http://dx.doi.org/10.1016/j.ijrobp.2020.05.002DOI Listing
September 2020

Comparative Study of the Clinical Application of 2 Bleeding Grading Systems for Pregnant Women With Immune Thrombocytopenia.

Clin Appl Thromb Hemost 2020 Jan-Dec;26:1076029620910790

Department of Haematology, Fujian Institute of Haematology, Fujian Provincial Key Laboratory on Haematology, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China.

To compare the clinical practicability of two bleeding grading systems (BGS) in pregnancy with Immune Thrombocytopenia (ITP). The clinical data of 154 cases were retrospectively analyzed with the 2016 version of the ITP Bleeding Scale (ITP-2016) and the ITP-specific bleeding assessment tool (ITP-BAT). The correlation between the two BGS and the relations among the platelet counts, gestational ages, and disease stages were respectively analyzed. There is no significant difference between the two BGS in the patients' ages, nor between the newly diagnosed and the persistent group or the chronic group, while the difference between the persistent and the chronic group was significant ( = 0.001; = 0.001). There is a negative correlation between the bleeding grade and platelet count (r = -0.436; r = -0.390), while the correlation between the two BGS was positive (r = 0.921). The proportions of identical scores provided by two different physicians using the two BGS were 94.8% and 93.5%. The difference before and after the treatment were significantly different ( = 0.013; = 0.037). It takes less time to score with the ITP-2016 ( = 0.011). Both systems can be useful for disease evaluations, risk assessments and efficacy evaluations in Chinese pregnant women with ITP. The ITP-2016 takes less time and is more suitable for Chinese pregnant patients with ITP.
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http://dx.doi.org/10.1177/1076029620910790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7370566PMC
January 2021

Safety and feasibility of CRISPR-edited T cells in patients with refractory non-small-cell lung cancer.

Nat Med 2020 05 27;26(5):732-740. Epub 2020 Apr 27.

Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.

Clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 editing of immune checkpoint genes could improve the efficacy of T cell therapy, but the first necessary undertaking is to understand the safety and feasibility. Here, we report results from a first-in-human phase I clinical trial of CRISPR-Cas9 PD-1-edited T cells in patients with advanced non-small-cell lung cancer (ClinicalTrials.gov NCT02793856). Primary endpoints were safety and feasibility, and the secondary endpoint was efficacy. The exploratory objectives included tracking of edited T cells. All prespecified endpoints were met. PD-1-edited T cells were manufactured ex vivo by cotransfection using electroporation of Cas9 and single guide RNA plasmids. A total of 22 patients were enrolled; 17 had sufficient edited T cells for infusion, and 12 were able to receive treatment. All treatment-related adverse events were grade 1/2. Edited T cells were detectable in peripheral blood after infusion. The median progression-free survival was 7.7 weeks (95% confidence interval, 6.9 to 8.5 weeks) and median overall survival was 42.6 weeks (95% confidence interval, 10.3-74.9 weeks). The median mutation frequency of off-target events was 0.05% (range, 0-0.25%) at 18 candidate sites by next generation sequencing. We conclude that clinical application of CRISPR-Cas9 gene-edited T cells is generally safe and feasible. Future trials should use superior gene editing approaches to improve therapeutic efficacy.
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http://dx.doi.org/10.1038/s41591-020-0840-5DOI Listing
May 2020

Tumor mutation burden derived from small next generation sequencing targeted gene panel as an initial screening method.

Transl Lung Cancer Res 2020 Feb;9(1):71-81

Department of Thoracic Oncology, West China Hospital, Chengdu 610041, China.

Background: With the increasing use of immune checkpoint inhibitors, tumor mutation burden (TMB) assessment is now routinely included in reports generated from targeted sequencing with large gene panels; however, not all patients require comprehensive profiling with large panels. Our study aims to explore the feasibility of using a small 56-gene panel as a screening method for TMB prediction.

Methods: TMB from 406 non-small cell lung cancer (NSCLC) patients was estimated using a large 520-gene panel simulated with the prospective TMB status for the small panel. This information was then used to determine the optimal cut-off. An independent cohort of 30 NSCLC patients was sequenced with both panels to confirm the cut-off value.

Results: By comparing sensitivity, specificity, and positive predictive value (PPV), the cut-off was set up as 10 mutations/megabase, yielding 81.4% specificity, 83.6% sensitivity, and 62.4% PPV. Further validation with an independent cohort sequenced with both panels using the same cut-off achieved 95.7% sensitivity, 71.4% specificity and 91.7% PPV. The decreasing trend of sensitivity with the increasing trend of both specificity and PPV with a concomitant increase in the cut-off for the small panel suggests that TMB is overestimated but highly unlikely to yield false-positive results. Hence, patients with low TMB (<10) can be reliably stratified from patients with high TMB (≥10).

Conclusions: The small panel, more cost-effective, can be used as a screening method to screen for patients with low TMB, while patients with TMB ≥10 are recommended for further validation with a larger panel.
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http://dx.doi.org/10.21037/tlcr.2019.12.27DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7082297PMC
February 2020

Durable response to combination radiotherapy and immunotherapy in EP-resistant lung large-cell neuroendocrine carcinoma with and mutations: a case report.

Immunotherapy 2020 03 11;12(4):223-227. Epub 2020 Mar 11.

Department of Thoracic Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China.

Lung large-cell neuroendocrine carcinoma (LCNEC) is a rare tumor with poor prognosis. Despite the increasing prevalence of immune checkpoint inhibitors (ICIs) across a broad spectrum of solid tumors, very limited information is available about the efficacy in LCNEC. Here, we report a case of advanced lung LCNEC treated with combined radiotherapy and ICIs, which resulted in a durable response. We also focused on the impressive reaction of metastatic and primary lesions to two different combination modes of radiotherapy and ICIs.
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http://dx.doi.org/10.2217/imt-2019-0166DOI Listing
March 2020

Crizotinib versus chemotherapy: a real-world cost-effectiveness study in China.

J Comp Eff Res 2020 01 21;9(2):93-102. Epub 2020 Jan 21.

Department of Thoracic Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China.

To assess the cost-effectiveness of crizotinib verses platinum-based doublet chemotherapy as the first-line treatment for anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) in the real-world setting. Data from 163 advanced ALK positive NSCLC patients were collected from West China Hospital, Sichuan University (Chengdu, China). They were categorized into two groups as treated with crizotinib (n = 83) or chemotherapy (n = 80) as a first-line therapy. The progression-free survival (PFS) as the primary clinical outcome, and the direct medical costs were collected from hospital information systems. Incremental cost-effectiveness ratio (ICER) was calculated with costs, quality-adjusted life-years, as well as the costs discounted at 3% annually. Additionally, two different kinds of medical insurance (MI) for pharma-economic assessment were considered. Crizotinib improved PFS versus chemotherapy in ALK positive patients (median PFS 19.67 m vs 5.47 m; p < 0.001). Moreover, crizotinib obtained an ICER of US$36,285.39 before the end of 2016, when crizotinib, pemetrexed and anti-angiogenesis drugs were not MI covered. This is more than the willingness to pay threshold (three-times of gross domestic product per capita in mainland China or Sichuan Province). However, ICER was US$7321.16, which is less than willingness to pay, when crizotinib and all chemotherapy drugs were covered by MI from the end of 2016. Sensitivity analysis demonstrated a 99.7% probability for crizotinib to be more cost-effective than chemotherapy, when crizotinib and all anticancer drugs were MI covered. One-way sensitivity analysis for the reimbursement ratio of crizotinib indicated that cost-effective tendency for crizotinib increased as reimbursement ratio increased. Crizotinib could be an effective, and cost-effective first-line treatment for ALK positive advanced NSCLC with the MI coverage currently available in Chengdu, Sichuan Province, China.
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http://dx.doi.org/10.2217/cer-2019-0075DOI Listing
January 2020

Radical esophagectomy for stage II and III thoracic esophageal squamous cell carcinoma followed by adjuvant radiotherapy with or without chemotherapy: Which is more beneficial?

Thorac Cancer 2020 03 14;11(3):631-639. Epub 2020 Jan 14.

Department of Thoracic Oncology, Cancer Center, West China Hospital, Medical School, Sichuan University, Chengdu, China.

Background: This retrospective study compared the efficacy and side effect profile between postoperative adjuvant radiotherapy and chemoradiotherapy in stage II or stage III thoracic esophageal squamous cell carcinoma (TESCC) patients who underwent curative (R0) esophagectomy.

Methods: A total of 272 TESCC patients who underwent radical esophagectomy from 2007 to 2016 were included in this retrospective analysis. All cases were pathologically confirmed with stage II or III disease and 148 patients received postoperative chemoradiotherapy (CRT), while the remaining 124 patients received postoperative radiotherapy (RT) alone.

Results: In CRT and RT groups, the three-year overall survival rates were 51.3 versus 31.5% (P < 0.01) and the median overall survival (OS) was 39 months (95% CI, 31.6 to 46.3 months) and 30 months (95% CI, 21.0 to 38.9 months), respectively (P = 0.213). Three-year disease-free survival rates (DFS) were 30.5% versus 15.9% (P = 0.008), while the median DFS times were 26 months (95% CI, 17.7 to 34.3 months) and 19 months (95% CI, 16.4 to 21.6 months), respectively (P = 0.156). Univariate and multivariate analyses showed AJCC (American Joint Committee on Cancer seventh edition) stage and N stage were independent prognostic factors for overall survival, while the N stage was an independent prognostic factor for disease-free survival.

Conclusions: Postoperative chemoradiotherapy led to one- and three-year overall survival benefits along with an obvious increase in treatment side effects for stage II to III TESCC patients, with no further improvement in five-year survival. However, the chemoradiotherapy benefits mainly favor stage III,number of resected lymph nodes less than 15, younger (less than 60 years old) and smoking patients.
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http://dx.doi.org/10.1111/1759-7714.13307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049519PMC
March 2020

Modular Engineering of Targeted Dual-Drug Nanoassemblies for Cancer Chemoimmunotherapy.

ACS Appl Mater Interfaces 2019 Oct 24;11(40):36371-36382. Epub 2019 Sep 24.

Department of Biomedical Engineering , Southern University of Science and Technology , Shenzhen , Guangdong , 518055 P. R. China.

Combination of chemotherapeutics and immunomodulators can generate synergistic anticancer efficacy, exerting efficient chemoimmunotherapy for cancer treatment. Nanoparticulate delivery systems hold great promise to promote synergistic anticancer efficacy for the codelivery of drugs. However, there remain challenges to precisely coencapsulate and deliver combinational drugs at designed ratios due to the difference of compatibility between drugs and nanocarriers. In this study, coassembled nanoparticles of lipophilic prodrugs (LPs) were designed to codeliver chemotherapeutics and immunomodulators for cancer treatment. Such nanoassemblies (NAs) could act as platforms to ratiometrically coencapsulate chemotherapeutics and immunomodulators. Based on this method, NAs formed by the self-assembly of iRGD peptide derivatives, paclitaxel (PTX) LPs, and imiquimod (R837) LPs were demonstrated to target the tumor at unified pharmacokinetics, further inducing the effective tumor inhibition and tumor recurrence prevention. This work provided an alternative to prepare chemoimmunotherapeutic NAs with advantages of ratiometric drug coencapsulation and unified pharmacokinetics, which may advance the future cancer chemoimmunotherapy.
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http://dx.doi.org/10.1021/acsami.9b11881DOI Listing
October 2019

Kinetic stability-driven cytotoxicity of small-molecule prodrug nanoassemblies.

J Mater Chem B 2019 09;7(36):5563-5572

State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China.

Nanoassemblies (NAs) of small-molecule lipophilic prodrugs have been widely investigated for efficient drug delivery in cancer therapy, but their kinetic stability has not attracted sufficient attention in the past studies. Herein, we reported that kinetic stability has a great influence on the drug release from the NAs of lipophilic prodrugs in physiologically relevant media. Based on the co-assembled FRET nanosystems of two lipophilic fluorescent prodrugs, we demonstrated that NAs constructed by lipophilic prodrugs containing shorter alkyl chains or those with higher unsaturated degrees displayed poorer kinetic stability, which further resulted in remarkably faster drug release in mouse plasma and various tissue homogenates. More importantly, these kinetically unstable NAs also induced rapid intracellular drug release, resulting in much more potent cytotoxicity. These findings highlight the crucial role of kinetic stability in determining the drug release from the NAs of lipophilic prodrugs, which would effectively guide their rational designs for cancer therapy.
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http://dx.doi.org/10.1039/c9tb01270bDOI Listing
September 2019