Publications by authors named "Yunpeng Yang"

152 Publications

Distinct Functional Metagenomic Markers Predict the Responsiveness to Anti-PD-1 Therapy in Chinese Non-Small Cell Lung Cancer Patients.

Front Oncol 2022 21;12:837525. Epub 2022 Apr 21.

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

Background: Programmed death 1 (PD-1) and the ligand of PD-1 (PD-L1) are central targets for immune-checkpoint therapy (ICT) blocking immune evasion-related pathways elicited by tumor cells. A number of PD-1 inhibitors have been developed, but the efficacy of these inhibitors varies considerably and is typically below 50%. The efficacy of ICT has been shown to be dependent on the gut microbiota, and experiments using mouse models have even demonstrated that modulation of the gut microbiota may improve efficacy of ICT.

Methods: We followed a Han Chinese cohort of 85 advanced non-small cell lung cancer (NSCLC) patients, who received anti-PD-1 antibodies. Tumor biopsies were collected before treatment initiation for whole exon sequencing and variant detection. Fecal samples collected biweekly during the period of anti-PD-1 antibody administration were used for metagenomic sequencing. We established gut microbiome abundance profiles for identification of significant associations between specific microbial taxa, potential functionality, and treatment responses. A prediction model based on random forest was trained using selected markers discriminating between the different response groups.

Results: NSCLC patients treated with antibiotics exhibited the shortest survival time. Low level of tumor-mutation burden and high expression level of HLA-E significantly reduced progression-free survival. We identified metagenomic species and functional pathways that differed in abundance in relation to responses to ICT. Data on differential enrichment of taxa and predicted microbial functions in NSCLC patients responding or non-responding to ICT allowed the establishment of random forest algorithm-adopted models robustly predicting the probability of whether or not a given patient would benefit from ICT.

Conclusions: Overall, our results identified links between gut microbial composition and immunotherapy efficacy in Chinese NSCLC patients indicating the potential for such analyses to predict outcome prior to ICT.
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http://dx.doi.org/10.3389/fonc.2022.837525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9069064PMC
April 2022

A CT-based radiomics model to predict subsequent brain metastasis in patients with ALK-rearranged non-small cell lung cancer undergoing crizotinib treatment.

Thorac Cancer 2022 Apr 18. Epub 2022 Apr 18.

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

Background: Brain metastasis (BM) comprises the most common reason for crizotinib failure in patients with anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC). We hypothesize that its occurrence could be predicted by a computed tomography (CT)-based radiomics model, therefore, allowing for selection of enriched patient populations for prevention therapies.

Methods: A total of 75 eligible patients were enrolled from Sun Yat-sen University Cancer Center between June 2014 and September 2019. The primary endpoint was brain metastasis-free survival (BMFS), estimated from the initiation of crizotinib to the date of the occurrence of BM. Patients were randomly divided into two cohorts for model training (n = 51) and validation (n = 24), respectively. A radiomics signature was constructed based on features extracted from chest CT before crizotinib treatment. Clinical model was developed using the Cox proportional hazards model. Log-rank test was performed to describe the difference of BMFS risk.

Results: Patients with low radiomics score had significantly longer BMFS than those with higher, both in the training cohort (p = 0.019) and validation cohort (p = 0.048). The nomogram combining smoking history and the radiomics signature showed good performance for the estimation of BMFS, both in the training (concordance index [C-index], 0.762; 95% confidence interval [CI], 0.663-0.861) and validation cohort (C-index, 0.724; 95% CI, 0.601-0.847).

Conclusion: We have developed a CT-based radiomics model to predict subsequent BM in patients with non-brain metastatic NSCLC undergoing crizotinib treatment. Selection of an enriched patient population at high BM risk will facilitate the design of clinical trials or strategies to prevent BM.
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http://dx.doi.org/10.1111/1759-7714.14386DOI Listing
April 2022

Embodied Carbon in China's Export Trade: A Multi Region Input-Output Analysis.

Int J Environ Res Public Health 2022 03 24;19(7). Epub 2022 Mar 24.

Faculty of Finance, City University of Macau, Macau 999078, China.

With the rapid growth of China's export trade and increasing pressure of domestic carbon emission reduction, the issue of carbon embodied in export trade has attracted increasing attention from academic circles. This paper has constructed a calculation model for embodied carbon in China's export trade by using the multi-region input-output model and the international input-output data from the World Input-Output Database (WIOD) database in order to calculate the amount of embodied carbon. Our objective is to analyze the main source industry and specific sectors of embodied carbon in China's export trade, and to provide a quantitative basis for emission reduction under the "carbon neutrality" strategy. The findings reveal that the embodied carbon in China's export trade mainly comes from the secondary industry, which accounts for more than 90% of the total embodied carbon in export trade, while the proportions of embodied carbon in the primary industry and the tertiary industry are relatively low, about 1% and 5-7%, respectively. In terms of specific sectors, the crop and animal production and hunting sectors have the largest share (over 60%) of embodied carbon in the export trade of the primary industry; in the export trade of the secondary industry, the main sources of embodied carbon are the manufacturing sector and the power, gas, steam and air-conditioning supply sectors, respectively accounting for around 50% and 45% of the total embodied carbon in the export trade of the secondary industry; as for the tertiary industry, the transport and storage sectors have the largest share of embodied carbon in the export trade, which is around 70%. Based on the above research results, this paper has provided relevant policy recommendations, which are optimizing the export structure, improving the energy consumption structure and the carbon emissions trading system.
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http://dx.doi.org/10.3390/ijerph19073894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8998101PMC
March 2022

Epidermal growth factor receptor-Mutated Non-small-cell Lung Cancer with Intracranial Progressions and Stable Extracranial Diseases Benefit from Osimertinib Regardless of T790M Mutational Status.

Cancer Control 2022 Jan-Dec;29:10732748221081360

Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 71067Sun Yat-sen University Cancer Center, Guangzhou, China.

Objectives: Osimertinib has exhibited promising central nervous system (CNS) efficacy in Epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer (NSCLC) patients. In real-world clinical practice, patients would turn to plasma genotyping or take osimertinib blindly after CNS progression on previous tyrosine kinase inhibitors (TKIs). However, the efficacy of osimertinib in those patients according to their T790M mutational status has not been explored.

Materials And Methods: Twenty-five patients who received osimertinib due to intracranial progressions with stable extracranial diseases after early-generation EGFR-TKI treatment were collected from 1032 EGFR-mutated NSCLC. Plasma samples were analyzed for EGFR mutations using next-generation sequencing (NGS) or polymerase chain reaction (PCR).

Results: Among the 25 patients, 17 patients took plasma genotyping before osimertinib treatment with 8 patients EGFR T790M mutation-positive and the rest started osimertinib blindly. The median progression-free survival (PFS) was 8.0 months (95% confidence interval [CI]: 6.12-9.94) and median intracranial PFS (iPFS) was 14.4 months (95% CI: 7.27-21.59) for the total population. No statistical difference was found in PFS and iPFS among patients with different EGFR T790M mutational statuses. Intracranial disease control rate (DCR) was 100.0% for 14 patients with evaluable intracranial lesions despite different T790M mutational statuses. DCR for extracranial lesions and overall lesions were 100.0%, 66.7%, and 87.5% for patients with T790M, no T790M, and unknown T790M mutational status, respectively.

Conclusion: For EGFR-mutated NSCLC patients with only intracranial progressions after previous TKI treatments, osimertinib is a promising treatment option regardless of T790M mutational status from plasma genotyping.
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http://dx.doi.org/10.1177/10732748221081360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8883386PMC
February 2022

Discovery of novel inhibitors of CDK2 using docking and physics-based binding free energy calculation.

Chem Biol Drug Des 2022 May 1;99(5):662-673. Epub 2022 Mar 1.

Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, China.

Cyclin-dependent kinase (CDK) is a serine/threonine protein kinase family that cooperates with cyclin and plays an important role in the regulation of cell cycle. Cyclin-dependent kinase 2 is an important member of the CDK family and holds great promise as an anti-cancer drug target. In this study, we used molecular docking and physics-based binding free energy calculation method AS-IE that explicitly calculated protein-ligand binding entropy to discover novel inhibitors of CDK2. A total of 17 inhibitors were discovered with the best IC reaching ~2 μM. Decomposition of the binding free energy using AS-IE reveals key protein-ligand interactions that determines the activity. These results provided a good example of drug design using physics-based free energy calculation method such as AS-IE and the novel compounds offered a good start point for further development of CDK2 inhibitors.
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http://dx.doi.org/10.1111/cbdd.14027DOI Listing
May 2022

Reducing number of target lesions for RECIST1.1 to predict survivals in patients with advanced non-small-cell lung cancer undergoing anti-PD1/PD-L1 monotherapy.

Lung Cancer 2021 Dec 31;165:10-17. Epub 2021 Dec 31.

State Key Laboratory of Oncology in South China, Guangzhou, China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China; Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China. Electronic address:

Objectives: The Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 provides conventional and standardized response assessment for multiple solid tumors. We investigated the smallest number of target lesions that can be measured without compromising response categorization and survival prediction in patients with advanced non-small-cell lung cancer (aNSCLC) undergoing anti-PD-1/PD-L1 monotherapy.

Material And Methods: 125 aNSCLC patients with at least two measurable lesions undergoing PD-1/PD-L1 inhibitor treatment were retrospectively studied. Tumor measurements allowing up to two lesions per organ and five lesions in total were reviewed. Inter-individual agreement and κ values for inter-method concordance on response status were evaluated based on up to five target lesions versus the largest one through four lesions. C-index was calculated to evaluate the prognostic accuracy of response categorization based on the selected number of target lesions for predicting overall survival (OS). Cox regression analysis was conducted for survival analysis.

Results: The highly consistent response assignment (99.2%) could be obtained when measuring the largest two lesions versus up to five lesions. Using the largest two through four lesions produced κ values of 0.986, 1.000 and 1.000 for response assessment, values significantly higher than those obtained when measuring the largest single lesion (κ = 0.850). C-index for overall survival (OS) was similar when assessing the largest one through five lesions, ranging from 0.646 to 0.654. Cox regression analyses showed that radiological response significantly predicted OS, irrespective of the number of target lesions selected.

Conclusions: Reducing the number of target lesions does not affect OS prediction in aNSCLC patients treated with anti-PD-1/PD-L1 therapy. Considering the high intra-individual and inter-method concordance, using the largest two lesions in total is proposed to assess response.
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http://dx.doi.org/10.1016/j.lungcan.2021.12.015DOI Listing
December 2021

Determinants of survival in advanced non-small cell lung cancer patients treated with anti-PD-1/PD-L1 therapy.

Ann Transl Med 2021 Nov;9(22):1639

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, China.

Background: The present study aimed to investigate the determinant factors of survival in patients with pretreated advanced stage non-small cell lung cancer (NSCLC) who received anti-PD-1/PD-L1 therapy.

Methods: In this observational retrospective study, the clinical profiles and laboratory parameters of patients with NSCLC treated with anti-PD-1/PD-L1 therapy were consecutively collected. Lung Immune Prognostic Index (LIPI) was calculated based on the derived neutrophil-to-lymphocyte ratio (dNLR) and lactate dehydrogenase level (LDH). Modified Glasgow Prognostic Score (mGPS) was calculated based on serum C reactive protein and albumin, and tumor mutation burden (TMB) was calculated using a targeted next-generation sequencing panel based on 422 cancer-relevant genes. The primary and secondary end points were overall survival (OS) and progression-free survival (PFS), respectively. The Cox regression model was used to identify the potential determinant factors of survival benefit. Trained oncologists at Sun Yat-sen University Cancer Center followed all of the participants through visits to doctors' offices or via telephone calls to determine their clinical status.

Results: Seventy-three patients were included in our study. With a median follow up time of 637 days, there was a significant difference in PFS between patients with high TMB compared to those with low TMB (3.7 2.1 months; P=0.004), while no significant difference was found in OS (14.0 16.4 months; P=0.972). Patients with a good LIPI score had a significantly longer OS compared to patients with a poor LIPI score (19.2 12.6 months; P=0.010). The median OS in patients with a good and a poor mGPS was 16.8 and 4.3 months, respectively (P=0.029). In multivariate analysis, TMB was found to be significantly associated with PFS (HR, 0.38; 95% CI: 0.21-0.69; P=0.002), while LIPI score was found to be significantly associated with OS (HR, 0.50; 95% CI: 0.28-0.89; P=0.012).

Conclusions: In the present study, LIPI score was a significant determinant of OS in patients with advanced NSCLC who received ICIs; however, TMB was only associated with PFS and not associated with OS.
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http://dx.doi.org/10.21037/atm-21-1702DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8667098PMC
November 2021

Efficacy, safety, and biomarker analysis of Camrelizumab in Previously Treated Recurrent or Metastatic Nasopharyngeal Carcinoma (CAPTAIN study).

J Immunother Cancer 2021 12;9(12)

Department of Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China

Background: This study aimed to evaluate the antitumor activity of camrelizumab, an antiprogrammed cell death-1 antibody, in pretreated recurrent or metastatic nasopharyngeal carcinoma (NPC) and to explore predictive biomarkers.

Methods: Patients with recurrent (not amenable to locally curative treatment) or metastatic NPC who had failed at least two lines of chemotherapy were eligible to receive camrelizumab (200 mg intravenously every 2 weeks) for 2 years or until disease progression, intolerable adverse events, withdrawal of consents, or investigator decision. The primary endpoint was objective response rate (ORR) assessed by an independent review committee (IRC). Programmed cell death-ligand 1 (PD-L1) expression was assessed by immunohistochemistry. Other immune-related biomarkers including major histocompatibility complex class I and major histocompatibility complex class II (MHC-II) were assessed by multiplex immunofluorescence staining.

Results: Between August 14, 2018, and December 30, 2019, a total of 156 patients were enrolled. The IRC-assessed ORR was 28.2% (95% CI 21.3% to 36.0%). The median progression-free survival was 3.7 months (95% CI 2.0 to 4.1) per IRC, and the median overall survival was 17.4 months (95% CI 15.2 to 21.9). The ORRs were 35.2% (95% CI 25.3% to 46.1%) vs 19.4% (95% CI 10.4% to 31.4%) in patients with tumor PD-L1 expression of ≥10% and<10%, respectively. Patients with durable clinical benefit (DCB), which was defined as complete response, partial response or stable disease of ≥18 weeks, had higher density of MHC-II+ cell in stroma than patients without DCB (median 868.1 (IQR 413.4-2854.0) cells/mm vs median 552.4 (IQR 258.4 to 1242.1) cells/mm). MHC-II+ cell density did not correlate with PD-L1 expression, and a composite of high stromal MHC-II+ cell density and tumor PD-L1 expression further enriched patients who could benefit from camrelizumab.

Conclusions: Camrelizumab had clinically meaningful antitumor activity in patients with recurrent or metastatic NPC. The composition of both MHC-II+ cell density and PD-L1 expression could result in better patient selection.
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http://dx.doi.org/10.1136/jitc-2021-003790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8693086PMC
December 2021

Genetic Liability to Insomnia and Lung Cancer Risk: A Mendelian Randomization Analysis.

Front Genet 2021 1;12:756908. Epub 2021 Dec 1.

Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China.

Lung cancer is the second most frequently diagnosed cancer and the leading cause of cancer death worldwide, making its prevention an urgent issue. Meanwhile, the estimated prevalence of insomnia was as high as 30% globally. Research on the causal effect of insomnia on lung cancer incidence is still lacking. In this study, we aimed to assess the causality between the genetic liability to insomnia and lung cancer. We performed a two-sample Mendelian randomization analysis (inverse variance weighted) to determine the causality between the genetic liability to insomnia and lung cancer. Subgroup analysis was conducted, which included lung adenocarcinoma and lung squamous cell carcinoma. In the sensitivity analysis, we conducted heterogeneity test, MR Egger, single SNP analysis, leave-one-out analysis, and MR PRESSO. There were causalities between the genetic susceptibility to insomnia and increased incidence of lung cancer [odds ratio (95% confidence interval), 1.35 (1.14-1.59); , < 0.001], lung adenocarcinoma [odds ratio (95% confidence interval), 1.35 (1.07-1.70); , 0.01], and lung squamous cell carcinoma [odds ratio (95% confidence interval), 1.35 (1.06-1.72), , 0.02]. No violation of Mendelian randomization assumptions was observed in the sensitivity analysis. There was a causal relationship between the genetic susceptibility to insomnia and the lung cancer, which was also observed in lung adenocarcinoma and lung squamous cell carcinoma. The underlying mechanism remains unknown. Effective intervention and management for insomnia were recommended to improve the sleep quality and to prevent lung cancer. Moreover, regular screening for lung cancer may be beneficial for patients with insomnia.
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http://dx.doi.org/10.3389/fgene.2021.756908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8672094PMC
December 2021

Incidence and risk factors of second primary cancer after the initial primary human papillomavirus related neoplasms.

MedComm (2020) 2020 Dec 3;1(3):400-409. Epub 2020 Dec 3.

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 China.

Comprehensive studies in second primary cancer (SPC) after the initial primary human papillomavirus (HPV)-related cancer still remain warranted. We aimed to analyze the incidence and risk factors of SPC after HPV-related cancer. We identified 86 790 patients diagnosed with initial primary HPV-related cancer between 1973 and 2010 in the SEER database. Standardized incidence ratio (SIR) and cumulative incidence were calculated to assess the risk of SPC after HPV-related cancer. The SIR of SPC after HPV-related cancer was 1.60 (95% confidence interval [CI], 1.55-1.65) for male and 1.25 (95% CI, 1.22-1.28) for female. SIR of second primary HPV-related cancer (7.39 [95% CI, 6.26-8.68] male and 4.35 [95% CI, 4.04-4.67] female) was significantly higher than that of HPV-unrelated cancer (1.54 [95% CI, 1.49-1.60] male and 1.16 [95% CI, 1.13-1.19] female). The 5-year cumulative incidence of SPC was 7.22% (95% CI, 6.89-7.55%) for male and 3.72% (95% CI, 3.58-3.88%) for female. Risk factors for SPC included being married and having initial primary cancer (IPC) diagnosed at earlier stage for both genders, and IPC diagnosed at older age as well as surgery performed for female. Patients diagnosed with HPV-related cancer are more likely to develop another primary cancer, compared with the age-specific reference population.
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http://dx.doi.org/10.1002/mco2.43DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8491207PMC
December 2020

Utility of comprehensive genomic profiling in directing treatment and improving patient outcomes in advanced non-small cell lung cancer.

BMC Med 2021 10 1;19(1):223. Epub 2021 Oct 1.

Department of Medical Oncology, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, 510060, China.

Background: With the identification of new targetable drivers and the recent emergence of novel targeted drugs, using comprehensive genomic profiling in lieu of the routine testing for classic drivers in the clinical care for advanced NSCLC has been increasingly advocated. However, the key assumption justifying this practice, that comprehensive genomic profiling could lead to effective anticancer therapies and improve patient outcomes, remains unproved.

Methods: Comprehensive genomic profiling was prospectively applied in 1564 advanced NSCLC patients to identify potentially actionable genomic alterations. Patients were assigned to genotype-matched targeted therapies or nonmatched therapies based on the profiling results. Its utility in directing treatments was determined by the proportion of patients receiving genotype-matched targeted therapies and the proportion of patients being enrolled into genotype-matched clinical trials. Its impacts on patient outcomes were assessed by comparing progression-free survival (PFS) and overall survival (OS) between patients who received a genotype-matched and nonmatched therapy.

Results: From October 2016 to October 2019, tumor genomic profiles were established in 1166 patients, leading to a matched targeted therapy in 37.7% (n = 440) and a genotype-matched trial enrollment in 20.9% of patients (n = 244). Potentially actionable alterations were detected in 781 patients (67.0%). For these patients, a genomic profiling-directed matched therapy significantly improved PFS (9.0 months vs 4.9 months, P < 0.001) and OS (3.9 years vs 2.5 years, P < 0.001) compared with a nonmatched therapy. Excluding patients with standard targeted therapies, genomic profiling led to a matched targeted therapy in 16.7% (n = 24) and a matched trial enrollment in 11.2% (n = 16) of patients. No PFS (4.7 months vs 4.6 months, P = 0.530) or OS (1.9 years vs 2.4 years, P = 0.238) benefit was observed with the use of genotype-matched targeted therapies in this population.

Conclusions: Comprehensive genomic profiling is of clinical utility in assisting treatment selection, facilitating clinical trial enrollment, and improving patient outcomes in advanced NSCLC. However, for patients carrying alterations without standard-of-care targeted drugs, the interpretation of genomic profiling results should be careful given the low likelihood of benefit from the investigational or off-label use of targeted therapies in this population in the current treatment landscape.

Trial Registration: ChiCTR1900027582 (retrospectively registered on 19 November 2019).
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http://dx.doi.org/10.1186/s12916-021-02089-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8485523PMC
October 2021

Afatinib as a Potential Therapeutic Option for Patients With NSCLC With G724S.

JTO Clin Res Rep 2021 Jul 24;2(7):100193. Epub 2021 May 24.

Department of Clinical Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China.

Introduction: G724S has been described to mediate resistance to first- and third-generation EGFR tyrosine kinase inhibitors (TKIs). In vitro experiments have provided compelling evidence that G724S retains sensitivity for afatinib. Nevertheless, limited data have reported the clinical efficacy of afatinib in patients with NSCLC harboring G724S mutation.

Methods: We identified 52 patients with NSCLC with G724S from an inhouse database and comprehensively profiled their concurrent mutation statuses. Treatments and clinical outcomes were also collected.

Results: Of 52 G724S-positive patients, 39 harbored concomitant exon 19 deletion (19del), and all 37 of the 39 patients who had available clinical data were detected with a G724S mutation after receiving EGFR TKIs. A rare variant of 19del E746_S752delinsV co-occurred with G724S the most frequently (n = 29), whereas 7 of 10 patients with concomitant exon 20 mutation were TKI treatment naive. S768I was the most common mutation in exon 20 (n = 7). One patient harbored a concomitant exon 21 mutation, and two lacked co-occurring mutations A total of 23 patients provided valid clinical outcome data, of whom eight were treated with afatinib after the emergence of G724S, whereas 15 received non-afatinib treatment (alternative EGFR TKI, chemotherapy, or best supportive care). The disease control rate in afatinib-treated patients (n = 8) reached 100% with a median progression-free survival of 4.5 months, significantly longer than that of non-afatinib-treated (n = 15, 1.7 mo, hazard ratio [HR] = 0.32,  = 0.037) and alternative EGFR TKI-treated (n = 11, 1.8 mo, HR = 0.28,  = 0.042) patients. In the subset who had progressed on osimertinib, afatinib also yielded a superior progression-free survival (6.2 mo) than non-afatinib therapies (1.0 mo, HR = 0.04,  = 0.005) and alternative EGFR TKIs (1.8 mo, HR = 0.06,  = 0.033). Analysis of acquired mutations at afatinib progression revealed re-emergence of T790M or amplification as the potential mechanism of afatinib resistance.

Conclusions: G724S emerges as a resistant mutation against EGFR TKI preferentially in the context of a rare variant of 19del, whereas it might mediate differential mechanisms in the context of exon 20 mutation. We also found that afatinib could be a potential therapeutic option for patients with NSCLC with G724S.
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http://dx.doi.org/10.1016/j.jtocrr.2021.100193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8474270PMC
July 2021

Multi-region exome sequencing reveals the intratumoral heterogeneity of surgically resected small cell lung cancer.

Nat Commun 2021 09 14;12(1):5431. Epub 2021 Sep 14.

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, China.

Small cell lung cancer (SCLC) is a highly malignant tumor which is eventually refractory to any treatment. Intratumoral heterogeneity (ITH) may contribute to treatment failure. However, the extent of ITH in SCLC is still largely unknown. Here, we subject 120 tumor samples from 40 stage I-III SCLC patients to multi-regional whole-exome sequencing. The most common mutant genes are TP53 (88%) and RB1 (72%). We observe a medium level of mutational heterogeneity (0.30, range 0.0~0.98) and tumor mutational burden (TMB, 10.2 mutations/Mb, range 1.1~51.7). Our SCLC samples also exhibit somatic copy number variation (CNV) across all patients, with an average CNV ITH of 0.49 (range 0.02~0.99). In terms of mutation distribution, ITH, TMB, mutation clusters, and gene signatures, patients with combined SCLC behave roughly the same way as patients with pure SCLC. This condition also exists in smoking patients and patients with EGFR mutations. A higher TMB per cluster is associated with better disease-free survival while single-nucleotide variant ITH is linked to worse overall survival, and therefore these features may be used as prognostic biomarkers for SCLC. Together, these findings demonstrate the intratumoral genetic heterogeneity of surgically resected SCLC and provide insights into resistance to treatment.
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http://dx.doi.org/10.1038/s41467-021-25787-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8440529PMC
September 2021

Gemcitabine Plus Cisplatin Versus Fluorouracil Plus Cisplatin as First-Line Therapy for Recurrent or Metastatic Nasopharyngeal Carcinoma: Final Overall Survival Analysis of GEM20110714 Phase III Study.

J Clin Oncol 2021 10 11;39(29):3273-3282. Epub 2021 Aug 11.

Department of Medical Oncology of Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University, Guangzhou, China.

Purpose: GEM20110714 (ClinicalTrials.gov identifier: NCT01528618), the first randomized, phase III study of systemic chemotherapy in recurrent or metastatic nasopharyngeal carcinoma (NPC), reported significant progression-free survival improvement with gemcitabine plus cisplatin (GP) versus fluorouracil plus cisplatin (FP; hazard ratio, 0.55; 95% CI, 0.44 to 0.68; < .001). Data from the final analysis of overall survival (OS) are presented here.

Methods: From February 2012 to October 2015, 362 patients were randomly assigned to receive either GP (gemcitabine 1 g/m once daily on days 1 and 8 and cisplatin 80 mg/m once daily on day 1; n = 181) or FP (fluorouracil 4 g/m in continuous intravenous infusion over 96 hours and cisplatin 80 mg/m once daily on day 1; n = 181) once every 21 days. The primary end point was progression-free survival, which has been previously reported; OS was a secondary end point.

Results: After a median follow-up time of 69.5 months with GP and 69.7 months with FP, 148 (81.8%) and 166 (91.7%) deaths occurred in the GP and FP arms, respectively. The estimated hazard ratio for OS was 0.72 (95% CI, 0.58 to 0.90; two-sided = .004). The median OS was 22.1 months (95% CI, 19.2 to 25.0 months) with GP versus 18.6 months (95% CI, 15.4 to 21.7 months) with FP. The OS probabilities at 1, 3, and 5 years were 79.9% versus 71.8%, 31.0% versus 20.4%, and 19.2% versus 7.8%, respectively. Poststudy therapy was administered in 51.9% and 55.2% of patients in the GP and FP arms, respectively.

Conclusion: Among patients with previously untreated advanced nasopharyngeal carcinoma, those who receive GP have longer OS than those receive FP. Gemcitabine plus cisplatin should be considered a preferred front-line option for these patients.
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http://dx.doi.org/10.1200/JCO.21.00396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8500603PMC
October 2021

Updated Overall Survival Data and Predictive Biomarkers of Sintilimab Plus Pemetrexed and Platinum as First-Line Treatment for Locally Advanced or Metastatic Nonsquamous NSCLC in the Phase 3 ORIENT-11 Study.

J Thorac Oncol 2021 12 3;16(12):2109-2120. Epub 2021 Aug 3.

New Drug Biology and Translational Medicine, Innovent Biologics, Inc., Suzhou, People's Republic of China.

Introduction: Sintilimab plus chemotherapy significantly prolonged progression-free survival (PFS) compared with chemotherapy alone in nonsquamous NSCLC in the ORIENT-11 study. Updated overall survival (OS) and PFS data and corresponding biomarker analyses are reported here.

Methods: In this study, a total of 397 patients with previously untreated, locally advanced or metastatic nonsquamous NSCLC were assigned to sintilimab plus chemotherapy combination treatment (combo) group or placebo plus chemotherapy treatment group. The patients were stratified by programmed death-ligand 1 (PD-L1) expression levels. Immune signature profiles from tumor RNA sequencing and PD-L1 immunohistochemistry were correlated with clinical outcome to identify predictive biomarkers.

Results: As of January 2021, with median follow-up of 22.9 months, median OS was significantly improved in the combo group compared with the placebo plus chemotherapy treatment group (not reached versus 16.8 mo; hazard ratio [HR] = 0.60, 95% confidence interval [CI]: 0.45-0.79, p = 0.0003). High or medium immune cell infiltration was strongly associated with improved PFS in the combo group, in contrast to absent or low immune cell infiltration, which suggests that chemotherapy could not prime "immune deserts" to obtain benefit from programmed cell death protein-1 inhibition. In particular, high major histocompatibility complex (MHC) class II presentation pathway expression was significantly correlated with prolonged PFS (HR = 0.32, 95% CI: 0.19-0.54, p < 0.0001) and OS (HR = 0.36, 95% CI: 0.20-0.64, p = 0.0005) in the combo group. Importantly, patients with low or absent PD-L1 but high MHC class II expression could still benefit from the combo treatment. In contrast, MHC class I antigen presentation pathway was less relevant in this combination setting.

Conclusions: The addition of sintilimab to chemotherapy resulted to significantly longer OS in nonsquamous NSCLC. Expression of MHC class II antigen presentation pathway could identify patients benefiting most from this combination.
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http://dx.doi.org/10.1016/j.jtho.2021.07.015DOI Listing
December 2021

Clinical Significance of Kinetics of Low-Density Lipoprotein Cholesterol and Its Prognostic Value in Limited Stage Small Cell Lung Cancer Patients.

Cancer Control 2021 Jan-Dec;28:10732748211028257

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, People's Republic of China.

Objectives: To investigate the clinical significance of dynamic alteration of serum lipids in limited stage small cell lung cancer (LS-SCLC) patients and the risk that different lipid profiles poses to patients' health.

Methods: We retrospectively analyzed the variation trends and prognostic values of serum lipids in 310 LS-SCLC patients who had received standard chemotherapy between 2002 and 2017. In addition to serum lipid level, which were measured at the time of pretreatment, after-chemotherapy and during disease progression and later analyzed, the dynamic lipid alteration trend and its correlation to progression-free survival (PFS) and overall survival (OS) were also statistically analyzed using Log-rank test and COX regression analyses.

Results: A significant decrease in HDL-C level was observed after standard chemotherapy (Post-CT baseline = -0.08 ± 0.34, < 0.001), and this trend of reduction was further enhanced by thoracic radiotherapy ( = 0.046). Increase in LDL-C level was also observed to be associated with higher likelihood of disease progression ( = 0.003). Moreover, the extent of the increase in LDL-C was also associated with the number of progression sites, as patients with higher increase in LDL-C in exhibiting a progression at more than 2 sites outside thorax ( = 0.037). The patients' median PFS and OS were 14.04 months (95%CI: 25.12-33.81) and 22.40 months (95%CI: 33.19-42.13), respectively. For both PFS and OS, LDL-C elevation remained an independent prognostic factor in the multivariate model ( = 0.007 and = 0.022, respectively).

Conclusion: Overall, for LS-SCLC patients, standard chemotherapy decreases the level of HDL-C, the level of increase in LDL-C could predict disease progression and even the number of progression sites, and LDL-C elevation could be an independent prognostic factor for poor OS and PFS.
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http://dx.doi.org/10.1177/10732748211028257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246505PMC
December 2021

Camrelizumab versus placebo in combination with gemcitabine and cisplatin as first-line treatment for recurrent or metastatic nasopharyngeal carcinoma (CAPTAIN-1st): a multicentre, randomised, double-blind, phase 3 trial.

Lancet Oncol 2021 08 23;22(8):1162-1174. Epub 2021 Jun 23.

Jiangsu Hengrui Pharmaceuticals, Shanghai, China.

Background: The addition of camrelizumab to gemcitabine and cisplatin showed promising activity as first-line therapy in patients with recurrent or metastatic nasopharyngeal carcinoma in a phase 1 trial. We therefore compared camrelizumab plus gemcitabine and cisplatin with placebo plus gemcitabine and cisplatin in a randomised phase 3 trial.

Methods: In this randomised, double-blind, phase 3 trial done at 28 hospitals in China, patients were eligible if they were aged 18-75 years, had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and had previously untreated recurrent or metastatic nasopharyngeal carcinoma. Patients were randomly assigned (1:1; using an interactive web-response system with a block size of four) to receive either camrelizumab (200 mg on day 1) or matching placebo intravenously, plus gemcitabine and cisplatin (gemcitabine 1000 mg/m on days 1 and 8; cisplatin 80 mg/m on day 1) intravenously every 3 weeks for four to six cycles, followed by maintenance therapy with camrelizumab or placebo, until radiographic progression, unacceptable toxicity, start of new anticancer treatment, investigator decision, or withdrawal of consent. Stratification factors used in randomisation were liver metastases, previous radical concurrent chemoradiotherapy, and ECOG performance status. The allocation sequence was generated by an independent randomisation group. The primary endpoint was progression-free survival per independent review committee. The significance threshold for independent review committee-assessed progression-free survival was p=0·0086 (one-sided) at the interim analysis. Efficacy and safety analyses included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT03707509, and is closed for enrolment but is ongoing.

Findings: Between Nov 13, 2018, and Nov 29, 2019, 343 patients were screened and 263 were eligible and were randomly assigned to the camrelizumab group (n=134) or placebo group (n=129). At the prespecified interim analysis (June 15, 2020), independent review committee-assessed progression-free survival was significantly longer in the camrelizumab group (median 9·7 months [95% CI 8·3-11·4]) than in the placebo group (median 6·9 months [5·9-7·3]; hazard ratio 0·54 [95% CI 0·39-0·76]; one-sided p=0·0002). As of Dec 31, 2020, the most common grade 3 or worse adverse events of any cause were decreased white blood cell count (89 [66%] of 134 patients in the camrelizumab group vs 90 [70%] of 129 patients in the placebo group), decreased neutrophil count (86 [64%] vs 85 [66%]), anaemia (53 [40%] vs 57 [44%]), and decreased platelet count (53 [40%] vs 52 [40%]). Serious adverse events were reported in 59 (44%) of 134 patients in the camrelizumab group and 48 (37%) of 129 patients in the placebo group. Treatment-related deaths occurred in five (4%) patients in the camrelizumab group (two unknown cause of death, one multiple organ dysfunction syndrome, one pharyngeal haemorrhage, and one arrhythmia) and one (<1%) patient in the placebo group (unknown cause of death).

Interpretation: Our findings suggest that camrelizumab plus gemcitabine and cisplatin could be a new standard of care for patients with recurrent or metastatic nasopharyngeal carcinoma in the first-line setting. Longer follow-up is needed to confirm this conclusion.

Funding: Jiangsu Hengrui Pharmaceuticals (formerly Jiangsu Hengrui Medicine).

Translation: For the Chinese translation of the abstract see Supplementary Materials section.
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http://dx.doi.org/10.1016/S1470-2045(21)00302-8DOI Listing
August 2021

Hypofractionated Intensity Modulated Radiation Therapy With Concurrent Chemotherapy in Locally Advanced Non-Small Cell Lung Cancer: A Phase II Prospective Clinical Trial (GASTO1011).

Pract Radiat Oncol 2021 Sep-Oct;11(5):374-383. Epub 2021 Jun 20.

Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou; Lung Cancer Institute of Sun Yat-sen University, Guangzhou; Guangdong Association Study of Thoracic Oncology, Guangzhou. Electronic address:

Purpose: We aimed to explore the efficacy and toxicity of split-course hypofractionated radiation therapy with concurrent chemotherapy (HRT-CHT) in patients with locally advanced non-small cell lung cancer (LANSCLC) in this single-arm, phase II study.

Methods And Materials: Patients with LANSCLC were considered eligible if their forced expiratory volume in 1 second/forced vital capacity (FEV/FVC%) and carbon monoxide diffusing capacity (DLCO%) were ≥40% and ≥45%, respectively. HRT-CHT using the intensity modulated radiation therapy technique was administered with 51 Gy in 17 fractions as the first course followed by a break. Patients without disease progression or persistent ≥grade 2 toxicities had an HRT-CHT of 15 to 18 Gy in 5 to 6 fractions as a boost. The primary endpoint was progression-free survival, and the secondary endpoint was overall survival (OS).

Results: Eighty-nine patients were enrolled and analyzed. The median follow-up was 29.5 months for all patients and 35.3 months for the survivors. The objective response rate was 97.8%; the median progression-free survival and OS were 11.0 and 27.0 months, respectively. Grade 3 acute esophagitis/pneumonitis occurred in 15 (16.9%)/7 (7.9%) patients. Grade 3/5 late pneumonitis occurred in 2 (2.2%)/1 (1.1%) patients. Of the 78 (87.6%) who completed the split-course HRT-CHT per protocol, patients with better FEV/FVC% and DLCO% after the break had significantly better OS (for the FEV/FVC1% ≥ 80% vs 60%-79% vs 41%-59% groups, 2-year OS values were 57.2% vs 56.9% vs 0%, respectively, P = .024; for the DLCO% ≥ 80% vs 60%-79% vs 45%-59% groups, 2-year OS values were 70.4% vs 48.4% vs 37.5%, respectively, P = .049).

Conclusions: Split-course HRT-CHT achieved a promising response rate and survival with tolerable toxicity in LANSCLC. Pulmonary function tests are necessary indicators for radiation treatment planning and dose escalation.
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http://dx.doi.org/10.1016/j.prro.2021.06.004DOI Listing
September 2021

Quantitative analysis of artificial dam failure effects on debris flows - A case study of the Zhouqu '8.8' debris flow in northwestern China.

Sci Total Environ 2021 Oct 11;792:148439. Epub 2021 Jun 11.

Technology & Innovation Centre for Environmental Geology and Geohazards Prevention, School of Earth Sciences, Lanzhou University, Lanzhou 730000, P. R. China; College of Earth and Environmental Sciences, Lanzhou University, Lanzhou 730000, P. R. China.

Artificial dams are one of the most common hydraulic structures for mitigating debris flow disasters in alpine valley regions. However, performance alteration and failure after successive debris flows can lead to dam failure, releasing large amounts of materials within a very short time; moreover, the contribution of artificial dam failures to debris flows is poorly understood. This study quantitatively analyzed the artificial dam failure effects based on the numerical simulations of the Zhouqu '8.8' debris flow, with three scenarios: all nine dams failed (S1); no dams were ever built (S2); all nine dams remained intact (S3). The results showed that artificial dam failures had a significant amplifying effect on the magnitude of a debris flow. The maximum velocity and flow depth decreased by 20% and 11.2% if all the dams did not collapse; comparison of S1 and S2 showed that discharge and velocity at the front of the debris flow increased by 54.6% and 89%, the bulk density and yield stress increased by 3.3% and 5.7%, due to artificial dam failures. This could increase the destructive capacity of a debris flow and the possibility of a river blockage. A single artificial dam failure could locally amplify the magnitude of debris flow. Overall, on the catchment scale, the magnitude of a debris flow was dominated by topography and channel geometry, which can reduce the amplification effect of dam failures at locations where the channel was curved. However, where the channel was straight and flat, the flow velocity and discharge increased cumulatively by 3 m/s and 637 m/s due to cascading failure. In addition, a comprehensive scheme combining ecological and engineering measures to mitigate debris flow disasters is discussed. This quantitative study is important and urgent needed to understand the amplification effect of dam failures and to implement debris flow mitigation in alpine valley regions.
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http://dx.doi.org/10.1016/j.scitotenv.2021.148439DOI Listing
October 2021

Current Advancements in Sactipeptide Natural Products.

Front Chem 2021 20;9:595991. Epub 2021 May 20.

State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic and Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.

Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a growing class of natural products that benefited from genome sequencing technology in the past two decades. RiPPs are widely distributed in nature and show diverse chemical structures and rich biological activities. Despite the various structural characteristic of RiPPs, they follow a common biosynthetic logic: a precursor peptide containing an N-terminal leader peptide and a C-terminal core peptide; in some cases,a follower peptide is after the core peptide. The precursor peptide undergoes a series of modification, transport, and cleavage steps to form a mature natural product with specific activities. Sactipeptides (Sulfur-to-alpha carbon thioether cross-linked peptides) belong to RiPPs that show various biological activities such as antibacterial, spermicidal and hemolytic properties. Their common hallmark is an intramolecular thioether bond that crosslinks the sulfur atom of a cysteine residue to the α-carbon of an acceptor amino acid, which is catalyzed by a rSAM enzyme. This review summarizes recent achievements concerning the discovery, distribution, structural elucidation, biosynthesis and application prospects of sactipeptides.
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http://dx.doi.org/10.3389/fchem.2021.595991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172795PMC
May 2021

Baseline and early changes in circulating Serum Amyloid A (SAA) predict survival outcomes in advanced non-small cell lung cancer patients treated with Anti-PD-1/PD-L1 monotherapy.

Lung Cancer 2021 08 28;158:1-8. Epub 2021 May 28.

State Key Laboratory of Oncology in South China, Guangzhou, China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China; Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China. Electronic address:

Background: Systemic inflammation plays an important role in carcinogenesis and is associated with overall survival in patients with different cancer types, including those treated with immune checkpoint blockade (ICB). Serum Amyloid A (SAA) is an acute-phase protein and a marker of persistent inflammation. We hypothesized that circulating SAA may predict outcomes in advanced non-small cell lung (aNSCLC) patients treated with PD-1/PD-L1 ICB.

Materials And Methods: This retrospective study included 91 aNSCLC patients who received anti-PD-(L)1 monotherapy in Sun Yat-sen University Cancer Center (Guangzhou, China) between August 2016 and June 2018. We examined the impact of circulating SAA at baseline and 8 (±2) weeks later on overall survival (OS). X-tile program was used to determine the cut-off values which optimized the significance of the split between Kaplan-Meier survival curves. Kaplan-Meier methodology and Cox regression analyses were conducted for survival analyses.

Results: The optimal cut-off value of baseline SAA for OS stratification was 137.6 mg/L. In univariate analysis, both high level of baseline SAA (hazard ratio [HR], 2.76; 95% confidence interval [CI], 1.47-5.18; P = 0.002) and lack of early SAA descent (HR, 1.51; 95% CI, 1.11-2.06; P = 0.009) were significantly associated with inferior OS. In multivariate analysis, gender, smoking status, performance status, liver metastasis, neutrophil-to-lymphocyte ratio, baseline SAA and early changes in SAA independently predicted OS (all with P < 0.05). A combined baseline SAA ≥ 137.6 mg/L and without early SAA descent identified a small cohort with remarkably worse OS (median, 3.2 months).

Conclusions: Both high baseline and lack of early decline in circulating SAA are significantly associated with inferior outcomes in aNSCLC patients treated with PD-1/PD-L1 ICB. Combined these two SAA indexes provided improved risk stratification. The prognostic value of this simple, readily-available, and cost-effective biomarker warrants larger, prospective validation before definitive recommendation can be made.
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http://dx.doi.org/10.1016/j.lungcan.2021.05.030DOI Listing
August 2021

A modifiable risk factors atlas of lung cancer: A Mendelian randomization study.

Cancer Med 2021 07 2;10(13):4587-4603. Epub 2021 Jun 2.

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, China.

Background: There has been no study systematically assessing the causal effects of putative modifiable risk factors on lung cancer. In this study, we aimed to construct a modifiable risk factors atlas of lung cancer by using the two-sample Mendelian randomization framework.

Methods: We included 46 modifiable risk factors identified in previous studies. Traits with p-value smaller than 0.05 were considered as suggestive risk factors. While the Bonferroni corrected p-value for significant risk factors was set to be 8.33 × 10 .

Results: In this two-sample Mendelian randomization analysis, we found that higher socioeconomic status was significantly correlated with lower risk of lung cancer, including years of schooling, college or university degree, and household income. While cigarettes smoked per day, time spent watching TV, polyunsaturated fatty acids, docosapentaenoic acid, eicosapentaenoic acid, and arachidonic acid in blood were significantly associated with higher risk of lung cancer. Suggestive risk factors for lung cancer were found to be serum vitamin A1, copper in blood, docosahexaenoic acid in blood, and body fat percentage.

Conclusions: This study provided the first Mendelian randomization assessment of the causality between previously reported risk factors and lung cancer risk. Several modifiable targets, concerning socioeconomic status, lifestyle, dietary, and obesity, should be taken into consideration for the development of primary prevention strategies for lung cancer.
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http://dx.doi.org/10.1002/cam4.4015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8267159PMC
July 2021

Records of iodine isotopes (I, I) in the Barkol peat bog from northwest China and their sources, transport and preservation.

Chemosphere 2021 Sep 7;279:130531. Epub 2021 Apr 7.

State Key Laboratory of Loess and Quaternary Geology, Xi'an AMS Center, Institute of Earth Environment, Chinese Academy of Sciences, Xi'an 710061, Shaanxi Key Laboratory of Accelerator Mass Spectrometry Technology and Application, Xi'an, 710061, PR China.

The research on geochemical behaviors of iodine is significant for deep understanding of the source and distribution of iodine on the earth. However, as one of the most important sources, the ocean emissions and relative transport pathways of iodine, as well as the preservation after deposition are still not well known, especially in the arid areas of central Asia. A peat sediment core collected nearby Barkol Lake from northwest China was analyzed for iodine isotopes (I and I). The observed high I concentration in the top 2 cm indicated a significant accumulation of iodine in the surface oxic conditions due to the continuous sources of incompletely decomposed organic matter. Dissociation of iodine into pore waters occurred once the anoxic conditions established beneath the surface by a serial reduction reaction during the degradation of organic matter. The temporal variation of anthropogenic I in the peat sediment recorded its sources and transport pathways. Besides the global fallout I during late 1950s and early 1960s, the significantly increased air releases from the European nuclear fuel reprocessing plants during 1975-1997 and the increased marine discharges since 1990s contributed the major portion of I in the peat core. The major transport pathway of I from the Europe was through Westerlies following the re-emission of the marine discharged I to the atmosphere, indicating a clearly ocean emitted iodine in the concerned central Asia.
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http://dx.doi.org/10.1016/j.chemosphere.2021.130531DOI Listing
September 2021

Experimental study on variation law of electrical parameters and temperature rise effect of coal under DC electric field.

Sci Rep 2021 Mar 30;11(1):7138. Epub 2021 Mar 30.

State Key Laboratory Cultivation Base for Gas Geology and Gas Control, Henan Polytechnic University, Jiaozuo, 454000, China.

Joule heats which are generated by coals in an applied electric field are directly correlated with variation resistivity of electrical parameters of coals. Moreover, the joule heating effect is closely related with microstructural changes and relevant products of coal surface. In the present study, a self-developed applied direct current (DC) field was applied onto an experimental system of coals to investigate variation resistivity of electrical parameters of highly, moderately and lowly metamorphic coal samples. Moreover, breakdown voltages and breakdown field intensities of above three coal samples with different metamorphic grades were tested and calculated. Variation resistivity of electrical parameters of these three coal samples in 2 kV and 4 kV DC fields were analyzed. Results show that internal current of all coal samples increases continuously and tends to be stable gradually after reaching the "inflection point" at peak. The relationship between temperature rise effect on anthracite coal surface in an applied DC field and electrical parameters was discussed. The temperature rise process on anthracite coal surface is composed of three stages, namely, slowly warming, rapid warming and slow cooling to stabilize. The temperature rise effect on anthracite coal surface lags behind changes of currents which run through coal samples. There's uneven temperature distribution on anthracite coal surface, which is attributed to the heterogeneity of coal samples. In the experiment, the highest temperature on anthracite coal surface 65.8 ℃ is far belower than the lowest temperature for pyrolysis-induced gas production of coals 200 ℃. This study lays foundations to study microstructural changes and relevant products on coal surface in an applied DC field.
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http://dx.doi.org/10.1038/s41598-021-86598-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009919PMC
March 2021

Copy number loss in granzyme genes confers resistance to immune checkpoint inhibitor in nasopharyngeal carcinoma.

J Immunother Cancer 2021 03;9(3)

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, China

Background: Anti-programmed death (PD)-1 therapy has recently been used in recurrent or metastatic (R/M) nasopharyngeal carcinoma (NPC). The long-term survival and its biomarkers responding to anti-PD-1 treatment in patients with R/M NPC remain unclear.

Methods: Patients with R/M NPC were enrolled between March 2016 and January 2018 from two phase I clinical trials. The median follow-up period was 24.7 months. Eligible patients progressed on standard chemotherapy had measurable disease by Response Evaluation Criteria in Solid Tumor V.1.1. Non-obligatory contemporaneous tumor samples were collected for whole-exome sequencing. The primary outcome was objective response rate (ORR). Duration of response (DOR), progression-free survival (PFS), and overall survival (OS) were secondary outcomes assessed in all patients.

Results: Among 124 evaluable patients, anti-PD-1 therapy achieved an ORR of 29.8% and a durable clinical benefit rate of 60.5%. The median OS (mOS) was 17.1 months (95% CI 14.2 to 24.7), median PFS (mPFS) was 3.8 months (95% CI 3.4 to 6.0), and median DOR was 9.5 months. Significant OS benefit from treatment was observed in patients without liver metastasis (23.8 vs 13.3 months, p=0.006). Copy number deletion in genes encoding granzyme B or granzyme H () was associated with poor treatment outcome (mPFS altered vs wildtype: 1.7 vs 3.6 months, p=0.03; mOS altered vs wildtype: 10.1 vs 18 months, p=0.012).

Conclusions: Anti-PD-1 treatment provided promising clinical benefit in pretreated patients with R/M NPC. Copy number loss in either or genes was associated with reduced survival.
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http://dx.doi.org/10.1136/jitc-2020-002014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7978327PMC
March 2021

Intratumoral heterogeneity as a predictive biomarker in anti-PD-(L)1 therapies for non-small cell lung cancer.

Mol Cancer 2021 02 23;20(1):37. Epub 2021 Feb 23.

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 Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, 651 Dongfeng Road East, Guangzhou, 510060, Guangdong, China.

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http://dx.doi.org/10.1186/s12943-021-01331-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901210PMC
February 2021

Decoding the Evolutionary Response to Ensartinib in Patients With ALK-Positive NSCLC by Dynamic Circulating Tumor DNA Sequencing.

J Thorac Oncol 2021 05 13;16(5):827-839. Epub 2021 Feb 13.

2nd Department of Thoracic Surgery, Yunnan Cancer Hospital, Kunming, People's Republic of China.

Introduction: By implementing dynamic circulating tumor DNA (ctDNA) analysis, we explored the impact of TP53 mutations on tumor evolution and resistance mechanisms to ensartinib in patients with ALK-positive NSCLC.

Methods: In a multicenter phase 2 trial, patients with ALK-positive NSCLC who progressed on crizotinib were treated with ensartinib. Blood samples for ctDNA analysis were collected at baseline, cycle 3 day 1, and progression disease (PD) and analyzed with a 212-gene panel.

Results: A total of 440 samples were collected from 168 patients. Baseline TP53 mutations (20.2%) significantly correlated with inferior progression-free survival (4.2 mo versus 11.7 mo, p < 0.0001). Patients with TP53 mutations had higher mutation load than those without TP53 mutations at baseline (13.79 ± 3.72 versus 4.67 ± 0.39, p < 0.001). Although there was no significant difference in mutation load between these groups at cycle 3 day 1 (5.89 ± 2.25 versus 3.72 ± 0.62, p = 0.425), patients with mutated TP53 developed more mutations at PD (7.07 ± 1.25 versus 3.20 ± 0.33, p = 0.003). Frequency and abundance of secondary ALK mutations G1269A, G1202R, and E1210K increased markedly at PD than baseline. In patients without secondary ALK mutations, we identified ALK-independent resistance mechanisms including bypass signaling activation, downstream effector protein reactivation, epithelial-mesenchymal transformation, and epigenetic dysregulation.

Conclusions: Our study highlighted the advantage of ctDNA analysis for monitoring tumor evolution. TP53 mutations promoted genetic evolution and accelerated occurrence of resistance. We also unveiled ALK-dependent resistance mechanisms, mainly by G1269A, G1202R, and E1210K mutations, and ALK-independent resistance mechanisms to ensartinib.
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http://dx.doi.org/10.1016/j.jtho.2021.01.1615DOI Listing
May 2021

Cholesterol synthesis disruption combined with a molecule-targeted drug is a promising metabolic therapy for EGFR mutant non-small cell lung cancer.

Transl Lung Cancer Res 2021 Jan;10(1):128-142

Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China.

Background: Acquired resistance is a challenge for epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer. Here, we propose a novel treatment strategy based on recent lipid metabolism work.

Methods: We applied a variety of experimental methods such as immunoblotting, MTT, si-RNA, and animal models, to demonstrate the relationship between EGFR and low-density lipoprotein receptor (LDLR) and the effects of statin monotherapy, and TKI monotherapy, and their combination on cell proliferation at the cell level and animal level.

Results: LDLR has a positive correlation with EGFR, EGFR signaling upregulates LDLR expression through the SREBP-1 dependent pathway, EGFR mutation cells count on lipids to survive and grow. Combined with a molecule-targeted drug, atorvastatin not only enhances the treatment effect , but also mitigates the growth of NSCLC . In this animal experiment, the combination medicine (atorvastatin with TKI) has a better tumor suppression effect on NSCLC. In HCC827 cell line, the average tumor shrinkage is about 68% in Gefitinib group, and about 49% in atorvastatin group, but about 89% in combination group. In H1975 cell line, the average tumor shrinkage is about 18% in Osimertinib group, and about 8% in atorvastatin group, but about 44% in combination group.

Conclusions: the combination of an EGFR-TKI and a statin for EGFR mutant NSCLC may be a novel tumor inhibiting treatment.
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http://dx.doi.org/10.21037/tlcr-20-812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867776PMC
January 2021

Pre-Treatment Tumor Growth Rate Predicts Clinical Outcomes of Patients With Advanced Non-Small Cell Lung Cancer Undergoing Anti-PD-1/PD-L1 Therapy.

Front Oncol 2020 19;10:621329. Epub 2021 Jan 19.

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

Tumor growth rate (TGR; percent size change per month [%/m]) is postulated as an early radio-graphic predictor of response to anti-cancer treatment to overcome limitations of RECIST. We aimed to evaluate the predictive value of pre-treatment TGR (TGR) for outcomes of advanced non-small cell lung cancer (aNSCLC) patients treated with anti-PD-1/PD-L1 monotherapy. We retrospectively screened all aNSCLC patients who received PD-1 axis inhibitors in Sun Yat-Sen University Cancer Center between August 2016 and June 2018. TGR was calculated as the percentage change in tumor size per month (%/m) derived from two computed tomography (CT) scans during a "wash-out" period before the initiation of PD-1 axis inhibition. Final follow-up date was August 28, 2019. The X-tile program was used to identify the cut-off value of TGR based on maximum progression-free survival (PFS) stratification. Patients were divided into two groups per the selected TGR cut-off. The primary outcome was the difference of PFS between the two groups. The Kaplan-Meier methods and Cox regression models were performed for survival analysis. A total of 80 eligible patients were included (54 [67.5%] male; median [range] age, 55 [30-74] years). Median (range) TGR was 21.1 (-33.7-246.0)%/m. The optimal cut-off value of TGR was 25.3%/m. Patients with high TGR had shorter median PFS (1.8 months; 95% CI, 1.6 - 2.1 months) than those with low TGR (2.7 months; 95% CI, 0.5 - 4.9 months) ( = 0.005). Multivariate Cox regression analysis revealed that higher TGR independently predicted inferior PFS (hazard ratio [HR] 1.97; 95% CI, 1.08-3.60; = 0.026). Higher TGR was also significantly associated with less durable clinical benefit rate (34.8% vs. 8.8%, = 0.007). High pre-treatment TGR was a reliable predictor of inferior PFS and clinical benefit in aNSCLC patients undergoing anti-PD-1/PD-L1 monotherapy. The findings highlight the role of TGR as an early biomarker to predict benefit from immunotherapy and could allow tailoring patient's follow-up.
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http://dx.doi.org/10.3389/fonc.2020.621329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863973PMC
January 2021
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