Publications by authors named "Shun Lu"

307 Publications

Safety but Limited Efficacy of Ensartinib in ROS1-Positive Non-small Cell Lung Cancer: A Single-arm, Multicenter Phase II study.

J Thorac Oncol 2021 Jul 12. Epub 2021 Jul 12.

Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiaotong University, Shanghai, China. Electronic address:

Introduction: Some Anaplastic lymphoma kinase (ALK) inhibitors with good inhibition of ROS1 in preclinical studies has been reported possibly beneficial in ROS1-positive non-small cell lung cancer (NSCLC). In this work, we studied the efficacy and safety of ensartinib in the treatment of patients with ROS1-positive NSCLC.

Methods: The exploratory study was a phase II single-arm, multicenter design (NCT03608007). ROS1-positive NSCLC patients with a prior chemotherapy line number of ≤1 who received ensartinib at the dose of 225 mg once daily were enrolled. The primary endpoint was objective response rate (ORR) evaluated by investigator per Response Evaluation Criteria in Solid Tumors version 1.1.

Results: From June 2018 to July 2019, 59 patients were enrolled at 23 centers in China. At the time of data cutoff, the median follow-up was 19.8 months (range 0.8-22.5). The median ORR was 27.0% (95 % CI 13.8, 44.1) with 10 partial responses. Median duration of response (DoR) was 4.8 months (95% CI 1.8-10.8). The median progression-free survival (PFS) was 4.6 months (95% CI 4.0-6.4). The median overall survival (OS) was not estimable (95% CI 14.9-not estimable). Of 4 patients with brain metastases, intracranial disease control was reported in 3 (75.0%; 95% CI 19.4-99.4). The most common treatment-related adverse events (TRAEs) were rash and liver enzyme abnormalities, with good prognosis after adjustment for dosage and concomitant medication. The most of TRAEs were grade 1-2, and incidence of grade ≥3 TRAEs was 25.4%.

Conclusions: Ensartinib had a moderset efficacy in patients with ROS1-positive NSCLC with an acceptable safety profile.
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http://dx.doi.org/10.1016/j.jtho.2021.06.023DOI Listing
July 2021

Density Functional Theory Investigation of the [email protected] Composite as a Urea Oxidation Catalyst in the Alkaline Electrolyte.

ACS Omega 2021 Jun 26;6(22):14648-14654. Epub 2021 May 26.

Department of Agricultural and Biosystems Engineering, South Dakota State University, Brookings, South Dakota 57007, United States.

Developing efficient and low-cost urea oxidation reaction (UOR) catalysts is a promising but still challenging task for environment and energy conversion technologies such as wastewater remediation and urea electrolysis. In this work, NiO nanoparticles that incorporated graphene as the [email protected] composite were constructed to study the UOR process in terms of density functional theory. The single-atom model, which differed from the previous heterojunction model, was employed for the adsorption/desorption of urea and CO in the alkaline media. As demonstrated from the calculated results, [email protected] prefers to adsorb the hydroxyl group than urea in the initial stage due to the stronger adsorption energy of the hydroxyl group. After [email protected] was formed in the alkaline electrolyte, it presents excellent desorption energy of CO in the rate-determining step. Electronic density difference and the d band center diagram further confirmed that the Ni(III) species is the most favorable site for urea oxidation while facilitating charge transfer between urea and [email protected] Moreover, graphene provides a large surface for the incorporation of NiO nanoparticles, enhancing the electron transfer between NiOOH and graphene and promoting the mass transport in the alkaline electrolyte. Notably, this work provides theoretical guidance for the electrochemical urea oxidation work.
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http://dx.doi.org/10.1021/acsomega.1c01758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260271PMC
June 2021

Integrated Analysis of Genomic and Immunological Features in Lung Adenocarcinoma With Micropapillary Component.

Front Oncol 2021 17;11:652193. Epub 2021 Jun 17.

Translational Medicine Research Center, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Cancer Center, Zhejiang University School of Medicine, Hangzhou, China.

Background: Micropapillary adenocarcinoma is one of the most aggressive histologic subtypes of lung adenocarcinoma (LADC), and even a minor proportion of micropapillary component (MPC) within the LADC could contribute to poor prognosis. Comprehensive analysis of genetic and immunological features of LADC with different percentages of MPC would help better understand cancer biology of this LADC subtype and direct future treatments.

Methods: We performed next-generation sequencing (NGS) for a discovery cohort of 43 LADC patients whose tumors were micro-dissected to separate MPC and non-MPC lesions and a reference cohort of 113 LADC patients. MPC-enriched genetic alterations that were detected in the discovery cohort were then confirmed using a validation cohort of 183 LADC patients. Immunological staining was also conducted on the MPC-containing samples in the discovery cohort.

Results: Tumors with a higher percentage of MPC tended to harbor more tumor mutation burdens (TMBs) and chromosome instability (CIN). Some rare genetic events may serve as the genetic landscape to drive micropapillary tumor progression. Specifically, alterations in transcription termination factor 1 (), brain-specific angiogenesis inhibitor 3 (), mammalian target of rapamycin (), and cyclin-dependent kinase inhibitor 2A () were cross-validated to be enriched in MPC-contained LADC. Additionally, tumors with a higher percentage of MPC were associated with a higher percentage of CD4+, CD8+, and PD-L1+ staining, and some genetic changes that were enriched in MPC, including amplification and mutation, were correlated with increased PD-L1 expression.

Conclusion: We identified multiple novel MPC-enriched genetic changes that could help us understand the nature of this aggressive cancer subtype. High MPC tumors tended to have elevated levels of TMBs, T cell infiltration, and immunosuppression than low MPC tumors, implying the potential link between MPC content and sensitivity to immunotherapy.
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http://dx.doi.org/10.3389/fonc.2021.652193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248503PMC
June 2021

Icaritin Attenuates Lipid Accumulation by Increasing Energy Expenditure and Autophagy Regulated by Phosphorylating AMPK.

J Clin Transl Hepatol 2021 Jun 8;9(3):373-383. Epub 2021 Mar 8.

West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, Sichuan, China.

Background And Aims: Lipid accumulation is the major characteristic of non-alcoholic fatty liver disease, the prevalence of which continues to rise. We aimed to investigate the effects and mechanisms of icaritin on lipid accumulation.

Methods: Cells were treated with icaritin at 0.7, 2.2, 6.7, or 20 µM for 24 h. The effects on lipid accumulation in L02 and Huh-7 cells were detected by Bodipy and oil red O staining, respectively. Mitochondria biogenesis of L02 cells was detected by MitoTracker Orange staining. Glucose uptake and adenosine triphosphate content of 3T3-L1 adipocytes and C2C12 myotubes were detected. The expression levels of proteins in the adenosine 5'-monophosphate-activated protein kinase (AMPK) signaling pathway, biomarkers of autophagy, and mitochondria biogenesis were measured by western blotting. LC3 puncta were detected by immunofluorescence.

Results: Icaritin significantly attenuated lipid accumulation in L02 and Huh-7 cells and boosted the mitochondria biogenesis of L02 cells. Icaritin enhanced glucose uptake, decreased adenosine triphosphate content, and activated the AMPK signaling pathway in 3T3-L1 adipocytes and C2C12 myotubes. Icaritin boosted autophagy and also enhanced the initiation of autophagic flux in 3T3-L1 preadipocytes and C2C12 myoblasts. However, icaritin decreased autophagy and promoted mitochondria biogenesis in 3T3-L1 adipocytes and C2C12 myotubes.

Conclusions: Icaritin attenuates lipid accumulation by increasing energy expenditure and regulating autophagy by activating the AMPK pathway.
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http://dx.doi.org/10.14218/JCTH.2021.00050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237137PMC
June 2021

Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung: Final analysis of the randomised phase 3 LUX-Lung 8 trial.

EClinicalMedicine 2021 Jul 18;37:100940. Epub 2021 Jun 18.

Vall d'Hebron University Hospital and Institute of Oncology (VHIO), UVic-UCC, IOB-Quiron, Barcelona, Spain.

Background: LUX-Lung 8 was a randomised, controlled, phase 3 study comparing afatinib and erlotinib as second-line treatment of patients with advanced squamous cell carcinoma (SCC) of the lung. We report the final overall survival (OS) and safety analyses of LUX-Lung 8 and investigate the characteristics of patients who achieved long-term benefit (≥12 months' treatment).

Methods: LUX-Lung 8 (NCT01523587) enroled patients between March 2012 and January 2014 in 183 cancer centres located in 23 countries worldwide and this final analysis had a data cut-off of March 2018. Eligible patients had stage IIIB or IV lung SCC and had progressed after at least four cycles of platinum-based chemotherapy. Patients were randomly assigned (1:1) to receive afatinib (40 mg per day) or erlotinib (150 mg per day) until disease progression. Endpoints included OS and safety; a post-hoc analysis of patients with long-term benefit (≥12 months on treatment) was also conducted.

Findings: 795 eligible patients were randomly assigned (398 to afatinib, 397 to erlotinib). OS was significantly prolonged with afatinib compared with erlotinib (median 7·8 months vs 6·8 months; hazard ratio 0·84; 95% CI 0·73-0·97;  = 0·0193). These findings were consistent with those of the primary analysis and were consistent across subgroups. Adverse events (AEs) were manageable with dose interruption and reduction, with similar AEs being experienced between both groups. Twenty-one (5·3%) patients receiving afatinib and 13 (3·3%) patients receiving erlotinib achieved long-term benefit; median OS was 34·6 months and 20·1 months, respectively. Amongst 132 afatinib-treated patients who underwent tumour genetic analysis, family mutations were more common in patients with long-term benefit than in the overall population (50% vs 21%).

Interpretation: Afatinib is a treatment option for patients with SCC of the lung progressing on chemotherapy who are ineligible for immunotherapy, particularly those with family genetic aberrations. Afatinib has a predictable and manageable tolerability profile, and long-term treatment may be well tolerated.
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http://dx.doi.org/10.1016/j.eclinm.2021.100940DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8225678PMC
July 2021

Durable Response to the Combination of Atezolizumab With Platinum-Based Chemotherapy in an Untreated Non-Smoking Lung Adenocarcinoma Patient With V600E Mutation: A Case Report.

Front Oncol 2021 10;11:634920. Epub 2021 Jun 10.

Department of Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.

Background: Immune checkpoint inhibitor (ICPi) has become a major treatment in advanced non-small cell lung cancer (NSCLC) and demonstrated a clinical benefit for NSCLC patients with high programmed death ligand-1 (PD-L1) expression without drivers; however, the benefit in V600E NSCLC is so far unknown. Here, we report a case of prolonged tumor response to the combination of immunotherapy with chemotherapy in a non-smoking V600E NSCLC patient.

Materials And Methods: We verify a co-expression of V600E mutation and PD-L1 high expression more than 50% on formalin-fixed paraffin-embedded tumor sample of a newly diagnosed lung adenocarcinoma patient by immunohistochemistry and V600E/// Mutations Detection Kit. The tissue and liquid biopsies were further subjected to next-generation sequencing (NGS) for identification of mutations with progression on immunotherapy and BRAF inhibitor (BRAFi). The patient had provided written informed consent and authorized the publication of clinical case.

Results: We demonstrate the case of 62-year-old female non-smoker with high PD-L1 expression and V600E mutated NSCLC. The progression-free survival (PFS) of first-line combination of atezolizumab with platinum-based chemotherapy and sequential second-line treatment with BRAFi Vemurafenib are 20 and 5.5 months, respectively.

Conclusion: This case shows a durable response to ICPi in V600E non-smoking lung adenocarcinoma with PFS of 20 months under first-line atezolizumab plus chemotherapy treatment. The case supports the idea that the combination immunotherapy may be an attractive option for V600E mutated non-smoking NSCLC with high PD-L1 expression.
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http://dx.doi.org/10.3389/fonc.2021.634920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8222507PMC
June 2021

Enhancer of zeste homolog 2 contributes to apoptosis by inactivating janus kinase 2/ signal transducer and activator of transcription signaling in inflammatory bowel disease.

World J Gastroenterol 2021 Jun;27(22):3073-3084

Department of Radiation Oncology, Sichuan Cancer Hospital, Chengdu 610041, Sichuan Province, China.

Background: Inflammatory bowel disease (IBD) is a prevalent worldwide health problem featured by relapsing, chronic gastrointestinal inflammation. Enhancer of zeste homolog 2 (EZH2) is a critical epigenetic regulator in different pathological models, such as cancer and inflammation. However, the role of EZH2 in the IBD development is still obscure.

Aim: To explore the effect of EZH2 on IBD progression and the underlying mechanism.

Methods: The IBD mouse model was conducted by adding dextran sodium sulfate (DSS), and the effect of EZH2 on DSS-induced colitis was assessed in the model. The function of EZH2 in regulating apoptosis and permeability was evaluated by Annexin V-FITC Apoptosis Detection Kit, transepithelial electrical resistance analysis, and Western blot analysis of related markers, including Zona occludens 1, claudin-5, and occludin, in NCM460 and fetal human colon (FHC) cells. The mechanical investigation was performed by quantitative reverse transcriptionpolymerase chain reaction, Western blot analysis, and chromatin immunoprecipitation assays.

Results: The colon length was inhibited in the DSS-treated mice and was enhanced by the EZH2 depletion in the system. DSS treatment caused a decreased histological score in the mice, which was reversed by EZH2 depletion. The inflammatory cytokines, such as tumor necrosis factor-α, interleukin-6, and interleukin-1β, were induced in the DSS-treated mice, in which the depletion of EZH2 could reverse this effect. Moreover, the tumor necrosis factor-α treatment induced the apoptosis of NCM460 and FHC cells, in which EZH2 depletion could reverse this effect in the cells. Moreover, the depletion of EZH2 attenuated permeability of colonic epithelial cells. Mechanically, the depletion of EZH2 or EZH2 inhibitor GSK343 was able to enhance the expression and the phosphorylation of janus kinase 2 (JK2) and signal transducer and activator of transcription in the NCM460 and FHC cells. Specifically, EZH2 inactivated JAK2 expression by regulating histone H3K27me3. JAK2 inhibitor TG101348 was able to reverse EZH2 knockdown-mediated colonic epithelial cell permeability and apoptosis.

Conclusion: Thus, we concluded that EZH2 contributed to apoptosis and inflammatory response by inactivating JAK2/ signal transducer and activator of transcription signaling in IBD. EZH2 may be applied as a potential target for IBD therapy.
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http://dx.doi.org/10.3748/wjg.v27.i22.3073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192283PMC
June 2021

Once-daily savolitinib in Chinese patients with pulmonary sarcomatoid carcinomas and other non-small-cell lung cancers harbouring MET exon 14 skipping alterations: a multicentre, single-arm, open-label, phase 2 study.

Lancet Respir Med 2021 Jun 21. Epub 2021 Jun 21.

Hutchison MediPharma, Shanghai, China.

Background: Savolitinib is a selective MET tyrosine-kinase inhibitor. We investigated the activity and safety of savolitinib in patients with pulmonary sarcomatoid carcinoma and other non-small-cell lung cancer (NSCLC) subtypes positive for MET exon 14 skipping alterations (METex14-positive).

Methods: We did a multicentre, single-arm, open-label, phase 2 study across 32 hospitals in China. Eligible patients were 18 years or older with locally advanced or metastatic METex14-positive pulmonary sarcomatoid carcinoma or other NSCLC subtypes, had either presented with disease progression or toxicity intolerance towards one or more standard treatments or were deemed clinically unsuitable for standard treatment, were MET inhibitor-naive, and had measurable disease. Patients received either 600 mg (bodyweight ≥50 kg) or 400 mg (bodyweight <50 kg) of oral savolitinib once daily until disease progression, death, intolerable toxicity, initiation of other anti-tumour therapy, non-compliance, patient withdrawal, or patient discontinuation. Radiographic tumour evaluation was done at baseline, every 6 weeks within 1 year of the first dose, and every 12 weeks thereafter. The primary endpoint was objective response rate, defined as the proportion of patients with confirmed complete or partial responses by independent review committee (IRC) assessment. The primary endpoint was assessed in the tumour response evaluable set, which comprised all treated patients with a measurable lesion at baseline and at least one adequate scheduled post-baseline tumour assessment or the presence of radiological disease progression, with a sensitivity analysis done in the full analysis set, which comprised all patients who received at least one dose of savolitinib. Safety was also evaluated in the full analysis set. This study is registered with ClinicalTrials.gov, NCT02897479, and recruitment is complete, with treatment and follow-up ongoing.

Findings: From Nov 8, 2016, to Aug 3, 2020, 84 patients with METex14 skipping alterations were screened for eligibility, of whom 70 were enrolled, received savolitinib, and comprised the full analysis set. The IRC-assessed tumour response evaluable set comprised 61 patients. At a median follow-up of 17·6 months (IQR 14·2-24·4), the IRC-assessed objective response rate was 49·2% (36·1-62·3; 30 of 61 patients) in the tumour response evaluable set and 42·9% (95% CI 31·1-55·3; 30 of 70 patients) in the full analysis set. All 70 patients reported at least one treatment-related adverse event. Treatment-related adverse events of grade 3 or more occurred in 32 (46%) patients, the most frequent of which were increased aspartate aminotransferase (n=9), increased alanine aminotransferase (n=7), and peripheral oedema (n=6). Treatment-related serious adverse events occurred in 17 (24%) patients, the most common being abnormal hepatic function (n=3) and hypersensitivity (n=2). One death due to tumour lysis syndrome in a patient with pulmonary sarcomatoid carcinoma was assessed to be probably related to savolitinib by the investigator.

Interpretation: Savolitinib yielded promising activity and had an acceptable safety profile in patients with pulmonary sarcomatoid carcinoma and other NSCLC subtypes positive for METex14 skipping alterations. Savolitinib could therefore be a novel treatment option in this population.

Funding: Hutchison MediPharma and AstraZeneca.

Translation: For the Chinese translation of the abstract see Supplementary Materials section.
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http://dx.doi.org/10.1016/S2213-2600(21)00084-9DOI Listing
June 2021

Knockdown of CDK5 down-regulates PD-L1 via the ubiquitination-proteasome pathway and improves antitumor immunity in lung adenocarcinoma.

Transl Oncol 2021 Sep 12;14(9):101148. Epub 2021 Jun 12.

Department of Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 Huaihai West Road, Shanghai 200030, PR China. Electronic address:

Although immunotherapy (anti-PD-1/PD-L1 antibodies) has been approved for clinical treatment of lung cancer, only a small proportion of patients respond to monotherapy. Hence, understanding the regulatory mechanism of PD-L1 is particularly important to identify optimal combinations. In this study, we found that inhibition of CDK5 induced by shRNA or CDK5 inhibitor leads to reduced expression of PD-L1 protein in human lung adenocarcinoma cells, while the mRNA level is not substantially altered. The PD-L1 protein degradation is mediated by E3 ligase TRIM21 via ubiquitination-proteasome pathway. Subsequently, we studied the function of CDK5/PD-L1 axis in LUAD. In vitro, the absence of CDK5 in mouse Lewis lung cancer cell (LLC) has no effect on cell proliferation. However, the attenuation of CDK5 or combined with anti-PD-L1 greatly suppresses tumor growth in LLC implanted mouse models in vivo. Disruption of CDK5 elicits a higher level of CD3, CD4 and CD8 T cells in spleens and lower PD-1 expression in CD4 and CD8 T cells. Our findings highlight a role for CDK5 in promoting antitumor immunity, which provide a potential therapeutic target for combined immunotherapy in LUAD.
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http://dx.doi.org/10.1016/j.tranon.2021.101148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8215302PMC
September 2021

Serum Metabolite Biomarkers Predictive of Response to PD-1 Blockade Therapy in Non-Small Cell Lung Cancer.

Front Mol Biosci 2021 21;8:678753. Epub 2021 May 21.

CAS-Key Laboratory of Synthetic Biology, CAS Center for Excellence in Molecular Plant Sciences, Chinese Academy of Sciences, Shanghai, China.

Despite remarkable success of immunotherapies with checkpoint blockade antibodies targeting programmed cell death protein 1 (PD-1), the majority of patients with non-small-cell lung cancer (NSCLC) have yet to receive durable benefits. We used the metabolomic profiling of early on-treatment serum to explore predictors of clinical outcomes of anti-PD-1 treatment in patients with advanced NSCLC. We recruited 74 Chinese patients who had stage IIIB/IV NSCLC-proven tumor progression and were treated with PD-1 inhibitor. The study was comprised of a discovery cohort of patients treated with nivolumab and two validation cohorts of patients receiving tislelizumab or nivolumab. Serum samples were collected 2-3 weeks after the first infusion of PD-1 inhibitor. Metabolomic profiling of serum was performed using ultrahigh performance lipid chromatograph-mass spectrometry. The serum metabolite biomarkers were identified using an integral workflow of nontargeted metabolomic data analysis. A serum metabolite panel consisting of hypoxanthine and histidine was identified and validated as a predictor of response to PD-1 blockade treatment in patients with advanced NSCLC. High levels of both hypoxanthine and histidine in early on-treatment serum were associated with improved progression-free survival [hazard ratio (HR) = 0.078, 95% confidence interval (CI), 0.027-0.221, 0.001] and overall survival (HR = 0.124, 95% CI, 0.039-0.397, 0.001) in the discovery cohort. The serum metabolite panel showed a high sensitivity and specificity in distinguishing responders and non-responders in the validation cohorts 1 and 2, with an area under the receiver-operating characteristic curve of 0.933 and 1.000, respectively. High levels of serum hypoxanthine and histidine were correlated with improved progression-free survival in the validation cohort 1 (HR = 0.137, 95% CI, 0.040-0.467, 0.001) and in the validation cohort 2 (HR = 0.084, 95% CI, 0.009-0.762, 0.028). Our results revealed that hypoxanthine and histidine in early on-treatment serum are predictive biomarkers of response to PD-1 blockade therapy in patients with advanced NSCLC. The serum biomarker panel would enable early identification of NSCLC patients who may benefit from PD-1 blockade therapy.
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http://dx.doi.org/10.3389/fmolb.2021.678753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8176105PMC
May 2021

Pro-cachectic factors link experimental and human chronic kidney disease to skeletal muscle wasting programs.

J Clin Invest 2021 Jun;131(11)

Michigan Medicine, Ann Arbor, Michigan, USA.

Skeletal muscle wasting is commonly associated with chronic kidney disease (CKD), resulting in increased morbidity and mortality. However, the link between kidney and muscle function remains poorly understood. Here, we took a complementary interorgan approach to investigate skeletal muscle wasting in CKD. We identified increased production and elevated blood levels of soluble pro-cachectic factors, including activin A, directly linking experimental and human CKD to skeletal muscle wasting programs. Single-cell sequencing data identified the expression of activin A in specific kidney cell populations of fibroblasts and cells of the juxtaglomerular apparatus. We propose that persistent and increased kidney production of pro-cachectic factors, combined with a lack of kidney clearance, facilitates a vicious kidney/muscle signaling cycle, leading to exacerbated blood accumulation and, thereby, skeletal muscle wasting. Systemic pharmacological blockade of activin A using soluble activin receptor type IIB ligand trap as well as muscle-specific adeno-associated virus-mediated downregulation of its receptor ACVR2A/B prevented muscle wasting in different mouse models of experimental CKD, suggesting that activin A is a key factor in CKD-induced cachexia. In summary, we uncovered a crosstalk between kidney and muscle and propose modulation of activin signaling as a potential therapeutic strategy for skeletal muscle wasting in CKD.
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http://dx.doi.org/10.1172/JCI135821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159690PMC
June 2021

Tislelizumab Plus Chemotherapy as First-Line Treatment for Locally Advanced or Metastatic Nonsquamous NSCLC (RATIONALE 304): A Randomized Phase 3 Trial.

J Thorac Oncol 2021 May 23. Epub 2021 May 23.

Peking Union Medical College Hospital, Department of Pulmonary Medicine, Beijing, People's Republic of China.

Introduction: Tislelizumab, an anti-programmed cell death protein-1 antibody, was specifically engineered to minimize FcɣR macrophage binding to abrogate antibody-dependent phagocytosis. Compared with chemotherapy alone, tislelizumab plus chemotherapy may improve clinical outcomes in patients with advanced nonsquamous NSCLC (nsq-NSCLC).

Methods: In this open-label phase 3 trial (RATIONALE 304; NCT03663205), patients with histologically confirmed stage IIIB or IV nsq-NSCLC were randomized (2:1) to receive either arm A: tislelizumab plus platinum (carboplatin or cisplatin) and pemetrexed every 3 weeks (Q3Ws) or arm B: platinum and pemetrexed alone Q3W during induction treatment, followed by intravenous maintenance pemetrexed Q3W. The primary end point was progression-free survival (PFS) assessed by an independent review committee; clinical response and safety and tolerability were secondary end points.

Results: Overall, 332 patients (n = 222 [A]; n = 110 [B]) received treatment. With a median study follow-up of 9.8 months, PFS was significantly longer with tislelizumab plus chemotherapy compared with chemotherapy alone (median PFS: 9.7 versus 7.6 mo; hazard ratio = 0.645 [95% confidence interval: 0.462-0.902], p = 0.0044). In addition, response rates were higher and response duration was longer with combination therapy versus chemotherapy alone. Hematologic adverse events (AEs) were common in both treatment arms; the most reported AEs were grades 1 to 2 in severity. The most common grade greater than or equal to 3 AEs were associated with chemotherapy and included neutropenia (44.6% [A]; 35.5% [B]) and leukopenia (21.6% [A]; 14.5% [B]).

Conclusions: Addition of tislelizumab to chemotherapy resulted in significantly prolonged PFS, higher response rates, and longer response duration compared with chemotherapy alone, identifying a new potential option for first-line treatment of advanced nsq-NSCLC irrespective of disease stage.
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http://dx.doi.org/10.1016/j.jtho.2021.05.005DOI Listing
May 2021

Identification of immune subtypes of cervical squamous cell carcinoma predicting prognosis and immunotherapy responses.

J Transl Med 2021 05 24;19(1):222. Epub 2021 May 24.

Department of Radiation Oncology, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, No.55, South Renmin Avenue Fourth Section, Chengdu City, 610041, Sichuan Province, People's Republic of China.

Background: The main limitation of current immune checkpoint inhibitors (ICIs) in the treatment of cervical cancer comes from the fact that it benefits only a minority of patients. The study aims to develop a classification system to identify immune subtypes of cervical squamous cell carcinoma (SCC), thereby helping to screen candidates who may respond to ICIs.

Methods: A real-world cervical SCC cohort of 36 samples were analyzed. We used a nonnegative matrix factorization (NMF) algorithm to separate different expression patterns of immune-related genes (IRGs). The immune characteristics, potential immune biomarkers, and somatic mutations were compared. Two independent data sets containing 555 samples were used for validation.

Results: Two subtypes with different immunophenotypes were identified. Patients in sub1 showed favorable progression-free survival (PFS) and overall survival (OS) in the training and validation cohorts. The sub1 was remarkably related to increased immune cell abundance, more enriched immune activation pathways, and higher somatic mutation burden. Also, the sub1 group was more sensitive to ICIs, while patients in the sub2 group were more likely to fail to respond to ICIs but exhibited GPCR pathway activity. Finally, an 83-gene classifier was constructed for cervical SCC classification.

Conclusion: This study establishes a new classification to further understand the immunological diversity of cervical SCC, to assist in the selection of candidates for immunotherapy.
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http://dx.doi.org/10.1186/s12967-021-02894-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8142504PMC
May 2021

Plasma mutation abundance affects clinical response to first-line EGFR-TKIs in patients with advanced non-small cell lung cancer.

Ann Transl Med 2021 Apr;9(8):635

Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.

Background: Activated epidermal growth factor receptor () mutation is the main pathogenic cause of non-small cell lung cancer (NSCLC) in Asia. However, the impact of plasma mutation abundance, especially of the ultra-low abundance of mutation detected by highly sensitive techniques on clinical outcomes of first-line EGFR tyrosine kinase inhibitors (TKIs) for advanced NSCLC patients remains unclear.

Methods: We qualitatively detected baseline status of NSCLC tissues using amplification-refractory mutation system and quantified the plasma abundance of mutations through next-generation sequencing (NGS). Every 8-12 weeks, we performed dynamic detection of plasma mutation abundance and imaging evaluation. We analyzed the association between plasma abundance of sensitizing mutations, tumor size, tumor shrinkage percentage, concomitant mutations, and clinical response to TKIs.

Results: This prospective study enrolled 135 patients with advanced NSCLC. The objective response rate (ORR) and disease control rate (DCR) for mutation-positive patients were 50.0% and 87.0%, respectively. When the cutoff value of plasma mutation abundance was 0.1%, the ORRs of TKI-treated patients were significantly different (60.0% for the >0.1% group 21.4% for the ≤0.1% group, P=0.028). Median progression-free survival (PFS) was significantly longer for participants with a mutation abundance above 0.1% compared to those with a 0.01-0.1% abundance (log rank, P=0.0115). There was no significant association between plasma abundance of sensitizing mutations and tumor size, tumor shrinkage percentage, or concomitant mutations. Cox multivariate analysis demonstrated that plasma mutation abundance was an independent predictive factor for PFS [hazard ratio (HR) 2.41, 95% confidence interval (CI): 1.12-5.20; P=0.025]. We identified 11 participants with the acquired T790M resistance mutation according to serial dynamic plasma samples.

Conclusions: Liquid biopsy screening based on highly sensitive NGS is reliable for detecting drug resistance and actionable somatic mutations. The plasma abundance of the driver mutation affected clinical response to EGFR-TKIs in advanced NSCLC patients; prolongation of PFS was also observed in patients with an ultra-low abundance of sensitizing mutations.
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http://dx.doi.org/10.21037/atm-20-7155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106032PMC
April 2021

Mini-patient-derived xenograft assay based on microfluidic technology promises to be an effective tool for screening individualized chemotherapy regimens for advanced non-small cell lung cancer.

Cell Biol Int 2021 May 4. Epub 2021 May 4.

Department of Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.

Patient-derived xenograft (PDX) assay has been widely used in preclinical research in patients with multidrug-resistant lung cancer. One hundred patients with non-small cell lung cancer (NSCLC) were divided into MiniPDX group and conventional group, with 50 cases in each group. The MiniPDX assay was established by enriching high-purity tumor cells using microfluidic technology to detect the drug sensitivity of NSCLC cells. All patients underwent conventional computed tomography (CT) scans of lung and mediastinum at baseline and during follow-up. Kaplan-Meier method was used to compare the overall survival and progression-free survival of two groups. The sensitivity of the same drug in different tumor xenograft varied greatly. The overall survival, progression-free survival, and clinical benefit rate of patients in the MiniPDX-guided chemotherapy group were significantly longer than those in the conventional chemotherapy group. MiniPDX assay may be an effective tool for screening chemotherapy regimens in NSCLC patients.
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http://dx.doi.org/10.1002/cbin.11622DOI Listing
May 2021

Efficacy and Safety of Niraparib as Maintenance Treatment in Patients With Extensive-Stage SCLC After First-Line Chemotherapy: A Randomized, Double-Blind, Phase 3 Study.

J Thorac Oncol 2021 Apr 26. Epub 2021 Apr 26.

Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang, People's Republic of China.

Introduction: ZL-2306-005 is a randomized, double-blind, multicenter phase 3 study evaluating the efficacy and safety of niraparib, a poly(adenosine diphosphate-ribose) polymerase inhibitor, as first-line maintenance therapy in Chinese patients with platinum-responsive, extensive-stage SCLC (ES-SCLC).

Methods: Patients with complete response (CR) or partial response (PR) to standardized, platinum-based first-line chemotherapy were randomized 2:1 to receive niraparib or placebo (300 mg [baseline body weight ≥ 77 kg, platelet count ≥ 150,000/μL] or 200 mg) once daily until progression or unacceptable toxicity. Primary end points were progression-free survival (PFS) (blinded independent central review) and overall survival (sample size planned: 591 patients). Secondary end points included investigator-evaluated PFS and safety.

Results: ZL-2306-005 was terminated early owing to ES-SCLC treatment landscape changes (data cutoff: March 20, 2020). During July 2018-February 2020, a total of 185 of 272 patients screened were randomized (niraparib: n = 125 [CR = 1, PR = 124]; placebo: n = 60 [CR = 1, PR = 59]). Median (95% confidence interval [CI]) PFS (blinded independent central review) was 1.54 months (1.41-2.69, niraparib) and 1.36 months (1.31-1.48, placebo); hazard ratio (HR) = 0.66 (95% CI: 0.46-0.95, p = 0.0242). Median overall survival was 9.92 months (9.33-13.54, niraparib) and 11.43 months (9.53-not estimable, placebo); HR = 1.03 (95% CI: 0.62-1.73, p = 0.9052). Median investigator-evaluated PFS was 1.48 months (1.41-2.56, niraparib) and 1.41 months (1.31-2.00, placebo); HR = 0.88 (95% CI: 0.61-1.26; p = 0.4653). Grade greater than or equal to 3 adverse events occurred in 34.4% (niraparib) and 25.0% (placebo) of patients.

Conclusions: ZL-2306-005 did not reach primary end points. Nevertheless, niraparib as maintenance therapy modestly improved PFS in patients with platinum-responsive ES-SCLC, with acceptable tolerability profile and no new safety signal.
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http://dx.doi.org/10.1016/j.jtho.2021.04.001DOI Listing
April 2021

Oral Tongue Cancer in a Patient with Fanconi Anemia: A Case Report and Literature Review.

Cancer Manag Res 2021 12;13:3145-3154. Epub 2021 Apr 12.

Department of Radiation Oncology, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, People's Republic of China.

Purpose: Fanconi anemia (FA) is a rare genetic disorder characterized by congenital anomalies, progressive bone marrow failure and high susceptibility to solid tumors, especially head and neck squamous cell carcinoma (HNSCC). Management of FA patients with head and neck cancer is a challenge due to increased risk of surgery, poor tolerance of chemotherapy, and severe myelotoxicity of radiotherapy.

Patients And Methods: We present a case of a 33-year-old man with carcinoma of oral tongue (T1N2M0), who experienced prolonged and profound bone marrow failure as a consequence of concurrent cisplatin/radiation. The young patient who developed HNSCC without risk factors, the myelotoxicity after exposure to platinum-based agent cisplatin and the further evaluation of phenotypic characteristics raised suspicion of FA. Whole exome sequencing performed for the patient and parents ultimately established the diagnosis of FA.

Results: Genetic testing in 23 FANC genes revealed two novel heterozygous mutations, c.367C>T and c.3971_3972delCGinsTT in FANCA gene of the patient, which were inherited from his father and mother, respectively. Radiotherapy with reduced dose has successfully alleviated the symptoms of tumor invasion and progression, and the radiation-related side effects were acceptable. Unfortunately, the patient eventually died of locoregional disease progression.

Conclusion: This case highlights the importance of considering the diagnosis of FA in young patients who develop HNSCC in the absence of risk factors, thus permitting more effective oncological treatment strategies and improved outcomes. In conclusion, any decision on different modalities of management in such patients should be based on a balance between locoregional control and therapeutic toxicity.
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http://dx.doi.org/10.2147/CMAR.S301582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8053604PMC
April 2021

Hexokinase 2 discerns a novel circulating tumor cell population associated with poor prognosis in lung cancer patients.

Proc Natl Acad Sci U S A 2021 Mar;118(11)

Institute for Systems Biology, Seattle, WA 98109;

Unlike other epithelial cancer types, circulating tumor cells (CTCs) are less frequently detected in the peripheral blood of non-small cell lung cancer (NSCLC) patients using epithelial marker-based detection approaches despite the aggressive nature of NSCLC. Here, we demonstrate hexokinase-2 (HK2) as a metabolic function-associated marker for the detection of CTCs. In 59 NSCLC patients bearing cytokeratin-positive (CK) primary tumors, HK2 enables resolving cytokeratin-negative (HK2/CK) CTCs as a prevalent population in about half of the peripheral blood samples with positive CTC counts. However, HK2/CK tumor cells are a minority population in pleural effusions and cerebrospinal fluids. Single-cell analysis shows that HK2/CK CTCs exhibit smaller sizes but consistent copy number variation profiles compared with CK counterparts. Single-cell transcriptome profiling reveals that CK expression levels of CTCs are independent of their epithelial-to-mesenchymal transition (EMT) status, challenging the long-standing association between CK expression and EMT. HK2/CK CTCs display metastasis and EGFR inhibitor resistance-related molecular signatures and are selectively enriched in patients with driver oncogene mutation as opposed to , which is more frequently found in patients with prevalent CK CTCs in the blood. Consistently, treatment-naïve patients with a larger number or proportion of HK2/CK CTCs in the blood exhibit poor therapy response and shorter progression-free survival. Collectively, our approach resolves a more complete spectrum of CTCs in NSCLC that can potentially be exploited to identify patient prognosis before therapy.
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http://dx.doi.org/10.1073/pnas.2012228118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980452PMC
March 2021

An efficient primary screening of COVID-19 by serum Raman spectroscopy.

J Raman Spectrosc 2021 Feb 19. Epub 2021 Feb 19.

Department of Radiation Oncology Sichuan Cancer Hospital & Institute Chengdu China.

The outbreak of COVID-19 coronavirus disease around the end of 2019 has become a pandemic. The preferred method for COVID-19 detection is the real-time polymerase chain reaction (RT-PCR)-based technique; however, it also has certain limitations, such as sample-dependent procedures with a relatively high false negative ratio. We propose a safe and efficient method for screening COVID-19 based on Raman spectroscopy. A total of 177 serum samples are collected from 63 confirmed COVID-19 patients, 59 suspected cases, and 55 healthy individuals as a control group. Raman spectroscopy is adopted to analyze these samples, and a machine learning support-vector machine (SVM) method is applied to the spectrum dataset to build a diagnostic algorithm. Furthermore, 20 independent individuals, including 5 asymptomatic COVID-19 patients and 5 symptomatic COVID-19 patients, 5 suspected patients, and 5 healthy patients, were sampled for external validation. In these three groups-confirmed COVID-19, suspected, and healthy individuals-the distribution of statistically significant points of difference showed highly consistency for intergroups after repeated sampling processes. The classification accuracy between the COVID-19 cases and the suspected cases is 0.87 (95% confidence interval [CI]: 0.85-0.88), and the accuracy between the COVID-19 and the healthy controls is 0.90 (95% CI: 0.89-0.91), while the accuracy between the suspected cases and the healthy control group is 0.68 (95% CI: 0.67-0.73). For the independent test dataset, we apply the obtained SVM model to the classification of the independent test dataset to have all the results correctly classified. Our model showed that the serum-level classification results were all correct for independent test dataset. Our results suggest that Raman spectroscopy could be a safe and efficient technique for COVID-19 screening.
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http://dx.doi.org/10.1002/jrs.6080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014023PMC
February 2021

Bioinformatics Analysis and Identification of Genes and Molecular Pathways Involved in Venous Thromboembolism (VTE).

Ann Vasc Surg 2021 Apr 2. Epub 2021 Apr 2.

Department of Vascular Surgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi Zhuang Autonomous Region, China. Electronic address:

Objectives: To explore the key genes, and correlated pathways in venous thromboembolism (VTE) via bioinformatic analysis, and expected our findings could contribute to the development of new biomarkers and therapeutic target for VTE.

Methods: Two VTE-related microarray expression profiles (GSE48000 and GSE19151) were downloaded from the Gene Expression Ominibus (GEO) database. Differentially expressed genes (DEGs) were analyzed using limma package, and overlapping DEGs were identified form the above two expression profiles. Then, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEEG) pathway enrichment analyses were performed by DAVID. Protein-protein interaction (PPI) network was constructed by using STRING and visualized with Cytoscape. Furthermore, module analysis plus centrality analysis of the PPI network were executed to identify the potential key genes. Finally, the pathway analysis was performed using GenCLiP 3.0.

Results: A total of 173 DEGs (125 upregulated and 48 downregulated) were identified. GO analysis demonstrated that DEGs were mainly enriched in viral life cycle, ribosome and structural constituent of ribosome. Meanwhile, KEGG pathway analysis showed that these genes were enriched in ribosome, Parkinson's disease and cell cycle. Additionally, one most significant module and 12 hub genes were found. Finally, 6 key genes, namely ISG15, RPS15A, MRPL13, ICT1, MRPL15 and RPLP0, with high centrality features were identified. These key genes were mainly involved in translation, metabolism of proteins and ribosome pathway.

Conclusions: In summary, these 6 identified genes and correlated pathways should play an important role in VTE, which can provide new insight into the molecular mechanism, potential biomarkers and therapeutic targets associated with VTE.
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http://dx.doi.org/10.1016/j.avsg.2021.02.020DOI Listing
April 2021

Tislelizumab Plus Chemotherapy vs Chemotherapy Alone as First-line Treatment for Advanced Squamous Non-Small-Cell Lung Cancer: A Phase 3 Randomized Clinical Trial.

JAMA Oncol 2021 May;7(5):709-717

Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.

Importance: This study demonstrates that tislelizumab in combination with chemotherapy is associated with improved progression-free survival (PFS) in patients with advanced squamous non-small-cell lung cancer (sq-NSCLC).

Objective: To assess the efficacy and safety/tolerability of tislelizumab plus chemotherapy vs chemotherapy alone as first-line treatment for patients with advanced sq-NSCLC.

Design, Setting, And Participants: This open-label, randomized phase 3 clinical trial was conducted at 46 sites in China between July 2018 and June 2019 and included patients with treatment-naive, histologically confirmed stage IIIB/IV sq-NSCLC. The data cutoff for these analyses was December 6, 2019; data extraction occurred on January 7, 2020.

Interventions: Patients were randomized (1:1:1) to receive 1 of the following regimens intravenously on a 21-day cycle: tislelizumab (200 mg, day 1) plus paclitaxel (175 mg/m2, day 1) and carboplatin (area under the concentration of 5, day 1) (arm A); tislelizumab plus nab-paclitaxel (100 mg/m2, days 1, 8, and 15) and carboplatin (arm B); and paclitaxel and carboplatin (arm C). Patients were stratified by disease stage and tumor programmed cell death 1 ligand 1 (PD-L1) expression (<1% vs 1%-49% vs ≥50%).

Main Outcomes And Measures: The primary end point was progression-free survival (PFS) assessed by an independent review committee (IRC). Secondary end points included overall survival, investigator-assessed (INV) PFS, IRC-assessed objective response rate (ORR), and IRC-assessed duration of response, as well as the incidence and severity of adverse events (AEs).

Results: Overall, 355 patients (median [range] age, 62 [34-74] years; 330 men [91.7%]) with sq-NSCLC received treatment. After a median study follow-up of 8.6 months (95% CI, 8.1-9.0 months), IRC-assessed PFS was significantly improved with tislelizumab plus chemotherapy (arm A, 7.6 months; arm B, 7.6 months) vs chemotherapy alone (arm C, 5.5 months; hazard ratios were 0.524 (95% CI, 0.370-0.742; P < .001 [A vs C]) and 0.478 (95% CI, 0.336-0.679; P < .001 [B vs C]). Higher IRC-assessed ORR and longer IRC-assessed duration of response were observed in arms A (72.5%; 8.2 months) and B (74.8%; 8.6 months) vs C (49.6%; 4.2 months). No association was observed between PD-L1 expression and IRC-assessed PFS or ORR. Discontinuation of any treatment because of AEs was reported in 15 (12.5%; arm A), 35 (29.7%; arm B), and 18 (15.4%; arm C) patients. In each arm, the most common grade of 3 or greater AE was decreased neutrophil levels, which aligned with known chemotherapy toxic effects. Six treatment-related AEs leading to death occurred; however, no deaths were solely attributed to tislelizumab.

Conclusions And Relevance: In this phase 3 randomized clinical trial, adding tislelizumab to chemotherapy was associated with significantly prolonged IRC-assessed PFS, higher IRC-assessed ORRs, and a manageable safety/tolerability profile in patients with advanced sq-NSCLC, regardless of PD-L1 expression.

Trial Registration: ClinicalTrials.gov Identifier: NCT03594747.
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http://dx.doi.org/10.1001/jamaoncol.2021.0366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017481PMC
May 2021

Outcome of Adenoid Cystic Carcinoma of Head and Neck After Postoperative Intensity Modulation Radiotherapy: A Single Institution Study.

Cancer Manag Res 2021 15;13:2411-2417. Epub 2021 Mar 15.

Department of Radiation Oncology, Sichuan Cancer Hospital and Research Institute, Chengdu, People's Republic of China.

Objective: This study was retrospectively evaluated the outcome of postoperative intensity modulation radiotherapy (IMRT) for patients with adenoid cystic carcinoma of head and neck (ACCHN), and identified the unfavorable prognostic factors.

Methods: Fifty-five ACCHN patients treated in Sichuan Cancer Hospital between January 2007 and December 2016 were retrospectively evaluated. Median age of patient was 47 years (range, 21-73 years). Thirty-five patients were male and 20 were female. In 30 patients, tumors were located in major salivary glands (54.5%), and 25 patients in minor salivary glands (45.5%). The numbers of R0, R1, and R2 surgical resection classification patients were 22 (40.0%), 20 (36.4%), and 13 (23.6%). The median total RT dose was 62 Gy (range, 46-72 Gy), and 54.5% of patients were treated with adjuvant chemotherapy. Statistical analyses were performed using the Log rank test for univariate analysis and the Cox proportional hazard model for multivariate analysis.

Results: Median follow-up period was 68.5 months (12-132 months). The 5-year local-regional recurrence-free survival (LRRFS), distant metastasis-free survival (DMFS) and overall survival (OS) were 93.9%, 75.3% and 82.5%. In univariate analysis, T stages (=0.025) and AJCC stages (=0.036) were the prognostic factors for OS; Age (=0.042), T stages (=0.025), N stages (=0.021), AJCC stages (=0.021) and adjuvant chemotherapy (=0.010) were the prognostic factors for DMFS; T stage (=0.049) was the prognostic factor for LRRFS. In multivariate factors analyses, T stages (=0.026), AJCC stages (=0.028) and RT dose (=0.025) were the significant prognosticators for OS. The most common acute toxicities over three degrees were myelosuppression (5.5%), mucositis (9.1%) and dermatitis (1.8%).

Conclusion: Postoperative IMRT seems to achieve reasonable local-regional control and OS in patients with adenoid cystic carcinoma of head and neck, with acceptable treatment relative toxicities.
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http://dx.doi.org/10.2147/CMAR.S283494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979337PMC
March 2021

Identification and validation of hypoxia-derived gene signatures to predict clinical outcomes and therapeutic responses in stage I lung adenocarcinoma patients.

Theranostics 2021 5;11(10):5061-5076. Epub 2021 Mar 5.

Department of Radiation Oncology, University Hospital, LMU Munich, Munich D-81377, Germany.

The current tumour-node-metastasis (TNM) staging system is insufficient for precise treatment decision-making and accurate survival prediction for patients with stage I lung adenocarcinoma (LUAD). Therefore, more reliable biomarkers are urgently needed to identify the high-risk subset in stage I patients to guide adjuvant therapy. This study retrospectively analysed the transcriptome profiles and clinical parameters of 1,400 stage I LUAD patients from 14 public datasets, including 13 microarray datasets from different platforms and 1 RNA-Seq dataset from The Cancer Genome Atlas (TCGA). A series of bioinformatic and machine learning approaches were combined to establish hypoxia-derived signatures to predict overall survival (OS) and immune checkpoint blockade (ICB) therapy response in stage I patients. In addition, enriched pathways, genomic and copy number alterations were analysed in different risk subgroups and compared to each other. Among various hallmarks of cancer, hypoxia was identified as a dominant risk factor for overall survival in stage I LUAD patients. The hypoxia-related prognostic risk score (HPRS) exhibited more powerful capacity of survival prediction compared to traditional clinicopathological features, and the hypoxia-related immunotherapeutic response score (HIRS) outperformed conventional biomarkers for ICB therapy. An integrated decision tree and nomogram were generated to optimize risk stratification and quantify risk assessment. In summary, the proposed hypoxia-derived signatures are promising biomarkers to predict clinical outcomes and therapeutic responses in stage I LUAD patients.
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http://dx.doi.org/10.7150/thno.56202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7978303PMC
March 2021

Afatinib as First-Line Treatment in Asian Patients with EGFR Mutation-Positive NSCLC: A Narrative Review of Real-World Evidence.

Adv Ther 2021 05 17;38(5):2038-2053. Epub 2021 Mar 17.

Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiaotong University, 159 Tianzhou Road, Shanghai, 200030, China.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) are a standard of care in the first-line treatment of patients with EGFR mutation-positive metastatic non-small-cell lung cancer (NSCLC). EGFR mutations are relatively common in Asian patients with NSCLC, and there is an increasing number of studies supporting the effectiveness of the second-generation TKI afatinib in routine clinical practice in Asia. This article reviews these real-world studies investigating afatinib as first-line treatment for EGFR mutation-positive NSCLC in Asian patients. Evidence from real-world studies with afatinib in this patient population supports findings from randomized controlled trials (RCTs) showing that afatinib is associated with more favorable outcomes compared with the first-generation EGFR TKIs. The effectiveness of afatinib has also been shown in real-world studies in Asian patients with poor prognostic factors, who are often under-represented or excluded from RCTs, such as those with uncommon EGFR mutations, brain metastases, or poor performance status, and elderly patients. The tolerability profile of afatinib in the real-world setting reflects that seen in RCTs, with no new safety signals reported in real-world studies in Asian patients with EGFR mutation-positive NSCLC. Dose-modification strategies also seem to be effective in the real world, with results of the RealGido study, which included 44% Asian patients, confirming findings from prospective clinical trials showing that tolerability-guided afatinib dose modifications can reduce the incidence of adverse events without adversely affecting clinical outcomes. While further research, including clinical trial data, is needed, real-world data have also demonstrated the feasibility of sequential afatinib followed by the third-generation TKI osimertinib in T790M-positive EGFR mutation-positive patients, which showed longer overall survival. Together, these real-world results demonstrate the real-world clinical effectiveness of afatinib as first-line treatment for patients with EGFR mutation-positive NSCLC.
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http://dx.doi.org/10.1007/s12325-021-01696-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107068PMC
May 2021

Safety and efficacy of first-line dacomitinib in Asian patients with EGFR mutation-positive non-small cell lung cancer: Results from a randomized, open-label, phase 3 trial (ARCHER 1050).

Lung Cancer 2021 04 23;154:176-185. Epub 2021 Feb 23.

Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China. Electronic address:

Objectives: To compare efficacy and safety of dacomitinib versus gefitinib as first-line therapy for EGFR mutation-positive advanced NSCLC in Asian patients enrolled in the ongoing ARCHER 1050 trial.

Materials And Methods: In this ongoing, randomized, open-label, phase 3 trial (NCT01774721), eligible patients with newly diagnosed advanced EGFR mutation-positive NSCLC were randomized (1:1) to receive oral dacomitinib 45 mg/day or oral gefitinib 250 mg/day. Randomization, by a central computer system, was stratified by race and EGFR mutation type (exon 19 deletion mutation/exon 21 L858R substitution mutation). The primary endpoint was PFS by blinded independent review.

Results: Of 346 Asian patients, 170 were randomized to dacomitinib and 176 to gefitinib. The hazard ratio (HR) for PFS with dacomitinib versus gefitinib was 0.509 (95 % confidence interval [CI]: 0.391-0.662; 1-sided p < 0.0001; median 16.5 months [95 % CI: 12.9-18.4] vs. 9.3 months [95 % CI: 9.2-11.0]). HR for OS with dacomitinib versus gefitinib was 0.759 (95 % CI: 0.578-0.996; median 37.7 months [95 % CI: 30.2-44.7] vs. 29.1 months [95 % CI: 25.6-36.0]). The OS benefit was still maintained in those patients who had a stepwise dose reduction of dacomitinib (to 30 and 15 mg/day). The most common adverse events (AEs) were diarrhea (154 [90.6 %] patients), paronychia (110 [64.7 %]), dermatitis acneiform (96 [56.5 %]), and stomatitis (87 [51.2 %]) with dacomitinib, and diarrhea (100 [56.8 %]), alanine aminotransferase increased (81 [46.0 %]), and aspartate aminotransferase increased (75 [42.6 %]) with gefitinib. Treatment-related serious AEs were reported in 16 (9.4 %) and 8 (4.5 %) patients treated with dacomitinib and gefitinib, respectively.

Conclusion: First-line dacomitinib was associated with significant prolongation of PFS and improved OS compared with gefitinib in Asian patients with EGFR mutation-positive advanced NSCLC. The AE profiles of dacomitinib and gefitinib in Asian patients were consistent with the overall ARCHER 1050 population.
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http://dx.doi.org/10.1016/j.lungcan.2021.02.025DOI Listing
April 2021

Fruquintinib with gefitinib as first-line therapy in patients carrying EGFR mutations with advanced non-small cell lung cancer: a single-arm, phase II study.

Transl Lung Cancer Res 2021 Feb;10(2):839-854

Hutchison MediPharma, Shanghai, China.

Background: Fruquintinib is an oral vascular endothelial growth factor receptor inhibitor. Previous gefitinib studies with anti-angiogenics show promising efficacy. This phase II trial assessed efficacy and safety of fruquintinib in combination with gefitinib, in patients with advanced non-small cell lung cancer (NSCLC).

Methods: Fifty patients with stage IIIB/IV NSCLC and an epidermal growth factor receptor (EGFR) exon-19 deletion or exon-21 L858R mutation were enrolled between January 2017 and June 2019. Per protocol (version 1.0), patients received 4 mg fruquintinib once daily (qd) Days 1-21 of Cycle 1, using a 3-week-on/1-week-off schedule, plus continuous gefitinib 250 mg qd. If tolerated, patients proceeded to fruquintinib 5 mg qd (fruquintinib 5 mg group, n=26). Following protocol updates, dose escalation of fruquintinib from 4 mg qd to 5 mg qd was not allowed. The primary efficacy endpoint was objective response rate (ORR); secondary endpoints included progression-free survival (PFS), disease control rate (DCR), time to response, duration of response and adverse events (AEs).

Results: ORR was 73.5% (95% CI, 58.9-85.1) and DCR was 98.0% (95% CI, 89.2-100.0). Median PFS was 14.7 months for both groups; PFS was highest for patients with exon-19 deletion (16.5 months; 95% CI, 12.9-21.2). Grade ≥3 treatment-emergent AEs occurred in 17 (65.3%; fruquintinib 5 mg,) and 11 patients (45.8%; 4 mg). Serious AEs were recorded for nine patients (fruquintinib 5 mg, six patients; 4 mg, three).

Conclusions: Fruquintinib and gefitinib treatment showed an acceptable safety profile and promising efficacy in patients with NSCLC.
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http://dx.doi.org/10.21037/tlcr-20-1028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947379PMC
February 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

Multigene PCR using both cfDNA and cfRNA in the supernatant of pleural effusion achieves accurate and rapid detection of mutations and fusions of driver genes in patients with advanced NSCLC.

Cancer Med 2021 04 3;10(7):2286-2292. Epub 2021 Mar 3.

Department of Pathology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis And Thoracic Tumor Research Institute, Beijing, China.

Background: Pleural effusion from patients with advanced non-small cell lung cancer (NSCLC) has been proved valuable for molecular analysis, especially when the tissue sample not available. However, simultaneous detection of multiple driver gene alterations especially the fusions is still challenging.

Methods: In this study, 77 patients with advanced NSCLC and pleural effusion were enrolled, 49 of whom had matched tumor tissues. Supernatants, cell sediments, and cell blocks were prepared from pleural effusion samples for detection of driver alterations by a PCR-based 9-gene mutation detection kit.

Results: Mutations in EGFR, KRAS, and HER2 were detected in DNA and cfDNA, fusions in ALK was detected in RNA and cfRNA. Compared with matched tumor tissue, the supernatant showed the highest overall sensitivity (81.3%), with 81.5% for SNV/Indels by cfDNA and 80% for fusions by cfRNA, followed by cell blocks (71.0%) and the cell sediments (66.7%). Within the group of treatment-naïve patients or malignant cells observed in the cell sediments, supernatant showed higher overall sensitivity (89.5% and 92.3%) with both 100% for fusions.

Conclusions: CfDNA and cfRNA derived from pleural effusion supernatant have been successfully tested with a PCR-based multigene detection kit. Pleural effusion supernatant seems a preferred material for detection of multigene alterations to guide treatment decision of advanced NSCLC.
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http://dx.doi.org/10.1002/cam4.3769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982639PMC
April 2021

Distinct profile of cell-free DNA in malignant pleural effusion of non-small cell lung cancer and its impact on clinical genetic testing.

Int J Med Sci 2021 30;18(6):1510-1518. Epub 2021 Jan 30.

Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.

Cell-free DNA (cfDNA) in supernatant of pleural effusion from advanced NSCLC patients has been proved as surrogate sample detecting therapeutic targets as well as tumor mutation burden (TMB). As recently reported, cfDNA in pleural effusion supernatant is superior to plasma in TMB evaluation. It is reasonable to hypothesize that cfDNA profile in pleural effusion (PE) and plasma might be different. It remains to be elucidated why cfDNA in PE supernatant impacts on genetic analysis. Consequently, the approach dealing with cfDNA from PE supernatant might need to be different from that for plasma cfDNA in order to obtain accurate clinical genetic testing result. Pleural effusion samples from 32 patients with stage IV lung adenocarcinoma were collected. Supernatant and sediment were processed separately to extract Cell-free DNA as well as sediment DNA (PE-S). cfDNA from pleural effusion was analyzed by Agilent 2100 bioanalyzer. Libraries were prepared by 1) direct use of the total cfDNA without fragmentation step (PE-FL) or 2) use of full-length cfDNA fragmented to 150-250bp (PE-F), 3) use of cfDNA fragments enriched to ~167bp (PE-E167) as well as 4) use of cfDNA fragments larger than 500bp enriched (PE-E500). All samples were subjected to targeted next-generation sequencing (NGS) with a panel of 448 cancer-related genes as well as a panel of 10 NSCLC driver genes. cfDNA were successfully extracted from 30 MPE samples. cfDNA displayed distinct profile in supernatant of malignant pleural effusion from that of plasma cfDNA. No statistical difference in detection of hotspot variations between PE-E167 and PE-F by 448-gene or 10-gene panel. While TMB from PE-F samples was significantly higher than that from PE-E167 and PE-FL. Higher TMB from PE-F was resulted from cancer-unspecific variants with low allele frequency (0.1%-1%) which were mainly introduced by long-fragment cfDNA. Similar genetic profile was observed between paired cfDNA of PE-FL and cfDNA of PE-E167. Long-fragment cfDNA in the PE supernatant will introduce low abundant cancer unrelated variants which leads overestimation of TMB. Paired PE-FL and PE-E167 gave comparable outcomes. Direct use of the total cfDNA without fragmentation step (PE-FL) is recommended for library preparation of NGS testing in clinical practice to exclude interference from long fragments of the cfDNA.
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http://dx.doi.org/10.7150/ijms.52306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893565PMC
January 2021

A multi-omics-based serial deep learning approach to predict clinical outcomes of single-agent anti-PD-1/PD-L1 immunotherapy in advanced stage non-small-cell lung cancer.

Am J Transl Res 2021 15;13(2):743-756. Epub 2021 Feb 15.

Department of Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University Shanghai, China.

Only 20% NSCLC patients benefit from immunotherapy with a durable response. Current biomarkers are limited by the availability of samples and do not accurately predict who will benefit from immunotherapy. To develop a unified deep learning model to integrate multimodal serial information from CT with laboratory and baseline clinical information. We retrospectively analyzed 1633 CT scans and 3414 blood samples from 200 advanced stage NSCLC patients who received single anti-PD-1/PD-L1 agent between April 2016 and December 2019. Multidimensional information, including serial radiomics, laboratory data and baseline clinical data, was used to develop and validate deep learning models to identify immunotherapy responders and nonresponders. A Simple Temporal Attention (SimTA) module was developed to process asynchronous time-series imaging and laboratory data. Using cross-validation, the 90-day deep learning-based predicting model showed a good performance in distinguishing responders from nonresponders, with an area under the curve (AUC) of 0.80 (95% CI: 0.74-0.86). Before immunotherapy, we stratified the patients into high- and low-risk nonresponders using the model. The low-risk group had significantly longer progression-free survival (PFS) (8.4 months, 95% CI: 5.49-11.31 . 1.5 months, 95% CI: 1.29-1.71; HR 3.14, 95% CI: 2.27-4.33; log-rank test, <0.01) and overall survival (OS) (26.7 months, 95% CI: 18.76-34.64 . 8.6 months, 95% CI: 4.55-12.65; HR 2.46, 95% CI: 1.73-3.51; log-rank test, <0.01) than the high-risk group. An exploratory analysis of 93 patients with stable disease (SD) [after first efficacy assessment according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1] also showed that the 90-day model had a good prediction of survival and low-risk patients had significantly longer PFS (11.1 months, 95% CI: 10.24-11.96 . 3.3 months, 95% CI: 0.34-6.26; HR 2.93, 95% CI: 1.69-5.10; log-rank test, P<0.01) and OS (31.7 months, 95% CI: 23.64-39.76 . 17.2 months, 95% CI: 7.22-27.18; HR 2.22, 95% CI: 1.17-4.20; log-rank test, =0.01) than high-risk patients. In conclusion, the SimTA-based multi-omics serial deep learning provides a promising methodology for predicting response of advanced NSCLC patients to anti-PD-1/PD-L1 monotherapy. Moreover, our model could better differentiate survival benefit among SD patients than the traditional RECIST evaluation method.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868825PMC
February 2021