Publications by authors named "Tianshu Liu"

144 Publications

Tumor-derived LIF promotes chemoresistance via activating tumor-associated macrophages in gastric cancers.

Exp Cell Res 2021 Jul 13;406(1):112734. Epub 2021 Jul 13.

Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China; Center of Evidence-based Medicine, Fudan University, Shanghai, China. Electronic address:

Chemotherapy is the preferred clinical treatment for advanced stage gastric cancer (GC) patients, of which efficacy could be markedly impaired due to the development of chemoresistance. Alternatively activated or M2-type tumor associated macrophages (TAMs) are recruited under chemotherapy and are highly implicated in the chemoresistance development, but underlying molecular mechanism for TAM activation is largely unknown. Here, we present that tumor-derived Leukemia inhibitory factor (LIF) induced by chemo drugs represses the chemo sensitivity of gastric tumor cells in a TAM-dependent manner. Mechanistically, cisplatin-induced HIF1α signaling activation directly drive the transcription of LIF, which promotes the resistance of gastric tumors to chemo drug. Further study revealed that tumor cell-derived LIF stimulates macrophages into tumor-supporting M2-type phenotype via activating STAT3 signaling pathway. Therapeutically, blocking LIF efficiently elevates chemo sensitivity of tumor cells and further represses the growth rates of tumors under chemotherapy. Therefore, our study reveals a novel insight in understanding the cross talking between tumor cells and immune cells and provides new therapeutic targets for gastric cancer.
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http://dx.doi.org/10.1016/j.yexcr.2021.112734DOI Listing
July 2021

Identification of a metabolic signature to predict overall survival for colorectal cancer.

Scand J Gastroenterol 2021 Jul 14:1-10. Epub 2021 Jul 14.

Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China.

Purpose: Metabolic genes are associated with the occurrence and development of tumors. Metabolic-related risk models have showed partly prognostic predictive ability in cancers. However, the correlation between metabolic-related genes (MRGs) and the outcome of colorectal cancer is still poorly understood.

Patients And Methods: TCGA database is used as the training cohort; while GSE39582 is the verification cohort. The least absolute shrinkage and selection operator Cox regression analysis were utilized to identify the MRGs and establish a genetic risk scoring model. A nomogram by integrating MRGs risk scores with TNM stage was constructed. The potential biological mechanisms were explored using gene set enrichment analysis. Associations of the signature with immune cell infiltrations and the tumor mutation burden (TMB) were also uncovered by Spearman rank test.

Results: A six-gene metabolic signature was identified. Based on the risk scoring model with the signature, patients were divided into two groups (high-risk versus low-risk). The overall survival (OS) duration of patients with high-risk were quite shorter than those of low-risk patients (TCGA:  < .001, GSE39582:  < .001). Metabolic-related pathways were major enriched in low-risk group, while the high-risk group exhibited multiple immune-related pathways. Moreover, our signature was more linear dependent with antigen-presenting cell than effector immune cells, and a positive correction were seen between our signature and TMB.

Conclusion: Our research has discovered a six-gene metabolic signature to predict the OS of colorectal cancer. These genes may play significant roles in colorectal cancer regulating tumor microenvironment and serving as potential biomarkers for anti-cancer therapy.
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http://dx.doi.org/10.1080/00365521.2021.1948605DOI Listing
July 2021

First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial.

Lancet 2021 Jul 5;398(10294):27-40. Epub 2021 Jun 5.

Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Background: First-line chemotherapy for advanced or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric or gastro-oesophageal junction adenocarcinoma has a median overall survival (OS) of less than 1 year. We aimed to evaluate first-line programmed cell death (PD)-1 inhibitor-based therapies in gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma. We report the first results for nivolumab plus chemotherapy versus chemotherapy alone.

Methods: In this multicentre, randomised, open-label, phase 3 trial (CheckMate 649), we enrolled adults (≥18 years) with previously untreated, unresectable, non-HER2-positive gastric, gastro-oesophageal junction, or oesophageal adenocarcinoma, regardless of PD-ligand 1 (PD-L1) expression from 175 hospitals and cancer centres in 29 countries. Patients were randomly assigned (1:1:1 while all three groups were open) via interactive web response technology (block sizes of six) to nivolumab (360 mg every 3 weeks or 240 mg every 2 weeks) plus chemotherapy (capecitabine and oxaliplatin every 3 weeks or leucovorin, fluorouracil, and oxaliplatin every 2 weeks), nivolumab plus ipilimumab, or chemotherapy alone. Primary endpoints for nivolumab plus chemotherapy versus chemotherapy alone were OS or progression-free survival (PFS) by blinded independent central review, in patients whose tumours had a PD-L1 combined positive score (CPS) of five or more. Safety was assessed in all patients who received at least one dose of the assigned treatment. This study is registered with ClinicalTrials.gov, NCT02872116.

Findings: From March 27, 2017, to April 24, 2019, of 2687 patients assessed for eligibility, we concurrently randomly assigned 1581 patients to treatment (nivolumab plus chemotherapy [n=789, 50%] or chemotherapy alone [n=792, 50%]). The median follow-up for OS was 13·1 months (IQR 6·7-19·1) for nivolumab plus chemotherapy and 11·1 months (5·8-16·1) for chemotherapy alone. Nivolumab plus chemotherapy resulted in significant improvements in OS (hazard ratio [HR] 0·71 [98·4% CI 0·59-0·86]; p<0·0001) and PFS (HR 0·68 [98 % CI 0·56-0·81]; p<0·0001) versus chemotherapy alone in patients with a PD-L1 CPS of five or more (minimum follow-up 12·1 months). Additional results showed significant improvement in OS, along with PFS benefit, in patients with a PD-L1 CPS of one or more and all randomly assigned patients. Among all treated patients, 462 (59%) of 782 patients in the nivolumab plus chemotherapy group and 341 (44%) of 767 patients in the chemotherapy alone group had grade 3-4 treatment-related adverse events. The most common any-grade treatment-related adverse events (≥25%) were nausea, diarrhoea, and peripheral neuropathy across both groups. 16 (2%) deaths in the nivolumab plus chemotherapy group and four (1%) deaths in the chemotherapy alone group were considered to be treatment-related. No new safety signals were identified.

Interpretation: Nivolumab is the first PD-1 inhibitor to show superior OS, along with PFS benefit and an acceptable safety profile, in combination with chemotherapy versus chemotherapy alone in previously untreated patients with advanced gastric, gastro-oesophageal junction, or oesophageal adenocarcinoma. Nivolumab plus chemotherapy represents a new standard first-line treatment for these patients.

Funding: Bristol Myers Squibb, in collaboration with Ono Pharmaceutical.
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http://dx.doi.org/10.1016/S0140-6736(21)00797-2DOI Listing
July 2021

Anticorrosion Performance of PVDF Membranes Modified by Blending PTFE Nanoemulsion and Prepared through Usual Non-Solvent-Induced Phase Inversion Method.

Membranes (Basel) 2021 May 31;11(6). Epub 2021 May 31.

Center for Separation and Purification Materials & Technologies, Suzhou University of Science and Technology, Suzhou 215009, China.

In this study, PVDF/PTFE composite membranes were prepared by adding a PTFE nanoemulsion to a PVDF solution and casting it through the conventional non-solvent-induced phase separation method. The objective was to explore the effectiveness of using a simple and economical method to modify PVDF membranes with PTFE to enhance their anticorrosion performance, especially under highly acidic or alkaline conditions. PTFE nanoparticles (of around 200 nm in size) in nanoemulsion form were blended with PVDF at a mass ratio of PTFE:PVDF in the range of 0-0.3:1. The obtained membranes were examined to determine the effect of the added PTFE nanoparticles on the structure of the modified PVDF membranes as well as on their mechanical strength and surface characteristics. The membranes were then immersed in various concentrations of acidic or alkaline solutions for varied durations ranging from a few days up to as long as 180 days (6 months). The impacts of by the corrosive solutions on the tensile strength, surface roughness, and water flux of the membranes with different exposure times were quantified. The results showed that although a certain extent of change may occur with extended immersion times, greatly enhanced anticorrosion performance was obtained with the prepared PVDF/PTFE membranes compared with the unmodified PVDF membrane. For example, after being immersed in 5 mol-H·L HSO, HCl, and HNO solutions for 6 months, the tensile strength at breaking point remained at up to 69.70, 74.07, and 71.38%, respectively, of the initial strength for the PVDF/PTFE (M30) membrane. This was in contrast to values of only 55.77, 70.43, and 61.78% for the unmodified PVDF membrane (M0). Although the water flux and surface roughness showed a change trends to the tensile strength, the PVDF/PTFE (M30) membrane had much higher stability than the PVDF (M0) membrane. In a continuous filtration experiment containing HSO at 0.01 mol-H·L for 336 h (14 days), the PVDF/PTFE membrane showed a maximum flux change of less than 30%. This was in comparison with a change of up to 50% for the PVDF membrane. However, the PVDF/PTFE membranes did not seem to have a greatly enhanced anticorrosion performance in the alkaline solution environment tested.
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http://dx.doi.org/10.3390/membranes11060420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8228311PMC
May 2021

Mass spectrometry-based serum lipidomics strategy to explore the mechanism of Eleutherococcus senticosus (Rupr. & Maxim.) Maxim. leaves in the treatment of ischemic stroke.

Food Funct 2021 May 23;12(10):4519-4534. Epub 2021 Apr 23.

School of Pharmaceutical Sciences, Jilin University, Changchun 130021, China.

Eleutherococcus senticosus (Rupr. & Maxim.) Maxim. leaves (ESL) were reported to have neuroprotective function and are also used to treat cranial and cerebral traumas as a traditional Chinese medicine and food herbage plant. However, there has been no previous study on ESL treatment for stroke at the level of lipid disorders. To clarify the mechanism of ESL in treating ischemic stroke, this study was carried out from 3 aspects, namely, the regulation of lipid disorders, protection of the nervous system, as well as anti-inflammatory and antioxidant actions. This study established a lipidomics research strategy that was developed by UPLC-Q-TOF/MS analysis. The quantification of neurotransmitters in the serum and brain tissue of rats was performed using UPLC-TQ/MS. Also, we quantified the oxidative stress and inflammatory reaction by measuring the contents of SOD, MDA, TNF-α, IL-6, and IL-10 via the ELISA kits for serum and brain tissue. According to UPLC-Q-TOF/MS-based lipidomics analysis, 27 lipidomics biomarkers were identified in this study, including PC, PE, SM, and TG, which were distributed in various lipid metabolic pathways, including glycerophospholipid, linoleic acid, alpha-linolenic acid, glycerolipid, sphingolipid, and arachidonic acid metabolism pathways. By reversing the changes in the lipid content caused by the disease, ESL has a therapeutic effect on ischemic stroke. Furthermore, quantitative results of neurotransmitters indicated that they can be regulated by ESL. Finally, the results of ELISA showed that ESL can treat ischemic stroke to a certain extent by reducing the oxidative and inflammatory damage. Therefore, ESL may play a therapeutic role in the treatment of ischemic stroke in different ways. This research preliminarily revealed the mechanism of ESL in the treatment of ischemic stroke and provided support for the further application of ESL.
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http://dx.doi.org/10.1039/d0fo02845bDOI Listing
May 2021

Solute carriers as potential oncodrivers or suppressors: their key functions in malignant tumor formation.

Drug Discov Today 2021 Mar 15. Epub 2021 Mar 15.

Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China. Electronic address:

Solute carrier (SLC) transporters are primarily known for their function in the transportation of various exogenous/endogenous substances via influx/efflux mechanisms. In addition to their diverse role in several tumor-modulating functions, such as proliferation, migration, angiogenesis, epithelial-mesenchymal transition (EMT), epigenetic modification, chemoresistance, immunoregulation, and oncometabolism, influx/efflux-independent contributions of SLCs in the activation of various signaling network cascades that might drive metastatic tumor formation have also been uncovered. Disappointingly, even after two decades and the discovery of >450 SLCs, many of their members remain orphans in terms of cancer pathogenesis. In this review, we summarize the current understanding of the tumor-modulating functions, mechanisms, and complexity of SLCs, as well as their potential as targets for cancer therapy.
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http://dx.doi.org/10.1016/j.drudis.2021.03.004DOI Listing
March 2021

Chemotherapy-associated clonal hematopoiesis mutations should be taken seriously in plasma cell-free DNA KRAS/NRAS/BRAF genotyping for metastatic colorectal cancer.

Clin Biochem 2021 Jun 15;92:46-53. Epub 2021 Mar 15.

Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai 200032, PR China; Department of Laboratory Medicine, Xiamen Branch, Zhongshan Hospital, Fudan University, 668 Jin Hu Road, Xiamen 361015, PR China; Department of Laboratory Medicine, Wusong Branch, Zhongshan Hospital, Fudan University, 101 Tong Tai North Road, Shanghai 200940, PR China. Electronic address:

Background: Genotyping of plasma cell-free DNA (cfDNA) is an increasingly important method to assess the tumor mutation status in colorectal cancer (CRC) patients. Clonal hematopoiesis (CH) releases non-tumor somatic mutations into blood, causing false positive results in cfDNA-based tumor genotyping. It is still not clear if CH should be examined in all CRC patients undergoing cfDNA analysis.

Methods: We analyzed cfDNA KRAS, NRAS and BRAF genotypes in 236 metastatic CRC patients, who had matched tissue genotyping results, by next-generation sequencing using plasma cfDNA. The cfDNA-only mutations with allele frequencies (AFs) < 5% were highly suspicious for being CH-derived mutations. The origins of cfDNA mutations were confirmed by droplet digital polymerase chain reaction (ddPCR) using paired peripheral blood cells (PBCs) and CH-derived mutations were finally determined. One patient with a CH-derived mutation was followed up and the subpopulation of blood cells, in which CH was present, was investigated.

Results: Three CH-derived mutations, KRAS Q61H, KRAS G12D and KRAS G12V, were identified in the patient cohort. All three patients harboring corresponding CH-derived mutations had a prior chemotherapy history. The CH-derived KRAS G12V mutation in a patient was found only present in lymphocytes and persisting under treatment. For all cfDNA mutations, the CH-derived ones were clustered in the patients with < 5% mutation AF and prior chemotherapy.

Conclusion: The prevalence of CH in CRC patients was limited, and prior chemotherapy was a contributing factor of CH. It is recommended for patients with < 5% mutation AF and prior chemotherapy to have genotyping analysis of their PBCs following plasma cfDNA genotyping.
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http://dx.doi.org/10.1016/j.clinbiochem.2021.03.005DOI Listing
June 2021

Bazedoxifene Regulates Th17 Immune Response to Ameliorate Experimental Autoimmune myocarditis via Inhibition of STAT3 Activation.

Front Pharmacol 2020 10;11:613160. Epub 2021 Feb 10.

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

Myocarditis is a type of inflammatory cardiomyopathy that has no specific treatment. Accumulating evidence suggests that Th17 cells play a prominent role in the pathogenesis of myocarditis. Interleukin-(IL)-6-mediated signal transducer and activation of transcription 3 (STAT3) signaling is essential for Th17 cell differentiation and secretion of inflammatory cytokines. Bazedoxifene inhibits IL-6/STAT3 signaling in cancer cells, but its effect on the Th17 immune response induced by myocarditis remains unknown. Here we explore the effect of Bazedoxifene on Th17 immune response and cardiac inflammation in a mouse model of experimental autoimmune myocarditis, which has been used to mimic human inflammatory heart disease. After eliciting an immune response, we found Bazedoxifene ameliorated cardiac inflammatory injury and dysfunction. Th17 cells and related inflammatory factors in splenic CD4 T cells at day 14 and in the heart at day 21 were increased, which were reduced by Bazedoxifene. Furthermore, Bazedoxifene could regulate autophagy induction in polarized Th17 cells. In conclusion, Bazedoxifene affected STAT3 signaling and prevented cardiac inflammation deterioration, so may provide a promising therapeutic strategy for the treatment of experimental autoimmune myocarditis (EAM).
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http://dx.doi.org/10.3389/fphar.2020.613160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903338PMC
February 2021

Identification of key genes involved in tumor immune cell infiltration and cetuximab resistance in colorectal cancer.

Cancer Cell Int 2021 Feb 25;21(1):135. Epub 2021 Feb 25.

Department of Medical Oncology, Zhongshan Hospital, Fudan University, No. 180, Fenglin Road, Xuhui District, Shanghai, 200032, People's Republic of China.

Background: The anti-epidermal growth factor receptor (EGFR) antibody introduces adaptable variations to the transcriptome and triggers tumor immune infiltration, resulting in colorectal cancer (CRC) treatment resistance. We intended to identify genes that play essential roles in cetuximab resistance and tumor immune cell infiltration.

Methods: A cetuximab-resistant CACO2 cellular model was established, and its transcriptome variations were detected by microarray. Meanwhile, public data from the Gene Expression Omnibus and The Cancer Genome Atlas (TCGA) database were downloaded. Integrated bioinformatics analysis was applied to detect differentially expressed genes (DEGs) between the cetuximab-resistant and the cetuximab-sensitive groups. Then, we investigated correlations between DEGs and immune cell infiltration. The DEGs from bioinformatics analysis were further validated in vitro and in clinical samples.

Results: We identified 732 upregulated and 1259 downregulated DEGs in the induced cellular model. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses, along with Gene Set Enrichment Analysis and Gene Set Variation Analysis, indicated the functions of the DEGs. Together with GSE59857 and GSE5841, 12 common DEGs (SATB-2, AKR1B10, ADH1A, ADH1C, MYB, ATP10B, CDX-2, FAR2, EPHB2, SLC26A3, ORP-1, VAV3) were identified and their predictive values of cetuximab treatment were validated in GSE56386. In online Genomics of Drug Sensitivity in Cancer (GDSC) database, nine of twelve DEGs were recognized in the protein-protein (PPI) network. Based on the transcriptome profiles of CRC samples in TCGA and using Tumor Immune Estimation Resource Version 2.0, we bioinformatically determined that SATB-2, ORP-1, MYB, and CDX-2 expressions were associated with intensive infiltration of B cell, CD4 T cell, CD8 T cell and macrophage, which was then validated the correlation in clinical samples by immunohistochemistry. We found that SATB-2, ORP-1, MYB, and CDX-2 were downregulated in vitro with cetuximab treatment. Clinically, patients with advanced CRC and high ORP-1 expression exhibited a longer progression-free survival time when they were treated with anti-EGFR therapy than those with low ORP-1 expression.

Conclusions: SATB-2, ORP-1, MYB, and CDX-2 were related to cetuximab sensitivity as well as enhanced tumor immune cell infiltration in patients with CRC.
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http://dx.doi.org/10.1186/s12935-021-01829-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905896PMC
February 2021

Identification of immune checkpoint and cytokine signatures associated with the response to immune checkpoint blockade in gastrointestinal cancers.

Cancer Immunol Immunother 2021 Feb 23. Epub 2021 Feb 23.

Department of Gastrointestinal Oncology, The Fifth Medical Center, Chinese PLA General Hospital, No. 8 East Street, Fengtai District, Beijing, 100071, China.

Immune checkpoint blockade (ICB) of the programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) immune checkpoint pathway has led to unprecedented advances in cancer therapy. However, the overall response rate of anti-PD-1/PD-L1 monotherapy is still unpromising, underscoring the need for predictive biomarkers. In this retrospective study, we collected pretreatment plasma samples from two independent cohorts of patients receiving ICB. To determine whether a signature of plasma cytokines could be associated with therapeutic efficacy, we systemically profiled cytokine clusters and functional groups in the discovery and validation datasets by using 59 multiplexed bead immunoassays and bioinformatics analysis. We first attempted to functionally classify the 59 immunological factors according to their biological classification or functional roles in the cancer-immunity cycle. Surprisingly, we observed that two signatures, the "checkpoint signature" and "trafficking of T-cell signature", were higher in the response subgroup than in the nonresponse subgroup in both the discovery and validation cohorts. Moreover, enrichment of the "checkpoint signature" was correlated with improved overall survival and progression-free survival in both datasets. In addition, we demonstrated that increased baseline levels of three checkpoint molecules (PD-L1, T-cell immunoglobulin mucin receptor 3 and T-cell-specific surface glycoprotein CD28) were common peripheral responsive correlates in both cohorts, thus rendering this "refined checkpoint signature" an ideal candidate for future verification. In the peripheral blood system, the "refined checkpoint signature" may function as a potential biomarker for anti-PD-1/PD-L1 monotherapy in gastrointestinal (GI) cancers.
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http://dx.doi.org/10.1007/s00262-021-02878-8DOI Listing
February 2021

Chronic respiratory dysfunction due to diaphragmatic paralysis following penetrating neck trauma: A case report.

Medicine (Baltimore) 2021 Jan;100(4):e24043

Department of Critical Care Medicine, the First Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China.

Rationale: Respiratory dysfunction resulting from unilateral diaphragmatic paralysis during neck trauma is very rare in adults. We describe the symptoms, diagnosis and treatment of 1 patient with chronic respiratory insufficiency, in whom the diaphragmatic paralysis was associated with phrenic nerve injury due to penetrating neck trauma.

Patient Concerns: A 50-year-old worker was admitted because of left penetrating neck trauma. Imaging investigations demonstrated elevation of the left hemidiaphragm and the C5 and C6 roots avulsion. He complained of gradually worsening dyspnea on exertion 2 months later.

Diagnoses: The patient was diagnosed with chronic respiratory dysfunction secondary to diaphragmatic paralysis, which caused by phrenic nerve injury.

Interventions: A conventional video-assisted thoracoscopic diaphragm plication was performed after failed conservative management.

Outcomes: The respiratory status improved markedly, and he did well without recurrence until 2 years' follow-up.

Lessons: The possibilities of phrenic nerve palsy and diaphragmatic paralysis should not be overlooked during the evaluation of neck trauma.
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http://dx.doi.org/10.1097/MD.0000000000024043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850730PMC
January 2021

NOTCH3 is a Prognostic Factor and Is Correlated With Immune Tolerance in Gastric Cancer.

Front Oncol 2020 5;10:574937. Epub 2021 Jan 5.

Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China.

Introduction: Although traditional treatments confer survival benefits to patients with gastric cancer (GC), many patients experience relapse soon after postoperative adjuvant therapy. Immune-related mechanisms play an important role in GC, and immunotherapeutic strategies are considered to be a promising direction for the treatment of GC. Thus, our study aimed to investigate the expression and prognostic significance of immune-related genes in GC.

Methods: Formalin-fixed, paraffin-embedded samples were collected from 48 resectable GC patients. The transcriptome data of the tumor immune microenvironment were assessed using an immuno-oncology 395-gene panel RNA sequencing platform. The prognostic value of the 395 genes was analyzed and validated in the KM plotter and GEPIA databases. The data from The Cancer Genome Atlas (TCGA, downloaded from UCSC Xena repository) and Tumor IMmune Estimation Resource (TIMER) were used to evaluate the correlations between prognostic factors and immune signatures.

Results: Among the 395 genes, NOTCH3 was identified as a good prognostic factor for GC patients. Its prognostic value was also suggested in both our GC cohort from Zhongshan Hospital and the public databases (KM plotter and GEPIA database). Mechanistically, high NOTCH3 expression correlated with a lower infiltration of activated CD8 T cells and a higher infiltration of immunosuppressive cells including Tregs and M2 macrophages in the tumor microenvironment. Moreover, high NOTCH3 expression was accompanied by the increased expression of a series of immune checkpoint inhibitors, resulting in a dampened immune response. Interestingly, NOTCH3 expression had a negative association with well-documented predictive biomarkers of immune checkpoint blockade (ICB) immunotherapy, including tumor mutation burden (TMB), gene expression profiling (GEP) score and innate anti-PD-1 resistance (IPRES) signature.

Conclusion: These findings uncovered a new mechanism by which NOTCH3 participates in the immune tolerance of GC, implying the potential of NOTCH3 as a therapeutic target or predictive marker for GC patients.
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http://dx.doi.org/10.3389/fonc.2020.574937DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814877PMC
January 2021

Guidelines for the Diagnosis and Treatment of Hepatocellular Carcinoma (2019 Edition).

Liver Cancer 2020 Dec 11;9(6):682-720. Epub 2020 Nov 11.

Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.

Background: Primary liver cancer, around 90% are hepatocellular carcinoma in China, is the fourth most common malignancy and the second leading cause of tumor-related death, thereby posing a significant threat to the life and health of the Chinese people.

Summary: Since the publication of in 2018, additional high-quality evidence has emerged with relevance to the diagnosis, staging, and treatment of liver cancer in and outside China that requires the guidelines to be updated. The new edition was written by more than 70 experts in the field of liver cancer in China. They reflect the real-world situation in China regarding diagnosing and treating liver cancer in recent years.

Key Messages: Most importantly, the new guidelines were endorsed and promulgated by the Bureau of Medical Administration of the National Health Commission of the People's Republic of China in December 2019.
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http://dx.doi.org/10.1159/000509424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768108PMC
December 2020

Bazedoxifene exhibits anti-inflammation and anti-atherosclerotic effects via inhibition of IL-6/IL-6R/STAT3 signaling.

Eur J Pharmacol 2021 Feb 23;893:173822. Epub 2020 Dec 23.

Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address:

Atherosclerosis is regarded as chronic inflammatory disease. The IL-6/STAT3 pathway plays an important role in inflammation. We previously described a small-molecule compound, Bazedoxifene, which target IL-6/STAT3 pathway and has been approved for clinical use for osteoporosis in postmenopausal women. The aim of this study is to evaluate the effect of Bazedoxifene in the progression of atherosclerosis in apolipoprotein E-deficient (ApoE-/-) mice. Five-week-old male ApoE-/- mice were fed with High-fat diet (HFD) containing 5 mg/kg Bazedoxifene or a matching control for 12 weeks. Oil red O (ORO) staining was used to detect plaque size; immunohistochemical staining was used to detect the presence of endothelial cells, vascular muscle cells and phosphorylated STAT3 (P-STAT3) in localized plaques. The potential underlying mechanisms in human umbilical vein endothelial cells (HUVECs) and vascular muscle cells (VSMCs) was detected by Western blot analysis, Wound healing assay and Elisa assay. In the ApoE-/- mice fed with HFD, daily Bazedoxifene administration effectively attenuated atherosclerotic plaque area (P < 0.01), down-regulated IL-6 levels (P < 0.01), decreased STAT3 phosphorylation, reduced VSMCs proliferation and increased endothelial coverage in aortic vessels. Interestingly, we found HUVECs lack of membrane IL-6 receptor (IL-6R) compared to VSMCs (P < 0.01). Furthermore, we found that the soluble IL-6 receptor (sIL6R) participates in the activation of STAT3 induced by IL-6 or TNF-α in HUVECs and primary HUVECs. Bazedoxifene did not inhibit the growth of HUVECs while suppressing the proliferation of VSMCs. Bazedoxifene is an attractive novel therapeutic reagent for atherosclerosis diseases. This mechanism may be partially attributed to regulating IL-6/IL-6R/STAT3 signaling pathway.
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http://dx.doi.org/10.1016/j.ejphar.2020.173822DOI Listing
February 2021

Subgroup analysis by prior anti-VEGF or anti-EGFR target therapy in FRESCO, a randomized, double-blind, Phase III trial.

Future Oncol 2021 Apr 16;17(11):1339-1350. Epub 2020 Dec 16.

Eli Lilly and Company, Shanghai, 200041, China.

FRESCO study demonstrated efficacy and safety of fruquintinib in metastatic colorectal cancer patients. Impact of prior targeted therapy (PTT) on efficacy and safety of fruquintinib was evaluated. In this subgroup analysis of FRESCO trial, patients were divided into PTT and non-PTT subgroups, and efficacy and safety of fruquintinib were assessed, respectively. In non-PTT subgroup, fruquintinib significantly prolonged overall survival (OS) and progression-free survival (PFS) of patients compared with placebo. In PTT subgroup, the median OS and PFS of patients in fruquintinib arm was significantly higher than those in placebo. Treatment-emergent adverse events (TEAEs) rates were similar in both subgroups. Fruquintinib demonstrated clinically meaningful improvement in OS, PFS, objective response rate, and disease control rate with manageable TEAEs in both subgroups. Clinical trial registration: NCT02314819 (ClinicalTrials.gov).
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http://dx.doi.org/10.2217/fon-2020-0875DOI Listing
April 2021

Preoperative Hepatic and Regional Arterial Chemotherapy in Patients Who Underwent Curative Colorectal Cancer Resection: A Prospective, Multi-center, Randomized Controlled Trial.

Ann Surg 2021 06;273(6):1066-1075

Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.

Objective: To evaluate the effects of the addition of preoperative hepatic and regional arterial chemotherapy (PHRAC) on prognosis of stage II and III colorectal cancer (CRC) in a multicenter setting.

Summary Of Background Data: Our previous single-center pilot trial suggested that PHRAC in combination with surgical resection could reduce the occurrence of liver metastasis (LM) and improve survival in CRC patients.

Methods: A prospective multi-center randomized controlled trial was conducted from December 2008 to December 2012 at 5 hospitals in China. Eligible patients with clinical stage II or III CRC who underwent curative resection were randomized to receive PHRAC plus adjuvant therapy (PHRAC arm) or adjuvant therapy alone (control arm). The primary endpoint was DFS. Secondary endpoints were cumulative LM rates, overall survival (OS), and safety (NCT00643877).

Results: A total of 688 patients from 5 centers in China were randomly assigned (1:1) to each arm. The five-year DFS rate was 77% in the PHRAC arm and 65% in the control arm (HR = 0.61, 95% CI 0.46-0.81; P = 0.001). The 5-year LM rates were 7% and 16% in the PHRAC and control arms, respectively (HR = 0.37, 95% CI 0.22-0.63; P < 0.001). The 5-year OS rate was 84% in the PHRAC arm and 76% in the control arm (HR = 0.61, 95% CI 0.43-0.86; P = 0.005). There were no significant differences regarding treatment related morbidity or mortality between the two arms.

Conclusions: The addition of PHRAC could improve DFS in patients with stage II and III CRC. It reduced the incidence of LM and improved OS without compromising patient safety.

Trial Registration: ClinicalTrials.gov identifier: NCT00643877.
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http://dx.doi.org/10.1097/SLA.0000000000004558DOI Listing
June 2021

Effect of Immune Checkpoint Inhibitors Plus Chemotherapy on Advanced Gastric Cancer Patients with Elevated Serum AFP or Hepatoid Adenocarcinoma.

Cancer Manag Res 2020 2;12:11113-11119. Epub 2020 Nov 2.

Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China.

Purpose: Alpha-fetoprotein-producing gastric cancer (AFPGC) and hepatoid adenocarcinoma of stomach (HAS) are rare types of gastric cancer, with specific clinical manifestations and poor prognosis. The standardized treatment process of such cancers remains elusive. We aim to investigate the efficacy of immunotherapy combined with chemotherapy on patients with AFPGC or HAS.

Patients And Methods: AFPGC and HAS patients who underwent immunotherapy and/or chemotherapy as the first-line treatment at our institute from June 2016 to December 2018 were enrolled in this observational study. Their clinicopathological characteristics, serum AFP level and treatment methods were collected. The progression-free survival (PFS) and overall survival (OS) were analyzed and compared between patients who received immunotherapy plus chemotherapy and those received chemotherapy.

Results: A total of 21 patients with advanced AFPGC or HAS were included in the study and the median follow-up time was 28.0 months. Of the 21 patients, 7 patients received immunotherapy of PD-1 antibody (nivolumab) plus chemotherapy and 14 patients as control received chemotherapy with or without Herceptin/Apatinib. The median progression-free survival (mPFS) time was 5.0 months (4.3 months in the control group and 22.0 months in the immunotherapy group). The median overall survival (mOS) time of the control group was 16.0 months (14.0 months in chemotherapy alone subgroup, 20.0 months in chemotherapy plus Apatinib or Herceptin subgroup), while the mOS of patients receiving immunotherapy was not reached.

Conclusion: This study suggested PD-1 checkpoint inhibitor plus chemotherapy could benefit AFPGC and HAS patients. Its mechanism of action warrants further investigation.
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http://dx.doi.org/10.2147/CMAR.S276969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7646478PMC
November 2020

Prognosis of Adjuvant SOX vs XELOX Chemotherapy for Gastric Cancer After D2 Gastrectomy in Chinese Patients.

Cancer Manag Res 2020 13;12:10091-10101. Epub 2020 Oct 13.

Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China.

Introduction: To compare the prognosis of adjuvant SOX (S-1 and oxaliplatin) vs XELOX (capecitabine and oxaliplatin) chemotherapy in Chinese patients with gastric cancer (GC) after D2 gastrectomy.

Methods: This was a real-world study of patients with GC (stages II-III) who underwent D2 gastrectomy and received adjuvant SOX or XELOX between 01/2010 and 06/2017 in Zhongshan Hospital affiliated to Fudan University. The patients were matched by propensity score matching. The primary and secondary endpoints were disease-free survival (DFS) and overall survival (OS), respectively. Adverse events (AEs) were compared.

Results: A total of 552 patients were included. The median follow-up time was 24.9 months. There were no differences in DFS (median, 44.4 vs 41.2 months; HR=1.17, 95% CI: 0.92-1.48) and OS (median, 61.5 vs 65.3 months; HR=1.01, 95% CI: 0.73-1.39) between the XELOX and SOX groups. Both DFS and OS had no significant differences between SOX and XELOX for all subgroups based on sex (P=0.949, P=0.990), age (P=0.303, P=0.392), Lauren type (P=0.362, P=0.573), type of gastrectomy (P=0.607 P=0.989), and pathological TNM stage (P=0.899, P=0.888). A total of 86 patients in the SOX subgroup (34.2%) experienced AEs, similar to the rate found in the XELOX subgroup (104 patients or 41.4%; P=0.098).

Discussion: The results suggested that adjuvant SOX chemotherapy has similar survival benefits compared to XELOX chemotherapy in Chinese patients with pathological stage II or III GC after D2 gastrectomy.
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http://dx.doi.org/10.2147/CMAR.S270387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7568598PMC
October 2020

Role of circulating free DNA in evaluating clinical tumor burden and predicting survival in Chinese metastatic colorectal cancer patients.

BMC Cancer 2020 Oct 16;20(1):1006. Epub 2020 Oct 16.

Department of Oncology, Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai, 200032, PR China.

Background: The aim of this study was to explore the utility of circulating free DNA (cfDNA) in the evaluation of clinical tumor burden and survival in Chinese patients with metastatic colorectal cancer (mCRC) and to preliminarily summarize some metastatic characteristics associated with mutational status.

Methods: A panel covering a total of 197 hotspot mutations of KRAS, NRAS, BRAF and PIK3CA was used to evaluate the mutational status in plasma by next-generation sequencing (NGS) technology in 126 patients with mCRC. An amplification-refractory mutation system (ARMS) was used to analyze genomic DNA from matched tissue samples. Clinical markers including carcinoembryonic antigen (CEA), carbohydrate antigen 199 (CA199), carbohydrate antigen 125 (CA125), neuron-specific enolase (NSE) and lactate dehydrogenase (LDH) in serum and the sum of all tumor diameters on CT or PET/CT were collected to indicate clinical tumor burden. The correlations between cfDNA and clinical tumor burden were analyzed using Pearson correlation and linear regression models. The median progression-free survival (PFS) and 1-year overall survival (OS) rates were calculated by Kaplan-Meier (K-M) survival analysis.

Results: Of the 126 enrolled patients, patients who were tested positive for mutations in plasma accounted for 45.2% (57/126). Mutations in KRAS, NRAS, BRAF and PIK3CA were detected in 37.3% (47/126), 1.6% (2/126), 3.2% (4/126) and 13.5% (17/126) of patients, respectively. The overall concordance rate of mutational status between plasma and matched tissues was 78.6% (99/126). Sixteen patients had mutations in plasma that were not detected in tissue, including some rare hotspot mutations. The cfDNA concentration was significantly correlated with the levels of clinical markers, especially CEA (P < 0.0001, Pearson r = 0.81), LDH (P < 0.0001, Pearson r = 0.84) and the sum of tumor diameters (P < 0.0001, Pearson r = 0.80). Patients with a high cfDNA concentration (> 17.91 ng/ml) had shorter median progression-free survival (6.6 versus 11.7 months, P < 0.0001) and lower 1-year overall survival rate (56% versus 94%, P < 0.0001) than those with a low cfDNA concentration (≤17.91 ng/ml). The most common metastatic site was the liver (77.8%), followed by the lymph nodes (62.7%), lung (40.5%), peritoneum (14.3%) and bone (10.3%), in all patients. There was no significant difference in metastasis between different mutational statuses.

Conclusion: Analyzing mutations in plasma could provide a more comprehensive overview of the mutational landscape than analyzing mutations in tissue. The cfDNA concentration could be a quantitative biomarker of tumor burden and could predict survival in Chinese patients with mCRC.
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http://dx.doi.org/10.1186/s12885-020-07516-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566057PMC
October 2020

Familial juvenile polyposis syndrome with a de novo germline missense variant in BMPR1A gene: a case report.

BMC Med Genet 2020 10 8;21(1):196. Epub 2020 Oct 8.

Department of Medical Oncology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China.

Background: Juvenile polyposis syndrome (JPS) is a rare autosomal dominant hereditary disorder characterized by the development of multiple distinct juvenile polyps in the gastrointestinal tract with an increased risk of colorectal cancer. Germline mutations in two genes, SMAD4 and BMPR1A, have been identified to cause JPS.

Case Presentation: Here, we report a germline heterozygous missense variant (c.299G > A) in exon 3 BMPR1A gene in a family with juvenile polyposis. This variant was absent from the population database, and concluded as de novo compared with the parental sequencing. Further sequencing of the proband's children confirmed the segregation of this variant with the disease, while the variant was also predicted to have damaging effect based on online prediction tools. Therefore, this variant was classified as likely pathogenic according to the American College of Medical Genetics and Genomics (ACMG) guidelines.

Conclusions: Germline genetic testing revealed a de novo germline missense variant in BMPR1A gene in a family with juvenile polyposis. Identification of the pathogenic variant facilitates the cancer risk management of at-risk family members, and endoscopic surveillance is recommended for mutation carriers.
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http://dx.doi.org/10.1186/s12881-020-01135-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545562PMC
October 2020

Surufatinib in advanced extrapancreatic neuroendocrine tumours (SANET-ep): a randomised, double-blind, placebo-controlled, phase 3 study.

Lancet Oncol 2020 11 20;21(11):1500-1512. Epub 2020 Sep 20.

Department of Clinical Development and Regulatory Affairs, Hutchison MediPharma, Shanghai, China.

Background: Therapeutic options for advanced neuroendocrine tumours (NETs) are limited. We investigated the efficacy and safety of surufatinib (HMPL-012, sulfatinib) in patients with extrapancreatic NETs.

Methods: SANET-ep was a randomised, double-blind, placebo-controlled, phase 3 trial undertaken at 24 hospitals across China. Patients (aged 18 years or older) with unresectable or metastatic, well differentiated, extrapancreatic NETs, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and progression on no more than two types of previous systemic regimens were enrolled. Patients were centrally randomly assigned (2:1) using stratified block randomisation (block size 3) via an interactive web response system to receive oral surufatinib at 300 mg per day or matching placebo. Randomisation was stratified by tumour origin, pathological grade, and previous treatment. Patients, investigators, research staff and the sponsor study team were masked to treatment allocation. Crossover to the surufatinib group was allowed for patients in the placebo group at disease progression. The primary endpoint was investigator-assessed progression-free survival, which was analysed in the intention-to-treat population. A preplanned interim analysis was done at 70% of predicted progression-free survival events. This study was registered with ClinicalTrials.gov, NCT02588170. Follow-up is ongoing.

Findings: Between Dec 9, 2015, and March 31, 2019, 198 patients were randomly assigned to surufatinib (n=129) or placebo (n=69). Median follow-up was 13·8 months (95% CI 11·1-16·7) in the surufatinib group and 16·6 months (9·2-not calculable) in the placebo group. Investigator-assessed median progression-free survival was 9·2 months (95% CI 7·4-11·1) in the surufatinib group versus 3·8 months (3·7-5·7) in the placebo group (hazard ratio 0·33; 95% CI 0·22-0·50; p<0·0001). As the trial met the predefined criteria for early discontinuation of the study at the interim analysis, the study was terminated early, as recommended by the independent data monitoring committee. The most common treatment-related adverse events of grade 3 or worse were hypertension (47 [36%] of 129 patients in the surufatinib group vs nine [13%] of 68 patients in the placebo group) and proteinuria (25 [19%] vs zero). Treatment-related serious adverse events were reported in 32 (25%) of 129 patients in the surufatinib group and nine (13%) of 68 patients in the placebo group. Treatment-related deaths occurred in three patients in the surufatinib group (disseminated intravascular coagulation and hepatic encephalopathy, liver injury, and death with unknown reason) and one patient in the placebo group (cachexia and respiratory failure).

Interpretation: Progression-free survival was significantly longer in patients given surufatinib compared with patients given placebo, and surufatinib has a favourable benefit-to-risk profile in patients with progressive, advanced, well differentiated extrapancreatic NETs. Our results suggest that surufatinib might be a new treatment option for this population.

Funding: Hutchison MediPharma.
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http://dx.doi.org/10.1016/S1470-2045(20)30496-4DOI Listing
November 2020

Safety Profile and Adverse Events of Special Interest for Fruquintinib in Chinese Patients with Previously Treated Metastatic Colorectal Cancer: Analysis of the Phase 3 FRESCO Trial.

Adv Ther 2020 11 8;37(11):4585-4598. Epub 2020 Sep 8.

Lilly China, Drug Development and Medical Affairs Center, Shanghai, China.

Introduction: In FRESCO (Fruquintinib Efficacy and Safety in 3+ Line Colorectal Cancer Patients) trial, fruquintinib demonstrated a statistically significant and clinically meaningful overall survival benefit in Chinese patients with metastatic colorectal cancer (mCRC). However, its safety profile, including adverse events of special interest (AESIs) and treatment-emergent adverse events (TEAEs) by age, sex, and body mass index (BMI), is not well known. The present analysis evaluated the safety profile and AESIs for fruquintinib in the FRESCO trial.

Methods: In FRESCO, eligible Chinese patients were randomized (2:1) to receive fruquintinib (5 mg once daily for 3 weeks, followed by 1 week off in 28-day cycles) or placebo plus best supportive care. Treatment-related AESIs and time to first occurrence of AESIs were summarized. Treatment-related TEAEs by age, sex, and BMI were also summarized.

Results: A total of 266 patients (95.7%) in the fruquintinib group and 97 (70.8%) in the placebo group had at least one treatment-related TEAE; the mean relative dose intensity was 92% and 98%, respectively. In the fruquintinib group, the most common (in > 40% of patients) treatment-related AESIs were hypertension (55.4%), palmar-plantar erythrodysesthesia syndrome [known as hand-foot skin reaction (HFSR)] (49.3%), and proteinuria (42.1%). The most common treatment-related grade ≥ 3 AESIs (≥ 3% of patients) were hypertension (21.2%), HFSR (10.8%), and proteinuria (3.2%); the median time to onset of these events was 10, 21, and 20 days, respectively. Subgroup analysis by age, sex, and BMI revealed that the frequencies of treatment-related TEAEs were similar across all subgroups, and were consistent with the overall safety profile of fruquintinib.

Conclusions: The most common treatment-related grade ≥ 3 AEs were hypertension, HFSR, and proteinuria. The treatment-related TEAE profile of fruquintinib in Chinese patents with mCRC was comparable among different subgroups and consistent with that reported in the overall population.

Trial Registration: Clinical Trials identifier NCT02314819.
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http://dx.doi.org/10.1007/s12325-020-01477-wDOI Listing
November 2020

Identification of a Novel EHBP1-MET Fusion in an Intrahepatic Cholangiocarcinoma Responding to Crizotinib.

Oncologist 2020 12 12;25(12):1005-1008. Epub 2020 Oct 12.

Department of Medical Oncology, Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China.

As an aggressive tumor, intrahepatic cholangiocarcinoma (ICC) originates in the epithelium of the bile duct and has a poor prognosis. The therapeutic options for ICC are challenging and limited because of poor response to chemotherapy and the lack of targeted therapy. Here we report on a 41-year-old female patient with ICC with EHBP1-MET fusion and multiple intrahepatic metastases responding to crizotinib. Next-generation sequencing-based tumor mutation profiling was performed on the tumor biopsy and circulating tumor DNA from plasma. A novel EHBP1-MET fusion was identified and confirmed by Sanger sequencing. Immunohistochemistry of biopsy sample also revealed c-MET positivity. Subsequently, the patient started treatment with MET inhibitor crizotinib. Magnetic resonance imaging scan demonstrated a partial response for 8 months. To the best of our knowledge, this is the first clinical case report of a patient with MET-rearranged ICC successfully treated with crizotinib. This case suggests that crizotinib may be a promising treatment option for patients with ICC with MET fusion, warranting further clinical investigation. KEY POINTS: To the authors' knowledge, this is the first reported case of EHBP1-MET fusion. This is also the first clinical case report of clinical benefit from crizotinib treatment in an intrahepatic cholangiocarcinoma (ICC) with MET fusion. MET fusion is rare in ICC, and inhibition of MET could be a viable option for ICC that warrants further clinical investigation.
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http://dx.doi.org/10.1634/theoncologist.2020-0535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938406PMC
December 2020

Intra-tumor metabolic heterogeneity of gastric cancer on F-FDG PETCT indicates patient survival outcomes.

Clin Exp Med 2021 Feb 3;21(1):129-138. Epub 2020 Sep 3.

Department of Nuclear Medicine, Zhongshan Hospital, Fudan University, No. 180 in Fenglin Road, Shanghai, 200032, People's Republic of China.

The present study aimed to investigate the prognostic value of intra-tumor metabolic heterogeneity on 2-[18F] Fluoro-2-deoxy-D-glucose (F-FDG) positron emission tomography/computed tomography (PET/CT) for patients with gastric cancer. Fifty-five patients with advanced gastric cancer that had received neoadjuvant chemotherapy and radical surgery were included. Clinicopathological information, F-FDG PET/CT before chemotherapy, pathological response, recurrence or metastasis, progression-free survival (PFS), and overall survival (OS) of the patients were collected. The maximum, peak, and mean standardized uptake values (SUV, SUV, and SUV), tumor-to-liver ratio (TLR), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) on PET/CT were measured. Heterogeneity index-1 (HI-1) was calculated as SUV divided by the standard deviation, and heterogeneity index-2 (HI-2) was evaluated through linear regressions of MTVs according to different SUV thresholds. Associations between these parameters and patient survival outcomes were analyzed. None of the parameters on PET were associated with tumor recurrence. Pathological responders had significantly smaller TLR, MTV and HI-2 values than non-responders (P = 0.017, 0.017 and 0.013, respectively). In multivariate analysis of PFS, only HI-2 was an independent factor (hazard ratio [HR] = 2.693, P = 0.005) after adjusting for clinical tumor-node-metastasis (TNM) stage. In multivariate analysis of OS, HI-2 was also an independent predictive factor (HR = 2.281, P = 0.009) after adjusting for tumor recurrence. Thus, HI-2 generated from baseline F-FDG PET/CT is significantly associated with survival of patients with gastric cancer. Preoperative assessment of HI-2 by F-FDG PET/CT might be promising to identify patients with poor prognosis.
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http://dx.doi.org/10.1007/s10238-020-00659-8DOI Listing
February 2021

Raloxifene inhibits IL-6/STAT3 signaling pathway and protects against high-fat-induced atherosclerosis in ApoE mice.

Life Sci 2020 Nov 20;261:118304. Epub 2020 Aug 20.

Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address:

Aims: The signal transducer and activator of transcription 3 (STAT3) pathway plays an important role in inflammatory cascade process. Our previous studies found that Raloxifene targeted against IL-6/GP130 protein-protein interface and inhibited STAT3 phosphorylation induced by IL-6 in cancer cells. However, whether Raloxifene could suppress IL-6/STAT3 signaling pathway and attenuate atherosclerosis in high-fat diet (HFD)-induced mice remains unknown. The objective of this study was to explore the potential effect of Raloxifene on the prevention of atherosclerosis.

Main Methods: HFD-induced atherosclerosis was established in apoliprotein E-deficient (ApoE ) mice. Mice by daily intragastric gavage with Raloxifene or vehicle as controls were provided. The human umbilical vein endothelial cells (HUVEC), Rat VSMC and RAW264.7 cell lines were used to evaluate the effect of Raloxifene in vitro.

Key Findings: We demonstrated that Raloxifene was effective in ameliorating HFD- induced atherosclerosis plaque burden and size. Histological analysis showed that the expression of IL-6, P-STAT3, ICAM-1, VCAM-1, CD68 and α-SMA were significantly decreased in the Raloxifene intervention group compared to HFD group. Moreover, we observed that IL-6 increased migration and cell viability of VSMCs and RAW264.7 cells, while Raloxifene treatment decreased migration and reduced cell viability of VSMCs and RAW264.7 cells stimulated by IL-6. Furthermore, this effect was related to blocking IL-6/STAT3 pathway.

Significance: Raloxifene has effects on inhibiting atherosclerosis development, the underlying mechanisms might involve in inhibiting inflammation-related IL-6/STAT3 signaling pathway.
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http://dx.doi.org/10.1016/j.lfs.2020.118304DOI Listing
November 2020

High Level of Legumain Was Correlated With Worse Prognosis and Peritoneal Metastasis in Gastric Cancer Patients.

Front Oncol 2020 16;10:966. Epub 2020 Jul 16.

Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China.

Accumulating evidence has demonstrated that legumain (LGMN) is abnormally expressed in several malignancies and functions as an oncogene. However, the association between LGMN and gastric cancer (GC) has not yet been fully elucidated. In this study, we performed a comprehensive analysis of the role of LGMN in clinicopathologic characteristics and survival of GC patients. The study had two patient cohorts, The Cancer Genome Atlas (TCGA) cohort and the Zhongshan Hospital cohort, both of which were used to analyze the role of LGMN in GC samples. The relationship between LGMN and clinicopathologic characteristics was determined by the Chi-square test and logistic regression analysis. The Kaplan-Meier method and Cox proportional hazards regression analysis were conducted to investigate the prognostic role of LGMN in GC patients. Moreover, a nomogram was constructed based on the factors that were independently associated with peritoneal metastasis. Finally, the gene set enrichment analysis (GSEA) was conducted to explore the underlying pathways through which LGMN was involved in GC progression. The mRNA and protein levels of LGMN were significantly upregulated in GC tissues, especially for diffuse-type GC. High level of LGMN was independently associated with poor prognosis in both TCGA and Zhongshan cohorts. Further analysis showed that increased protein level of LGMN was related to peritoneal metastasis in GC patients. In a nomogram model, the LGMN expression could help predict the possibility of peritoneal metastasis in GC patients. LGMN was a strong determinant for prediction of peritoneal metastasis. GC patients with high LGMN expression tended to have worse survival together with more frequent diffuse-type tumors and increased risk of peritoneal metastasis. The GSEA results showed that focal adhesion, ecm receptor interaction, cell adhesion molecules cams, TGF-β signaling pathway, JAK-STAT signaling pathway, gap junction, etc. were differentially enriched in the phenotype with high LGMN expression. LGMN was an independent prognostic factor for OS in GC patients. Increased expression of LGMN was significantly associated with peritoneal metastasis. The nomogram based on LGMN might guide the clinical decisions for patients with GC.
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http://dx.doi.org/10.3389/fonc.2020.00966DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378441PMC
July 2020

Bevacizumab Plus mFOLFOX6 Versus mFOLFOX6 Alone as First-Line Treatment for Mutant Unresectable Colorectal Liver-Limited Metastases: The BECOME Randomized Controlled Trial.

J Clin Oncol 2020 09 4;38(27):3175-3184. Epub 2020 Aug 4.

Department of General Surgery, Zhongshan Hospital, Fudan University, and Shanghai Engineering Research Center of Colorectal Cancer Minimally Invasive, Shanghai, People's Republic of China.

Purpose: To assess the effects of bevacizumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) as first-line treatment of mutant unresectable colorectal liver metastases.

Methods: From October 2013 to December 2017, patients with mutant unresectable liver-limited metastases from colorectal cancer were randomly assigned to receive mFOLFOX6 plus bevacizumab (arm A) or mFOLFOX6 alone (arm B). The resectability of liver metastases was determined by a local multidisciplinary team. The primary end point was the actual rate of patients converted to R0 resection for liver metastases. Secondary end points included tumor response, survival, and toxicity. The block randomization method was used.

Results: The intention-to-treat population comprised 241 patients. A total of 121 patients were randomly assigned to arm A and 120 to arm B. The median follow-up time was 37.0 months for all patients. The R0 resection rates for liver metastases were 22.3% (27 of 121 patients) in arm A and 5.8% (7 of 120 patients) in arm B, with a significant difference ( < .01). Patients in arm A had significantly better objective response rates (54.5% 36.7%; < .01), median progression-free survival (9.5 5.6 months; < .01) and median overall survival (25.7 20.5 months; = .03) compared with those in arm B. The addition of bevacizumab was associated with more frequent proteinuria (9.9% 3.3%; = .04) and hypertension (8.3% 2.5%; < .05).

Conclusion: For patients with initially unresectable mutant colorectal liver metastases, bevacizumab combined with mFOLFOX6 increased the resectability of liver metastases and improved response rates and survival compared with mFOLFOX6 alone.
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http://dx.doi.org/10.1200/JCO.20.00174DOI Listing
September 2020

Tislelizumab in Chinese patients with advanced solid tumors: an open-label, non-comparative, phase 1/2 study.

J Immunother Cancer 2020 06;8(1)

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

Background: Tislelizumab is an investigational, humanized, IgG4 monoclonal antibody with high affinity and binding specificity for programmed cell death-1 (PD-1) that was engineered to minimize binding to FcγR on macrophages in order to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy.

Methods: The purpose of this phase 1/2, open-label, non-comparative study was to examine the safety, tolerability, and antitumor activity of tislelizumab in adult (≥18 years) Chinese patients with histologically or cytologically confirmed advanced solid tumors with measurable disease. The phase 1 portion of the study consisted of a dose-verification study and a pharmacokinetic (PK) substudy; phase 2 was an indication-expansion study including 11 solid tumor cohorts. Patients previously treated with therapies targeting PD-1 or its ligand, programmed cell death ligand-1 were excluded. During dose-verification, dose-limiting toxicities (DLTs) were monitored; safety and tolerability were examined and the previously determined recommended phase 2 dose (RP2D) was verified. The primary endpoint of phase 2 was investigator-assessed objective response rate per Response Evaluation Criteria in Solid Tumors V.1.1.

Results: As of December 1, 2018, 300 patients were treated with tislelizumab 200 mg intravenously once every 3 weeks (Q3W). Median duration of follow-up was 8.1 months (range 0.2-21.9). No DLTs were reported during the phase 1 dose-verification study and the RP2D was confirmed to be 200 mg intravenously Q3W. Most treatment-related adverse events (62%) were grade 1 or 2, with the most common being anemia (n=70; 23%) and increased aspartate aminotransferase (n=67; 22%). Of the 251 efficacy evaluable patients, 45 (18%) achieved a confirmed clinical response, including one patient from the PK substudy who achieved a complete response. Median duration of response was not reached for all except the nasopharyngeal carcinoma cohort (8.3 months). Antitumor responses were observed in multiple tumor types.

Conclusions: Tislelizumab was generally well tolerated among Chinese patients. Antitumor activity was observed in patients with multiple solid tumors.

Trial Registration Number: CTR20160872.
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http://dx.doi.org/10.1136/jitc-2019-000437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7304812PMC
June 2020