Jiajia Yuan

Programmed death-ligand-1 expression in advanced gastric cancer detected with RNA in situ hybridization and its clinical significance

PD-L1 expression may be a predictive marker for anti-PD-1 therapeutic efficacy. No standard detection method of PD-L1 expression was available for advanced gastric cancer (AGC), which would be investigated in this study using RNA in situ hybridization and immunohistochemistry. Patients (N = 165) with AGC treated at Peking University Cancer Hospital from October 2008 to February 2013 were retrospectively studied. Tissue samples prior to chemotherapy were assessed for PD-L1 expression using RNA in situ hybridization (an RNAscope assay) and immunohistochemistry (IHC). The correlations of PD-L1 expression to patient characteristics and clinical outcomes were statistically analyzed. PD-L1 mRNA signals were located in tumor compartments or the mesenchyme in a brown dotted or clustered pattern, and PD-L1 mRNA expression in gastric cancer was heterogeneous. PD-L1-positive expressions were observed in 33.9% (56/165) and 35.1% (46/131) patients in mRNA level and protein level, respectively. A positive relationship was found between PD-L1 mRNA and PD-L1 protein, and compared to IHC, RNAscope assay could provide an intuitional and quantitative data with potential clinical application. No statistically significant differences occurred between PD-L1 expression and clinical response to chemotherapy, or survival. However, we found that PD-L1 expression was higher in intestinal type than in diffuse type. These findings suggested that the RNAscope assay may be a promising method for patient assessment in gastric cancer clinical trials, which would be illustrated in further study.

Risk prediction for early-onset gastric carcinoma: a case-control study of polygenic gastric cancer in Han Chinese with hereditary background

Recent genomewide studies have identified several germline variations associated with gastric cancer. The aim of the present study was to identify, in a Chinese Han population, the individual and combined effects of those single nucleotide polymorphisms (SNPs) that increase the risk of early-onset gastric cancer. We conducted a case-control study comprising 116 patients with gastric cancer as well as 102 sex- and age-matched controls and confirmed that the SNPs MUC1 (mucin 1) rs9841504 and ZBTB20 (zinc finger and BTB domain containing 20) rs4072037 were associated with an increased gastric cancer risk. Of the 116 patients diagnosed with cancer, 65 had at least 1 direct lineal relative with carcinoma of the digestive system or breast/ovarian cancer. These 65 had another 4 SNPs associated with gastric cancer susceptibility: PSCA (prostate stem cell antigen) rs2294008, PLCE1 (phospholipase C epsilon 1) rs2274223, PTGER4/PRKAA1 (prostaglandin E receptor 4/protein kinase AMP-activated catalytic subunit alpha 1) rs13361707, and TYMS (thymidylate synthetase) rs2790. However, each of these low-penetrance susceptibility polymorphisms alone is not considered influential enough to predict the absolute risk of early-onset gastric cancer. Thus we decided to study different combinations of polygenes as they affected for our population. Those subjects with both the risk alleles MUC1 rs9841504 and ZBTB20 rs4072037 had a greater than 3-fold increased risk of gastric cancer. Also those with a hereditary background including the risk alleles PLCE1 rs2274223 and PTGER4/PRKAA1 rs13361707 were 3 times more susceptible to cardia cancer than those without. These findings show that the study of combined polymorphisms, instead of single low-penetrance variations in susceptibility, may lead to a high-risk classification for a specific population.

CDK4/6 inhibitor-SHR6390 exerts potent antitumor activity in esophageal squamous cell carcinoma by inhibiting phosphorylated Rb and inducing G1 cell cycle arrest

BackgroundCell cycle dysregulation is common in human malignancies, and CDK4/6 inhibitors targeting cell cycle have potential antitumor activity. SHR6390 is a novel small molecule inhibitor specifically targeting the CDK4/6 pathway. However, the role of SHR6390 in esophageal squamous cell carcinoma (ESCC) remains unknown, which will be investigated in our study.MethodsEca 109, Eca 9706, and KYSE-510 ESCC cell lines were chosen for further analysis. The effect of SHR6390 on cell viability, cell cycle and cell apoptosis, the status of kinases in Cyclin D1-CDK4/6-Rb pathway were determined by MTS assay, flow cytometry, and western blotting, respectively. Cell-derived and patient-derived xenografts were established to investigate the effects of drugs in vivo.ResultsSHR6390 could suppress cell proliferation in vitro cell lines and inhibit tumor growth in vivo PDX models with different drug susceptibility. The effective treatment of SHR6390 induced the inhibition of phosphorylated Rb and cell cycle arrest at G1 phase both in cell lines and in xenografts. SHR6390 combined with paclitaxel or cisplatin offered synergistic inhibitory effects in cell-derived xenografts especially in Eca 9706 xenografts which showed relative lower sensitivity of SHR6390 single. Moreover, low expression of CDK6 and/or high expression of Cyclin D1 might be associated with high sensitivity of SHR6390, which would be validated in the future.ConclusionsCDK4/6 inhibitor-SHR6390 exerted potential antitumor activity against ESCC cell lines and xenografts, and evaluation of CDK6 and Cyclin D1 expressions might be helpful to select patients beneficial from SHR6390, which provided evidences for future clinical trials.

Author Correction: A proteomic landscape of diffuse-type gastric cancer

The original version of this Article contained an error in the email address of the corresponding author Jun Qin. The correct email is jqin1965@126.com. The error has been corrected in the HTML and PDF versions of the Article.

Survival Benefit of Palliative Local Treatments and Efficacy of Different Pharmacotherapies in Colorectal Cancer With Lung Metastasis: Results From a Large Retrospective Study

Background For most colorectal cancer patients with initial lung metastasis (LM), the only suitable treatments are palliative, including palliative local therapy and pharmacotherapy. We investigated the role of palliative local treatments in prolonging survival and the efficacy of different pharmacotherapies. Patients and Methods After performing a medical record review of 2233 patients with metastatic colorectal cancer, 684 were identified as having LM. Their clinicopathologic characteristics, treatment patterns, and outcomes were analyzed retrospectively. Results For nonresectable initial LM, patients receiving palliative local therapy had significantly longer median progression‐free survival (PFS) and overall survival (OS) than those treated with pharmacotherapy alone: PFS 16.1 months versus 7.4 months (P < .001) and OS 51.8 months versus 23.8 months (P < .001), respectively. Cox multivariate analysis confirmed the survival benefit induced by palliative local therapy. Chemonaive patients receiving single‐agent fluoropyrimidine had shorter PFS and longer OS compared to oxaliplatin‐ or irinotecan‐based doublets when used as first‐line treatment (PFS 4.8, 7.4, and 7.3 months; and OS 28.7, 21.2, and 20.1 months, respectively); however, these differences were not statistically significant. The addition of targeted agents to cytotoxic drugs prolonged PFS (10.5 vs. 7.2 months, P = .005) but not OS (27.8 vs. 21.2 months, P = .454). Carcinoembryonic antigen level, LM‐associated symptoms, extrapulmonary disease, and histopathologic type were independent pretreatment prognostic factors. Conclusion Local treatments of LM may confer a survival benefit in the palliative setting. First‐line single‐agent fluoropyrimidine may be used in patients with good prognosis. Micro‐Abstract The role of palliative local treatments and the efficacy of different pharmacotherapies in colorectal cancer with initial lung metastasis was retrospectively investigated. Palliative local treatments resulted in better survival benefit than pharmacotherapy alone. First‐line nonintensive pharmacotherapy showed similar survival durations compared to intensive regimens.

Abstract 2204: A proteomic landscape of diffuse-type gastric cancer

Gastric cancer is a heterogeneous disease characterized by poor clinical outcomes and limited targeted treatment options. Among them, diffuse-type gastric cancer (DGC) is the subtype with worst prognosis. Here we describe the first proteomic landscape of DGC. We carried out proteome profiling and targeted exome DNA sequencing of 84 DGC samples. We analyzed the 1,008 (168 x 6) raw files together for uniformed quality control and protein identification with 1% global protein false discovery rate (FDR), which resulted in the identification of 11,340 gene products (GPs). A SAM (significance analysis of microarray) analysis identified 1,641 proteins as differentially expressed between T (tumor) and N (nearby) with statistical significance (FDR q value 0.5/ Citation Format: Sai Ge, Xia Xia, Chen Ding, Bei Zhen, Quan Zhou, Jinwen Feng, Jiajia Yuan, Rui Chen, Yumei Li, Zhongqi Ge, Jiafu Ji, Lianhai Zhang, Jiayuan Wang, Zhongwu Li, Yumei Lai, Ying Hu, Yanyan Li, Yilin Li, Jing Gao, Lin Chen, Jianming Xu, Chunchao Zhang, Sung Yun Jung, Mingwei Liu, Lei Song, Wanlin Liu, Gaigai Guo, Tongqing Gong, Yin Huang, Yang Qiu, Tieliu Shi, Weimin Zhu, Yi Wang, Fuchu He, Lin Shen, Jun Qin, CNHPP. A proteomic landscape of diffuse-type gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2204. doi:10.1158/1538-7445.AM2017-2204

Metabolic complications and quality of life in prostate cancer patients after receiving endocrine treatment

OBJECTIVE To compare the incidences of anemia, osteoporosis, and irritable bowel syndrome (IBS) after the application of different endocrine therapies in patients with prostate cancer. METHODS Totally 125 patients aged 58 to 84 years with biopsy-confirmed local prostate cancer were recruited between September 2008 and September 2010. Of them 52 treated with orchiectomy (castration group) and 73 with luteinizing hormone-releasing hormone analogue (goserelin acetate 3.6mg/month) combined with androgen antagonist (bicalutamide 50mg/d) for at least 12 months (hormone group), but without blood transfusion or erythropoietin. Changes in total testosterone (TT), free testosterone (FT), prostate specific antigen (PSA), hemoglobin (Hb), red blood cell (RBC), hematocrit (Hct), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), red blood cell distribution width (RDW), bone mineral density (BMD) and gastrointestinal symptom rating scales (GSRS) were recorded and analyzed before treatment and 12 months after the initiation of treatment. RESULTS In the castration group, after 12 months, TT (P=0.0007), FT (P=0.0003), PSA (P=0.0006), Hb (P=0.0001), RBC (P=0.020), Hct (P=0.016), Z-score of lumbar spine (P=0.008), and femoral neck (P=0.004) decreased significantly, and GSRS (P=0.029) increased significantly. In hormone group, after 12 months, TT (P=0.0008), FT (P=0.0006), PSA (P=0.0006), Hb (P=0.0003), RBC (P=0.0001), Hct (P=0.0002), Z-score of lumbar spine (P=0.002), femoral neck (P=0.0002), and RDW (P=0.045) decreased significantly, and GSRS (P=0.010) increased significantly. After 12 months, TT (P=0.004), FT (P=0.012), PSA (P=0.007), Hb (P=0.016), Z-score of lumbar spine (P=0.033), and femoral neck (P=0.015) in hormone group were significantly lower than in the castration group, while GSRS (P=0.027) in hormone group was significantly higher than in the castration group. The incidences of anemia (P=0.006), osteoporosis (P=0.009), and IBS (P=0.022) were significantly different between these two groups. The serum level of testosterone was positively correlated with Hb, RBC, Hct, and BMD in both groups (P=0.039). Negative linear correlations could be seen between serum level of testosterone and GSRS in both groups (P=0.021), and between serum level of testosterone and RDW in medical group only (P=0.044). CONCLUSION The endocrine therapies, particularly maximal androgen blockage, in patients with prostate cancer can be associated with anemia, osteoporosis, and IBS.

Metabolic disorder after androgen deprivation therapy in patients with prostate cancer

The prevalence of prostate cancer, a common malignancy of urinary system in elderly males, has increased rapidly in China in recent years. Currently most prostate cancer patients are treated with androgen deprivation therapy (ADT). However, ADT-induced metabolic disorders such as metabolic syndrome has remarkably impaired the quality of life and decreased the survival rate.