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08 December 2019, Volume 46 Issue 12 Previous Issue    Next Issue

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Molecular targeted therapy for advanced kidney cancer Xiong Bobo, Zhang Jinsong, Li Ning, Wang Haifeng, Zuo Yigang, Wang Jiansong 2019, 46 (12):  705-710.  doi: 10.3760/cma.j.issn.1673-422X.2019.12.001 Abstract ( 444 )   PDF (719KB) ( 272 )   Save Sorafenib is the first molecularly targeted drug for first-line treatment of patients with advanced kidney cancer and has achieved satisfactory results. Since then, a variety of molecularly targeted drugs have emerged, and the treatment of patients with advanced kidney cancer has entered a new era of molecular targeting. Molecular targeted therapy improves the clinical efficacy and response rate of patients, and prolongs the progression-free survival and overall survival of patients. Current targeted drugs include vascular endothelial growth factor inhibitors, mammalian target of rapamycin, immunological checkpoint inhibitors, etc. Understanding the mechanism of action and clinical efficacy of different targeted drugs, and analyzing the challenges of current targeted drugs from the perspective of gene mutation and drug resistance are helpful to the personalized treatment of patients with advanced renal cancer. References | Related Articles | Metrics

Original Articles

Mitochondrial energy metabolism mediated via HIF-1 involves the proliferation and apoptosis of renal clear cell carcinoma cells regulated by propofol Li Zhengmin, Zhang Yuming, Zhang Zhen, Zhang Ru, Zhu Jing, Wang Jun 2019, 46 (12):  711-717.  doi: 10.3760/cma.j.issn.1673-422X.2019.12.002 Abstract ( 478 )   PDF (1228KB) ( 239 )   Save Objective  To investigate the role of mitochondrial energy metabolism mediated via hypoxia-inducible factor-1 (HIF-1) in the proliferation and apoptosis of renal clear cell carcinoma cells regulated by propofol. Methods  We chose human renal clear cell carcinoma cell line RCC4 as the research object, which did not express VHL gene. The pcDNA3VHL plasmid and the pcDNA3 empty plasmid were respectively transfected into RCC4 cells to obtain RCC4-VHL(+) cells stably expressing the exogenous VHL protein and RCC4-VHL(-) cells without expressing the VHL protein. These two kinds of cells were then exposed to propofol at dosage of 0, 25, 50 and 100 μmol/L. HIF-1 protein expression was detected by Western blotting in the two kinds of cells, cell proliferation activity and apoptosis rate were detected by flow cytometry, and mitochondrial energy metabolism was detected by energy metabolism analyzer. Results  Compared with RCC4-VHL(-) cells, the relative expression of HIF-1α protein in RCC4-VHL(+) cells was significantly decreased (0.05±0.02 vs. 1.23±0.10, t=16.016, P＜0.001). When propofol concentrations were 50 μmol/L and 100 μmol/L, the proliferation activity of RCC4-VHL(+) cells was significantly lower than that of RCC4-VHL(-) cells (50 μmol/L: 0.10±0.02 vs. 0.13±0.04, t=3.502, P=0.032; 100 μmol/L: 0.05±0.02 vs. 0.10±0.01, t=6.771, P=0.017), and the apoptotic rate was significantly higher than that of RCC4-VHL (-) cells ［50 μmol/L: (35.50±1.84)% vs. (22.15±1.06)%, t=7.082, P=0.004; 100 μmol/L: (54.35±2.97)% vs. (35.10±3.25)%, t=10.241, P＜0.001). Compared with 0 μmol/L propofol, 100 μmol/L propofol increased HIF-1α protein expression in RCC4-VHL (+) cells (0.93±0.05 vs. 0.04±0.02, t=18.500, P＜0.001). Compared with RCC4-VHL(-) cells, the oxygen consumption rate (OCR) ［(130.42±11.81) pmol/min vs. (48.27±7.66) pmol/min, t=11.672, P＜0.001］, basal aerobic respiration ［(98.55±8.09) pmol/min vs. (41.63±6.21) pmol/min, t=11.162, P＜0.001］, aerobic maximum ［(226.79±13.51) pmol/min vs. (70.18±6.82) pmol/min, t=20.697, P＜0.001］, non-mitochondrial respiration ［(28.36±4.29) pmol/min vs. (8.92±1.70) pmol/min, t=8.426, P=0.001］ and oxygen consumption rate of proton leak ［(23.85±5.08) pmol/min vs. (7.80±1.24) pmol/min, t=6.139, P=0.006］ were significantly increased in RCC4-VHL(+) cells, while the extracellular acidification rate (ECAR) was significantly decreased ［(26.76±4.35) mpH/min vs. (39.48±5.17) mpH/min, t=3.765, P=0.010］. Compared with 0 μmol/L propofol added in RCC4-VHL(+) cells, 100 μmol/L propofol decreased OCR ［(72.44±8.15) pmol/min vs. (131.56±9.04) pmol/min, t=9.751, P＜0.001］, basal aerobic respiration ［(54.31±5.35) pmol/min vs. (96.49±6.86) pmol/min, t=9.697, P＜0.001］, aerobic maximum ［(116.71±12.39) pmol/min vs. (219.53±11.80) pmol/min, t=12.019, P＜0.001］, non-mitochondrial respiration ［(13.25±4.01) pmol/min vs. (29.04±5.11) pmol/min, t=4.862, P=0.002］ and oxygen consumption rate of proton leak ［(10.24±3.79) pmol/min vs. (22.92±4.12) pmol/min, t=4.530, P=0.003］, and increased ECAR significantly ［(37.69±3.75) mpH/min vs. (25.87±4.03) mpH/min, t=4.294, P=0.004］. Conclusion  Loss of VHL up-regulates expression of HIF-1 protein, and mitochondrial energy metabolism mediated via HIF-1 involves the proliferation and apoptosis of RCC4 cells regulated by propofol. References | Related Articles | Metrics

Expressions of MMP2, TIMP2, Ki-67 and P53 in glioma tissues and their significance Yu Xuejuan, An Hongwei, Sun Yamei, Jiang Zheng, Zhang Xuehai, Yang Wenjing, Zhang Wei 2019, 46 (12):  718-722.  doi: 10.3760/cma.j.issn.1673-422X.2019.12.003 Abstract ( 464 )   PDF (3009KB) ( 377 )   Save Objective  To investigate the expressions and significance of matrix metalloproteinase 2 (MMP2), tissue inhibitor of metalloproteinase 2 (TIMP2), Ki-67 and P53 in human glioma tissues. Methods  The expressions of Ki-67 and P53 in paraffin samples of 50 gliomas (immunohistochemistry SP method) from January 1995 to December 2015 in Qilu Hospital of Shandong University was analyzed retrospectively, and the expressions of MMP2 and TIMP2 were detected by immunohistochemistry. The differences of parameters between high- and low-grade gliomas were compared by χ2 test and their correlations were assessed by Spearman correlation analysis. Results  In the high-grade group (grade Ⅲ-Ⅳ, n=37), the high expression rate of MMP2 was 81.08% (30/37), the positive expression rates of Ki-67 and P53 were 78.38% (29/37) and 72.97% (27/37). In the low-grade group (grade Ⅰ-Ⅱ, n=13), there were 2 patients with high expression of MMP2, 3 patients with positive expression of Ki-67 and P53 respectively, and there were significant differences between the two groups (χ2=15.282, P＜0.001; χ2=10.482, P=0.001; χ2=9.979, P=0.002). A significant correlation was found between them and pathological grade (r=0.600, P＜0.001; r=0.505, P＜0.001; r=0.447, P=0.001). The high expression of TIMP2 was found in 8 cases of low-grade group and 19 cases (51.35%) of high-grade group, with no significant difference (χ2=0.402, P=0.526). The expression of MMP2 was positively correlated with Ki-67 and P53 (r=0.392, P=0.005; r=0.323, P=0.022), while TIMP2 was negatively correlated with Ki-67 (r=−0.441, P=0.001). The expression of P53 was positively correlated with Ki-67 (r=0.748, P＜0.001). Conclusion  MMP2, Ki-67 and P53 may play important role in the proliferation and invasiveness of glioma. The mechanism of TIMP2 is complicated and needs further study. References | Related Articles | Metrics

Clinical efficacy of S-1 combined with gefitinib in the treatment of advanced NSCLC with EGFR-TKI acquired drug resistance Shen Jingxia, Han Bin, Wang Shuying, Kang Haili, Wang Lidong, Liu Xuhui, Cui Qinggui 2019, 46 (12):  723-727.  doi: 10.3760/cma.j.issn.1673-422X.2019.12.004 Abstract ( 664 )   PDF (785KB) ( 233 )   Save Objective  To explore the clinical effect of S-1 combined with gefitinib in the treatment of advanced non-small cell lung cancer (NSCLC) with acquired resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI). MethodsA total of 74 patients with advanced NSCLC were selected as the study subjects from January 2016 to August 2017 in Qian′an People′s Hospital of Hebei Province. The patients were divided into control group (n=37) and experimental group (n=37) by random number table method. The control group was given sequential gefitinib with pemetrexed, and the experimental group was given S-1 combined with gefitinib. The clinical efficacy and adverse reactions of the two groups were compared. Results  The effective rates of the control group and the experimental group were 21.62% (8/37) and 27.03% (10/37) respectively, and the difference was not statistically significant (χ2=0.294, P=0.588). The disease control rates were 75.68% (28/37) and 78.38% (29/37) respectively, and the difference was not statistically significant (χ2=0.076, P=0.782). The median progression-free survival of the control group and the experimental group were 8.4 months and 8.2 months, and the median overall survival were 9.8 months and 10.5 months respectively, and the differences were not statistically significant (χ2=0.186, P=0.666; χ2=0.608, P=0.436). The occurrence rate of diarrhea was 56.76% (21/37) in the control group and 62.16% (23/37) in the experimental group, with no significant difference (χ2=0.224，P=0.636). The occurrence rates of rash in the control group and the experimental group were 62.16% (23/37) and 13.51% (5/37), the occurrence rates of leukopenia were 35.14% (13/37) and 5.41% (2/37), the occurrence rates of thrombocytopenia were 27.03% (10/37) and 2.70% (1/37), the occurrence rates of anemia were 40.54% (15/37) and 10.81% (4/37), and the occurrence rates of liver damage were 18.92% (7/37) and 0 (0/37). The occurrence rates of the above adverse reactions in the experimental group were significantly lower than those in the control group, and the differences were statistically significant (χ2=18.615, P＜0.001; χ2=10.118, P=0.001; χ2=8.650, P=0.003; χ2=8.568, P=0.003; χ2=5.680, P=0.017). There were no grade Ⅲ-Ⅳ adverse reactions in the two groups. ConclusionThe combination of S-1 and gefitinib is effective in the treatment of advanced NSCLC with acquired resistance to EGFR-TKI  and well tolerated, with mild adverse reactions, and oral administration is easy for patients to accept. It is an ideal way for clinical treatment of advanced NSCLC with EGFR-TKI acquired resistance. References | Related Articles | Metrics

Application of 18F-FDG PET-CT in evaluating the prognosis of locally advanced non-small cell lung cancer Lu Huiling, Ji Shengjun, Fu Zhaoyi, Zhang Min 2019, 46 (12):  728-733.  doi: 10.3760/cma.j.issn.1673-422X.2019.12.005 Abstract ( 425 )   PDF (912KB) ( 274 )   Save Objective  To explore the value of 18F-FDG PET-CT in evaluating the prognosis of locally advanced non-small cell lung cancer (NSCLC) patients. Methods  The clinical characteristics and 18F-FDG PET-CT parameters of 138 locally advanced NSCLC patients from 2013 to 2016 in Suzhou Municipal Hospital and People′s Hospital of Suzhou New District were analyzed retrospectively. The maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were measured. Area under the curve (AUC) of SUVmax, MTV and TLG were calculated to determine optimal cut-off value for patients grouping, with receiver-operating characteristic curve (ROC) analysis. Progression-free survival (PFS) and overall survival (OS) were assessed by Kaplan-Meier method and the survival difference between the two groups was estimated by log-rank test. Multivariate survival analysis was performed by Cox proportional hazard model. Results  According to ROC analysis, SUVmax (AUC=0.716, cut-off value was 11.8, P<0.001) had a better predictive value for OS, whereas the predictive values of MTV (AUC=0.580, P=0.101) and TLG (AUC=0.635, P=0.005) were less. There was no significant correlation between SUVmax and patients′ age (χ2=1.222, P=0.269), gender (χ2=0.029, P=0.865), TNM stage (χ2=0.073, P=0.787), pathologic subtype (χ2=0.541, P=0.462), smoking (χ2=0.266, P=0.606), differentiation (χ2=0.285, P=0.593) or tumor location (χ2=0.509, P=0.476). The 1-year, 2-year and 3-year OS rates of low SUVmax group (n=59) were 93.2%, 67.0% and 15.6% respectively, and those of high SUVmax group (n=79) were 77.2%, 25.0% and 5.62% respectively. The OS rate of low SUVmax group was higher than that of high SUVmax group (χ2=19.153, P<0.001). The 1-year and 2-year PFS rates of low SUVmax group were 79.3% and 56.9% respectively, and those of high SUVmax group were 46.2%, 13.0% respectively. The PFS rate of low SUVmax group was higher than that of high SUVmax group (χ2=25.945, P<0.001). Single factor analysis showed that differentiation (HR=1.839, 95%CI: 1.161-2.913, P=0.017), SUVmax (HR=0.357, 95%CI: 0.231-0.550, P<0.001), MTV (HR=0.470, 95%CI: 0.270-0.819, P=0.001) and TLG (HR= 0.508, 95%CI: 0.327-0.789, P=0.002) were independent influencing factors of OS. The degree of differentiation (HR=1.909, 95%CI: 1.167-3.123, P=0.018) and SUVmax (HR=0.250, 95%CI: 0.160-0.410, P<0.001) were the independent influencing factors of PFS. Multivariate analysis showed that only SUVmax was an independent influencing factor of OS (HR=2.189, 95%CI: 1.222-3.189, P=0.008）and PFS (HR=4.412, 95%CI: 2.318-8.398, P<0.001). Conclusion  PET-CT SUVmax of primary tumor is significantly correlated with OS and PFS of patients. It has important guiding value for prognosis judgment and treatment plan selection of patients with locally advanced NSCLC. References | Related Articles | Metrics

Predictive value of serum low density lipoprotein for first-line treatment in extensive-stage small cell lung cancer Tian Meng, Li Zhenxiang, Fu Chengrui, Li Baosheng, Sun Xinchen 2019, 46 (12):  734-740.  doi: 10.3760/cma.j.issn.1673-422X.2019.12.006 Abstract ( 506 )   PDF (1142KB) ( 214 )   Save Objective  To investigate the relationship between serum low density lipoprotein (LDL) and the progression-free survival (PFS) of small cell lung cancer (SCLC) patients. Methods  A total of 271 SCLC patients admitted to Shandong Cancer Hospital from May 1, 2014 to October 31, 2018 were selected. These patients were divided into limited-stage group (n=126) and extensivestage group (n=145) according to Veteran′s Administration Lung Cancer Study Group (VALSG) evaluation standard. The correlation between the level of serum LDL before treatment and PFS was analyzed by Spearmen test in the two groups. After finding the cutoff value of LDL level by receiver operating characteristic curve (ROC) analysis, the relationship between LDL level before treatment and PFS was analyzed. According to the dynamic change of serum LDL during the treatment, extensive-stage patients were divided into four groups: normalized LDL group (n=25, patients whose LDL≤2.55 mmol/L and never increased until progression), increased LDL group (n=31, patients whose LDL≤2.55 mmol/L and increased at least once until progression), never-normalized LDL group (n=33, patients whose LDL>2.55 mmol/L and never normalized until progression), and decreased LDL group (n=56, patients whose LDL>2.55 mmol/L and decreased at least once until progression). Then the PFS among the four groups was compared. The survival curves were plotted by the Kaplan-Meier method and compared using the log-rank test. The significance of the independent variables for PFS in extensive-stage patients was analyzed using the Cox proportional hazards model. Results  The median PFS for the whole cohorts was 7.1 months (1.4-27.1 months). The median PFS for limited-stage patients and extensive-stage ones was 8.8 months and 6.1 months respectively, with a significant statistical difference (χ2=28.723, P＜0.001). LDL levels before treatment were negatively associated with PFS in all the patients (r=-0.234, P＜0.001) and extensive-stage group (r=-0.329, P＜0.001), but there was no statistical significance in limitedstage group (r=-0.119, P=0.183). The cutoff point of LDL was 2.55 mmol/L, with the highest value of sensitivity (55.56%) and specificity (81.69%) in the ROC analysis using PFS as an end point for extensive-stage patients. Patients in the low-LDL group （≤2.55 mmol/L, n=107） had relatively longer PFS compared to the ones in the high-LDL group （＞2.55 mmol/L, n=164） for whole cohorts (9.0 months vs. 6.2 months, χ2=16.064, P＜0.001). The serum LDL level before treatment showed a prognostic power mainly related to PFS within the extensive-stage cohort (χ2=21.419, P＜0.001), with no difference in the limited-stage cohort (χ2=2.718, P=0.099). In the extensive-stage cohort, the median PFS in the normalized LDL group, the increased LDL group, the nevernormalized LDL group and the decreased LDL group was 9.2, 6.5, 5.0 and 6.2 months respectively, and there was a significant difference in the PFS among the four groups (χ2=16.411, P＜0.001). Univariate analysis showed that the LDL>2.55 mmol/L before treatment (HR=0.436, 95%CI: 0.297-0.640, P＜0.001) and LDL>2.55 mmol/L and never normalized until progression (HR=2.215, 95%CI: 1.403-3.497, P＜0.001) were risk factors for PFS, LDL normal during treatment (HR=0.343, 95%CI: 0.190-0.618, P＜0.001) was the protective factor of PFS in extensive-stage patients. Multivariate Cox regression analysis showed that the LDL>2.55 mmol/L before treatment (HR=0.435, 95%CI: 0.300-0.632, P＜0.01) and LDL>2.55 mmol/L and never normalized until progression (HR=2.028, 95% CI: 1.386-2.966, P＜0.001) were independent risk factors for PFS, LDL normal during treatment (HR=0.318, 95%CI: 0.186-0.542, P＜0.001) was independent protective factors of PFS. Conclusion  The serum LDL level may be used as a potential predictive marker for PFS in extensive-stage SCLC patients subjected to the first-line chemotherapy.  References | Related Articles | Metrics

Reviews

Advances in nonsurgical treatment of head and neck squamous cell carcinoma Zang Shoumei, Yan Danfang, Yan Senxiang 2019, 46 (12):  741-744.  doi: 10.3760/cma.j.issn.1673-422X.2019.12.007 Abstract ( 569 )   PDF (627KB) ( 332 )   Save Locally advanced head and neck squamous cell carcinoma requires a multidisciplinary approach, including surgery followed by radiotherapy, with or without chemotherapy, or definitive concurrent chemoradiotherapy. The application of induction chemotherapy remains controversial. Cetuximab has achieved satisfactory results in the treatment of head and neck squamous cell carcinoma. Immunocheckpoint inhibitors against the receptor programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) have demonstrated clinical efficacy in head and neck squamous carcinoma. However, only a small subset of patients can benefit from anti-PD-1 and anti-PD-L1 monotherapy. To improve the effectiveness of immunotherapy, combined of immunotherapy and other treatments has become an alternative strategy. References | Related Articles | Metrics

Research progress on targeted treatment in ROS1-positive non-small cell lung cancer Jin Yao, Weng Yiming, Xu Zexi, Peng Min 2019, 46 (12):  745-749.  doi: 10.3760/cma.j.issn.1673-422X.2019.12.008 Abstract ( 569 )   PDF (634KB) ( 214 )   Save ROS1 fusion gene is a new potential target for molecular targeted therapy of non-small cell lung cancer (NSCLC). In recent years, more and more scholars focus on ROS1 fusion gene. The results of in vitro experiments and clinical research both show that anaplastic lymphoma kinase (ALK) inhibitors have potent anti-tumor activity in ROS1-positive NSCLC patients, but drug resistance is still inevitable. At present, there is no standardized diagnosis and treatment path for ROS1-positive NSCLC. Therefore, further study on the ALK inhibitors of ROS1 is very important, which can provide a new therapeutic idea for targeted treatment and research of NSCLC patients. References | Related Articles | Metrics

Research progress of tumor vascular targeting drugs combined with PD-1/PD-L1 antibody in the treatment of digestive system tumors Qi Ruili, Wang Huaqing 2019, 46 (12):  750-754.  doi: 10.3760/cma.j.issn.1673-422X.2019.12.009 Abstract ( 479 )   PDF (636KB) ( 263 )   Save In recent years, tumor vascular targeting drugs and programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) inhibitors have made great progress in tumor therapy. However, monotherapy not only has limited efficacy, but also has drug resistance. The results of many clinical trials at home and abroad showed that the combination of the two were used in the treatment of different tumors of digestive system, such as esophageal cancer, gastric cancer and gastroesophageal junction cancer, liver cancer and so on, so the combination of vascular targeting drugs and PD-1/PD-L1 antibody may be a breakthrough program in tumor therapy because of their good efficacy and safety. References | Related Articles | Metrics

Molecular signaling pathways and cancer pain in gastric cancer Xing Ziyang, Sun Chunxia 2019, 46 (12):  755-759.  doi: 10.3760/cma.j.issn.1673-422X.2019.12.010 Abstract ( 447 )   PDF (634KB) ( 292 )   Save The molecular signaling pathways in gastric cancer, such as mitogen-activated protein kinase, phosphoinoinositide 3-kinase/protein kinase B, AMP-activated protein kinase, cyclooxygenase 2/nuclear factor-κB and Wnt/β-catenin pathways are closely related to the occurrence and development of cancer pain. To understand the expression and role of gastric cancer molecular signaling pathway in cancer pain is expected to provide a new idea for the treatment of cancer pain. References | Related Articles | Metrics

Research progress on the mechanism of β human papillomavirus induced cutaneous squamous cell carcinoma Ma Qingyu, Liang Junqin 2019, 46 (12):  760-763.  doi: 10.3760/cma.j.issn.1673-422X.2019.12.011 Abstract ( 404 )   PDF (627KB) ( 344 )   Save Human papillomaviruse （HPV） infects squamous epithelium and induces hyperproliferative lesions. β human papillomavirus (β-HPV) is a common type of HPV according to the nucleic acid sequence of L1 protein. In recent years, the incidence of cutaneous squamous cell carcinoma (CSCC) has increased, βHPV may be involved in the pathogenesis of CSCC. Besides, β-HPV inhibits p53 and pRb tumor suppressor genes through virus E6 and E7 proteins, which plays an important role in the initial stage of cancer. Therefore, the β-HPV is a target for preventing CSCC, especially for patients with immunosuppression who have received organ transplantation. References | Related Articles | Metrics

Research progress of prognostic evaluation in thymoma Zhang Ruiyun, Luo Hui, Duan Yongjian, Ge Hong 2019, 46 (12):  764-768.  doi: 10.3760/cma.j.issn.1673-422X.2019.12.012 Abstract ( 515 )   PDF (635KB) ( 595 )   Save Thymoma is the most common primary malignant tumor which occurs in the anterior mediastinum. The incidence of thymoma is relatively low with scarce large sample and multicenter studies available on the prognostic factors of these patients, and the related indexes for evaluating the prognosis are still under investigation. Looking for possible predictive indicators for prognosis evaluation, we can grasp the initiative of diagnosis, seize the opportunity of treatment, and intervene in the poor prognostic factors, thereby improving the prognosis of patients. References | Related Articles | Metrics