Treatment efficacy and safety profile of Nab-paclitaxel and carboplatin combined with antiangiogenic drugs as salvage regimen in advanced melanoma patients / 中国肿瘤生物治疗杂志

@#[摘 要] 目的：本研究旨在评估白蛋白紫杉醇+卡铂联合抗血管生成药物（nab-paclitaxel, carboplatin, antiangiogenic drug, NCA）方案用于既往治疗失败的晚期黑色素瘤患者的疗效和安全性。方法：收集2012年4月1日至2019年5月31日在北京大学肿瘤医院肾癌黑色素瘤科住院的黑色素瘤患者，回顾性分析NCA方案在既往治疗失败后的不可切除Ⅲ c期和Ⅳ期黑色素瘤患者中的疗效和安全性。主要终点指标为无进展生存期（PFS），次要指标为客观缓解率（ORR）、总生存期（OS）、疾病控制率（DCR）和不良反应。根据使用的抗血管药物分为恩度治疗组（n=73）和贝伐珠单抗治疗组（n=103），采用倾向性评分匹配以均衡不同抗血管生成药物组间基线变量的差异。结果：共计176例患者被纳入本项分析中。所有患者中位年龄51岁（范围为18~78岁）。Ⅳ期患者占97%，50%的患者LDH水平高于正常值，28%的患者存在肝转移。既往治疗线数占比分别为1线57%、2线33%、3~4线10%。所有患者的中位PFS为3.8个月（95%CI：3.0~4.6），中位OS为10.5个月（95%CI： 8.9~12.1）。2例患者获得完全缓解，9例患者获得部分缓解，全组的ORR为6%，DCR达70%。恩度治疗组和贝伐珠单抗治疗组的中位PFS分别为4.7个月（95%CI：3.5~5.9）和3.4个月（95%CI：3.0~4.6），两组中位OS分别为12.2个月（95% CI：11.1~13.2）和9.1个月（95%CI： 7.8~10.4）。对所有患者的年龄、性别、既往治疗线数和LDH水平进行倾向性评分匹配，贝伐珠单抗和恩度治疗组间PFS和OS差异无统计学意义。常见的不良反应包括脱发、周围神经病变、中性粒细胞减少、疲劳和恶心。26名（15%）患者由于不良反应停止了治疗。结论：白蛋白紫杉醇+卡铂联合抗血管生成药物对既往治疗失败的晚期黑色素瘤患者具有一定的疗效，不良反应可耐受。

Soluble PD-L1 as a prognostic factor for advanced acral and mucosal melanoma / 中国肿瘤生物治疗杂志

@#[Abstract] Objective: Elevated levels of soluble PD-L1 (sPD-L1) are associated with worse prognosis of renal cell carcinoma and multiple myeloma. However, the regulatory roles and functions of sPD-L1 in advanced melanoma are not fully understood. This study was designed to evaluate the association between circulating sPD-L1 concentrations and prognosis of patients with advanced acral or mucosal melanoma. Methods: A total of 102 untreated patients with advanced acral and mucosal melanoma admitted to Peking University Cancer Hospital between January 2012 and December 2015 were enrolled in this study. In the meanwhile, peripheral blood samples were obtained from 40 healthy donors. Circulating sPD-L1 concentrations were determined using an enzyme-linked immunosorbent assay. Results: The advanced melanoma cohort included 58 acral melanoma patients and 44 mucosal melanoma patients. The pre-treatment concentration of sPD-L1 (2.91±2.23 ng/ml) in plasma of patients group was elevated as compared with that in healthy donors (0.59 ng/ml). The concentration of sPD-L1 in serum was significantly upregulated in 39/102 (38.2%) patients and significantly associated with increased LDH level (P=0.021) and number of Tregs (P=0.017). The overall survival rates of patients with high or low concentrations of sPD-L1 were statistically different (8.5 months [high level] vs 11.6 months [low level], P=0.022). Conclusion: sPD-L1 concentration is elevated in patients with advanced acral or mucosal melanoma, which may play an important role in predicting prognosis.

DKC1 affects proliferation, apoptosis and cell cycle of mucosal melanoma cells relating to MEK-ERK pathway / 中国肿瘤生物治疗杂志

@#[Abstract] Objective: To investigate the effects of dyskerin pseudouridine synthase 1 (DKC1) on the proliferation, cell cycle and apoptosis of mucosal melanoma cells and its potential mechanisms. Methods: qPCR was used to detect the mRNA expression of DKC1 in mucosal melanoma cell lines HMV II, GAK and normal skin cell line BJ. HMV II and GAK cells were interfered with DKC1 siRNA (si-DKC1 group) and control siRNA(si-Ctrl group) respectively; 48 h later, qPCR and Western blotting were used to verify the interfer‐ence efficiency. CCK-8 assay was used to detect the effect of DKC1 knockdown on the proliferation of mucousal melanoma cells. Flow cytometry was used to detect the apoptosis and cell cycles. Western blotting and qPCR were used to detect the molecule expressions of related pathways. Results: The mRNA and protein expression levels of DKC1 in HMV II and GAK cells were significantly higher than those in BJ cells (all P<0.01). After 48 h of siRNA transfection, compared with the si-Ctrl group, the mRNA and protein levels of DKC1 in HMV II and GAK cells of the si-DKC1 group significantly reduced (all P<0.01), the cell proliferation level significantly re‐duced (P<0.05 or P<0.01), and the apoptosis rate of cells significantly increased (all P<0.01); in addition, the mRNA expressions of proapoptotic molecules caspase 9, BAK and PUMA increased significantly (P<0.05 or P<0.01) and the cell cycle was blocked (P<0.05 or P<0.01); moreover, the phosphorylation levels of MEK and ERK1/2 were significantly reduced (P<0.05). Conclusion: Knockdown of DKC1 can inhibit the proliferation of mucousal melanoma cells, promote cell cycle arrest and induce apoptosis, and its mechanism may be related to MEK/ERK signal pathway.

Expression level and clinical significance of phosphorylated retinoblastoma in tissues of advanced malignant melanoma:An analysis of 66 cases / 中国肿瘤生物治疗杂志

@#Objective: To investigate the expression of phosphorylated retinoblastoma (p-Rb) in advanced melanoma tissues and to analyze its correlation with clinical pathological characteristics and prognosis. Methods: The clinical data and paraffin-embedded tissue sections of 66 patients with advanced melanoma, who were diagnosed and treated in the Department of Renal Cancer and Melanoma of Peking University Cancer Hospital from 2011 to 2014, were collected. Expression of p-Rb in primary tumor tissues was detected by immunohistochemistry. Correlation analysis was performed on the relationship between the expression level of p-Rb in tumor tissues and clinical data such as clinicopathological features and overall survival. Results: The positive expression rate of p-Rb in advanced melanoma tissues was 57.6% (38/66). The positive rates of p-Rb in non-acral cutaneous type, acral type and mucosal type were 73.7% (14/ 19), 63.0% (17/27) and 35.0% (7/20), respectively, and the difference was statistically significant (P=0.039). The positive rate of p-Rb in different gene mutation subgroups was also different, with 83.3% (5/6) in the BRAF mutation group, 100.0% (2/2) in the c-KIT mutation group, and 100.0% in the N-RAS mutation group (9/9), 50.0% (1/2) in the PDGFRA mutation group, and 50.0% (1/2) in group with 2-gene mutation, and 44.4% (20/45) in the wild type gene group, and the difference was statistically significant (P=0.004). There was no correlation between p-Rb expression levels and age, gender, stage, ulcer, and serum LDH levels. The median overall survival (OS) of patients with positive p-Rb expression was slightly shorter than that of the patients with negative expression (30.0 vs 39.2 months), but the difference was not statistically significant (P=0.555). Conclusion: More than half of the advanced melanoma tissues have positive expression of p-Rb, and the positive rate of p-Rb in non-acral cutaneous type is higher than that of acral and mucosal types.And the positive rate of p-Rb in melanoma tissues of patients carrying c-KIT and N-RAS mutations is higher.

Accuracy and prognostic ability of the SARC-F questionnaire and Ishii's score in the screening of sarcopenia in geriatric inpatients

Sarcopenia remains poorly managed in clinical practice due to the lack of simple and accurate screening tools. This study aimed to identify the cutoff values of the SARC-F questionnaire and Ishii's score using the variables age, grip strength, and calf circumference in older inpatients in China to compare the accuracy of the two methods and to explore their predictive ability for adverse outcomes (rehospitalization, falls, fracture, and death). Hospitalized patients (n=138) aged ≥60 years were included. The accuracy of the two tools was evaluated using the reference diagnosis recommended by the Asian Working Group on Sarcopenia (assessing patients with measurements of muscle mass, handgrip strength, and usual gait speed). Follow-up data were obtained by telephone and clinical visits combined with the inpatient medical record system after discharge for at least one year. The results showed that the SARC-F score reached the highest Youden's index when a score of 3 was set as the cutoff value. Ishii's score presented a higher accuracy than SARC-F (area under the receiver operating curve: 0.78 vs 0.64, P=0.01). The Kaplan-Meier survival analysis demonstrated a higher cumulative incidence of rehospitalization in sarcopenic individuals compared to non-sarcopenic individuals according to SARC-F (log-rank test, P<0.001). Cox analysis revealed that SARC-F was an independent risk factor for rehospitalization (adjusted hazard ratio: 4.23, 95%CI: 2.12-9.79, P<0.001). The SARC-F and Ishii's scores might facilitate the early detection of sarcopenia and help identify older adults at risk for adverse outcomes in clinical practice.

Effects of different extracts of kanggushu on osteoporosis in model rats and the underlying mechanisms / 中国结合医学杂志

<p><b>OBJECTIVE</b>To investigate the preventive effects and possible underlying mechanism of different extracts of Kanggushu () on osteoporosis in ovariectomized rats.</p><p><b>METHODS</b>One hundred and sixtyfive female SD rats were divided into 11 groups: control, sham, model, Xianling Gubao Capsule (), nilestriol, Kanggushu aqueous extract high-, medium-, and low-dose and suet extract high-, medium-, and low-dose groups. The osteoporosis model was made by ovariectomizing the rats. The latter 8 groups were administered intragastricly with Xianling Gubao Capsule, nilestriol, Kanggushu aqueous extract and suet extract for 12 weeks, respectively, while the other 3 groups were administered orally saline. The whole body bone mineral density, bone mineral content, organ coefficient of uterus, serum estradiol and alkaline phosphatase contents, blood calcium, phosphorus, interleukin 6 and bone Gla-protein levels after treatment were monitored. Additionally, three-point bending test of femur, HE staining, and scanning electron microscope were performed to explore the pharmacodynamics and underlying mechanisms.</p><p><b>RESULTS</b>In comparison with ovariectomized rats of model group, Kanggushu aqueous extract high-dose resulted in an increased bone mineral density, bone mineral content and organ coefficient of uterus, improved estradiol level, and improved maximum load and structural stiffness (P<0.05 or P<0.01). Two-dimensional and three-dimensional trabecular structure was also observed under HE staining and scanning electron microscopy, and the number and thickness of trabecular bone in Kanggushu aqueous extract high-dose group was significantly increased compared to the model group, while the lipid droplets in bone marrow cavity were significantly less. However, there were no significant differences in blood calcium, total serum alkaline phosphatase and bone Gla protein among different treatment groups. Overall, the osteoprotective effects of Kanggushu aqueous extract were comparable to those of nilestriol and were significantly more effective than those of Xianling Gubao Capsule.</p><p><b>CONCLUSION</b>The preventive effects of Kanggushu aqueous extract might be partly due to the increased estradiol level, accelerated restoration of bone trabecular reticulate structure, and accordingly increased bone mineral density in osteoporosis rats.</p>