特瑞普利单抗联合舒尼替尼治疗晚期肾细胞癌的初步疗效分析

目的：评估特瑞普利单抗联合舒尼替尼治疗晚期肾细胞癌的疗效与安全性。方法：回顾性分析2020年1月—2022年3月海军军医大学第二附属医院接受特瑞普利单抗联合舒尼替尼治疗的25例晚期肾癌患者临床资料,其中男21例,女4例,中位年龄为59 (33~80)岁。25例患者病理类型均为透明细胞癌,其中2例为TFE3融合基因相关肾癌,1例部分肉瘤样变,25例患者均发生局部进展或远处转移。评价其生存获益和相关不良反应发生情况。结果：中位随访时间11.0(2.5～24)个月,25例患者均可评价疗效,总体人群ORR 36.0%,DCR 84.0%,9例患者部分缓解,12例患者病情稳定,4例患者疾病进展,中位PFS 12.7个月(95%置信区间：10.7～14.7),中位OS尚未达到。治疗总体不良反应发生率为88.0%,常见不良反应包括皮疹、腹泻、手足皮肤反应、高血压等,90%的不良反应为1~2级。     

Risk of mucocutaneous toxicities in patients with solid tumors treated with sunitinib: a critical review and meta analysis

Introduction: we performed a systematic review and meta-analysis of mucocutaneous toxicities associatedwith sunitinib, an oral multi-tyrosine kinase inhibitor. Methods: eligible studies included randomized Phase II and III trials of patients with solid tumors on sunitinib daily, describing events of hand–foot syndrome, skin rash, stomatitis, and skin and hair discoloration. Results: the relative risk (RR) of all-grade hand–foot skin reaction, skin rash, stomatitis, skin and hair discoloration were 2.12 (95% CI: 1.28–3.51; p < 0.004), 1.33 (95% CI: 1.15–1.54; p < 0.0002), 1.88 (95% CI: 1.36–2.59; p = 0.0001), 16.6 (95% CI: 4.18–64.94 p < 0.003), 4.42 (95% CI: 0.8–24.5; p < 0.09); respectively. Conclusions: our meta-analysis has demonstrated that sunitinib is associated with a higher risk of developing all-grade hand–foot skin reaction, skin rash, stomatitis and skin discoloration compared with control. Clinicians should be aware of these risks and perform regular clinical monitoring.     

Sunitinib malate for the treatment of solid tumours: a review of current clinical data

Receptor tyrosine kinases (RTKs) play important roles in the regulation of cellular growth, and mutated or overexpressed RTKs have been implicated in various human cancers. Sunitinib malate is an oral multitargeted tyrosine kinase inhibitor with antitumour and antiangiogenic activity that recently received approval from the FDA for the treatment of advanced renal cell carcinoma and of gastrointestinal stromal tumours after disease progression on or intolerance to imatinib mesilate therapy. Sunitinib has also demonstrated promising clinical activity in the treatment of other advanced solid tumours. The present review provides an updated summary of emerging clinical experience with this promising new anticancer agent.     

Myeloid-derived Suppressor Cells Adhere to Physiologic STAT3- vs STAT5-dependent Hematopoietic Programming,Establishing Diverse Tumor-Mediated Mechanisms of Immunologic Escape

The receptor tyrosine kinase inhibitor, sunitinib, is astonishingly effective in its capacity to reduce MDSCs in peripheral tissues such as blood (human) and spleen (mouse), restoring responsiveness of bystander T lymphocytes to TcR stimulation. Sunitinib blocks proliferation of undifferentiated MDSCs and decreases survival of more differentiated neutrophilic MDSC (n-MDSC) progeny. Ironically, sunitinib’s profound effects are observed even in a total absence of detectable anti-tumor therapeutic response. This is best explained by the presence of disparate MDSC-conditioning stimuli within individual body compartments, allowing sensitivity and resistance to sunitinib to coexist within the same mouse or patient. The presence or absence of GM-CSF is likely the major determinant in each compartment, given that GM-CSF’s capacity to preempt STAT3-dependent with dominant STAT5-dependent hematopoietic programming confers sunitinib resistance and redirects differentiation from the n-MDSC lineage to the more versatile monocytoid (m-MDSC) lineage. The clinical sunitinib experience underscores that strategies for MDSC and Treg depletions must be mindful of disparities among body compartments to avoid sanctuary effects. Ironically, m-MDSCs manifesting resistance to sunitinib also have the greatest potential to differentiate into tumoricidal accessory cells, by virtue of their capacity to respond to T cell-secreted IFN-γ or to TLR agonists with nitric oxide and peroxynitrate production.     

Experience with Sunitinib in metastatic renal cell carcinoma (mRCC) patients: pooled analysis from 3 Spanish observational prospective studies

Background: A pivotal, randomized, phase III trial demonstrated a statistically significant superiority of sunitinib over interferon-α in metastatic renal cell carcinoma (mRCC) patients.

Objective: To evaluate the effectiveness and safety of sunitinib in patients with advanced or mRCC in routine clinical practice.

Methods: Retrospective pooled analysis of clinical data from three observational and prospective studies carried out between 2007 and 2011 in 33 Spanish hospitals. Tumor response, Progression-free survival (PFS) and overall survival (OS), and main sunitinib-related toxicities were registered.

Results: 224 patients were analyzed. Median PFS 10.6 months (95% CI: 9.02–12.25), median OS 21.9 months (95% CI: 17.2–26.6). Objective response rate (ORR) 43.8% (95% CI: 36.8–50.7). Median time to PR was 3.8 months (95% CI: 3.86–5.99) and to CR 8.2 months (95% CI: 4.75–9.77). The most common ≥ grade-3 AEs were asthenia/fatigue (18.7%), hand-foot syndrome (6.2%), hypertension (5.8%) and neutropenia (4.8%). Hand-foot syndrome, diarrhea and mucositis were confirmed as independent predictors for PFS and/or OS in a multivariate analysis (p < 0.05)

Conclusions: Outcomes with sunitinib in daily clinical practice resemble those obtained in clinical trials. Long-term benefit with sunitinib is possible in advanced RCC patients but the appropriate management of toxicities is mandatory to enable patients to remain on treatment.     

Effects of sunitinib and bevacizumab on VEGF and miRNA levels on corneal neovascularization

Aim: To evaluate the effects of sunitinib (0.5?mg/ml) and bevacizumab (5?mg/ml) on VEGF-A, VEGFR-2 and microRNA (miRNA) levels on corneal neovascularization (CNV).

Methods: In this study, CNV was induced by silver nitrate application to the cornea, and 40 Albino male rats were equally divided into four subgroups:

Group 1 (sunitinib): After silver nitrate application to the cornea, 0.5?mg/ml sunitinib eyedrop was administered twice daily for two weeks (n?=?10).

Group 2 (bevacizumab): After silver nitrate application to the cornea, 5?mg/ml bevacizumab eyedrop was administered twice daily for two weeks (n?=?10).

Group 3 (control): After silver nitrate application to the cornea, normal saline eyedrop was administered twice daily for two weeks (n?=?10).

Group 4 (vehicle): After silver nitrate application to the cornea, 1% DMSO eyedrop was administered twice daily for two weeks (n?=?10).

After two weeks from the silver nitrate application, corneas were evaluated by hand-held biomicroscope for their vascularization status. Then, corneas were excised and the expression levels of VEGFR-2, VEGF-A and the common miRNA markers for neovascularization (miR-15?b, miR-16, miR-23a, miR-126, miR-188, miR-210, miR-221, miR-222, miR-410 and miR-423) were evaluated by real-time PCR.

Results: It was seen that the CNV was decreased in sunitinib- and bevacizumab-administered groups compared to the control and DMSO groups. Also, in comparison with the control group; VEGF-A expression was downregulated by nearly 0.75 times in sunitinib group and nearly 0.52 times in bevacizumab group. VEGFR-2 expression was downregulated by 0.89 times in sunitinib group and 0.68 times in bevacizumab group, compared to the control group. miR-15?b, miR-16 and miR-126 levels were statistically lower in sunitinib and bevacizumab groups, but miR-188 and miR-410 levels were two-fold higher compared to the control group. The miR-210 level was found higher only in sunitinib group compared to the control group. There were no statistically significant changes in miR-23a, miR-221, miR-222 and miR-423 levels among the groups.

Conclusion: Topical application of bevacizumab (5?mg/ml) and sunitinib (0.5?mg/ml) decreases the levels of VEGFR-2 and VEGF-A in CNV. Further studies are needed for detailed analysis of genes which are targeted by up- or downregulated miRNAs in this study.     

舒尼替尼耐药内皮细胞HMEC-su与EndMT的关系及其耐药特性

目的：研究舒尼替尼（sunitinib）耐药内皮细胞HMEC-su细胞的耐药特性,并对其与内皮间质转化（EndMT）之间的关系进行初步探讨。方法：结晶紫染色法观察HMEC-su细胞的形态学变化;MTT法检测HMEC-su细胞对阿霉素（DOX）的敏感性,并计算耐药指数（resistance index,RI）;罗丹明123（rhodamine 123,Rho 123）外排实验评价HMEC-su细胞的耐药性;流式细胞仪检测细胞周期分布;划痕修复实验评价细胞的迁移能力;Western blot实验检测HMEC-1和HMEC-su细胞中EndMT相关蛋白血管内皮细胞钙黏素（VE-cadherin）和α-平滑肌肌动蛋白（α-SMA）的表达差异。结果：与HMEC-1细胞相比,HMEC-su细胞的形态发生明显变化,增殖速度减慢;HMEC-su细胞对DOX产生交叉耐药,RI为2.15（P<0.01）;Rho123蓄积实验显示,与HMEC-1细胞相比,HMEC-su细胞内Rho123荧光强度明显降低（P<0.01）,给予维拉帕米（verapamil,VRP）处理1 h后,HMEC-su细胞中Rho123荧光强度明显升高（P<0.01）;与HMEC-1细胞相比,HMEC-su细胞G₀/G₁期的细胞比例显著降低（P<0.01）,然而S期和G₂/M期显著增加（P<0.01,P<0.05）;划痕修复实验表明HMEC-su细胞的迁移能力明显高于HMEC-1细胞（P<0.01）;Western blot实验表面,与HMEC-1细胞比较,HMEC-su细胞中VE-cadherin表达显著降低（P<0.01）,α-SMA蛋白表达显著增加（P<0.05）。结论：HMEC-su细胞对DOX产生了交叉耐药,其细胞形态和周期分布存在着明显变化,初步确定EndMT与HMEC-su细胞耐药性的产生有关。