免疫检查点抑制剂联合血管生成抑制剂治疗MSS型转移性结直肠癌的疗效与营养状态的相关性

摘 要：［目的］ 探讨营养状态与免疫检查点抑制剂(immune checkpoint inhibitor,ICI)联合血管生成抑制剂治疗微卫星稳定性（microsatellite stability,MSS）转移性结直肠癌（metastatic colorectal cancer,CRC）的疗效相关性。［方法］ 收集经一、二线标准治疗后,三线使用ICI联合血管生成抑制剂治疗的MSS型mCRC患者15例,记录患者临床资料及营养状态,客观描述不同营养状态下肿瘤指标和营养指标的变化情况,以客观缓解率（objective response rate,ORR）、疾病控制率（disease control rate,DCR）、无进展生存期（progress-free survival,PFS）为研究指标,通过COX回归分析疗效与营养状态的关系。 ［结果］ 对15例三线治疗患者中位随访3个月的数据显示,ORR为13%,DCR为53%,PFS为4.05个月（1.10个月~11.40个月）。基于描述性统计分析,PG-SGA ≥9分组患者的肿瘤指标上升幅度总体较PG-SGA 2~3分组患者偏高;PG-SGA 2~3分组患者的视黄醇结合蛋白较PG-SGA≥9分组患者的偏高,观察终点的视黄醇结合蛋白较PG-SGA 4~8分组患者的偏高,差异均有统计学意义（P＜0.05）;基于PFS指标,PG-SGA评分2～3分患者优于评分4～8分患者,评分4~8分患者优于评分≥9分患者,差异有统计学意义（P＜0.05）。PG-SGA 4~8分组患者相比较于PG-SGA 2~3分组患者和PG-SGA≥9分组患者对PFS的影响更大（HR=0.020,95%CI为0.001~0.549）。［结论］ 免疫检查点抑制剂联合血管生成抑制剂治疗MSS型转移性结直肠癌的疗效与营养状态密切相关,良好的营养状态可提高其治疗疗效,改善预后。     

First-Line Treatment with a Cyclin-Dependent Kinase 4/6 Inhibitor Plus an Aromatase Inhibitor for Metastatic Breast Cancer in Alberta

In this analysis, we describe population-based outcomes for first-line treatment with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) combined with an aromatase inhibitor (AI). All patients who were prescribed CDK4/6i + AI from January 2016 through June 2019 were included. Patient demographics, tumour and treatment characteristics were collected and described. Survival distributions were estimated using the Kaplan–Meier method. Multivariate analysis (MVA) was constructed to examine associations between potentially prognostic clinical variables and progression-free survival (PFS). In total, 316 patients were included. The median age was 61 years. After a median follow-up of 28.1 months, the median PFS was 37.9 months (95% CI, 26.7–NR). In the MVA, PR-negative tumour (HR, 2.37; 95% CI, 1.45–3.88; p = 0.001) and CDK4/6i dose reduction (HR, 1.51; 95% CI, 1.06–2.16; p = 0.022) predicted worse PFS. Median overall survival (OS) was not reached. The 30-month and 36-month OS rates were 74% and 68%, respectively. Of patients who progressed, 89% received second-line treatment. Median time to progression on second-line chemotherapy was 9.0 (5.8–17.6) months, and median time to progression on second-line hormonal therapy +/− targeted agent was 4.0 (3.4–8.6) months (p = 0.012). CDK4/6i + AI as first-line treatment for HR-positive, HER2-negative MBC in Alberta is justified based on favourable PFS and early OS outcomes.     

Inhibitor cells in spleens of mice with low natural killer activity

Inbred strains of mice differ markedly in levels of natural killer (NK) cytotoxic activity. BPS mice normally have very low spleen cell NK activity. However, their NK activity can be significantly augmented with the use of interferon inducer, which suggests that this basic low reactivity is not a result of low numbers of precursor cells or defects in the lytic mechanism. Normally, their spleens contain suppressor cells, as evidenced by the ability of BPS spleen cells to inhibit in vitro the NK activity of spleen cells from high-responder strains of mice. Cells responsible for the suppression are located in the dense fraction after separation in Ficoll-Hypaque and are nylon wool-adherent. Studies on the kinetics of inhibition indicate that the mechanism of inhibition is not merely competition for target-binding sites. Although these suppressor cells can act on mature NK effectors in vitro, their activity in vivo may be more complex, since mature BPS NK effectors are not revealed when the suppressors are removed.     

Inhibition of the Growth of Patient-Derived Pancreatic Cancer Xenografts with the MEK Inhibitor Trametinib Is Augmented by Combined Treatment with the Epidermal Growth Factor Receptor/HER2 Inhibitor Lapatinib

Mutations of the oncogene KRAS are important drivers of pancreatic cancer progression. Activation of epidermal growth factor receptor (EGFR) and human EGFR2 (HER2) is observed frequent in pancreatic adenocarcinomas. Because of co-activation of these two signaling pathways, we assessed the efficacy of inhibition of EGFR/HER2 receptors and the downstream KRAS effector, mitogen-activated protein kinase/extracellular-signal regulated kinase (ERK) kinase 1 and 2 (MEK1/2), on pancreatic cancer proliferation in vitro and in a murine orthotopic xenograft model. Treatment of established and patient-derived pancreatic cancer cell lines with the MEK1/2 inhibitor trametinib (GSK1120212) inhibited proliferation, and addition of the EGFR/HER2 inhibitor lapatinib enhanced the inhibition elicited by trametinib in three of eight cell lines. Importantly, in the orthotopic xenograft model, treatment with lapatinib and trametinib resulted in significantly enhanced inhibition of tumor growth relative to trametinib treatment alone in four of five patient-derived tumors tested and was, in all cases, significantly more effective in reducing the size of established tumors than treatment with lapatinib or trametinib alone. Acute treatment of established tumors with trametinib resulted in an increase in AKT2 phosphorylation that was blunted in mice treated with both trametinib and lapatinib. These data indicate that inhibition of the EGFR family receptor signaling may contribute to the effectiveness of MEK1/2 inhibition of tumor growth possibly through the inhibition of feedback activation of receptor tyrosine kinases in response to inhibition of the RAS-RAF-MEK-ERK pathway. These studies provide a rationale for assessing the co-inhibition of these pathways in the treatment of pancreatic cancer patients.     

乌司他丁对胃癌患者围手术期免疫功能的影响

目的　探讨围手术期应用乌司他丁对胃癌根治术后患者免疫功能的影响。方法　将行胃癌根治术的患者随机分为实验组 (n =2 3 )和对照组 (n =2 3 )。实验组于术前 1天和术后第 1、3、5和 7天 ,每天给予 2 0万单位乌司他丁 (UTI)静脉注射 ;对照组不应用乌司他丁 ,予以等量生理盐水注射。 2组患者均于术前 1天和术后第 1、3、5、7天采血 ,检测T细胞亚群及白介素 -2 (IL 2 )和NK细胞活性的变化。结果　胃癌患者术前均有不同程度的免疫功能低下 ,术后第 1天CD 4 细胞数量、CD 4 /CD 8比值、IL-2水平和NK细胞活性均较术前显著下降 (P <0 .0 5 ) ,术后第 7天试验组上述指标迅速恢复 ,并超过术前水平 ,与对照组比较有显著性差异 (P <0 .0 5 )。结论　UTI可明显减轻胃癌患者围手术期细胞免疫抑制程度 ,增强细胞免疫功能     

HSP90抑制剂AUY-922逆转人神经母细胞瘤细胞ALK抑制剂耐药的机制

目的 探讨HSP90抑制剂AUY-922逆转人神经母细胞瘤细胞对二代ALK抑制剂TAE684耐药的机制.方法 MTT法检测AUY-922对携有ALK F1174L基因突变的人神经母细胞瘤细胞SH-SY5Y和KELLY增殖的影响.流式细胞技术检测AUY-922对SH-SY5Y和KELLY细胞周期的影响.Western b...     

FLT3抑制剂在急性髓细胞白血病中的研究进展

 FLT3是一种受体酪氨酸激酶（RTK）,是急性髓细胞白血病（AML）中最常见的突变基因之一,有内部重复串联序列和激活环点突变两种形式,FLT3基因突变与AML的发病密切相关,作为一项独立指标,在疾病的发生中具有重要的意义,并且是AML的独立预后因素。以FLT3为靶点的研究已成为当今AML治疗的热点。文章阐述了FLT3的临床意义、FLT3抑制剂的作用机制以及数种新型药物的最新研究进展,并针对目前FLT3抑制剂存在的困难及前景进行了讨论。     

蛋白酶体抑制剂联合TRAIL杀伤骨肉瘤细胞的研究

目的观察蛋白酶体抑制剂与肿瘤坏死因子相关细胞凋亡诱导配体(TRAIL)对骨肉瘤细胞株MG-63的杀伤作用。方法骨肉瘤细胞株MG-63分别经蛋白酶体抑制剂Z-LLL-CHO和(或)TRAIL作用24h,采用MTT法检测细胞毒性作用,流式细胞仪定量分析凋亡细胞所占比例,并镜下观察细胞形态学改变。结果0.5μmol/L的Z-LLL-CHO与500ng/ml的TRAIL合用于MG-63细胞24h后,细胞存活率为61.6%±1.3%,明显高于单用Z-LLL-CHO(0.5μmol/L)时的96.6%±0.2%及单用TRAIL(500ng/ml)时的89.5%±0.7%(P<0.01)。流式细胞术、电镜及荧光显微镜观察证实,协同性杀伤作用主要通过诱导细胞凋亡实现。结论蛋白酶体抑制剂能增强TRAIL杀伤骨肉瘤细胞和诱导骨肉瘤细胞的凋亡。     

Effects of a Multikinase Inhibitor Motesanib (AMG 706) Alone and Combined with the Selective DuP-697 COX-2 Inhibitor on Colorectal Cancer Cells

In the present study, we investigated the effects of motesanib (AMG 706), a multikinase inhibitor alone and in combination with DuP-697, an irreversible selective inhibitor of COX-2, on cell proliferation, angiogenesis, and apoptosis induction in a human colorectal cancer cell line (HT29). Real time cell analysis (RTCA, Xcelligence system) was used to determine the effects on colorectal cancer cell proliferation. Apoptosis was assessed with annexin V staining and angiogenesis was determined with chorioallantoic membrane model. We found that motesanib alone exerted antiproliferative, antiangiogenic and apoptotic effects on HT29 colorectal cancer cells. Combination with DUP-697 increased the antiproliferative, antiangiogenic and apoptotic effects. Results of this study indicate that motesanib may be a good choice in treatment of colorectal tumors. In addition, the increased effects of combination of motesanib with DuP-697 raise the possibility of using lower doses of these drugs and therefore avoid/minimize the dose-dependent side effects generally observed.     

Immune Checkpoint Inhibitor Toxicity

Purpose of review

Immune checkpoint inhibitors have revolutionised the treatment of multiple malignancies and have a growing list of indications. As our familiarity with these agents grows, so does our understanding of their unique spectrum of toxicities. Here, we will review the literature regarding the toxicities of checkpoint inhibitors and address challenges encountered in day-to-day clinical practice.

Recent findings

Inhibitors of the PD-1/PD-L1 axis are considerably less toxic than the anti-CTLA-4 antibody ipilimumab. The combination of ipilimumab and anti-PD-1 agents is being trialled in multiple malignancies and is associated with increased toxicity. There is accumulating evidence suggesting a potential correlation between a subset of toxicities and clinical benefit in several tumour types, although conflicting data exists. Retrospective series have shown that anti-PD-1 can be safely administered to patients with prior high-grade toxicity from ipilimumab or combination immunotherapy.

Summary

The management of checkpoint inhibitor toxicity is complex and requires collaboration with our subspecialty colleagues. Identifying predictive biomarkers of both efficacy and toxicity would likely help guide treatment decisions, and should be a research priority in the years ahead.

     

端粒酶抑制剂与丝裂霉素联合应用对膀胱癌的作用研究

 目的 探讨端粒酶抑制剂与化疗药物联合应用对荷瘤小鼠肿瘤生长的影响。方法 应用端粒酶抑制剂齐夫多啶（AZT）联合化疗药物丝裂霉素（MMC）治疗小鼠移植性膀胱癌（T24），观察其对抑瘤率、肿瘤端粒酶的表达及肿瘤细胞凋亡的影响。结果 AZT、MMC、MMC＋AZT抑瘤率分别为12．1％、29．6％和43．6％，TUNEL法检测肿瘤细胞凋亡指数分别为（20．23±0．89）％、（8．04±0．12）％和（24．09±1．81）％。肿瘤端粒酶活性检测显示各组端粒酶阳性率分别为36．5％、43．6％和11．8％，与对照组比较，AZT、MMC均有减少肿瘤端粒酶活性的作用（P〈0．05）。AZT与MMC联用明显优于两者单独应用（P〈0．05）。结论 MMC及AZT均能抑制小鼠膀胱癌T24细胞的生长及降低其端粒酶活性、诱导细胞凋亡，二者联用有相加作用。     

大豆蛋白酶抑制物和皂甙抑瘤作用的实验研究

已有研究表明从大豆中提取的蛋白酶抑制物（ＰＩ）和皂甙有预防肿瘤的作用。本研究发现它们增加环磷酰胺（ＣＴＸ）对小鼠的抑瘤作用，又能减低对小鼠外周血细胞和骨髓有核细胞的毒性副作用，同是也发现它们对小鼠的免疫功能有促进作用。这些提取物可望作为人体肿瘤化疗的辅助用药。     

Relationship between protease activity and neu oncogene expression in patients with oral leukoplakia treated with the Bowman Birk Inhibitor.

The protease catalyzing the hydrolysis of the tripeptide fluorescence substrate, butoxycarbonyl-valine-proline-arginine-(7-amino-4-methylcoumarin) (Boc-Val-Pro-Arg-MCA) and the neu oncogenic protein are potentially useful biomarkers for human cancer prevention studies. In the present study, we standardized a specific substrate hydrolysis method for measuring this protease activity in human oral mucosal cells and characterized the relationship between neu oncogene expression and protease activity in patients enrolled in an oral cancer prevention trial using Bowman Birk Inhibitor Concentrate (BBIC) as the cancer preventive agent. The results demonstrate that changes in the protease activity in oral mucosal cells after BBIC treatment correlated with the changes in the neu protein levels in oral mucosal cells (r = 0.726, P < 0.001) and serum (r = 0.675, P < 0.001), suggesting that the Boc-Val-Pro-Arg-MCA hydrolyzing activity can be as useful as neu oncogene expression as a cancer biomarker. In the 25 patients enrolled in the study, the level of neu protein in oral mucosal cells correlated with the serum neu protein concentration in the patients before BBIC treatment (r = 0.645, P < 0.001). However, such a correlation was not observed after the BBIC treatment, suggesting that BBI may inhibit serine protease(s) involved in the cleavage of neu protein on the cell surface, thereby preventing the release of the extracellular domain of neu protein into the circulation. By inhibiting the cleavage of neu protein on the cell surface, BBI could prevent malignant and premalignant cells expressing high levels of neu protein antigen from escaping host immunological surveillance control.