Anti-CD30 antibody conjugated liposomal doxorubicin with significantly improved therapeutic efficacy against anaplastic large cell lymphoma

The use of nano-carriers has been shown to improve the delivery and efficacy of chemotherapeutic agents in cancer patients. Recent studies suggest that decoration of the surface of nano-carriers with various targeting moieties may further improve the overall therapeutic efficacy. In this study, we compared the therapeutic efficacy of Doxil^® (commercial doxorubicin-loaded liposomes) and that of Doxil^® conjugated with anti-CD30 antibodies (CD30-targeted Doxil^®) in treating anaplastic large cell lymphoma (ALCL), a type of T-cell lymphoma characterized by a high CD30 expression. Compared to Doxil^®, the CD30-targeted Doxil^® showed a significantly higher binding affinity to ALCL cells (5.3% versus 27%, p = 0.005) and a lower inhibitory concentration at 50% (IC50) in-vitro (32.6 μg/mL versus 12.6 μg/mL, p = 0.006). In a SCID mouse xenograft model, CD30-targeted Doxil^® inhibited tumor growth more significantly than the unconjugated formulation; specifically, tumors in mice treated with CD30-targeted Doxil^® were significantly smaller than those in mice treated with Doxil^® (average, 117 mm³ versus 270 mm³, p = 0.001) at 18 days after the tumors were inoculated. Our findings have provided the proof-of-principle of using CD30-targeted nano-carriers to treat cancers that are characterized by a high level of CD30 expression, such as ALCL.     

Microdistribution of MC1R-targeted polyplexes in murine melanoma tumor tissue

Targeted sodium-iodide symporter (NIS) gene transfer can be considered as a promising approach for diagnostics of specific types of cancer. For this purpose we used targeted polyplexes based on PEI–PEG–MC1SP block-copolymer containing MC1SP-peptide, a ligand specific for melanocortin receptor-1 (MC1R) overexpressed on melanoma cells. Targeted polyplexes demonstrated enhanced NIS gene transfer compared to non-targeted (lacking MC1SP) ones in vitro. Using dorsal skinfold chamber and intravital microscopy we evaluated accumulation and microdistribution of quantum dot-labeled polyplexes in tumor and normal subcutaneous tissues up to 4 h after intravenous injection. Polyplexes demonstrated significantly higher total accumulation in tumor tissue in comparison with subcutaneous ones (control). Targeted and non-targeted polyplexes extravasated and penetrated into the tumor tissue up to 20 μm from the vessel walls. In contrast, in normal subcutaneous tissue polyplexes penetrated not more than 3 μm from the vessel walls with the level of extravasated polyplexes 400-fold less than in tumor. Accumulated polyplexes in tumor tissue caused NIS gene expression. Subsequent ¹²³I⁻ intravenous injection resulted in 6.8 ± 1.1 and 4.5 ± 0.8% ID/g (p < 0.001) iodide accumulation in tumors in the case of targeted and non-targeted polyplexes, respectively, as was shown using SPECT/CT.     

神经母细胞瘤的治疗进展

神经母细胞瘤是儿童期比较常见的恶性实体肿瘤,发病时临床表现多种多样,初期诊断具有一定困难性,且易发生早期转移,是引起儿童期死亡的主要疾病之一,高危神经母细胞瘤患儿的临床治疗效果仍具有很大挑战性.目前神经母细胞瘤的治疗方法主要集中在手术治疗、系统化疗、放射治疗、移植技术等.近年来更着重于靶向治疗及分子生物学(即基因学)治疗上的研究.靶向治疗是靶向性地与肿瘤的不同特异性位点发生作用,从而杀死肿瘤细胞,减少对正常组织的影响,为神经母细胞瘤患儿提供更加安全有效的治疗方案.     

Targeted cancer theranostics using alpha-tocopheryl succinate-conjugated multifunctional dendrimer-entrapped gold nanoparticles

Development of multifunctional theranostic nanoplatforms for targeted cancer imaging and therapy still remains a great challenge. Herein, we report the use of multifunctional dendrimer-entrapped gold nanoparticles (Au DENPs) covalently linked with α-tocopheryl succinate (α-TOS) as a platform for targeted cancer computed tomography (CT) imaging and therapy. In this study, amine-terminated poly(amidoamine) dendrimers of generation 5 (G5.NH₂) conjugated with fluorescein isothiocyanate (FI), polyethylene glycol (PEG)-modified α-TOS, and PEGylated folic acid (FA) were used as templates to synthesize Au DENPs, followed by acetylation of the remaining dendrimer terminal amines. The formed multifunctional Au DENPs were characterized via different techniques. We show that the Au DENPs conjugated with approximately 9.8 α-TOS molecules per dendrimer and with an Au core size of 3.3 nm are water-dispersible, and stable under different pH and temperature conditions and in different aqueous media. The FA modification onto the Au DENPs enables efficient targeting of the particles to cancer cells overexpressing FA receptors (FAR), and effective targeted CT imaging of the cancer cells in vitro and the xenografted tumor model in vivo. Likewise, the covalent conjugation of α-TOS does not compromise its therapeutic activity, instead significantly improves its water solubility. Importantly, thanks to the role of FA-directed targeting, the formed multifunctional Au DENPs are able to exert the specific therapeutic efficacy of α-TOS to the FAR-overexpressing cancer cells in vitro and the xenografted tumor model in vivo. The developed multifunctional Au DENPs may hold a great promise to be used as a unique theranostic nanoplatform for targeted CT imaging and therapy of different types of cancer.     

Intracellular redox-activated anticancer drug delivery by functionalized hollow mesoporous silica nanoreservoirs with tumor specificity

In this study, a type of intracellular redox-triggered hollow mesoporous silica nanoreservoirs (HMSNs) with tumor specificity was developed in order to deliver anticancer drug (i.e., doxorubicin (DOX)) to the target tumor cells with high therapeutic efficiency and reduced side effects. Firstly, adamantanamine was grafted onto the orifices of HMSNs using a redox-cleavable disulfide bond as an intermediate linker. Subsequently, a synthetic functional molecule, lactobionic acid-grafted-β-cyclodextrin (β-CD-LA), was immobilized on the surface of HMSNs through specific complexation with the adamantyl group, where β-CD served as an end-capper to keep the loaded drug within HMSNs. β-CD-LA on HMSNs could also act as a targeting agent towards tumor cells (i.e., HepG2 cells), since the lactose group in β-CD-LA is a specific ligand binding with the asialoglycoprotein receptor (ASGP-R) on HepG2 cells. In vitro studies demonstrated that DOX-loaded nanoreservoirs could be selectively endocytosed by HepG2 cells, releasing therapeutic DOX into cytoplasm and efficiently inducing the apoptosis and cell death. In vivo investigations further confirmed that DOX-loaded nanoreservoirs could permeate into the tumor sites and actively interact with tumor cells, which inhibited the tumor growth with the minimized side effect. On the whole, this drug delivery system exhibits a great potential as an efficient carrier for targeted tumor therapy in vitro and in vivo.     

Prognostic factors of brain metastases from breast cancer: Impact of targeted therapies

IntroductionBrain metastases (BM) from breast cancer are associated with poor prognosis. This study was made to determine the prognostic influence of breast cancer biological subtypes, and to define the best therapeutic options in this setting, with a special focus on the HER2-positive population.Patients and methodsBreast cancer patients with known hormone receptors (HR) and HER2 status presenting with BM treated between 1995 and 2010 in our two institutions were considered for this retrospective study.Results250 patients were included. The study population consisted of 25.6% patients categorized as triple-negative (HR?/HER2?), 30.8% as HR+/HER2? and 43.6% as HER2+ breast cancer. Median overall survival (OS) was 8.9 months (95% CI, 6.9–10.3 months). Cerebral progression remained the most frequent cause of death (57.1%). On multivariate analysis, HER2 positivity and the RPA score were the two most important prognostic factors. Local treatment (surgery or stereotactic radiotherapy) and chemotherapy were significantly associated with an increased survival. On multivariate analysis of the RPA1-2 population, local treatment and chemotherapy were independent prognostic factors in addition to biological subtypes, RPA class, liver metastases and clinical signs of intra-cranial hypertension. Anti-HER2 therapies administered after BM diagnosis significantly and independently increased OS. Median OS in patients receiving both trastuzumab and lapatinib after BM diagnosis was significantly better than that the one of patients receiving only one of the 2 targeted therapies (25.7 vs. 9.6 months, p < 0.001).ConclusionsBiological subtypes are independent prognostic determinants. Chemotherapy and targeted therapies positively affect the prognosis after first BM.     

St. Gallen 2013: Brief Preliminary Summary of the Consensus Discussion

Zusammenfassung

Die diesjährige St. Gallen Konsensuskonferenz 2013 für das frühe Mammakarzinom gab im Wesentlichen weltweit gültige, evidenzbasierte Empfehlungen für die Behandlung, mit einem breiten Spektrum an annehmbarer klinischer Praxis. Der vorliegende Bericht fasst die Abstimmungsergebnisse des internationalen Panels im Hinblick auf Lokaltherapie, endokrine Therapie, Chemotherapie, zielgerichtete Therapie und adjuvante Bisphos-phonatgabe zusammen. Dieser Bericht soll eine rasche Übersicht über die Diskussion vor Ort geben. Er kann nicht die offizielle St. Gallen Konsensus-Publikation ersetzen, einige Empfehlungen werden sicher noch überarbeitet und geändert werden.IntroductionThe St. Gallen Consensus Conference 2013 (March 13–16) focused again on therapy recommendations for early breast cancer which are based on evidence as well as clinical expertise of the international faculty, predominantly from Europe and the USA (table ​(table1).1). The panel openly disclosed any potential conflict of interest (http://www.oncoconferences.ch); the COI committee was again chaired by Harold Burstein (Boston, USA). It was recognized as being unavoidable that individual panel members have financial relationships with commercial organizations engaged in research, innovation, and education. None of the declared conflicts were judged to substantially impact the voting procedure and warrant exclusion of a panel member. However, members with a specific COI were asked to refrain from voting at certain questions.

Table 1

Participants of the St. Gallen 2013 international breast cancer consensus panel (as announced in the conference program – not all were present at the voting process in St. Gallen)

针对性护理干预对老年冠心病患者负面精神状态及生活质量的影响

目的探讨老年冠心病患者采取针对性护理对其生活质量及负面精神状态的影响。方法选择2015年10月~2017年10月本院收治的84例老年冠心病患者为研究对象,进行分组,实行常规护理干预的患者为对照组(n=42),实行针对性护理干预的患者为实验组(n=42),分析并比较两组患者的护理满意度、HAMD评分、HAMA评分、生活质量评分。结果实验组老年冠心病患者护理满意度、HAMD评分、HAMA评分、生活质量评分与对照组比较,差异有统计学意义(P0.05)。结论针对性护理干预应用于老年冠心病患者中具有显著的疗效,对于改善患者生存质量意义显著。     

脊柱手术部位病原菌分布及危险因素

目的通过目标性监测探讨脊柱手术部位病原菌分布和耐药性以及手术部位感染的危险因素,为临床合理用药及防治提供依据。方法回顾性分析随机抽取的2015年5月~2016年12月间816例首次在我院脊柱科就诊的各类疾病患者的病历资料,统计分析手术部位感染患者的病原菌以及耐药性,通过病历资料分析相关的危险因素。将手术部位感染患者中出现诊断时的临床表现和相关实验室炎性指标输入EXCEL软件中,统计阳性率。结果 816例患者脊柱手术部位切口分泌物培养阳性38例,目标性监测术后手术部位中的感染率为4.66%;38例患者分离得到55株病原菌,其中64.82%为革兰阳性菌;革兰阳性菌前三位分别是金黄色葡萄球菌、表皮葡萄球菌、粪肠球菌;35.18%为革兰阴性菌,其中以大肠埃希菌为主,8株占14.55%;未检测出对万古霉素耐药的金黄色葡萄球菌,耐甲氧西林的表皮葡萄球菌的检出率高于金黄色葡萄球菌,革兰阴性菌的耐药性严重;单因素分析显示,年龄、糖尿病、手术时间等6项因素与脊柱手术切口感染的发生有关。进一步多因素回归分析显示糖尿病、手术持续时间≥180 min、住院天数≥15 d与脊柱手术切口感染有关。结论脊柱手术切口感染病原菌主要以金黄色葡萄球菌为主,耐药性高,糖尿病、手术持续时间≥180 min、住院天数≥15 d均是感染的独立危险因素。     

肿瘤靶向治疗患者皮肤不良反应预防及管理的证据总结

目的 遴选并总结肿瘤靶向治疗患者皮肤不良反应预防及管理的最佳证据,为临床决策提供参考。方法 计算机检索BMJ最佳临床实践、UpToDate临床决策系统、乔安娜布里格斯研究所循证卫生保健中心数据库、国际指南协作网、英国国家卫生与临床优化研究所、苏格兰院际指南网、医脉通指南网、美国国立临床诊疗指南数据库、美国医疗保健与研究质量局、加拿大安大略注册护士协会、世界肿瘤学网站、美国国家癌症综合网站、中国抗癌协会肺癌专业委员会、中国抗癌协会肿瘤护理专业委员协会、Cochrane Library、Embase、CHINAL、Web of Science、OVID、PubMed、SinoMed、中国知网、万方数据和维普数据库等相关网站,检索关于肿瘤靶向治疗患者皮肤不良反应预防及管理的指南、证据总结、最佳实践、专家共识、系统评价及原始研究。检索时限为2011年1月1日—2021年10月3日。由2名研究者进行文献质量评价和资料提取。 结果 共纳入15篇文献,其中3篇指南、4篇证据总结、1篇系统评价、3篇随机对照试验、1篇类实验研究和3篇专家共识,围绕皮肤评估、危险因素、药物治疗、皮肤护理、皮肤不良反应处理、健康教育等6个方面形成19条最佳证据。结论 该研究总结了肿瘤靶向治疗患者皮肤不良反应预防及管理的最佳证据,为医护人员提供循证依据,医护人员应结合临床情景,充分评估患者皮肤状况,做好皮肤方面的健康教育、检查和护理,预防皮肤不良反应的发生。