An Italian, multicenter, real-world, retrospective study of first-line pazopanib in unselected metastatic renal-cell carcinoma patients: the 'Pamerit' study.
一项意大利，多中心，真实世界，在未经选择的转移性肾细胞癌患者中一线帕唑帕尼的回顾性研究: “pamerit” 研究。
- 作者列表："Mosca A","De Giorgi U","Procopio G","Basso U","Cartenì G","Bersanelli M","Naglieri E","Galli L","Caffo O","Fornarini G","Boccardo F","Porta C
OBJECTIVE:Despite the current immunotherapy era, VEGFR inhibitors maintain effectiveness in metastatic renal cell cancer. Real-world data concerning pazopanib are limited. The aim of this study is to add information about efficacy and safety of pazopanib as first-line treatment in metastatic renal cell cancer patients not enrolled into clinical trials. METHODS:Retrospective analysis (the PAMERIT study) of first-line pazopanib in real-world metastatic renal cell cancer patients among 39 Centers in Italy. Outcomes were progression-free survival, overall survival, objective response rate and treatment-related adverse events. Kaplan-Meier curves, log-rank test and multivariable Cox's models were used and adjusted for age, histology, previous renal surgery, International Metastatic RCC Database Consortium score and pazopanib initial dose. RESULTS:Among 474 patients, 87.3% had clear cell metastatic renal cell cancer histology. Most of them (84.6%) had upfront renal surgery. Median progression-free survival and overall survival were 15.8 and 34.4 months, respectively, significantly correlating with International Metastatic RCC Database Consortium's good prognosis (P < 0.001), ECOG PS 0 (P < 0.001), age (<75 years, P = 0.005), surgery (P < 0.001) and response to pazopanib (P < 0.001). After 3 months of pazopanib, overall disease control rate have been observed in 76.6% patients. Among International Metastatic RCC Database Consortium's favorable group patients, 57/121 (47%) showed complete/partial response. No unexpected AEs emerged. CONCLUSIONS:In this real-world study, metastatic renal cell cancer patients treated with first-line pazopanib reached greater progression-free survival and overall survival than in pivotal studies and had high response rates when belonging to International Metastatic RCC Database Consortium's favorable group, without new toxicities. Pazopanib has been confirmed a valid first-line option for International Metastatic RCC Database Consortium's good prognosis metastatic renal cell cancer patients who cannot be submitted to immunotherapy.
目的: 尽管目前的免疫治疗时代，VEGFR抑制剂在转移性肾细胞癌中保持有效性。关于帕唑帕尼的真实世界数据有限。本研究的目的是增加帕唑帕尼作为一线治疗未参加临床试验的转移性肾细胞癌患者的疗效和安全性的信息。 方法: 意大利39个中心的真实世界转移性肾细胞癌患者中一线帕唑帕尼的回顾性分析 (PAMERIT研究)。结果为无进展生存期、总生存期、客观缓解率和治疗相关不良事件。使用Kaplan-Meier曲线、时序检验和多变量Cox模型，并根据年龄、组织学、既往肾脏手术、国际转移性RCC数据库联盟评分和帕唑帕尼初始剂量进行校正。 结果: 474例患者中，87.3% 例有透明细胞转移性肾细胞癌组织学。其中大多数 (84.6%) 进行了前期肾脏手术。中位无进展生存期和总生存期分别为15.8和34.4个月，与国际转移性肾细胞癌数据库联盟的良好预后 (P < 0.001) 、ECOG PS 0 (P < 0.001) 、年龄 (<75岁，P = 0.005) 、手术 (P < 0.001) 显著相关和对帕唑帕尼的反应 (P <0.001)。帕唑帕尼治疗3个月后，观察到76.6% 例患者的总体疾病控制率。在国际转移性RCC数据库联盟的有利组患者中，57/121 (47%) 显示完全/部分缓解。未出现意外不良事件。 结论: 在这项真实世界的研究中，接受帕唑帕尼一线治疗的转移性肾细胞癌患者比关键研究达到更高的无进展生存期和总生存期，并且当属于国际转移性RCC数据库联盟的有利组时，具有高缓解率，没有新的毒性。帕唑帕尼已被证实是国际转移性RCC数据库联盟预后良好的不能接受免疫治疗的转移性肾细胞癌患者的有效一线选择。
METHODS::The ATP binding-cassette superfamily corresponds the mostly transmembrane transporters family found in humans. These proteins actively transport endogenous and exogenous substrates through biological membranes in body tissues, so they have an important role in the regulation of many physiological functions necessary for human homeostasis, as well as in response regulation to several pharmacological substrates. The development of multidrug resistance has become one of the main troubles in conventional chemotherapy in different illnesses including cancer, being the increased efflux of antineoplastic drugs the main reason for this multidrug resistance, with a key role of the ABC superfamily. Likely, the interindividual variability in the pharmacological response among patients is well known, and may be due to intrinsically factors of the disease, genetic and environmental ones. Thus, the understanding of this variability, especially the genetic variability associated with the efficacy and toxicity of drugs, can provide a safer and more effective pharmacological treatment, so ABC genes are considered as important regulators due to their relationship with the reduction in pharmacological response. In this review, updated information about transporters belonging to this superfamily was collected, the possible role of these transporters in cancer, the role of genetic variability in their genes, as well as some therapeutic tools that have been tried to raise against main transporters associated with chemoresistance in cancer.
METHODS:BACKGROUND:Cholinergic neurotransmission regulates neuroinflammation in Parkinson disease (PD). RESEARCH DESIGN AND METHODS:The authors conducted a delayed-start study of donepezil for cognitive decline in non-demented PD patients. The study consisted of a 96-week randomized placebo-controlled double-blind phase 1, followed by a 24-week donepezil extension phase 2. The primary outcome measure was a change in the Mini-Mental State Examination (MMSE) at week 120. RESULTS:A total of 98 patients were randomly allocated to the early-start (donepezil-to-donepezil) and delayed-start (placebo-to-donepezil) groups. Mean (SD) of the baseline MMSE was 27.6 (2.0) and 28.0 (2.1), respectively. MMSE change at week 120 was better in the early-start group than in the delayed-start group, but the difference was not significant. The MMSE declined in apolipoprotein ε4 carriers, but not in non-carriers, and the factor interaction (intervention × ε4 genotype) was highly significant (P < 0.001). Analyzed with the interaction, the difference was significant (group difference 1.95 [0.33 to 3.57], P = 0.018). The MMSE decline slope in phase 1 was significantly better in the early-start group than in the delayed-start group (P = 0.048). CONCLUSIONS:Cognitive function deteriorated in ε4 carriers, but not in non-carriers, and early-start donepezil may postpone cognitive decline in the former.
METHODS::Since the discovery of dental pulp stem cells, a lot of teams have expressed an interest in dental pulp regeneration. Many approaches, experimental models and biological explorations have been developed, each including the use of stem cells and scaffolds with the final goal being clinical application in humans. In this review, the authors' objective was to compare the experimental models and strategies used for the development of biomaterials for tissue engineering of dental pulp with stem cells. Electronic queries were conducted on PubMed using the following terms: pulp regeneration, scaffold, stem cells, tissue engineering and biomaterial. The extracted data included the following information: the strategy envisaged, the type of stem cells, the experimental models, the exploration or analysis methods, the cytotoxicity or viability or proliferation cellular tests, the tests of scaffold antibacterial properties and take into account the vascularization of the regenerated dental pulp. From the 71 selected articles, 59% focused on the "cell-transplantation" strategy, 82% used in vitro experimentation, 58% in vivo animal models and only one described an in vivo in situ human clinical study. 87% used dental pulp stem cells. A majority of the studies reported histology (75%) and immunohistochemistry explorations (66%). 73% mentioned the use of cytotoxicity, proliferation or viability tests. 48% took vascularization into account but only 6% studied the antibacterial properties of the scaffolds. This article gives an overview of the methods used to regenerate dental pulp from stem cells and should help researchers create the best development strategies for research in this field.