Review of phase I and II trials for Wilms' tumour – Can we optimise the search for novel agents?

Survival rates for patients with Wilms' tumour (WT) approximate 90% with refined use of currently available interventions. However, a subgroup of patients, with initial high-risk histopathology or relapsing disease, have a poor prognosis, and it is a challenge to identify and prioritise the development of new innovative approaches for these subgroups. We conducted a systematic literature search for published phase I and II clinical trials that registered patients with WTs and characterised the early phase trial activity, quantified response rates and highlighted avenues for further development. We identified 63 trials (48 phase I, three phase I/II, and 12 phase II trials) enrolling 214 patients with WTs, alongside other malignancies. The number of annually recruited WTs did not change significantly and was less than 20% of the potential candidates. The vast majority of the trials were conducted in North America, and 56 different interventions were investigated, including conventional chemotherapy and biologically targeted therapies. Overall, 33 WTs revealed some degree of tumour control. Of these, five patients demonstrated complete remission (2%), 15 patients partial response (7%) and 13 patients stable disease (6%). None of the included novel biologically targeted therapies emerged as promising interventions, and only conventional chemotherapy was able to induce a complete and partial response. We conclude that early phase trial recruitment of WTs is below expected levels, and the clinical outcome of the included patients is dismal. Improvement of the availability and recruitment to early phase trials for WTs, especially in Europe, is needed.     

St. Gallen 2011: Summary of the Consensus Discussion

SUMMARY: The 2011 St. Gallen Consensus Conference on early breast cancer provided mostly evidence-based treatment recommendations with a broad spectrum of acceptable clinical practice for global breast cancer care. This report summarizes the results of the 2011 international panel voting procedures with regard to locoregional and endocrine treatment, chemotherapy, targeted therapy as well as adjuvant bisphosphonate use.     

重症监护室医院感染目标性监测综合干预效果评价的Meta分析

目的 分析目标性监测综合干预在我国ICU医院感染防控中的效果.方法 文献检索中国知网、维普和万方数据库,将基于ICU医院感染目标性监测综合干预的前后对照研究纳入,并应用R 3.0.3软件进行Meta分析.结果 共纳入11篇文献.综合干预前后,各项感染率的合并相对危险度(RR)分别为:感染率0.70(95 ％CI:0.56～0.87),例次感染率0.70(95％ CI:0.58～0.84),千日感染率0.76(95％CI:0.60～0.95),千日例次感染率0.66(95％CI:0.54～0.80),干预前后差异均有统计学意义(P均＜0.05).干预前后各项器械使用率合并RR分别为:中心静脉插管0.96 (95％CI:0.82～1.12),呼吸机1.06(95％CI:0.97～1.15),导尿管0.93(95％CI:0.86～1.00),差异均无统计学意义(P均＞0.05);中心静脉插管、呼吸机相关感染率干预后合并RR分别为:0.75 (95％CI:0.53～0.88)、0.63(95％CI:0.56～0.72),差异均有统计学意义(P均＜0.05),但导尿管相关感染干预后仅有下降趋势0.85 (95％CI:0.68～1.06),差异并无统计学意义(P均＞0.05).结论 基于目标性监测的综合干预措施对医院感染防控效果显著,并且具有进一步挖掘空间,值得进一步临床推广应用.     

多形性胶质母细胞瘤中表皮生长因子受体的研究进展

表皮生长因子受体（ epidermal growth factor receptor ， EGFR ）是一种重要的跨膜受体，与细胞增殖、分化、凋亡密切相关。在多形性胶质母细胞瘤（ glioblastoma multiforme ， GBM ）中， EGFR 普遍高扩增高表达，且在部分 GBM 样本中以双微体（ double minute chromosomes ， DMs ）的形式存在，对 GBM 的发生发展，以及不良预后起着重要作用。本文简述了 EGFR 的功能，其与 GBM 的关系及其靶向治疗药物。     

Self-assembled pH-responsive hyaluronic acid–g-poly(l-histidine) copolymer micelles for targeted intracellular delivery of doxorubicin

Hyaluronic acid (HA) was conjugated with hydrophobic poly(l-histidine) (PHis) to prepare a pH-responsive and tumor-targeted copolymer, hyaluronic acid–g-poly(l-histidine) (HA-PHis), for use as a carrier for anti-cancer drugs. The effect of the degree of substitution (DS) on the pH-responsive behaviour of HA-PHis copolymer micelles was confirmed by studies of particles of different sizes. In vitro drug release studies demonstrated that doxorubicin (DOX) was released from HA-PHis micelles in a pH-dependent manner. In vitro cytotoxicity assays showed that all the blank micelles were nontoxic. However, MTT assay against Michigan Cancer Foundation-7 (MCF-7) cells (overexpressed CD44 receptors) showed that DOX-loaded micelles with a low PHis DS were highly cytotoxic. Cellular uptake experiments revealed that these pH-responsive HA-PHis micelles taken up in great amounts by receptor-mediated endocytosis and DOX were efficiently delivered into cytosol. Moreover, micelles with the lowest DS exhibited the highest degree of cellular uptake, which indicated that the micelles were internalized into cells via CD44 receptor-mediated endocytosis and the carboxylic groups of HA are the active binding sites for CD44 receptors. Endocytosis inhibition experiments and confocal images demonstrated that HA-PHis micelles were internalized into cells mainly via clathrin-mediated endocytosis and delivered to lysosomes, triggering release of DOX into the cytoplasm. These results confirm that the biocompatible pH-responsive HA-PHis micelles are a promising nanosystem for the intracellular targeted delivery of DOX.     

Presurgical sunitinib reduces tumor size and may facilitate partial nephrectomy in patients with renal cell carcinoma

ObjectiveTo determine whether presurgical sunitinib reduces primary renal cell carcinoma (RCC) size and facilitates partial nephrectomy (PN).MethodsData from potential candidates for PN treated with sunitinib with primary RCC in situ were reviewed retrospectively. Primary outcome was reduction in tumor bidirectional area.ResultsIncluded were 72 potential candidates for PN who received sunitinib before definitive renal surgery on 78 kidneys. Median primary tumor size was 7.2 cm (interquartile range [IQR]: 5.3–8.7 cm) before and 5.3 cm (IQR: 4.1–7.5 cm) after sunitinib treatment (P<0.0001), resulting in 32% reduction in tumor bidirectional area (IQR: 14%–46%). Downsizing occurred in 65 tumors (83%), with 15 partial responses (19%). Tumor complexity per R.E.N.A.L. score was reduced in 59%, with median posttreatment score of 9 (IQR: 8–10). Predictors of lesser tumor downsizing included clinical evidence of lymph node metastases (P<0.0001), non–clear cell histology (P = 0.0017), and higher nuclear grade (P = 0.023). Surgery was performed for 68 tumors (87%) and was not delayed in any patient owing to sunitinib toxicity. Grade≥3 surgical complications occurred in 5 patients (7%). PN was performed for 49 kidneys (63%) after sunitinib, including 76% of patients without and 41% with metastatic disease (P = 0.0026). PN was completed in 100%, 86%, 65%, and 60% of localized cT1a, cT1b, cT2, and cT3 tumors, respectively.ConclusionPresurgical sunitinib leads to modest tumor reduction in most primary RCC, and many patients can be subsequently treated with PN with acceptable morbidity and preserved renal function. A randomized trial is required to definitively determine whether presurgical therapy enhances feasibility of PN.     

FLT3 Antibody-Based Therapeutics for Leukemia Therapy

Antibodies represent a unique class of therapeutics because of their high specificity toward a defined target antigen. Recent clinical success with antibody-based cancer therapeutics has led to an upsurge in the development of these agents. Antibodies directed against FLT3 represent a promising approach for the treatment of human leukemia. We discuss some basic aspects of antibody-based cancer therapeutics, including their mechanisms of action, with a focus on recent progress in the generation and development of anti-FLT3 antibodies as well as their therapeutic potentials in the treatment of human hematologic malignancies.     

Histopathological characteristics of early rheumatoid arthritis: a case one month after clinical onset

A 68-year-old woman with early rheumatoid arthritis (RA) was admitted to the hospital because of tender and swollen knee joints. We performed a targeted synovial biopsy under arthroscopy to examine the histopathological characteristics 1 month after clinical onset. The synovia showed the typical histopathology of RA. Although the inflammatory changes were predominantly limited to the surface area of the synovia, associated with neovascularization and cell infiltrates composed mainly of T cells, plasma cells, and macrophages, lesions with fibrin deposition, mesenchymoid transformation and/or immature lymphoid follicles were also observed in part, indicating that this case was in the progression phase of RA. What we regularly call "early" might be "too late" even if it is within 1 month of clinical onset. Received: February 12, 2000 / Accepted: May 31, 2000