Interaction of arsenic trioxide and etoposide in Ewing sarcoma cell lines.
- 作者列表："Lenz JE","Riester R","Schleicher SB","Handgretinger R","Boehme KA","Traub F
:Ewing sarcomas (ES) are highly malignant mesenchymal tumors, which most often occur in children and adolescents. The current treatment of choice comprises wide resection in combination with multimodal chemotherapy including etoposide (Eto). Due to the serious side effects associated with common chemotherapeutics and prevalent multidrug resistance in recurrent and metastatic ES, there is a growing demand for alternative strategies and add‑on drugs. Previous research has demonstrated efficient cell death induction by Eto in combination with arsenic trioxide (ATO) in ES cell lines. The aim of the present study was to investigate the effect of different temporal sequences of ATO and Eto administration on apoptosis induction and to explore the effect of both drugs on inhibitory glycogen synthase kinase‑3β (GSK3‑β) phosphorylation as well as multidrug transporter gene expression. The intensity of caspase activation was mainly determined by the Eto doses in A673 and TC‑71 cells, whereas in RD‑ES cells ATO application actively suppressed Eto‑induced apoptosis. This coincided with an increase in inhibitory GSK‑3β phosphorylation in ATO‑treated RD‑ES cells. Inherent mRNA expression of multidrug resistance‑associated protein 1 (MRP1) was low in the ES cell lines compared to that observed in the mesenchymal stem cells (MSC), whereas multidrug resistance protein 1 (MDR1) gene expression was considerably increased in the ES cell lines. ATO treatment reduced MRP1 mRNA expression in the A673 and TC‑71 cells, while expression was induced in the MSC and RD‑ES cells. In contrast, MDR1 mRNA expression was specifically induced by ATO in the A673 and TC‑71 cells, reinforcing the expression differences between MSC and the ES cell lines. Although a reliable cell death induction by the combination of ATO and Eto has been previously shown in ES cell lines, the present study showed marked heterogeneity of the ES cell response to ATO and Eto treatment, illustrating the difficulty of prediction of individual treatment outcome in ES.
: 尤因肉瘤 (Ewing sarcomas，ES) 是高度恶性的间叶性肿瘤，最常发生在儿童和青少年。目前的治疗选择包括广泛切除联合包括依托泊苷 (Eto) 在内的多模式化疗。由于常见化疗药物相关的严重副作用以及复发和转移性ES中普遍存在的多药耐药，对替代策略和添加药物的需求日益增长。以前的研究已经证明Eto与三氧化二砷 (ATO) 联合在ES细胞系中诱导细胞死亡是有效的。本研究的目的是研究ATO和Eto给药的不同时间序列对凋亡诱导的影响，并探讨两种药物对抑制性糖原合成酶激酶 ‑ 3 β (GSK3 ‑ β) 的影响。) 磷酸化以及多药转运蛋白基因表达。Caspase激活的强度主要由A673 和tc ‑ 71 细胞中的Eto剂量决定，而在rd‑ es细胞中ATO应用积极抑制Eto ‑ 诱导的凋亡。这与at ‑ 处理的rd‑ es细胞中抑制性gsk ‑ 3 β 磷酸化的增加相一致。与间充质干细胞 (MSC) 中观察到的相比，ES细胞系中多药耐药相关蛋白 1 (MRP1) 的固有mRNA表达较低，而多药耐药蛋白 1 (MDR1) ES细胞系的基因表达显著增加。ATO处理降低了A673 和tc ‑ 71 细胞中MRP1 mRNA的表达，而在MSC和rd ‑ es细胞中诱导了表达。相反，ATO在A673 和tc ‑ 71 细胞中特异性诱导MDR1 mRNA表达，加强了MSC和ES细胞系之间的表达差异。虽然以前在ES细胞系中已经证明了ATO和Eto组合诱导的可靠的细胞死亡，但是本研究显示ES细胞对ATO和Eto处理的反应存在明显的异质性，说明ES中个体治疗结果的预测难度。
METHODS:OBJECTIVE:Large inoperable sacral chordomas show unsatisfactory local control rates even when treated with high dose proton therapy (PT). The aim of this study is assessing feasibility and reporting early results of patients treated with PT and concomitant hyperthermia (HT). METHODS: :Patients had histologically proven unresectable sacral chordomas and received 70 Gy (relative biological effectiveness) in 2.5 Gy fractions with concomitant weekly HT. Toxicity was assessed according to CTCAE_v4. A volumetric tumor response analysis was performed. RESULTS: :Five patients were treated with the combined approach. Median baseline tumor volume was 735 cc (range, 369-1142). All patients completed PT and received a median of 5 HT sessions (range, 2-6). Median follow-up was 18 months (range, 9-26). The volumetric analysis showed an objective response of all tumors (median shrinkage 46%; range, 9-72). All patients experienced acute Grade 2-3 local pain. One patient presented with a late Grade 3 iliac fracture. CONCLUSION:Combining PT and HT in large inoperable sacral chordomas is feasible and causes acceptable toxicity. Volumetric analysis shows promising early results, warranting confirmation in the framework of a prospective trial. ADVANCES IN KNOWLEDGE: :This is an encouraging first report of the feasibility and early results of concomitant HT and PT in treating inoperable sacral chordoma.
METHODS:BACKGROUND:National guidelines recommend screening and treatment for cancer-related bone disease and continued monitoring of bone-modifying agents. It is unclear whether a standardized screening tool is utilized to identify eligible patients and ensure appropriate supportive care is implemented. The purpose of this study was to evaluate current prescribing practices and optimize management of bone-modifying agents. METHODS:A retrospective chart review was performed to identify patients who received hormone deprivation therapy or had bone metastases through Hematology/Oncology or Urology clinics from 1 November 2016 to 31 October 2017. The primary endpoints of this study were the incidence of completed baseline dual-energy X-ray absorptiometry (DEXA) scan for patients on hormone deprivation therapy and percent of patients started on a bone-modifying agent for the prevention of skeletal-related events secondary to bone metastasis. Secondary endpoints included percent of patients with dental examinations prior to initiation, adequate calcium and vitamin D supplementation, incidence of osteonecrosis of the jaw or flu-like symptoms and education, and percent of bisphosphonate doses appropriately adjusted based on renal function. RESULTS:A total of 375 patients were assessed for baseline DEXA scans and bone-modifying therapy. Of the 226 patients on hormone deprivation therapy, 111 (49%) patients were appropriately screened with a DEXA scan prior to initiation of hormone deprivation therapy. Among the 149 patients with bone metastases, only 94 (63.1%) patients were started on a bone-modifying agent. CONCLUSIONS:Opportunities have been identified to optimize management of patients with cancer-related bone disease. Implementation of standardized tools may increase the rate of appropriate screening and initiation of bone-modifying therapy when warranted.
METHODS:PURPOSE:Low skeletal muscle mass has been associated with poor prognosis in patients with advanced lung cancer. However, little is known about the relationship between skeletal muscle mass and overall survival in patients with bone metastases from lung cancer. The objective of the present study was to evaluate the prognostic value of low trunk muscle mass in predicting overall survival in these patients. METHODS:The data from 198 patients who were diagnosed with bone metastases from lung cancer from April 2009 to May 2017 were retrospectively reviewed. The areas of the psoas and paravertebral muscles were measured at the level of the third lumbar vertebra on computed tomography scans taken at the time nearest to the diagnosis of bone metastasis. Muscle area was evaluated for male and female cohorts separately using different cutoff points. Cox proportional hazards analysis was performed to evaluate the factors independently associated with overall survival. RESULTS:The overall survival of patients in the lowest quartile for psoas muscle area or paravertebral muscle area was significantly shorter than that of patients above the 25th percentile for muscle area (p < 0.001). Multivariate analyses showed that paravertebral muscle mass (hazard ratio, 1.73; 95% confidence interval, 1.17-2.56; p = 0.006), epidermal growth factor receptor-targeted therapy, and performance status were independent prognostic factors. CONCLUSIONS:Low paravertebral muscle mass was associated with shorter survival, independently of known prognostic factors.