Systemic treatment of patients with gastrointestinal stromal tumor: Current status and future opportunities

Imatinib mesylate is considered the standard first-line systemic treatment for patients with advanced gastrointestinal stromal tumor (GIST). Results from recent research have expanded the knowledge of tyrosine kinase inhibitors in management of GIST. In the setting of unresectable and metastatic GIST, long-term follow-up of the B2222 study showed that imatinib 400 and 600 mg/d produced objective responses in 68% of patients and clinical benefit in 84%; it also extended median survival from 19 months in historical controls to 57 months. The MetaGIST analysis in two large phase 3 trials consisting of more than 1600 patients with metastatic and/or unresectable GIST showed that imatinib 800 mg/d compared with the standard 400-mg/d dose conferred a progression-free survival advantage in patients with KIT exon 9 mutations but not in other subpopulations. The higher starting dose does not significantly improve overall survival. The BFR14 trial demonstrated that interrupting imatinib is associated with a high risk of rapid disease progression. For patients with imatinib-intolerant or imatinib-resistant GIST, sunitinib or a variety of investigational agents, including the next-generation kinase inhibitor nilotinib, may be viable options for achieving disease control. In the setting of primary localized GIST, function- sparing surgical resection is the standard treatment approach, but some patients may be at substantial risk of disease recurrence and metastasis depending on tumor size, mitotic count, and possibly other factors. Initial results from ACOSOG Z9001 indicate that adjuvant imatinib for 1 year prolongs recurrence-free survival following surgical resection of larger (at least 3 cm) KIT-expressing GIST. Other ongoing studies are further exploring the role of imatinib in both adjuvant and neoadjuvant therapy. Recent updates to clinical practice guidelines and recommendations now incorporate some of these new findings.     

Recombinant murine cytomegalovirus vector activates human monocyte-derived dendritic cells in a NF-κB dependent pathway

To evaluate the potential use of recombinant murine cytomegalovirus (MCMV) as an antigen delivery vector, we examined the cytokine and CD80 and CD86 expression profiles of MCMV encoding either enhanced green fluorescent protein gene (MCMV-EGFP) or human immunodeficiency virus-1 glycoprotein gp120 gene (MCMV-gp120) infected monocyte-derived dendritic cells (Mo-DC) and investigated the role of nuclear factor kappa B (NF-κB) in Mo-DC activation. Results showed that MCMV triggered the induction of inflammatory cytokines and/or CD80 and CD86 up-regulation in Mo-DC. UV-inactivated MCMV exhibited a reduced production of inflammatory cytokines and a lowered expression of CD80 and CD86 compared with live MCMV infection. Treatment of cells with a NF-κB peptide inhibitor prior to MCMV infection reduced the induction of cytokines and CD80 and CD86 up-regulation. Overall, the results suggest that recombinant MCMV vectors activate human Mo-DC in a NF-κB dependent pathway. The abortive infection or de novo gene expression greatly enhances the activation of Mo-DC by MCMV vectors.     

Impact of an autologous oxygenating matrix culture system on rat islet transplantation outcome

Disruption of the pancreatic islet environment combined with the decrease in oxygen supply that occurs during isolation leads to poor islet survival. The aim of this study was to validate the benefit of using a plasma-based scaffold supplemented with perfluorodecalin to improve islet transplantation outcome.Rat islets were cultured in three conditions: i) control group, ii) plasma based-matrix (P-matrix), and iii) P-matrix supplemented with emulsified perfluorodecalin. After 24 h culture, matrix/cell contacts (Integrinβ1, p-FAK/FAK, p-Akt/Akt), survival (caspase 3, TUNEL, FDA/PI), function, and HIF-1α translocation were assessed. Afterwards, P-matrices were dissolved and the islets were intraportally transplanted. Graft function was monitored for 31 days with glycaemia and C-peptide follow up. Inflammation was assessed by histology (macrophage and granulocyte staining) and thrombin/anti-thrombin complex measurement.Islet survival correlated with an increase in integrin, FAK, and Akt activation in P-matrices and function was maintained. Perfluorodecalin supplementation decreased translocation of HIF-1α in the nucleus and post-transplantation islet structure was better preserved in P-matrices, but a quicker activation of IBMIR resulted in early loss of graft function.“Oxygenating” P-matrices provided a real benefit to islet survival and resistance in vivo. However, intraportal transplantation is not suitable for this kind of culture due to IBMIR; thus, alternative sites must be explored.     

我院114例抗感染药致严重不良反应报告分析

目的:了解抗感染药致严重不良反应的特点,为临床安全、合理用药提供参考。方法:对我院2000～2009年收集到的抗感染药致严重不良反应报告进行分析与评价。结果:114例严重不良反应涉及14种抗感染药。其中居前3位的是抗结核药、头孢菌素类与喹诺酮类。不良反应的临床表现主要为肝损害(占34.59%),其次为肾损害(占26.32%)与皮肤及其附件损害(占14.29%)。108例好转或治愈,3例死亡,2例预后不详,1例有后遗症。38例患者有明确的药物过敏史(33.33%)。结论:常用抗感染药致严重不良反应主要为肝、肾损害,部分患者发生不良反应过程隐匿,若及时发现适当处理,大部分患者可短期内治愈或好转。临床医药人员应根据这些特点加强对相关药物的监测,提高合理用药水平。     

西藏地区肾穿刺活检术后出血风险分析

目的: 观察我国西藏地区肾穿刺活检术(percutaneous renal biopsy,PRB)术后出血情况,分析总结与高原地区患者出血相关的危险因素,提高手术安全性。方法: 选择西藏自治区人民医院肾脏内科2016年5月至2018年5月收治的经皮肾穿刺活检术患者临床资料进行回顾性研究,分析诸因素(性别、年龄、血压、血红蛋白、血小板、血肌酐、凝血酶原时间和活化部分凝血酶原时间)与术后出血事件的相关性。结果: 共收集病例150例,平均年龄(41.2±15.6)岁,其中男性比例为58.7%(88/150),女性为41.3%(62/150),术后出血12例(男、女各6例),出血比例8.0%(12/150)。出血组平均年龄与无出血组相比,有偏高趋势[(48.3±20.0)岁vs. (40.6±15.1)岁,P=0.099]。出血组较无出血组高血压发生率、血红蛋白增多症发生率、尿素氮、凝血酶原时间差异均无统计学意义(P>0.05)。出血组血肌酐水平有高于无出血组趋势(P=0.090),出血组较无出血组活化部分凝血酶原时间有延长趋势(P=0.069)。出血组血小板计数明显低于无出血组(P<0.05)。多因素Logistic回归分析发现,活化部分凝血酶原时间延长和较低的血小板计数具有相对较高的出血风险,差异有统计学意义(P=0.079,P=0.082)。结论: 高原地区行PRB总体上是安全、可靠的;高龄、低血小板、肾功能下降、活化部分凝血酶原时间延长与PRB术后出血相关,高血红蛋白不是高原地区PRB术后出血的危险因素。     

Predictors of Survival in Patients Undergoing Surgery for Renal Cell Carcinoma and Inferior Vena Cava Tumor Thrombus

IntroductionSurgical resection of renal cell carcinoma (RCC) with inferior vena cava (IVC) thrombus is a complex procedure with significant morbidity. Patient selection is critical to determining whether the benefits of the procedure outweigh the risks. In this study, we identified and stratified the risk factors that were associated with overall survival (OS) and recurrence-free survival (RFS) in patients undergoing surgical resection of RCC with IVC thrombus.MethodsWe identified all patients with RCC with IVC tumor thrombus (stages cT3b and cT3c) who had undergone radical nephrectomy with tumor thrombectomy between December 1, 1993 and June 30, 2009. Kaplan-Meier method was used to estimate OS and RFS. Cox proportional hazards models were used to determine the association between risk factors and OS. Patients were stratified into 3 groups based on the number of risk factors present at diagnosis.ResultsTwo hundred twenty-four patients were included in the study. A total of 45.3% of patients had metastasis at presentation, 84.5% had cT3b, and 90.2% had clear cell RCC. cT3c, cN1, and cM1 were significantly associated with the risk of death. Group 1 patients (0 risk factors) had a median OS duration of 77.6 months (95% CI 50.5-90.4), group 2 (1 risk factor) 26.0 months (95% CI 19.5-35.2), and group 3 (≥2 risk factors) 8.9 months (95% CI 5.2-12.9; P < .001).ConclusionsStratification of patients with RCC and IVC thrombus by risk factors allowed us to predict survival duration. In patients with ≥2 risk factors, new treatment strategies with preoperative systemic therapy may improve survival.