The High-Dose Aldesleukin (IL-2) “Select” Trial: A Trial Designed to Prospectively Validate Predictive Models of Response to High-Dose IL-2 Treatment in Patients With Metastatic Renal Cell Carcinoma

For patients with metastatic renal cell carcinoma (RCC), the prognosis is poor. Despite the recent approval of drugs such as sorafenib, sunitinib, and temsirolimus, durable remissions of metastatic disease are rare. This is largely due to the fact that these drugs, while effective, do not result in the eradication of disease. In 1992, the FDA approved the use of high-dose interleukin-2 (IL-2) for the treatment of patients with metastatic RCC because of a small number of patients that achieved durable responses. However, IL-2 has not become a mainstay of treatment because of the expense and toxicity associated with this therapy. This review article discusses a phase II trial that investigates predictive biomarkers that might help clinicians identify the patient population with metastatic RCC that would benefit from IL-2 therapy and therefore limit patients who receive this toxic therapy to those most likely to benefit.     

杏仁对吸烟导致DNA氧化损伤的保护作用

背景与目的： 研究美国加州杏仁对吸烟诱导的DNA氧化损伤是否具有保护作用。材料与方法： 选取30个吸烟的志愿者,随机分3组（每组10人）,每天分别给予0, 84和168 g的杏仁,共28 d;试验期间各组对象膳食和吸烟量相同,在实验开始前和试验结束后分别收集新鲜尿液测定柯替宁,采静脉血做彗星实验,收集24 h尿测定8-OH-dG。结果： 彗星实验显示,168 g/d剂量组DNA损伤程度比对照组和试验前均显著降低(P<0.05);8-OH-dG 测定结果显示,84 g / d和168 g / d剂量组的8-OH-dG水平明显低于试验前和对照组(P<0.05)。结论： 食用美国加州杏仁可能具有降低吸烟人群DNA氧化损伤的作用。     

Treatment of ifosfamide-induced urothelial toxicity by oral administration of sodium 2-mercaptoethane sulphonate (MESNA) to patients with inoperable lung cancer

The protective effect of oral administration of the thiol compound sodium 2-mercaptoethane sulphonate (MESNA) against urothelial toxicity induced by ifosfamide (IF) was tested in a group of 45 patients with inoperable lung cancer under treatment with IF (2250 mg/m² on days 2–5) as part of a polychemotherapy regimen repeated in a 4-week cycle. MESNA was given orally on the days of treatment with IF in 3 doses of 840 mg/m², each administered at 0 hr (= injection of IF), 4 hr and 8 hr p.i. Out of a total of 88 courses of this treatment we observed 10 episodes of asymptomatic microscopic haematuria and no episodes of gross haematuria. In this group of 45 patients under protection with MESNA there were 5 complete remissions and 9 partial remissions (total 31%). A further group of 25 patients under polychemotherapy with IF were treated by conventional prophylactic measures (raised fluid intake and forced diuresis). In this group there were 1 complete and 5 partial remissions (total 24%), but nearly all patients developed either gross haematuria and/or symptoms of bladder irritation (cystitis and pollakisuria). There were no appreciable differences between the MESNA series and the conventional prophylaxis series with respect to either haematological or systemic toxicity of the cytostatic treatment. Our results support the view that MESNA, given orally in conjunction with combined cytostatic regimens which include IF, simplifies the treatment and provides optimum protection for the urinary epithelium. Protection with oral MESNA is particularly suitable for outpatients.     

欧必亭与康泉预防化疗引起恶区呕吐的临床对比试验

目的：比较欧必亭（Tropisetron)和康（Kytril）预防化疗所致恶心呕吐的疗效和不良反应。方法：采用随机自身对照方法，将34例受联合化疗（19例含顺铂）的患者随机分为A、B两组，均接脘2个周期相同方案的化疗。A组第1周期用欧必亭，第2周期用康泉吐；B组第1周期和康泉，经2周期用欧必亭止吐。结果：欧必亭和康泉第1天止吐的有效率分别为94．1％和97．1％，中位呕吐次数分别为4．5次，经统计学处理两线差异无显著性，对迟发性呕吐和副作用也进行了对比，欧必亭和康泉也无明显差异。结论：欧必亭是一种预防化疗所致心呕吐的有效药物，它的不良反应很轻。     

欧必亭与康泉预防化疗引起恶心呕吐的临床对比试验

目的:比较欧必亭(Tropisetron)和康泉(Kytril)预防化疗所致恶心呕吐的疗效和不良反应。方法:采用随机自身对照方法,将34例接受联合化疗(19例含顺铂)的患者随机分为A、B两组,均接受2个周期相同方案的化疗。A组第1周期用欧必亭,第2周期用康泉止吐;B组第1周期用康泉,第2周期用欧必亭止吐。结果:欧必亭和康泉第1天止吐的有效率分别为94.1%和97.1%,中位呕吐次数分别为4.5次和3次,经统计学处理两组差异无显著性。对迟发性呕吐和副作用也进行了对比,欧必亭和康泉也无明显差别。结论:欧必亭是一种预防化疗所致恶心呕吐的有效药物,它的不良反应很轻。     

High-Dose Cytarabine (HD araC) in the Treatment of Leukemias: a Review

Cytarabine (araC) has served as the backbone of acute myeloid leukemia (AML) treatment for nearly forty years. High-dose cytarabine (HD araC) therapy resulted from a theoretical model developed in the 1970s that attempted to maximize the anti-leukemia effect of cytarabine. Since that time, HD araC has been utilized mostly in consolidation therapy for AML and in patients with relapsed or resistant AML. The development of araC and HD araC preceded our current understanding of AML biology–that it is a heterogeneous disease, not a single clinical entity. Thus, the optimal dose, schedule, and clinical setting for the use of cytarabine in hematologic malignancies remain uncertain. Research is now better defining the optimal use of HD araC based on leukemia cell karyotype and molecular signature. Here we review the pharmacodynamics of araC, the landmark studies that established the role of HD araC in AML, and research defining the role of HD araC based on the unique biologic properties of the leukemia cell.     

注射用磷酸肌酸钠对阿霉素心脏毒性的保护作用

目的 观察注射用磷酸肌酸钠对含阿霉素类化疗方案所致心脏毒性的保护作用.方法 120例恶性肿瘤随机分为治疗组(60例)和对照组(60例),治疗组和对照组均采用含阿霉素类方案化疗,3～4周为1个疗程,共3个疗程;治疗组在化疗的同时应用注射用磷酸肌酸钠1.0+生理盐水100 mL,连用8～14 d.化疗3个疗程后评价疗效和心脏毒性.结果 治疗组和对照组的瘤体稳定率分别为76.67%和71.67%.差异无统计学意义(P>0.05).治疗组和对照组的治疗前生活质量比较差异无统计学意义(P>0.05);治疗后治疗组生活质量改善情况好于对照组(P<0.05).治疗组的心电图改变发生率(41.67%)低于对照组(61.67%)(P<0.05);治疗组心肌缺血、心律失常和心肌酶异常发生率分别为45.00%、11.67%、10.00%,低于对照组的75.00%、41.67%、71.67%,差异均有统计学意义(P<0.01).结论 注射用磷酸肌酸钠能够降低含阿霉素类方案所致心脏毒性的发生率,改善化疗患者的生活质量.     

Effect of Prophylactic Sucralfate Suspension on Stomatitis Induced by Cancer Chemotherapy a Randomized, Double-Blind Cross-Over Study

We have studied whether mouth-swishing with sucralfate, a well-known gastric mucosal protective agent, may be used as prophylaxis against chemotherapy-induced stomatitis. Using ra-dioactively labelled sucralfate we found that 20-30% was still bound to the oral mucosal lining 2 1/2 h after mouth-swishing. Forty patients receiving cisplatin and continuous infusion with 5-fluorouracil (5-FU) for 5 days entered a double-blind placebo-controlled cross-over study. Among 23 evaluable patients a significant reduction (p=0.04) in an objective score of edema, erythema, erosion and ulcerations was seen during treatment with sucralfate. Patient preference favored sucralfate, but this preference failed to reach statistical significance (p=0.06). Seven patients were inevaluable for reasons not associated with the studied treatment. However, ten patients did not complete the study since the swishing procedure aggravated chemotherapy-induced nausea. An equal rate of non-compliance was seen with sucralfate and placebo. To overcome this problem, the oral medication should have a neutral taste, the solution should not be swallowed after the swishing, which should not be started until the nausea had ceased.     

Adjuvant Treatment with High Dose Medroxyprogesterone Acetate in Node-Negative Early Breast Cancer A 3-year Interim Report on a Randomized Trial (I)

After initial surgery, 240 pre-, peri- or postmenopausal patients with early node-negative breast carcinoma were randomized to receive either no hormone therapy or adjuvant therapy with medroxyprogesterone acetate at high dosage (HD-MPA; 500 mg IM per day times 28 or 500 mg intramuscularly (i.m.) 5 days a week for 5 weeks then 500 mg i.m. twice weekly for the 5 following months. After a median follow-up time of 3 years, relapse-free survival and overall survival appeared significantly improved in the HD-MPA arm. Side effects were tolerable.     

A Randomized Open-Label Phase III Trial Evaluating the Addition of Denosumab to Standard First-Line Treatment in Advanced NSCLC: The European Thoracic Oncology Platform (ETOP) and European Organisation for Research and Treatment of Cancer (EORTC) SPLENDOUR Trial

IntroductionReceptor activator of NF-kB ligand stimulates NF-kB–dependent cell signaling and acts as the primary signal for bone resorption. Retrospective analysis of a large trial comparing denosumab versus zoledronic acid in bone metastatic solid tumors suggested significant overall survival (OS) advantage for patients with lung cancer with denosumab (p = 0.01). The randomized open-label phase III SPLENDOUR trial was designed to evaluate whether the addition of denosumab to standard first-line platinum-based doublet chemotherapy improved OS in advanced NSCLC.MethodsPatients with stage IV NSCLC were randomized in a 1:1 ratio to either chemotherapy with or without denosumab (120 mg every 3–4 wks), stratified by the presence of bone metastases (at diagnosis), Eastern Cooperative Oncology Group performance status, histology, and region. To detect an OS increase from 9 to 11.25 months (hazard ratio [HR] = 0.80), 847 OS events were required. The trial closed prematurely owing to decreasing accrual rate.ResultsA total of 514 patients were randomized, with 509 receiving one or more doses of the assigned treatment (chemotherapy: 252, chemotherapy-denosumab: 257). The median age was 66.1 years, 71% were men, and 59% were former smokers. Bone metastases were identified in 275 patients (53%). Median OS (95% confidence interval [CI]) was 8.7 (7.6–11.0) months in the control arm versus 8.2 (7.5–10.4) months in the chemotherapy-denosumab arm (HR = 0.96; 95% CI: 0.78–1.19; one-sided p = 0.36). For patients with bone metastasis, HR was 1.02 (95% CI: 0.77–1.35), whereas for those without, HR was 0.90 (95% CI: 0.66–1.23). Adverse events grade 3 or greater were observed in 40.9%, 5.2%, 8.7% versus 45.5%, 10.9%, 10.5% of patients. Conditional power for OS benefit was less than or equal to 10%.ConclusionsDenosumab was well-tolerated without unexpected safety concerns. There was no OS improvement for denosumab when added to chemotherapy in the intention-to-treat population and the subgroups with and without bone metastases. Our data do not provide evidence of a clinical benefit for denosumab in patients with NSCLC without bone metastases.     

The Effect of Gluten Free Diet on Components of Metabolic Syndrome: A Randomized Clinical Trial

Background: This study aimed to assess the effects of Gluten free diet (GFD) on components of metabolic syndrome(MES). Materials and Methods: In this randomized clinical trial, 50 subjects diagnosed with MES were randomlydivided into two groups (n=25). The first group received a GFD and the second group continued their regular diet.Biochemical markers of MES and blood pressure were measured before and after 8-week intervention. Results: Fortyfive subjects completed the study. A post-hoc comparison of the groups showed no effects of the GFD and controldiet on LDL cholesterol, total cholesterol, fasting insulin, HOMA-IR, systolic and diastolic blood pressure levels. TheGFD reduced fasting blood glucose, waist circumference (WC) and serum triglyceride concentration significantlycompared with the control diet (p<0.05). Conclusion: Short-term GFD reduced WC and improved glycemic controland Triglyceride level in subjects with the metabolic syndrome.     

氯喹对阿霉素心脏毒性的保护作用初步研究

摘 要：［目的］ 探讨自噬抑制剂氯喹对阿霉素所致心肌细胞损伤的保护作用。［方法］ 应用MTT法检测氯喹预处理不同时间后给予不同浓度阿霉素作用24h时的心肌细胞存活率,倒置显微镜观察心肌细胞形态,荧光定量PCR比较氯喹、阿霉素及联合作用对Beclin1表达水平的影响。［结果］ 氯喹可以提高不同浓度阿霉素作用下心肌细胞的存活率,其中氯喹预处理24h可以分别提高低中浓度阿霉素作用下的心肌细胞存活率2.5倍左右,高浓度阿霉素作用下心肌细胞存活率2倍。细胞形态学也显示,同为阿霉素作用下,氯喹预处理可不同程度维持心肌细胞原有正常形态。氯喹可以抑制阿霉素诱导的心肌细胞Beclin1表达水平升高。［结论］ 氯喹对阿霉素引起的心肌细胞损伤有一定的保护作用,可能与其抑制Beclin表达水平有关。     

Protective Effect of Astragalus polysaccharides on Liver Injury Induced by Several Different Chemotherapeutics in Mice

Side effects are an unavoidable consequence of chemotherapy drugs, during which liver injury often takes place.The current study was designed to investigate the protective effect of Astragalus polysaccharides (APS) againstthe hepatotoxicity induced by frequently-used chemical therapy agents, cyclophosphamide (CTX), docetaxel(DTX) and epirubicin (EPI)) in mice. Mice were divided into five groups, controls, low or high dose groups(DTXL, CTXL, EPIL or DTXH, CTXH, EPIH), and low or high dose chemotherapeutics+APS groups (DTXL+APS,CTXL+APS, EPIL+APS or DTXH+APS, CTXH+APS, EPIH+APS). Controls were treated with equivalent normalsaline for 28 days every other day; low or high dose group were intraperitoneal (i.p) injected with low or highdoses of CTX, DTX and EPI for 28 days every other day; low or high dose chemotherapeutics+APS group wereseparately intraperitoneal (i.p) injected with chemotherapeutics for 28 days every other day and i.p with APS(100 mg/kg) for 7 days continually from the 22th to the 28th days. The body weight, serum levels of alanineaminotransferase (ALT) and aspartate aminotransferase (AST), histopathological features, and ultrastructuremorphological change of liver tissues, protein expression level of caspase-3 were estimated at different time points.With high dose treatment of DTX, CTX and EPI, weight gain was inhibited and serum levels of ALT and ASTwere significantly increased. Sections of liver tissue showed massive hepatotoxicity in CTXH group comparedto the control group, including hepatic lobule disorder, granular and vacuolar degeneration and necrosis inhepatic cells. These changes were confirmed at ultrastructural level, including obvious pyknosis, heterochromatinaggregation, nuclear membrane resolution, and chondrosome crystal decrease. Western blotting revealed that theprotein levels of caspase-3 increased in CTXH group. The low dose groups exhibited trivial hepatotoxicity. Moreinterestingly, after 100 mg/kg APS, liver injury was redecued not only regarding serum transaminase activities(low or high dose chemotherapeutics+APS group), but also from pathological and ultrastructural changes andthe protein levels of caspase-3 (CTXH+APS group). In conclusion, DTX, CTX and EPI induce liver damage ina dose dependent manner, whereas APS exerted protective effects.