人类平衡型核苷转运蛋白1高表达晚期非小细胞肺癌患者术后应用不同剂量吉西他滨治疗的临床效果观察

目的 观察晚期非小细胞肺癌(NSCLC)中人类平衡型核苷转运蛋白1(hENT1)高表达患者应用不同剂量吉西他滨治疗的临床效果.方法 选取2008年7月至2013年12月于浙江金华广福医院行晚期NSCLC手术后,病理确诊晚期NSCLC患者,采用免疫组织化学SP法检测肺癌组织中hENT1抗体的表达水平.62例hENT1高表达患者入组,按随机数字表分组法分为对照组(30例)和观察组(32例).对照组采用常规剂量吉西他滨(1 000 mg/m2)联合顺铂进行化疗,观察组用低剂量吉西他滨(250 mg/m2)联合顺铂进行化疗,观察2组近期疗效、化疗不良反应.采用生活质量调查核心量表QLQ-C30和肺癌专用量表QLQ-LCl3比较2组化疗后生活质量.结果 对照组和观察组近期有效率和疾病控制率差异无统计学意义[43.3％ (13/30)比46.9％ (15/32),76.9％ (23/30)比81.2％(26/32)](x2 =0.08,x2 =0.20,P＞0.05).观察组Ⅲ、Ⅳ度白细胞减少、血小板减少及恶心、呕吐发生率低于对照组,差异有统计学意义(P＜0.05);除角色功能外,观察组化疗后总体生活评分及躯体功能、情绪功能、认知功能、社会功能、经济状况各项评分均优于对照组[(54±20)分比(54±16)分,(72±25)分比(62 ±20)分、(85 ±20)比(72±19)分、(76±28)分比(62±25)分、(61 ±24)分比(49 ±30)分、(36±24)分比(56±21)分],差异均有统计学意义(均P＜0.05).观察组除乏力症状外其他症状评分均优于对照组(P＜0.05).结论 对于晚期NSCLC术后hENT1高表达患者,在保证化疗效果的同时,相对于常规剂量吉西他滨,低剂量用药可有效降低化疗过程中不良反应,提高患者的生活质量.     

吉西他滨联合奥沙利铂或顺铂治疗非小细胞肺癌的临床疗效观察

目的：比较吉西他滨联合奥沙利铂与吉西他滨联合顺铂治疗非小细胞肺癌（ NSCLC）患者的临床效果。方法2013年6月＿2014年6月收治确诊的非小细胞肺癌患者68例,根据联合用药不同分为奥沙利铂组与顺铂组各34例。奥沙利铂组患者给予吉西他滨1000mg/ m2,d1、d8＋奥沙利铂130mg/ m2,d1,静脉滴注,3周为1个疗程;顺铂组给予吉西他滨1000mg/ m2,d1、d8＋顺铂25mg/ m2,d 1、2、3,静脉滴注,3周为1个疗程。2组均治疗2个疗程,随访6~24个月,比较2组临床疗效、近期不良反应、1年生存率。结果奥沙利铂组总有效率为41.2％（14/34）,顺铂组为35.3％（12/34）,2组比较差异无统计学意义（P ﹥0.05）。奥沙利铂组患者中位 PFS、OS 分别为24.5周、44.6周,顺铂组分别为18.2周、36.5周,2组中位 PFS 和中位 OS 比较差异无统计学意义（P ﹥0.05）。奥沙利铂组1年生存率为47.0％（16/34）,顺铂组为41.2％（14/34）,2组比较差异无统计学意义（P ﹥0.05）。2组患者不良反应主要表现为骨髓抑制、胃肠道反应和神经毒性等,以1~2级为主。奥沙利铂组1~2级神经毒性发生率为79.4％（27/34）,高于顺铂组35.3％（12/34）（P ＜0.01）,而3~4级不良反应发生率顺铂组为52.9％（18/34）,高于奥沙利铂组的20.6％（7/34）（P ＜0.01）,2组比较差异均有统计这意义（P ﹥0.05）。结论吉西他滨联合顺铂或奥沙利铂对非小细胞肺癌患者临床疗效相当,但联合奥沙利铂不良反应少,因而患者耐受性好,临床应用更安全。     

Efficacy of chemotherapy for patients with metastatic or recurrent pancreatic adenosquamous carcinoma: A multicenter retrospective analysis

Background/objectivesPancreatic adenosquamous carcinoma (PASC) is a rare variant of pancreatic ductal adenocarcinoma (PDAC). The usual treatment for metastatic or recurrent PASC is systemic chemotherapy in accordance with the PDAC treatment strategy. This study aimed to investigate the efficacy of chemotherapy, especially the benefit of recent combination therapies, in patients with metastatic or recurrent PASC.MethodsWe conducted a multicenter retrospective analysis of 116 patients with metastatic or recurrent PASC treated with first-line chemotherapy between April 2001 and December 2017 at 24 Japanese institutions.ResultsCombination chemotherapies included gemcitabine + nab-paclitaxel (GnP, n = 28), fluorouracil/leucovorin + irinotecan + oxaliplatin (FFX, n = 10), gemcitabine + S-1 (GS, n = 10), and others (n = 9). Monotherapies included gemcitabine (n = 51) and S-1 (n = 8). The median overall survival (OS) was 6.5, 7.3, and 4.3 months for the whole cohort, the combination therapy group, and the monotherapy group, respectively. Multivariate analysis indicated that combination therapy showed a better trend in OS than monotherapy (hazard ratio = 0.68; 95% confidence interval, 0.38–1.20). GnP or FFX were selected in 58.7% of patients after FFX was approved in Japan, and revealed a median OS, median progression-free survival, and objective response rate of 7.3 months, 2.8 months, and 26.9% in GnP and 7.2 months, 2.3 months, and 20.0% in FFX respectively.ConclusionsThis study suggests that combination therapy may be more effective than monotherapy. GnP and FFX showed similar and clinically meaningful efficacy for patients with metastatic or recurrent PASC.     

Protocol digest of randomized phase II study of modified FOLFIRINOX versus gemcitabine plus nab-paclitaxel combination therapy for locally advanced pancreatic cancer: Japan clinical oncology group study (JCOG1407)

Gemcitabine is one of the standard treatments for locally advanced pancreatic cancer. Recent studies on metastatic pancreatic cancer have shown that combination chemotherapy with oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX) and gemcitabine plus nab-paclitaxel (GnP) prolonged the overall survival compared with gemcitabine alone. To select the most promising chemotherapy, a randomized phase II selection design trial was started in July 2016 to compare between modified FOLFIRINOX and GnP for patients with locally advanced pancreatic cancer. A total of 124 patients will be enrolled from 36 Japanese institutions within 2.5 years. The primary endpoint is the proportion of 1-year overall survival, and secondary endpoints are progression-free survival, distant metastasis-free survival, response rate in patients with target lesions, CA19-9 response, adverse events, treatment-related death, early death, grade 4 non-hematological toxicity, and dose intensity. This trial has been registered with the UMIN Clinical Trials Registry [http://www.umin.ac.jp/ctr/index.htm], and the registration number is UMIN000023143.     

吉西他滨对CD34+CD38-髓系白血病干细胞的增殖抑制和凋亡诱导作用

 目的：探讨与阿糖胞苷(Ara-C)结构相似的新型脱氧胞苷相似物和核苷还原酶抑制剂--吉西他滨(gemeitabine,GEM)对CD34+CD38-KG1a髓系白血病干细胞(LSCs)增殖抑制和诱导凋亡的影响。方法：流式细胞术检测急性髓系白血病KG1a细胞表面CD34和CD38的表达; 24 h和持续用药软琼脂克隆形成实验观察不同浓度GEM对KG1a细胞增殖的影响,流式细胞术检测不同浓度GEM对KG1a细胞周期的影响,Annexin V/PI双染法检测不同浓度GEM对KG1a细胞凋亡的影响。结果：急性髓系白血病KG1a细胞中CD34+ CD38-占(98.02±0.72)%。0.05 mg/L、0.1 mg/L和0.5 mg/L的GEM分别作用KG1a细胞24 h、48 h和72 h后, 0.5 mg/L GEM作用KG1a细胞24 h后,G0/G1期细胞高于盐水对照组 (P<0.05),而0.05 mg/L 和0.1 mg/L GEM作用KG1a细胞24 h后,G0/G1期细胞与盐水对照组相比,差异无统计学意义(P>0.05)。0.05 mg/L、0.1 mg/L和0.5 mg/L GEM作用KG1a细胞24 h后,软琼脂培养第14 d和21d后, 0.1 mg/L和0.5 mg/L组形成的克隆数,低于盐水对照组 (P<0.05), 0.05 mg/L GEM组14 d、21 d的克隆数与对照组相比,差异无统计学意义(P>0.05)。0.05 mg/L、0.1 mg/L、0.5 mg/L GEM和Ara-C持续作用组,软琼脂培养14 d和21d均未见集落生长,与对照组相比差异显著(P<0.05)。0.05 mg/L、0.1 mg/L GEM作用KG1a细胞后其凋亡率与盐水对照组相比,差异无统计学意义(P>0.05）,而0.5 mg/L GEM作用24 h后KG1a细胞凋亡率显著高于盐水对照组（P<0.05）。结论：GEM能抑制CD34+CD38-髓系白血病干细胞增殖和克隆形成,并将CD34+CD38-KG1a细胞阻滞在G0/G1期和诱导其凋亡。     

Cost-effectiveness analysis of second-line chemotherapy strategies for patients with advanced non-squamous non-small cell lung cancer

Lung cancer is the most widespread type of cancer and the primary cause of cancer-related death in the world. In this study, we aimed to analyze the cost-effectiveness of second-line chemotherapy strategies based on gemcitabine, pemetrexed, and docetaxel for advanced non-squamous non-small cell lung cancer patients in China.A Markov model based on three states, progression-free survival, progressed survival and death, was constructed to simulate the progression of the disease in a 6-year horizon. Sensitivity analysis was performed to evaluate the robustness of the model. The primary outcome of the model was the incremental cost-effectiveness ratio at a willingness-to-pay threshold of 3× per capita GDP of China in 2018 ($29 383). The baseline model results showed that the quality-adjusted life years over the course of the disease associated with second-line chemotherapy strategies were 0.233, 0.417 and 0.272 for gemcitabine, pemetrexed and docetaxel, respectively, and the corresponding total costs were $5321.02, $12 143.94, and $9479.42. Gemcitabine, pemetrexed and docetaxel resulted in the incremental cost-effectiveness ratios of $37 081.09 and $106 625.64 per quality-adjusted life year gained. The incremental cost-effectiveness ratio of pemetrexed and docetaxel compared with gemcitabine exceeded the willingness-to-pay threshold. One-way sensitivity analysis showed that the utility value of gemcitabine in the progressed survival state was the most influential parameter.     

Downregulation of GSTM2 enhances gemcitabine chemosensitivity of pancreatic cancer in vitro and in vivo

Glutathione-S-transferases (GSTs) not only show cytoprotective role and their involvement in the development of anticancer drug resistance, but also transmit signals that control cell proliferation and apoptosis. However, the role of GST isoforms in chemotherapy resistance remains elusive in pancreatic cancer. Here, we demonstrated that gemcitabine treatment increased the GSTM2 expression in pancreatic cancer cell lines. Knockdown of GSTM2 by siRNA elevated apoptosis and decreased viability of pancreatic cancer cells treated with gemcitabine. Moreover, in vivo experiments further showed that shRNA induced GSTM2 downregulation enhanced drug sensitivity of gemcitabine in orthotopic pancreatic tumor mice. We also found that GSTM2 levels were lower in tumor tissues than in non-tumor tissues and higher GSTM2 expression was significantly associated with longer overall survival. In conclusion, our findings indicate that GSTM2 expression is essential for the survival of pancreatic cancer cells undergoing gemcitabine treatment and leads to chemo resistance. Downregulation of GSTM2 in pancreatic cancer may benefit gemcitabine treatment. GSTM2 expression in patients also shows significant correlation with overall survival. Thus, our study suggests that GSTM2 is a potential target for chemotherapy optimization and prognostic biomarker of pancreatic cancer.     

Metastatic Bladder Cancer: Role of Chemotherapy and New Agents

The M-VAC chemotherapy regimen has been widely used in locally advanced as well as in metastatic disease. Since only a proportion of patients with advanced disease will survive, there is a dire need to identify patients who will respond to chemotherapy and to identify new agents, targets and strategies to improve treatment outcome. Approaches to the management of advanced urothelial cancer include: intensifying the dose intensity, doublet and triplet combination chemotherapy, sequential regimens, reducing toxicity in unfit or elderly patients, and the use of biologic targeted therapies and promising new chemotherapeutic agents. These include MTA, the epothilones, topoisomerase inhibitors and vinflunine which act upon folate metabolism or upon different phases of the cell cycle. New agents that are coming into clinical trials include farnesyl transferase inhibitors, several growth factors receptor inhibitors, anti-sense therapy and COX-2 inhibitors. Significant progress has been made in understanding the molecular biology of cancer. Numerous novel agents, many of which are in clinical trials, have been developed to target various processes of tumor progression. The rationale behind application of these molecularly targeted therapies is to overcome resistance to cytotoxic therapies. Bladder cancer represents a unique model for targeted therapy. As our understanding increases, integration of newer biologic agents will condition future trials, and our ability to target bladder and urothelial cancers will be enhanced.     

吉西他滨对Beclinl基因沉默的人胰腺癌MiaPaCa-2细胞的周期及凋亡的影响

目的 探讨吉西他滨对Beclinl基因沉默的人胰腺癌MiaPaCa-2细胞周期及凋亡的影响.方法 构建靶向Beclinl的siRNA,插入表达质粒,转染MiaPaCa-2细胞.采用RT-PCR法和蛋白质印迹法检测细胞Beclinl mRNA及蛋白的表达,应用吉西他滨处理Beclinl基因沉默的MiaPaCa-2细胞,应用流式细胞仪检测细胞周期及细胞凋亡状况.结果 成功获得Beclin1基因沉默的MiaPaCa-2细胞,转染后细胞的Beclin1 mRNA表达量从对照组的1.0下降到0.295;S、G2期细胞数减少,而G1期细胞增多;细胞凋亡未受影响.应用吉西他滨处理后,Beclin1基因沉默的MiaPaCa-2细胞的S期细胞数进一步减少,而G1、G2期细胞增多,细胞凋亡被抑制.结论 Beclinl表达沉默使人胰腺癌细胞系MiaPaCa-2细胞周期发生改变,并影响吉西他滨对细胞周期及凋亡的作用.     

Sorafenib does not improve efficacy of chemotherapy in advanced pancreatic cancer: A GISCAD randomized phase II study

BackgroundThe RAF–MEK–ERK pathway is commonly activated in pancreatic cancer because of a high frequency of KRAS-BRAF mutations. A phase II randomized trial was designed to investigate the activity of sorafenib in combination with chemotherapy in advanced pancreatic cancer.MethodsLocally advanced or metastatic pancreatic adenocarcinoma patients were randomized in a 1:1 ratio to receive cisplatin plus gemcitabine with sorafenib 400 mg bid (arm A) or without sorafenib (arm B).ResultsOne hundred and fourteen patients were enrolled; of these, 43 (74.6%) patients progressed in arm A and 44 (82.4%) in arm B. Median progression-free survival was 4.3 months (95% CI: 2.7–6.5) and 4.5 months (95% CI: 2.5–5.2), respectively (HR = 0.92; 95% CI: 0.62–1.35). Median overall survival was 7.5 (95% CI: 5.6–9.7) and 8.3 months (95% CI: 6.2–8.7), respectively (HR = 0.95; 95% CI: 0.62–1.48). Response rates were 3.4% in arm A and 3.6% in arm B.ConclusionsSorafenib does not significantly enhance activity of chemotherapy in advanced pancreatic cancer patients, and therefore should not be assessed in phase III trials.