瘤内注射重组溶瘤病毒联合吉西他滨化疗治疗中晚期胰腺癌19例疗效观察

目的 探讨内镜超声引导下瘤体内注射重组溶瘤病毒(H101)联合吉西他滨化疗治疗中晚期胰腺癌的疗效及安全性.方法 选择无手术指证的未行抗肿瘤治疗的中晚期胰腺癌患者共19例,于内镜超声引导下行H101瘤体内注射,并于注射后第3、10、17 d行吉西他滨静脉化疗(1000 mg/m2),共2个疗程.记录注射前后肿瘤体积,评定疗效;记录患者疼痛及Karnofsky评分变化、不良反应及并发症发生率、生存期.结果 12例肿瘤体积缩小5.3%～69.7%,但治疗前后的平均体积差异无统计学意义(P=0.275).19例患者均完成2周期联合治疗.3例(15.8%)部分缓解;10例(52.6%)稳定;无治愈患者.治疗后平均疼痛评分明显低于治疗前(3.1±1.7比3.9±1.6,P=0.004).治疗后Karnofsky 评分明显提高[(68.4±12.1)%比(61.1±9.9)%,P=0.003)].未发生与操作相关的并发症,与治疗相关的不良反应主要为发热与腹泻.19例患者生存期为2.5～10个月,随访截止时9例患者仍存活.结论 内镜超声引导下瘤体内注射重组溶瘤病毒联合吉西他滨化疗治疗中晚期胰腺癌的方法是安全、有效的,能改善患者生存质量、降低疼痛评分.     

超声内镜引导基因重组人腺病毒植入治疗晚期胰腺癌一例

胰腺癌是常见的消化道恶性肿瘤之一，晚期胰腺癌预后极差，治疗手段匮乏，至今人们不断探索新的介入治疗手段，期望延长患者的生存期。我们于2006年11月11日首次进行超声内镜（EUS）引导基因工程重组人5型腺病毒（H101，商品名：安柯瑞）植入治疗一例晚期胰腺癌患者，现报告如下。     

125I粒子植入联合吉西他滨化疗治疗胰腺癌临床受益疗效评价

目的 评价EUS引导下125I粒子植入联合吉西他滨化疗治疗胰腺癌的临床收益疗效.方法 41例不能手术切除的胰腺癌患者按完全随机法分为放射性125I粒子植入联合吉西他滨化疗组(21例)和单纯吉西他滨化疗组(20例).吉西他滨化疗方案为1 000 mg/m2,1次/周,静脉滴注,连用3周,休息1周;联合组在125I粒子植入后1周行化疗.评价临床受益疗效(CBR).结果 125I粒子联合吉西他滨化疗组临床受益率为57.1%,达到CBR的中位时间为1周,临床受益疗效持续的中位时间为21周;单纯化疗组分别为25%、4周和15周,两组前2项相差非常显著(P<0.05),而临床受益疗效持续的中位时间无显著差异(P>0.05).结论 EUS引导下125I粒子组织间植入联合吉西他滨化疗治疗不能手术切除的胰腺癌的CBR明显优于单纯吉西他滨化疗组.     

超声内镜引导下碘125粒子植入联合化疗治疗腹腔实体肿瘤的前瞻性研究

目的评价内镜超声检查术(EUS)引导下肿瘤内植入放射性碘125(~125 I)粒子联合化疗治疗胰腺癌的疗效和安全性,并探讨该方法用于其他腹腔原发或继发实体肿瘤治疗的可行性。方法对28例不能手术切除的腹腔实体肿瘤患者进行了EUS引导~(125)Ⅰ粒子植入内照射治疗,术后1周内采用吉西他滨 氟脲嘧啶化疗方案。包括中晚期胰腺癌25例(胰头癌8例、胰体尾癌17例),胆管癌腹膜后转移、腹膜后腺癌和贲门癌术后腹腔转移各1例。所有病例术前均参照TPS系统估算期望植入粒子数量,比较术前及术后不同时期的肿瘤直径、生活质量评分以及疼痛VAS评分等项目。结果 28例患者均经EUS成功植入~(125)Ⅰ粒子,平均每次植入粒子数量的中位数为10颗(5～20颗),最多1例胰腺癌分3次共植入30颗粒子,平均单颗粒子的放射性活度为26.2MBq。术后平均随访4.8个月(0.3～14个月),Kaplan-Meier法评估的中位生存期为9.4个月(95%CI6.5～11.6个月)。术后1个月评估疗效,达到部分缓解3例(10.7%),疾病稳定12例(42.9%),进展恶化10例(35.7%,其中8例死亡),3例失访。粒子植入1周后疼痛VAS评分由5.07±2.63下降至1.73±1.91(ρ<0.01),1个月后仍低于术前评分(3.53±1.51,ρ<0.05)。有52.9%的患者于术后24h内出现发热,无其他并发症出现。结论 EUS引导下~(125)Ⅰ粒子组织间植入是治疗包括胰腺癌在内的腹腔实体肿瘤的新型介入技术,可明显延缓肿瘤进展,具有稳定的止痛疗效,安全性高,值得进一步探讨其临床应用价值。     

超声内镜引导125I粒子组织间植入治疗晚期胰腺癌的疗效及粒子移位分析

目的分析胰腺癌超声内镜（EUS）引导下^125I粒子种植术治疗晚期胰腺癌的肿瘤变化及粒子移位，并评价其治疗效果。方法对17例不能手术切除的中晚期胰腺癌患者行EUS引导下放射性^125I粒子内照射治疗。所有患者治疗前均参照治疗设计系统估算期望植入粒子数量。治疗后每月复查，观察治疗前、后肿瘤变化及粒子移位、脱落等情况。结果17例患者均经EUS植入^125I粒子成功。治疗前肿瘤最大长径平均值为5．4cm（3．7～9．0cm），平均植入粒子数量为27颗，平均每次植入粒子中位数为14（7～24）颗，平均植入2次。平均单颗粒子的放射性活度为（0.689±0．016）mCi。治疗后平均随访4．8个月（2～14个月）。治疗后3个月评估疗效，部分缓解5例（29．4％），疾病稳定7例（41．2％），进展恶化5例（29．4％）。治疗后腹部平片示5例（29．4％）出现粒子丢失移位。1例脾区移位，1例肝脏移位，3例肠腔移位。治疗后粒子丢失4例。1例出现脾脏及左膈下囊肿。结论EUS引导下^125I粒子内照射治疗晚期胰腺癌，可使粒子照射区域内病灶明显萎缩。但需注意放射性粒子对周围脏器的损害及粒子脱落移位等并发症的发生。     

晚期胰腺癌治疗的研究进展

胰腺癌是恶性程度最高的消化系统肿瘤,多数患者确诊时肿瘤已发生远处转移,5年存活率仅5%。吉西他滨为治疗晚期胰腺癌的最佳药物,以吉西他滨为基础的疗法广泛用于晚期患者的一线治疗,一旦吉西他滨治疗失败,目前尚缺乏统一的替代方法。晚期胰腺癌的治疗包括联合化疗、区域性动脉灌注、靶向放疗、HIFU、冷冻治疗、PDT等,本文就其研究进展作一综述。     

动脉灌注吉西他滨治疗晚期胰腺癌临床研究

目的评价吉西他滨 (健择) 动脉灌注治疗晚期胰腺癌的疗效和安全性.方法对20例胰腺癌病人采用吉西他滨动脉灌注结合静脉化疗,并与9例采用5-氟尿嘧啶(1000mg)、阿霉素(40～50mg)、卡铂(200mg)经胰十二指肠动脉灌注治疗的胰腺癌病人为对照,对病人的疾病相关症状改善、疗效和毒副反应进行评价.结果吉西他滨组治疗后疼痛改善率为75%,对照组疼痛改善率为44.4%,两者比较无显著性差异.治疗后Karnofsky评分吉西他滨组好转率为60%,对照组为44.4%.吉西他滨组部分缓解率(PR)为30%,半年及1年生存率分别为85%及25%,中位生存时间为9.2个月;对照组PR为22.2%,半年生存率为66.7%,无1年生存者,中位生存时间为7.9个月(P>0.05).两组均有不同程度的胃肠道和骨髓抑制等不良反应(P>0.05),3、4级不良反应较少见.结论吉西他滨动脉灌注治疗晚期胰腺癌能够改善病人的生存质量,延长病人的生存期,无严重毒副反应.     

替吉奥联合吉西他滨化疗、同步放疗治疗晚期胰腺癌28例疗效观察

目的：探讨替吉奥联合吉西他滨化疗、同步放疗治疗局部晚期胰腺癌的临床疗效。方法选择晚期胰腺癌患者28例,采用三维适形放疗,总剂量45～50 Gy,5周左右完成;放疗同时行同步化疗,方案：饭后口服替吉奥60 mg,2次/d,,第1～14天;静脉滴注,吉西他滨1000 mg/m2第1、8天,3周为1个疗程,放疗结束后1个月巩固化疗2～4个疗程。观察治疗有效率、不良反应、生存率及中位生存期。结果本组有效率为46．4％,主要不良反应为消化道反应、血液学毒性,患者可耐受,无死亡病例;中位生存期为17．5个月,1、2年生存率分别为42．9％和21．0％。结论替吉奥联合吉西他滨化疗、同步放疗治疗晚期胰腺癌疗效较好,不良反应较轻。     

动脉灌注吉西他滨治疗晚期胰腺癌临床研究

目的：评价吉西他滨（健择）动脉灌注治疗晚期胰腺癌的疗效和安全性。方法：对20例胰腺癌病人采用吉西他滨动脉灌注支结合静脉化疗，并与9例采用5－氟尿嘧啶（1000mg)、阿霉素（40－50mg)、卡铂（200mg)经胰十二指肠动脉灌注治疗的胰腺癌病人为对照，对病人的疾病相关症状改善、疗效和毒副反应进行评价。结果：吉西他滨组治疗后疼痛改善率为75％，对照组疼痛改善率为44．4％，两比较无显性差异。治疗后Karnofsky评分吉西他滨组好转率为60％，对照组为44．4％。吉西他滨组部分缓解率（PR）为30％，半年及1年生存率分别为85％及25％，中位生存时间为9．2个月；对照组PR为22．2％，半年生存率为66．7％，无1年生存，中位生存时间为7．9个月（P＞0．05）。两组均有不同程度的胃肠道和骨髓抑制等不良反应（P＞0．05），3、4级不良反应较少见。结论：吉西他滨动脉灌注治疗晚期胰腺癌能够改善病人的生存质量，延长病人的生存期，无严重毒副反应。     

内镜超声引导下125I粒子腹腔神经节植入术治疗晚期胰腺癌腹痛的初步研究

目的 评价内镜超声(EUS)引导下125I粒子腹腔神经节植入术治疗晚期胰腺癌患者腹痛的疗效以及其安全性.方法 对23例伴有中重度腹痛的晚期胰腺癌患者行EUS引导下125I粒子腹腔神经节植入术,术后每周随访1次,观察手术前后白细胞、血生化,患者的生存期、腹痛评分、麻醉药物的使用情况并记录手术相关的并发症.结果 所有患者均一次性手术成功,平均每例患者植入4枚粒子(2～6枚).术后有6例(26％)患者诉腹痛加重,但术后2周,患者的疼痛评分由平均6.09分降至4.48分(P＜0.05),所需要麻醉药物的剂量由术前71.74 mg迅速减少到55.22 mg(P＜0.05);未观察到并发症的发生.结论 EUS引导下125I粒子腹腔神经节植入术能有效缓解晚期胰腺癌患者的疼痛评分及麻醉药物的使用量.     

The differential effects of metronomic gemcitabine and antiangiogenic treatment in patient-derived xenografts of pancreatic cancer: treatment effects on metabolism,vascular function,cell proliferation,and tumor growth

Background

Metronomic chemotherapy has shown promising activity against solid tumors and is believed to act in an antiangiogenic manner. The current study describes and quantifies the therapeutic efficacy, and mode of activity, of metronomic gemcitabine and a dedicated antiangiogenic agent (DC101) in patient-derived xenografts of pancreatic cancer.

Methods

Two primary human pancreatic cancer xenograft lines were dosed metronomically with gemcitabine or DC101 weekly. Changes in tumor growth, vascular function, and metabolism over time were measured with magnetic resonance imaging, positron emission tomography, and immunofluorescence microscopy to determine the anti-tumor effects of the respective treatments.

Results

Tumors treated with metronomic gemcitabine were 10-fold smaller than those in the control and DC101 groups. Metronomic gemcitabine, but not DC101, reduced the tumors’ avidity for glucose, proliferation, and apoptosis. Metronomic gemcitabine-treated tumors had higher perfusion rates and uniformly distributed blood flow within the tumor, whereas perfusion rates in DC101-treated tumors were lower and confined to the periphery. DC101 treatment reduced the tumor’s vascular density, but did not change their function. In contrast, metronomic gemcitabine increased vessel density, improved tumor perfusion transiently, and decreased hypoxia.

Conclusion

The aggregate data suggest that metronomic gemcitabine treatment affects both tumor vasculature and tumor cells continuously, and the overall effect is to significantly slow tumor growth. The observed increase in tumor perfusion induced by metronomic gemcitabine may be used as a therapeutic window for the administration of a second drug or radiation therapy. Non-invasive imaging could be used to detect early changes in tumor physiology before reductions in tumor volume were evident.

     

EUS-Guided Antitumor Therapy for Pancreatic Tumors

Endoscopic ultrasound (EUS) is a very useful modality for the diagnosis and staging of pancreatic masses. With the advent of EUS-guided fine-needle aspiration technology, this modality has made a tremendous leap from imaging modality to histologic diagnosis and therapeutic intervention. EUS offers high-resolution images of and unparalleled access to the pancreas. After locating the tip of the echoendoscope in the duodenum or stomach, several drugs or local treatment modalities can be delivered directly into the pancreas. EUS-guided ethanol lavage with/without paclitaxel injection has been tested for the treatment of cystic tumors of the pancreas, with complete resolution of cystic tumor being observed in up to 70-80% of patients. Ethanol injection is also performed for the management of solid neuroendocrine tumors of the pancreas. Various type of EUS-guided injection have also been investigated for the treatment of pancreatic cancer. An activated allogenic mixed lymphocyte culture (Cytoimplant) was injected in patients with advanced pancreatic cancer. A replication-deficient adenovirus vector carrying the tumor necrosis factor-alpha gene was also delivered intratumorally by EUS. ONYX-015 is an oncolytic attenuated adenovirus that exhibits replication preferentially in malignant cells, causing cell death, and this has also been injected into pancreatic cancers under EUS guidance. EUS-guided local ablation therapies such as radiofrequency ablation, photodynamic therapy, and brachytherapy are also under investigation. EUS-guided fine-needle injection for various solid or cystic lesions is a rapidly expanding field. This article reviews the various applications of EUS for the treatment of pancreatic tumors.     

Intervention of mirtazapine on gemcitabine-induced mild cachexia in nude mice with pancreatic carcinoma xenografts

AIM: To investigate the effect of Mirtazapine on tumor growth, food intake, body weight, and nutritional status in gemcitabine-induced mild cachexia.METHODS: Fourteen mice with subcutaneous xenografts of a pancreatic cancer cell line (SW1990) were randomly divided into Mirtazapine and control groups. Either Mirtazapine (10 mg/kg) or saline solution was orally fed to the mice every day after tumor implantation. A model of mild cachexia was then established in both groups by intraperitoneal injection of Gemcitabine (50 mg/kg) 10 d, 13 d, and 16 d after tumor implantation. Tumor size, food intake, body weight, and nutritional status were measured during the experiment. All mice were sacrificed at day 28.RESULTS: (1) After 7 d of gemcitabine administration, body-weight losses of 5%-7% which suggested mild cachexia were measured; (2) No significant difference in tumor size was detected between the Mirtazapine and control groups (P > 0.05); and (3) During the entire experimental period, food intake and body weight were slightly greater for the Mirtazapine group compared with controls (although these differences were not statistically significant). After 21 d, mice in the Mirtazapine group consumed significantly more food than control mice (3.95 ± 0.14 g vs 3.54 ± 0.10 g, P = 0.004). After 25 d, mice in the Mirtazapine group were also significantly heavier than control mice (17.24 ± 0.53 g vs 18.05 ± 0.68 g, P = 0.014).CONCLUSION: Mild cachexia model was successfully established by gemcitabine in pancreatic tumor-bearing mice. Mirtazapine can improve gemcitabine-induced mild cachexia in pancreatic tumor-bearing mice. It was believed to provide a potential therapeutic perspective for further studies on cachexia.     

A new endoscopic ultrasonography image processing method to evaluate the prognosis for pancreatic cancer treated with interstitial brachytherapy

AIM:To develop a fuzzy classification method to score the texture features of pancreatic cancer in endoscopic ultrasonography(EUS)images and evaluate its utility in making prognosis judgments for patients with unresectable pancreatic cancer treated by EUS-guided interstitial brachytherapy.METHODS:EUS images from our retrospective database were analyzed.The regions of interest were drawn,and texture features were extracted,selected,and scored with a fuzzy classification method using a C++program.Then,patients with unresectable pancreatic cancer were enrolled to receive EUS-guided iodine 125 radioactive seed implantation.Their fuzzy classification scores,tumor volumes,and carbohydrate antigen 199(CA199)levels before and after the brachytherapy were recorded.The association between the changes in these parameters and overall survival was analyzed statistically.RESULTS:EUS images of 153 patients with pancreatic cancer and 63 non-cancer patients were analyzed.A total of 25 consecutive patients were enrolled,and they tolerated the brachytherapy well without any complications.There was a correlation between the change in the fuzzy classification score and overall survival(Spearman test,r=0.616,P=0.001),whereas no correlation was found to be significant between the change in tumor volume(P=0.663),CA199 level(P=0.659),and overall survival.There were 15 patients with a decrease in their fuzzy classification score after brachytherapy,whereas the fuzzy classification score increased in another 10 patients.There was a significant difference in overall survival between the two groups(67 d vs 151 d,P=0.001),but not in the change of tumor volume and CA199 level.CONCLUSION:Using the fuzzy classification method to analyze EUS images of pancreatic cancer is feasible,and the method can be used to make prognosis judgments for patients with unresectable pancreatic cancer treated by interstitial brachytherapy.     

抗抑郁药米氮平对吉西他滨治疗胰腺癌模型的辅助作用

目的 探讨抗抑郁药米氮平对吉西他滨治疗的胰腺癌移植瘤裸鼠进食量、体重和肿瘤生长的影响.方法 24只胰腺癌裸鼠皮下移植瘤模型随机分为对照组、吉西他滨组(术后第1、4、7、10天腹腔注射吉西他滨100 mg/kg体重)和联用组(吉西他滨组+米氮平10 mg·kg~(-1)·d~(-1)灌胃,持续21曲,每组8只.术后21 d处死裸鼠,比较3组动物体重、进食量、肿瘤体积的变化.结果 吉西他滨组具有显著的抗肿瘤生长作用,但存在显著的胃纳减少和体重降低等不良反应.术后第21天,联用组和吉西他滨组胰腺癌移植瘤体积无明显差异,抑瘤率分别为69.13%和71.60%(P>0.05);联用组进食量(3.12±0.11)g、体重(14.68±0.42)g,稍高于吉西他滨组的(2.96±0.14)g和(14.38±0.61)g(P值均>0.05),但显著低于对照组的(4.65±0.13)g和(17.46±0.52)g(P值均<0.05).结论 吉西他滨化疗具有显著的抗胰腺癌作用,米氮平虽无显著增效作用,但可在一定程度上减轻大剂量吉西他滨化疗的不良反应.     

Tumors and new endoscopic ultrasound-guided therapies

With the advent of linear echoendoscopes, endoscopic ultrasound (EUS) has become more operative and a new field of oncological application has been opened up. From tumor staging to tissue acquisition under EUS-guided fine-needle aspiration, new operative procedures have been developed on the principle of the EUS-guided puncture. A hybrid probe combining radiofrequency with cryotechnology is now available, to be passed through the operative channel of the echoendoscope into the tumor to create an area of ablation. EUS-guided fine-needle injection is emerging as a method to deliver anti-tumoral agents inside the tumor. Ethanol lavage, with or without paclitaxel, has been proposed for the treatment of cystic tumors in non-resectable cases and complete resolution has been recorded in up to 70%-80%. Many other chemical or biological agents have been investigated for the treatment of pancreatic adenocarcinoma: activated allogenic lymphocyte culture (Cytoimplant), a replication-deficient adenovirus vector carrying the tumor necrosis factor-α gene, or an oncolytic attenuated adenovirus (ONYX-015). The potential advantage of treatment under EUS control is the real-time imaging guidance into a deep target likethe pancreas which is extremely difficult to reach by a percutaneous approach. To date there are no randomized controlled trials to confirm the real clinical benefits of these treatments compared to standard therapy so it seems wise to reserve them only for experimental protocols approved by ethics committees.     

原位注射法建立人胰腺癌SW1990裸鼠种植瘤模型及高频内镜超声探头对其的监测

目的 建立裸小鼠人胰腺癌原位种植瘤模型,探索监测种植瘤生长的方法.方法 将对数生长期的人胰腺癌细胞株SW1990制备成细胞悬液,原位注射于Balb/c-nu裸小鼠胰腺尾部包膜下,利用高频内镜超声(EUS)探头体表观察肿瘤结节的生长及声像图像.结果 20只裸小鼠均接种成功,1只裸鼠于接种后25 d时死亡.接种后14 d,EUS检查的瘤体大小为(8.09±2.61)mm3,肿瘤结节呈均质低回声,边界清楚,周边有包膜及声晕,形态规则,30%的肿瘤结节周边可见低速环绕彩色血流信号;接种后28 d,瘤体增大至(12.40±3.51)mm3,70%的肿瘤结节呈不规则形,部分为分叶状,肿块呈低回声,不均质,未见液化坏死区,70%的肿瘤结节周边可见低速环绕彩色血流信号.结论 原位注射法是建立裸小鼠人胰腺癌原位种植瘤模型较理想的方法,操作简便,成瘤率高;高频内镜超声显像是可靠的监测胰腺原位种植瘤的手段.     

Intra-arterial continuous infusion for treatment of pancreatic and biliary tract cancer.

BACKGROUND: Systemic chemotherapy does not satisfactorily improve the poor prognosis of pancreas and biliary tract cancer unresectable or metastatic to the liver. Intra-arterial infusion of antineoplastic agents can give higher concentrations to the tumor and slighter concentrations to the whole body, with a potential of efficacy and lower toxicity, due to the hepatic clearance. METHODS: Based on a safe and ambulatorial technique of transcutaneous arterial port implantation, this study was designed to evaluate feasibility and toxicity of 5-fluorouracil (5-FU) intra-arterial continuous infusion combined with systemic gemcitabine with dose escalation. Seventeen patients affected by pancreatic (14) or biliary tract (3) cancer received up to six cycles of treatment. Treatment consisted of intravenous gemcitabine on d 1 and 8 and intra-arterial 5-FU continuous infusion on d 1-14 every 21 d. Dose-escalation levels were 900 and 1000 mg/m2 for gemcitabine and 8, 10, 12, 15, and 17 mg/kg/d for 5-FU. Consecutive cohorts of three patients were planned at each dose level. RESULTS: Gastrointestinal toxicity (vomiting and diarrhea [3rd-4th degree] and gastritis), constituted the dose-limiting toxicity, with a maximum-tolerated dose of 1000 mg/m2 for gemcitabine and 15 mg/kg/d for 5-FU. Hematological toxicity was present in a minority of patients. No patient had acute or later complications such as arterial thrombosis related to the implanted arterial port, sclerosis cholangitis, or chemical cholecistitis. CONCLUSION: 5-Fluorouracil intra-arterial continuous infusion, combined with systemic gemcitabine, seems to be a feasible and safe regimen that could give interesting results in pancreatic cancer.