吉西他滨与胰腺癌化疗耐药

目的探讨胰腺癌对吉西他滨化疗产生耐药性的相关机理。方法复习近年国、内外相关文献，对介导胰腺癌吉西他滨耐药性的主要基因及信号通路加以综述。结果癌基因c—Src与bcl—X1、NF-κB炎症信号通路、细胞因子IL-1β及NO等与介导胰腺癌对吉西他滨的耐药性密切相关；多药耐药基因MDR1／P-gP与胰腺癌吉西他滨耐药的相关性仍有待研究。结论癌基因c—Src与bcl—X1、NF-κB炎症信号通路等可能成为新的治疗靶点以增加胰腺癌的化疗敏感性；介导胰腺癌化疗耐药的关键基因与中心信号通路尚有待阐明。     

Docetaxel/Gemcitabine Followed by Gemcitabine and External Beam Radiotherapy in Patients With Pancreatic Adenocarcinoma

Background Pancreatic cancer remains highly lethal. Previous attempts with neoadjuvant therapy in this disease have been inconclusive, but a potential for benefit exists. We conducted a phase II trial of dose-intense docetaxel and gemcitabine followed by twice-weekly gemcitabine and external beam radiotherapy in patients with pancreatic adenocarcinoma. Methods Patients with stage I to III disease were eligible. Docetaxel 65 mg/m² intravenously over 1 hour and gemcitabine 4000 mg/m² given intravenously over 30 minutes were given on days 1, 15, and 29. On day 43, radiotherapy was begun at 50.4 Gy with gemcitabine 50 mg/m² intravenously over 30 minutes twice weekly for 12 doses. After treatment, patients were considered for resection. Results Twenty-four assessable patients were recruited onto the trial. All but one patient completed a full 12 weeks of therapy. Grade 3 and 4 hematological and nonhematological toxicities were common but manageable, and neutropenic fever did not occur. No patient had local tumor progression. Twelve patients (50%) responded by Response Evaluation Criteria in Solid Tumors Group (RECIST) criteria, including one radiographic complete response. Seventeen patients underwent resection after therapy. Margin-negative resections were performed in 13 patients, including 9 patients whose disease was borderline or unresectable before treatment. A treatment effect was seen in all resection specimens. There have been no local recurrences of tumor, and several patients remain alive without evidence of disease. Conclusions Docetaxel/gemcitabine followed by gemcitabine/radiotherapy is active in the treatment of pancreatic adenocarcinoma, with manageable toxicity. Tumor downstaging occurs in some patients to allow complete resection. Further investigation of this regimen is warranted. M.A.B. is now at Wake-Forest University Baptist Medical Center, Winston-Salem, North Carolina; J.M.C. is now at Vanderbilt University, Nashville, Tennessee.     

A Randomized Phase 2 Trial of Neoadjuvant Chemotherapy in Resectable Pancreatic Cancer: Gemcitabine Alone Versus Gemcitabine Combined with Cisplatin

Background Survival after surgery for pancreas cancer remains low. This improves with adjuvant chemotherapy, but up to 30% patients do not receive the prescribed treatment. Neoadjuvant therapy may increase the proportion of patients who receive all treatment components, may downstage disease before surgery, and may provide early treatment of micrometastases. This randomized phase 2 study compares gemcitabine-based chemotherapy regimens to identify the most promising regimen for future study. Methods Fifty patients with potentially resectable pancreas lesions were enrolled onto the study. Twenty-four patients were randomized to gemcitabine (1000 mg/m²) every 7 days for 43 days; 26 patients were randomized to gemcitabine (1000 mg/m²) and cisplatin (25 mg/m²), 7 to the original schedule (omitting day 22) and 19 to a revised schedule due to neutropenia (omitting days 15 and 36). The primary outcome measure was resection rate. Results Patients who were allocated to gemcitabine received a median of 85% of the planned dose. Patients who were allocated to combination treatment received a median of 88% and 92% of the planned gemcitabine and cisplatin doses, respectively. There were 10 episodes of grade III/IV hematological toxicity in each group. Twenty-seven patients (54%) underwent pancreatic resection, 9 (38%) in the gemcitabine arm and 18 (70%) in the combination arm, with no increase in surgical complications. To date, 34 patients (68%) have died. Twelve-month survival for the gemcitabine and combination groups was 42% and 62%. Conclusions Chemotherapy can be safely administered before pancreatic surgery. Combination therapy with gemcitabine and cisplatin is associated with a high resection rate and an encouraging survival rate, suggesting that further study is warranted.     

A Multi-Institutional Phase II Trial of Preoperative Full-Dose Gemcitabine and Concurrent Radiation for Patients With Potentially Resectable Pancreatic Carcinoma

Background We report the results of a multi-institutional phase II trial that used preoperative full-dose gemcitabine and radiotherapy for patients with potentially resectable pancreatic carcinoma. Methods Patients were treated before surgery with three cycles of full-dose gemcitabine (1000 mg/m² intravenously), with radiation during the second cycle (36 Gy in daily 2.4-Gy fractions). Patients underwent surgery 4 to 6 weeks after the last gemcitabine infusion. Results There were 10 men and 10 women, with a median age of 58 years (range, 50–80 years). Nineteen patients (95%) completed therapy without interruption, and one experienced grade 3 gastrointestinal toxicity. The mean weight loss after therapy was 4.0%. Of 20 patients taken to surgery, 17 (85%) underwent resections (16 pancreaticoduodenectomies and 1 distal pancreatectomy). The complication rate was 24%, with an average length of stay of 13.5 days. There were no operative deaths. Pathologic analysis revealed clear margins in 16 (94%) of 17 and uninvolved lymph nodes in 11 (65%) of 17 specimens. One specimen contained no residual tumor, and three specimens revealed only microscopic foci of residual disease. With a median follow-up of 18 months, 7 (41%) of the 17 patients with resected disease are alive with no recurrence, 3 (18%) are alive with distant metastases, and 7 (41%) have died. Conclusions Preoperative gemcitabine/radiotherapy is well tolerated and safe when delivered in a multi-institutional setting. This protocol had a high rate of subsequent resection, with acceptable morbidity. The high rate of negative margins and uninvolved nodes suggests a significant tumor response. Preliminary survival data are encouraging. This regimen should be considered in future neoadjuvant trials for pancreatic cancer.     

吉西他滨联合伊立替康一线治疗晚期胰腺癌随机对照试验的Meta分析

目的 通过Meta分析,探讨吉西他滨联合伊立替康治疗晚期胰腺癌的地位和价值。方法 通过MEDLINE、EMBASE、ASCO论文集等数据库检索国内外已发表和未发表的相关文献。选择治疗组为吉西他滨联合伊立替康化疗,对照组为吉西他滨单药化疗的晚期胰腺癌随机对照试验（randomized controlled trial,RCT）。由2位评价者分别按上述检索策略收集资料,按纳入标准入选,主要对总生存率进行Meta分析,其次是客观缓解率和毒副反应。结果 共纳入3个RCT。吉西他滨联合伊立替康化疗与吉西他滨单药化疗比较,前者半年生存率及一年生存率均无差别（P值分别为0.88,0.97）,客观缓解率提高9%（P=0.0009）;同时WHO3/4度骨髓毒性（除中性粒细胞减少症外）及非骨髓毒性可能增加：血小板减少症增加2%（P=0.46）、贫血增加1%（P=0.58）,恶心/呕吐增加6%（P=0.34）、腹泻增加10%（P=0.10）,但均未取得统计学意义。结论 现有证据不推荐吉西他滨联合伊立替康一线治疗晚期胰腺癌。     

ATP生物荧光肿瘤药敏检测技术在胰腺癌中的应用

目的探讨ATP肿瘤化疗药敏实验（ATP tumor chemosensitivity assay，ATP—TCA）对胰腺癌化疗药敏测定并指导临床个性化治疗的可行性。方法2003年～2006年，采用ATP—TCA法对40例胰腺癌进行药敏检测。结果对胰腺癌未发现强敏感药物和部分敏感药物，轻度敏感的药物有：吉西他滨（GEM），氟尿嘧啶（5-FU），紫杉醇（PTX），奥沙利铂（OXA）；耐药的药物有：卡铂（DDP），表柔比星（EPI），长春瑞滨（NVB），丝裂霉素（MMC），拓扑替康（TPT），卡莫司汀（BCNU），多西他赛（TXT）。结论ATP—TCA法对胰腺癌进行药敏检测是可行的，但尚未发现胰腺癌强敏感和部分敏感的药物；ATP—TCA法指导胰腺癌个体化治疗的临床疗效有待进一步观察。     

动态监测CA19-9对判断胰腺癌术后病人预后的意义

探讨CA19-9动态变化在判断胰腺癌术后病人预后中的意义。方法：选择术前CA19-9显著升高的胰腺癌病例,对其CA19-9在术后进行动态检测并结合其临床表现和影像学结果,以判断CA19-9高低是否与肿瘤复发或转移有关。结果：术前CA19-9升高的胰腺癌病人,术后CA19-9均降至正常,但术后动态观察发现CA19-9出现再次升高者,其临床表现和影像学结果往往提示有肿瘤的复发或转移;而CA19-9稳定者则无肿瘤复发或转移的临床表现或影像学证据。结论：对于术前CA19-9升高的胰腺癌病人,术后降至正常而后又出现反跳者,往往提示胰腺癌术后有肿瘤复发或远处转移,CA19-9动态监测为临床判断胰腺癌综合治疗措施疗效的一个重要方法。     

Successful Resection of Advanced Pancreatic Tail Cancer After Neoadjuvant Gemcitabine Chemotherapy: Report of a Case

Pancreatic cancer with distant metastasis is not an indication for surgery, and the median survival of these patients is less than 3 months. We report the case of a patient who has survived for 21 months without any signs of recurrence after resection of advanced pancreatic cancer following a course of chemotherapy with gemcitabine (GEM). A 75-year-old man was hospitalized for anorexia and emaciation. Examinations showed pancreatic cancer with distant peritoneal metastasis. After the main tumor and metastasis had been shrunk by GEM chemotherapy, we performed distal pancreatectomy combined with splenectomy. Microscopically, the main tumor was confirmed as moderately differentiated tubular adenocarcinoma with interstitium and fibrosis. The radicality of the surgery was R0, according to the TNM classification of the UICC. The patient recovered well and has had no clinical symptoms for 40 months since the initial chemotherapy. This case suggests that multidisciplinary treatment with GEM may prolong the survival of some patients with unresectable pancreatic cancer.     

Results of Regional Chemotherapy Using the Aortic Stop-Flow Technique in Advanced Pancreatic Carcinoma

Purpose Systemic palliative chemotherapy provides only a disappointing response and almost no prolongation of the survival time in patients with pancreatic carcinoma. Isolated perfusion may lead to a higher concentration of cytostatics within the target tissue, which can be associated with a high response rate and longer survival in addition to a low rate of side effects. The aim of the study was to investigate the feasibility of the aortic stop-flow technique using commercially available tools in patients with advanced pancreatic carcinoma. Methods Seventeen patients with either unresectable or metastasized pancreatic carcinoma (diagnosed by histologic investigation) were enrolled in the study. In total, a 20-min hypoxic perfusion of the isolated abdominal compartment with 20 mg/m² of mitomycin C (Medac, Hamburg, Germany) was carried out 22 times. The cytostatic concentration was determined intrainterventionally within the systemic and regional compartment. The tumor response was assessed using computed tomography and a tumor marker (CA19-9) every 4 weeks. Results While 12 patients underwent one cycle, in 5 patients two complete perfusions were performed. Mitomycin C concentration was 10-fold higher within the regional compared with the systemic compartment at its maximum. The area under the curve (AUC) was 4.02 times larger. The degree of toxicity was considerable: World Health Organization grade I/II in 8/17, III/IV in 9/17 cases. Three treatment-related deaths were documented. The objective response rate was 17.6% (3 of 17 cases; 1 complete remission [CR], 2 partial remissions [PR]). In 3 subjects, a stable disease (SD) and in 11 individuals tumor progression (PD) was registered. The median survival was 4.1 months. Conclusion The aortic stop-flow technique was associated with a high toxicity rate but no improvement in the tumor response and survival was seen in comparison to the systemic chemotherapy of the historical group. Despite detectable pharmacokinetic advantages, the aortic stop-flow technique is therefore not considered to be feasible for palliative chemotherapy in patients with pancreatic carcinoma for routine use.     

Gd-DTPA 3D FSPGR MR动态增强在胰腺癌诊断和术前可切除性评估中的价值

目的探讨钆喷酸葡胺三维快速扰相梯度回波(Gd-DTPA 3D FSPGR)MR动态增强成像在胰腺癌诊断和术前可切除性评估中的价值。方法32例经手术病理证实的胰腺癌，手术前2周行MRI检查。MRI序列包括脂肪抑制梯度回波T1W(GRET1W)、快速自旋回波呼吸门控脂肪抑制T2W(FSERGT2W)、单次激发快速自旋回波T2W(SSFSE T2W)、单次激发自旋快速回波MRI胰胆管成像(MRCP)和Gd—DTPA 3DFSPGR MRI动态增强。回顾性分析胰腺癌的MRI征象，根据肿瘤病灶特征、局部侵犯、血管受累和转移情况进行可切除性评估，并与手术结果对照分析。结果32例中MRI正确诊断29例，准确率达90．6％。肿块检出率：脂肪抑制GRET1W FSE RG T2W序列为84．4％(27／32)．Gd—DTPA 3D FSPGR动态增强成像为93．8％(30／32)。MRI动态增强成像对胰周血管受累、胰周侵犯评价准确性分别为87．0％(20／23)、87．5％(21／24)；对淋巴结、肝脏转移和腹膜癌变诊断准确性分别为80．0％(12／15)、88．9％(8／9)及83．3％(5／6)。3DFSPGR动态增强MRI认为手术可切除8例，实际术中切除7例；24例认为不可切除，实际手术不可切除23例；判断胰腺癌可切除的敏感性、特异性及准确性分别为87．5％、95．8％及93．8％。结论Gd-DTPA 3D FSPGR MR动态增强成像提高了胰腺癌的肿瘤病灶及转移灶的检出和定性诊断，评价胰周侵犯和胰周血管受累情况准确性高，判断其手术可切除性准确率亦高。MRI动态增强对胰腺癌的诊断和术前可切除性评估具有重要的临床参考价值。     

HIFU联用双氟他滨治疗晚期胰腺癌的初步临床研究

目的 初步探讨高强度体外聚焦超声(High intensity focused ultrasound,HIFU)热疗联用双氟他滨治疗晚期胰腺癌的疗效及安全性。方法 29例患者符合入组条件。治疗组15例接受HIFU及双氟他滨治疗,对照组14例仅予双氟他滨化疗。两组病例一般临床资料分布均衡。结果 治疗组有效率33.3％,对照组14.3％(P=0.390);临床受益反应率(ClinicalBenefit Respeonse,CBR)80.0％,高于对照组28.6％(P=0.016);中位生存期两组分别为26周和25周(P=0.4962),两组毒副作用轻微,3/4度血小板减少发生率相似(23.7％vs20.8％,P=0.666)。结论 HIFU联用双氟他滨治疗晚期胰腺癌能取得较好的疗效,治疗安全性高,值得临床进一步观察研究。     

Resection of a Solitary Pancreatic Metastasis from Renal Cell Carcinoma with a Gallbladder Carcinoma: Report of a Case

Most metastatic pancreatic tumors are detected at an advanced stage and are not considered suitable for surgery; however, resection is sometimes indicated for a solitary pancreatic metastasis from renal cell carcinoma (RCC) and improves the prognosis. We report such a case, in which the hilar liver was resected with lymph node dissection and distal pancreatectomy. Histological examination revealed regional lymph node metastasis of gallbladder carcinoma (GBC), but all the surgical margins were free of cancer. Postoperative extra-beam radiation therapy was delivered to the hepatic portal lesion to prevent GBC recurrence. The patient remains disease-free 14 months after the completion of radiation therapy. Thus, if all affected areas can be resected, the prognosis associated with pancreatic metastasis from RCC may be favorable.     

胰腺癌患者外周血中树突状细胞的分离、纯化与扩增

目的 探讨从胰腺癌患者外周血中分离、纯化与扩增树突状细胞（DC）的有效方法。方法 分别从健康人（10例，对照组）和胰腺癌患者（12例，实验组）外周血中分离出单核细胞，而后将实验组的单核细胞与GM－CSF及IL－4共同培养，用免疫荧光法和流式细胞仪检测培养前、后的DC数量及DC表面HLA－DR及B7－2的表达水平，并与对照组比较。结果 与对照组相比，实验组DC表面HLA－DR及B7－2表达水平较低（P＜0.01）；经GM－CSF及IL－4联合培养7天后，其单核细胞中的DC数较培养前明显增多（P＜0.01），且DC表面HLA－DR及B7－2表达水平较培养前明显增高（P＜0.01），与对照组相比则无明显差异（P＞0.05）。结论 GM－CSF与IL－4的联合应用能有效地从胰腺癌患者外周血中制备出大量具有功能活性的DC。     

磁共振血管成像术前判断胰腺癌侵及血管程度的价值

探讨磁共振血管成像术对胰腺癌侵及血管的判断。方法：对胰腺癌术前进行磁共振血管成像检查并对病灶与门静脉血管进行分级判断,将其与术中发现或病理结果相对照。结果：根据磁共振血管成像将肿瘤与门静脉血管关系分为０级２例;Ｉ级３例,Ⅱ级３例,Ⅲ级２例;其中行根治术者３例,根治切除并血管重建４例,内引流术３例。结论：术前磁共振血管成像可提供可靠的肿瘤与门静脉血管关系的影像学资料,对指导手术选择有重要价值。     

胰腺癌预后相关因素的分析研究

目的研究胰腺癌临床相关因素与预后的关系.方法：回顾性分析115例胰腺癌患者相关临床资料,进行是否影响预后的单因素方差分析,符合条件的纳入Cox比例风险模型进行多因素分析.结果：胰腺癌患者的预后与性别、糖尿病史、胰腺炎病史、肿瘤家族史、肿瘤部位、CA19-9异常无明显相关（P〉 0.05）;而与初诊原因、肿瘤大小、临床分期、胰周侵犯、远处转移、治疗方法、CEA是否异常有关（P〈 0.05）.其中初诊原因、肿瘤分期、胰周侵犯、远处转移、治疗方法与预后关系最密切（P〈 0.01）.结论：早期发现、根治性手术是改善胰腺癌预后最关键因素,TNM临床分期是判断预后的最可靠依据,血清CEA可评价胰腺癌疾病进展程度.     

Phase 2 Trial of Gemcitabine,Cisplatin, plus Ipilimumab in Patients with Metastatic Urothelial Cancer and Impact of DNA Damage Response Gene Mutations on Outcomes

Background

Chemotherapy may exert immunomodulatory effects, thereby combining favorably with the immune checkpoint blockade. The pharmacodynamic effects of such combinations, and potential predictive biomarkers, remain unexplored.

CD10基因表达与胰腺神经内分泌癌诊断

目的为研究CD10与胰腺神经内分泌癌的关联性,探讨CD10在胰腺神经内分泌癌中的表达情况。方法采用免疫组织化学方法,检测28例胰腺神经内分泌癌和10例正常胰腺组织中CD10的表达,分析CD10在胰腺神经内分泌癌中的表达情况。结果胰腺神经内分泌癌中CD10的表达率为82.13%,明显高于正常对照阴性组（P〈0.05）。结论胰腺神经内分泌癌可能存在着CD10的高表达,这种高表达也许能够成为胰腺神经内分泌癌的诊断指标之一。     

肛管鳞癌的诊断与治疗(附15例分析)

目的探讨肛管癌诊断、治疗和预后的相关因素。方法北京医院1984-1998年间收治15例肛管鳞癌,首次诊断为肛管癌者仅5例。15例中行放疗化疗11例,8例行Miles手术。结果病理均证实为鳞癌。根据NCCN(2003年)分期,Ⅰ期6例,Ⅱ期4例,ⅢA期2例,ⅢB期3例。免疫组织化学染色显示肿瘤组织间质纤维化(+++)者4例,(++)者7例,(+)者4例。随诊最长10年,平均生存期(47±27.6)个月。结论肛门指诊是发现和诊断肛管癌的重要手段。放疗以及以放疗为主,化疗、手术为辅的综合治疗是肛管癌的主要治疗方法。肿瘤分期、腹股沟淋巴结转移、治疗方法以及肿瘤组织间质纤维化对病人的预后均有影响。     

Gemcitabine plus vinorelbine chemotherapy in patients with advanced bladder carcinoma who are medically unsuitable for or who have failed cisplatin-based chemotherapy

Objective: To evaluate the efficacy and toxicity of gemcitabine plus vinorelbine chemotherapy in patients with advanced bladder carcinoma who are unsuitable for or who have failed cisplatin-containing chemotherapy.Patients and Methods: Thirty-one patients with advanced transitional cell carcinoma (TCC) of the bladder were scheduled to receive gemcitabine and vinorelbine chemotherapy. Twenty-one patients had received no prior chemotherapy and their creatinine clearance was below 50 ml/min (group 1), and the remaining 10 patients did not respond to previous cisplatin-containing chemotherapy (group 2).Results: In group 1, objective response rate was 47.6%, including 2 (9.5%) complete and 8 (38.9%) partial responses. In group 2, partial response was observed in 2 (20%) patients. The median survival time for patients in group 1 and 2 were 15 months (range 3–23) and 7 months (range 3–21), respectively. Grades 3 or 4 leukopenia developed in 16.1% of patients. Overall, 12.9% of the patients suffered from grade 3 nonhematologic toxicity.Conclusion: Our preliminary data indicate that the combination of gemcitabine and vinorelbine is active and well tolerated especially in patients with advanced TCC who are unsuitable for cisplatin-based chemotherapy.     

The effect of adjuvant and neoadjuvant chemo(radio)therapy on survival in 1,679 resected pancreatic carcinoma cases in Japan: report of the national survey in the 34th annual meeting of Japanese Society of Pancreatic Surgery

Background  Pancreatic carcinoma causes more than 20,000 deaths every year in Japan. The role of (neo-) adjuvant chemotherapy for pancreatic carcinoma is still controversial. Methods  At the 34th Annual Meeting of the Japanese Society of Pancreatic Surgery in 2007, questionnaires were distributed regarding the use of (neo-) adjuvant chemo(radio)therapy for pancreatic carcinoma between 2001 and 2005. Results   Sixty of the 146 member institutions responded to the questionnaires. There were a total of 1,846 cases of resected pancreatic carcinoma between 2001 and 2005. The study population had a greater proportion of males, and a mean age of 65.3 years (range 34–90 years). The lesion was located in the head of the pancreas in 1,204 cases (71.7%), in the body in 353 cases (21.0%), and in the tail in 111 cases (6.6%). Overall survival rates were 67.3% at 1 year, 36.0% at 2 years, and 23.9% at 3 years, respectively. Adjuvant chemotherapy (usually involving gemcitabine) was used in 66.0% of cases. The use of adjuvant chemotherapy was found to improve the overall survival rate. Interestingly, adjuvant chemotherapy only improved survival in late-stage (UICC stages IIB, III, and IV) but not early stage (IA, IB, and IIA) patients. Survival was treatment duration-dependent, with patients who received more than 12 months of therapy having a 3-year survival rate of 51.2%. Conclusion  This high volume retrospective data indicated the promising effect of gemcitabine-based adjuvant chemotherapy and the rational duration of adjuvant chemotherapy should be determined in the future prospective studies.