Management of advanced pancreatic cancer

Each year, approximately 37,000 new patients are diagnosed with pancreatic cancer (PC) in the USA. The incidence has been increasing since the 1930s. Prognosis of PC is extremely poor. In the USA, approximately 34,000 patients die from PC each year, making it the fourth leading cause of cancer-related death in the USA. The 5-year overall survival rate for advanced pancreatic cancer is less than 5%. Poor prognosis has been attributed to the inability to diagnose, while the tumor is resectable and its propensity toward early vascular dissemination and spread to regional lymph nodes. One of the greatest challenges in the treatment of pancreatic cancer remains its inherent lack of beneficial response to cytotoxic chemotherapy. For inoperable PC, gemcitabine is the only cytotoxic agent approved by the US FDA since 1997. Several trials have evaluated whether there is any benefit for gemcitabine-based combinations, including molecular targeted agents, over gemcitabine alone. Although several of these have shown a higher response rate favoring the combined regimens, a clear benefit in overall survival has yet to be shown. Despite the benefit of gemcitabine, most patients with advanced disease still do poorly, with a median time-to-tumor progression between 2 and 3 months and median overall survival of 4–6 months. The authors review slow progress and the recent developments with newer chemotherapeutic and molecular-targeted agents in the management of pancreatic cancer.     

Folinic acid modulation of fluorouracil: tissue kinetics of bolus administration

Summary Thymidylate synthase (TS) is the enzyme target of 5-fluorouracil (FUra) that recent laboratory and clinical studies with folinic acid (calcium leucovorin) suggest may mediate important antitumor cytotoxicity. Measurement in carcinoma tissue of parameters related to TS inhibition by 5-fluorodeoxyuridylate (FdUMP), by analogy to hormone receptor analysis, should be useful to determine which patients should receive fluoropyrimidine drug therapy and to evaluate folinic acid requirements. Folinic acid is metabolized to 5,10-methylenetetrahydropteroylglutamine (CH₂FH₄), which must be present in large excess to effect desired levels of maximal inhibition of TS, by promoting formation and stabilization of TS-FdUMP-CH₂FH₄ ternary complexes. In patients with metastatic disease, serial biopsies of tumor and normal tissues for studies of pharmacodynamic responses to test-dose FUra or folinic acid are shown to be easily added to routine intraoperative management. A suitable methodologic approach is described and examples given of assays of free TS, FdUMP, dUMP, and CH₂FH₄ levels after FUra or folinic acid, that may be useful in future studies aimed at improving the cost-effectiveness of FUra-folinic acid combinations.Abbreviations TS Thymidylate Synthase (EC 2.1.1.45) - FUra 5-fluorouracil - FdUMP 5-fluorodeoxyuridylate - dUMP deoxyuridylate - CH₂FH₄ 5,10-methylenetetrahydropteroylglutamate - 5-CH₃FH₄ 5-methyltetrahydropteroylglutamate     

尼妥珠单抗联合DCF治疗晚期胃癌疗效观察

目的观察尼妥珠单抗联合DCF方案治疗晚期胃癌的近期疗效及不良反应。方法30例晚期胃癌患者随机分成治疗组和对照组。治疗组采用尼妥珠单抗联合DCF方案治疗，对照组单用DCF方案治疗。结果30例患者均可进行评价。治疗组有效率（RR）为60．0％，疾病控制率（DCR）为80．0％；对照组RR为40．0％，DCR为53．3％。两组间RR、DCR比较均无统计学差异（P〉0．05）。治疗组与对照组主要的不良反应有疲乏、白细胞减少、恶心呕吐、脱发等，两组间比较无统计学差异（P〉0．05）。结论尼妥珠单抗联合DCF方案治疗晚期胃癌安全有效，值得进一步扩大样本研究。     

胸苷磷酸化酶在进展期胃癌中的表达及其临床意义

目的　研究胸苷磷酸化酶 (TP)在进展期胃癌中的表达与癌组织的分化程度、肿瘤内微血管密度(IMVD)及 5 -氟尿嘧啶化疗患者预后的关系。方法　对 6 1例进展期胃癌标本 (患者术后均经过常规的以 5 - FU为主的化疗 )及 30例正常胃粘膜组织进行免疫组化染色测定 TP的表达情况 ;通过 CD34免疫组化染色检测胃癌组织中的IMVD。结果　胃癌细胞的 TP表达阳性率高于正常胃粘膜上皮 (P<0 .0 5 ) ;TP阳性组中 IMVD明显高于 TP阴性组(P<0 .0 0 1) ;TP表达阳性组的 5年生存率及总生存率明显高于 TP表达阴性组 (P<0 .0 5 ) ;胃癌中高、中低分化癌组之间的 TP阳性率无明显差异 (P>0 .0 5 )。结论　胃癌中 TP的表达与胃癌内血管生成及胃癌患者的预后关系密切 ;与胃癌的分化程度无关     

顺铂加5-氟脲嘧啶治疗恶性腹水的疗效观察

目的 :观察应用顺铂 (DDP)加 5 氟脲嘧啶 ( 5 FU)治疗恶性腹水效果。方法 :先将腹水尽量抽尽 ,然后将DDP 10 0mg加生理盐水 3 0 0ml、5 FU 10 0 0mg、胃复安 3 0mg、地塞米松 (DXM) 2 0mg依次注入腹腔内。结果 :40例患者中 ,CR2 4例 ( 60 %) ;PR12例 ( 3 0 %) ,总有效率 90 %。结论 :DDP加 5 FU应用治疗恶新和腹水有效率高 ,毒副反应轻 ,值得在临床上推广应用     

高效液相色谱法测定人体5-氟尿嘧啶血药浓度

目的 :以高效液相色谱法测定人血浆中5 -氟尿嘧啶的浓度。方法 :用硫酸铵作为蛋白沉淀剂 ,血浆样品用乙酸乙酯 -异丙醇(85∶15 ,V/V )提取 ,氮气吹干 ,残留物用流动相溶解后进样。色谱柱为DiamonsilC18 柱 (4 6mm×150mm ,5μm ) ,流动相为0 01mol/LKH2PO4(pH5 5) ,流速1 5ml/min ,紫外检测波长267nm ,5 -溴尿嘧啶为内标。结果 :本法最低检测浓度为0 025μg/ml ,线性范围为0 3～10μg/ml ,日内RSD≤5 0 % (n=5) ,日间RSD≤11 5 % (n=5)。结论 :本法简便、灵敏、经济 ,可作为5 -氟尿嘧啶药代动力学研究时血药浓度的测定方法。     

Effect of one session of ER:YAG laser ablation plus topical 5Fluorouracil on the outcome of short‐term NB‐UVB phototherapy in the treatment of non‐segmental vitiligo: a left–right comparative study

Background: NB‐UVB phototherapy is a very important modality in treating vitiligo but the treatment course usually exceeds 1 year. Skin ablation with mechanical dermabrasion with 5Fluorouracil (5FU) was introduced to treat vitiligo in 1983. This was modified replacing the mechanical dermabrasion by erbium‐YAG (ER:YAG) laser ablation and resulted in better prognosis in periungual vitiligo. Purpose: In the present study, we are exploring the effect of the use of ER:YAG laser skin ablation and application of 5FU on the outcome of short‐term NB‐UVB therapy for patients with non‐segmental vitiligo (NSV). Methods: This study included 50 adult patients with a total of 65‐paired symmetrical NSV lesions in different body parts. One side was treated with ER:YAG laser ablation, followed by 5FU application before simultaneous NB‐UVB therapy of both sides for a maximum period of 4 months. The outcome was then evaluated both qualitatively and quantitatively. Results: The overall response to therapy was better using the combination therapy. Fifty patients (78.1%) experienced a moderate‐marked repigmentation response in the combination group compared with 23.4% in the mono‐therapy group. The response was significantly higher when using the combination therapy in different body parts (P value is <0.05), except for feet lesions, which were better but not statistically significant (P value=0.15). Tolerable pain during ablation or at sites of 5FU application was reported in all cases. Transient hyperpigmentation occurred in 30% of cases and 3.1% of lesions healed by a transient slate blue color. Half of the treated periungual lesions showed a temporary tiny brownish spot on nail plates and Köebnerization was not detected in any patient. Conclusion: We concluded that prior use of ER:YAG laser skin ablation, followed by 5FU application before NB‐UVB phototherapy for vitiligo is a safe and tolerable technique that improves the outcome of short‐term NB‐UVB therapy and is expected to increase patient compliance.     

双模抗肿瘤光敏剂二氢卟吩e6-偕氟尿嘧啶的合成和生物活性

目的 文献报道氟尿嘧啶（5-Fu）与光敏剂联用具有协同抗肿瘤作用，笔者设计合成二氢卟吩e₆（化合物3）与5-Fu经酰腙键偶联的pH响应性、光化疗双模抗肿瘤光敏剂（化合物1），研究其初步体外光动力抗癌活性及作用机制。方法 首先，5-Fu与五硫化二磷于吡啶中回流反应形成4-硫代-5-氟尿嘧啶，再和水合肼于甲醇中反应制得5-氟尿嘧啶-4-腙（化合物2）；然后，将脱镁叶绿素a（化合物4）酸碱降解产物3经EDC·HCl催化缩合形成二氢卟吩e₆-13¹,15²-酸酐中间体后，直接与2发生选择性酰化反应，制得目标化合物1，并考察其体外pH响应性5-Fu释放及对黑素瘤B16-F10和肝癌HepG2细胞的光动力抗癌活性和作用机制。结果 化合物1在微酸（pH 5.0）环境中能有效释放5-Fu，24 h累积释放率可达60.3%；其在光照下对黑素瘤B16-F10和肝癌HepG2细胞的半数抑制浓度（IC₅₀）分别为0.73 μmol/L和0.90 μmol/L，均显著优于先导物3和上市药物他拉泊芬（talaporfin），且能显著提升肿瘤细胞内活性氧（ROS）水平和诱导肿瘤细胞凋亡，并阻滞肿瘤细胞周期于S期。其结构经紫外、电喷雾质谱、氢谱和元素分析确证。结论 新型双模抗肿瘤光敏剂化合物1具有光动力抗癌活性强、治疗指数（暗毒/光毒比）高，且可在微酸（pH 5.0）环境响应性释放5-Fu等优点，从而实现“单分子”光化疗双重抗肿瘤作用，值得进一步开发研究。