直肠癌Duke’s B_2,C_1,C_2期术后放射治疗的价值

目的　探讨直肠癌Duke’sB2 ,C1,C2 期术后放射治疗的价值。方法　我院在 1992年 1月至1998年 3月期间收治 10 5例Duke’sB2 ,C1,C2 期直肠癌患者 ,将其随机分为两组 :单纯手术组 5 5例 ,术后放疗组 5 0例。采用60 Co体外等中心放疗 ,瘤床DT 5 0～ 5 5Gy/ 5～ 6周 ,亚临床病灶DT 4 0Gy/ 4周。 结果　术后放疗组和单纯手术组 5年生存率B2 ,C1,C2 期分别为 :81 8%、6 0 0 % (P >0 0 5 ) ;6 1 5 % ,32 5 % (P <0 0 5 ) ;38 7% ,11 7% (P <0 0 5 )。 5年局部复发率 :术后放疗组和单纯手术组B2 ,C1,C2 期分别为 18 2 % ,33 3% (P >0 0 5 ) ;17 4 % ,6 4 0 % (P <0 0 1) ;2 5 0 % ,6 6 7% (P <0 .0 1)。远处转移率 :术后放疗组 10 0 % ,单纯手术组 2 7 3% (P >0 .0 5 )。结论　Duke’sB2 ,C期直肠癌根治术后根治性放疗可以提高长期生存率 ,降低局部复发率     

手术联合放疗治疗直肠癌疗效观察

目的观察直肠癌手术联合术前、术后放疗的临床疗效。方法 92例（A组）,术前给予快速超分割照疗,DT15Gy/6f/3d后手术,术后根据病理推量照射,DT35～40Gy/3.5～4周;手术加术后放疗组98例（B组）,Miles术后行常规盆腔照射DT50Gy/25f/5周;单纯Miles手术70例（C组）。结果随访率96.4%。局部复发率A组5.4%（5/92）,B组16.3%（16/98）,C组64.3%（45/70）,差异有统计学意义（P〈0.05）;远处转移率：A组6.5%（6/92）,B组28.6%（28/98）,C组31.4%（22/70）（P〈0.01）。3年生存率：A组86.9%（80/92）,B组62.2%（61/98）,C组51.4%（36/70）（P〈0.01）;5年生存率：A组68.5%（64/92）,B组54.1%（54/98）,C组41.4%（29/70）（P〈0.05）。A组、B组Ⅰ,Ⅱ级放射性肠炎发生率分别为7.6%（7/92）和6.1%（6/98）（P〉0.05）。结论手术加术前、术后放疗疗法能降低Ⅱ,Ⅲ期直肠癌的局部复发率,提高3、5年生存率。     

低位直肠癌术后辅助放疗的临床研究

目的:探讨手术后辅助放射治疗对低位直肠癌局部复发的影响.方法:72例低位直肠癌患者,分为单纯手术组和术后放疗组各36例.术后放疗组于术后半个月行三维适形调强放疗方法分割照射治疗,照射总剂量为5 000 cGy.比较两组的局部复发率.结果:随访4年,术后放疗组和单纯手术组肿瘤局部复发率分别为13.3%和30.6%(P＜0.05).结论:对低位直肠癌患者,术后进行辅助放疗有助于降低肿瘤局部复发.     

241例直肠癌临床分析

目的 :探讨直肠癌预后的因素。方法 :通过回顾分析我院1985年1月～1997年12月收治的241例直肠癌的5年生存率 ,并研究其影响因素。结果 :总5年生存率为43 2% ,Dukes'A、B、C、D期的5年生存率分别为71 4%、63 2 %、32 2 %、0;肿瘤距肛门≥7cm的5年生存率为52 % ,<7cm的生存率为38 5% ,两组差异有显著性 (P<0 05) ;不同病理类型的5年生存率差异有显著性(P<0 05) ;DuckesB、C期组病例单纯手术、术后放疗、术后化疗、术后放化疗组的5年生存率分别为45 5 %、38 9%、61 %、44 4 % ,术后放、化疗与单纯手术5年生存率比较差异无统计意义 ;B、C期组术后5年局部复发率和转移率分别为25 8 %、38 4 % ,术后放疗与单纯手术比较可能降低局部复发率 (16 7 % :30 3% ) ,而术后化疗组与单纯手术组比较能降低远处转移率 (26 8 % :45 5 % ) ,两者差异有显著性 (P<0 05)。结论 :临床分期、肿瘤距肛门距离、病理类型是影响直肠癌5年生存率的重要因素 ,术后化疗能降低远处转移率 ,术后放疗可能减少局部复发率     

32例局部晚期直肠癌患者术前放疗的临床疗效分析

目的观察局部晚期直肠癌术前放疗的临床疗效。以降低直肠癌的局部复发率,提高生存率。方法选择我院64例直肠癌患者,采用随机分组,其中治疗组32例行术前放疗,采用6MvX线加大分割的三维适形放疗,DT：46Gy/20f,放疗结束后5周手术。对照组32例行单纯手术治疗。比较两组治疗效果。结果手术切除率放疗组84.3%、手术组为62.5%,差异有统计学意义（P〈0.05）。结论局部晚期直肠癌术前放疗可降低局部复发率,提高手术切除率,改善患者的生活质量,取得满意临床疗效,值得临床推广应用。     

术前同步放化疗在Ⅱ B期宫颈癌患者中的临床研究

目的 探讨Ⅱ B期宫颈癌患者术前同步放化疗的可行性及疗效.方法 回顾性分析56例ⅡB期宫颈癌患者的治疗过程.按照治疗方式的不同分为2组,术前同步放化疗组(26例)和单纯放疗组(30例),比较2组患者不良反应及远期疗效.结果 与单纯放疗组比较,同步放化疗组骨髓抑制发生率、恶心及呕吐发生率高于单纯放疗组(P＜0.05),但经过对症处理,不影响治疗进程.与单纯放疗组比较,术前同步放化疗组3年的局部复发率明显降低,3年生存率提高(P＜0.05),而1年的局部复发率、1年生存率两组无明显差异.结论 Ⅱ B期宫颈癌患者术前行同步放化疗可降低肿瘤复发率,提高3年生存率.     

术后辅助化疗联合免疫治疗在ⅢB及ⅢC期结直肠癌患者术后的应用效果分析

目的:回顾性分析术后辅助化疗联合免疫治疗在ⅢB及ⅢC期结直肠癌患者术后的应用效果。方法:选取ⅢB及ⅢC期结直肠癌根治术患者235例,均接受术后辅助化疗。按是否接受免疫治疗差异分为单一辅助化疗组(n=112)和化疗联合免疫组(n=123)。对比分析两组患者术后3年无病生存期、总生存期及不良反应事件。结果:化疗联合免疫组的第1、2、3年及3年总无病生存率、病灶转移率及局部复发率均低于单一辅助化疗组(P0.05);化疗联合免疫组患者的总生存期明显长于单一辅助化疗组(P0.05);在化疗联合免疫组123例患者中,免疫治疗频次4周患者的术后无病生存率(55.56%)和术后生存率(66.67%)均显著低于免疫治疗频次≥4周患者的术后无病生存率(79.10%)和术后生存率(82.61%)(P0.05)。结论:术后辅助化疗联合免疫治疗不仅可显著降低患者治疗期间的不良反应事件发生率,而且可显著提升ⅢB及ⅢC期结直肠癌患者的3年无病生存期、总生存期。     

腹腔镜下经肛门括约肌间切除超低位直肠癌 158例分析

目的探讨腹腔镜下部分切除、次全切除及完全切除经肛门括约肌间切除术(Intersphincter resection,ISR)术式对 Ⅰ～Ⅲ期超低位直肠癌病人肛门功能、安全性及生存结局的影响。方法回顾性分析达州市中心医院 2013年 1月至 2016年 1月收治 Ⅰ～Ⅲ期超低位直肠癌病人共 158例临床资料,根据手术方案不同分为 A组(54例)、 B组(70例)及 C组(34例),分别采用腹腔镜下部分切除、次全切除及完全切除 ISR术式治疗;比较三组围手术期临床指标,术后肛门功能相关指标、吻合口相关并发症发生率及随访结局指标。结果三组手术时间、术中出血量、淋巴结清扫数目及术后住院时间比较差异无统计学意义(P＞0.05);三组术后排便急迫率、止泻药物依赖率、失禁率、 Wexner失禁评分及 Kinwan失禁分级比较差异无统计学意义(P＞0.05);三组术后吻合口周围黏膜缺血、吻合口瘘、直肠阴道瘘及直肠坏死发生率比较差异无统计学意义(P＞0.05); A组、 B组及 C组术后吻合口慢性狭窄发生率分别为 9.26%,10.00%,29.41%(P＜0.05);三组术后复发率、 3年无病生存率及无局部复发生存率比较差异无统计学意义(P＞0.05)。结论腹腔镜下部分切除、次全切除及完全切除 ISR术式治疗 Ⅰ~Ⅲ期超低位直肠癌在术后肛门功能保护和生存结局方面均较为接近;但完全切除 ISR术式应用可能增加术后吻合口慢性狭窄发生风险。     

食管癌根治性放疗后复发患者手术和再放疗效果

目的 比较食管癌根治性放疗后复发患者行手术和再放疗效果.方法 食管癌根治性放疗后复发患者57例中,手术治疗23例(A组),再放疗34例(B组).比较两组的并发症和生存率.结果 A组术后并发吻合口瘘1例,肺部感染3例;B组再放疗后并发食管穿孔1例,食管气管瘘2例.A组3年复发率低于B组(43.5% vs.82.4%,P＜0.05).A组1、2、3年无病生存率分别为56.5%、34.8%、26.1%,明显高于B组的41.2%、20.6%、8.8%(P＜0.05).但两组1、2、3年总生存率相仿.结论 食管癌根治性放疗后复发患者可考虑手术治疗,能提高无病生存率.     

38例高分级脑胶质瘤术后残留放疗联合替莫唑胺化疗的临床观察

目的：观察高分级脑胶质瘤患者术后放疗联合替莫唑胺化疗的疗效。方法38例经病理证实为高分级脑胶质瘤患者随机分为观察组（A组）和对照组（B组）,Ⅲ级18例,Ⅳ级20例。 A组：替莫唑胺化疗联合放疗（Ⅲ级9例,Ⅳ级11例）,给予放疗肿瘤剂量（DT）60Gy,并于DT20Gy后行同步替莫唑胺化疗,28d为1个周期,于放疗开始后4-6个月内完成4-6周期的化疗。 B组：给予术后单纯放疗肿瘤剂量（DT）60Gy（Ⅲ级9例,Ⅳ级9例）。结果高分级脑胶质瘤患者总的中位生存期（MST）为17.1个月,1、2、3年生存率分别为76.32%、52.63%、13.16%。 B组与A组中位生存期分别为14.0个月、19.8个月,B组1、2、3年生存率分别为66.67%、33.33%、11.11%;A组为85.00%、70.00%、15.00%,近期缓解率A组明显优于B组,2年生存率有显著统计学（P〈0.05）,但3年生存率无统计学意义。A组常见不良反应为Ⅰ、Ⅱ度恶心、呕吐、白细胞和血小板下降,经对症处理后迅速缓解,副反应可以耐受。结论高分级脑胶质瘤术后放疗联合替莫唑胺化疗较单纯放疗可显著提高患者生存率,副反应可以耐受。     

Polymorphism of CYP2D6, CYP2C19, CYP2C9 and CYP2C8 in the Faroese population

Objective The purpose of the study was to study the distribution of poor and extensive metabolizers of CYP2C19 and CYP2D6 and to genotype for CYP2C8 and CYP2C9 among 312 randomly selected Faroese.Methods and results The participants were phenotyped for CYP2D6 with the use of sparteine. The distribution of the sparteine metabolic ratio (sparteine/didehydrosparteines) was bimodal, and 14.5% (n=44; 95% CI: 10.7–18.9%) of the subjects were phenotyped as poor metabolizers. The frequency of poor metabolizers was higher (P=0.0002; ² test) among the Faroese than in other European populations (7.4%). Genotype analyses for the CYP2D6*3, *4, *6 and *9 alleles were performed using real-time polymerase chain reaction (PCR) (TaqMan, Foster City, CA, USA), and we found 14.6% (n = 45) (95% CI: 10.8–19.0%) with deficient CYP2D6 genes (*3/*4, *4/*4, *4/*6, *6/*6) in the Faroese population. The subjects were phenotyped for CYP2C19 with the use of mephenytoin and 10 subjects, i.e., 3.2% (95% CI: 1.6–5.9%) were phenotyped as poor metabolizers. Genotype analysis for the CYP2C19*2 and *3 alleles was performed by means of PCR analysis, and 2.9% (n=9) (95% CI: 1.3–5.4%) of the Faroese were found to have a deficient CYP2C19 gene all explained by the CYP2C19*2/*2 genotype. The allele frequencies of the CYP2C9*2 and CYP2C9*3 alleles were 8.8% (95% CI: 6.7–11.4%) and 5.3% (95% CI: 3.7–7.4%), respectively, while the CYP2C8*3 allele frequency was 6.9% (95% CI: 5.0–9.2%). Real-time PCR (TaqMan) was used for both CYP2C9 and CYP2C8 genotype analyses.Conclusion The frequency of CYP2D6 poor metabolizers is twofold higher among the Faroese population than other Caucasians, while the frequencies of Faroese subjects with decreased CYP2C19, CYP2C8 and CYP2C9 enzyme activity are the same as seen in other Caucasian populations. A possible consequence might be a higher incidence of side effects among Faroese patients taking pharmaceuticals that are CYP2D6 substrates.     

Monoclonal antibodies specific and inhibitory to human cytochromes P450 2C8, 2C9, and 2C19.

Hybridomas were isolated that produce 13 monoclonal antibodies (mAbs) that are specific and highly inhibitory to members of the human P450 2C subfamily, 2C8, 2C9, 2C9*2, and 2C19. Many of the mAbs to P450 2C8, 2C9, and 2C19 are specific and exhibit potent inhibitory activity (85-95%). mAb 281-1-1 specifically binds, immunoblots, and strongly inhibits the activity of P450 2C8. mAb 763-15-5 specifically binds and strongly inhibits the activity of P450 2C9. mAb 1-7-4-8 specifically binds and strongly inhibits the activity of P450 2C19. The other mAbs bind and inhibit sets and subsets of the P450 2C family. The single and the combinatorial use of the mAbs can "reaction phenotype", i.e., determine the metabolic contribution and interindividual variation of a P450 isoform for the metabolism of a drug or nondrug xenobiotic in human liver microsomes. The utility of the mAb-based analytic system was examined with the model substrates Taxol (paclitaxel), diazepam, tolbutamide, diclofenac, mephenytoin, and imipramine. The mAb system can identify drugs metabolized by a common P450 or several P450s and polymorphic P450s. The mAb system identifies drugs or drug metabolic pathways that are catalyzed by a single P450 and thus may be used for in vivo phenotyping. The mAb system can identify whether a particular drug is metabolized by a single P450 that may exhibit polymorphic expression in humans. The mAb system offers large potential for studies of cytochrome P450 function useful in drug discovery and reduces the possibility of adverse drug reactions due to polymorphisms and drug interactions.     

Analysis of selective regions in the active sites of human cytochromes P450, 2C8, 2C9, 2C18, and 2C19 homology models using GRID/CPCA.

This study demonstrates a selectivity analysis using the GRID/CPCA strategy on four human cytochrome P450 2C homology models (CYP2C8, 2C9, 2C18, and 2C19). Although the four enzymes share more than 80% amino acid sequence identity, the substrate specificity differs. To investigate the selectivity of the enzymes and the amino acids that determine the specificity of each CYP2C enzyme, a selectivity analysis was made using GRID/CPCA. In the GRID calculations 10 probes were used covering hydrophobic, steric, and hydrogen bond acceptor and donor interactions. The selectivity analysis showed that the most important determinants of selectivity among the CYP2C models are the geometrical features of the active sites and the hydrophobic interactions. The selectivity analysis singled out CYP2C8 as the most different of the four CYP2C enzymes with amino acids with distinct properties in positions 114, 205, and 476 (Ser, Phe, and Ile, respectively) compared to the other enzymes. An inverse pharmacophore model for CYP2C9 was constructed from the selective regions, and the model agreed with the docking of diclofenac where the properties of the ligand overlapped with the pharmacophoric points in the model.     

Detection of human CYP2C8, CYP2C9, and CYP2J2 in cardiovascular tissues.

The cytochrome P450 (P450) enzymes CYP2C8, CYP2C9, and CYP2J2 metabolize arachidonic acid to epoxyeicosatrienoic acids, which are known to be vital in regulation of vascular tone and cardiovascular homeostasis. Because there is limited information regarding the relative expression of these P450 enzymes in cardiovascular tissues, this study examined the expression of CYP2C8, CYP2C9, and CYP2J2 mRNA and protein in human heart, aorta, and coronary artery samples by real-time polymerase chain reaction, immunoblotting, and immunohistochemistry. CYP2J2 and CYP2C9 mRNA levels were highly variable in human hearts, whereas CYP2C8 mRNA was present in lower abundance. CYP2J2 mRNA was approximately 10(3) times higher than CYP2C9 or CYP2C8 in human heart. However, CYP2C9 mRNA was more abundant than CYP2J2 or CYP2C8 in one ischemic heart. In human aorta, mean CYP2C9 mRNA levels were approximately 50 times higher than that of CYP2J2 and 5-fold higher than that of CYP2C8. In human coronary artery, mean values for CYP2C9 mRNA were approximately 2-fold higher than that of CYP2J2 mRNA and 6-fold higher than that of CYP2C8 mRNA. Immunoblotting results show relatively high levels of CYP2J2 and CYP2C8 protein in human hearts, which was confirmed by immunohistochemistry. CYP2C9 protein was also detected at high levels in one ischemic heart by immunoblotting. CYP2C9 was present at higher levels than CYPJ2 in aorta and coronary artery, whereas CYP2C8 protein was below the limits of detection. The expression of CYP2J2 and CYP2C8 in human heart, and CYPC9 and CYP2J2 in aorta and coronary artery is consistent with a physiological role for these enzymes in these tissues.     

Pharmacokinetic assessment of a five-probe cocktail for CYPs 1A2, 2C9, 2C19, 2D6 and 3A

AIMS

To assess the pharmacokinetics (PK) of selective substrates of CYP1A2 (caffeine), CYP2C9 (S-warfarin), CYP2C19 (omeprazole), CYP2D6 (metoprolol) and CYP3A (midazolam) when administered orally and concurrently as a cocktail relative to the drugs administered alone.

METHODS

This was an open-label, single-dose, randomized, six-treatment six-period six-sequence William''s design study with a wash-out of 7 or 14 days. Thirty healthy male subjects received 100 mg caffeine, 100 mg metoprolol, 0.03 mg kg⁻¹ midazolam, 20 mg omeprazole and 10 mg warfarin individually and in combination (cocktail). Poor metabolizers of CYP2C9, 2C19 and 2D6 were excluded. Plasma samples were obtained up to 48 h for caffeine, metoprolol and omeprazole, 12 h for midazolam, 312 h for warfarin and the cocktail. Three different validated liquid chromatography tandem mass spectrometry methods were used. Noncompartmental PK parameters were calculated. Log-transformed C_max, AUC_last and AUC for each analyte were analysed with a linear mixed effects model with fixed term for treatment, sequence and period, and random term for subject within sequence. Point estimates (90% CI) for treatment ratios (individual/cocktail) were computed for each analyte C_max, AUC_last and AUC.

RESULTS

There was no PK interaction between the probe drugs when administered in combination as a cocktail, relative to the probes administered alone, as the 90% CI of the PK parameters was within the prespecified bioequivalence limits of 0.80, 1.25.

CONCLUSION

The lack of interaction between probes indicates that this cocktail could be used to evaluate the potential for multiple drug–drug interactions in vivo.     

Effect of eurycomanone on cytochrome P450 isoforms CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2E1 and CYP3A4 in vitro

Eurycomanone, an active constituent isolated from Eurycoma longifolia Jack, was examined for modulatory effects on cytochrome P450 (CYP) isoforms CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2E1 and CYP3A4 using in vitro assays. The IC₅₀ value was determined to assess the potencies of modulation for each CYP isoform. Our results indicated that eurycomanone did not potently inhibit any of the CYP isoforms investigated, with IC₅₀ values greater than 250 μg/ml. Hence there appears to be little likelihood of drug–herb interaction between eurycomanone or herbal products with high content of this compound and CYP drug substrates via CYP inhibition.     

Effects of polymorphisms in CYP2D6, CYP2C9, and CYP2C19 on trimipramine pharmacokinetics

Little is known about the impact of cytochrome P450 polymorphisms on the metabolism of trimipramine, which is still widely used as antidepressant due to its positive effect on sleep patterns. A single oral dose of 75 mg trimipramine was given to 42 healthy volunteers selected according to their CYP2D6, CYP2C19, and CYP2C9 genotypes. The reference group included 8 subjects with homozygous active wild-type genotypes of all 3 enzymes (EM). This group was compared with 7 intermediate (IM) with 1 and 7 poor metabolizers (PM) with zero active alleles of CYP2D6 and CYP2C19, respectively, and with 4 subjects with the genotype CYP2C9*3/*3. Pharmacokinetics of trimipramine and its demethylated metabolite strongly depended on the CYP2D6 genotype. Median oral clearance of trimipramine was 276 L/h (range 180-444) in the reference group but only 36 L/h (range 24-48) in CYP2D6 PMs (P < 0.001). These differences could only be explained by an effect of CYP genotypes on both parameters, systemic clearance and bioavailability, the latter being at least 3-fold higher in CYP2D6 PMs than in the reference group. The desmethyltrimipramine area under the concentration-time curve was 40-fold greater in CYP2D6 PMs than in the reference group (1.7 vs. 0.04 mg/L x h in EMs), but below the quantification limit in most carriers of deficiencies of CYP2C19 or CYP2C9. This indicates that both CYP2C enzymes contribute to the demethylation of desmethyltrimipramine and CYP2D6 to further metabolism.