Conditional estimation of sensitivity and specificity from a phase 2 biomarker study allowing early termination for futility

Development of a disease screening biomarker involves several phases. In phase 2 its sensitivity and specificity is compared with established thresholds for minimally acceptable performance. Since we anticipate that most candidate markers will not prove to be useful and availability of specimens and funding is limited, early termination of a study is appropriate, if accumulating data indicate that the marker is inadequate. Yet, for markers that complete phase 2, we seek estimates of sensitivity and specificity to proceed with the design of subsequent phase 3 studies. We suggest early stopping criteria and estimation procedures that adjust for bias caused by the early termination option. An important aspect of our approach is to focus on properties of estimates conditional on reaching full study enrollment. We propose the conditional‐UMVUE and contrast it with other estimates, including naïve estimators, the well‐studied unconditional‐UMVUE and the mean and median Whitehead‐adjusted estimators. The conditional‐UMVUE appears to be a very good choice. Copyright © 2008 John Wiley & Sons, Ltd.     

胰岛素样生长因子1对新生大鼠缺氧缺血性脑损伤保护机制的研究

目的　建立单侧缺氧缺血性脑损伤 (HIBD)动物模型 ,研究胰岛素样生长因子 1(IGF 1)对HIBD的影响和可能机制。　方法　选择健康 7日龄Wistar大鼠 12 0只 ,建立HIBD模型 ,随机分成假手术组、HIBD组、HIBD后 0 .2mg/kg人基因重组IGF 1干预组 (RH IGF 1组 )、0 .0 6 6mg/kg人基因重组IGF 1干预组 (SRH IGF 1组 )及盐水对照组 (对照组 )。各组按观察时段进一步分为 2 4、4 8、72h组 ,每组 8只。各组于规定时刻观测脑形态学改变、谷氨酸 (Glu)含量、凋亡细胞计数、Bcl 2蛋白表达。　结果　 (1)HIBD 4 8h组Glu(116 2 .2± 10 8.1)mg/kg ,较假手术组(75 0 .9± 5 3.4 )mg/kg明显升高 (P <0 .0 5 ) ;HIBD组凋亡细胞计数 [2 4h :(7.6± 1.9) % ,4 8h(12 .6±1.2 ) % ,72h :(13.8± 0 .9) % ],较假手术组 [2 4h(2 .0± 0 .2 ) % ,4 8h(2 .0± 0 .3) % ,72h(2 .0±0 .2 ) % ]明显增加 (P均 <0 .0 5 )。 (2 )与对照组相比 ,RH IGF 1组脑组织病变减轻 ;干预 4 8h组Glu[SRH IGF 1组 (781.4± 5 4 .2 )mg/kg ,RH IGF 1组 (74 0 .5± 4 6 .6 )mg/kg],较对照组 (112 6 .6± 4 8.0 )mg/kg明显降低 (P均 <0 .0 5 ) ;RH IGF 1组凋亡细胞计数 [2 4h :(3.6± 0 .9) % ,4 8h(8.2± 2 .2 ) % ,72h(9.4± 1.4 ) % ],较对     

腹腔镜辅助下大隐静脉隔绝术治疗大隐静脉曲张60例

目的探讨腹腔镜辅助下大隐静脉隔绝术的疗效。方法2000年1月～2004年1月对60例66条大隐静脉曲张腹腔镜辅助下行大隐静脉隔绝术,腹腔镜辅助下高位结扎、电灼大腿段大隐静脉,阻断其小腿段所有属支及交通支,使大隐静脉与体循环隔绝。结果手术时间30～60min,(50±9)min;术后住院时间3～5d,(3.5±0.6)d。60例随访1～36个月,平均28个月,无复发。结论腹腔镜辅助下大隐静脉隔绝术创伤小,疗效好,复发率低,是治疗大隐静脉曲张的理想术式。     

Effects of self-management training in Type 2 diabetes: a randomized, prospective trial.

AIMS: The efficacy of three education programmes for Type 2 diabetic patients was tested in a randomized trial. A didactic-oriented training programme (treatment A) was compared with a self-management-oriented programme delivered in group sessions (treatment B). The latter programme was compared with a more individualized approach (treatment C). METHODS: One hundred and eighty-one Type 2 diabetic patients (age 55.6 +/- 6.3 years, diabetes duration 6.6 +/- 6.2 years, HbA(1c) 7.8 +/- 1.6%, female 49.7%) took part. Efficacy was assessed 3 months (t1) after baseline (t0) and at a follow-up 15 months (t2) after baseline. RESULTS: The fall in HbA(1c) in treatment B at t1 was sustained at t2 (t0 8.1 +/- 1.8%, t1 7.3 +/- 1.7%, t2 7.4 +/- 1.9%). In treatment A, HbA(1c) was unchanged throughout (t0 7.6 +/- 1.5%, t1 7.5 +/- 1.3%, t2 7.7 +/- 1.7%; treatment A vs. treatment B; P < 0.05). With the more individualized approach of treatment C, there was a fall in HbA(1c) at t1, but this was not sustained at t2 (t0 7.8 +/- 1.6%, t1 7.1 +/- 1.3%, t2 7.6 +/- 1.6%; treatment B vs. treatment C; P = 0.73). There were also significant benefits in treatment B subjects compared with treatment A in further medical (body mass index and fasting blood glucose), psychological (control, irritability and hunger dependency of eating behaviour, and trait anxiety) and behavioural (exercise) variables. There were no significant benefits of the more individualized treatment C compared with group treatment B. No significant differences were found regarding triglyceride levels, high-density lipoprotein, diabetes-related knowledge, negative well-being, urine or blood glucose levels or foot care. CONCLUSION: Self-management training had a significantly higher medium-term efficacy than didactic diabetes education. The group sessions were more effective than a more individualized approach.     

RGD-based strategies for selective delivery of therapeutics and imaging agents to the tumour vasculature

During the past decade, RGD-peptides have become a popular tool for the targeting of drugs and imaging agents to alphavbeta3-integrin expressing tumour vasculature. RGD-peptides have been introduced by recombinant means into therapeutic proteins and viruses. Chemical means have been applied to couple RGD-peptides and RGD-mimetics to liposomes, polymers, peptides, small molecule drugs and radiotracers. Some of these products show impressive results in preclinical animal models and a RGD targeted radiotracer has already successfully been tested in humans for the visualization of alphavbeta3-integrin, which demonstrates the feasibility of this approach. This review will summarize the structural requirements for RGD-peptides and RGD-mimetics as ligands for alphavbeta3. We will show how they have been introduced in the various types of constructs by chemical and recombinant techniques. The importance of multivalent RGD-constructs for high affinity binding and internalization will be highlighted. Furthermore the in vitro and in vivo efficacy of RGD-targeted therapeutics and diagnostics reported in recent years will be reviewed.     

冠心病患者血清对氧磷酶活性的测定

目的探讨冠心病患者血清对氧磷酶1活性及其与冠心病之间的关系。方法选择冠状动脉造影确诊的冠心病患者106例和非冠心病组62例,用乙酸苯酯法和比色法分别测定两组血脂、血清对氧磷酶1活性、超氧化物歧化酶及丙二醛含量,并进行对比分析。结果冠心病组血清中对氧磷酶1活性和超氧化物歧化酶水平分别为113±64μkat/L和43.8±8.2 kU/L,均较对照组降低(134±72μkat/L和63.4±5.7 kU/L)(P<0.05);而丙二醛含量较对照组升高(9.4±1.8μmol/L比4.1±0.5μmol/L,P<0.01)。对氧磷酶1活性与高密度脂蛋白和超氧化物歧化酶水平呈正相关,与丙二醛水平呈负相关。冠状动脉狭窄者对氧磷酶1活性较无狭窄者明显减低(P<0.001),2、3支血管病变者较1支血管病变者对氧磷酶1活性降低(P<0.05)。结论冠心病患者血清对氧磷酶1活性降低,低对氧磷酶1活性与冠心病严重程度有关。     

The patella and tibial condyle position after combined and after closing wedge high tibial osteotomy

High tibial osteotomy changes the patella and tibial condyle position, which makes the subsequent total knee replacement technically demanding. From 1 January 1993 to 31 December 2000, combined osteotomy [After the first osteotomy made 2 cm distally to the joint line, a bone wedge is removed based laterally. Its tip ends at the center of the tibial condyle (half bone wedge). The distal part of the tibia is placed into the valgus position and the half bone wedge is placed into the gap opened medially.] was performed on 103 knees and closing wedge osteotomy was performed on 47 consecutive knees. Eighty combined (group A) and 41 closing wedge (group B) osteotomy were studied. All knees were assessed radiologically before surgery, in the 10th postoperative week, in the 12th postoperative month and at the time of the final follow-up (in group A—66.15 months, in group B—66.61 months). We examined the change of the femorotibial angle, of the patellar height according to the method of Insall and Salvati, of the tibial slope angle according to the method of Bonnin, of the tibial condylar offset according to the method of Yoshida and of the distance between the lateral tibial plateau and the top of the fibular head. In group A and B, the recurrence of the varus deformity was not noted and valgus alignment did not increase in any case. In group-A, the Insall–Salvati ratio remained unchanged in 65% of knees. The tibial slope angle decreased in both groups. There was correlation between the change of the tibial condylar offset and the angle of the correction in both groups. There was correlation between the change of the distance between the lateral tibial plateau and the top of the fibular head. After combined osteotomy, the transposition of the tibial condyle and the decrease of the distance between the lateral tibial plateau and the top of the fibular head was less than after closing wedge osteotomy, although the average angle of correction was more after combined osteotomy (11.835°), than after closing wedge osteotomy (9.465°). Theoretically, the recurrence of the varus deformity, the increase of the valgus alignment and (in majority of cases) the shortening of the patellar tendon do not compromise the likelihood of successful conversion to the subsequent total knee replacement, either after combined or after closing wedge osteotomy. The combined osteotomy does not lead to considerable transposition of the tibial condyle and to considerable lateral tibial bone loss; therefore, theoretically, the combined osteotomy does not impair the subsequent total knee replacement.     

胫骨高位截骨手术并发症23例次分析

[目的] 探讨胫骨高位截骨手术并发症的发生情况，并提出预防和治疗措施。[方法]2000年1月～2004年10月采用胫骨高位截骨术治疗膝骨关节炎合并内翻畸形患者126人，21人发生手术并发症，男4例，女17例；年龄48～64岁，平均61岁。术前拍摄站立膝关节正位X线片，测量股骨一胫骨角，计算截骨角度，采用外侧闭合胫骨高位截骨术矫正膝内翻畸形。[结果] 术后随访6～12个月，平均7．5个月。共21名患者发生各类并发症23例次．发生率为16．7％。其中发生胫骨骨折4例，腓总神经麻痹3例，出现深静脉血栓形成5例，膝内翻复发病例6例，内固定失败4例（其中2例合并膝内翻复发），感染1例。[结论] 降低胫骨高位截骨手术并发症需要术者熟悉局部解剖和精确的术前设计，提高手术技巧及完善的围手术期护理。     

乳腺癌99mTc-MIBI影像与P-糖蛋白表达的相关性

为了探讨活体乳腺恶性肿瘤对99mTc-甲氧基异丁基异腈(99mTc-MIBI)的摄取和肿瘤细胞P-糖蛋白(P-glyco-protein,P-gp)表达间的关系。2003年10月~2005年12月对40例未经治疗的乳腺癌患者进行99mTc-MIBI早期(10min)与延迟(120min)平面显像,计算其外排率(WOR)。显像后1周内进行手术治疗或化疗,术后应用免疫组化方法检测肿瘤标本P-gp表达,结果进行统计学计算。结果:WOR在P-gp阳性者为(12.8±8.2)%,高于P-gp阴性者(1.2±6.2)%,差异有统计学意义,t=3.42,P=0.01;WOR与肿瘤大小成正相关。初步研究结果显示,乳腺恶性肿瘤对99mTc-MIBI的摄取与P-gp表达呈明显负相关,即肿瘤细胞高度表达P-gp时,99mTc-MIBI摄取较低,99mTc-MIBI显像和肿瘤细胞P-gp表达相关性好,可成为体内无创检测肿瘤组织P-gp表达及耐药性的重要手段。