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.     

BKV in Simultaneous Pancreas-Kidney Transplant Recipients: A Leading Cause of Renal Graft Loss in First 2 Years Post-Transplant

With the introduction of more potent immunosuppressive agents, rejection has decreased in simultaneous pancreas/kidney transplant (SPK) recipients. However, as a consequence, opportunistic infections have increased. The purpose of this report is to outline the course of SPK patients who developed polyomavirus-associated nephropathy (PVAN). A retrospective review of 146 consecutive SPK recipients from January 1, 1996 to December 31, 2002 was performed. Immunosuppression, rejection and development of PVAN were reviewed. Nine patients were identified. All received induction with either OKT3 or thymoglobulin. Immunosuppression included tacrolimus/cyclosporine, MMF/azathioprine and sirolimus/prednisone. Two patients were treated for kidney rejection prior to the diagnosis of PVAN. Time to diagnosis was an average of 359.3 days post-transplantation. Immunosuppression was decreased but five ultimately lost function. However, none developed pancreatic abnormalities as demonstrated by normal glucose and amylase. Two underwent renal retransplantation after PVAN diagnosis and both have normal kidney function. PVAN was the leading cause of renal loss in SPK patients in the first 2 years after transplantation and is a serious concern for SPK recipients. The pancreas, however, is spared from evidence of infection, and no pancreatic rejection occurred when immunosuppression was decreased.     

王焕禄老中医治疗哮喘发作期的用药经验

王焕禄老中医在长期的临床实践中，总结出治疗哮喘病的一些用药体会，兹介绍如下，以飨读者。     

应用输尿管镜放置双J管早期治疗输尿管阴道瘘

Objective To evaluate the clinical effect of placing double J stent using a ureteroscope in early managing ureterovaginal fistula.Methods Twenty-eight patients cases with ureterovaginal fistula from 2002 to 2008 were treated early with placing double J stent using a ureteroscope and the clinical data were reviewed.Results Twenty-two of 28 cases were treated and double J stent was placed in them by a uretero-scope and 75% (21/28)of cases were cured.Four of 21 cases were treated twice by a ureteroscope and were cured finally.7 cases with failure ureterovaginal treatment underwent ureterocystostomy and were cured.The follow-up from 6 months to 33 months (average 10.1±6.4 months)showed that all of the 28 cases had been cured and had no urinary fistula.Conclusion Placing double J stent using a ureteroscope is the first choice of operative procedure for the early treatment of ureterovaginal fistula.     

Angiopoietin1/Tie2 and VEGF/Flk1 induced by MSC treatment amplifies angiogenesis and vascular stabilization after stroke.

Bone marrow stromal cells (MSCs) increase vascular endothelial growth factor (VEGF) expression and promote angiogenesis after stroke. Angiopoietin-1 (Ang1) and its receptor Tie2 mediate vascular integrity and angiogenesis as does VEGF and its receptors. In this study, we tested whether MSC treatment of stroke increases Ang1/Tie2 expression, and whether Ang1/Tie2 with VEGF/ vascular endothelial growth factor receptor 2 (VEGFR2) (Flk1), in combination, induced by MSCs enhances angiogenesis and vascular integrity. Male Wistar rats were subjected to middle cerebral artery occlusion (MCAo) and treated with or without MSCs. Marrow stromal cell treatment significantly decreased blood-brain barrier (BBB) leakage and increased Ang1, Tie2, and occludin (a tight junction protein) expression in the ischemic border compared with MCAo control. To further test the mechanisms of MSC-induced angiogenesis and vascular stabilization, cocultures of MSCs with mouse brain endothelial cells (MBECs) or astrocytes were performed. Supernatant derived from MSCs cocultured with MBECs significantly increased MBEC expression of Ang1/Tie2 and Flk1 compared with MBEC alone. Marrow stromal cells cocultured with astrocytes also significantly increased astrocyte VEGF and Ang1/Tie2 expression compared with astrocyte culture alone. Conditioned media from MSCs alone, and media from cocultures of MSCs with astrocytes or MBECs, all significantly increased capillary tube-like formation of MBEC compared with control Dulbecco's modified Eagle's medium media. Inhibition of Flk1 and/or Ang1 significantly decreased MSC-induced MBEC tube formation. Knockdown of Tie2 expression in MBECs significantly inhibited MSC-induced tube formation. Our data indicate MSC treatment of stroke promotes angiogenesis and vascular stabilization, which is at least partially mediated by VEGF/Flk1 and Ang1/Tie2.     

EEG source imaging: correlating source locations and extents with electrocorticography and surgical resections in epilepsy patients.

SUMMARY: It is desirable to estimate epileptogenic zones with both location and extent information from noninvasive EEG. In the present study, the authors use a subspace source localization method (FINE), combined with a local thresholding technique, to achieve such tasks. The performance of this method was evaluated in interictal spikes from three pediatric patients with medically intractable partial epilepsy. The thresholded subspace correlation, which is obtained from FINE scanning, is a favorable marker, which implies the extents of current sources associated with epileptic activities. The findings were validated by comparing the results with invasive electrocorticographic (ECoG) recordings of interictal spike activity. The surgical resections in these three patients correlated well with the epileptogenic zones identified from both EEG sources and ECoG potential distributions. The value of the proposed noninvasive technique for estimating epileptiform activity was supported by satisfactory surgery outcomes.     

改良W形回肠代膀胱术的疗效观察(附36例报告)

目的 :探讨改良W形回肠代膀胱术的疗效。方法 :对 36例膀胱肿瘤患者行根治性膀胱切除、W形回肠代膀胱术 ,并对术式进行改进。结果 :36例手术时间平均 4 .2h。术后 31例随访 4～ 19个月 ,平均 10 .6个月 ,无严重并发症 ,均无瘤生存。患者一般于术后 3周自主可控性排尿 ,日间尿控率为 10 0 % ,术后 3、6、12个月夜间尿失禁发生率分别为 2 2 .5 %、11.1%及 6 .2 %。术后 6个月尿动力学检查膀胱容量 (36 0± 30 )ml,最大尿流率 (13.6± 2 .6 )ml/s,剩余尿量 (11.5± 5 .8)ml,充盈期膀胱压力明显低于尿道闭合压。新膀胱造影发现新膀胱呈球形 ,完全位于盆腔 ,未见输尿管反流。B超及IVU检查发现原上尿路积水 4例均明显减轻 ,其余未发现输尿管狭窄和上尿路积水征象。无高氯性酸中毒 ,肾功能正常。结论 :改良W形回肠代膀胱术手术时间短 ,操作简单 ,创伤轻 ,并发症少 ;新膀胱容量大 ,内压低 ,顺应性好 ,功能接近于正常膀胱 ,保持原位排尿 ,明显提高了患者术后生活质量 ,值得临床推广应用。     

Location of lectin UEA-I receptors in histological diagnosis of nasopharyngeal precancerous lesion.

Three kinds of lectins (UEA-I, ConA, PNA) were used to study normal, dysplastic, neoplastic nasopharyngeal epithelium by lectin affinitive histochemical method. UEA-I (ulex europeus agglutinin-I) displayed membrane distribution in normal squamous epithelium, but most of nasopharyngeal carcinoma cells were negative. Notably, severe dysplastic epithelium (precancerous lesion) exhibited a strong membranous and cytoplasmic affinity, which contrasted sharply with the normal epithelium and carcinoma cells. The statistically significant difference in the content and distribution of lectin UEA-I in these three groups suggest that UEA-I is a hopeful marker for diagnosing precancerous lesion of the nasopharynx. However, PNA and ConA are of less diagnostic value.