科学杂志:中国的争议迟滞美国神经改道临床实验

　　美国《科学》杂志

　　来自中国的争议迟滞了美国的神经改道（临床）实验

　　中国的批评者挑战肖传国宣称的成功治疗脊柱裂患者

　　一个在中国历时五年的医学争斗波及到了密执根，那里已经延迟招收病人继续一项临床实验。在威廉姆贝蒙特医院开展的这项实验目的在于通过手术将脊柱裂患者的神经改道，从而使他们能控制自身的膀胱。主持实验研究的 Kenneth Peter 上周证实，该实验的资助机构美国国家健康（卫生）研究院（ NIH ）已经要求进行重审。

　　这种神经改道手术的发明者、泌尿科医生肖传国在中国宣称手术取得了惊人的成果，包括对 110 名脊柱裂患者手术后一年随访的数据达到 87% 的成功率。但是，随之而来的争议也同样惊人。

　　今年早些时候，警察指控华中科技大学附属医院泌尿科主任肖传国组织了对批评者中的两个人实施街头袭击。被袭击致伤者是方是民，他以笔名方舟子经营新语丝网站，另一位是记者方玄昌（与方是民无亲属关系），他曾经编辑发表过一些关于肖氏手术失败病例患者的杂志文章。

　　肖（传国）以“寻衅滋事”罪被判 5 个半月拘役，他已经提出上诉。《科学》曾向肖传国的律师用电子邮件询问相关事件的解释，但至此文发稿时尚没有收到回复。

　　美国健康与公众服务部（ HHS ）三月份收到了关于密执根医院开展肖氏手术临床实验的争议。一个跟踪肖的研究活动多年，自称新语丝志愿者的监督小组发了一封信给科研诚信办公室（ ORI ）和人类研究保护办公室（ OHRP ）。信中的指控之一是“美国正在开展的临床实验是基于不可靠的数据资料。”

　　据发信人，软件工程师、志愿小组成员之一、博客撰写人程鹗（ Eddie Cheng ）所称， ORI 拒绝（原意并不是拒绝――译者注）采取行动。程说 ORI 三月的回信认为指控不够具体，而且肖的工作是在中国，他们没有评判的权力。尽管如此， OHRP 上周在给程的一封电子邮件中确认，它已经要求该实验资助机构评估来信中提出的指控。

　　肖在科学界有许多朋友，贝蒙特医院泌尿科主任 Peter 和另外 30 名研究者九月份联名签署了一封支持肖的公开信，敦促中国“保护他的人权”，并且赞扬肖是“一个富有同情心的人，他的诚信和创新对社会做出了贡献而在世界范围内受到尊敬。”

　　肖研发了一种神经改道手术治疗脊髓损伤（ SCI ）患者的神经性膀胱功能障碍。神经搭桥的想法是一位澳大利亚医生在 1907 年第一次提出的，医学文献中记录过一些部分成功的案例。而肖在 80 年代末提出的方法是将一条下部腰椎神经与一或两条脊髓损伤部位以下的骶骨神经嫁接，这样来绕过中枢神经，让神经信号改道传至膀胱和泌尿（控制）肌群。肖宣称，这种新建立的神经通路使得（病人）可以通过挠或挤压大腿皮肤触发自主排尿。

　　这个想法在经过鼠、猫实验后， 1994 年肖申请并获得了 NIH 的拨款在纽约布鲁克林长岛学院医院开始在狗身上实验。根据肖自己发表的文章， 1995 年他就在中国河南省的一个煤矿附属医院对中国 SCI （脊髓损伤）病人开始临床实验，并且 2003 年在《泌尿外科》杂志上发表了关于这些 SCI 病人临床实验的最后报告。这份经同行评议的文章宣称， 15 个男性 SCI 病人――全部都是反射亢进神经性膀胱（无意识排尿）――接受了手术，其中 10 个获得了满意的膀胱功能，两个部分恢复，两个失败，一个失去随访。

　　批评者在这份报告的数据中发现了自相矛盾，比如，在早期的报告（有些是中文）中肖描述病人的恢复是在手术后 10 到 12 个月，但在 2003 年的最后报告中病人获得膀胱功能是在手术后 12 到 18 个月。另外， 2003 年的最后报告中说明 15 个病人全部都是反射亢进神经性膀胱功能障碍，而在肖早期报告中描述的病人是既有反射亢进也有无反射（无法排尿）神经性膀胱功能障碍。

　　加利福尼亚大学儿童医院儿童泌尿科主任 Eric Kurzrock 认为由于“病人选择的偏差”（经过特殊挑选的病人――译者注）认为肖的研究存在“极为严重的缺陷”。 Kurzrock 特别对宣称的高成功率提出批评，因为它不是基于随机的并可对照的数据。

　　在经过对 SCI 患者的治疗后，肖开始用神经改道手术治疗因脊柱裂造成膀胱功能失常的儿童，这些儿童的脊髓一般都没有像 SCI 患者那样受到损伤。（在美国）第一次私人资助的临床实验是 2006 到 2007 年在贝蒙特医院，包括九名脊柱裂患者和两名 SCI 患者； Peter 与合作者报告了脊柱裂患者的最初手术结果，但是 SCI 患者的结果至今没有报告。目前 NIH 资助的临床实验准备招收 16 名脊柱裂患者；最初的方案是非盲，也没有设对照组。 Peter 告知：“ NIH 已经为我们的研究成立了一个监督委员会。几个星期前我们已经开过会，现正在研究他们的意见，很快会提交一个经过修改的规程（方案）供他们复审。”

　　张一帆译

　　附英文原文：

　　http://www.sciencemag.org/cgi/content/summary/330/6005/741

　　http://www.sciencenet.cn/m/user_content.aspx?id=380535

　　NEWS OF THE WEEK

　　RESEARCH ETHICS

　　Questions From China Snag U.S. Trial Of Nerve-Rerouting Procedure

　　（Photo） Under fire. Xiao Chuan-Guo’s reports of success in treating

　　spina bifida patients have been challenged by Chinese critics.

　　A running 5-year medical brawl in China has spilled over into Michigan,

　　where it has delayed a clinical trial about to enroll patients. The

　　trial, based at the William Beaumont Hospital in Royal Oak, Michigan,

　　aims to surgically reroute the nerves of spina bifida patients to give

　　them control of their bladder. Principal investigator Kenneth Peters

　　confirmed last week that the U.S. National Institutes of Health （NIH）

　　―which is funding the work―has asked for a review.

　　The urologist who invented the nerve-rerouting procedure, Xiao

　　Chuan-Guo, has claimed phenomenal results in China―including an 87%

　　success rate for 110 spina bifida patients at their 1-year follow-up

　　visits. But the controversy surrounding his work is phenomenal, too.

　　Earlier this year police charged Xiao, head of urology at the Union

　　Hospital affiliated with Huazhong University of Science and Technology

　　in Wuhan, with organizing street attacks on two of his critics. Those

　　injured were Fang Shimin, who under the pen name Fang Zhouzi operates

　　the Xin Yu Si or New Threads Web site （www.xys.org）, and journalist

　　Fang Xuanchang （no relation to Fang Shimin）, who has edited magazine

　　articles about Chinese patients who failed to benefit from Xiao’s

　　procedure.

　　Xiao was convicted of “causing disturbance” and sentenced to 5.5

　　months of detention （http://scim.ag/doctor-sentenced- Beijing）. He has

　　appealed the verdict. Science sent a request for comment to Xiao’s

　　lawyer by e-mail but did not receive a response by presstime.

　　Questions about the clinical trial in Michigan based on Xiao’s

　　procedure reached the U.S. Department of Health and Human Services in

　　March, when the so-called New Threads Volunteers, a watchdog group

　　that tracks Xiao’s research, sent a letter to the Office of Research

　　Integrity （ORI） and the Office for Human Research Protections （OHRP）.

　　The letter alleged, among other things, that “the current clinical

　　trials in the United States are based on dubious data.”

　　ORI declined to take action, according to Eddie Cheng, a blogger,

　　software engineer, and member of the Volunteers, who mailed letters

　　about Xiao’s study to ORI and OHRP. Cheng says ORI wrote back in

　　March that the allegations weren’t specific and that Xiao’s work in

　　China was out of its jurisdiction. Last week, however, OHRP confirmed

　　in an e-mail to Cheng that it had asked the funding agency to evaluate

　　the allegations.

　　Xiao has many friends in the scientific community. Peters, head of

　　urology at the Beaumont Hospital, and 30 researchers signed an open

　　letter in support of Xiao in September urging China to “protect his

　　human rights” and praising Xiao as “a compassionate man who is

　　respected worldwide for his integrity and his innovative scientific

　　contributions to society.”

　　Xiao developed a nerve-rerouting procedure to treat neurogenic bladder

　　disorder in patients with spinal cord injury （SCI）. Nerve crossover

　　was first proposed by an Australian surgeon in 1907; medical

　　literature holds a scattering of partial success stories. But Xiao’s

　　approach―which he proposed in the late 1980s―bypasses the central

　　nervous system by grafting a lower lumbar nerve to one or two sacral

　　nerves below the spinal cord lesion, rerouting signals to bladder and

　　urinary muscles. Xiao claims to have established a new pathway that

　　can be used to initiate voluntary urination by scratching or squeezing

　　skin on the thigh.

　　After testing the idea on rats and cats, Xiao applied for and received

　　an NIH grant in 1994 to study dogs at the Long Island College Hospital

　　in Brooklyn, New York. According to his own published account, Xiao

　　began a trial of the procedure with Chinese SCI patients at a hospital

　　affiliated with a coal mine in Henan Province in 1995 and published

　　final results from the SCI patients in 2003 in The Journal of Urology.

　　This peer-reviewed article reported that of 15 male SCI patients―all

　　with hyperreflexic neurogenic bladder （involuntary voiding）― who had

　　the surgery, 10 gained satisfactory bladder function, two had partial

　　recovery, two failed, and one was lost to follow-up.

　　Critics see inconsistencies in the data. For example, in early reports

　　（some in Chinese）, Xiao described patients’ recovery taking place

　　between 10 and 12 months post-op, but the 2003 final report says that

　　patients gained bladder function 12 to 18 months post-op. In addition,

　　the depiction of all 15 patients as hyperreflexic in the 2003 report

　　seems at odds with Xiao’s previous reports, which described treating

　　a mix of patients with hyperreflexic bladder and areflexic bladder

　　（failure to void）.

　　Eric Kurzrock, chief of pediatric urology at the University of

　　California, Davis, Children’s Hospital in Sacramento, California,

　　says Xiao’s study is “extremely flawed” because of “patient

　　selection bias.” Kurzrock is particularly critical of the claimed

　　high success rate, because it is not based on data from a randomized,

　　controlled trial.

　　After treating SCI patients, Xiao began using nerve rerouting to treat

　　bladder malfunction in children with spina bifida, whose spinal cords

　　are generally not as damaged as those of SCI patients. The first

　　privately funded trial at Beaumont Hospital, which took place in 2006

　　and 2007, included nine spina bifida patients and two SCI patients;

　　Peters and co-authors reported preliminary results from spina bifida

　　patients, but results on SCI patients have not been reported. The

　　current NIH-funded trial aims to enroll about 16 spina bifida patients;

　　the original design was not blind and had no control group. Peters

　　says NIH has “created an oversight committee for our study. We met

　　with them a few weeks ago and are addressing their comments. We will

　　be submitting a revised protocol soon for their review.”

　　HAO XIN

　　www.sciencemag.org

　　SCIENCE VOL 330 5 NOVEMBER 2010 Published by AAAS