[1] Translation of Fang Zhouzi’s micro blog.

2013-8-3 09:00

The U.S. National Institutes of Health (NIH) has withdrawn the “Xiao Procedure” clinic trial, the reason is that “protocol as presented by investigator was not approved by the NIDDK (the funding agency)” http://t.itc.cn/mghCq. The Xiao Procedure trial in the U.S. comes to a dead end. Not long ago, Xiao Chuanguo still bragged on Southern Metropolis Daily that “the Xiao Procedure has been carried out in several universities in the U.S., with very good results. this is the only one surgery learned by U.S. from China.”

[2] Translation of Xu Peiyang’s blog (deleted under the pressure from Xiao Chuanguo)
National Institutes of Health (NIH) Withdrew “Xiao Procedure” Clinic Study

2013-8-3 09:23
On Aug. 1, 2013, National Institutes of Health (NIH) Withdrew the “Xiao Procedure” clinic study. The reason is “protocol as presented by investigator was not approved by the NIDDK.”
http://clinicaltrials.gov/archive/NCT01096459/2013_08_01/changes

[3] Translation of Xiao Chuanguo’s blog (ranked the top most of the Hottest ScienceNet Blogs, recommended by 44 persons)

The NIH Extends the Inclusion Criteria to Further Assess the Effectiveness of Xiao Procedure, Continues to Fund the Xiao Procedure Study

2013-8-3 13:54

Thanks Xu Peiyang for removing the blog post containing misleading information. I was at first reluctant to waste time to talk about it before the US results being officially published.

The truth is:

http://www.clinicaltrials.gov/ct2/results?term=rerouting

1. The NIH has determined that Xiao Procedure is safe, therefore the safety assessment of the original study [translator’s note: from the context, “the original study” refers to NIH sponsored NCT01096459] would no longer be needed.

2. The NIH has determined that, so far the amount of SB cases and the results of Xiao Procedure can sufficiently draw statistical conclusions, so that this study does not need to increase the number of cases (otherwise there would be another 3 years of delay to complete the study). Therefore, the NIH has withdrawn the original plan funding 15 more cases, but instead continues to proceed and to fund the study in the name of the current title and contents [translator’s note: from the context, “the current title and contents” refers to that of 2006 study NCT00378664].

3. The NIH has determined in principle the efficacy of Xiao Procedure on the bowel and bladder disorders caused by spina bifida, and requires the new study [translator’s note: from the context, “the new study” refers to NCT00378664] to add research to further assess the level of improvement of Xiao Procedure on urinary incontinence caused by SCI and other diseases. (level of improvement, note: not to assess whether or not effective, but the level of improvement)

It’s realy funny to look at those clowns and Fang Zhouzi barking on the “withdraw”. After I first saw this on the microblog this morning, I deliberately waited for and finally saw Fang Zhouzi jumped into the mud This Dr. Plagiarism who lives on Baidu [translator’s note: the predominate Chinese search engine], actually too stupid to understand even basic medical search.

[translator’s note: omitted the following the screen shot of the NCT00378664 web page http://clinicaltrials.gov/ct2/show/NCT00378664]

Xiao reported his results of “the first 15 patients with SCI” (”clinical trial was started in 1995″) in his 2003 paper [1]. Before that, he also reported the results of “14 SCI patients since 1995″ in his 1998 abstract [2]. It is not the problem that there is a difference of one in the total numbers of patients. The problem is that all 15 patients are of hyperreflexic bladder in the 2003 paper, whereas only 6 patients are of hyperreflexic bladder in the 1998 abstract. Where did the other 9 patients with hyperreflexic bladder in [1] come from? and where had the 8 patients with areflexic bladder in [2] gone?

The pre-operative residual urine should remain the same no matter how long the follow-up is. But this is not the case in Xiao’s data. The pre-operative residual urine of his 6 patients with hyperreflexic bladder is 300 ml in his 1998 abstract, but this data becomes 317 ml in his 6 patients with hyperreflexic bladder, among the same “first 14 SCI patients”, described in his achievement [3] that was presented to the Holeung Ho Lee Foundation when he applied for the award from the Foundation in 2002.

Xiao reported the 18-month follow-up results of the “first” 20 patients with spina bifida in his 2005 paper [4], one failed among 6 patients with hyperreflexic bladder. Before that, he reported the 12-month results of 13 patients with spina bifida, published in Chinese in the Journal of Clinical Urology [5]. There were also 6 patients with hyperreflexic bladder. The difference is that the 6 cases in [5] were all successful. From the context of both two papers, the 6 cases were the same. Xiao did not mention in [4] that there was one case that was once successful but then failed later, which may suggest that there exists a problem in long-term prognosis of the procedure.

There is also an inconsistency in residual urine between his 2005 paper in English [4] and 2003 paper in Chinese [5]. The residual urine of the 6 patients with hyperreflexic bladder is 70.17 ml in [4], whereas that of the same 6 patients is 102 ml in [5].

Besides, the 13 patients in [5] were classified as 2 to 25 years old, whose spinal defects were closed within 2 years of birth. In contrast, the 20 patients in [4] were 5 to 14 years old and their spinal defects were closed within 48 hours of birth. This means that some patients disappeared in the later paper [4]: those of 2 and 25 years old and whose spinal defects were closed between 48 hours and 2 years of birth.

So many inconsistencies in Xiao’s papers cannot be attributed to clerical errors. The above described inconsistencies in the numbers of patients, in the residual urine and in the patient characteristics can only be explained by that Xiao Chuanguo fabricated and falsified his clinical data.

There are other inconsistencies in Xiao’s papers. The source of funding is indicated to be NIH and PVA in Xiao’s 1998 abstract [2], while it becomes 4 grants from China in his 2003 paper [1].

In addition, there are changes in the lists of authors. Comparing to 1998 abstract [2], Victor Nitti and William C. de Groat were added in 2003 paper [1]. Comparing to 2003 paper in Chinese [5], Ellen Shapiro and Herbert Lepor were added in 2005 paper in English [4]. What are their roles in the clinical trial in China? What are their contributions to the papers [1,4], after the initial results had already been reported in [2,5] by others? Are they responsible for the grant misuse and the ethical violation while enjoying the right of authorship?

Moreover, Xiao failed to disclose in [4] what he had described in [5] that “most of patients need the help of different level of abdominal pressure in order to completely empty bladders”, which can well explain the contradiction in the urodynamic data in [4], found by a peer expert from China [6]. The expert pointed out that the postoperative urodynamic studies in Fig. 3B and Fig. 4B of [4] clearly show that the patients urinate by intra-abdominal pressure instead of the detrusor pressure, suggesting the failure of establishment of the reflex arc. But Xiao misrepresented that it is the reflex arc that causes the urination. We note that Beaumont Hospital’s results [7] also received same criticism in the editorial comment that the voiding might be the result of intra-abdominal pressure rather than the reflex arc.

Furthermore, Xiao failed to disclose in [4] that all of the first 13 patients had tethered cord syndromes [5], and that detethering was performed in addition to never rerouting, revealed by Xiao’s partner [8]. Xiao has the reason to conceal this information, since detethering is a standard surgical procedure of spinda bifida, whose effects have already been confirmed in numerous clinical reports [9] and mentioned by a peer expert [8]. In fact, voluntary voiding and bladder sensory in some patients with spinda bifida after his procedure can be explained by “the fact that the connection between spinal cord and brain has not been disrupted” as discussed in [5] by Xiao himself, but was mystified later by doctors at Beaumont [7] as remodeling of the central nerve system. We note that the effects of Xiao’s procedure can alao be partly attributed to denervation of the S2 or S3 nerves, as pointed out by peer experts in [6] and in the editorial comment on Beaumont’s report [7]. The difference is that denervation of the L5 ventral (motor) nerve results in serious side effects in patients’ lower extremities. Xiao has never conducted a controlled study or done a historic review on these conventional treatments, even though his private hospital has performed his procedure on thousands of patients for profit.

Xiao’s 2003 and 2005 papers [1,4] were cited by his 2006 review article [10] (NIH is one of the sponsors). Besides these two papers, he also cited a conference report [11] that does not exist in the said Proceedings. Later on, the review article became the major reference of Beaumont Hospital’s pilot clinical trial [12], while the claim of more than 85% success rate originated from the non-existent report became the major supporting data in Beaumont Hospital’s application to their NIH grant [13].

We are not surprised to find out that Xiao committed the aforementioned academic misconducts. It has already been discovered that he once fabricated an official document [14] testifying the 85% success rate of 117 patients after 8 months of follow-up, but the hospital itself came into existence and performed its first surgery less than 8 months before.

Finally, Xiao’s fabrication and falsification in his data can well explain why his results could not be replicated by the doctors at Beaumont Hospital, who were commented by peer experts that their one-year outcomes [7] “challenge the excellent, previously published results”, and that “the clinical benefit of the procedure is not at all similar to previous reports”.

We will file a complaint to the Journal of Urology and European Urology on Xiao’s fabrication and falsification. We will also present this case to related authorities.

(Written by Yush. Volunteers contributed their findings.)

References

[1] Xiao’s 2003 article
http://www.ncbi.nlm.nih.gov/pubmed/14501733
Xiao CG, Du MX, Dai C, Li B, Nitti VW, de Groat WC. An artificial somatic-central nervous system-autonomic reflex pathway for controllable micturition after spinal cord injury: preliminary results in 15 patients. J Urol 2003; 170: 1237.
A total of 15 male volunteers with hyperreflexic neurogenic bladder…Of the 15 patients 10 (67%) regained satisfactory bladder control within 12 to 18 months after VR micro anastomosis. Average residual urine decreased from 332 to 31 ml and
urinary infection as well as overflow incontinence disappeared. Urodynamic studies revealed a change from detrusor hyperreflexia with DESD and high detrusor pressure to almost normal storage and synergic voiding without DESD.
…After successful experiments in animals, clinical trial was started in 1995. We report results in the first 15 patients with SCI.

[2] Xiao’s 1998 conference abstract
http://xysblogs.org/wp-content/blogs/107/uploads/1998xiao14sci.gif
Xiao CG, Godec CJ, Du MX, Dai C, and Zhu X. A new procedure to restore bladder functions after SCI: Preliminary report on 14 patients. J.Urol. 159:304A, 1998
We have performed this procedure on 14 SCI patients since 1995 to try to restore controllable voiding….
Of 6 patient with hyperreflexic badder, 5 had successful recovery of bladder function. They are able to void by initiating the skin-CNS-Bladder reflex, which became functional from the 10th to 12th month postoperatively. Residual urine decreased from 300 ml to 31 ml in average, and no UTI occurred since the sixth month postsurgically. CMG study documented the changes of the bladder from hyperreflexia and high pressure to relatively normal…. Among 8 patients with areflexic bladder, 3 showed remarkable recovery and 1 had patial recovery.
SOURCE OF FUNDING: NIH, PVA

[3] Xiao’s achievement, from the Holeung Ho Lee Foundation
http://www.hlhl.org.cn/news/findnews/showsub.asp?id=476
(Translation) We started the clinical study in 1995 and have treated 14 SCI patients, and conducted 2.5 to 3.5 years of follow-up. Of 6 patient with hyperreflexic bladder, 5 restored bladder storage and emptying function. Average residual urine decreased from 317 ml to 29 ml. Six months after operations, they no longer suffer urinary tract infection. One case failed because of other reasons. Among 8 patients with areflexic bladder, 5 completely restored bladder storage and emptying function, 1 had partial recovery, average residual urine decreased from 288 ml to 32 ml.

[4] Xiao’s 2005 article
http://www.ncbi.nlm.nih.gov/pubmed/15879861
Xiao CG, Du MX, Li B, Liu Z, Chen M, Chen ZH, Cheng P, Xue XN, Shapiro E, Lepor H. An artificial somatic-automonic reflex pathway procedure for bladder control in children with spina bifida. J Urol 2005; 173: 2112.
Preoperative urodynamic studies revealed 2 types of bladder dysfunction— areflexic bladder (14 patients) and hyperreflexic bladder with detrusor external sphincter dyssynergia (6). All children were incontinent. Of the 20 patients 17 gained satisfactory bladder control and continence within 8 to 12 months after VR microanastomosis. Of the 14 patients with areflexic bladder 12 (86%) showed improvement. In these cases bladder capacity increased from 117.28 to 208.71 ml, and mean maximum detrusor pressure increased from 18.35 to 32.57 cm H2O. Five of the 6 patients with hyperreflexic bladder demonstrated improvement, with resolution of incontinence…..In these cases mean bladder capacity increased from 94.33 to 177.83 ml, and post-void residual urine decreased from 70.17 to 23.67 ml. Overall, 3 patients failed to exhibit any
improvement.
…Based on our success in restoring bladder function and continence associated with spinal cord injury (SCI) by means of artificial somatic-central nervous system (CNS)-autonomic reflex pathway surgery, we investigated the effectiveness of this innovative surgical procedure in children with spina bifida and neurogenic bladder. To our knowledge this report represents the first published experience applying this technique to the management of spina bifida.
…Patient characteristics. The spinal defect had been closed surgically in all cases within 48 hours of birth. The group included 12 males and 8 females 5 to 14 years old (mean age 11 years)…

[5] Xiao’s 2003 article (in Chinese)
http://xysblogs.org/wp-content/blogs/107/uploads/2003xiaochn.pdf
http://en.cnki.com.cn/Article_en/CJFDTOTAL-LCMW200311001.htm
http://www.cnki.com.cn/Article/CJFDTOTAL-LCMW200311001.htm
Xiao CG, Du X-X, Liu Z, Li B, Chen ZH, Cheng P, Chen M. An artificial somatic-central nervous system-autonomic reflex pathway for spina bifida patients with neurogenic bladder and bowel. Journal of Clinical Urology 18(11).
Abstract (in English, provided by the authors)
A total of 30 patients with bladder and bowel dysfunctions caused by spina bifida underwent linited laminectomy and ventral root microanastomosis since 2000…. 13 patients had been followed up for at least one year. Four of 7 cases with areflexia bladder gained bladder control and automatic micturition abiliti within 6 months and 1 year after surgery…. All 6 cases with hyperreflexia bladder achieved controllable voiding, whose residual urine decreased from (102+/-39) ml to (22+/-15) ml and the detrusor external sphincter dyssynergia (DESD) disappeared.
(Translation of the text) After our success in treating bladder and bowel dysfunction in patients with spinal cord injury started in 1995, we have applied the theory and the technique to treat bladder and bowel dysfunction in 30 patients with spina bifida. So far we have followed up 13 cases for at least 1 year….
Clinical Information. …Total 13 patients have been followed up for more than 1 year, including 7 males and 6 females 2 to 25 years old, mean age 11 years. All patients had their spinal defects surgically closed within 2 years of birth. … MRI examinations (of all patients) exhibit typical images of tethered cord syndrome.
Results. …Most of patients need the help of different level of abdominal pressure in order to completely empty bladders.
Discussion. …After the operation, most of patients with spinal cord injury need stimulation of the dermatome to initiate voiding. In contrast, patients with spina bifida can void voluntarily, this is explained by the fact that the connection between spinal cord and brain has not been disrupted.

[6] Criticism from a peer expert from China
http://www.sciencenet.cn/m/user_content.aspx?id=280348
(Translation) Opinions on Xiao’s Reflex Arc
Science News. Dec 8, 2009
First, no control group has been set up. Selective sacral neurectomy has been used for treatment of neurogenic bladders. Even the artificial reflex arc itself doesn’t work at all, the surgery may have some effect as it denervates S2 and S3 nerves. Such effect at the early stage is not caused by the reflex arc. Without a control group, we cannot tell whether the effect is the result of selective sacral neurectomy or of the reflex arc.
Second, the urodynamic data contradict themselves….The figures reveal the truth inside the reflec arc. The postoperative urodynamic studies in Fig. 3B and Fig. 4B clearly show that the patients urinated by intra-abdominal pressure. But Xiao explained that it is the reflex arc that causes the urination. The flaw was ignored by editors. The evidence is that the intra-abdominal pressure (Pabd) is the same as intravesical pressure (Pves). And the detrusor pressure (Pdel) is very low (a flat line), nearly zero. Voiding happened only when intra-abdominal pressure existed.

[7] Beaumont Hospital’s one-year outcomes
http://www.ncbi.nlm.nih.gov/pubmed/20639040
Peters KM, Girdler B, Turzewski C, Trock G, Feber K, Nantau W, Bush B, Gonzalez J, Kass E, de Benito J, Diokno A. Outcomes of lumbar to sacral nerve rerouting for spina bifida. J Urol. 2010 Aug;184(2):702-7. Epub 2010 Jun 19.

[8] Xiao’s partner revealed that detethering was performed in addition to never rerouting.
http://bkb.ynet.com/article.jsp?oid=59384400
(Translation) An investigation of Shenyuan Hospital. Beijing Sci-Tech Weekly. Dec 08, 2009
Former president of Henan Shenyuan Hospital Gao Xiaoqun told the Weekly, the conventional treatment of spinda bifida is detethering a tethered cord…. As for the Xiao Reflex Arc, doctors also perform detethering in addition to never rerouting….
“I specialize in the research of nerve regeneration. I believe that this idea is simply nonsense”. Yu Yanbing, director of Neurosurgery of China-Japan Friendship Hospital, told Beijing Sci-Tech, that the standard surgical procedure for congenital spina bifida is detethering, which has a success rate of 50% to 70%.

[9] Clinical reports on detethering and denervation.
http://www.ncbi.nlm.nih.gov/pubmed/12145516
von Koch CS, Quinones-Hinojosa A, Gulati M, Lyon R, Peacock WJ, Yingling CD. Clinical outcome in children undergoing tethered cord release utilizing intraoperative neurophysiological monitoring. Pediatr Neurosurg. 2002 Aug;37(2):81-6.
“Significant bowel and bladder improvement was seen in 4 out of 25 patients”
http://www.ncbi.nlm.nih.gov/pubmed/17328264
Hsieh MH, Perry V, Gupta N, Pearson C, Nguyen HT. The effects of detethering on the urodynamics profile in children with a tethered cord. J Neurosurg. 2006 Nov;105(5 Suppl):391-5.
“in five (50%) of the 10 children with abnormal preoperative UDS results, the postoperative UDS demonstrated improved or normal urodynamics.”
http://www.ncbi.nlm.nih.gov/pubmed/7609174
Schneidau T, Franco I, Zebold K, Kaplan W. Selective sacral rhizotomy for the management of neurogenic bladders in spina bifida patients: long-term followup. J Urol. 1995 Aug;154(2 Pt 2):766-8.
“remarkable success in maintaining bladder volume and low pressures after rhizotomy and cord untethering.”
http://www.ncbi.nlm.nih.gov/pubmed/3359125
Lucas MG, Thomas DG, Clarke S et al: Long-term follow-up of selective sacral neurectomy. Br J Urol 1988; 61: 218.
“Thirteen of the 22 patients had significant symptomatic improvement lasting for more than 4 years post-operatively (59%), 8 of whom had stable bladders.”
http://www.ncbi.nlm.nih.gov/pubmed/11445474
Hohenfellner M, Pannek J, Botel U et al: Sacral bladder detethering for treatment of detrusor hyperreflexia and autonomic dysreflexia. Urology 2001; 58: 28.
“Detrusor hyperreflexia and autonomic dysreflexia were eliminated in all cases.”

[10] Xiao’s 2006 review
http://www.ncbi.nlm.nih.gov/pubmed/16314037/
Xiao CG: Reinnervation for neurogenic bladder: historic review and introduction of a somatic-autonomic reflex pathway procedure for patients with spinal cord injury or spina bifida. Eur Urol 2006; 49: 22.
Supported by grants from … NIH (R01 DK44877 and R01 DK53063)

[11] Non-existent conference report cited by [10]
Xiao CG. A somatic-autonomic reflex pathway procedure for neurogenic bladder and bowel: results on 92 patients with SCI and 110 children with spina bifida. In: Proceedings of the International Conference of Urology; Shanghai, July 2-4, Shanghai, China; 2005.

[12] Clinical trial information of Beaumont Hospital’s pilot study
http://www.clinicaltrials.gov/ct/show/NCT00378664
Lumbar to Sacral Ventral Nerve Re-Routing.
Identifier: NCT00378664

[13] Project information of Beaumont Hospital’s NIH grant
http://projectreporter.nih.gov/project_info_description.cfm?aid=7696321
Safety and Efficacy of Nerve Rerouting for Treating Neurogenic Bladder in Spina Bifida.
Project Number: 1R01DK084034-01
He has reported that in 92 SCI patients, 88% regained bladder control within one year after the nerve rerouting surgery and in 110 children with spina bifida, reported success in 87% at one year.

[14] Faked certificate of success rate supporting Xiao’s membership application to the Chinese Academy of Sciences.
http://xysblogs.org/wp-content/blogs/107/uploads/shenyuan.jpg
(Translation) Neuro-Urologic Surgery Research Center (a.k.a Shenyuan Hospital) at Zhengzhou University, February 28, 2007
Starting from Jan. of 2006, the Neuro-urological Surgery Research Center at Zhengzhou University has applied the “artificial somatic-autonomic reflex arc” technique invented by Professor Xiao Chuanguo to 117 patients with neurogenic bladder caused by spina bifida or meningomyelocele. Sixty cases were followed up for more than eight months. 85% of the patients have regained normal bladder and bowel functions.
(Note: The hospital was established in Auguest 2006.)

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

HAO XIN
SCIENCE VOL 330 5 NOVEMBER 2010 Published by AAAS

(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.”

Today, an email arrived from a different office, the Office for Human Research Protections, indicating that they are taking actions on this issue:

From: Borror, Kristina C (HHS/OASH)
To: Eddie Cheng
CC: Menikoff, Jerry (HHS/OASH)
Subject: “Xiao Procedure”

Dear Mr. Cheng:

The Office for Human Research Protections (OHRP) has received your letter concerning research conducted at William Beaumont Hospital. I apologize for the delay in responding to you.

OHRP has responsibility for oversight of compliance with the U.S. Department of Health and Human Services (HHS) regulations for the protection of human research subjects (see 45 CFR Part 46 at http://www.dhhs.gov/ohrp/humansubjects/guidance/45cfr46.htm). In carrying out this responsibility, OHRP evaluates, at OHRP’s discretion, substantive allegations of noncompliance involving human subject research projects conducted or supported by HHS or that are otherwise subject to the regulations (see OHRP memorandum dated October 14, 2009 at http://www.hhs.gov/ohrp/compliance/ohrpcomp.pdf for an explanation of OHRP’s jurisdiction).

OHRP has initiated an evaluation of the matter referenced in your letter. We notified the funding agency of your allegations and they have stopped enrollment into the study. We will advise you when the evaluation has been completed.

OHRP appreciates your concern about the protection of human research subjects. Please do not hesitate to contact me at any time should you have any questions or wish to provide additional information.

Sincerely

Kristina C. Borror, Ph.D.
Director
Division of Compliance Oversight
Office for Human Research Protections
1101 Wooton Parkway, Suite 200
The Tower Building
Rockville, MD 20852

(Note: email address and phone number are also included in the above email. Although they are public records, they are omitted here to limit spam.)

More recently, the hospital has also become the first institute to publish clinical results of Xiao Procedure in an established scientific journal. Dr. Kenneth Peters and his coauthors wrote in the Journal of Urology of their results:

At 1 year 7 patients (78%) had a reproducible increase in bladder pressure with stimulation of the dermatome. Two patients were able to stop catheterization and all safely stopped antimuscarinics. No patient achieved complete urinary continence. The majority of subjects reported improved bowel function. One patient was continent of stool at baseline and 4 were continent at 1 year. Of the patients 89% had variable weakness of lower extremity muscle group at 1 month. One child had persistent foot drop and the remainder returned to baseline by 12 months.

In their conclusion, they noted that “this procedure should remain on a research protocol, and more patients and longer followup are needed to assess the risk/benefit ratio of this novel procedure.”

The Journal, however, appears to be less than impressed. It published two pieces of editorial comments to accompany the paper, both are quite negative. In one, Dr. Eric Kurzrock of UC Davis Children’s Hospital wrote:

The authors present the first North American experience with lumbar to sacral nerve rerouting for patients with spina bifida. The results from this study and previous animal and clinical studies by Xiao clearly demonstrate that nerve rerouting produces a somatic-autonomic or cutaneous/bladder reflex with stimulation of the lower extremity dermatome. What is also clear is that the clinical benefit of the procedure is not at all similar to previous reports.

Although the authors did an excellent job of following the patients and characterizing their changes, the results are hard to validate without a control population going through the same rigorous surveillance regimen. In particular the improved bowel continence and minimal changes in bladder compliance may not be statistically significant. The fact that most patients were still on clean intermittent catheterization and none achieved complete urinary continence is troubling in light of the report of 87% success with 110 children with spina bifida presented by Xiao. One has to wonder if most of these children are not voiding volitionally or using the newly developed cutaneous reflex, and how much reinnervation has a role in this surgery. Is it possible that unilateral denervation of the S3 ventral motor nerve produced improved compliance and continence, as previously reported in numerous clinical series?

I congratulate the authors for taking on this challenge. I hope this study leads to a rebirth or refocus regarding neurosurgical treatments of neuropathic bowel and bladder. I strongly agree with the authors that this procedure should remain on a research protocol only.

In another, Dr. John Park of University of Michigan was even more blunt:

One of the most curious findings is the discrepancy between urodynamic data and subjective voiding. One patient exhibited a decrease in capacity and an absence of reflex arc, and yet he subjectively reported improved bladder and bowel function! I could not help but speculate that his voiding after the procedure could simply be the bladder emptying via intra-abdominal pressure generation against an open bladder neck, given his preoperative stress incontinence. Xiao reported that more than 87% of 110 patients gained sensation and continence within 1 year (reference 7 in article). In comparison, the current patients undergoing the identical procedure with the help of Xiao himself only showed a modest improvement in objective urodynamic studies and subjective reporting. Unless the innovators provide a sound argument and data for the validity of the procedure, there is a great danger of its improper and rapid adaptation by patients and the medical community at large.

Along with the editorial comments, Dr. Piet Hoebeke of Ghent University Hospital in Belgium also commented on Beaumont’s results in his editorial:

… in this issue of The Journal the results of the study by Peters et al (page 702) are the first to challenge the excellent, previously published results of nerve rerouting that showed up to 85% success.8 Despite proof that nerve rerouting can create a novel reflex arc generating a detrusor contraction, this group learned that after 1 year no patient became continent and only 2 of 9 were able to stop catheterization. Effects on bladder compliance and cystometric bladder capacity were remarkable despite stopping antimuscarinic treatment. Persistent foot drop cannot be considered a minor complication in children who are already motor disabled. Although promising, this study cautions us that further controlled studies are needed before this nerve rerouting procedure can be used more routinely.

Finally, We cite below how Beaumont described their one-year results in a much more “promising” way in their press release and their project information for the NIH grant they were rewarded in 2009.

Beaumont sees results in nation’s 1st urinary nerve rewiring surgeries for spina bifida patients
4/17/2008

Seven children from across the United States are gaining bladder control through a revolutionary, first-in-the-nation nerve rerouting surgery for patients with spina bifida. The surgeries were conducted in 2007 at Beaumont Hospital in Royal Oak, Mich.

The children previously required the insertion of a catheter to empty their bladder or endured significant incontinence. But as a result of the surgery, they are beginning to void on their own and are also seeing improvement in bowel function. Initially they signaled the bladder to urinate by scratching or pinching their leg or buttocks. But, remarkably, in most patients the brain was able to take over and control urination normally.

This will allow them to attend school without being catheterized and to play with other children without the embarrassment of soiling themselves. It also means fewer urinary tract infections resulting from catheterization, and reduces their need for antibiotics for infection control.

…
Possible side effects of the surgery include mild postoperative spinal fluid leakage, lower extremity weakness and headache. Recent changes in the surgical technique have dramatically decreased the incidence of these complications. Standard risks associated with any surgery may include bleeding and infection.

Project Information
Project Number: 1R01DK084034-01
Our preliminary data are very promising, and with 9 subjects now 12 months post procedure, 7/9 subjects are voiding either voluntarily or by stimulating the new reflex mechanism.

Update: Dr. J.W. Thüroff presents a thorough theoretical analysis of the Xiao Procedure in European Urology. 2011 Jan;59(1):173-5. Summary of his comments:

Transection of the lumbar nerve will cause muscle weakness and even permanent muscle paralysis, as in the one reported case with persistent foot drop. Transection of the sacral nerve will cause some improvement of hyperreflexia, but the effect is limited. Reinnervation of the sacral nerve, even if completely successful, will result in limited efficacy, and may cause some DSD.

Dr. Thüroff examined the published urodynamic tracings of Xiao, and found that “voiding is predominantly achieved by abdominal straining with concomitant pelvic floor activity and by only weak detrusor contraction with indiscernible DSD because of the simultaneous abdominal straining.”

Dr. Thüroff concluded that “the important message of the paper by Peters et al is that the functional results of lumbar to sacral nerve rerouting in spina bifida, in their experience, are less favorable in terms of achieving voluntary micturition and urinary continence in children with spina bifida compared with the excellent reports of Xiao… the clinical results of Peters et al are expected based on the theoretical considerations noted.”

Update: more comments from peer expets:

http://f1000.com/4390959

Re: Outcomes of lumbar to sacral nerve rerouting for spina bifida.
Peters KM, Girdler B, Turzewski C, Trock G, Feber K, Nantau W, Bush B, Gonzalez J, Kass E, de Benito J, Diokno A. J Urol. 2010 Aug; 184(2):702-7

——————————–

Rosalia Misseri, Indiana University, IN, USA. F1000 Urology
29 Jul 2010 | Clinical Trial, Controversial

The concept of restoring bowel and bladder function by creation of a skin-central nervous system-bladder reflex arc via lumbar to sacral nerve rerouting is curious and has lead to much enthusiasm. This study is the report of the 1-year results of the first North American trial. I found the difference in success between a prior study by Xiao (85%) {1} and the current study interesting.

The authors reported the feasibility of nerve rerouting and their results in subjects at 1 year. No patient achieved complete urinary continence. Most patients had subjective improvement in bowel and bladder function. Despite some improvement in voiding and bowel function, most improvement appeared to be related to bowel function. Transient lower extremity weakness occurred commonly post-operatively, and one patient unfortunately suffered foot drop. The authors are to be applauded for their careful patient follow-up. They stress the importance of a rigorous research protocol and longer follow-up. Despite this innovative neurosurgical approach to neurogenic urinary and fecal incontinence, it is clear that patients undergoing this procedure must be carefully monitored and that very select centers should perform this procedure with strict research protocols in place.

References: {1} Xiao CG, Eur Urol 2006, 49:22-8 [PMID:16314037].

Competing interests: No potential interests relevant to this article were reported.

——————————–

Chris Cooper and Kathleen Kieran, University of Iowa Hospitals and Clinics, IA, USA. F1000 Urology
09 Aug 2010 | Clinical Trial, Controversial

We found this small study of a novel neurosurgical technique for the management of neurogenic bladder and bowel provocative. This paper takes the first steps towards allowing us to more accurately define clinical success rates and identify the subset of patients most likely to benefit from this intervention.

Peters et al. report their single-center experience with lumbar-to-sacral nerve rerouting for the treatment of bladder and bowel incontinence in nine patients with spina bifida. Patients were assessed for continence as well as bowel and bladder symptoms at baseline and at 12 months after surgery. Cutaneous nerve stimulation was begun three months postoperatively. All but one patient had motor weakness, two had substantial gait alterations, and one had foot drop evident early in the postoperative period; all symptoms improved by 12 months except the foot drop. Over the postoperative period, some patients did experience worsening of bladder and bowel incontinence; this was followed by increased awareness of bladder and bowel sensation and the authors postulated that this represented a period of reinnervation. Improvements in bowel function generally preceded improvements in urinary function. At one year, seven out of nine patients had a reproducible bladder reflex with cutaneous stimulation and were able to void spontaneously; their bladder compliance had also improved. Although no patient achieved complete urinary continence, 44% had bowel continence by 12 months, and renal function was stable in all patients. The authors note that the conclusions drawn by their study must be interpreted in light of the small number of patients, relatively short follow-up period, and the limitations of urodynamic studies. Interestingly, the reported success rate in this series was lower than the 87% previously reported in a series of 100 Chinese children, suggesting not only the need for further study of this novel technique but also the importance of carefully selecting patients for study participation as well as establishing a universal operational definition of clinical success.

For further reading, please see refs {1-6}.

References: {1} Xiao et al. J Urol 1990, 143:356A. {2} Xiao CG, Eur Urol 2006, 49:22-9 [PMID:16314037]. {3} Xiao and Godec, Paraplegia 1994, 32:300-7 [PMID:8058346]. {4} Xiao et al. J Urol 1999, 162:936-42 [PMID:10458412]. {5} Xiao et al. J Urol 2003, 170:1237-41 [PMID:14501733]. {6} Xiao et al. J Urol 2005, 173:2112-6 [PMID:15879861].

Competing interests: No potential interests relevant to this article were reported.

——————————–

Bradley Kropp and Blake Palmer, University of Oklahoma, OK, USA. F1000 Urology
20 Jul 2011 | Clinical Trial

I found this article interesting because of the speculation surrounding Dr Xiao’s procedure and reports of 87% sensation and continence at 12 months in spina bifida patients {1}. This is the first report of the procedure and outcomes by someone other than Dr Xiao and done outside of China.

These authors presented their 12-month outcome data on 9 spina bifida patients who underwent an L5 motor root (total in four and partial in five) transection and anastomosis to the transected S3 nerve root. This procedure was done by local neurosurgeons at William Beaumont Hospital in Michigan under the guidance and training of Dr Xiao himself. These patients all underwent thorough preoperative evaluation from a neurology and urology standpoint and were followed closely and studied extensively for the 12 months postoperatively.

They reported no intraoperative complications and a fairly well-tolerated procedure. Lower extremity weakness was expected given the L5 motor root transaction and was seen in 8/9 patients at 1 month. At 12 months, 8/9 were described as at or near baseline function except for one with persistent ipsilateral foot drop and significant worsening of their gait.

The subjective urologic and bowel function seemed to be more improved than the objective evidence to support this. The report does state frankly that the outcomes fall short of what has previously been reported by Dr Xiao as no patient achieved complete urinary continence or stopped intermittent catheterization.

From a neurourologic standpoint, the intended reflex arc was demonstrated objectively in 7/9 patients. This is an extremely important finding that shouldn’t be overlooked, seeing as previous reports falls short of in terms of the amount of clinical data provided. The fact that this procedure failed to show a ‘leap’ forward in the treatment of spina bifida patients shouldn’t mean that it does not contribute to our understanding of the neurogenic bladder in patients with spinal dysraphism and lead to more innovative thinking in terms of neuropathic bladder management.

I also think the rigorously designed study and open reporting of the results should be applauded. I agree with the authors and reviewers that this procedure and others like it should only be done in this manner with the utmost care for the patient and scientific principles applied.

References:

{1} Xiao CG, Eur Urol 2006, 49:22-8 [PMID:16314037].

Competing interests: No potential interests relevant to this article were reported.

 

http://www.spinabifidaassociation.org/site/c.liKWL7PLLrF/b.6701685/k.D5F2/Research_Articles_January_2010_to_January_2011.htm

Research Articles
January 13, 2010 to January 31, 2011

SBA’s National Resource Center is now providing summaries of research on Spina Bifida and related topics. The following topics are frequently requested by Resource Center patrons. The purpose of this list is to highlight professional literature on the subject of spina bifida and related topics.

Urology

Peters KM, Girdler B, Turzewski C, Trock G, Feber K, Nantau W, Bush B, Gonzalez J, Kass E, de BJ, Diokno A. Outcomes of lumbar to sacral nerve rerouting for spina bifida. J Urol 2010 August;184(2):702-7.

[A few years ago Dr. C G Xiao in China described a surgical procedure in which spinal nerves on one side of the body were rerouted, with the ventral lumbar (L5) nerve attached to the sacral (S2) nerve. He reported a success rate of 87%. In the current study the authors reported on the use of this procedure in 9 children who were followed for a year after surgery. The majority of the children in this study had improved bowel continence and improvement in bladder compliance. However, none achieved complete urinary continence. Most also had some weakness of the leg on the side of the surgery. This is a preliminary trial with no comparison group. However, as noted in the two editorials that followed this article, the results are thus far disappointing compared to the glowing reports from China.]

 

http://www.ncbi.nlm.nih.gov/pubmed/22037959

Gregory E. Dean and Christopher Long. Updates in the Management of the Overactive Bladder in Patients with Myelomeningocele. Curr Urol Rep (2011) 12:413–418. Published online: 25 October 2011

Abstract

… Nerve rerouting for neurogenic bladder is a novel, albeit unproven, approach, its use remaining experimental at this point.

Rerouting

Initially developed in China, bladder rerouting is a novel procedure that creates an artificial somatic–autonomic reflex arc to restore neurologic control of bladder filling and emptying in patients with spina bifida [15]. In summary, a midline approach exposes the lumbar and sacral spinal column and a limited laminectomy is performed between L4 and S2. After identification of the L5 and S3 vertebral roots, the arc is created by anastomosing the proximal end of the ventral root of L5 to the distal end of the ventral root of S3. Xiao et al. [15] reported a success rate in 87% of 110 patients at 1 year of follow-up, with nearly all patients achieving continence. Peters et al. [16] were the first group in North America to report their experience with the technique. A total of nine patients enrolled in the study, with seven patients experiencing a response in bladder pressure with dermatome stimulation (suggesting successful rerouting). All patients were able to remain off antimuscarinic therapy postoperatively, although no patients achieved complete continence. The authors also noted improved bowel function for the patient population. Nearly all participants experienced increased bladder and bowel sensation, although consistent improvement documented by urodynamic analysis was lacking [16]. Motor weakness of L5 is a complication highlighted in both studies, ranging from partial weakness (that eventually was shown to recover) to persistent full foot drop [15, 16]. While this approach promises much, no recent published studies have confirmed the degree of success reported by Xiao et al. [15]. Caution should be employed by any clinician who pursues this approach given the lack of confirming data at this point in time.

 

http://www.hindawi.com/journals/au/2012/816274/

Advances in Urology. Volume 2012 (2012), Article ID 816274
Review Article
Neurogenic Bladder

Peter T. Dorsher and Peter M. McIntosh

7.1. Lumbar to Sacral Nerve ReroutingRestoring bladder function in spina bifida by creation of a skin-central nervous system bladder reflex arc via lumbar (L5 motor) to sacral (S3) nerve rerouting has a reported success rate of 87% in 110 children in China [83]. Recently the one-year results of the first North American trial were reported, with 7/9 (87%) of spina bifida subjects having measurable increase in bladder pressure with L5 dermatomal stimulation (>10?cm H2O), most demonstrating a modest increase in bladder compliance, and all stopping antimuscarinic drugs. Two subjects were able to stop catheterization, but none achieved complete urinary continence [84]. One patient had a persistent foot drop after this surgery. These outcomes differ substantially from the Chinese experience, and the improvements in continence and bladder compliance may relate to sectioning of the S3 nerve root in the procedure. This should still be considered an experimental procedure until further prospective data on its efficacy and effects on quality of life can be determined.

 

Who will evaluate Xiao Chuanguo?
Science News. Oct 28, 2009

Gong Ju, who is engaged in basic neurology research, said frankly on the other hand that the basic research done by Xiao Chuanguo at the very beginning was not convincing enough, for example the tissue slice performed by using an electronic microscope; moreover, Xiao had drawn a scheme of reflex, but the middle part is not correct in neuroanatomy. “The reason is, the nerve reflections stimulated by scratching skin cannot reach motoneurons directly to form a reflex arc, as he had drawn. Such kind of reflex arc reaches muscle directly, which is only possible to reach the anterior horn of the spinal cord through an interneuron instead of to reach by skin-sense. He missed a connection, but he just drew in his way; he never concerned other’s arguments, but insisted that it is very correct”, said Gong Ju, “I don’t like such kind of things.”

…
Professor Jin Xiyu of the Third Military Medical University in Chong Qing was a specialist in urological surgery….During the evaluation, Xiao Chuanguo specially brought several patients to the panel to show the effects of the procedure. A non-specialist would see that the patients started to urinate normally after their lower abdomens being slightly pressed. But Jin Xiyu, being an expert in urodynamics, suggested that it could imply that the urination was caused mainly by the pressure (applied to abdomens), rather than the recovery of neurological functions.

“Artificial Reflex Arc”, Who can explain it?
China News Weekly. Nov 11, 2009

In the evaluation report, the reporter noticed it also mentioned, “The spinal continuity of this type of children patients is not broken. A functioning healthy somatic motor nerve bundle must be sacrificed in order to construct an artificial reflex arc to control the bladder, which carries very high risks.”

About this potential risk, Xiao provided an explanation, “There were indeed 4 or 5 children having some problems among the initial 20 cases. This is like ‘robbing Peter to pay Paul’. There is very little side effect to lower limbs, which may have a little weakness. But now we have solved it. Only a third of the nerve bundle, at most a half, is used, and it will fully recover after a year. So this is not a problem any more.”
…

If the Xiao procedure has 85% success rate, why cannot it be popularized in any major hospitals?

To find out the answer, we interviewed several experts in urological surgery. “We also have this concern!”, said Guo Yinglu, the honorary director of the Institute of Urological Surgery at Peking University and the only Academician in urological surgery in Chinese Academy of Engineering. Guo said, “It makes some sense in the theory of the Xiao procedure. But not for all the patients can it achieve nerve reconnection”. He then took the case of SCI patients as an example. “The injury of spinal cord happens at different levels. Only for those at lower levels, their bladder nerve may be reconnected, and you can only do this when you are able to find the nerve”. Guo continued to say, “So, it means that even if he (Xiao) is correct, the effectiveness (of the procedure) is limited”. Guo said that he was not aware of the situation of implementing the Xiao procedure to spina bifida, and he did not have much contact with Xiao in person.

Most of the urosurgical experts interviewed were not willing to talk much about Xiao’s reflex arc procedure. They all said that this technique needs to face the evaluation along the time. “If it is proven to be effective, it would gain extensive clinical implementation, because the needs from the affected patient population are overwhelming.”

But there are doctors expressed doubt on the Xiao procedure. Dr. Ji Xiaolong, director of the Pathology Department of the Armed Police General Hospital, said that the healing of nerves remains a big challenge in medical field. “It’s hard (for nerve) to grow into one piece. Imagine that each nerve is like a telephone cable with many contacts in it. Only when every contact is connected, can we say it is healed. No current technique in any microscopic surgery can achieve this. Leaving the two nerve stumps searching for each other (for reconnecting), it involves uncertainty”.

The cure rate of “Xiao procedure”: 85% or 0%?
Science News. Nov 23, 2009

“I use two sentences to describe (my opinion): first, this procedure is absolutely not like what he described, that it has solved the problem of neurogenic bladder; second, the procedure may be effective for some patients, because there are some pertinent indications. Some patients can be treated with this procedure, but absolutely not all.” Professor Song Bo at the Third Military Medical University in Chongqing held this opinion.

Song Bo indicated that he did not agree to blindly gloss over or promote this type of procedures, because, after all, it was not a business activity. “I am all against the statement that it has solved the problem of neurogenic bladder; I did not really agree with its application for the National Prize for Progress in Science and Technology either.” In the meantime, he believes there has not enough evidence so far to assert that the procedure is completely useless. “But his research is not finished yet. What are the indications for the procedure, ultimately, is not even clear. It is unfounded at this stage to say things like a grand problem has been solved.” Song Bo said.

“He applied the (neuro-surgical) techniques to urological surgery. We could see very few clinical patients, and we did not observe his operations either. We simply were not able to make any comments. They brought the patients in. I did not watch the operation. He had no publication at that time. We knew even less about the international evaluation on his procedure. Everything was based on his own words. We could not see any comments from other countries. He said we would not be able to conduct the operation, but why they themselves were not able to popularize it either? We are also wondering.” Guo Yinglu, a professor at the Beijing Medical University and an academician of China Engineering Academy, told Science News.

“When doing science, we should allow mistakes, exploration, and all kinds of efforts. But we should not allow claims such as what has been solved and what has been created, when there is no complete scientific evidence, nor a large amount of evidence-based medical data. They are not scientific statements. I oppose these statements.” Song Bo summed up.

An investigation of Shenyuan Hospital
Beijing Sci-Tech Weekly. Dec 08, 2009

Former president of Henan Shenyuan Hospital Gao Xiaoqun told the Weekly, the conventional treatment of spinda bifida is detethering a tethered cord…. As for the Xiao Reflex Arc, doctors also perform detethering in addition to never rerouting….

In August 2004, a panel was formed by seven academicians and a professor, including top experts Qiu Fazu from Tongji Medical College and Han Jisheng from Beijing University Medical School. The panel concluded that Xiao’s achievement had “important implications and outstanding novelty” on solving the urinary and fecal incontinence caused by congenital spinal meningocele。

Han Jisheng, academician of the Chinese Academy of Sciences and professor of Peking University Medical School, told the Weekly, experts of the evaluation panel only witnessed the postoperative situation of two patients. One urinated after scratching the leg; another discharged both urine and stool with the help of electrical stimulation. “I cannot remember exactly how much the cure rate was. we did not see all the successful cases, we believed that this technique feasible in theory,” Han said, now that the cure rate of this technique has been questioned, I think that Xiao really needs to provide more successful cases to substantiate his statement.

Another expert of the evaluation panel also recalled that Xiao only presented the panel with partial selective information of seven or eight patients. The panel did not see all of the data of the 20 patients that Xiao claimed he had done.

Guo Yinglu, the honorary director of the Institute of Urosurgery at Peking University and the only Academician on Urosurgery in the Chinese Academy of Engineering, commented that, “It makes some sense in the theory of the Xiao procedure. But not for all the patients can it achieve nerve reconnection, and you can only do this when you are able to find the nerve”. Guo said, “So, it means that even if he (Xiao) is correct, the effectiveness (of the procedure) is limited”.

Dr. Ji Xiaolong, director of the Pathology Department of the Armed Police General Hospital, said that the healing of nerves remains a big challenge in medical field. “It’s hard for nerve to grow into one piece. Imagine that each nerve is like a telephone cable with many contacts in it. Only when every contact is connected, can we say it is healed. But current technique in any microscopic surgery can’t achieve this point but leaving the two nerve stumps searching for each other (for reconnecting), this procedure involves uncertainty”.

“I specialize in the research of nerve regeneration. I believe that this idea is simply nonsense”. Yu Yanbing, director of Neurosurgery of China-Japan Friendship Hospital, told Beijing Sci-Tech, that the standard surgical procedure for congenital spina bifida is detethering, which has a success rate of 50% to 70%. The mechanism of Xiao procedure is said to regenerate the rerouted central nerves, but it is basically impossible to regenerate the central nerves. An organ is under an integrated control of multiple nerves and it is extremely difficult to find out those that control a specific organ. If you make a wrong connection or damage the original nerve, the surgery may compromise the original function of the organ without the intended recovery.

Opinions on Xiao’s Reflex Arc
Science News. Dec 8, 2009

An Letter from an anonymous expert

So far, concerns over the Xiao Procedure are as follows.

First, no control group has been set up. Selective sacral neurectomy has been used for treatment of neurogenic bladders. Even the artificial reflex arc itself doesn’t work at all, the surgery may have some effect as it denervates S2 and S3 nerves. Such effect at the early stage is not caused by the reflex arc. Without a control group, we cannot tell whether the effect is the result of selective sacral neurectomy or of the reflex arc.
…
Second, the urodynamic data contradict themselves. One of Xiao’s paper titled “Reinnervation for neurogenic bladder: historic review and introduction of a somatic-autonomic reflex pathway procedure for patients with spinal cord injury or spina bifida” was published on Eur Urol, 2006 Jan;49(1):22-8. The figures reveal the truth inside the reflec arc. The postoperative urodynamic studies in Fig. 3B and Fig. 4B clearly show that the patients urinated by intra-abdominal pressure. But Xiao explained that it is reflex arc to cause the urination. The flaw was ignored by editors. The evidence is that the intra-abdominal pressure (Pabd) is as same as intravesical pressure (Pves). And the detrusor pressure (Pdel) is very low (a flat line), nearly zero. Voiding happened only when intra-abdominal pressure existed.
…
Third, other reports by Xiao et al on the reflex arc have showed no effect either. A web post, “Comparison of clinical outcomes of the Xiao reflex arc procedure in domestic and foreign cases”, summarized the 2 cases in the U.S.A: the max flow rate was 8cc/s and post-void residual was 200cc/s. “At last follow-up (15 months) L5 stimulation caused a detrusor contraction of 59cm H20, a Q max of 8 cc/sec and no DESD. Voided volume was 150cc and post-void residual was 200 cc’s. (AUA 2005). Urologists know that the normal value of the max flow rate is ≥ 20 ml/s for male, and ≥ 25ml/s for female. If the max flow rate is ≤ 10ml/s, it should be considered as abnormal results due to lower ureteral obstruction or neurogenic bladder. (See Urosurgery, by Jieping Wu, p804). These 2 cases have the max flow rate of 8cc/s and residual of 200ml. How could those results show efficacy?

…
Conclusion: The reflex arc itself does not take effect. The improvement in some patients is the efficacy of selective sacral neurectomy. Since the reflex arc procedure transects limited number of nerve roots, its efficacy is less than that of selective sacral neurectomy.

Expert’s opinion
(by a member of the expert panel who evaluated the Xiao Procedure orginized by the Ministry of Health of China)

The above-mentioned urodynamic studies obviously show that it is intra-abdominal pressure that causes voiding. The maximum flow rate 8cc/s and post-void residual 200cc Obviously indicate there is no effect.

Last October, Xiao was invited to give a presentation on the 30th anniversary of the Institute of Urological Surgery at the Peking University. He showed his video which was more like a commercial to me. In the video, a patient’s mother from the US told a story after the operation. It was not a scientific presentation.

He once got a fairly large amount of grant in the US, and wanted to study 40 cases. We have not seen his final report till 2009. His AUA report was an abstract, which tell us little.

The urological community in China do not well accept the Xiao Procedure. Otherwise, we have already popularized the procedure long time ago. About two years ago in Kunming, in a national conference on urology, Xiao Chuanguo gave a presentation. Song Bo commented afterwards, made some rather objective remarks on the procedure. We run into each other on all kinds of occasions, so it is hard to comment in a direct manner, we do not want to corner him, so that Song Bo refrained himself in the conference. The author of the above letter specializes in neurology, he gives a relatively objective comment. He is sure of that there is no establishment of the reflex arc, and the reflex arc procedure has no effect at all.

In case the procedure has no effect, to void using intra-abdominal pressure instead of detrusor contraction would harm upper urinary tract in the long run, result in vesicoureteral reflux leading to hydronephrosis and hydroureter, and eventually damage the kidney.

Besides, after the denervation of normal nerve, there are questions such as whether it would lead to ED, or how the erectile function is affected, after the children grow up. For these reasons, the procedure is very controversial.

The Division of Investigative Oversight (DIO) of the Office of Research Integrity (ORI) has received your letter of March 1, 2010, and additional documentation describing concerns over a controversial procedure first described by Dr. Chuan-Guo Xiao to treat neurologenic bladder in subjects with spinal cord injury (SCI) or spina bifida. The material you provide raises concerns about the extent and quality of long-term followup of the many subjects that Dr. Xiao and his colleagues have operated on in China and suggests that the high success rate that he and others have claimed of this procedure (the “Xiao Procedure”) has been overstated. This material also notes that Dr. Xiao, while working at New York University prior to his return to China, and others at the William Beaumont Hospital Research Institute, have received funds from the National Institutes of Health to conduct clinical trials to test the safety and efficacy of similar nerve re-routing procedures in children with spina bifida.

After reviewing your concerns, DIO has determined that this office cannot assist you. There are several reasons for this determination. Nearly all of the patients who have received this surgical procedure are in China and ORI does not have jurisdictional authority to intervene.[footnote] The procedure as practiced in the United States has to some extent been funded by PHS funds at NYU and the Beaumont Hospital Research Institute. However, these grant applications clearly identify the procedure as experimental and high risk, and as safety and efficacy trials. The preliminary results of the pilot studies described in the applications are described as providing some benefit for otherwise extremely compromised patients, and the risks and benefits are adequately described. Long term follow-up results will have an impact, when available, on determining the viability of the procedure for more patients.

More important for this office is the absence of specific allegations of possible research misconduct in NIH funded research that are suitably specific to claims that could be shown to be significant and intentional falsification or fabrications of data that could be ascribed to specific individuals. Broad claims that the procedure has been shown to not work in China are not sufficient to establish that appropriate care has been taken in NIH funded research to ensure appropriate care of subjects, and that the risks and possible benefits have been appropriately explained to patients. I also wish to point out that it seems likely that the conflicting opinions on the efficacy of this procedure may, at least in part, be due to honest differences of opinion in what constitutes therapeutic success.

Thank you for raising your concerns with ORI. However, as noted, we are unable to assist you at this time.

John E. Dahlberg, Ph.D.
Director
Division of Investigation Oversight
Office of Research Integrity

[footnote] For ORI to have jurisdiction, allegations must meet the definition of research misconduct at 42 C.F.R. 93.103 and the questioned research must be supported by funds from Public Health Services agencies such as the National Institutes of Health.

1. According to Dr. Xiao, he has “dedicated my live to SCI research since 1976″ [1]. His first animal studies on rats [2] and cats [3], as well as his first clinical trial of 15 patients [4] are all for SCI.

2. Dr. Xiao’s papers on SCI were published “in highly regarded western journals” in 1999 and 2003, co-authored with Dr. de Groat, “the most respected name in bladder physiology” [5]. We note that, in his recent reviews [6, 7] on bladder function recovery after SCI, Dr. de Groat gave no word to Dr. Xiao’s work.

3. From 1999 to 2007, the NIH awarded Dr. Xiao more than 2.4 million dollars for the clinical trial in SCI at New York University (NYU) [8]. It was said that 40 SCI patients had been involved with an 80% response rate [9], but so far no official results have been released, except for a conference abstract [10] that reported two cases with much worse urodynamic results than Dr. Xiao’s first 15 SCI patients in China [4]. Nevertheless, NYU discontinued its clinical study after running out of the multi-million dollar funding after several years of extension.

4. In December 2006, William Beaumont Hospitals started the clinical trial [11] in both SCI and spina bifida (SB). The key data of the trial, such as the success rate and the occurrence rate of the complications, can be traced back to Dr. Xiao’s unpublished report [12] (see “How Xiao Procedure Trials Started in U.S.”). The trial was also believed to be based on false information regarding the acceptance of the procedure in China, which was exposed by Dr. Xiao when he was interviewed by the meida [13] and was confirmed by Dr. Wise Young on the CareCure forums [14].

5. No SCI case was reported in Beaumont’s one-year clinical outcomes [15]. We know from media [16] that “the three with spinal cord injuries were not helped by the procedure”. More over, in May 2009, the mother of one of the Beaumont’s first SCI patients asked for help to buy catheters for her son [17]. Furthermore, in the most recent presentation on the trial results by Dr. Peters of Beaumont [18], no SCI case was presented either.

6. In December 2009, Beaumont obtained a grant from the NIH for the clinical trial in SB [19]. The current trial no longer includes SCI, even though Dr. Peters recently said “need to further explore this technique in spinal cord injury” in his presentation [18].

7. All of the 6 SCI cases in Tubingen, Germany have failed, “only 2 showed some improvement” [20].

8. Dr. Xiao blamed the failure of SCI cases to “incorrect patient selection” and “inappropriate postoperative care” [20]. In his several posts on Chinese forums [21, 22, 23], he further blamed the misuse of Ditropan and catheters. But according to the mother of the patient [24], the patients at Beaumont had already been required to quit Ditropan.

References

[1] http://sci.rutgers.edu/forum/showpost.php?p=1183019&postcount=36

[2] Xiao CG, Godec CJ. A possible new reflex pathway for micturition after SCI. Paraplegia. 32(5):300-307, 1994

[3] Xiao CG, de Groat WC, Godec CJ, Dai C and Xiao Q. “Skin-CNS-bladder” reflex pathway for micturition after spinal cord injury and its underlying mechanisms. J Urol 162: 936-42.

[4] Xiao CG, Du MX, Dai C, Li B, Nitti VW and de Groat WC (2003). An artificial somatic-central nervous system-autonomic reflex pathway for controllable micturition after spinal cord injury: preliminary results in 15 patients. J Urol 170: 1237-41.

[5] http://sci.rutgers.edu/forum/showpost.php?p=1118680&postcount=33

[6] de Groat WC, Yoshimura N. Mechanisms underlying the recovery of lower urinary tract function following spinal cord injury. Progress in Brain Research. 2006;152:59-84.

[7] Fowler CJ, Griffiths D, de Groat WC. The neural control of micturition. Nature Reviews Neuroscience. 2008 Jun;9(6):453-66.

[8] http://projectreporter.nih.gov/project_info_description.cfm?aid=6698512

[9] Blount JP and Tuite G. Xiao Procedure. Pediatric ShortCuts Newsletter. Spring 2009
http://www.neurosurgery.org/xiaoS09.asp
Note: Dr. Tuite is one of the neurosurgeons who lead the clinical trial at All Children’s Hospital in Fla., see:
http://www.wctv.tv/medicalminute/interviewheadlines/47870982.html

[10] http://www.urotoday.com/264/conference_reports/selected_abstracts/female_urology__part_10.html

[11] http://www.clinicaltrials.gov/ct/show/NCT00378664

[12] Xiao CG. A somatic-autonomic reflex pathway procedure for neurogenic bladder and bowel: results on 92 patients with SCI and 110 children with spina bifida. Proceedings of the International Conference of Urology; Shanghai, July 2-4, Shanghai, China; 2005.

[13] http://xysblogs.org/wp-content/blogs/107/uploads/xpletter.html#nw3

[14] http://sci.rutgers.edu/forum/showpost.php?p=1180817&postcount=53

[15] http://linkinghub.elsevier.com/retrieve/pii/S0022534709608843

[16] http://www.tampabay.com/features/humaninterest/article984049.ece

[17] http://sci.rutgers.edu/forum/showthread.php?t=118791

[18] http://www.glsuna.com/PetersGLSUNA2010.pdf

[19] http://projectreporter.nih.gov/project_info_description.cfm?aid=7696321

[20] http://webcasts.prous.com/netadmin/webcast_viewer/Preview.aspx?type=0&lid=10196&pv=2

[21] http://www.chinagonet.com/main/view_post.php?pid=2251853

[22] http://www.starlakeporch.net/bbs/read.php?1,52103,52175#msg-52175

[23 http://www.starlakeporch.net/bbs/read.php?1,53199,53199#msg-53199

[24] http://sci.rutgers.edu/forum/showpost.php?p=586207&postcount=34

For the situations of other SCI patients of the clinical trials outside China, please see the Open Letter against Xiao Procedure, or see Slide 80 of Xiao Chuanguo’s presentation at SIU 2009 and the report from St. Petersburg Times.

http://sci.rutgers.edu/forum/showthread.php?t=70481
10-09-2006, 05:09 PM #1
BeeBee
My son has been contacted by his urologist to participate in a study involving nerve rerouting to restore bladder function. Still vague on the details, only one phone call so far. Has anyone (Dr. Young???) had this done or have any information on it? Apparently the physician is from China, sorry I don’t know his name. Is this the same proceedure that is done in Europe for this purpose and (separately ) to restore facial innervation after injury?

10-11-2006, 09:35 AM #14
BeeBee
Dr. Chuan-Guo Xiao is the physician. Dr Young: do you have any information on him or his previous results?

10-12-2006, 08:10 AM #18
Wise Young
Administrator
BeeBee, Dr. Chuan-Guo Xiao is the surgeon who has been doing peripheral nerve rerouting for restoration of bladder function in Shanghai (Tongji University) and New York University Medical Center). His approach is different from the one taken by Dr. Shaochen Zhang who has been connecting nerves from above the injury site to the nerves of the bladder. Dr. Xiao’s approach has been to use nerves below the injury sit and then use the segmental reflexes of the spinal cord to activate the micturition (the pissing) reflex. He presented his work in the December ISCITT meeting in Hong Kong. He showed impressive video pictures of people who were able to micturate by stimulating the skin innervated by the spinal cord root that had been reconnected. Dr. Zhang’s approach is trying to restore voluntary micturition but I have not seen all the data and am uncertain that it works as well. In my opinion, a lot of work needs to be done to improve both procedures.

10-16-2006, 03:28 PM #19
BeeBee
The study group will be fowarding their information this week. Possible benefits are: return of bladder function, possible partial return of bowel function (control ability, not sensory) and possible possible sexual return.

Reletively “minor” surgery: a 2 day stay and couple more days at home. (No large incisions or hardware placement: that’s OUR definition of major surgery).

Dr Young: do you have links or copies of the published research?

11-30-2006, 02:15 PM #27
BeeBee
My son will have the surgery on Dec 21. Mike: actual expected results are within 2 years of the surgery. No idea on further trials.

They remove a small portion of the bone from L-5 and re-route a nerve to S-3. He should be able to feel when he needs to void, and actually void by scratching or pinching a place on the hip that will “trigger” the nerves to relax the muscles and allow the bladder to empty. No more caths

He will likely be making some type of presentation to the media inconjuction with this surgery.

12-30-2006, 11:15 AM #44
sexy wheel man
This is BeeBee’s son kevin, the one who had the surgury. i got home from the hospital the saturday after the procidure. it was a very minor surgury, i’ve had 8 before and this was by far the the easiest and fastest i’ve ever recovered from from a surgury. its going to take 15 months to know if it’ll work because the nerve grows at a milimeter per day, but i’ll keep everyone updated on how its going..

http://www.youtube.com/watch?v=1kzO5XJZ69o
http://www.foxnews.com/story/0,2933,237479,00.html
Nerve Surgery May Repair Bladder Problems
Tuesday, December 19, 2006

https://www.beaumonthospitals.com/research-institute-research-by-department-urology
Beaumont Hospitals’ Research by Department, Urology.
Beaumont Hospitals launched a research study to “rewire” nerves in the spinal cord in the hope of giving bladder control to people with spinal cord injury or spina bifida who otherwise depend on self-catheterization to urinate. The first procedure garnered national attention and appeared in more than 160 news outlets including U.S. News & World Report, The Washington Post and Forbes.

http://sci.rutgers.edu/forum/showthread.php?t=74610
12-19-2006, 02:49 PM #3
BeeBee
That’s my boy!
His surgery will be on Thursday. His will be a little different than originally planned. They will be rerouting a nerve from above his injury level, due significant perifrieal (sorry, this is spelled wrong and I don’t have time to check) nerver damage from the accident. It will, as a result, most likely take longer to heal (18 vs. 9 months), but will provide actual sensory control. They will also decompress his spinal cord and remove any scar tissue.

12-19-2006, 04:52 PM #6
Wise Young
BeeBee, thank you for posting the information. I spent several days with Dr. Chuan-Gao Xiao at the Fifth Asia-Pacific Neural Regeneration Symposium where he presented his latest results. He has now done several hundred patients, including children with spina bifida and people with chronic spinal cord injury. The patients that he did at NYU were in a clinical trial funded by NIH. About 80% of the people are able to urinate by stimulating the skin of the spinal cord segment whose ventral root has been re-routed to the nerves to the bladder. I am quite impressed by the procedure. Apparently, he will soon be publishing some additional changes in the procedure that improves the reliability of the method. Interestingly, he says that some patients also have improvement of their anal sphincter. However, there is not much information about sexual function. The most impressive cases were the children with spina bifida where they apparently not only recover bladder function but often regain voluntary control of their bladder.

12-28-2006, 04:08 PM #34
BeeBee
We went for our post-op follow up today. Removed the stitches. They’ve done 3, so far. All male, my son @ 19 2.5 years post, another Kevin, 49 and about 20 years post and a 6 year old Spinal Bifida patient. That all were male was a coincidence, not a specific choice or goal. They said my Kevin’s incision was healing the best. We think its because he’s had the most practice.:D

He is completely without pain, now. He’s had some fairly extreme pain in his lower back/upper hip since his third (I think) surgery, 2 years ago. This is gone. At least for now. His temperature also seems to be better regulated. He doesn’t sit in front of the fireplace while we sweat anymore. Hoping these changes last!!

Next follow-up will be in 3 weeks, at one month post. Then at 3 months. At 6 months he will have an extensive follow-up exam.

He was not taking any Ditropan, etc., before the surgery. But the other 2 patients were. They were asked to cut it by 1/3 a week prior to surgery, they will cut again in 3 months and completely stop at 6. Just FYI for you drug followers…:)

http://sci.rutgers.edu/forum/showthread.php?t=79794
04-10-2007, 04:52 PM #10
BeeBee
Posts: 593 Best of luck, Lynn. This is the trial my son’s participating in. Surgery was very easy, recovery fast. His latest appointment showed some promise. He’ s experiencing some leaking when he coughs or sneezes and that’s apparently a good sign. They just did the next series of trial surgeries, maybe a week ago. Most excellent!

http://www.tampabay.com/features/humaninterest/article984049.ece
Experimental surgery helps relieve kids with spina bifida and spinal injuries
By John Barry, Times Staff Writer
In Print: Sunday, March 15, 2009
The three with spinal cord injuries were not helped by the procedure.

http://sci.rutgers.edu/forum/showthread.php?t=118791
05-14-2009, 04:56 PM #1
BeeBee
Washington DC Self Catheters please help.

My son was visiting and will now have to stay for longer than expected. He has his script for his self caths, but we’re having a problem finding a local supplier. He uses Mentor 14fr straight caths, these are the clear, rigid plastic with an aqua connector at one end. (all the suppliers the hospital found for us only have the soft latex and they just don’t work). We’re in Northern Virginia - Alexandria. Any recommendations? PLEASE??

http://www.sophiesvoicefoundation.org/prevention.html
The Xiao Procedure holds the promise that children with spina bifida will be able to self-initiate bladder and bowel functions - eliminating the life-long need for catheterization and the use of diapers to guard against accidents.

http://sci.rutgers.edu/forum/showthread.php?t=176798
01-26-2012, 12:53 PM
BeeBee2
My Son

I haven’t been around much lately and had to even start a new ID - I just never could get my old ID working, but some of you will remember me as “BeeBee”. My son is a T12 from an MVA 7.5 years ago.

I wanted to let those of you who do remember me know that he died Tuesday night. I found him in his bed when I got home from work yesterday. No cause yet. Just dead. 

Drawing directly from media sources in Chinese, notably the Science News reports (sn1 and sn2) previously translated by the New Threads Volunteers, the article’s author xgz recounted the case and asked “Do we want that kind of health care in the US?”