Sunday, July 22, 2012

#UCDavis neurosurgeons conducted experimental surgery w/o IRB approval

Not really sure what to say about this other than that this story should be read by many/all who are interested in medical research and/or UC Davis: 2 UC Davis neurosurgeons accused of experimental surgery are banned from human research - Investigations - The Sacramento Bee.

UPDATE 7/23.  Added a summary: Two UC Davis neurosurgeons were treating terminally ill brain cancer patients with an unapproved, experimental treatment that is referred to as "Probiotic Intracranial Therapy for Malignant Glioma".  The treatment involved purposefully infecting patients brains with a bacterium Enterobacter aerogenes apparently because of prior anecdotes and case reports that suggested that patients with these brain cancers who also had brain infections might live longer than those with the cancer but without the infection.  According to the article, there was an investigation at UC Davis into the practices of the surgeons.  It was determined by UC Davis that they did not have IRB approval to carry out the treatments and that there were some other issues with the practice going on.  At the conclusion of the investigation UC Davis wrote a letter to the FDA detailing the case and has banned the two neurosurgeons from performing medical research on humans.  Read the article for much more detail and see the link below.

Many interconnected issues in here involving IRB approval, human experimental treatments and informed consent, UC Davis, and even "probiotics".  Still taking it all in ...  Uggh ...

Other stories posted in the SacBee at the same time:
See also
UPDATE 7/22/12. Some tidbits to consider
  • The doctors used the bacterium Enterobacter aerogenes for the treatment.  It wear obtained from ATCC and grown by a graduate student at UC Davis.
  • The use of the bacterium for human treatments violated the ATCC MTA.
  • It is unclear from the details here why this bacterial strain/species was selected.  But I assume it is related to the referenced Neurosurgery article (see more below).
  • The hypothesis that purposefully causing an infection may help glioblastoma patients seems to come from the observation that patients with glioblastoma w/ postoperative infections have better survival than those who do not get infections.  This could be due to many many factors jumping to purposefully causing infections with E. aerogenes seems a big big jump.
  • It would be nice to know more about the statement "Early this year, as required by University policy Drs. Muizelaar and Schrot submitted a Record of ~Invention for the bacterial intervention to UCD's technology transfer office." in the letter from UCD to the FDA.  Was this just a formality or were the surgeons looking to patent/protect the bacterial treatment method?
  • The Neurosurgery article discussing infection and glioblastoma may be "Long-term Remission of Malignant Brain Tumors after Intracranial Infection: A Report of Four Cases" Neurosurgery: March 1999 - Volume 44 - Issue 3 - pp 636-642.  This reported that some of the patients with infections that seemed to have a longer survival with glioblastoma were infected with E. aerogenes.
    • "In three of the cases described above, Enterobacter aerogenes was recovered from microbial cultures. Whether the presence of Enterobacter aerogenes was coincidental or whether this organism plays an important role in tumor defense is not known and cannot be proven from the cases reported. "
  • See also
UPDATE 2
UPDATE 3 - some papers on bacterial infections and glioblastoma and other cancers
  • Biocrime or a Passion to Save a Life?.  This pointed me to the article below:
  • A key article of interest: Post-operative infection may influence survival in patients with glioblastoma: simply a myth?: Glioblastoma, infection and survival from 2011. The article casts some doubt on the basis for the treatment used here
    • Citation: De Bonis P, M D AA, M D GL, de Waure C, Mangiola A, Pettorini BL, Pompucci A, Balducci M, Fiorentino A, Lauriola L, Anile C, Maira G. 2011. Post-operative infection may influence survival in patients with glioblastoma: simply a myth?: Glioblastoma, infection and survival. Neurosurgery. 2011 Oct;69(4):864-8; discussion 868-9.
    • "One of the myths that continues to be perpetrated in neurosurgery relates to the observation that a postoperative infection may actually confer a survival advantage in patients with malignant glial tumors"
    • The take-home message of this study, which can be applied to any aspect of neurosurgery, is to do everything possible to prevent a postoperative wound or cavity infection. The association between infection and prolonged survival is not definitive; we acknowledge the considerable difficulties in undertaking this type of study in a retrospective manner in view of the numerous clinical variables. A prospective randomized study on this subject is clearly not possible. Nevertheless, we believe the results of this study are important and can be used as a stimulus for further multicentric studies (to increase the number of patients) or for experimental studies using genetically modified bacteria for the treatment of GBM.
  • Also see The survival impact of postoperative infection in patients with glioblastoma multiform from 2009.
    • "In this single-center study, postoperative infection did not confer any survival advantage in patients with glioblastoma multiforme". 
    • Available free online here. 
    • "This study did not show a causal relationship between postoperative infection and prolonged survival in patients with GBM. Although targeted immunotherapy may provide antitumoral effects, simple infection does not appear to do so. Modern aseptic and antiseptic surgical techniques continue to be integral to the care of patients with gliomas."
  • Also see  Cancer J. 2012 Jan-Feb;18(1):59-68. Immunotherapy for the treatment of glioblastoma. Thomas AA, Ernstoff MS, Fadul CE. (though I cannot seem to be able to get a copy ..)
UPDATE 6: 7/23 10 AM - some info. on UC Davis IRB, Med School, etc
UPDATE 9: SacBee Editorial calling for Muizelear to step down as Chair
  • The Sac Bee has an editorial today calling for the doctor involved in this issue to step down as chair of the Neurosurgery department.  Some quotes below
  • "Experimentation on terminal patients requires a specific set of protections for good reason. People who are, quite literally, on death's doorstep are extremely vulnerable, and therefore not always able to give informed consent."
  • "University officials conceded that "systemic issues" within the medical center may have contributed to errors made and that "additional measures designed to avoid future confusion" have been put in place."
  • "Curiously, even after it was imposed last fall, the university named Muizelaar to fill its new Julian R. Youmans endowed chair in neurological surgery. The donor specified, university officials explained, that the chair be filled with the head of the department, a fact that begs the question: Why is Muizelaar still chairman of the department?"
UPDATE 9: some new stories
UPDATE 11: Muizelaar steps down as chair of department, at least temporarily
  • UC Davis neurosurgeon department chair steps down pending ...
    • "One advocate for ethical human subjects research questioned the university's decision to keep the matter in-house instead of seeking outside review. "The time is long gone for another internal investigation," said Elizabeth Woeckner, founder and director of Citizens for Responsible Care and Research, or CIRCARE. The nonprofit group works to improve protections for human subjects in research. Woeckner called the doctors' work on the patients – intentionally infecting them with bacteria restricted to use in lab rats only – as "the worst thing I've seen in my 12 years with CIRCARE.""
UPDATE 12 - September 7, 2012 - some new news stories on Federal investigations
UPDATE 16: August 15, 2015

Well, many things have happened since 2012 - here are some stories to look at
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5 comments:

  1. Dinesh Cyanam7/30/2012 3:17 PM

    Thanks a lot for all the info...
    This is very appalling...

    ReplyDelete
  2. Kate Dunkin10/05/2012 11:04 AM

    Great post! I am actually getting Oklahoma neurosurgery performed and I was reading articles online about it when I came across your post. Thank you for sharing this with us, it was very informative!

    ReplyDelete
  3. Brian Hanley11/13/2012 11:08 AM

    I'll start by observing that medicine is not science. Science has lots of time, the pressures are minimal in that way. Medicine has people dying before your eyes, disintegrating, pleading and desperate. In a terminal case, it isn't hard to argue see why extraordinary measures would be taken.

    After studying this in depth, it has a lot more rationale than what has been presented here. The work of Coley prior to the antibiotic era was focused on this for many types of cancers and quite successful. But Coley decided it was too dangerous to use live cultures after a few patients died. So he switched to killed cultures. (The Nauts paper has 14 formulas that Coley used.) It is plausible that the E. aerogenes was selected due to its possible patentability in light of Coley's work as Coley's work precludes most patent claims.

    Patient #2 was discharged, after the treatment and the tumor regressed. That patient was out and about, coming in for appointments 10 months later, when they decided to try it on patient #3. It needs to be appreciated that patient #2 was extraordinary, a great success at that point.

    I see this incident as Schrot and Muizelaar recapitulating Coley's observations. It is still a bit of a puzzle to me why they decided to use live cultures after reading the Nauts review of Coley (over 100 pages, that), unless they didn't actually read fully it, but found it in passing and cited it as a support thinking it was fully consonant with their personal observations. (But that idea conflicts with the possible selection of E. aerogenes to enable patentability.)

    Their personal observations were of 2 patients who had full remissions after accidental infection treated promptly and aggressively. It isn't hard to understand how that could lead them to want to try it deliberately for a disease with 5% remission rates.

    It does make sense that patients could do better after high intensity infection for a variety of reasons that would require a full manuscript to elucidate. The immunology is sound. It also makes sense that infection in the brain (an immune privileged site) would be uniquely problematic, and DeBonis' paper makes sense. It remains the case that should a person recover from septic infection their odds of remission go up significantly. All those facts are not in conflict.

    There is an area of immunology that Schrot and Muizelaar can be faulted for. But - that same area has been missed by the blue-ribbon panel of prominent scientists who reviewed the Jolee Mohr death. Most scientists are unaware of it - to say nothing of most physicians. So I think it is a bit much to tie them to make these two walk the plank for trying. Nobody knows it all.

    ReplyDelete
    Replies
    1. Jonathan Eisen12/11/2012 11:53 PM

      Brian - I disagree with most of your assessment here. I see no evidence for careful reasoned thought into what they did. Sure - the big picture "stimulate the immune system" or "infections in the brain" one could say they had some interesting threads of ideas. But threads of ideas are not enough to go and take a bacteria ordered from ATCC, with no evidence or even a suggestion of evidence for any real potential benefit, and injecting it into people's brains especially when not authorized to do so. Seems completely ridiculous to me. And dangerous. And arrogant. And potentially criminal.

      Delete
  4. Anonymous8/26/2013 11:08 AM

    "Medicine has people dying before your eyes, disintegrating, pleading and desperate. In a terminal case, it isn't hard to argue see why extraordinary measures would be taken."

    Yes, you can take the extraordinary measures, once you have the IRB approval to do so.

    ReplyDelete

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