May 2011 Archives
Given the not-inconsequential risk of PML with Tysabri (natalizumab) use in multiple sclerosis—particularly with prolonged use—neurologists have taken the unproven track of intermittently stopping the drug in an effort to reduce that risk. And although noone really knows if this measure leads to the intended result (ie, a reduced risk of PML), it almost certainly increases the risk of MS disease activity. But when the risk of disease activity returns and to what extent has been unknown—until now.In an assessment of 1866 patients enrolled in pivotal Tysabri clinical trials* who stopped the drug (owing to the voluntary removal of the drug from the market in 2005), O'Connor et al found that disease activity** returned shortly after Tysabri was discontinued. Then disease activity peaked between 4 and 7 months but, importantly, did not "rebound" beyond baseline levels.
The study authors concluded,
These data indicate that a return of disease activity to pretreatment levels should be anticipated soon after natalizumab treatment is interrupted, underscore that the consequences of reucrrent MS disease activity should be weighed against potential benefits of PML risk reduction, and should motivate the search for suitable alternatives to a mere treatment interruption.
How to address the interruption of Tysabri therapy (which is taken, rightly or wrongly, as a given to reduce the PML risk) will be answered to some extent by the ongoing RESTORE study. This Biogen-sponsored multicenter US study, in which Tysabri therapy will be interrupted for 24 weeks, is designed to assess 1) how quickly the immune effects of Tysabri disappear; 2) when MS symptoms return; 3) if other immunomodulatory drugs (eg, interferon beta) can control MS symptoms; and 4) how quickly the effects of Tysabri return after resuming therapy. The estimated primary completion date of RESTORE is December of this year, and the estimated study completion date is December of 2012.
* The AFFIRM, SENTINEL, and GLANCE studies.
** As measured by the annualized relapse rate (ARR) and gadolinium-positive lesions on MR images.
PML = progressive multifocal leukoencephalopathy.
The Whistle Blower (1986): I know of one essential way to describe this week's selection. It is yet another example of how master film actor Michael Caine can sustain—nay, elevate—a movie, despite the clunky translation of a necessarily complex spy thriller (by John Hale) and a barely TV-worthy musical score.
Riffing on the seemingly growing trend of former professional athletes providing their brains to the Center for Traumatic Encephalopathy (see here, for example), writers for The Onion report, "Neurologists Implore Professional Athletes to Wait Until They Are Dead to Send in Brains for Research."The God-bless-em scribblers even went so far as to fact-check the president of the American Academy of Neurology.*
* Although I suspect they used an actor in their accompanying photo to convey a presumptive neurologist's on-the-mark expression of worry, confusion, and mild exasperation.
Loosely based on Joseph Conrad's novel The Secret Agent, Sabotage (1936) is an early Hitchcock effort released the year after the more famous The 39 Steps and during the same year as the confoundingly named Secret Agent. It is the story of a German-accented spy, Mr. Verloc (Oskar Homolka), posing as a London cinema owner. Verloc takes his instructions from some unidentified group to wreak havoc in the city—first by creating a power outage and second by considerably more destructive means.*Attempting to thwart the state-sponsored terrorism is a very handsome undercover agent from Scotland Yard (John Loder), who poses as a green grocer and develops a fondness for Verloc's unsuspecting wife (Sylvia Sydney) and her younger brother (Desmond Tester). The boy becomes an unintended target of Verloc's clandestine activities, which significantly raises his evil quotient and pushes his pretty, slim wife over the edge.
An important technical aspect of the plot, which may not be completely transparent to modern viewers,** is the explosive potential of nitrate film, the stuff of early 20th-century movie reels, which the boy is asked to cart through the streets of London.
* Which anticipates, by nearly 70 years, al Qaeda's 7/7 attacks on London's public transportation system.
** Except to those familiar with Tarantino's Inglorious Bastards (2009).
Movie poster of Sabotage from Wikipedia and reproduced under fair use law.
A follow-up study of 35 MS patients with Tysabri-associated PML provides a somewhat encouraging survival rate of about 70%. This percentage is more than twice the quoted survival rate of other patient types with PML (eg, those with HIV infection or following transplantation), and the authors speculate that the improved survival in Tysabri-related cases may be due (partially) to the ability to reconstitute the immune system more easily in these cases.Factors that appeared to improve the chances of survival among Tysabri-treated patients specifically were generally not surprising: relative youth, less MS-related disability, a shorter time between symptom onset and the diagnosis of PML, and less extensive disease (ie, unilobar PML vs global disease).
The provided overall risk of PML with Tysabri treatment remains within the ranges observed during the clinical development of the drug (1/1000) and the postmarketing experience (0.9/1000). However, the risk of PML is acknowledged to increase substantially as the duration of treatment increases:
- from 0.01/1000 during months 1-12,
- to 0.39/1000 during months 13-24,
- to 1.46/1000 during months 25-36.
The authors, 3 of whom work for Biogen Idec, the maker of Tysabri, admit that one major deficiency of their follow-up report is the lack of long-term data. Only 12 of 25 PML survivors had follow-up data beyond 6 months at the time of the analysis. However, most Tysabri-treated patients with PML who died did so within 2 months of diagnosis; so the authors predict that the ~70% survival rate will be maintained as the data continue to accumulate.
MS = multiple sclerosis; PML = progressive multifocal leukoencephalopathy.
* I added all sorts of other infectious disease names--including "gonorrhea," "measles," "mumps," "rubella," "diphtheria," "streptococcus," "varicella," etc--and they didn't rank very highly, so I left them out of the graph to avoid crowding. The biggies, like TB, syphilis, and malaria, are shown.
There is no kicking back and very little levity in Incendies (2010), a familial mystery that requires adult twins, a sister and brother, to discover the truth of their nuclear family in someplace very much like Lebanon. It is the possibly crazy postmortem request of their dead mother, who led—it is revealed in a sequence of installments—a humorless existence during the ultraviolent Middle-East conflict between Muslims and Christians in the 1970s. It'd be hard to find grimmer, more draining material; but rarely does a movie offer such an immersive experience of such an unfamiliar landscape with such deft artistry.Actress Lubna Azabal, as mother Nawal Marwan, experiences high-level trauma in the Middle East.
I'm not sure what it means when Public Citizen and I are in
agreement. Possibly the Earth's about to blow up. Or we're both really right about opposing a really wrong issue—like the possible FDA approval of Lilly's amyloid-imaging
tracer, Amyvid (or florbetapir F18 injection for PET).I've taken my objections about the dubious clinical utility of this product to a blog, namely this one (see here, here, and here, for instance),* and Public Citizen's taken overlapping objections to its own web site. As well, the pharma watchdog group is expressing its dissent in a more formal and official manner: namely, in a newly submitted letter to the editors of JAMA, who published a seminal, but problematic, company-funded study of the tracer back in January (access to both the published study and the letter require subscription).
Public Citizen seems to be particularly troubled by the inter-reader variability of Amyvid-enhanced PET images, as expressed previously by FDA reviewers. Moreover, the group is really disturbed that the study authors did not provide individuals scores of the 3 PET readers but, instead, supplied a median score. (For details and excerpted text from the JAMA letter, read yesterday's post at Pharmalot.) Public Citizen is also concerned that the study authors compared the PET results from widely disparate groups: relatively young adults** and end-of-life elderly. And even then, the readers apparently still had trouble agreeing on rating scores, in some cases.
Public Citizen concluded that inter-reader variability would "only get worse," once the tracer is approved and its enhanced images are read by a wider group of variably trained physicians. "As a result," the group predicted, "tens of thousands of patients will have either a false-positive test or a false-negative test. This will lead to unnecessary anxiety and treatment in some patients, false reassurance in others and a waste of millions of health-care dollars."
* Or alternatively, perform a search of this blog with "florbetapir."
** As opposed to cognitively normal and healthy elderly.
Photograph: Atrophied brain from person with AD from National Institute on Alcohol Abuse and Alcoholism.
Twelve days ago (April 29, 2011), the US Court of Appeals for the DC Circuit finally ruled (in a 2-1 decision) against a preliminary injunction that banned the use of federal funds to support research on human embryonic stem cells (hESCs).* (So, to sift through the multiple negatives in that sentence, there is now no preliminary injunction against the use of hESCs in medical research. In other words, the government can fund hESC work...at least for now.)The preliminary injunction was granted by Judge Royce Lamberth way back on August 23 of last year in the case of Sherley et al v. Silbelius et al (for essential background on this issue, see last year's no. 3 story at Pathophilia). Given the strike down, it is presently up to Lamberth to rule on a permanent injunction against federally funded hESC research.
And so now, given the appeals court 2-1 split decision, the original plaintiffs (Sherley et al) want to amend their complaint, reports The Great Beyond blog. Their proposed additional arguments are presumably informed by the opinion of the dissenting appeals court judge, Karen LeCraft Henderson, who called her colleagues' reasoning "linguistic jujitsu." The defendants (ie, the government), in no surprise, oppose the plaintiffs' "unnecessary" motion to amend their complaint.
When Judge Lamberth will make his ruling on a permanent injunction in this case is a big, useless guess—like, oh, sometime in the future.
* The appellate arguments were made in December of last year.
Image of undifferentiated hESCs from http://www.nih.gov/catalyst/2007/07.01.01/page1.html.
Odds Against Tomorrow (1959): Film noir meets the civil-rights movement.
Harry Belfonte's production company, HarBel, produced this New York-based story of a has-been cop (the remarkable Ed Begley), a racist ex-con (the perpetually snarly Robert Ryan), and a musician and inveterate gambler (the uber-cool Harry Belafonte).* To land an "easy" bank score, Begley's character recruits the racist and the musician, both of whom spend arguably too much time resisting the idea of working together. But to noone's surprise, dire times make for strange partnerships.
The movie, directed by Robert Wise, really shines, however, during the last act, when the bank heist goes down. Wise's editing skills at this point in the story are nonpareil, and a lingering piece of racist behavior, perpetrated by Ryan's character, is cleverly introduced to heighten the tension and threaten the getaway. Although the film's conclusion is ridiculously heavy handed by today's standards, any criticism of thought-provoking elements should really be dispensed according to the time of production.
* Oh yeah, and the movie also features Shelley Winters in an otherwise thankless role.
Poster image of Odds Against Tomorrow from Wikipedia and reproduced under fair use law.
Congressional leaders agree that the SGR formula, the legislated formula used to calculate ongoing cuts in Medicare reimbursement to physicians, has to go. But passing a permanent fix has been stymied, in part, by the nature of the legislative calendar, said Congressman Michael Burgess, MD (R-TX) yesterday to MedPage Today. Congress has consistently had trouble getting its act together to pass a reform bill before the August recess, Burgess implied to the medical news source.
Several medical societies, including the AMA, recently submitted their SGR alternatives to the House Energy and Commerce Committee, which requested the proposals in late March, reported Medscape's Robert Lowes 3 days ago. The committee, which held a public hearing on the topic yesterday, is in charge of spearheading some type of Medicare-reimbursement reform measure.
The current stop-gap measure to suspend the SGR formula, enacted in December, delays the legislated cut until January 1 of next year, at which time Medicare reimbursement will drop by a practice-shocking 30%.
SGR = sustainable growth rate.
Photo of weathered can from magannie at Flickr.
A big HT to the neurodiversity weblog on this story.
The medical license of Mark Geier, MD, PhD—whose dubious studies of and conclusions about autism (particularly with respect to the thoroughly debunked risks of vaccination) have been criticized ad nauseum at this blog—was suspended in Maryland. The state's medical board issued its 48-page order last week, April 27th.
The board concluded "that the public health, safety, or welfare required emergency action." The board's review was prompted by complaints from a concerned citizen (in 2006), a referring pediatrician (in 2008), and the mother of a former patient (in 2008). In October of last year, a "peer review" was conducted of 9 of 11 patient cases referred by the board.*
Among the board's peer-reviewed findings:
- Mark Geier falsely claimed to be a board-certified geneticist and board-certified epidemiologist.
- He "misdiagnosed six (6) of the nine (9) autistic children...with precocious puberty," whose care was reviewed.
- He treated these misdiagnosed children with Lupron or chelation therapy or both, which "exposed the children to needless risk of harm."
- Mark Geier's "assessment and treatment of autistic children...far exceeds his qualifications and expertise." Moreover, his ordering of laboratory tests was determined to be "outside the standard of quality care," and he "failed to conduct adequate physical examinations of any of the patients..." (It is noted in at least one instance that Mark Geier recommended Lupron therapy on the sole basis of a phone consultation.)
- Mark Geier "failed to provide adequate informed consent to the parents of the autistic children he treated."
In summary, the board wrote,
The Respondant [Mark Geier] endangers autistic children and exploits their parents by administering to the children a treatment protocol that has a known substantial risk of serious harm and which is neither consistent with evidence-based medicine nor generally accepted in the relevant scientific community.
A "post-deprivation" hearing has been scheduled for May 11th, and Geier may request an "evidentiary hearing" if he is dissatisfied with the result.
The order also reveals that Mark Geier holds licenses to practice medicine in numerous other states, including California, Florida, Hawaii, Illinois, Indiana, Kentucky, Missouri, New Jersey, Virginia, and Washington. Reciprocity actions in these states are unclear (to me); some license suspensions may be automatic, others may require hearings.
The board's order also strongly suggests that Mark Geier's son, David, who has only a bachelor's degree, is practicing medicine (ie, making diagnoses) without medical training or licensure. Nevertheless the board did not comment further on any actions against David Geier for this presumed unlicensed activity.**
The published work of Mark Geier (along with that of his son, David) has been criticized extensively at this blog and elsewhere (for relevant posts at Pathophilia, search for "Geier.")
* The peer-review organization declined to offer an opinion in 2 cases, citing that the care provided was beyond their scope of expertise. (Ha. Would it be that Mark Geier had the same reservations in judgment.)
** It is not clear if unlicensed medical practice in Maryland is within the scope of the medical board or if it is the purview of the state's criminal justice system.
05/05/11 update: The Chicago Tribune reported yesterday that the Illinois Department of Professional Regulation could only suspend Mark Geier's Illinois medical license if there was an "imminent danger" to Illinois patients or if the Maryland board takes permanent action (presumed here to be license revocation). This information came by way of Sue Hofer, the public information officer for the IDPR.
The IDPR's website indicates that "Mark Robin Geier" obtained a physician license in Illinois on October 30, 2008, which expires July 31, 2014.
Online searches for Mark Geier's medical licenses at other state's web sites provide the following information, tabulated by Pathophilia:
|
State |
Issue Date |
Expiration Date |
|
California |
07/01/2010 |
05/31/2012 |
|
Florida |
12/17/2008 |
01/31/2013 |
|
Hawaii |
11/07/2008 |
01/31/2012 |
|
Illinois |
10/30/2008 |
07/31/2014 |
|
Indiana |
10/10/2008 09/23/2009* |
06/30/2011 06/30/2011 |
|
Kentucky |
01/05/2010 |
02/29/2012 |
|
Maryland |
09/20/1979 |
Suspended 04/27/2011 |
|
Missouri |
10/14/2009 |
01/31/2012 |
|
New Jersey |
04/02/2009 |
06/30/2011 |
|
Virginia |
10/01/1992 |
05/31/2012 |
|
Washington |
12/01/2008 |
05/03/2013 |
* For "CSR-Physician."
Former Chicago Bears safety Dave Duerson had "moderately advanced" chronic traumatic encephalopathy (CTE), according to yesterday's press release from Boston University's Center for CTE. Duerson, 50, who committed suicide in February, had, in an unusual move, specifically directed that his brain be studied by the Center. He shot himself in the chest to facilitate the thorough examination of his brain.
Coverage of this story from MedPage Today and the WSJ Health Blog are short on specifics, but the latter indicates that 13 of 14 brains of former NFL players that have been studied so far by the Center showed signs of CTE. Changes in Duerson's brain were located in the frontal and temporal lobes, the amygdala, and the hippocampus, according to reports.
It is difficult, if not impossible, to focus on any blog-relevant news in the wake of the death of Osama bin Laden, who died simply of this: a gunshot wound to the head delivered by a US military operative. The mastermind, or really inspirator, of the 9/11 attacks was 54.
05/02/11 addendum: The Great Beyond blog explains "How DNA may have confirmed bin Laden's death." At least one expert guesses that the US government had already sequenced some of UBL's surreptiously confiscated DNA for a quick postmortem comparison.
