March 2011 Archives

What's missing among the SEC's detailed charges of insider trading against FDA chemist Cheng Yi Liang is how the government was tipped off to Liang's (alleged) shootin'-fish-in-a-barrel, clandestine trades—which occurred (again, allegedly) over a span of at least 4-1/2 years and to the tune of more than $3.6 million in profits. It's mere speculation here, but the tipoff (or at least a contributory tipoff) may have been what it always seems to be historically. That is, living too large for one's income.

A hint that leads to this highly speculative conclusion is provided by the SEC's complaint, in which it's charged that Liang wrote $65,000 worth of checks to car dealerships for a "luxury" Infiniti sedan and Honda Odyssey minivan sometime between 2006 and the present. The complaint doesn't provide Liang's salary, but the FDA website indicates that a chemist most commonly earns an annual salary at the General Schedule levels of 9 through 13—which ranges presently (according to this site) from about $51,000 to $155,500 in the DC area. The higher end isn't chump change (particularly for a government job), but in the grand scheme of chemist's salaries, it's not huge either.

It's a brand new car! Promotional photo of Honda Odyssey minivan from http://automobiles.honda.com/odyssey/exterior-photos.aspx.

Addendum: Industry chemist and blogger-extraordinaire Derek Lowe suspects that the tipoff was Liang's profits from the "suprise approval" of the antipsychotic iloperidone (Fanapt; Vanda Pharmaceuticals) on March 6, 2009. He writes,

It wouldn't surprise me if this was the one that blew up the whole business. That was such an unexpected [Lowe's link] move by the FDA (after which the stock went up by a factor of six) that the SEC must have gone back and carefully checked to see if anyone had been building up a position beforehand.

Here's Vanda's stock price chart, from MSN Finance, for the relevant period, showing an astonishing 10-fold jump after the FDA announced iloperidone's approval.

According to the SEC, between March 30 and April 29, Liang acquired 125,065 shares at an average unit price of $1.08. From May 6th to the 14th, he sold all of his shares at an average unit price of $9.40, for a profit of more than $1 million. Liang's other alleged insider transactions yielded much lower gains, ranging from $9287 to $379,602. Of course, Lowe's suspicion relies on the assumption that the SEC is or has been appropriately vigilant for such exceptional trading activity.

The litigation phase of the tainted-heparin scandal (start here and here for important background) appears to be well underway, and veiled milestones of the personal-injury suits will evidently be given by the blogging lawyers at Drug and Device Law, who are "involved in the litigation" (presumably representing Baxter, given their unwavering pro-defendent stance).

Yesterday's DDL post crows about a recent ruling on the limited permissible testimony from a plaintiff's expert (ie, Daubert rulings).* Topics of expertise are confined, ruled US District Court Judge James G. Carr, who rejected testimony on wider issues on the potential risks of doing business in China.

If I'm correctly reading the subtext of the DDL post and the ruling, the foundation of the heparin litigation appears to rest on what Baxter should have done to ensure that its Chinese raw heparin wasn't tainted. Although, given that the contaminant, OSCS, was a heretofore unknown heparin contaminant, and the fact that the FDA still hasn't identified the ultimate source of the contaminant in China, I'm not sure how it would have been possible for Baxter (or its heparin supplier) to police for it.

Now it may be a matter of arguing (per the plaintiffs) that Baxter should have known when it was dealing with reputable Chinese suppliers. But (the counterargument might go), obviously not everything that comes of out China is dangerous, so how or when should a US company know with whom to do overseas business? (And especially when that Chinese company has its own set of potentially murky suppliers.)

I'm not necessarily a fan of Baxter, but it seems like a very difficult argument** for the plaintiffs in this era of undeniable globalization.

OSCS = oversulfated chondroitin sulfate.

* And the DDL team directed a particular slam at the "ubiquitous plaintiff's expert," Suzanne Parisian, MD, who may be prone to "elaboration," the ruling implied.

** At least a difficulat argument outside of a sympathetic jury. 

When watching any Hitchcock classic, we make some intangible accommodation that preserves the movie's effectiveness and, by extension, cements its timelessness. But at the same time, we can acknowledge the implausibility of the story in the present (or the difficulty of adapting the story to the present). For instance, think of the headache to be had when attempting to update Vertigo, Rear Window, or The Birds. Or better yet, just watch a few minutes of the existing remakes of Hitchcock's masterpieces—including Gus Van Sant's shot-by-shot misfire of Psycho (from 1998).

The same paradox can be found when viewing Henri-Georges Clouzot's Les Diaboliques (1955), a mesmerizing tale of revenge-as-murder with Simone Signoret. Suffice it to say that a critical plot point rests on the cardiac fragility of one the perpetrators—an aspect of the story that remains acceptable (and, in the end, utterly horrifying) in situ, but that would be ridiculous (and potentially laughable) in any attempted update.*

My point being (if I have one): Pop some popcorn and watch the original.

* Which was, nevertheless, foolishly made in 1996--with Sharon Stone in the Simone Signoret role.

As reported by yesterday's NYT, a court-authorized psychological review of Bruce Ivins found the USAMRIID scientist capable of mailing letters containing spores of Bacillus anthracis in 2001, which led to the deaths of 5 people. The review, authorized in 2009 by Judge Royce Lamberth* of the US District Court in Washington, DC, and conducted by a 9-member panel (consisting of 6 university-based psychiatrists, 1 attorney, and 2 representives of the American Red Cross) concluded,

Dr. Ivins was psychologically disposed to undertake the mailings; his behaviorial history demonstrated his potential for carrying them out; and he had the motivation and the means.

The panel's assessment was based on examination of previously sealed records, including psychiatric records.

Two repeatedly raised objections to fingering Ivins as the bioterrorist—namely that he didn't have the opportunity to drive 200 miles to mail the tainted letters at a Princeton, NJ, mailbox and that his close colleagues had trouble suspecting him as the culprit are met with these rebuttals by the panel:

1. Ivins had a "long-established habit of making secret, night-time drives to faraway locations — many much more distant than Princeton University."
2. Ivins was adept at compartmentalizing and hiding his deepest troubles, so that colleagues perceived him to be an eccentric, but otherwise harmless, individual.

Also noted in the 285-page redacted report, the first 20 pages of which are available here, is Ivins's bizarre obsession with the sorority Kappa Kappa Gamma and his strange or outrightly criminal acts against a former laboratory colleague and KKG member, labeled "Sorority Sister #2" in the report and identified elsewhere as microbiologist Nancy Haigwood (for background posts, go here and here).

* He of stem-cell litigation fame.

Public domain photograph of Daschle "anthrax" letter from Wikipedia.

While updating information on the victims of the mass poisoning due to Elixir of Sulfanilamide in 1937 (see here for the work in progress), I came across 3 intriguing articles published just this month on the detection of diethylene glycol (DEG) in consumer products. Two of these articles report the discovery of DEG (albeit at tiny levels) or a chemical cousin, ethylene glycol.

In the Journal of Toxicology Journal of Medical Toxicology,* investigators from the CDC quantified the amount of DEG and triethylene glycol (TEG), a related compound, in a "convenience sample" of over-the-counter "health products" imported from Asia. The investigators found detectable, but miniscule, DEG levels in 15 (22%) of 68 samples and TEG levels in 2 (3%). The range of DEG levels, in volume-to-volume units, 0.00007%-0.01%, was at least 810 times less than that found in the DEG-contaminated cough syrup in Panama in 2006 (which was reported at a level of 8.1%). The CDC researchers concluded that "these levels probably do not represent an acute public health threat," but that "additional research focusing on why DEG is found [at all] in these products...is needed." Furthermore the minimum amount of DEG necessary for toxicity is unknown.** [See important update/addendum below.]

Then in Molecular Pharmaceutics, investigators at the University of Wisconsin and in South Africa wrote of their discovery of ethylene glycol crystals in a compounded suspension of rifampin. The "exact source" of the ethylene glycol in the antimicrobial is unknown. The authors concluded, "[T]he results of this study show how important it is to ensure that the drug and excipients comply with pharmacopeial or FDA standards."

Perhaps to show that the surveillance for DEG is top-of-mind at the FDA, scientists at the agency wrote in Applied Spectroscopy (who doesn't subscribe?)* that "portable Raman spectrometers" reliably detect DEG in pharmaceutical-grade glycerin at a limit of 0.32%.

* By the way, I do believe that reports of research supported by US tax dollars should be freely and readily available to American citizens, without having to pay for the article (and regardless of the policies of the journal in which an article's published).

** DEG toxicity appears to depend on the production of the toxic metabolite 2-hydroxyethoxyacetic acid (HEAA) through the enzymatic actions of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ADLH), which are known to vary on the basis of genotype and other factors. Variations in enzyme activity may explain the susceptibility of some individuals to DEG poisoning, while others remain unaffected. Notably the administration of fomepizole, an inhibitor of ADH, is a known antidote to DEG poisoning (along with dialysis).

Update: Melgardt de Villiers, lead author of the Molecular Pharmaceutics article, responds by e-mail that the rifampin-derived ethylene glycol crystals were from (or originally observed in) South Africa.

04/06/11 addendum: A review of the full CDC article (which was supplied gratis by the publisher, Springer, at the presumptive request of the corresponding CDC author) reveals the following pertinent facts:

• TEG was assessed in OTC products on the basis of its detection in DEG-contaminated teething syrup in Nigeria (in 2009).
• The convenience sample consisted of OTC liquid- or ointment-based products imported from Asia and sold locally (in Chamblee, Georgia, a suburb of Atlanta). The products were obtained from 9 different stores selling "Asian medicinal products" in the area. (So we're not talking about OTC brandname drugs, like liquid Tylenol.)
• The products were classified by the authors as "dietary/herbal supplements, eye drops/ointment, ear drops/ointment, miscellaneous health-related tonics, nasal spray, throat/cough drops, or topical agent," and had names like "Cough Be Gone," "First Lady Cough and Cold Syrup," and "Shenji Royal Jelly in honey base." 
• Most of the 85 products analyzed came from China (71). Ten originated in Hong Kong; 2 came from Singapore, and 1 each were imported from Taiwan and Mayalsia.
• Only 68 products were "analyzable," because 17 weren't water soluble—a requirement for the analytic technique used.
• The median amount of DEG (in volume-to-volume [v/v] units) in the 1995 mass poisoning in Haiti was 14.4%, and that in the 2009 mass poisoning in Nigeria was 19.3% (see the Pathophilia-constructed table below).
• Although information about TEG toxicity is scarce, write the authors, the substance "is considered to have a low order of toxicity." There are only 2 reports of human poisoning with TEG in the medical literature (see here and here). Both were cases of attempted suicide by, for instance, drinking brake fluid.
• The percentage of TEG (v/v) in the Nigeria mass poisoning was 0.6% (vs the miniscule 0.0012% and 0.0018% found in the 2 products in this study).
• On the basis of data from historical poisonings, including the Elixir of Sulfanilamide incident of 1937, the median or average doses of DEG associated with toxicity or lethality in humans range widely from 14 mg of the substance per kg of body mass (Argentina, 1992) to 1500 mg/kg (Haiti, 1995).
• Given the very low levels of DEG detected in the study (and only in some products), the authors speculate that it "may simply be a minor impurity created during the manufacturing processes of chemicals used to formulate drugs and consumer products."

Contamination Source	DEG, v/v %	TEG, v/v %
Imported OTC products, 2009	0.00007–0.01 (n = 15 of 68)	0.0012, 0.0018 (n = 2 of 68)
Haiti, 1995 (median)	14.4	—
Panama, 2006 (mean)	8.1	—
Nigeria, 2009 (mean)	19.3	0.6

 

While Greek investigators report the favorable long-term results of hematopoietic (not embryonic) stem cells in "aggressive"* multiple sclerosis, the price of approved MS drugs goes up, up, up.

In an unblinded phase 1/2 trial of 35 patients who underwent HSCT (published in the latest issue of Neurology),

• 16 experienced improvements in their EDSS scores by a median of 1 point (range, 0.5-5.5), which lasted for a median of 2 years. (Of note, a "lifesaving response" was observed in 1 patient with "malignant" MS.)
• The median progression-free survival (PFS) lasted 5.4 years in patients with secondary or relapsing MS and 1.5 years in patients with primary progressive disease.
• Good prognostic factors were relative youth (age, <35 years) and a shorter time between the diagnosis of MS and transplantation.
• PFS at 15 years was significantly greater in patients with active MR lesions (44% vs 10%).
• The number and volume of enhancing MR lesions dropped significantly, starting with stem-cell mobilization and increasing after transplantation. Enhancing lesions were persistently suppressed for 12-14 years.

The rationale for using HSCT (in an effort to reconstitute the immune system) in MS is based on the suspected autoimmune nature of the disease and favorable animal-model data.

Meanwhile, Bloomberg reports that the price of injected disease-modifying MS drugs rose as much as 39% last year. The reason: To offset the expected erosion of market share due to Gilenya (fingolimod; Novartis), the first disease-modifying pill for MS. But Gilenya comes with its own considerable sticker shock.

A price survey at this blog in October provided the following monthly costs for the big 4 MS drugs (per destinationrx.com):

• Avonex, $2941.92
• Betaseron, $6196.61
• Rebif, $2809.91
• Copaxone, $3267.05

Bloomberg quotes the approval price of Gilenya at $4800 per month (although the company promises a little financial respite for non-Medicare patients).

Today's visit to destinationrx.com provides the following monthly prices, suggesting a smaller (but still sizeable) increase in medication costs during the last 5 months.

• Gilenya: $4268.16 
• Avonex: $3119.04 (6% increase from October) 
• Betaseron: $6196.61 (no change) 
• Rebif: $3048.84 (8.5% increase) 
• Copaxone: $3753.83 (15% increase)

EDSS = Expanded Disability Status Scale; HSCT = hematopoietic stem cell transplantation.

* "[A]dvanced and refractory disease with increasing disability."

T2-weighted supraventricular horizontal MR image from Harvard's Whole Brain Atlas. Multiple subcortical MS lesions are evident, including a very prominent lesion in the frontal area. The web site also offers a very cool time-lapsed movie of developing MS lesions.

P.S. The monthly cost of Biogen Idec's Tysabri (natalizumab)—a highly effective, but potentially risky, second-line agent—is $3554.66.  

The median cost of HSCT in 2004, according to an analysis at the Dana-Farber Cancer Institute, was $102,574 during the first 100 days and $128,800 for the first year of treatment. The bulk of these costs were for hospitalization (particularly in the early phase of treatment). 

On Friday, Lilly announced that the FDA will require the company to establish a reader training program before it can approve the amyloid-imaging agent Amyvid (florbetapir F18 injection). (For background reading on this arguably useless radioactive PET tracer, go here, here, and here.) News of the agency's stipulation was received by way of an all-but-damning complete response letter on Friday, March 18. The response "was primarily focused on the need to establish a reader training program for market implementation that helps to ensure reader accuracy and consistency of interpretations of existing Amyvid scans," said Lilly.

As written here, Lilly is heavily invested in the once-hugely popular, but probably misguided, idea that amyloid is the chief diagnostic and therapeutic target for established Alzheimer disease. The company's singular investment in the amyloid theory—including the development of 2 amyloid-directed agents* and last year's purchase of Avid Pharmaceuticals (the original owner of Amyvid)—may have led to the abrupt departure of the company's head of neuroscience research, David S. Bredt, last month.

PET = positron emission tomography.

* The clinical development for 1 of which (semagacestat) was scrapped, and for the other (solanezumab) may be in danger.

Photograph of atrophied brain from person with AD: National Institute on Alcohol Abuse and Alcoholism.

The September Issue (2009): A limited portrait of the inner workings of Vogue magazine and its notoriously (and weirdly) frigid editor-in-chief, Anna Wintour*—the model for Meryl Streep's much more engaging (and comparatively accessible) Miranda Priestly of The Devil Wears Prada (2006). 

Documentarian R. J. Cutler, seemingly working on the fly, appears to be in search of a real story here—one that concerns more than the construction of the magazine's phonebook-sized fall issue for 2007, Wintour's bobby-pin arms, or her strangely immutable pageboy. That's possibly because there's little substance to be found within the offices of Vogue. But Cutler ultimately stumbles on a film-sustaining push-me-pull-you dynamic between Wintour and the magazine's frizzy-haired creative director, the relatively Earth Mother-ish Grace Coddington.

You may ask now (as the NYT's Maureen Dowd did in 2009) if Vogue has been able to advance beyond its general haute-couture cluelessness during the last 3 years of the nation's retrenchment. The magazine's March 2011 issue, which features a head-shaking puff piece on Asma al-Assad, the first lady of Syria (Wha—?), is your answer.

* There's a reason it's pronounced "winter."

Geoff Brumfiel of Nature's The Great Beyond blog provides a series of useful primer posts on radiation numbers (see here and here, for example). The convention is to gauge radiation levels in sieverts—or really, millisieverts (mSv) or microsieverts (microSv).

Most in the health professions are familiar with quantifying radiation exposure (typically from X-rays) in units of gray (Gy), which can be equivalent in a 1:1 fashion with sievert; although the latter unit importantly considers the type of radiation and the type of tissue (eg, brain, abdomen, etc) exposed. The most important caveat, however, when considering radiation exposure from a potential environmental disaster is, not only the radiation level, but the time exposed to that level.

According to TGB blog, radiation levels in Tokyo on the afternoon of March 15 were 0.144 microSv per hour—an elevated, but still tiny, level. By comparison, yesterday's level at the Fukushima nuclear plant gate was 10 mSv per hour (or 10,000 microSv per hour); although there was a transient spike to 400 mSv per hour on Tuesday (March 15).

Brumfiel writes that the cancer risk begins to increase at a threshold of 100 mSv per year. According to various other sources, symptoms of acute radiation sickness (eg, nausea, vomiting) may begin with levels as low as 500 mSv and are almost certain when levels exceed 2000 mSv (or 2 Sv).

According to one Danish study, a chest CT provides a one-time exposure of 6-18 mSv.* A mammogram poses a 3-mSv risk. Other routine background exposures (like those from transcontinental flights or dental radiographs) are provided by Reuters and, of course, Wikipedia.**

* For a rough comparison, the estimated exposure from an abdominal CT is 14 milligray (mGy).

** Unfortunately Wikipedia articles are not consistent in their use of sievert (vs Gy) when describing radiation risks.

03/18/11 update: Today's TGB blog posts an animated map of the recent-past, current, and near-future radioactive fallout from Fukushima, courtesy of Austria's weather service. The wind-directed exposure ranges from 100 mSv per hour (in a transient magenta focus at the plant) to the negligible 100 nanoSv per hour (in a diffuse purple trail, over the Pacific). The model suggests that Tokyo will suffer the greatest exposure (but still at microSv levels), due to changes in wind direction, on March 20.

03/21/11 update: A revision of the animated fallout map from Austria's weather service is at yesterday's TGB blog. The bulk of the fallout, in purple, represents 0.3 microSv per hour—"which corresponds to the amount of the natural background radiation dose." In addition, Forbes's Matthew Herper put the risks of Fukushima's radiation in much-needed perspective.  

Friday's update

on the clinical status and recovery of Gabrielle Giffords from the NYT. 

Most notable:

• Giffords has recovered sufficient right body strength to "walk with assistance."
• Her vision does not appear to be impaired (suggesting that she doesn't have visual field deficits due to an occipital lobe injury).
• Her personality is re-emerging and appears to be preserved.
• Except for memory of the event, her memory—both antegrade and retrograde—appears to be preserved.
• Her speech is recovering.

Giffords is reportedly repeating words with ease and "is starting to string words together." Although categories of aphasia can be arbitrary and somewhat artificial, the described deficits suggest a transcortical motor aphasia due to some disruption between the supplementary motor area (located in the superior frontal lobe) and the frontal perisylvian speech zone (generally described as being an anterior extension of Broca's area).* This aphasia is frequently associated with right hemiparesis.

The speech deficit is consistent with descriptions of Giffords's brain injury (see here and here) due to a gunshot wound in January.

* Although Giffords's ability to name objects (which can be limited in transcortical motor aphasia) was not described.

Winner of last year's Oscar for the Best Foreign Language Film, The Secret in Their Eyes (2009) is an impeccably crafted Argentinian crime thriller that actually improves on repeat viewing. A plot description can be found on numerous sites. Suffice it to say (cryptically) that the story glides on the theme of passion—specifically for the discovery of truth and for romantic love.

Viewing in HD is urged, if only to fully appreciate a stunning, seamlessly edited scene shot at a professional soccer match. I can only guess that filming required a helicopter, a crane, and a steadicam operator with wings.

I wrote about the "Belimumab Buzz" as a top 10 story of 2009. Now, some 14 short months later, the FDA announces its approval of the molecule, trade name Benlysta, for the treatment of systemic lupus erythematosus (SLE). The IV monoclonal antibody, developed by Human Genome Sciences and comarketed by GSK, is indicated for patients with active, autoantibody-positive SLE, who are already receiving standard immunosuppressive therapy (eg, corticosteroids). According to the Lupus Foundation of America, belimumab is the first treatment for SLE to be FDA approved in about 30 years.*

Belimumab approval is based on the results of 2, placebo-controlled, phase 3 trials involving a total of 1684 patients: BLISS-52 and BLISS-76. However, only the results of the former trial have been published in a peer-reviewed journal (last month in The Lancet).** A user-friendly tabulation of the non-peer-reviewed BLISS trial results can be found here. The major safety issues associated with belimumab appear to be serious infections and, to a lesser extent, infusion reactions. Notably neither trial enrolled patients with kidney or CNS involvement.

Another caveat, per the FDA: African Americans did not appear to respond to the drug; although the studies "lacked sufficient numbers to establish a definite conclusion."  (About 3%-4% of enrollees in BLISS-52 were of Af-Am descent.) "To address this concern," the FDA continued, "the sponsor has agreed to conduct an additional study of people with those backgrounds to further evaluate the safety and effectiveness of Benlysta for this subgroup of lupus patients."

Belimumab acts by inhibiting the activity of B-lymphocyte stimulator (BLys), which otherwise promotes the survival of antibody-producing B cells. The drug's mechanism of action supports its use in autoimmune disorders, like SLE. The LFA estimates that there are about 1.5 million Americans with the disease.

Yesterday's approval was associated with a 12% spike in HGSI's share price: from 25.68 to 28.91.

* As previously written, even the almighty Rituxan (rituximab; Genentech/Roche) bit the dust in phase 3 studies of patients with SLE. And another recent great hope for SLE, CellCept (mycophenolate mofetil; Roche), died a death of noninferiority after it performed no better than cyclophosphamide for the induction treatment of lupus nephritis.

** Although the results of BLISS-76 have been reported.

The shockingly haggard appearance and increasingly pressured rants of unemployed actor Charlie Sheen in the latest episode of his homemade web show, "Sheen's Korner," beg the question, now more than ever:

What is the process for involuntarily commitment in the state of California?

Fortunately (or unfortunately), we've been down this road before—specifically with Ms. Britney Spears, who was very publicly involuntarily committed twice for psychiatric evaluation in 2008. And the behaviors that led to Spears's commitment—public head shaving, attacking a car with an umbrella, sobbing in public—don't seem any more disturbing than those of Mr. Sheen during the last 2 weeks. On the contrary, I would argue that Sheen's recent behavior has been more troubling than that of Spears, given his allusions to extreme violence in his verbal tirades (eg, slitting throats) and yesterday's bizarre wielding of a machete on the roof of the Live Nation office building in Beverly Hills.

In California, the process of involuntary commitment is performed under the state statute known as 5150, in which a designated clinician (prompted by family members), a public safety officer, or an EMT may initiate the process for a 72-hour hold. But the criteria for probable cause are relatively strict in California and dictate that a person must pose a danger to himself or others or is "gravely disabled."

The latter term, according to the 5150 application, "means a condition in which a person, as a result of a mental disorder, is unable to provide for his or her basic personal needs for food, clothing and shelter." It is a criterion that might be difficult to establish in Sheen's case, unless it can be reasonably documented through photographs and film (and I think that it could be) that he has lost a considerable amount of weight in a brief period of time.

Nevertheless, according to Keith Valone, a clinical psychologist* who was quoted by the LA Times in 2008, "Getting a 5051 isn't a very hard [process] to do. Families can either call a hospital, ask if they write holds and then just present at the hospital. Or if the patient is uncooperative, they can call the police."

Here's hoping that someone acts shortly. 

* Who wasn't involved in Spears's care.

Screen capture of episode 3 of "Sheen's Korner."

03/09/11 addendum: There are veiled and certainly not-so-veiled indications that Sheen might pose a danger to others. In addition to a current restraining order, granted on the basis of alleged physical threats toward his estranged wife, it has been reported that one of Sheen's live-in girlfriends abruptly left his home late last week. Sheen's own words (through Tweeting and the first episode of "Sheen's Korner") suggest that the woman escaped after being exposed to Sheen's misdirected anger.

There also may be indications that Sheen is a danger to himself. According to Life & Style magazine, for what this source is worth, Sheen's friends now fear that he is suicidal.

Saturday marked the beginning of the 2011 Iditarod Trail Sled Dog Race, spanning more than 1150 miles from Anchorage to Nome. The trail was first raised in the American consciousness in 1925, as 20 mushers and 150 sled dogs relayed life-saving diphtheria antitoxin through blizzard conditions from Nenana, where the antitoxin had been shipped by train, to epidemic-stricken Nome.

A brief account of the historic event is provided by Stanley Scheindlin in the August 2008 issue of Molecular Interventions. A much more comprehensive record is available from Salisbury and Salisbury: The Cruelest Miles: The Heroic Story of Dogs and Men in a Race Against an Epidemic.

From Alaska's Digital Archives: Image of sledder Gunnar Kaason with Balto, who traversed the last 78 miles to Nome during the 1925 "Great Race of Mercy."

HT: Terry Glauser.

Not an innovative TV documentary (certainly not as innovative as its subject), but Azorian: The Raising of the K-129 (2009) is, nevertheless, recommended for telling a little-known or forgotten Cold War event: the CIA's clandestine project to raise an imploded Soviet nuclear sub (K-129) from the floor of the north Pacific. The project's code name, Azorian, demonstrated the partial triumph of unprecedented American engineering in the 1970s, while the Russians believed their vessel to be unrecoverable.

This time from the NEJM.

Multiple authors, lead by disgraced, former Duke geneticist Anil Potti, retracted their 2006 article, "A Genomic Strategy to Refine Prognosis in Early-Stage Non–Small-Cell Lung Cancer." (For background, start here.) The authors (all of them) wrote in a nearly inconspicuous letter to the editor that they had "tried and failed to reproduce results supporting the validation of the lung metagene model described in the article." Deep regret was expressed for "the effect of this action on the work of other investigators," but regret for any patients who enrolled in clinical trials on the basis of the unreproducible work was not mentioned.

This is now the fourth Potti-authored article to be retracted since the veracity of Potti's work was called into serious question last year in The Cancer Letter.

1. A 2007 article in the Journal of Oncology was retracted in December of last year.
2. A 2006 Nature Medicine article was pulled in January.
3. And, on the basis of this action, a 2007 article in the Lancet Oncology was retracted, also in January.

The Duke Chronicle reports that the NEJM retraction is "somewhat unexpected," because a journal spokesperson told the web site Retraction Watch in January that there were no plans to pull the article.

Today's PubMed search reveals that "A Potti" is coauthor on 128 returned articles, beginning in 2000, and first author on 33 articles—including 2 of the 4 retracted articles. The Potti-authored articles include a self-promoting piece in an April 2010 issue of Science Translational Medicine, in which Potti (along with Richard Schilsky of the University of Chicago and Joseph Nevins, Potti's Duke mentor) wrote "that it is now imperative that future clinical trials be designed with a plan to incorporate biomarker development."

Photo of Anil Potti, formerly from Duke's ISGP web site.

Delivering a minor shock, the FDA issued a complete response letter to Merck KGaA* today, indicating that the agency will not approve cladribine tablets for the treatment of relapsing-remitting multiple sclerosis (RRMS). While the FDA concluded that there is "substantial evidence" of the drug's efficacy from the CLARITY study (the results of which were published in the NEJM about a year ago), the agency was apparently underwhelmed by the volume of safety data to justify a favorable risk-benefit profile for the drug.

In response, "Merck intends to request an end-of-review meeting with the FDA to clarify next steps and to identify whether data from completed and ongoing clinical study can address the Agency's questions." The struggle for cladribine approval may not be completely over, implies the company in a press release, as "top-line" results from the extension phase of the CLARITY trial, the ORACLE MS study, and the ONWARD study are expected during the second half of this calendar year or the first half of 2012.** Both CLARITY and ORACLE MS were/are 2-year, placebo-controlled, phase 3 trials of monotherapy. ONWARD is a phase 2 study of oral cladribine as add-on therapy to interferon beta.

In Australia and Russia, oral cladribine is approved for the treatment of RRMS under the comic-book-sounding trade name, Movectro.

Presently the only disease-modifying pill option for US patients with RRMS is Novartis's astronomically priced Gilenya (fingolimod)—which was, at one time, in a nail-biting approval horse race with oral cladribine.

CLARITY = Cladribine Tablets Treatment MS Orally; ORACLE MS = Oral Cladribine in Early MS; ONWARD = Oral Cladribine Added on to Interferon Beta-1a in Patients With Active Relapsing Disease.

* The US subsidiary of which is EMD Serono.

** Although clinicaltrials.gov gives an estimated study completion date (primary outcome) of October 2013 for ONWARD.

Although noone knows exactly why vasogenic brain edema occurs in patients* treated with anti-amyloid antibodies (like Pfizer/JNJ's bapineuzumab and possibly Lilly's solanezumab), the speculation is that the antibodies attack amyloid deposits surrounding cerebral blood vessels—thus causing fluid leakage from the cerebral vasculature. Support for the idea is now available in a case study in the most recent issue of Neurology.

Italian investigators report the case of a 68-year-old man with cerebral amyloid angiopathy (CAA) who developed autoantibodies (detected in CSF) against beta amyloid proteins 1-40 and 1-42. Autoantibody titers, importantly, paralleled the rise and fall of clinical and radiographic signs of vasogenic edema.

In an accompanying editorial ("Life Imitates Art"), Greenberg and Frosch of Harvard are intrigued but advise caution. The Italian case was not confirmed pathologically, they note, and, in their experience, the identification of autoantibodies in other cases of CAA has been elusive. They speculate, nevertheless, that therapeutic anti-amyloid antibodies, despite their apparently significant limitations in the treatment of Alzheimer disease, may have, on the basis of this report, some role in the management of CAA.

CSF = cerebrospinal fluid.

* About 10% in the bapineuzumab phase 2 trial (Salloway S et al. Neurology. 2009;73:2061-2070).

Photograph of atrophied brain from person with AD: National Institute on Alcohol Abuse and Alcoholism.