Pathophilia

Watching The Final Countdown (1980), starring the recently departed James Farentino, is more of an exercise in "How could I make this movie really good?" as opposed to recognizing its few merits—one of which is the evergreen premise of rewriting history through time travel. This is a solid, if not always entertaining, sci-fi theme, which is unfortunately directed and scored here in cringe-inducing, ham-handed fashion. And let's not even talk about the special effects, which are laughably rudimentary, even for 1980. One wonders what Spielberg and John Williams would have done with the not-so-terrible screenplay in their prime (and if Spielberg had actually passed on the project at some point during its development).

The setup: For some completely inexplicable reason, the USS Nimitz, the world's largest aircraft carrier, is transported through a freakish Pacific wormhole on December 7, 1980, to—you guessed it—39 years earlier.* The conflict (shouldered largely by the ship's commander, who is played solidly by an otherwise too-old Kirk Douglas): To prevent the Japanese raid on Pearl Harbor or to not fuck with the Day of Infamy and the world's destiny generally. Military men being military men, most are completely up for a technology-fueled ass-kicking of Japan's propeller air fleet; while an on-board civilian from the Defense Department (Martin Sheen**) warns of the so-called butterfly effect and other pesky philosophical stuff. The ship's commander must also have the safety of his crew in mind, especially given the haphazard nature of the arbitrary wormhole. What if the warship accidentally travels back to 1980 while its F-16 pilots are in flight, chasing the Japanese?

The movie also stars a sputtering (no matter what decade he's in) Charles Durning and a forever-young Katharine Ross—whose character (like us) worries most about what happens to her gorgeous collie.

* When "Nimitz"--ha, ha--was only the name of the guy who commanded the US Pacific fleet.
** This must have been a refreshing walk in the park after Apocalypse Now.

Implementation of the Sustainable Growth Rate, or SGR, formula—the formula ostensibly used to control Medicare spending and physician reimbursement for Medicare services—has been stayed numerous times since it was legislated in the late 1990s. As Harvard policy analysts describe in a newly published study at the NEJM website, the law dictates that Medicare spending targets be set on the basis of several national targets (eg, per capita GNP, Medicare growth), and that, if actual Medicare expenditures on physicians' services exceed the target, the SGR-defined cuts kick in to rein in these expenditures.

Almost every year since 2002, the Harvard analysts affirm, the actual expenditures have surpassed the targets, and the SGR formula has dictated cuts to close these spending gaps or "holes." But Congress—for economic and political (Congress? political?) reasons—has repeatedly sustained these cuts, which are cumulative with each passing stay. The most recent SGR-defined cut in physician fees, now an untenable, practice-killing 27.4%, was temporarily stayed by Congress in December. However, the cut will, at least theoretically, occur at the end of this temporary stay, the end of February—unless Congress votes on yet-another stay. Abolishing the SGR formula altogether has been terribly problematic, because canning the law adds tremendously to the already tremendous US deficit, and pundits either differ or are entirely at sea about a replacement bill that would mitigate the costs of trashing the formula.

In the Harvard study, sources of the spending gaps or holes, from 2002 to 2009, were examined by state and specialty, and considerable differences were found by either parameter. For instance, the specialty of cardiology—perhaps justifiably, perhaps not—contributed substantially to total expenditures and excess growth during the examined time period. Between 2003 and 2009, the specialty overshot its SGR target by nearly 80%. On the other hand, general surgery undershot its estimated SGR target by more than 100%. The point: it would be unfair to penalize general surgeons with across-the-board SGR cuts if they didn't contribute to excessive Medicare spending.

The authors' conclusion, however, is not to readjust the SGR-defined cuts by specialty or state, but to go more granular to control physicians' Medicare reimbursement. In an accompanying audio commentary, anchor author Michael Chernew calls Congress's short-term fixes "shameful" and argues that the least-reprehensible solution is to have Medicare reimbursements based on the expenditures of smaller physicians' organizations (something like accountable care organizations), which would accept "global payments or payments bundled by episode of care." These smaller organizations would allow physicians to control fees, he argues, and to take greater responsibility for their expenditures by "eliminating lower-value therapies and delivering higher-value health care." On the basis of observed experience in Massachusetts, Chernew estimates that MDs could be pushed into these organizations "very rapidly," say within the next 3-4 years, depending on how the SGR formula is "fixed" by Congress.

Image of the Grand Canyon from the Association of Environmental and Engineering Geologists.

At last, something positive (albeit very preliminary) to report about the use of human embryonic stem cells (hESCs)...in disease, no less.

Yesterday The Lancet published (and made freely available—!) early safety results from Advanced Cell Technology's 2 prospective phase 1/2 clinical studies of hESC-derived retinal pigment epithelium in 2 blind patients, one with dry age-related macular degeneration and the other with a much rarer, genetic equivalent, Stargardt's disease. Both diseases result from the degeneration of the RPE, which leads to photoreceptor loss, and the former condition is the leading cause of blindness in the developed world.*

During the 4 months after subretinal transplantation of RPE cells, the investigators confirmed structural attachment and no evidence of hyperproliferation, other signs of abnormal growth, or rejection in either patient. In addition, the patients reported very modest improvements in vision from baseline; although a placebo effect in these cases is probably very strong. Most important, however, is that neither patient described a deterioration in vision.

The authors conclude that the "future therapeutic goal will be to treat patients earlier in the disease processes, potentially increasing the likelihood of photoreceptor and central visual rescue." The estimated enrollment for each of the ongoing studies is 12.


* For leading causes of blindness in the world, go here.

Graphic of retina with evidence of AMD from an NIH web page.

01/25/12 addendum: According to an astute ophthalmologist, it should be noted that patients in these hESC transplantation studies require immunosuppression to reduce the risk of graft rejection, namely in the form of tacrolimus (eg, Prograf) and mycophenylate mofetil (eg, CellCept). Although it's been previously reported that hESC transplantation may be more feasible in the eye, because the environment is relatively immune privileged, this is only really true for the cornea and natural lens of the eye, which lack blood vessels. The retina and the underlying choroid are highly vascular; consequently immunosuppression is a must with the subretinal grafting of hESC RPE cells. Autologous retinal grafts (which appear to be in an even earlier state of development) would preclude the need for immunosuppressants. This recent review describes the current status of using stem cells for the treatment of retinal diseases.

Friday the FDA announced that it's permitting the marketing of the first test for antibodies to the JC virus (Stratify JCV Antibody ELISA test; Quest Diagnostics), the cause of progressive multifocal leukoencephalopathy (PML) in immunocompromised individuals and now an official risk factor for the disease in patients taking Tysabri (generic name, natalizumab; Biogen Idec). The presence of anti-JC virus antibodies is added to the previously identified risk factors for PML of 1) a longer duration of Tysabri treatment (>2 years) and 2) previous immunosuppresant therapy. The risk of PML in the presence of all 3 factors is 11 in 1000, or 1.1%. The FDA reports that there have been 201 reported cases of PML among approximately 96,582 patients who have been treated with Tysabri (for the indicated conditions of multiple sclerosis or Crohn's disease) as of January 4th; the overall PML rate is consequently 0.21%.

The "JC" in JC virus stands for John Cunningham, and like the previously anonymous Henrietta Lacks of the immortal HeLa cells, this John Cunningham remains largely unknown. The virus itself is ubiquitous and harmless in most people (40%-60% of the general population are seropositive), but it creates a potentially devastating and often fatal white matter disease in immunocompromised persons.

A cursory search leads to a Google-available (or really, partially available) book entitled Human Polyomavirus, which was edited by Kamil Khalili and Gerald Stoner and published in 2001. The first 3 chapters concern the search for the cause of PML, which was first described or recognized in 1958 (first published paper by Astrom et al..."a hitherto unrecognized complication of chronic lymphatic leukaemia and Hodgkin's disease"). Chapter 2, written by Dr. Gabriele M. Zu Rhein, a codiscover of JC virus, reveals that John F. Cunningham was a patient at the VA Hospital in Wood, Wisconsin, in the summer of 1970. Cunningham had Hodgkin's disease and "rather rapidly progressing neurologic deficits." He was given a diagnosis of PML during life on the basis of a brain biopsy and thereafter "expressed the wish that his brain should aid research into this fatal disease." A "new human polyoma virus" was subsequently detected by Rhein and her colleagues in Cunningham's postmortem brain tissue, and the virus was named JC virus in honor of the patient.

A Wisconsin death record reveals that John F. Cunningham was 36 (born August 30, 1933) when he died on July 12, 1970, in Milwaukee. As a military veteran, his likely service would have been in the Korean or Vietnam War.

01/26/12 follow-up: The 1971 Lancet article by Padgett et al indicates that Cunningham was 38 in 1970 (although his death certificate indicates that he was about 6 weeks shy of his 37th birthday at the time of his death). Cunningham had been diagnosed with Hodgkin's disease for 8 years before he developed a "progressive left central facial palsy, left hypoglossal palsy, and palsy of the left upper extremity" in the Spring of 1970. (His cancer had been treated with nitrogren-mustard derivatives since 1968.) These neurologic deficits were attributed to PML, a diagnoses confirmed by brain biopsy (which showed "pathognomonic oligodendrocytes along the periphery of demyelinating lesions") during life. He reportedly granted permission for the postmortem examination of his brain only (examination occurred 10½ hours after death). Gross and microscopic study confirmed the diagnosis of PML, and extracts of his brain were used to grow and identify the newly recognized intracellular virions in culture—which were dubbed JC virus.

"Life on Mars" (2006-2007): A modern-day Manchester policeman (played by the terrific John Simm) is transported back to politically incorrect 1973 after being struck by a car. Is he mad, in a coma, or back in time? The nifty opener to the equally nifty British TV series*—which was really just an excuse to produce a 70s cop show—asks this question repeatedly, and we're given kind of an answer in the show's remarkably satisfactory finale (at the end of the second season).

Because of the show's popularity and critical acclaim in the UK, it was predictably bought for an American treatment, and the results were almost as predictably disappointing. A glimpse of both shows indicates that a successful trans-Atlantic adaptation is heavily dependent on casting, which may be about 99.44% of the formula in my estimation. (The lead for the NYC version was, somewhat ironically, an Irish actor, and his charisma as an American detective was sorely lacking, also somewhat astonishingly.) There's also something a bit disingenuous about a 70s show in the US drawing on inspiration from a Bowie song (ie, "Life on Mars"). Glam rock was and always will be the purview of England, while urban soul would be the period equivalent for Manhattan, I would think. Eh, the whole US rendition just didn't work, in definite contradistinction to the gritty, groovy, and frequently comical British production.

* Two seasons, 8 episodes each.

In a Pharmalot interview, money manager, blogger, and diabetic David Kliff absolutely excoriates "Buttah Queen" Paula Deen and insulin-maker Novo Nordisk for their newly announced, and arguably duplicitous, promotional relationship. Kliff easily tosses out words like "hypocrite," "shyster," and "bastardizing" like so many fat calories in a bacon-and-fried-egg hamburger with doughnut buns.

Medivation and partner Pfizer will cease development of Dimebon (latrepirdine), a now thoroughly defunct antihistamine, "for all indications and will terminate the ongoing open label extension study in Alzheimer's disease." The small biopharm company announced the official end of Dimebon development yesterday in a press release, and the story was picked up by the WSJ. Dimebon's demise is based on flat results in the companies' CONCERT trial, a phase 3 study in which Dimebon was assessed as add-on treatment to symptomatic treatment donepezil (Aricept) in patients with mild-moderate AD.

Previous news on Dimebon (March 2010) was that it failed to improve cognition or global functioning in a placebo-controlled phase 3 study of patients with AD, and Medivation's share price plummeted 30 points on the dated news. In 2008, Pfizer agreed to pay Medivation $225 million upfront and another $500 million when Dimebon was FDA approved. The agreement—which split development costs and potential profits on a 60-40 basis (Pfizer assumed the larger share)—also conferred licensing rights to Pfizer for use of the drug in Huntington's disease. But Dimebon also disappointed in this devastating condition.

Pfizer was evidently betting on the chance that Dimebon would sail through US clinical development, given very favorable phase 2 results published in The Lancet in July of 2008.  In a randomized, double-blind, placebo-controlled, multicenter study (N = 183) that was conducted entirely within Russia and funded by Medivation, patients with mild-moderate AD who received Dimebon demonstrated significantly less cognitive decline at 6 months, as measured by the ADAS-cog (mean score difference, 4.0; P < .0001). Although some were scratching their heads as to why an antihistamine would have a disease-delaying or merely symptomatic effect in AD. The ultimate, tired lesson: promising phase 2 results are not a harbinger of anything, except chancy phase 3 study.

Medivation reminds us that it's also developing an investigational drug (MDV3100) with Astellas for the treatment of advanced prostate cancer. The compound is in the phase 3 stage, and Medivation got a huge bump in its stock price in late October just before news of very favorable survival data was publicly released.

The October Man (1947): Seriously brain injured in a bus crash (which takes the life of his young companion), a recovered, but terribly guilt-ridden, man (John Mills) is suspected of murdering a needy female acquaintance. Given his mental handicap, he, himself, is not sure of his innocence and spends the remainder of the film vacillating between suicide and a desperate search for the real murderer. A very acute eye will catch a young and wholly charming Juliet Mills, the real-life daughter of the collectively beloved leading man.

Sherley et al v Sebelius et al. The case that won't go away...to the chagrin of scientists who rely on government funding for research with human embryonic stem cells (hESCs).

The Nature News Blog reports today that scientists James Sherley and Theresa Deisher, who choose to work with adult stem cells, are appealing Judge Royce Lamberth's reluctant decision in July to shoot down a permanent injunction against federal funding for hESC research. The scientists submitted their legal brief yesterday to the US Court of Appeals for the DC Circuit. The appeals court, which ruled against Sherley et al last April (with respect to their request for a preliminary injunction), will hear oral arguments on April 23rd in this new appeal to overturn Lamberth's ruling against a permanent injunction.

But a similar decision granting federal funds for hESC research by the appeals court is not a given. The randomly selected, 3-judge panel for the April hearing will be somewhat different than the one that ruled last year, the Nature News Blog reveals. The judges for the upcoming appeals hearing will be Republican appointees Chief Judge David Sentelle, Judge Janice Rogers Brown, and Judge Karen LeCraft Henderson. The lone, common panel member is Henderson, who dissented in the previous appeals hearing by calling the government's favorable interpretation of existing law (ie, the highly ambiguous Dickey-Wicker amendment) "linguistic jujitsu."

Image of undifferentiated hESCs from http://www.nih.gov/catalyst/2007/07.01.01/page1.html. 

About one-third of cognitively normal elderly demonstrate an elevated load of beta-amyloid,* a pathologic hallmark of Alzheimer disease, in the brain, according to a newly published study from the Mayo Clinic. These data support previous observations, in which the PET-imaged brains of about a third of elderly, nondemented subjects will exhibit an abnormal accumulation of the AD-associated protein.

However, the Mayo investigators went a bit further by examining the potential association between the load of beta-amyloid, as measured with an established radiolabeled tracer (Pittsburgh compound B, or PiB) on PET images, and cognitive performance on various memory, language, attention, and visuospatial tests. As well, a relationship among brain amyloid, cognitive performance, and APOEe4 status (a well-known genetic marker for AD) was examined. What the researchers found was that poorer cognitive performance was associated with greater amyloid deposition, and that this relationship was more robust in APOEe4 carriers. Conversely the association between amyloid load and relative cognitive impairment was much weaker (ie, only "modest") in subjects who did not carry an APOEe4 allele, suggesting (the authors concluded) "that APOE isoforms modulate the harmful effects of [beta-amyloid] on cognitive function."

What any of this information means practically is very murky, however. Will some of these cognitively normal subjects with heavier amyloid burdens (and who perform less well on cognitive tests) develop AD—that is, if they live long enough? Is AD more likely in these subjects if they're APOE e4 carriers? We don't know, and obviously further longitudinal work is necessary. The Mayo authors do imply that follow-up is ongoing.

In an accompanying editorial, Buchman and Bennett commended the Mayo investigators for the size of the study (a highly respectable 408 subjects [with a median age of about 80 years]) and their "important contribution to our understanding of AD, illustrating that even among persons without dementia or [mild cognitive impairment], amyloid deposition is associated with very mild symptoms, especially among carriers of the APOE e4 allele." But "[w]hether...amyloid imaging agents will have clinical utility remains to be determined," the editorialists appropriately caution. They advise about the lack of data concerning the prognostic value of amyloid retention (presumably in any subjects, whether demented or not) and how amyloid retention may change over time. And they add that the utility of amyloid-imaging agents "will remain low in the absence of an effective amyloid modulating agent." In other words, what's the point of knowing the amyloid burden if you can't do anything to lighten the load?

A related issue, however, not explored by the editorial authors, is whether even removing amyloid in the context of cognitive impairment, is beneficial or, in fact, does more harm. Existing AD trials suggest that amyloid-modulating agents (eg, bapineuzumab) can cause brain edema—presumably due to the removal of vascular amyloid—and that they do so without improving cognition to any substantial degree overall.

Intervening earlier with anti-amyloid drugs in less cognitively impaired subjects, as proposed by some industry investigators, is a tricky move: obviously primum non nocere in persons with only mild cognitive impairment and certainly in individuals with no practical cognitive problems (regardless of their amyloid burden).

PET = positron emission tomography.

* Defined by a "global cortical PiB retention ratio" of greater than 1.50.

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