bmartin: July 2009 Archives

A new (re)release on DVD: Alfred Hitchcock's The Paradine Case (1947).

A happily married and notable defense attorney (Gregory Peck) becomes infatuated with his client (the enigmatic Valli from The Third Man), who is accused of murdering her blind husband. At trial, the case balances on the moral fiber of the accused and her ambiguous relationship with her husband's valet (Louis Jourdan).

Not one of Hitchcock's best but still a Hitchcock joint, with the expected hallmarks—including brief visual nods to carnal appetites; the sharp, supportive single gal; and the director's fleeting cameo. Perhaps most notable is the moving shot of the valet's entry into the courtroom to testify, contrasted with the filming of his exit.

Visualization of the central nervous system—namely the brain and spinal cord—with MR imaging has been routinely available for about 2 decades. But assessment of the peripheral nerves is largely confined to biopsy data or physiologic measurements (eg, nerve conduction studies and electromyography).* Historically the problem of using common MR methods to inspect long stretches of peripheral nerve has been confounded by similarities in signal intensities between the nerve and its surrounding tissues.

Now investigators in Japan and The Netherlands report their technique of "whole-body MR neurography" to support the diagnosis of chronic inflammatory demyelinating polyneuropathy, or CIDP, an acquired, autoimmune disorder of the peripheral nerves. Their MR method is provided in correspondence within the latest issue of the NEJM.

In short, the technique suppresses background signals from surrounding body tissues to enable detailed views of diseased, thickened nerves. Abnormalities are readily apparent in comparison views of the brachial plexus in a healthy 23-year-old man (A) and that in a 73-year-old man with CIDP (B).

The practical utility of MR neurography is questionable, however, given that the diagnosis of many peripheral-nerve disorders—and specifically those in which the nerves are not subtly diseased—can be made by using currently available methods. Also the technique would seem to have its limitations in cases of atretic nerve disorders, like advanced axonal neuropathies. But the pictures are way cool.

MR = magnetic resonance.

* Although the condition of very proximal nerve roots is typically assessed with spinal MR imaging.

Detail from Figure 1 in Yamashita T, Kwee TC, Takahara T. Whole-body magnetic resonance neurography. N Engl J Med. 2009;361:538-539.

When attempting to discriminate among Alzheimer disease (AD), mild cognitive impairment (aMCI),* and normal cognition, structural abnormalities on MR images are more useful than known CSF biomarkers; but the use of both together is more diagnostically helpful than each individually. This conclusion is based on data from the Alzheimer Disease Neuroimaging Initiative, now available in the latest issue of Neurology.

In a statistical analysis of data from 399 subjects, the degree and location of AD-related brain atrophy on 3D MR images (condensed into the so-called Structural Abnormality Index, or STAND, score) correlated with clinical measures of cognition (eg, the MMSE score). However, known CSF biomarkers for AD—total tau, amyloid beta(1-42), and phosphorylated tau(181P)—did not. Nevertheless, the diagnostic accuracy for AD was best with the combined use of the STAND score, CSF total tau, and CSF amyloid beta. (Measures of total tau are expected to directly reflect neurofibrillary tangle pathology in AD.) In a related study, the STAND score was also a better predictor of clinical cognitive decline—namely the progression of aMCI to AD—than CSF biomarkers.

The Alzheimer Disease Neuroimaging Initiative is a longitudinal, multisite, observational study of elderly individuals with normal cognition, aMCI, or AD at 56 US or Canadian institutes. Funding for the study originates from the National Institute of Aging, the National Institute of Bioimaging and Bioengineering, pharma, and "several foundations."

CSF = cerebrospinal fluid; MMSE = Mini-Mental State Examination; MR = magnetic resonance.

* Amnestic mild cognitive impairment.

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

The Spiral Staircase (1942): Ridiculous, preposterous, and thoroughly entertaining. A young Dorothy McGuire is a traumatized mute stalked by a serial killer in the early 1900s. Ethel Barrymore mugs it up as a bedridden invalid, warning the girl of her imminent danger. A good late-night change of pace for tweens.

People with amnestic mild cognitive impairment* (MCI) develop Alzheimer disease (AD) at an annual rate of 10%-15%, and about half show AD-type brain pathology—neurofibrillary tangles and beta-amyloid plaques—at autopsy. However, clinical conversion is not a given. Consequently a number of investigators have attempted to identify biomarkers that predict the conversion of MCI to AD, such as hippocampal volume on MR images.

Now researchers show that MCI patients with a relatively increased brain load of beta-amyloid, measured by using positron emission tomography** (PET), are much more likely to develop AD than MCI patients with control levels of beta-amyloid. Results of the small UK and Finnish study (N = 31) are available in an advanced e-printing of Neurology.

During a 1-3-year follow-up, 14 of 17 (82%) MCI patients with increased beta-amyloid on PET images and 1 of 14 (7%) MCI patients with nonincreased beta-amyloid converted to AD. The speed of clinical conversion was positively associated with the beta-amyloid load and the APOE ε4 carrier status in MCI patients.

APOE = apolipoprotein E.

* Defined as subjective and objective memory impairment for age but largely preserved general cognition and normal activities of daily living (Petersen, 2004).

** By using the thioflavin-based radiotracer Pittsburgh compound B (PIB).

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

Trachoma, the leading infectious* cause of blindness in the developing world, has been eliminated from Ghana, Mexico, and Saudi Arabia, according to a press release from the Carter Center and the International Trachoma Initiative. Ghana is the first sub-Saharan African country to purge the disease.

Elimination of trachoma** was achieved by using the so-called SAFE strategy of the World Health Organization—which includes eyelid surgery, antibiotics (ie, azithromycin), facial cleanliness, and environmental improvements. The strategy was used successfully 3 years ago to wipe out trachoma in Iran, Morocco, and Oman and is the basis of the WHO's Alliance for the Global Elimination of Blinding Trachoma by the year 2020.

Azithromycin (Zithromax) is currently being donated by Pfizer, in conjunction with the Edna McConnell Clark Foundation. The drug company and the foundation originated the International Trachoma Initiative in 1998.

* Caused by the bacteria Chlamydia trachomatis.

** Defined by WHO as 1) elimination of blinding cases of trachomatous trichiasis through surgery (or at least offering surgery to all cases); 2) reducing cases of trachomatous follicular conjunctivitis in adults to fewer than 1 per 1000; and 3) reducing the prevalence of trachomatous follicular conjunctivitis in children (age range, 1-9 years) to less than 5%.

Image of trachomatous conjunctival scarring from WHO trachoma grading cards.

Pharma biz sources

are buzzing with the PR news that belimumab (Benlysta*; GSK, Human Genome Sciences) improved the disease activity of systemic lupus erythematosus (SLE) in a 1-year, 2-dose, placebo-controlled, phase 3 study (BLISS-52). The mAb also enabled the reduction of the corticosteroid dosage.

The primary endpoint of the study, which was met with belimumab treatment, was a combination of 4 recognized measurements of SLE activity.** The reported patient response rates were 57.6% for belimumab 10 mg/kg; 51.7% for belimumab 1 mg/kg, and 43.6% for placebo (respective P values = .0006 and .011, vs placebo). All patients received "standard of care." Individual secondary measures were also consistent with the statistically significant primary-endpoint results.

The rates of serious infections were 6.1% and 5.9% with belimumab and placebo, respectively, and rates of common adverse advents—headache, arthralgia, URI, UTI, and influenza—were also comparable between the 2 treatments. An important footnote in this relatively short-term study: no observed malignancies.

Results of a longer-term, placebo-controlled, phase 3 study with belimumab in SLE, BLISS-76, are expected in November (although the combined primary endpoint will be assessed at 52 weeks). As in BLISS-52, 2 belimumab dosages, 1 and 10 mg/kg, have been randomly assigned. Positive results will undoubtedly bolster a biologics license application to the FDA.

Belimumab is a human mAb that inhibits the activity of B-lymphocyte stimulator (BLyS), which promotes the survival of (auto)antibody-producing B cells. The drug was discovered by Human Genome Sciences, which entered into a codevelopment and comarketing agreement with GSK 3 years ago. Other anti-B-cell therapies in clinical development for SLE include rituximab (Rituxan; Genentech), epratuzumab (Immunomedics), and ocrelizumab (Genentech, Biogen) aka Son of Rituxan.

The most recent great hope for SLE, mycophenolate mofetil (CellCept; Roche) died a death of noninferiority, after it performed no better than cyclophosphamide for the induction treatment of lupus nephritis.

According to the Lupus Foundation of America, roughly 1.5 million Americans and more than 5 million people in the world have lupus.

mAb = monoclonal antibody; URI = upper respiratory tract infection; UTI = urinary tract infection.

* Formerly LymphStat-B.

** A reduction from baseline in the SELENA SLEDAI score of at least 4 points; no worsening in Physician Global Assessment (PGA); no new BILAG-A organ domain score; and no more than one new BILAG-B organ domain score from baseline.

Although the Accreditation Council for Continuing Medical Education (ACCME) reports that total income for all CME providers dropped only 7% from 2007 to 2008, total income for publishing and education companies (ie, MECCs) dropped 20%. These data are derived from the ACCME's 2008 Annual Report, which was released last week. The income drop for MECCs is largely due to loss of commercial (ie, pharma) support, which fell 22% from 2007 to 2008. Also 6 fewer MECCs reported income data to the ACCME in 2008 (from 150 in 2007).

CME Income and Expense Data for Publishing/Education Companies, 2004-2008

Net income (total income – total expense) for all reporting MECCs in 2008 was $157,608,100, compared with $215,106,000 in 2007 (percentage drop, 27%). In addition, the percentage of total CME income for MECCs (among all providers) dropped below 30% (to 28%) for the first time in at least 5 years. General sentiment in the CME-MECC biz is that last year's income drop is the beginning of a downward trend, not a one-time aberration.

MECCs = medical education communications companies.

Just released on DVD is the underappreciated Lonely Are the Brave (1962), based on an Edward Abbey novel and adapted for the screen by the blacklisted Dalton Trumbo.

An easy-going cowboy (Kirk Douglas, in what has to be one of his best performances) refuses to be fenced in by urban sprawl and the law. With fine, complementary work from Gena Rowlands, Walter Matthau, and Whiskey the Horse and an over-the-top performance by George Kennedy.

HT: KTG

To conserve overtaxed resources—particularly laboratory resources—the World Health Organization will no longer provide its usual tabulated updates for the number of swine flu (H1N1) cases worldwide. Instead monitoring will focus on seminal cases in newly affected countries, clusters of fatal or otherwise severe cases, and evidence of unusual transmission. Details of the policy change were provided in a briefing note posted yesterday at the WHO web site.

WHO reports that the "overwhelming majority" of H1N1 cases have been mild, with spontaneous recovery, despite the fact that the virus has spread with "unprecedented speed." Confirming these cases with laboratory testing, however, is "extremely resource-intensive," WHO writes. "In some countries, this strategy is absorbing most national laboratory and response capacity, leaving little capacity for the monitoring and investigation of severe cases and other exceptional events."

For countries well ensconced in the H1N1 pandemic, surveillance procedures will now mirror those used to assess seasonal influenza activity. Countries with "well-established laboratory-based surveillance systems" will monitor any changes in the H1N1 virus.

According to WHO's most recent (and last) global update, on July 6, a total of 94,512 H1N1 cases had occurred throughout 135 countries or territories. The overall mortality rate remains steady, at 0.45% (429 deaths).

This week, 2 articles examine the possible benefit of closing a patent foramen ovale (PFO), the vestige congenital hole between the left and right atria. Individuals with isolated PFO are typically asymptomatic, but longstanding reason has dictated that PFO, as a conduit for cardiac emboli, increases the risk of stroke and is a prominent cause of brain infarction in young adults. At least 2 studies indicated that the prevalence of PFO is increased (up to 45%) in patients with cryptogenic stroke.

However, a meta-analysis of 4 trials (N = 1081), published in this week's Neurology, indicates that the pooled relative risk (RR) of recurrent ischemic stroke or TIA in patients with PFO (vs those without) is only 1.1 (P = .149). The pooled RR for ischemic stroke alone in patients with PFO is 0.8 (P = .666).* Post-event treatments in these studies included antiplatelet therapy, warfarin, and/or surgical closure (the latter in 28% of patients with PFO), but the authors advise against using their meta-analysis data—which cannot be adjusted for important study differences—to assess therapeutic efficacies.

In this week's JAMA, a second study, performed at the Cleveland Clinic, assessed the effects of closing an incidental PFO—which was seen in 2277 of 13,092 (17%) surgical patients. Surgical closure was performed in 639 patients (28%) with PFO. The investigators calculated similar rates of in-hospital death (3.4% vs 2.6%) and stroke (2.3% vs 2.3%) in matched PFO groups. But patients with a repaired PFO were significantly more likely to experience a longer-term postoperative stroke than patients whose PFO was not repaired (2.8% vs 1.2%; P = .04). Surgical closure was statistically more likely in younger patients, in patients undergoing atrial valve surgery, or in those with a history of stroke or TIA. Long-term survival was not affected by PFO closure.

Currently there are no completed randomized trials comparing medical therapy with surgery in patients with cryptogenic stroke and PFO. The NIH database indicates that at least 1 US-based controlled trial is active but not recruiting.

In 2004, the American Academy of Neurology concluded that PFO does not increase the risk of subsequent stroke or death in medically treated patients. However, the combination of PFO and an atrial septal aneurysm possibly increases the risk of recurrent stroke (but not death) in medically treated patients who are younger than 55 years of age.

TIA = transient ischemic attack.

* In patients with PFO, the pooled absolute rate of recurrent stroke or TIA is 4 events per 100 person-years; the pooled absolute rate of recurrent stroke is 1.6 events per 100 person-years. The authors write that this rate is similar to the annual rate of major bleeding with warfarin therapy for cryptogenic stroke.

Mini-graphic of atrial septal defect (ASD) attributed to the NIH.

Winner of Best US Drama at last year's Sundance, Frozen River (2008) is writer-director Courtney Hunt's very realistic feature debut about human trafficking along the New York-Canadian border. The movie's highly authentic feel begins with the amazing Melissa Leo, playing a desperate mom who merely wants her double-wide. There is absolutely no sense that Leo, who was nominated for an Academy Award last year, is the usual Hollywood glamourpuss-turned-frump for the sake of an Oscar bid. Not a trace of Botox, chemical peeling, or Restylane. Praise Jesus.

The supporting cast, including Misty Upham, Charlie McDermott, and Michael O'Keefe, is also beyond reproach.

And another thing that Avastin (bevacizumab; Genentech) may be good for:

The anti-VEGF monoclonal antibody improved hearing loss and reduced tumor volume in patients with growing vestibular schwannomas. The conclusions are based on data from a small, first-of-its-kind study of patients with neurofibromatosis (NF) type 2—data which are available in an early release article from The NEJM.

Ten consecutive patients with NF type 2 and progressive vestibular schwannomas (who were not candidates for or declined the standard treatment of surgery and radiation therapy*) received at least one dose of bevacizumab (5 mg/kg every 2 weeks). The median annual growth rate of schwannomas before treatment was 62%, and the median duration of treatment was 12 months. (The rationale for assessing bevacizumab in NF-associated schwannomas is based on the expression of VEGF in tumor cells. However, the expression of the VEGF receptor, VEGFR-2, on tumor vessels is not particularly high—which suggests that an anti-VEGF-receptor drug is less likely to be of benefit than bevacizumab.)

In a retrospective analysis, 9/10 tumors shrank (best median response, 26% reduction) after bevacizumab treatment, and 6 demonstrated an imaging response. Only 1 patient experienced an increase in tumor volume (of 32%). Tumor reduction strongly correlated with baseline vasogenic edema on MR images (ie, the mean apparent diffusion coefficent). Improvements in hearing (at <12 weeks) were observed in 5 of 7 eligible patients and were progressive and durable (up to 16 months) in most.

This pilot study was not funded by Genentech; although 1 author (Gregory Sorensen, MD) reported receiving grant support from the company.

NF2 is a dominantly inherited disorder with a prevalence of 1 in 25,000. The most common tumor type associated with the condition is vestibular (or acoustic) schwannomas, benign tumors of the 8th cranial nerve. Growth of tumors causes progressive hearing loss, as does surgical and radiation therapy. Progressive vestibular schwannomas can also produce brainstem compression.

In May, the FDA approved Avastin for the treatment of the uniformly fatal brain tumor, glioblastoma multiforme, after standard therapy.

VEGF = vascular endothelial-cell growth factor.

* Eight patients were at high risk for complete hearing loss with standard therapy.

Kiss of Death (1947): An armed robber (Victor Mature) sets up a hit on his accomplice through the DA's office. Mature then proceeds to go after the giggly, psychopathic hitman (a young Richard Widmark).* Karl Malden makes brief, but noticeable, appearances as an aggressive prosecutor.

P.S. The basis for the title remains a mystery to me.

* Widmark's over-the-top portrayal clearly informed Frank Gorshin's turn as The Riddler on TV's "Batman."

The latest update from the World Health Organization reveals the number of swine flu cases worldwide at 77,201—a nearly 50% increase from the June 22nd update. Deaths total 332 (up from 113) for an unchanged mortality rate of 0.43%.

H1N1 cases have now been reported in 120 countries or territories, and related deaths have occurred in 17. Countries disproportionately affected by new cases (where more than 500 cases have occurred) include Thailand, the United Kingdom, Brazil, Peru, and Spain. The number of swine flu deaths in the United States now surpasses those in Mexico.

Country	Cases	Deaths
Brazil	680	1
Honduras	118	1
Philippines	861	1
Spain	717	1
Uruguay	195	1
Colombia	93	2
Costa Rica	279	2
Dominican Republic	108	2
Guatemala	254	2
Thailand	1414	3
United Kingdom	6538	3
Australia	4090	7
Chile	6211	12
Canada	7983	25
Argentina	1587	26
Mexico	8680	116
United States	27,717	127