Integrated: Blogs  New Discovery Portal Search

Some urology groups have integrated intensity-modulated radiation therapy (IMRT) into their practice, which allows them to refer patients to their own practice for IMRT. This analysis showed a substantial increase in IMRT use by urologists who acquired ownership of IMRT services.

As permitted by the exception for in-office ancillary services in the federal prohibition against self-referral, some urology groups have integrated IMRT, a radiation treatment with a high reimbursement rate, into their practices.

Clinical Pearls

• What percentage of men in the United States with a new diagnosis of prostate cancer had clinically localized disease in 2011, and what is the overall 10-year survival among men with prostate cancer?

In 2011, nearly 240,900 men in the United States received a new diagnosis of prostate cancer. Approximately 90% of these men had clinically localized disease, which was indolent in most cases. The 10-year survival rate among all men with prostate cancer is 98%.

• What is IMRT, and how does it differ from brachytherapy?

IMRT is an advanced form of three-dimensional radiation therapy, which involves the use of a computer-driven machine that revolves around the patient as it delivers radiation. Radiation beams are aimed at the prostate from multiple angles. Intensity can be adjusted to maximize the dose targeted at the cancerous tissue and minimize the dose to surrounding healthy tissue. Brachytherapy with the use of low-dose-rate isotypes involves permanent implantation of seeds that emit a low dose of radiation over a period of several months. Some patients also receive a boost of external-beam radiation therapy or androgen-deprivation therapy. The authors indicate that despite substantial variation in reimbursement, evidence suggests that for low-risk disease, the alternative treatments are clinically equivalent in terms of survival, and that no single treatment approach is preferable with respect to the risk of adverse events and implications for quality of life.

Morning Report Questions

Q: What were the primary results of this study, which evaluated the use of IMRT by urologists who referred to their own practices (self-referred) for this therapy as compared to non-self-referring urologists?

A: The results of this study indicate that urologist self-referral is associated with large increases in the rate of IMRT use for Medicare beneficiaries with newly diagnosed, nonmetastatic prostate cancer.

Among beneficiaries treated by self-referring urologists in private practice, the rate of IMRT referral increased from 13.1 to 32.3%, an increase of 19.2 percentage points (P<0.001).

Table 2. Treatment Provided for Men with Newly Diagnosed, Nonmetastatic Prostate Cancer in the 35 Matched Groups of Self-Referring and Non-Self-Referring Urologists in Private Practice, According to Self-Referral Status and Ownership Period.

Q: During the study period, what changes were seen in other forms of treatment for prostate cancer among self-referring urologists, and how do the results compare with non-self-referring urologists?

A: Rates of brachytherapy and hormone use fell by 13 and 8 percentage points, respectively (P<0.001). Changes in use rates for prostatectomy and active surveillance were inconsequential. By contrast, the rate of IMRT referral among patients treated by non-self-referring urologists was virtually unchanged between the preownership and ownership periods, from 14.3 to 15.6%, which was an increase of 1.3 percentage points (P=0.05). Use rates for the remaining treatment options by non-self-referring urologists remained stable.

Speed Dating

The pharmaceutical chemicals sector returned to the miraculously unmolested Ocean Place Resort & Spa on the Jersey Shore this week. Unlike much of the coast to the north and south, Long Branch sustained only minor damage from Sandy, which hit shortly after last year’s meeting. The place has a fresh coat of paint, and the Tiki Bar looks pretty much like the one that was there last year.

There have been a few changes, however. Tighter security. Conference sessions held in the exhibit halls, and an increased emphasis on biopharma, reflecting the growing business in biotech drugs. There was also a kind of speed dating session—a stretch of the afternoon during which Merck, Pfizer, Novartis, Celegene, Gilead Sciences, Ironwood Pharma and other drug companies large and small had representatives at round tables around which contract chemical suppliers could sit and try to break the ice. This was a hit with attendees who are always looking for customers (ie drug company decision-makers) at pharma chemical trade shows,  usually finding very few.

“Large and small” was a big theme in discussions on the exhibit floor and in one of the panel sessions (which was technically also on the exhibit floor—taking the sessions out of the conference rooms was not such a big hit with attendees). Focusing on contract work, both manufacturing and research, with biotech and emerging drug companies, the panel came to the conclusion that extra up-front planning is in order when passing work from a small drug firm to a contractor, but that the time to do that work is generally extremely tight.

“As we learned in grad school, a day in the library is worth more than a week in a lab,” said Stuart Levy, principal at SBL Chemistry Consulting, who chaired the panel. It is especially important to get the technical package in order before transferring a project to a contract manufacturing organization (CMO), he said. “You need to write up a good request for proposal and set the tone. If you don’t, trying to back-fill that later is extremely difficult.”

But windows of opportunity don’t always allow for much time in the library, said panelist Richland Tester, principal scientist at Celgene Avilomics Research. “Sometimes we are asked to do crazy things.,” he said. There is generally a deadline to deliver the next data point in a clinical trial in order to receive the next tranche of venture funding. “If you have until a particular date to do it, you have to do it,” he said. “It’s not like having a six-month timeline from a big drug company. Sometimes you don’t have that luxury.”

Time, on the other hand, is money. “I have heard clients comment that money is no object,” said panelist Cheryl D Garr, director of business development at PharmaCore. Such comments are, she noted, more often than not disingenuous.

Jeff Saunders, vice president of small drug design at Ember Therapeutics, responded that the object is value, not money.

Overall, the companies in the sector continue to be optimistic about business. James Bruno, president of consulting firm Chemical and Pharmaceutical Solutions, told me, however, that a shift is underway in the work being done, one that puts the installed manufacturing base a bit out of kilter.

“I’ve said for a number of years that I’m concerned about is what I call simple assets,” he said. “Some companies just have the wrong assets. We have large reactors when we really need smaller ones. We have big vessels that can make 100 tons when the product is only going to be two tons.” Oncology drugs and other high potency, highly active drugs make up an increasing proportion of the work being outsourced. And drug company pipelines are filling with more.

“We are still not pushing drugs out at a rate that makes everyone happy,” he says. “And if your pipeline is weak, the generic pipeline is weak.”

The current business environment in China was a prominent subject of discussion today, with a panel on the subject (see previous post The China Conundrum). More on this topic in the magazine (C&EN) soon. Another panel of interest covered “crowdsourcing,” an online, open innovation technique, as employed by Pfizer and Purdue Pharma—another topic ripe for coverage in C&EN, so I will keep my powder dry for the moment. But it’s an interesting topic at a conference like this.

And in the interest of full disclosure, this from David Zimmerman, CEO of Kalexsyn: “I am actually going to walk away from here tonight with three very good leads. Frankly, I came out of ACS  [the Society's annual meeting in Indianapolis last week] with one!”

I’m not sure what type of spam the title of this post is going to attract, but I thought it might also catch the eyes of folks who might otherwise skip over offerings from the Newscripts gang (who are not, by the way, the subject of the titular pictures).

You might not be aware of it, but one little online corner of C&EN, known as Reel Science, is devoted to spurring discussion of how science is presented in film. Reel Science reviews new movies coming out in theaters and also recommends science-y films out on DVD.

Jovana Grbić, a contributing editor for Reel Science, recently filed a recommendation for the documentary “Dirty Pictures” about psychedelics maker and garage chemist Alexander Shulgin. She suggested that we give away the screener copy she watched to review the film.

So we came up with a little contest to decide who gets the screener. Reel Science has gotten woefully behind on Recommendations. You can see from the list here that there was a two-year gap between our last recommendation and “Dirty Pictures.” So here’s the contest: Suggest a film for us to recommend in the comments. Science doesn’t have to be its main focus, but the flick should have some relevance to science or scientists; it can even be sci-fi. Also, the movie should be something we haven’t already reviewed or recommended, and we should be able to get the film via Netflix or some other easy-to-access (and inexpensive) source.

I’ll select a winner by the end of the week and write up a recommendation of the person’s suggested film (not by the end of the week, but sometime soon). We have only one screener, but we may still recommend other films from the suggestions, so you’d win our thanks, which is good too, right?

UPDATE: Thanks to the folks who wrote in. I loved all of your suggestions, but we’ve only got one DVD, and that goes to Chemjobber. I can’t believe we haven’t already recommended “Lorenzo’s Oil.” I look forward to watching it and writing it up.

An economic indicator for the contract API market arrived this week. Make of it what you will: 

Growth in the global pharmaceuticals market is poised to rebound from 3-4% in 2012 to 5-7% by 2016, according to a new report from the IMS Institute for Healthcare Informatics. Much of the growth will take place in emerging markets, with small-molecule generics experiencing the most rapid increase in sales, the report says.

IMS estimates that global spending will increase from $956 billion in 2011 to nearly $1.2 trillion in 2016. Patent expiries and cost containment actions by insurers and other payers will crimp spending on branded drugs, which are predicted to grow at less than 3% annually.

Spending on medicines in developed nations will increase by as much as $70 billion overall between 2011 and 2016, following an increase of $104 billion from 2006 to 2011. Despite the wave of patent expiries, expected to peak this year, spending in the U.S. will grow by up to $45 billion over the next five years, IMS says, a 1-4% per year increase, thanks to new drugs targeting unmet medical needs and expanded access through the Affordable Care Act. In Europe, economic austerity programs and healthcare cost-containment initiatives will limit growth at 2% annually over the next five years.

Spending in emerging markets is expected to double over the same period to as much as $375 billion, driven by rising incomes and government-sponsored programs to increase access to drugs.

Branded drug sales, at $596 billion in 2011, could increase to between by as much as 3% annually to between $615- and $645 billion. On the other hand, IMS sees spending on generics increasing from $242 billion in 2011 to $400- to $430 billion by 2016.

The report also sees an uptick ahead in the launch of new molecular entities (NMEs), with 32- to 37 launched annually through 2016. The report sees between 160 and  185 NMEs introduced between 2011 and 2016 compared to 145 between 2007 and 2011.

[Photo courtesy of Accelrys]

Cereplast started out as a good idea when it was founded by Frederick Scheer 10 years ago. The company would compound biobased and compostable resins such polylactic acid. The companies developing biobased resins are, for the most part, focused on agricultural processing or biotechnology. There would be a place for a specialist sorting out the nitty gritty of making the plastics work in real-world applications.

But something, if not many things, have gone wrong for the company. And earlier this month, the Cereplast filed for chapter 11 bankruptcy protection.

What happened?

It’s hard to tell. The Cereplast story is a little vague.

2011 seemed to be a good year for Cereplast in terms of revenues, which climbed to a high of about $20 million. However, the company managed to lose $14 million on those sales.

The company might have been in the red, but CEO Scheer was securely in the black. He earned a more than $1 million: about $500,000 in salary, $400,000 in bonuses, and nearly in $100,000 in stock awards.

A year later, things were pretty unpleasant for Cereplast. The company had to write off $12 million in accounts receivable in 2012. (Can’t tell if these were booked as part of the 2011 sales.) It is tough to figure out what exactly happened here, but the default explanation is that some customer stiffed the company for $12 million worth of compounded plastic. Conference calls allude to efforts to get the inventory back. The company lost $30 million on $911,000 in sales in 2012. Scheer earned a mere $336,077.

The company delisted from NASDAQ in 2012. It picked up, earlier in the year, Paul Pelosi, Jr. as a director, who wanted to lend one of America’s most recognizable names to team Cereplast for some reason. As far as I can tell he was an uncompensated, outside director.

Cereplast also ran the stock certificate printing presses in 2012 to stave off bankruptcy. Ironridge Technology bought $5 million in Cereplast preferred shares. Some outfit named Magna promised to pay off $1 million Cereplast debt in exchange for common shares. Cereplast is suing Magna for breach of contract.

Last year brought new ways for Cereplast to lose money. The company had $2.1 million in revenues for the first nine months of the year. It lost $34 million. The biggest item on its income statements is a $21.6 million loss for “change in derivative liabilities.” Cereplastcs explanation is as follows:

“Our derivative financial instruments consist of embedded and free-standing derivatives related primarily to the convertibles notes. The embedded derivatives include the conversion features, and liquidated damages clauses in the registration rights agreement. The accounting treatment of derivative financial instruments requires that we record the derivatives and related warrants at their fair values as of the inception date of the agreement and at fair value as of each subsequent balance sheet date. The recorded value of all derivatives at September 30, 2013 totaled approximately $15.1 million. Any change in fair value of these instruments will be recorded as non-operating, non-cash income or expense at each reporting date. If the fair value of the derivatives is higher at the subsequent balance sheet date, the Company will record a non-operating, non-cash charge. If the fair value of the derivatives is lower at the subsequent balance sheet date, the Company will record non-operating, non-cash income. At September 30, 2013, derivatives were valued primarily using the Black-Scholes Option Pricing Model.”

The Chemical Notebook doesn’t know either.

In any case, the bankruptcy was filed, in response to a lender’s efforts to sell off its assets, which aren’t insignificant. The value of the company’s property and equipment amounts to $11.2 million.

A new review in the Disorders of Fluids and Electrolytes series summarizes the salient discoveries that culminated in the development of vasopressin antagonists, focusing on their actions, side effects, emerging safety concerns, and important gaps in data. The review also considers how and when to use these agents.

Ample evidence is available to implicate vasopressin, a small polypeptide that is synthesized in the hypothalamus and secreted from the posterior pituitary, in the pathogenesis of many hyponatremic disorders. As the most common electrolyte disorder, hyponatremia is consistently associated with increased mortality and morbidity. The treatment of hyponatremia has been plagued by a paucity of controlled studies and by a lack of reliable and safe approaches. Therefore, the regulatory approval of vasopressin antagonists represents a milestone in the field.

Clinical Pearls

- Describe the vasopressin receptors, and the mechanism of action of vasopressin antagonists.

The V1A receptor is found in liver, smooth muscle, myocardium, brain, and platelets; the V1B receptor is involved in the secretion of corticotropin in the anterior pituitary. The V2 receptor is located primarily in the basolateral membrane of collecting-duct cells. The binding of the hormone to the V2 receptor on the basolateral membrane of the principal cell of the collecting duct activates adenylyl cyclase and generates cyclic AMP (cAMP) from adenosine triphosphate (ATP). In turn, cAMP activates protein kinase A, which phosphorylates aquaporin water channels (AQP2) and induces them to relocate to the luminal membrane. This promotes the reabsorption of water from tubular fluid to blood, rendering the tubular fluid more concentrated (increased osmolality). In the presence of a vasopressin antagonist, the signaling pathway is not activated. As a consequence, the water permeability of the cell remains high and water is not reabsorbed, causing the excretion of dilute urine (decreased osmolality) and thereby increasing the level of sodium in the blood compartment.

Figure 1. Binding of Vasopressin to Its Receptor and Location of Antagonist.

Figure 2. Cellular Effects of Vasopressin and Consequences of Vasopressin Antagonism.

- What vasopressin antagonists are approved for use in the United States?

Tolvaptan and conivaptan (with the latter blocking both the V1A and V2 receptors) have garnered approval for the treatment of euvolemic and hypervolemic hyponatremia in the United States. Conivaptan and tolvaptan have differing affinities for the vasopressin receptor. The relative inhibition of the two receptors (V2:V1 selectivity ratio) is much greater with tolvaptan (by a factor of 29) than with conivaptan (by a factor of 5.7). Thus, conivaptan is a nonselective vasopressin inhibitor, whereas tolvaptan is a more selective V2 inhibitor. Each of the drugs has a half-life that ranges from 6 to 10 hours and has activity that peaks several hours after administration. Both increase urine flow and the excretion of electrolyte-free water, without substantial changes in sodium or potassium excretion, leading to their designation as aquaretic agents.

Table 2. Inhibitory Constants and Pharmacokinetics of Two Vasopressin Antagonists.

Morning Report Questions

Q: When should vasopressin antagonists be avoided?

A: Dependence on the excretion of free water makes the response to vasopressin antagonists too slow to benefit patients with hyponatremia who have severe cerebral symptoms. Such patients require a prompt decrease in the volume of brain water, which is best achieved with hypertonic saline. Similarly, patients with hypovolemic hyponatremia require volume repletion to halt nonosmotic release of vasopressin. Furthermore, V1A-receptor antagonists can cause hypotension in such patients. Neither drug is effective in patients with advanced chronic kidney disease (stage 4 or 5).

Q: Is there consensus regarding the use of vasopressin antagonists?

A: Despite the paucity of data, panels have put forth recommendations for the treatment of hyponatremia. Of the available guidelines, two have garnered the most attention. The first set of guidelines was prepared by an expert panel that was supported by the manufacturer of tolvaptan; the second set, the European Clinical Practice Guideline, was developed by members of three medical societies with an interest in hyponatremia without support from the pharmaceutical industry. The two panels have divergent recommendations regarding the use of vasopressin antagonists. The European guidelines do not recommend the use of vasopressin antagonists in patients with euvolemia who have SIADH [syndrome of inappropriate secretion of antidiuretic hormone] and recommend against their use in patients with heart failure, in whom the need for water restriction and the wider use of urea are recommended. In contrast, the expert panel recommends that vasopressin antagonists be used in patients with SIADH when water restriction fails and states that vasopressin antagonists are “a viable option along with loop diuretics” in patients with heart failure. The European panelists express concern regarding the neurologic consequences of overcorrection, the risk of hepatotoxicity, and the lack of data supporting a survival benefit. The recommendations of the expert panel also have merit, particularly since none of the alternative approaches have been subjected to the rigors of a regulatory process requiring randomized, controlled trials nor have they received the approval of any regulatory agency.

Table 3. Recommendations for the Use of Vaptans in the Treatment of Hyponatremia.

Otto Piene’s Harvest began to shed white tears in 2000, seven years after it was completed. Credit: ICOM-CC publications.

You don’t really expect a seemingly dry painting to suddenly start oozing streaks of wet paint, seven years after its completion.

So when Otto Piene’s Harvest, which was finished in 1993, began to weep white paint in 2000, owners, conservators and the artist were all rather surprised.

Although Harvest is Piene’s only work to start weeping, the strange liquefying process has happened to dozens of other artworks from contemporary artists as varied as Jonathan Meese and Frank von Hemert, explains Jenny Schulz, a conservator in Cologne, Germany, who’s made it her business to figure out why. “It’s quite a common thing,” she says.

Taking a closer look at several of these paintings, Schulz figured out something that all the weeping paintings had in common: The tears occurred in places on the canvas where the artist has laid down a thick layer of oil paint.

A close-up of the tears from the thick, white base layer on Harvest by Otto Piene. Credit: ICOM-CC publications.

Although the thickly-laid paint seems to dry, it turns out to be unstable and capable of liquefying. But why? It’s not as if applying thick layers of oil paint is a new thing among artists… Yet the weeping painting issue is relatively new, having emerged in the last two decades or so.

What’s changed, Schulz says, is formulation of oil paints. Until recently oil paint was made using linseed oil. But the problem with linseed, she says, is that it has a tendency to yellow over time.

So paint formulators began exchanging linseed oil for sunflower oil, because sunflower oil doesn’t yellow.

The problem is that sunflower oil doesn’t dry as well. That’s because the oil contains fewer reactive double bonds, which are required to form a permanently dried paint complex, Schulz says.

Thick layers of the sunflower oil paint may seem to dry, but they are unstable. Subjected to changes in temperature and humidity or even the jostling that occurs during transport, these layers can collapse, releasing component parts as a gooey tear running as fast as 2 centimeters per month.

Other paint components can help or hinder the instability, Schulz says. For example, formulators have been increasingly replacing lead-based pigments for titanium- or zinc-based ones in white paint. Unfortunately, lead seems to help paintings stay stable, while replacements are not as effective.

Additional ingredients in oil paints such as bees wax  (used to stabilize pigments) and aluminum stearate (used to improve viscosity) may also play a role in the ability of sunflower-oil paint to dry completely, Schulz adds.

She’s currently developing recommendations for formulators and artists on ways to avoid the weeping painting problem—and she’s also working on strategies for conservators tasked with stopping the flow.

A PVC crash test dummy leaking orange plasticizer. Credit: Yvonne Shashoua

As an aside, paintings aren’t the only cultural artifact to shed tears:

Plastic artifacts are also notorious weepers.

Here’s a photo of one of the first crash test dummies used to check seat belt safety in the 1970s.

The mannequin is made out of PVC plastic whose orange phthalate plasticizer is quite literally oozing out, leaving sticky drops on the display case, until conservation scientist Yvonne Shashoua came to their rescue.

In the latest Case Record of the Massachusetts General Hospital, a 30-year-old man with a history of IV drug use was admitted to this hospital because of fever, myalgias, polyarthritis, and rash. Results of liver-function tests were notable for mildly elevated hepatic aminotransferase levels and a normal bilirubin level.

Adulterants are compounds added to street drugs to increase profits for the seller. Levamisole, a veterinary antihelminthic agent, has become the most common adulterant of cocaine. The prevalence of levamisole in samples of cocaine sold on the street is estimated to be as high as 70%. Levamisole can lead to a dramatic vasculopathy and even vasculitis of small and medium-size blood vessels, conditions that are characterized by thrombosis, leukocytoclasis, and necrotizing lesions in blood vessels. This syndrome is accompanied by a confusing array of autoantibodies, including high titers of antineutrophil cytoplasmic antibodies (ANCA), antiphospholipid antibodies, and antibodies to double-stranded DNA. The cutaneous vasculopathy induced by levamisole has a predilection for fatty tissues, often leading to large ulcerative and necrotic lesions of the breasts, thighs, and flanks that mimic warfarin-induced necrosis.  Distinctive necrosis of the earlobe is common.

Clinical Pearls

• What musculoskeletal symptoms may accompany hepatitis C (HCV) infection?

HCV may cause arthralgias in patients with rheumatoid-factor positivity, generally caused by the high prevalence of mixed cryoglobulins among patients with HCV. Most patients with type II or type III cryoglobulinemia test positive for rheumatoid factor because the IgM component of the mixed cryoglobulin is directed against the Fc portion of IgG, which is the definition of rheumatoid-factor activity. HCV-associated cryoglobulinemic vasculitis is generally accompanied by purpura with a predilection for dependent areas, particularly the legs.

• What are the manifestations of serum sickness associated with acute hepatitis B (HBV) infection?

In a minority of patients, acute infection with HBV causes a syndrome resembling serum sickness. Polyarthritis and urticaria almost always occur as part of the prodromal stage of the syndrome, preceding the icteric phase by several days to several weeks. These symptoms are usually abrupt in onset. The polyarthritis is symmetric, with a predilection for small joints of the hands and knees, and may appear in an additive or migratory pattern associated with morning stiffness. A rash occurs at approximately the same time as the arthritis in half of all cases. The rash is most often urticarial, but erythematous macules and papules and petechiae are also reported. The syndrome usually persists for days or weeks, with a mean duration of approximately 20 days. Patients often have both fatigue and generalized weakness at some point in the course of the illness. The joint and skin manifestations typically resolve completely before or at the onset of the icteric phase of hepatitis. Approximately 40% of patients with the syndrome ultimately become jaundiced.

Morning Report Questions

Q: What is the cause of serum sickness associated with HBV? 

A: Serum sickness is a disorder caused by antigen-antibody or immune complexes formed in association with antigen excess. A spectrum of biologically active immune complexes contributes to the inflammation associated with serum sickness. In general, they are small, soluble antigen-antibody complexes that are not removed by the phagocytic macrophages that reside in the liver and spleen. The resultant circulating immune complexes contribute to the vascular and cellular phases of inflammation. The diverse antigens are composed of epitopes of HBsAg, HBc, and viral DNA. Antibodies to these antigens bind their specific antigens and form immune complexes. Complement proteins and phagocytic cells are also required for the development of serum sickness.

Q: What are the characteristic serologies associated with early HBV infection? 

A: The characteristic laboratory features of acute HBV infection include the detection of HBV DNA and HBsAg, the production of IgM antibody against hepatitis B core antigen (HBc), and less often, the presence of hepatitis B e antigen (HBeAg). The level of circulating HBV DNA is also typically elevated. Taken together, these features result in a molecular and serologic profile that is diagnostic of acute HBV infection.