Micro NMR (Sci Trans Med)

Miniaturization of technology continues to bring new innovations in science and technology. The very latest innovation which you probably have not seen yet is a miniature NMR. On a larger scale this is the old familiar MRI machine. The micro-NMR is coupled to a Smart Phone and used to analyze cell surface proteins. A study published this week in Science Translational Medicine showed that this micro-NMR (μNMR) device run by a smart phone could be used to analyze a series of proteins/markers (pCAM (epithelial cell adhesion molecule), MUC-1 (mucin 1, cell surface associated), HER2, EGFR (epidermal growth factor receptor), B7-H3, CK18, Ki-67, p53, and vimentin]) showed a 10% to 20% improved diagnostic accuracy over traditional cell staining and other traditional techniques.

The current study analyzed needle aspiration biopsies. The study was limited to intra-abdominal cancers. The researchers found that 4 markers: MUC-1, HER2, EGFR, and EpCAM provided high diagnostic accuracy. These 4 markers used in conjunction gave the  correct diagnoses in 48 of the 50 initial patients examined and in 20 of 20 in the next round. For biology, science and technology geeks this was a fascinating article. I’ll link below to the Editor’s summary.

As we wonder what our Smart Phones can do besides play music surf the web, and track our running mileage, we see that forward thinkers are finding new ways to use the smart phone along with creative and new ways to use current technology. And yes, genomics and proteomics have a future.

Reference:
Sci Transl Med 23 February 2011: Vol. 3, Issue 71, p. 71ra16 DOI: 10.1126/scitranslmed.3002048. Micro-NMR for Rapid Molecular Analysis of Human Tumor Samples. Haun J. et. al.

Hot Peppers

Red hot chili peppers just might be good for you. An article in the current issue of “Science Signaling” (Aug 10, 2010. Vol 3, Issue 134, p ec241) summarizes two articles and gives the details.

Capsaicin, in chili peppers, is what makes them taste hot. For several years it has been used in topical creams that are used to decrease pain from a variety of causes. The biochemical means of action is via a cation channel of a receptor group called TRPV1, which allows calcium ions to enter the cell. The authors of the current article found that the TRPV1 receptors were also found in the endothelial cells of blood vessels. They studied the activity in rats and found that exposure to capsaicin resulted in  an increase in the  “amount of phosphorylated endothelial nitric oxide synthase (eNOS), protein kinase A (PKA) activity, and NO production.” They found that a 6 month long diet high in capsaicin triggerred a relaxation response in the arteries and that hypertensive rats were found to have lowered their blood pressure when they continued to have a diet high in capsaicin.

While they seem to  suggest that a diet high in capsaicin may reduce blood pressure in humans or at least that targeting the receptor TRPV1 for further research, I think a direct test for a diet hypothesis would be to take your blood pressure before and after munching on a chili pepper. I’ll bet you may see a bit of a rise, at least in the short term.

References:

D. Yang, Z. Luo, S. Ma, W. T. Wong, L. Ma, J. Zhong, H. He, Z. Zhao, T. Cao, Z. Yan, D. Liu, W. J. Arendshorst, Y. Huang. M. Tepel, Z. Zhu, Activation of TRPV1 by dietary capsaicin improves endothelium-dependent vasorelaxation and prevents hypertension.Cell Metab. 12, 130–141 (2010). [PubMed]

W. C. Sessa, A new way to lower blood pressure: Pass the chili peppers please! Cell Metab. 12, 109–110 (2010). [PubMed]

N. R. Gough, Spicy Diet to Reduce Hypertension. Sci. Signal. 3, ec241 (2010).

PPE Coalition for Youth Sports and Safety
PPE Initiative Launch Event & Press Conference: May 13, 2010

Across the U.S. there is no formal standardization of the young athlete’s pre-participation medical evaluation (PPE or pre-participation evaluation). States have varying standards and requirements on what needs to be checked and who may perform the evaluation. These examinations are important since many disorders that can cause serious problems may be picked up during the evaluation.

The newly formed PPE Coalition for Youth Sports and Safety held a press conference at the National Press Club in Washington, DC this morning. This event launched an initiative to standardize and upgrade the pre-participation physical evaluation. This was done in conjunction with the publication of the fourth edition of the PPE Pre-participation Physical Evaluation, written with the collaboration of 6 medical societies, including the American Academy of Family Physicians, American Academy of Pediatrics, American College of Sports Medicine, American Medical Society for Sports Medicine, American Orthopaedic Society for Sports Medicine, and American Osteopathic Academy of Sports Medicine.

A standard and thorough pre-participation physical evaluation is vital for the health and safety of young athletes. The purpose of the Coalition is to encourage the use of a standard PPE. To provide a safer environment for the athletes, the coalition is pressing to create a specific standard.

A website has been established to promote the initiative. You may download the new standardized PPE H&P form

PPE 4th Edition

Information on the organization, the founding and participating organizations, and the newly published text is available at the new website: http://www.ppesportsevaluation.org/ .

The American Academy of Podiatric Sports Medicine is one of the founding members of the coalition and was recognized at the event along with the other founders. I attended this event as a representative of the AAPSM.

Among the speakers was Jim Ryun, was the first high school runner to run a mile in under 4 minutes. He set a high school record of  3:55.3 for the mile, which stood for 36 years.  Former Congressman Ryun also held the world record in the mile, 1500-meter, and 880 yard runs. He participated in three summer Olympic games in 1964, 1968, and 1972. He won the silver medal in the 1500 meter run in 1968. Recently ESPN declared him to be the best high school athlete ever, finishing ahead of Lew Alcindor (Kareem Abdul-Jabbar). Jim Ryun spoke of the importance of having physical education included within a revised “no child left behind” law. With the rise in childhood obesity there is no reason to have only one year of PE required in the 4 years of high school. To much amusement he told of not making the baseball or basketball team, but being able to join the cross country team. With a rapid increase from no running to up to 60 miles per week, he found that his first injury was an incredibly painful case of shin splints.

Also speaking was Congressman Mike McIntyre  of North Carolina. He is the founder of the Congressional Caucus on Youth Sports. As a member of the “Blue Dog Coalition” he attempts to forge a bipartisan agreement on health and fitness related issues. His feelings were strong on the importance of safely encouraging youth health and fitness. He spoke of how what we teach our children is our message to a far-off future that we will not be around to see.

Included in the initiative was recognition of the importance of serving children with special needs an including these special athletes in all of the initiatives that are now set in motion. The AAPSM has long supported initiatives along this line as evidenced by the Special Olympics “Fit Feet” project.

Many other initiatives were discussed including the fight against childhood obesity which has long been a goal of the American College of Sports Medicine, the American Academy of Podiatric Sports Medicine, the American Academy of Pediatrics and the President’s Council on Physical Fitness and Exercise along with all of the organizations which participate in the Joint Commission on Sports Medicine and Sports Science. The recently completed White House Task Force on Obesity and the newly created Let’s Move program were mentioned as hopeful programs to change the trend of increasing childhood obesity.

Encouraging healthy eating and regular exercise for everyone within the context of safe programs is all of our jobs.

PPE

This applies to young and old,  and for those who are slim and not so slim.  Everyone who can do so needs to move for optimal health and to keep both the mind and the body in good working order. The PPE initiative will help  young people as safe as possible and be an aid in detecting serious diseases which may put them at risk. For those who pass successfully through the PPE the greater risk will be in not participating.

Resources:

PPE H&P form (PDF)  http://www.ppesportsevaluation.org/evalform.pdf

Preparticipation Physical Evalution – 4th Edition and further information: http://www.ppesportsevaluation.org/body.html

You Got To Move!

Many people have played the facebook game “What’s Your Real Age”. My guess that those who played it wanted to feel they were younger than their biological age. Telomere length seems to be the real way to determine actual “biological age”. These are the real “biological clocks”. Telomeres are repetitive sequences at the ends of chromosomes that shorten with age and also shorten in certain metabolic and disease states. They are sometimes called the protective “caps” on the ends of chromosomes. Because of the manner in which chromosomes are replicated during cellular division, a bit of the telomere is not copied with each subsequent cellular generation resulting in a gradual shortening of the telomere restriction fragment (TRF) length.

Telomeres Shorten With Age

A recent study showed that people who perform more leisure time physical activity have longer telomeres. Another recent study, with an admitted low subject number, demonstrated that eating processed meat  such as sliced bologna would also slice down the size of your telomeres. This study, published in the American Journal of Clinical Nutrition did not find other expected dietary associations.

The Cardiovascular Health Study (2007) found inverse correlations (shortened telomeres) between TRF length and fasting glucose level, fasting insulin level, systolic and diastolic blood pressure, carotid intima-media thickness, interleukin-6, high BMI, overweight (in men).

Some studies including one with “voluntary running” in mice showed the production of telomere protective compounds with the “voluntary” running. On a side note,  I’ll have to look closer at this study. If we can can get mice to  voluntarily participate in a “fitness” program, maybe we can figure out the secret to get more people to do so. Perhaps cheese is the answer.

Aubert and Lansdorp (2008) published an excellent review of  the biology of telomeres and aging. They noted that Barbara McClintock, in her 1983 Nobel acceptance speech pointed out the significance of cellular response to stress and dangers. “In the future attention undoubtedly will be centered on the genome, and with greater appreciation of its significance as a highly sensitive organ of the cell, monitoring genomic activities and correcting common errors, sensing the unusual and unexpected events, and responding to them, often by restructuring the genome. We know about the components of genomes that could be made available for such restructuring. We know nothing, however, about how the cell senses danger and instigates responses to it that often are truly remarkable.”

Short Telomeres Trigger Cellular Defences

The shortened telomeres are likely sending more “damage” signals to the cells which lead to a number of biochemical pathways which degrade the contents of the cell. Studies on cellular senescence, apoptosis, and research on genomics is leading us to a better understanding, but we have a long ways to go. The complexity never ends, but it continues to unwind. And you can almost hear the tick tock of the biological clock. Your best means of slowing up the ticking are life habit changes: exercise regularly, maintain healthy body weight, don’t smoke and eat a healthy diet.
What’s my age again? – Blink 182

What's My Age Again?

References:

Lynn F. Cherkas, PhD; Janice L. Hunkin, BSc; Bernet S. Kato, PhD; J. Brent Richards, MD; Jeffrey P. Gardner, PhD; Gabriela L. Surdulescu, MSc; Masayuki Kimura, MD, PhD; Xiaobin Lu, MD; Tim D. Spector, MD, FRCP; Abraham Aviv, MD. Arch Intern Med. 2008;168(2):154-158.

Annette L. Fitzpatrick1, Richard A. Kronmal2, Jeffrey P. Gardner3, Bruce M. Psaty1,4, Nancy S. Jenny5, Russell P. Tracy5,6, Jeremy Walston7, Masyuki Kimura3 and Abraham Aviv . Leukocyte Telomere Length and Cardiovascular Disease in the Cardiovascular Health Study. American Journal of Epidemiology 2007 165(1):14-21; doi:10.1093/aje/kwj346.

J. A Nettleton, A. Diez-Roux, N. S Jenny, A. L Fitzpatrick, and D. R Jacobs Jr. Dietary patterns, food groups, and telomere length in the Multi-Ethnic Study of Atherosclerosis (MESA). Am. J. Clinical Nutrition, November 1, 2008; 88(5): 1405 – 1412

Liza S.M. Wong, Hisko Oeseburg, Rudolf A. de Boer, Wiek H. van Gilst, Dirk J. van Veldhuisen and Pim van der Harst.. Telomere biology in cardiovascular disease: the TERC–/– mouse as a model for heart failure and ageing. Cardiovascular Research 2009 81(2):244-252; doi:10.1093/cvr/cvn337

Aubert, G. and P. M. Lansdorp (2008). “Telomeres and Aging.” Physiol. Rev. 88(2): 557-579.

Training, dedication, and hard work (along with a good diet and a bit of rest carefully added) will go far in helping you improve your conditioning and body composition. Your performance will increase. But for most of us, we will not become world class athletes, or even national class athletes. That is no reason not to work at improvement and in many cases where it is needed very dramatic improvement. You should not accept or provide yourself with excuses that without trying hard you’ve reached the point where you are all you can possibly be.

from Wikipedia (Clopidogrel molecule)

In the future, genetics will be used to help determine the best possible training methods for each of us, the best diet, and even the best medications to take.  The FDA is now considering changing the label on the anti-clotting medication Plavix in view of several recent studies that indicate a genetic variation may make the medication ineffective for up to 30% of those taking it to prevent heart attacks and strokes. This is a dramatic step and an obviously important one based on the currently available research.

Genetic variants and mutations will become increasingly important in pharmaceutical development, design, prescription and use. Plavix is a new and developing case in point. Ultimately research will lead to the development and determination of improved training, diet, and even legal supplements. Until then, other studies, experience, and just changing things that are obviously wrong can and will go a long way in helping us all improve.

More information at the Wall Street Journal: http://tinyurl.com/g3n3ticDru7gs

The obesity epidemic is certainly spreading faster than the Nile Virus. Mississippi is reportedly the most obese state and cracks the previous record by having over 30% of its adult population classified as obese. Colorado is the leanest at around 18%. The CDC has declared obesity to be a serious problem and feels that there is a strong relationship between lack of exercise and obesity. D.C. has the highest percentage of obese youth, at 22.8%. It’s time for people to get moving!

This is covered by the AP at the WSJ, among other places.

A story cites a program sponsored by Merck as a conflict when Dr. Gupta touts the benefits of an incompletely tested vaccine for the papilloma virus produced by Merck which almost ended up as a mandatory vaccination for young girls.

This was pointed out in Julie Deardoff’s “Julie’s Health Club“, a blog which appears on the Chicago Tribune’s website, as well as being mentioned on Counterpunch:

“Eleven and twelve year old girls, the very target of proposed mandatory vaccination by Merck, were never tested at all for efficacy in pre-licensing clinical trials. Merck simply decided that the bodies of prepubescent girls would react the same as mature women to the vaccine.”

What also doesn’t sit well with Martens is that Gupta is co-host of a program called AccentHealth, a waiting room TV network that bills itself as “an integrated health education company” and reaches 132 million viewers. Merck is a financial sponsor.

“Given the incestuous nature of ‘integration,’ should Dr. Sanjay Gupta have revealed to his CNN viewers during his extolling of the virtues of Gardasil that its manufacturer, Merck, was a financial sponsor of this integrated marketing scheme he co-hosts at AccentHealth?” she asked. “Inquiring minds not yet ‘integrated’ want to know.

It is important that not only physicians lecturing and in a clinical setting need to be independent and to declare conflicts of interest, but those in the media need to state conflicts of interest both real and potential. It is not enough to think you are independent, but to be on the receiving end of financial benefits it should be noted in reporting on stories where such a conflict could exist. Corporate influence in media extends far beyond merely impacting medical stories.

In this case, a vaccine that had been called marginally effective by the pharmaceutical company manufacturing it was touted by Gupta and Laura Bush in far more laudatory terms than even the manufacturer did. The vaccine had only been tested for 5 years while it takes approximately 15-20 years for cervical cancer to develop. In spite of that congress was lobbied and urged to make this vaccine not optional, but a mandatory schoolgirl vaccination. Was this done in the name of business or medicine? To me, having it as an option, and having it optionally available through normal means via your insurance would have been a normal approach. Lobbying congress to make an incompletely tested vaccine for a disease that is not spread rapidly in an epidemic fashion, via airborne transmission or other simple transimission route, a mandatory vaccination is absurd.

This topic seems to generate heated opinions. It is important to remember that science and medicine needs to be evidence based and not emotion driven or driven by corporate interests and their lobbyists. No one is preventing anyone from having this vaccine. It is best to preserve freedom though in the absence of clear science indicating a distinct benefit. Don’t forget this vaccine, with uncertain efficacy, only handles one potentially sexually transmitted disease. It does nothing for Breast Cancer, Ovarian Cancer, genital herpes, or HIV. It is not a panacea. Why was there ever a lobby to make this mandatory? And yes, you can have it, your daughters can also, but I would not advise anyone in my family to have this barely tested vaccine, with no evidence that it is effective at what it is being proposed for.

Additional References and article: Alliance for Human Research Protection

Over the past several years the concept of well rounded young athletes playing 3 sports over the course of a year has died. Most want to be specialized in one sport. Whether the sport is soccer, baseball or running, we rarely see the child athlete playing football or soccer in the fall, basketball in the winter and baseball or track in the spring.

In fact, school centered sports is no longer the norm. Travel sports rules. Year long focus on one sport is it. This has resulted in more overuse injuries than there should be. It has also resulted in more teens having the “Tommy John” elbow surgery and even for parents to seek it to see if it may make what started as a normal arm, pitch faster. Read Fit Young Pitchers See Elbow Repair as Cure-All in the New York Times for a current journalistic perspective on the surgery aspects of this. The article neglected to mention the year long focus on pitching as the root cause.

…it is becoming more commonplace among teenage pitchers who are injuring their arms through overuse at what surgeons call an alarming rate.

Some parents and young pitchers, hoping for college scholarships or multimillion-dollar professional contracts, misguidedly view the surgery as a performance-enhancement technique instead of a last-resort corrective procedure, said Matt Poe, a speed and strength coach in Nashville.

Often, pitchers who are pushed the hardest and sustain the worst overuse injuries are the most talented, doctors said. In the late 1990s, Dr. Andrews said he performed 5 to 10 Tommy John operations a year on high school pitchers. This year, he said, he may perform 75. Last month, he operated on a 14-year-old.

And for two interesting pages the article goes on.

“I don’t think there’s as deep a talent pool anymore,” Dr. Petty said, because so many kids are coming out of high school with what he called “100,000-mile arms.”

It’s not the talent pool. Pitchers have always been in short supply. High schools have made do with very few pitchers for years. But, not until recently did they only pitch for most all of the year.

A variety of conflicting studies and articles are coming out regarding high glycemic foods in performance. What impact do they have and what conflicting studies show is a future topic for us. Fructose is not considered an optimal source of carbs and the sports drinks and gels you use should be examined to make sure that fructose is not high on the ingredients list.

It is lower down on the listing of ingredients in Gatorade, but it is number 2, after water on Powerade (Matrix Reloaded). Powerade is said to be the official drink of the US Olympics. Perhaps it is time to revisit that choice.

At the same time this is under discussion Abel Pharmboy at Terrasig has a fine post up entitled “The Questionable Dark Side of Fructose“. He notes that the consumption of fructose has been suggested to be one of the possible causes of obesity and metabolic syndrome. In conjunction with this he links to an article at Medscape which notes the atherogenic profile of fructose vs. glucose.

The question that plagues this research area is whether the growing (pun intended) obesity epidemic since the 1970s is due to HFCS or simply our overall increase in consumption of all sweetened beverages. I remember when Coke used to come in 8 oz bottles; now you can buy a 44 oz Big Gulp, or at least an average 20 oz bottle. The HFCS issue is also entangled with public aversion to genetically modified foods, including corn, and the fact that large corn-processing companies benefit from subsidies unavailable to conventional sugar cane producers.

Regardless of whether HFCS is more problematic than glucose or sucrose, the only sure way to reduce one’s risk of weight gain due to HFCS is to replace sweetened beverages with good old water.

quote from: Terra Sigillata – Abel Pharmboy

It is definitely up to you to carefully determine what should be in your sports replacement drinks and gels. For long distance running, it is possible that you will benefit from electrolyte replacement. Avoidance of hyponatremia in events of more than a few hours is important. Weighing in and monitoring your body weight over the course of a marathon or ultramarathon may help you reach the proper balance of fluid replaement vs. over or under hydration. During training for long distance events you can weigh yourself after an hour of exercise, if you are in good health, and your doctor clears this, to get an idea of how much fluid you need to replace per hour. At the end of your long runs, with a weigh in before and a weigh in after, you can see how close you are to meeting your goal of proper fluid replacement.

Evidence Based Medicine vs. Sensationalism
The New York Times, today, in a fairly sensational manner, discusses Non-Hodgkins Lymphoma and medications in vogue in reference to two medicines, including Zevalin, which at this time is used in cases of failure of other therapies. The accusastion being made is that physicians are not using Zevalin, a radioactive drug, that can only be administered in a hospital using a complex protocol, because of incentives to use more established and well studied protocols including Rituxan in conjunction with “CHOP”.

They highlight the essentially anecdotal evidence of 3 patients who have done well after failing other protocols. That is both the manner in which Bexxar and Zevalin are to be used and the manner in which they have been studied so far. While studies that will indicate if survival time is increased should be complete soon, there is no study that by the principles of Evidence Based Medicine (EBM) do this yet. EBM requires evidence of a high order in well conducted studies that effectively, objectively and statistically demonstrate the utility of a treatment.

This is a higher standard than media generated sensationalism or pharmaceutical company based marketing offer. The studies must stand on their own merit. So far the medications are being used as studied and demonstrated. They are used after failure of other treatment. They are complicated and difficult to administer. They should be used though where needed. Hopefully, the studies that will reportedly be completed soon will demonstrate their superiority, effectiveness, and utility for Non-Hodgkins Lymphoma. Knowledge is increasing fast in this area, but of course not fast enough.

A sensational article like this one, discussing treatment, witholding of treatment, and implying decicsion making is arbitrary and even selfish without even the mention of what EBM is, is not responsible.

You can do your own literature search at PUBMED for more information.

U.S. Clinical Trials – searchable database. You may find active studies using Zevalin or other products here.

Selected Literature Search ResultsExpert Rev Anticancer Ther. 2002 Oct;2(5):485-93
The current indications are: low-grade or follicular lymphoma refractory to rituximab, and relapsed or refractory, low-grade, follicular or transformed lymphoma. Additional studies have been initiated to further define the role of this new therapy in the treatment of patients with B-cell non-hodgkin’s lymphoma.

Semin Oncol. 2003 Dec;30(6 Suppl 17):17-22.
Gregory, SA. Selecting patients for treatment with 90Y ibritumomab tiuxetan (Zevalin).

Yttrium 90 ibritumomab tiuxetan (Zevalin; Biogen Idec Inc, Cambridge, MA) was the first radioimmunotherapeutic agent approved by the US Food and Drug Administration. It is indicated for treating patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin’s lymphoma, including patients with rituximab-refractory follicular non-Hodgkin’s lymphoma. Proper patient selection is essential for optimizing the efficacy and safety of treatment with (90)Y ibritumomab tiuxetan. It may be advisable to use (90)Y ibritumomab tiuxetan relatively early in a patient’s course of treatment because overall and complete response rates, and the estimated median duration of response, are higher among patients who have had fewer median prior antineoplastic regimens than among those who have had a greater median number of such regimens. Furthermore, the myeloablative effect of multiple courses of chemotherapy can preclude the later use of (90)Y ibritumomab tiuxetan. In contrast, other therapies, including chemotherapy and rituximab, can be used safely and successfully after (90)Y ibritumomab tiuxetan without concerns about increased hematologic toxicity from the previous radioimmunotherapy. The main adverse event associated with (90)Y ibritumomab tiuxetan therapy is hematologic toxicity and, as a result, only patients with adequate bone marrow reserves and less than 25% lymphoma marrow involvement should currently be considered for clinical therapy.

Cancer Biother Radiopharm. 2005 Apr;20(2):185-8.

Yttrium-90 (90Y) ibritumomab tiuxetan (Zevalin) induces long-term durable responses in patients with relapsed or refractory B-Cell non-Hodgkin’s lymphoma.
Wiseman GA, Witzig TE.
Mayo Clinic, Rochester, MN, USA. gwiseman@mayo.edu

AIM: Yttrium-90 ((90)Y) ibritumomab tiuxetan (Zevalin) radioimmunotherapy is an effective treatment for relapsed or refractory B-cell non-Hodgkin’s lymphoma (NHL), with overall response rates ranging from 74% to 82%. This retrospective analysis was conducted to determine the number of patients achieving long-term durable responses with (90)Y ibritumomab tiuxetan treatment. MATERIALS AND METHODS: The medical records of patients (n = 211) with relapsed, refractory, or transformed indolent CD20+ B-cell NHL who were treated with 90Y ibritumomab tiuxetan were reviewed. Time to progression (TTP) of > or =12 months was noted in 78 patients (37%), who were identified as long-term responders and were further characterized. RESULTS: Median age of the long-term responders was 58 years (range, 24-80 years) with 44% over 60 years, and 55% were male. Notably, 59% of patients had received > or =2 prior regimens, 33% had received > or =3 prior regimens, and 37% had failed to respond to immediate prior therapy. Median response duration was 28.1 months (range, 10.5-80.3+ months). Median TTP was 29.3 months (range, 12.1-81.5+ months). In patients with ongoing response, median TTP was 53.9 months (range, 49-82+ months). CONCLUSIONS: (90)Y ibritumomab tiuxetan produces durable long-term responses in patients with relapsed/refractory B-cell NHL. Failure to respond to prior therapy does not preclude achieving a long-term response with 90Y ibritumomab tiuxetan.