Targeted Therapies for the Treatment of Metastatic Renal Cell Carcinoma

Although systemic therapy for patients with metastatic renal cell carcinoma (mRCC) was once limited to the cytokines interleukin-2 and interferon (IFN)-α, in recent years several targeted therapies have become available for first- and second-line use. These include sorafenib, sunitinib, bevacizumab (plus IFN-α), temsirolimus, everolimus, and, most recently, pazopanib. This expanded list of treatment options arose from molecular biological research that revealed aberrant signal transduction activities in RCC, enabling the identification of specific molecular targets for therapy. Molecular-targeted therapies have better efficacy and tolerability than cytokine therapy, and many are administered orally. The superior outcomes achieved with molecular-targeted agents are prompting investigators to reconsider overall survival as a primary endpoint in clinical trials, given the inherent complications of a required long duration of follow-up, a required large population, and confounding caused by crossover trial designs or effects of subsequent therapy after progression on the agent of interest. In mRCC trials, progression-free survival has become a popular primary endpoint and has served as the basis of approval for several targeted therapies. In addition to the identification of new agents, current research is focused on the evaluation of combination therapy with targeted agents. As more information regarding mechanisms of disease and drug resistance becomes available, new targets, new targeted agents, and new combinations will be studied with the goal of providing maximal efficacy with minimal toxicity. This article reviews the clinical evidence supporting the benefits of targeted agents in mRCC treatment, discusses survival endpoints used in their pivotal clinical trials, and outlines future research directions.

source: the oncologist

Nitroglycerin May Increase Bone Density

Study Shows Heart Treatment May Have Benefit as Bone-Building Medicine


Women at risk of fractures who used the heart medicine nitroglycerin boosted their bone density modestly, according to a new study.

”We found nitroglycerin has a unique ability,” says researcher Sophie Jamal, MD, PhD, associate professor of medicine at the University of Toronto. “What it does is both increase bone formation and decrease bone breakdown.”

No osteoporosis drug does both to her knowledge, Jamal tells WebMD.

Her study, reported in the Journal of the American Medical Association, did not assess fracture risk with nitroglycerin use, only the effects on bone. She plans to look next at whether taking nitroglycerin for bones will reduce fractures.

While several medicines are on the market to treat osteoporosis, the brittle bone disease that can lead to fractures, Jamal says many are expensive and not all drugs are available worldwide. In the U.S., up to one of every two women and one of four men over age 50 is expected to have an osteoporosis-related fracture at some point, according to the National Institutes of Health.

Nitroglycerin for Bones

When used for heart conditions, nitroglycerin causes constricted blood vessels to dilate, relieving the severe chest pains known as angina.

Previous research by others has found that women taking nitroglycerin for heart problems had a lower risk of fractures, and other studies found its use is associated with a reduced fracture risk.

Jamal and colleagues assigned 243 women, average age about 62, to either a nitroglycerin ointment group or a placebo ointment group. The women applied either the nitroglycerin (15 milligrams) or placebo to their upper arm at bedtime, squeezing out about an inch of the medicine.

The researchers, who conducted the study from November 2005 to March 2010, did not accept women who already had osteoporosis or any medical condition that affected bone metabolism.

Bone density was evaluated at the study start and again at the 12-month and 24-month mark.

At the end, they found the women in the nitroglycerin group, compared to those in the placebo group, had a:

  • 6.7% increase in bone mineral density at the lumbar spine
  • 6.2% increase in bone mineral density at the hip
  • 7% increase in the thigh bone density

The group taking the nitroglycerin also had an increase in a marker of bone formation and a decrease in a marker for bone loss.

Headache was the most common side effect reported by those in the nitroglycerin group, with 35% of participants complaining of it compared to 5.4% in the placebo group in the first month. Over time, the headaches in the treated women declined.

The study was funded by the Canadian Institute of Health Research and the Physicians’ Services Incorporated.

Jamal has received support for board membership from Novartis, Amgen, and Warner-Chilcott and has been a consultant for Genzyme, Warner-Chilcott, Novartis, and Shire.

The study results are ”very intriguing,” says Sundeep Khosla, MD, a professor of medicine at the College of Medicine, Mayo Clinic, Rochester, Minn. He wrote an editorial to accompany the study results.

However, he adds, it ”would be a little premature to start using this.” The effect of the medicine on fracture risk needs more study, he tells WebMD.

For now, the good news of the new research may be for those women already taking nitroglycerin to relieve angina, he says. “If a woman is already on nitroglycerin for heart disease — she has to take it anyway — maybe she can take some comfort in the fact it may be helping her bones also.”

Khosla has served on a scientific advisory board for Amgen, which makes Prolia, an osteoporosis medicine.

source: web MD

Antibody Titers in Infants Born to HIV-Positive Women

HIV-exposed but uninfected newborns had decreased antibody levels to vaccine-preventable diseases.

HIV-negative infants of HIV-positive women are vulnerable to infectious illnesses, with high rates of pneumonia, meningitis, and death during the first year of life. To develop new strategies for protecting these infants, we need to understand how maternal HIV infection influences infant immune responses. Toward that end, investigators studied antibody titers to vaccine-preventable diseases in women and infants seen at a community health center in South Africa. In 2009, 32% of women attending prenatal clinics in that region were HIV positive, and the HIV vertical transmission rate was 3.3%.

Serum samples for antibody testing were collected from infants and their mothers 24 hours after delivery; follow-up samples were collected from the infants at 16 weeks. Infants born to HIV-positive mothers had HIV polymerase chain reaction performed at 4 and 16 weeks; only those who tested negative were included in the analysis.

Antibody titers against Haemophilus influenzae type B (Hib), Bordetella pertussis, Streptococcus pneumoniae, and tetanus toxoid were significantly lower in the 46 infants born to HIV-positive mothers than in the 54 born to HIV-negative mothers. The HIV-positive mothers had reduced antibody levels to Hib and S. pneumoniae but not to B. pertussis or tetanus toxoid; however, an analysis of infant:maternal antibody-level ratios showed a significant reduction in placental transfer of all four of these specific antibodies. The HIV-exposed infants did have robust antibody responses after immunization with the four corresponding vaccines.

Comment: These findings show that at birth, infants of HIV-positive mothers lack effective immunity to four important vaccine-preventable diseases. The insights provided will be valuable for finding new ways to protect this vulnerable population.

Richard T. Ellison III, MD

Published in Journal Watch Infectious Diseases February 23, 2011


Aspirin and Macular Degeneration

It is still not definitely known if aspirin increases the rate of bleeding within the eye in patients with wet age-related macular degeneration. Some studies report no increase in bleeding rates, while others report slightly increased bleeding rates. It is important to note that this research applies only for the wet subtype of macular degeneration. Since the risks of aspirin have not been conclusively established in age-related macular degeneration, it would not be appropriate to stop aspirin for this reason without talking with your doctor first.

It is still not definitely known if aspirin increases the rate of conversion of dry age-related macular degeneration to the wet form. One small study has suggested that those taking aspirin actually convert to the wet form at a lower rate than those not taking aspirin; however, this was a borderline finding.

All blood thinners can increase the chance of retinal bleeding, but this varies widely based on the type of blood thinner. Aspirin may increase the chance of bleeding slightly, while more powerful blood thinners such as warfarin (Coumadin) and clopidogrel (Plavix) increase the risk of retinal bleeding more prominently.

source: national glaucoma research

Gene Identified In Dogs with Glaucoma May Offer Hope for Future Therapies for Humans

  • Beagles born with an inherited form of glaucoma, similar to primary open angle glaucoma in humans, have a change or mutation in the “spelling” of a gene called ADAMTS10. This gene is expressed primarily in the trabecular meshwork, the filter for “draining” aqueous humor in the eye. The resulting change to the ADAMTS10 protein due to the mutation is thought to cause a blockage in aqueous humor drainage and an increase in eye pressure, leading to glaucoma in these dogs.
  • Relevance:

    So far, three genes have been found associated with risk of glaucoma in humans, but there are still many forms of glaucoma for which no genes have been found. This dog gene is a strong candidate for testing in humans, in particular since this is the third ADAM family gene found associated with eye disease. If this gene does turn out to be a major contributing factor, then gene therapy treatments could become a possibility for many people with this devastating disease.

source: national glaucoma research

Ancient Swimmers: coelacanth


The coelacanth was thought to have gone extinct with the dinosaurs. Rediscovered in 1938, it is chronicled here in a rare photographic account.

It’s not every day that a living fossil shows up in a fisherman’s net.

But that’s what happened in 1938, when a South African museum curator named Marjorie Courtenay-Latimer spied a bizarre creature with thick scales, unusual fins, and an extra lobe on its tail, amid an otherwise ordinary haul of fish. Though she didn’t know it straightaway, Courtenay-Latimer had rediscovered the coelacanth, which was assumed to have died out at the end of the Cretaceous period but somehow outlasted many of its prehistoric peers, dwelling deep in the ocean, undisturbed—and undetected—for eons.

Since this chance sighting, Latimeria chalumnae have been found in several pockets in the Indian Ocean. No one knows how many there are—maybe as few as 1,000 or as many as 10,000. Because of the depth of their habitat, they have mainly been photographed by submersibles and remotely operated vehicles. Divers first documented the fish in 2000; in January and February 2010, a specially trained team dived deep to take pictures of a small colony in Sodwana Bay, South Africa.

source: national geographic magazine

Cell Phones Seen Affecting Brain Biochemistry

You may be getting calls about a preliminary study showing that cell phone usage for about an hour can affect glucose metabolism in the area of the brain closest to the phone’s antenna. The study appears in JAMA.

Some 50 healthy participants had cell phones placed next to both ears for 50 minutes on two occasions. On one occasion the phones were off, and on the other only the right phone was activated, but the sound was muted while it received a recorded message.

Brain glucose metabolism, as measured by positron emission tomography, was significantly higher in the region of the brain closest to the activated phone’s antenna. Whole-brain glucose metabolism, however, did not differ between the active versus inactive phone conditions.

The authors conclude that the finding’s clinical significance is unknown.

Source: JAMA


Long-Term Bisphosphonate Use Linked to Subtrochanteric and Femoral Shaft Fractures in Older Women

Long-term oral bisphosphonate use is associated with an increased risk for subtrochanteric or femoral shaft fractures, but the absolute risk remains low, according to a JAMA study.

Researchers examined Canadian provincial databases to identify some 700 Ontario women over age 68 taking oral bisphosphonates who were hospitalized for a subtrochanteric or femoral shaft fracture. Cases were age-matched to 3500 controls — also taking bisphosphonates — without such fractures.

Women who took bisphosphonates for at least 5 years had an increased risk for subtrochanteric or femoral shaft fractures (adjusted odds ratio, 2.74), compared with women who used bisphosphonates for fewer than 100 days. Among women treated at least 5 years, the absolute risk of developing one of these fractures was low (0.13% within the following year, 0.22% within 2 years).

The authors note that clinicians should continue prescribing bisphosphonates for appropriate patients. However, “long-term use of these drugs may warrant reconsideration, especially in patients at relatively low risk of fracture. It may be appropriate to consider a drug holiday for selected patients.”

Source: JAMA


Antipsychotics’ Labels Updated to Include Risk to Newborns When Taken During Pregnancy

All antipsychotics must now carry a warning about the risk for the muscle movement disorder EPS (extrapyramidal signs) and signs of withdrawal in newborns whose mothers received the drugs during the last 3 months of pregnancy, the FDA announced on Tuesday.

The updated labeling applies to all generations of antipsychotics and is based on 69 cases of neonatal EPS or withdrawal reported to the agency’s Adverse Event Reporting System. Symptoms included agitation, tremor, respiratory distress, and difficulty feeding.

Newborns showing signs of EPS or withdrawal should be monitored. Symptoms can subside within hours and not require specific treatment, the FDA says, though some infants may be more severely affected and require prolonged hospital stays.

FDA MedWatch

Metabolic and Cardiovascular Consequences of Bariatric Surgery

Obesity is a disease state with polygenic inheritance, the phenotypic penetrance of which has been greatly expanded by the attributes of modern civilization. More than two-thirds of obese persons have comorbidities, many of which are characteristic of cardiometabolic risk syndrome (CMRS) in addition to other life-quality–reducing complaints. The CMRS is associated with increased cardiovascular events and mortality. Individuals with a body mass index greater than 35 infrequently achieve or maintain weight loss adequate to resolve these metabolic and anatomic issues by lifestyle or pharmacologic strategies. Data suggest that some of these patients may be better served by bariatric surgery.

source: science direct