Day: 08/12/2010

A Cancer Treatment That Sticks Around

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The shells of shrimp are a source of chitosan, a compound used in a number of clinical settings. Chitosan is derived from the shells of crustaceans such as shrimp and lobsters. It is used in a number of clinical applications, including in bandages to help control bleeding.

A new study in mice may help revive the clinical prospects of the cytokine interleukin-12 (IL-12), a drug that stimulates the immune system to attack tumors. Based on the results of this study and an earlier study by the same group of researchers, a phase I clinical trial is being planned to test the treatment in patients with bladder cancer. The new study will be published in the September Journal of Immunotherapy.

IL-12, a protein that has been the subject of intense investigation for several decades, modulates important components of the immune system and has demonstrated dramatic antitumor effects in numerous laboratory and animal model studies. Its clinical development, however, has been stunted by significant toxicities seen in several human trials in which it was given intravenously or subcutaneously.

In an effort to circumvent that problem, Dr. John Greiner of the Laboratory of Tumor Immunology and Biology in NCI’s Center for Cancer Research and colleagues mixed IL-12 with a compound called chitosan, a biological adhesive that can bind synthetic or biological molecules to tissue. The resulting mixture was injected directly into a tumor.

Chitosan, which is a polysaccharide derived from the shells of crustaceans such as shrimp or lobster, is an important part of a “delivery system” that brings IL-12 “directly into the tumor environment,” explained Dr. Greiner. The treatment was not only effective in the mouse studies, but appears to be very safe with no apparent toxic side effects.

In the team’s previous study, chitosan/IL-12 eradicated tumors in a mouse model of bladder cancer. In this new study, they used mouse models of colorectal and pancreatic cancer. First, using noninvasive imaging techniques, they showed that after injecting tumors with chitosan/IL-12 the cytokine remained within the tumor microenvironment for nearly a week, but when IL-12 alone was injected it remained there for only a day.

Study co-author Dr. David Zaharoff, now at the University of Arkansas, who initially developed the idea for combining IL-12 with a bioadhesive, likened chitosan to maple syrup. “The high viscosity of chitosan inhibits diffusion of co-formulated molecules,” he said. “As a result, chitosan is able to hold IL-12 in the tumor microenvironment and maintain it there for a long period of time.”

In a second set of experiments, they showed that intratumoral injection of chitosan/IL-12 once a week for 3 weeks completely eradicated tumors in 90 percent of the mice, whereas IL-12 alone had only limited efficacy. There was little impact on tumor shrinkage or survival when chitosan was combined with GM-CSF and IFN-γ, two other proteins that can stimulate the immune system. “This complete tumor regression seems to be unique to chitosan/IL-12,” the researchers wrote.

The treatment triggered the activity of two powerful types of immune cells, CD8+ T cells and natural killer cells. And in certain circumstances, when the researchers “rechallenged” the cured mice with tumor cells, the initial treatment offered lasting immune protection against cancer. But the extent of the protection, they cautioned, was dependent on how many tumor cells were injected into the mice and how often, and must be examined in “a more clinically relevant [animal] model.”

Despite its robust antitumor effects, the toxicities IL-12 induced in the initial human trials drove away industry interest in it, explained Dr. Jeffrey Weber from the H. Lee Moffitt Cancer Center & Research Institute in Tampa, FL. “But I still think that this is a drug that needs to be pursued,” he said.

Even so, Dr. Weber, who was not involved in the study and whose work focuses on vaccines to treat melanoma and other tumors, expressed doubts about the long-term prospects of IL-12 as a stand-alone therapy, arguing that the available evidence suggests it would be best pursued as an adjuvant to boost the performance of therapeutic vaccines. A requirement to inject the treatment directly into the tumor may also “limit its appeal and its indications,” he continued.

The phase I trial, which will be conducted at the NIH Clinical Center in Bethesda, MD, will enroll patients with superficial bladder cancer (cancer limited to the lining of the bladder wall) whose disease has returned after standard first-line therapy. In the case of bladder cancer, Dr. Greiner added, because chitosan/IL-12 appears to generate a strong adaptive immune response—that is, immune cells are spurred to action and develop a “memory” of the pathogens or cells that mandate a similar response in the future—it may also present “an opportunity for evaluating this approach in patients with metastatic lesions who cannot undergo surgical removal of the bladder.”

Similar efforts to target the delivery of IL-12 to tumors, including encapsulating the protein in viruses and liposomes, are being investigated. But combining IL-12 with chitosan may offer several advantages over these other approaches. Chitosan, for example, is already used in humans to promote blood clotting and reduce lipid absorption in the stomach, and it has a proven track record for safety, Dr. Zaharoff stressed, and the once-a-week treatment schedule will limit the type of systemic exposure that can cause toxicities.

In addition, unlike some other approaches to improve IL-12 delivery, preparing the IL-12 and chitosan mixture doesn’t require solvents and other processes that break down the protein, and it can actually be made at the bedside just prior to administration.

“It’s a very simple approach, but it was designed to be that way so it can be moved into human trials in a short period of time,” Dr. Zaharoff said. “As far as translational research goes, you can’t get much more efficient than this.”

source: NCI

microRNA May Regulate Growth of Tumor Blood Vessels

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The growth of blood vessels that supply tumors with essential nutrients may be regulated in endothelial cells by a small RNA molecule, or microRNA, a new study suggests. Researchers identified a microRNA called miR-132 that appears to act as a molecular switch for endothelial cell growth, causing the cells to transition out of their normal resting state and form new blood vessels (angiogenesis). The study, which could lead to a strategy for preventing angiogenesis and potentially for treating cancer, was published online by Dr. David Cheresh of the University of California, San Diego, and his colleagues August 1 in Nature Medicine.

Endothelial cells are among the least proliferative types of cells in adults, but they can be activated in response to certain cues, such as growth factors. Suspecting that microRNAs, which are known to regulate genes, might play a role, the researchers profiled microRNAs in a stem cell model of human vascular development and identified miR-132 as highly upregulated during the development of blood vessels. They then confirmed that miR-132 expression was also highly elevated in benign lesions of blood vessels, or hemangiomas, and in the blood vessels of human tumors, but was not detectable in normal blood vessels.

A molecular pathway analysis revealed that miR-132 suppresses the expression of a gene that encodes the protein p120RasGAP, which is a negative regulator of the protein Ras. Ras is frequently altered in cancer, so targeting miR-132 could be a way to intervene in an important pathway, the researchers said. And because miR-132 is found primarily in endothelial cells, these strategies would likely be specific to these cells, they noted.

As a proof of principle, the researchers used nanoparticle technologies they have developed to deliver an inhibitor of miR-132 directly to the vasculature of tumor-bearing mice. This treatment resulted in the blockade of tumor angiogenesis and tumor growth. Moreover, in mice with retinal disease that featured the growth of new blood vessels, direct injection of the anti-miR-132 into the eye was able to suppress angiogenesis in the retina.

“We essentially turned off the angiogenic switch during angiogenesis,” said Dr. Cheresh. The preponderance of growth in these cells was reduced, making it feasible to apply this kind of approach to patients with cancer and retinal diseases characterized by extensive angiogenesis, he added.

source:NCI

Protein Helps Predict Cancer Therapy-induced Heart Damage

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An echocardiogram showing a measurement of the heart's left ventricle.
Echocardiography measurements of the heart’s left ventricle help doctors monitor heart function during anticancer treatment. A reduction in left ventricle ejection fraction (LVEF) during treatment can indicate drug-induced heart damage. Click to Enlarge.

In a prospective study of 251 women with HER2-positive breast cancer, women with elevated blood levels of a protein called troponin I had significantly higher rates of cardiotoxicity (heart damage) during treatment with trastuzumab (Herceptin) than women who did not have elevated levels of troponin I before or during treatment. Women with elevated troponin I were also three times less likely to recover from the observed heart damage. The results came from a study led by Dr. Daniela Cardinale of the European Institute of Oncology in Milan, Italy, and were published online August 2 in the Journal of Clinical Oncology.

Measurement of troponin I levels “seems to allow us to distinguish patients with a more favorable cardiac outcome from those in whom close cardiologic monitoring is mandatory and for whom prophylactic strategies for prevention of…cardiotoxicity should be planned,” Dr. Cardinale and her colleagues wrote.

The new data add to the growing body of knowledge concerning the relationship between anthracycline-based chemotherapy, trastuzumab, and heart damage. Cardiotoxicity in patients receiving trastuzumab is more likely if they have had previous anthracycline treatment, and those patients treated with sequential anthracycline therapy and trastuzumab are less likely to recover cardiac function than patients not previously treated with this class of drugs. Anthracyclines cause heart damage through a well-understood pathway, and the Italian researchers had previously shown that elevated troponin I levels can predict chemotherapy-induced heart injury.

For the current study, the researchers prospectively enrolled 123 women receiving adjuvant trastuzumab for newly diagnosed breast cancer and 128 women receiving trastuzumab for metastatic breast cancer. All of the women had their left ventricular ejection fraction (LVEF)—a measurement of heart function—and troponin I concentrations evaluated before and during the study and during follow-up visits.

Patients who developed heart damage during the study discontinued trastuzumab and began heart failure treatment with the drugs enalapril and carvedilol, with additional heart treatments allowed as required. Doctors did not alter any patients’ treatment in response to changes in troponin I levels.

Overall, the researchers found elevated troponin I levels in 36 women, including 7 who had elevated levels even before trastuzumab treatment, most likely due to pre-existing heart damage from previous chemotherapy. In an analysis that looked at factors associated with risk for cardiac damage, including age, hypertension, high cholesterol, and smoking, elevated troponin I was the only independent predictor of heart damage during trastuzumab treatment, although previous treatment with an anthracycline neared statistical significance.

Sixty-two percent of the women who experienced trastuzumab-induced cardiotoxicity (TIC) had elevated troponin I levels during treatment. Sixty percent of all women with TIC recovered normal heart function after withdrawal of trastuzumab and treatment with heart-failure medications, but this recovery was not uniformly linked to low troponin I levels. While all of the women who did not recover heart function had elevated troponin I levels during treatment, 36 percent of women with elevated troponin recovered normal heart function.

Ninety percent of patients who experienced TIC had previously received chemotherapy with an anthracycline. The relationship between heart damage induced by these drugs is still being studied, explained Dr. Michael Ewer of the University of Texas M. D. Anderson Cancer Center and Dr. Steven Ewer of the University of Wisconsin, in an accompanying editorial.

One proposed explanation for the increased incidence of TIC in patients previously treated with anthracyclines is that trastuzumab by itself is not especially toxic to heart tissue, but that the drug aggravates anthracycline-induced heart damage by blocking HER2. HER2 is expressed in heart muscle as well as in breast tissue and may play a vital role in cardiac cellular repair mechanisms. Therefore, blocking HER2 may prevent the heart from repairing itself after exposure to anthracycline-based chemotherapy. “What we seem to be seeing is a modulating effect of trastuzumab on the vulnerable and previously damaged myocyte [heart muscle cell],” they wrote.

These results “are potentially very useful in terms of helping identify patients who may be at high risk for developing irreversible cardiac toxicity,” said Dr. Stanley Lipkowitz, senior investigator in the Laboratory of Cellular and Molecular Biology in NCI’s Center for Cancer Research and an attending physician at the National Naval Medical Center’s Breast Care Center. However, this relatively small study does have several limitations, he explained. Patients were treated in both the adjuvant and metastatic setting and with several different chemotherapy regimens. “It would be helpful to confirm the results in larger studies in each setting and ideally in studies where the chemotherapy is consistent,” he said.

In addition, Dr. Lipkowitz continued, longer-term follow-up is needed for women receiving adjuvant trastuzumab who have a longer life expectancy than women with metastatic disease. These women are at risk of late-stage side effects, and further research might refine the factors that predict TIC.

“Importantly, 10 out of 36 patients with elevated troponin I  during trastuzumab treatment did not develop cardiac toxicity, and 9 out of 26 patients with elevated troponin I and TIC during trastuzumab treatment recovered LVEF,” explained Dr. Lipkowitz. Additional studies are needed to confirm these results and to refine the levels or kinetics of troponin I elevation that correlate with cardiac outcomes, as well as how best to use such tests to guide treatment, he said.

source:NCI

Role of Vitamin and Mineral Supplementation and Aspirin Use in Cancer Survivors

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Multivitamins and multiminerals are widely used in the United States, but their efficacy and, perhaps more importantly, the potential for harm in individuals who have cancer have received relatively little study. Beyond their general effects on health, the use of vitamins and minerals by patients with cancer has unique implications because of their potential direct effects on existing cancers, effects on factors that may influence carcinogenesis, such as immunity, and interactions with treatment. Some evidence suggests that vitamin D at higher than standard doses may improve cancer-specific and overall survival for several cancer sites. Besides vitamin D, there is little evidence that nutritional supplements lower the risk of recurrence or improve survival from cancer, although some benefits may be possible in specific subgroups. Some data suggest that higher than standard doses of some vitamins or minerals could even enhance carcinogenesis or worsen survival in patients with cancer. For example, evidence suggests that although folate supplementation administered in preneoplastic stages may lower the risk of colorectal cancer, excessive folic acid in patients with established cancer may be harmful. For prostate cancer, some preliminary evidence indicates that excess consumption of one or a combination of components in a multivitamin/multimineral may accelerate cancer progression and increase fatality. Use of aspirin is proven to lower risk of colorectal cancer, and recent evidence suggests that aspirin use in patients with colorectal cancer improves cancer-specific and overall survival, especially in patients with tumors that express cyclooxygenase-2 (COX-2). The potential beneficial or adverse effects of dietary supplements and aspirin in survivors of cancer warrant further study.

Botox : before and after result

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At left, a look at a woman’s wrinkles before Botox injections. At right, the same woman pictured three weeks after Botox injections.

Muscle Involvement in Neuromyelitis Optica

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Are organs outside of the central nervous system affected in NMO?

Neuromyelitis optica (NMO) is an inflammatory central nervous system (CNS) disease associated with autoantibodies that target aquaporin-4, an astrocyte water channel. These researchers report on three patients who developed initial NMO symptoms following transient, self-limited episodes of fatigue and creatine kinase (CK) elevation (range, 12,520–59,660 IU/L) of unknown cause. The cases were identified through retrospective review of 733 serum samples from a diagnostic laboratory that provides testing for aquaporin-4 antibodies. In one pediatric case, CK elevation recurred without an associated NMO relapse (NMO relapses occurred independently). The authors could find no cause for the CK elevations; muscle biopsies were not performed.

Because aquaporin-4 is also the main water channel expressed in fast-twitch skeletal muscle fibers, the authors developed three hypotheses regarding NMO pathogenesis. In the first, exposure of muscle aquaporin-4 resulting from muscle destruction of any cause induces development of autoantibodies and T cells reactive against aquaporin-4. In the second, preexisting autoantibodies target aquaporin-4 in both muscle and the CNS. In the third, muscle injury activates preexisting autoantibodies and T cells reactive to aquaporin-4, resulting in blood–brain barrier disruption and facilitating an immune attack on CNS tissue.

Comment: Accumulating evidence, including from novel animal models of NMO, supports the pathogenic potential of aquaporin-4 autoantibodies in NMO. Spinal cord and optic nerve, and, to a lesser degree, the brain, are targets of inflammatory attacks. However, aquaporin-4 is also present on certain cells of the muscle, gut, kidney, and retinal systems, raising questions about why no dysfunction of these organs is clinically evident in NMO. The current report provides a systematic, albeit retrospective and nonspecific, assessment of muscle injury in NMO and suggests that such involvement may be underrecognized. Just as in the CNS, where some lesions are destructive and others are rapidly reversible, various physical and immunological factors may make systemic aquaporin-4 a less clinically important antigenic target. However, more-systematic pathological study of all tissues that express aquaporin-4 will enhance our understanding of NMO pathobiology.

— Dean M. Wingerchuk, MD, MSc, FRCP(C)

Dr. Wingerchuk is Professor of Neurology, Mayo Clinic College of Medicine, Mayo Clinic Arizona, Scottsdale.

Published in Journal Watch Neurology August 10, 2010

Bisphosphonates Not Associated with Risk for Esophageal, Gastric Cancers

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Despite reports suggesting a potential link between oral bisphosphonates and esophageal cancer, the drugs do not appear to pose increased risk, according to a case-control study in JAMA.

Using a national database, U.K. researchers identified some 46,000 adults (mostly older women) who filled a prescription for a bisphosphonate over an 11-year period, and matched them for age and sex to 46,000 controls. During about 4.5 years’ follow-up, 0.3% of all subjects developed gastric or esophageal cancer.

Cancer incidence did not differ between the groups. Findings were similar in subanalyses that examined specific types of bisphosphonates, as well as analyses limited to patients with gastroesophageal reflux disease or Barrett esophagus.

The authors conclude: “These drugs should not be withheld, on the basis of possible esophageal cancer risk, from patients with a genuine clinical indication for their use.”

source:JAMA

Why Don’t Implantable Cardioverter-Defibrillators Prevent Sudden Cardiac Death After Recent Myocardial Infarction?

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Recurrent MI and mechanical factors such as cardiac rupture may account for nearly 50% of SCD early after MI.

The risk for sudden cardiac death (SCD) is particularly high in the early months after a myocardial infarction (MI). However, two trials of prophylactic implantable cardioverter-defibrillator (ICD) placement after MI failed to show a survival benefit in ICD recipients (JW Cardiol Jan 28 2005 and Oct 7 2009), in contrast to results of other ICD trials. To examine this lack of benefit more closely, investigators studied data from VALIANT, an international trial of valsartan in MI survivors.

Of 14,703 participants with left ventricular dysfunction, clinical heart failure, or both, 2878 died during a median of 25 months of follow-up, and autopsy results were available for 398. Of these, the cause of death was clinically judged to be SCD in 105; autopsy revealed recurrent MI or cardiac rupture in 44; pump failure in 4; and stroke, pulmonary embolism, and drug overdose in 1 each. The proportion of clinically adjudicated SCDs that were nonarrhythmic on autopsy was even more dramatic during the first post-MI month (24 of 30 deaths).

Comment: This unique analysis of the causes of SCD early after MI yielded a surprising result: Nearly 50% of SCDs in the first 2 years — and 80% of SCDs within the first month — were nonarrhythmic. If confirmed in other populations, this finding would explain the failure of ICDs to prevent SCD in previous trials. This study appears to validate current guidelines that call for a 40-day delay in ICD placement after an acute MI.


Published in Journal Watch Cardiology August 11, 2010

Emerging Antibiotic Resistance in Enterobacteria Prompts Global Concern

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Patients may ask about a widely reported study describing emerging bacterial resistance to certain antibiotics. The study, published in Lancet Infectious Diseases, shows that a gene in E. coli and K. pneumoniae confers resistance to carbapenem antibiotics, especially in patients from India and Pakistan.

Researchers describe 180 isolates from patients in India, Pakistan, the U.K., and other countries. The isolates produce an enzyme, New Delhi metallo-beta-lactamase 1 (NDM-1) whose gene can be carried both on bacterial chromosomes and plasmids. NDM-1 was identified in up to 44% of carbapenem-resistant isolates in U.K. patients, some of whom had undergone elective surgical procedures in India or Pakistan.

Although few people have been identified with NDM-1, the authors call the potential for wider spread “clear and frightening.” A commentator warns that “patients who have had medical procedures in India should be actively screened for multiresistant bacteria before they receive medical care in their home country.”

SOURCE: Lancet Infectious Diseases