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New Study Begins for Kids with High Risk Cancer, Neuroblastoma

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Molecular Insight Pharmaceuticals has announced the initiation of a clinical trial of Azedra in pediatric neuroblastoma patients. Neuroblastoma is a type of neuroendocrine cancer that primarily affects children and is the most common solid tumor in children outside of the brain.

The drug Azedra is a small, targeted radiotherapeutic molecule that binds to the norepinephrine transporter, a protein highly expressed on neuroendocrine tumors such as neuroblastoma. Because of this preferential binding, Azedra can deliver a greater amount of radiation to the tumor cell, thus increase tumor killing while reducing side effects.

“Neuroblastoma is an aggressive and difficult to treat form of neuroendocrine cancer that usually affects children under five years of age,” said Katherine Matthay, M.D., Chief of Pediatric Hematology and Oncology at the University of California San Francisco Children’s Medical Center. “Unfortunately, the prognosis for many of these children is quite poor. There currently are no FDA-approved treatments available for patients who have progressive, recurrent or refractory disease, and our current treatment options are extremely limited.”

Usage of Testicular Cancer Markers Too Limited, Say Researchers

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A standard part of testicular cancer care isn’t used in more than half of all patients who have the condition, researchers have found.

Doctors generally rely on a series of three serum-based tumor markers for testicular cancer, since these are helpful with diagnosis, prognostication and surveillance for disease recurrence following treatment.

Reviewing 4,700 testicular cancer cases however, the researchers found that a combination of two of these tumor markers were used less than half of the time, while all three tumor markers were measured in just 16 percent of the cases.

The study authors also discovered that only 45% of cases used the tumor markers AFP (alpha fetoprotein) and HCG (human chiorionic gonadotrophin), with a third tumor marker, LDH or lactate dehydrogenates, used in combination with the other two, just 16% of the time. These results are reported in Urologic Oncology, Seminars and Original Investigations.

"Tumor markers play a central role in showing physicians how a patient is responding to treatment and whether the disease has recurred," says lead author Scott M. Gilbert, M.D., clinical lecturer in the University of Michigan Department of Urology. "We were extremely surprised by the low rates of usage."

Dr. Gilbert conduct regular checks on all three markers in their patients, because if the markers stay elevated after therapy, it shows the cancer remains; or if the markers begin to rise during the observation period following successful treatment, this too shows the cancer has returned.

One explanation for the low rates of marker usage could be poor documentation in medical records, since incidents of tumor marker use were not always recorded, says senior author Brent K. Hollenbeck, M.D., M.S., assistant professor in the U-M Department of Urology. "Even if it isn’t a problem related to the care of the patients, it is a quality problem at the medical centers that are not recording the data properly. Either way, major improvements need to occur," he says.

But other data in the study suggest that the reporting of tumor marker use may not be the problem. Using the data from the Surveillance, Epidemiology, and End Results (SEER) program, the researchers found substantially more documentation of PSA use in prostate cancer patients compared to the testicular cancer tumor markers. That information supports the notion that recording may not be the problem, but that the use of testicular cancer markers is in fact very low.

Source: University of Michigan

Researchers Find that a Small Molecule Can Block Cancer Cell Division

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By activating a cancer suppressor gene, a small molecule called nutlin-3a can block cancer cell division, according to researchers at the National Cancer Institute (NCI), part of the National Institutes of Health.

This activation of the p53 gene leads to cellular senescence, a process by which cells lose their ability to grow and divide. An opportunity for new genetic mutations occurs each time a cell divides, so limiting the number of cell divisions in a cancer cell inhibits tumor progression.

Activation of p53 can suppress tumor growth through more than one mechanism. It can interfere with the cell cycle, prompting a cell with unrepaired DNA damage to commit suicide through a complex signaling pathway called apoptosis. Alternatively, p53 may trigger cellular senescence in response to DNA damage or cellular stress.

The expression of p53 is regulated by Mdm2, a protein that is overexpressed in several human cancers. ,are small-molecule inhibitors that prevent the p53 protein from forming a complex with Mdm2, resulting in activation of p53. Previous studies have shown that nutlin can induce apoptosis in human cancer cells.

"Although p53 is mutated or deleted in about half of all cancers, it is still potentially functional in the other 50 percent," said Curtis C. Harris, M.D., chief of the Laboratory of Human Carcinogenesis at NCI’s Center for Cancer Research and an author of the study. "A better understanding of molecules, such as nutlin-3a, that can activate p53 may lead to the development of new treatment options for certain cancers."

To examine the effects of nutlin-3a on cellular senescence, the Harris team exposed human skin cells and cancer cells to two different forms of nutlin-3: forms a and b. (Nutlin-3a has a 150-fold greater affinity for Mdm2 than nutlin-3b.) After a seven-day exposure period, the scientists found that almost 100 percent of the cells treated with nutlin-3a had stopped proliferating. These cells did not regain the ability to proliferate even after being removed from nutlin-3a, indicating that they had undergone permanent senescence. By contrast, nutlin-3b had little effect on the cells.

Next, the researchers investigated whether the senescence induced by nutlin-3a is dependent on the presence of p53 protein. After exposure to nutlin-3a for seven or 14 days, more than 80 percent of the human cells containing a functional p53 gene exhibited signs of senescence. The researchers also found that nutlin-3 treatment increased the expression of p53. However, the researchers did not observe any changes in p53-deficient cells.

Previous research by this team showed that the genes affected by p53 activation differed depending on the type of activator. To gain a better understanding of nutlin-3a-induced senescence, the researchers used microarray analysis to determine the effect of p53 activation on gene expression after cancer cells were treated with nutlin-3a. Microarray analysis is a technique that allows researchers to examine the expression of thousand of genes simultaneously. Almost 3,000 genes were differentially expressed when cells with normal p53, cells with mutant p53, and p53-deficient cells were compared. Among the genes with increased expression after nutlin-3a-activation of p53 were several genes that play a role in cellular senescence and cell death.

The researchers also found that the inhibitor of growth 2 gene (ING2) was among those with decreased expression in response to nutlin-3a treatment. ING2 regulates gene activation or expression, and it may play a role in tumor development, cell proliferation, and senescence. The researchers found that p53 seemed to suppress ING2 expression by binding directly to two sites on the ING2 promoter.

"This study further characterizes the actions of nutlin-3a on genes that can play a role in the development of cancer," said Harris. "Our study reinforces the idea that using Mdm2 inhibitors, such as nutlin-3a, to promote the growth suppressive and cell-killing activity of p53 is a potentially valuable strategy to pursue in cancer treatment."

Source: Cancer Research, May 1, 2008 and National Institutes of Health (NIH)

Protecting Yourself from the Sun to Avoid Skin Cancer

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Before leaving home for a day of outdoor activity, take appropriate precautions to ensure that your and your family’s skin is well-protected, as the majority of all skin cancers are caused by the sun.

According to Susan Chon, M.D., assistant professor of dermatology at The University of Texas M. D. Anderson Cancer Center, a sunscreen with an SPF of at least 30 is a good choice for most people. One ounce of sunscreen (enough to fill a shot glass) is considered sufficient to properly cover sun-exposed areas. To get the most protection from sunscreen, generously reapply throughout the day. This is especially important because factors such as humidity, perspiration and uneven product application can cause sunscreen to lose its effectiveness.

Sun Protection Checklist
Chon recommends gathering the following items before heading outdoors.

  • Sunscreen with SPF 30 or greater
  • Lip balm with SPF 30
  • Hat with a brim or cap
  • Long-sleeved shirt (preferably sun protective clothing)
  • Sunglasses with UV protection

"These are great items to keep handy in your bag to prepare for the sun as it intensifies throughout the day," Chon said.

Application Time Line
Chon suggests the following time line for when to best use these items.

Morning: 8 – 10 a.m. Apply sunscreen with SPF 30, at least 30 minutes before sun exposure.
Reapply sunscreen every two hours.
Wear a hat, sunglasses and lip balm.

Midday: 11 a.m. – 2 p.m. (hottest time of the day)
Seek shade for extra protection.
Wear a long-sleeved shirt with a hat and sunglasses.
Reapply sunscreen and lip balm every two hours.

Afternoon: 3 – 5 p.m.
Keep wearing a hat and sunglasses.
Reapply sunscreen and lip balm every two hours.

"Remember, if you are sweating or swimming, you may need to reapply more often," Chon said. Avoid reflective surfaces such as water, sand, snow and concrete. "You can burn from indirect exposure to the sun, too," Chon said.

According to the American Cancer Society, more than one million cases of basal cell or squamous cell cancers, the most common types of skin cancer, occur annually. The most serious form of skin cancer is melanoma, of which more than 60,000 people are expected to be diagnosed in 2008.

Source: University of Texas M. D. Anderson Cancer Center

Obese Women Experience More Aggresive Breast Cancer

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Obese women with breast cancer have lower rates of survival, and suffer a more intense form of the disease, according to recently-published research.

"The more obese a patient is, the more aggressive the disease," said Massimo Cristofanilli, MD, associate professor of medicine in the Department of Breast Medical Oncology at The University of Texas M.D. Anderson Cancer Center. "We are learning that the fat tissue may increase inflammation that leads to more aggressive disease."

606 women with breast cancer were observed by Cristofanilli and colleagues, and classified by body mass index into three groups—normal/underweight (24.9 or below), overweight (at least 25 but less than 30), or obese (more than 30). At five years, overall survival was 56.8 percent among obese women, 56.3 percent among overweight women and 67.4 percent among normal weight women. The 10-year survival rate was 42.7 percent among obese women, 41.8 percent among overweight women and 56.5 percent among normal weight women. Researchers found that the rate of inflammatory breast cancer was 45% among obese women, compared with 30% in overweight women, and 15% in women with normal weight.

Obese or overweight women also displayed a higher risk of breast cancer recurrence. Obese women (50.8%) reported a recurrence after 5 years, compared with normal weight women (38.5%). After 10 years, the rate of recurrence was 58% in obese women and 45.4% in women with normal weight.

"Obesity goes far beyond just how a person looks or any physical strain from carrying around extra weight. Particular attention should be paid to our overweight patients," Cristofanilli said.

Drugs commonly used to treat cancer patients, such as tamoxifen, said Dr. Cristofanilli tend to increase weight gain during treatment – an effect physicians should note carefully. "We have actually become quite good at managing acute side effects such as nausea in our chemotherapy patients and it goes away within a couple of days," Cristofanilli said. "Following the nausea, our patients tend to overeat, which further increases their risk of weight gain. We need to implement lifestyle modifications interventions and develop better methods to follow these patients closely."

Clinical Cancer Research, March 15, 2008

Genistein in Soybeans May Halt Prostate Cancer Spread

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Genistein, an antioxidant found in soybeans, almost completely prevented the spread of human prostate cancer in mice, according to a study published in the journal Cancer Research. In the study, genistein was used in an amount equivalent to what a human being would consume in a soybean-rich diet.

Genistein decreased metastasis of prostate cancer to the lungs by 96% compared with mice that did not eat the compound, the first demonstration that genistein can stop prostate cancer metastasis in a living organism. "These impressive results give us hope that genistein might show some effect in preventing the spread of prostate cancer in patients," said the study’s senior investigator, Raymond C. Bergan, MD, director of experimental therapeutics for the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

"Diet can affect cancer and it doesn’t do it by magic," Bergan said. "Certain chemicals have beneficial effects and now we have all the preclinical studies we need to suggest genistein might be a very promising chemopreventive drug."

Bergan has already shown in prostate cell cultures that genistein slows detachment of cancer cells from a primary prostate tumor, and checks cell invasion. It does this by blocking activation of p38 MAP kinases, molecules which regulate pathways that activate proteins that loosen cancer cells from their tight hold within a tumor, pushing them to migrate. "In culture, you can actually see that when genistein is introduced, cells flatten themselves in order to spread out and stick strongly to nearby cells," he said.

Researchers implanted groups of mice with an aggressive form of prostate cancer, having first fed them genistein. The amount of the chemical in the mouses’ blood was equivalent to human blood concentrations after eating soy foods, said Bergan. Genistein stopped lung mestasis almost completely, although it did not reduce the size of the tumors that developed within the prostate. Repeating the experiment produced he same result.

The size of tumor cells’ nuclei in the animals’ tissue was checked, to see whether he cells had flattened t in rder to spread. "Within a tumor, it is hard to tell where the borders of cells stop, so one way to measure adherence is to look at the size of the nuclei in cells and see if they are wider due to cell spread," Bergan said. "And that is what we found, demonstrating that the drug is having a primary effect on metastasis."

"What we think is happening here is that the cells we put in the mice normally like to move. When genistein restricted their ability to do so, they tried to compensate by producing more protein involved in migration. But genistein prevented those proteins from being activated," he said. "This is really a lesson for researchers who depend on biomarker studies to test whether a treatment is working. They need to be aware that those biomarkers might be telling only half of the story."

Source: Cancer Research, a journal of the American Association for Cancer Research. March 15, 2008.

Genetic Markers Identify Probability of Lung Cancers Recurrence

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Genetic alterations in tumors and tissue taken from early-stage lung cancer patients are clear pointers to which cancers might recur. Researchers say the findings could change the approach to treating even the smallest lung cancers—the size of a pea—which are known to recur within five years in 30 to 40 percent of patients.

"This is DNA forensics for cancer," says Malcolm Brock, M.D., associate professor of surgery at Johns Hopkins. "While there may be no trace of cancer that we can spot after surgery with a microscope, the DNA evidence from these tumors may have been left at the scene, especially in lymph nodes."

The research team from Johns Hopkins Kimmel Cancer Center identified methyl groups that connect with the DNA structure of a gene. The development of cancers signals cells to switch certain genes on or off, and methylation is a common phenomenon in this process. Disruption to these signals may create abnormal proteins that lead to cancer or its recurrence.

In the study, Brock and his team checked more than 700 surgical samples from 167 early stage non-small lung cancer patients, looking for specific methylation patterns linked o cancer. For 51 patients, whose cancers recurred within 40 months, tumor and lymph node tissue was compared with samples from the remaining 116 patients whose cancer did no recur. The scientists tested all the samples for methylation on seven genes linked to the development of lung cancer. Four of them—p16, H-cadherin, APC and RASSF1A—showed the highest amounts of methylation in patients who had a recurrence of the cancer.

For many of the genes, the study revealed a twofold difference in methyl marks between recurrent cancers and those that did not return.

"The DNA evidence we see for many of the recurring cases suggests it may be wise if our work is confirmed to reclassify such cancers as advanced disease instead of early stage," says Brock.

Higher than normal methylation, combining two genes known as p16 and H-cadherin located in both tumor tissue and a lymph node remote from the tumor area, meant that cancers returned faster than average in 11 patients. For 8 of them this methylation pattern had cancers returning within a year; for the remaining 3 it took 30 months for the cancers to recur.

When analyzing the results to quantify the odds on a patient’s cancer returning, they noted a 5 to 25-fold in risk depending on the particular methylation pattern. While the small sample size meant that some of the gene markers lacked statistical significance, they believed that odds predictions were valid for p16 and H-cadherin.

Kimmel Cancer Center medical oncologist James Herman, M.D. says if these results are confirmed, it may lead doctors to consider treating high-risk patients more aggressively with chemotherapy after surgery. He also believes that therapies which target these gene patterns by stripping off methyl groups hold promise as well. "These marks of aggressive disease also are themselves targets for therapy."

The study appeared in the March 13 issue of the New England Journal of Medicine.

Researchers Find that Head and Neck Cancers May Be Different Diseases

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Different risk factors for head and neck cancer have been identified by researchers at Johns Hopkins Kimmel Cancer Center, raising the possibility that they are different forms of these diseases.

Head and neck tumors caused by the human papillomavirus (HPV) were generally associated with sexual behaviors and smoking marijuana, rather than tobacco and alcohol. It was also found that people with the viral-linked cancer were mostly white, younger, married, and college-educated with income of $50,000 or more. Those not attributable to HPV were associated with tobacco, alcohol and poor oral hygiene, most generally listed as the causes of head and neck cancer. The findings are to be published in the March 12 issue of the Journal of the National Cancer Institute.

"Our results indicate that HPV-positive and HPV-negative head and neck cancers have different risk-factor profiles and should be considered two distinct diseases," says Maura L. Gillison, M.D., Ph.D., an associate professor of oncology and epidemiology at Hopkins. "They just happen to occur in the same place."

HPV infection has been seen in up to 72% of patients, and is associated with the development of some neck and head cancers, mostly in the upper throat and back of the tongue. Gillison noted that the incidence of HPV-linked cancer has nearly doubled over the past 30 years, and that head and neck cancer patients with HPV-positive tumors are mlore responsive to treatment and survive longer than HPV-negative patients.

According to Gillison, the American Joint Committee on Cancer is now considering incorporating HPV status in its guidelines for determining clinical stages of head and neck cancer.

For this study, 240 patients at the Johns Hopkins Hospital with head and neck squamous cell carcinomas were studied between 2000 and 2006, to identify HPV-positive or negative tumors. All study participants completed a computerized interview that asked questions about their risk factors.

Source: Journal of the National Cancer Institute, March 12, 2008

Increased Risk of Breast Cancer Recurrence Tied To High Levels of Estrogen

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Women whose breast cancer returned after treatment had almost twice as much estrogen in their blood than did women who remained cancer-free, according to a newly published study.

The study’s lead author, Cheryl L. Rock, Ph.D., a professor in the Department of Family and Preventive Medicine at the University of California, San Diego, said that high levels of estrogen—which lead to the initial development of breast cancer—could be associated with an increased risk of recurring cancer.

"While this makes sense, there have been only a few small studies that have looked at the link between sex hormones in the blood and cancer recurrence," she said. "This is the largest study to date and the only one to have included women taking agents such as tamoxifen to reduce estrogen’s effect on cancer growth."

"What the results mean for women who have already been treated for breast cancer is that they should do as much as they can to reduce estrogen in their blood, such as exercising frequently and keeping weight down," she added. "Taking anti-estrogen drugs like tamoxifen may not completely wipe out the hormone’s effect in women who have high levels of estrogen."

The Women’s Healthy Eating and Living Study (WHEL) provided participants for the breast cancer study, a dietary intervention trial that monitored 3,088 women treated for breast cancer but cancer-free when recruited for the study. Subjects were placed in two groups—one that ate a " normal" healthy diet, one that ate extremely large amounts of fruits, fiber and vegetables. After 7 years, participants were checked for breast cancer, which was about the same for each group. Researchers interpreted the findings to mean that a normal diet that incorporates the U.S. Food and Drug Administration guidelines for recommended amounts of fruits and vegetables is sufficient.

In the current study, 153 WHEL participants whose cancer had recurred were matched with 153 participants who remained cancer-free. These pairs were alike in terms of tumor type, body size, age, ethnicity, use of chemotherapy and other variables. Two-thirds of the participants were using tamoxifen, Rock said.

When they enrolled, researchers tested the women’s blood for concentrations of the steroid hormones estradiol (the primary human estrogen) and testosterone. They analyzed different forms of estradiol and testosterone in the blood, such as how much was bound to transport proteins (such as to the sex hormone binding globulin, or SHBG) and how much was "free" circulating and able to enter a cell.

The study was published in the March issue of Cancer Epidemiology, Biomarkers and Prevention, a journal of the American Association for Cancer Research.

Stress May Increase HPV and Cervical Cancer Risk

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Sress can reduce the immune system’s ability to resist HPV, a common sexually transmitted disease that may lead to cancer, according to a recent study published in the Annals of Behavioral Medicine. No such association is seen, however, between past major life events, such as divorce or job loss, and the body’s response to the infection.

"HPV infection alone is not sufficient to cause cervical cancer," explained Fox Chase Cancer Center’s Carolyn Y. Fang, Ph.D. "Most HPV infections in healthy women will disappear spontaneously over time. Only a small percentage will progress to become precancerous cervical lesions or cancer."

Women with precancerous cervical lesions were asked to complete a questionnaire detailing their stress in the past month, such as divorced, death of a close family member or job loss. "We were surprised to discover no significant association between the occurrence of major stressful life events and immune response to HPV16. This could be due to the amount of time that has passed since the event occurred and how individuals assess and cope with the event," said Fang.

"Our findings about subjective daily stress told a different story, however. Women with higher levels of perceived stress were more likely to have an impaired immune response to HPV16. That means women who report feeling more stressed could be at greater risk of events that had occurred, such as divorce, death of a close family member or loss of a job.

"We were surprised to discover no significant association between the occurrence of major stressful life events and immune response to HPV16. This could be due to the amount of time that has passed since the event occurred and how individuals assess and cope with the event," said Fang. "Our findings about subjective daily stress told a different story, however. Women with higher levels of perceived stress were more likely to have an impaired immune response to HPV16. That means women who report feeling more stressed could be at greater risk of developing cervical cancer because their immune system can’t fight off one of the most common viruses that causes it."

Fang’s study was funded by a grant from the National Cancer Institute.


Source: Annals of Behavioral Medicine (Vol. 17, No. 1)