RxPG News : Ovarian Cancer

New technique to visualise tumour cells during surgery

Mon, 19 Sep 2011 17:22:40 PST

( from http://www.rxpgnews.com ) Ovarian cancer is one of the most frequent forms of cancer that affect women. As tumors can initially grow unchecked in the abdomen without causing any major symptoms, patients are usually diagnosed at an advanced stage and have to undergo surgery plus chemotherapy. During the operation, surgeons attempt to remove all tumor deposits as this leads to improved patient prognosis. To do this, however, they primarily have to rely on visual inspection and palpation - an enormous challenge especially in the case of small tumor nests or remaining tumor borders after the primary tumor excision.

Yet surgeons could now be getting support from a new multispectral fluorescence imaging system developed by a team of researchers in Munich, headed by Vasilis Ntziachristos, Professor of Biological Imaging. A study carried out on nine patients with ovarian cancer has shown that the new system can be used to localize cancer cells during surgery. Before the operation, the patients were injected with folic acid chemically coupled to a green fluorescent dye. Most ovarian tumors have a protein molecule on their surface that bonds with folic acid and transports it inside the cell. This protein is known as the folate receptor alpha. During abdominal surgery, the surgeon can then shine a special laser light onto the patient's ovaries, causing the green-labeled folic acid inside the cancer cells to emit light. Healthy tissue remains dark.

The fluorescent cancer cells, however, cannot be detected by the naked eye. Three cameras, mounted on a pivoting support arm over the operating table, detect optical and fluorescent signals at multiple spectral bands and then correct for light variations due to illumination and tissue discolorations in order to provide truly accurate fluorescence images that can be simultaneously displayed with corresponding color images on monitors in the operating room. The surgeon can thus check whether all the cancer cells have been removed by inspecting for remnant fluorescence light. In eight of the nine patients, doctors were able to remove small clusters of tumor cells that might otherwise have gone undetected. The multispectral fluorescence imaging system has thus passed its first OR test. However, it will have to prove its value to improve clinical outcome in further operations before it can be deployed for routine surgical procedures.

The researchers in Munich and Groningen also want to further develop the camera system so it can be used to detect other forms of tumors during operations. Of significant importance in future developments is the ability to offer accurate fluorescence imaging so that data collected reflect true presence of disease. "The use of advanced, real-time optical technology will allow us to standardize data collection and accuracy so that studies performed at multiple clinical centers can be accurately compared and analyzed" explains Prof. Vasilis Ntziachristos. This is important for the clinical acceptance of the technology and its approval by regulatory agencies. In the future patient selection through personalized medicine approaches, for example by obtaining a molecular profile of the tumor of each patient, would further enable custom-tailored surgical treatment of improved accuracy. The team is also planning to build a version for minimally invasive operations.

Autophagy helps ovarian cancer cells to survive

Sun, 04 Jan 2009 14:20:19 PST

( from http://www.rxpgnews.com ) A single tumor-suppressing gene is a key to understanding, and perhaps killing, dormant ovarian cancer cells that persist after initial treatment only to reawaken years later, researchers at The University of Texas M. D. Anderson Cancer Center report in the December Journal of Clinical Investigation.

The team found that expression of a gene called ARHI acts as a switch for autophagy, or self-cannibalization, in ovarian cancer cells. Often a mechanism for cancer cell death, in this case "self-eating" acts as a survival mechanism for dormant cancer cells.

"Prolonged autophagy is lethal to cancer cells, but a little autophagy can help dormant cancer cells survive, possibly by avoiding starvation," said senior author Robert Bast, M.D., vice president for translational research at M. D. Anderson.

"Dormant cells are a major problem in ovarian cancer, breast cancer and other malignancies," Bast said. "We often see ovarian cancer removed, leaving no remaining sign of disease. After two or three years, the cancer grows back. If any remaining cancer cells had continued to grow normally, the disease should have returned in weeks or months.

"So the assumption is that some cells remain dormant without dividing and without developing a blood supply, but the mechanism for this has not been well understood," Bast said.

Bast and colleagues focused on ARHI, short for aplasia Ras homolog member I, a gene found in normal cells, but that is underexpressed in 60-70 percent of ovarian cancers.

When normal levels of ARHI were restored to ovarian cancer cells in the laboratory, autophagy was induced and cancer cells died within a few days.

When the experiments moved to human ovarian cancer grafts in mice, a different effect was noted. ARHI stopped tumor growth and induced autophagy, but did not kill the cancer cells. When ARHI was turned off at 4 to 6 weeks, the ovarian cancer cells grew rapidly.

"Cancer cells had remained viable during ARHI-induced growth arrest and autophagy, which is consistent with a dormant state," Bast said. "When we blocked autophagy with chloroquine, a drug also used to treat malaria, regrowth of the cancers was inhibited, suggesting that autophagy had helped the cancer cells to survive in the absence of a blood supply."

Autophagy is a cellular survival mechanism that protects cells in a variety of ways. In the case of stress caused by lack of nutrients, autophagy is roughly comparable to a person burning body fat to survive the absence of food.

Several protein survival factors were detected within the microenvironment of the ovarian cancer grafts that could prevent autophagy-induced death of ovarian cancer cells in the laboratory. Blocking these survival factors could provide a novel strategy for eliminating dormant ovarian cancer cells and curing more patients.

Whether cancer cells die an autophagic death, remain dormant or exit dormancy to grow again depends on the balance between ARHI's tumor-suppressing activity and the anti-autophagic and proliferative activity of these environmental survival factors, the authors note.

The ARHI-autophagy pathway also provides an inducible model for tumor dormancy. Lack of a model has hindered understanding of dormant cells and the development of treatments to eliminate them, Bast noted.

Ovarian cancer vaccine trials show promise

Sat, 13 Oct 2007 14:23:02 PST

( from http://www.rxpgnews.com ) New York, Oct 13 - Scientists in the US have developed a vaccine to fight ovarian cancer, and it has shown encouraging results in preliminary trials.

The vaccine developed by scientists led by Kunle Odunsi at the Roswell Park Cancer Institute in Buffalo enhances the body's own immune response to the cancer, reported the online edition of BBC News.

The researchers tested the vaccine in women with epithelial ovarian cancer, a type of cancer that originates on the covering of the ovaries.

'There is now compelling evidence that the immune system has the capacity to recognise and kill ovarian cancer cells. We are confident that the vaccine will eventually be widely available,' Odunsi said.

Ovarian cancer is the development of a tumour on or within an ovary. It usually happens in women who are over 50 years of age but it can also affect younger women. Its cause is unknown. Treatment is usually surgery followed by treatment with medicines.

Most patients with advanced disease respond to drug treatments but more than 70 percent die from a recurrence of the cancer within five years of diagnosis.

It is the fourth most common type of cancer in women and fifth leading cause of cancer death in the US. In India, according to the Indian Council of Medical Research, the crude incidence rate of this cancer is 4.2 per 100,000 women.

VEGF Trap shows activity in patients with advanced ovarian cancer

Mon, 04 Jun 2007 16:00:00 PST

( from http://www.rxpgnews.com ) Preliminary results of a randomized, international Phase II trial of VEGF Trap (aflibercept) show activity in patients with recurrent epithelial ovarian cancer (EOC) who had received three or four prior chemotherapy regimens and had become resistant to platinum-based chemotherapy agents. The findings, which were presented at the American Society of Clinical Oncology's annual meeting, may indicate a role for this targeted therapy in women with ovarian cancer who have exhausted all other options.

To date, the trial has enrolled 162 patients with advanced ovarian cancer at 44 centers in twelve countries in Europe, Canada, and the United States. Favorable results were reported for 85 percent of participants after one month: 8 percent showed tumor shrinkage and 77 percent had stable disease. After fourteen weeks, 41 percent of patients continued to have stable disease.

"The interim analysis of the Phase II data was very promising," said Dr. William P. Tew, an oncologist at Memorial Sloan-Kettering Cancer Center and the study's lead author. "As a result, we are continuing to recruit patients to complete the study."

In this trial, VEGF Trap is administered intravenously as a single agent in one of two dose levels. It works by blocking the development of new blood vessels to the tumor (angiogenesis) which stops tumor growth and the spread of cancer to other parts of the body (metastasis). It can also result in tumor shrinkage. VEGF Trap is generally well-tolerated although both mild and severe side effects were reported. These included but were not limited to headache, fatigue, nausea, mild and severe hypertension, hoarseness, mild and severe protein in the urine, renal dysfunction, and a low incidence of bowel perforation (one percent).

"Ovarian cancer may be unusual among solid tumors because vascular-targeting agents like VEGF Trap appear to have significant single-agent activity in advanced ovarian cancer," said Dr. David R. Spriggs, Head of Solid Tumor Oncology at Memorial Sloan-Kettering and the study's senior author. "In most solid tumors, the efficacy of VEGF targeting is likely to be further enhanced by combining it with classic chemotherapy agents."<

UBC discovery may lead to focussed therapies for metastatic breast, ovarian cancer

Mon, 19 Mar 2007 23:01:56 PST

( from http://www.rxpgnews.com ) New non-toxic and targeted therapies for metastatic breast and ovarian cancers may now be possible, thanks to a discovery by a team of researchers at the University of British Columbia.

In a collaboration between UBC stem cell and cancer scientists, it was found that a protein called podocalyxin â which the researchers had previously shown to be a predictor of metastatic breast cancer â changes the shape and adhesive quality of tumour cells, affecting their ability to grow and metastasize. Metastatic cancer is invasive cancer that spreads from the original site to other sites in the body.

The discovery demonstrated that the protein not only predicted the spread of breast cancer cells, it likely helped to cause it. The findings were recently published online by the Public Library of Science.

"We believe weâve found a new important culprit in metastatic breast cancer, which opens up an entirely new avenue of cancer research," says Calvin Roskelley, an associate professor of cellular and physiological science who specializes in breast cancer and is co-senior principal investigator. "The culprit is hiding in plain sight on the surface of tumour cells, so we are now developing "smart" molecules to block its function. The ultimate goal is to generate new targeted, non-toxic treatments â very different from the standard âslash and burnâ chemotherapy."

The researchers found that podocalyxin significantly expands the non-adhesive face of cells, allowing individual cells to brush aside adhesion molecules situated between tumour cells. The "freed" cells then move away from the original site to form new tumours at other sites. Also, the protein causes tumour cells to sprout microvilli, or hair-like projections, that may help propel cancer cells to other sites.

In addition, when the protein expands the non-adhesive face of cells it drags along with it a second protein called NHERF-1 â a protein shown by others to be implicated in cell growth and invasion. The researchers now believe the mechanism applies to difficult-to-treat invasive breast and ovarian cancers.

"Weâre now tapping into what causes the characteristic cell shape changes seen in cancerous tumours and possibly how these cells grow and metastasize. It gives us a whole new target for therapy," says Assoc. Prof. of Medical Genetics and stem cell expert Kelly McNagny, co-senior principal investigator. "If we can block the protein, we may be able to stop the spread of cells."

Post-doctoral Fellow Julie Nielsen, of UBCâs Biomedical Research Centre, and PhD student Marcia Graves of the Dept. of Cellular and Physical Sciences, were instrumental in designing and executing the research experiments, he adds.

Next steps involve advancing the research in animal models, designing antibodies to block the function of the protein and working with the UBC-based Centre for Drug Research and Development to identify new therapies to combat metastasizing cancer.

The researchers say information from this discovery may speed development of new therapies to within 10 years.

In 2006, more than 22,000 women were diagnosed with breast cancer and 5,300 died of it, according to estimates from the Canadian Breast Cancer Foundation. The Canadian Cancer Society estimates that approximately 2,300 new cases of ovarian cancer were diagnosed and about 1,600 women died from the disease in 2006.

Ovariectomy may put younger women at risk for an earlier death

Thu, 14 Sep 2006 05:40:00 PST

( from http://www.rxpgnews.com ) Death rates rise when women under 45 years old undergo bilateral ovariectomy -- surgical removal of both ovaries -- and do not receive proper hormone replacement therapy, according to a new Mayo Clinic study to be published in the October 1 issue of The Lancet Oncology. Mortality from all causes increased 1.7 times for women in this age category, and was particularly increased for estrogen-related cancers and diseases of the brain and cardiovascular system. The increased risk was mainly restricted to those women who were not given estrogen after the surgery until at least age 45 (within five years of the approximate age of normal menopause). Also, the increased risk became evident only 10 or more years after the ovariectomy.

Walter Rocca, M.D., Mayo Clinic neurologist, epidemiologist and lead study investigator, made these discoveries serendipitously while investigating links between ovary removal and brain diseases such as Parkinson's disease and dementia.

"These findings reopen the debate about preventive removal of the ovaries for younger women," says Bobbie Gostout, M.D., Mayo Clinic gynecologic surgeon who is not a study author but consulted with Dr. Rocca. "We don't see a dramatic increase in risk for early death from any one condition, but Dr. Rocca's study did show some increase in risk of death from breast and uterine cancers, and neurologic and vascular conditions. Collectively, this information tells us that a procedure that previously looked advantageous in protecting women's health may actually have disadvantages. We need to be very thoughtful about ovariectomy, as it may put younger women at risk for an earlier death."

Dr. Rocca says that if a woman under 45 has ovarian cancer or a benign disease in the ovaries that requires removal, however, compelling reason remains to remove the ovaries. Removal may also be considered in older women and in women with a very high risk of ovarian cancer, he says.

Dr. Gostout indicates that these findings will change her surgical practice for women under age 45.

"For me this changes the nature of the discussion," she says. "Women in whom we've discovered ovarian cancer or benign disease of the ovary will still be counseled to have it treated, including ovariectomy. We will use the findings from the Mayo Clinic study to guide the discussion on estrogen replacement therapy and will encourage most young women to take estrogen until age 50. But, for women with average risk for breast and ovarian cancer where we might have considered preventive ovariectomy, the discussion will have more of an emphasis on conserving the ovaries for protecting the health of the woman."

Continuing preventive ovariectomies in average-risk younger women and emphasizing estrogen replacement therapy thereafter may not be an adequate solution to diminish the risk, however, as compliance is poor for taking estrogen replacement therapy, says Dr. Gostout. Dr. Rocca adds that the protective effect from endogenous estrogen -- estrogen coming naturally from one's own ovaries with daily and monthly cyclic variations -- may not be the same as the effect of estrogen replacement therapy.

The study's investigators propose several theories to explain the finding of increased early deaths for younger women who have preventive ovariectomy without adequate estrogen replacement:

Premature estrogen deficiency following the surgery increased the risk for various diseases that in turn reduced survival

The surgery revealed an underlying pre-existing condition in these women that caused early death following surgery

These women may have a genetic predisposition to uterine diseases or other symptoms that prompted hysterectomy, which then prompted preventive ovariectomy, while the same predisposition also increased the risk of cancer or other causes of death following the surgery

The study findings also have general research implications for the role of estrogen, according to Dr. Rocca. "Our results confirm that estrogen is probably protective of the brain and cardiovascular system," he says. "They also further establish that the effects of estrogen are age-dependent: estrogen may be clearly useful and protective at younger ages, but it may become less important after menopause and then may have no effect or may be disadvantageous if given as treatment in later years."

To conduct this study, Dr. Rocca and colleagues followed women who had undergone unilateral or bilateral ovariectomy between 1950 and 1987 while residing in Olmsted County, Minn., home of Mayo Clinic. All of these women had the surgery prior to menopause and for reasons other than cancer. The study evaluated 1,293 women with unilateral ovariectomy, 1,097 women with bilateral ovariectomy and, for comparison, 2,390 women who had not undergone ovariectomy. All women were followed until their deaths or until the end of the study, which was staggered between 2001 and 2006, via a combination of interviews with the women or a surviving relative, medical records and death certificates. A unique strength of this study, according to the investigators, was a 25- to 30-year median follow-up time. A total of 1,292 women
died during the follow-up; 33 of them died after undergoing bilateral ovariectomy for cancer prevention before age 45. Only a long-term study such as this can reveal these changes in death rates, says Dr. Rocca.

In the United States, 1.2 million ovariectomies are performed annually. Half are unilateral, in which one ovary is removed, and in the other half both ovaries (bilateral) are removed. Half of bilateral ovariectomies are prophylactic -- done to prevent the possibility of future ovarian cancer (approximately 300,000 women per year). The American Cancer Society has estimated approximately 20,000 new cases of ovarian cancer will occur in 2006, and approximately 15,000 women will die from the disease this year.

Chronic stress agitates ovarian cancer

Mon, 24 Jul 2006 23:22:00 PST

( from http://www.rxpgnews.com ) When mice with ovarian cancer are stressed, their tumors grow and spread more quickly, but that effect can be blocked using a medication commonly prescribed for heart disease, according to a preclinical study by researchers at The University of Texas M. D. Anderson Cancer Center.

The finding, published in the journal Nature Medicine, now available on-line, provides the first measurable link between psychological stress and the biological processes that make ovarian tumors grow and spread. Specifically, the researchers showed that stress hormones bind to receptors directly on tumor cells and, in turn, stimulate new blood vessel growth and other factors that lead to faster and more aggressive tumors.

"This study provides a new understanding of how chronic stress and stress factors drive tumor growth," says Anil Sood, M.D., associate professor of gynecologic oncology and cancer biology and director of ovarian cancer research.

In fact, when the researchers blocked the stress hormone receptors in their experimental system using a heart disease drug called propranolol, also known as a "beta blocker," they were able to stop the negative effects of stress on tumor growth. The researchers used the beta blocker because the same hormone receptors, called beta adrenergic receptors, are found in the heart and normally work to maintain blood flow.

"The concept of stress hormone receptors directly driving cancer growth is very new," says Sood, the study's senior author. "Not much had been known about how often these receptors are expressed in cancer, and more importantly, whether they had any functional significance. Our research opens a new area of investigation."

The research began when Sood and his colleague Susan Lutgendorf found an association between ovarian cancer patients who reported high levels of stress in their lives and an increase in a factor that stimulates blood vessel growth in tumors. By contrast, patients who had more social support in their lives had lower levels of this factor. Sood wondered if hormones associated with chronic stress might affect how cancers grow.

Sood's research team, led by investigators Premal Thaker, M.D., Liz Han, M.D., and Aparna Kamat, M.D., in the Department of Gynecologic Oncology, developed a mouse model of ovarian cancer to study the link. In their experiments, the researchers confined the mice in a small space for zero, two or six hours during the day.

The confinement caused the mice to produce the same stress hormones as humans produce when they are under stress. These beta adrenergic hormones are sometimes called the "fight-or-flight" hormones because they are released when people are fearful or threatened, and are also responsible for causing the heart to beat harder and faster.

Sood and his colleagues found that, surprisingly, cancer cells make receptors for these hormones on their surface and that when these receptors are activated they set in motion a chain of events that leads to formation of new blood vessels that feed tumors, a process called angiogenesis. New blood vessel formation is known to allow tumors to grow and spread more rapidly.

"We were quite surprised to find these beta adrenergic receptors on ovarian cancer cells," says Sood. "In fact, we found them in 17 of 19 ovarian cancer cell lines we tested."

After three weeks, the researchers measured the number and size of tumors in the mice. The number of tumors was 2.5 times greater in the mice that had been in the 2-hour stress group and 3.6 times greater in the 6-hour stress group compared to the mice with no stress. In addition, tumor growth was confined in the no-stress mice, but had spread to the liver or spleen in half of the stressed mice.

In additional experiments, the researchers gave the stressed mice propranolol, which blocked the effect of stress hormones. The medication completely neutralized the effect of stress on tumor growth," says Sood.

"Beta blockers have been shown to be protective against cardiac disease," he says. "No one has studied their effect on chronic stress as it relates to cancer in humans. There is a lot of interest now in this area of combining behavioral interventions to reduce stress, as well as using beta blockers in cancer patients."

Acetaminophen may lower ovarian cancer risk

Mon, 10 Jul 2006 20:47:00 PST

( from http://www.rxpgnews.com ) Regular intake of acetaminophen, found in several painkillers, may cut ovarian cancer risk in women, but scientists add that the findings need to be confirmed.

Women who regularly use acetaminophen may be 30 percent less likely to develop ovarian cancer than those who use the drug rarely or not at all.

Acetaminophen is an active ingredient found in several painkillers, including Tylenol.

Ovarian cancer is considered as the most fatal gynaecological cancer, largely because doctors do not have a good screening method to detect the disease in its early stages, said Bonovas in the July's issue of the British Journal of Clinical Pharmacology.

However, the researchers have advised women against taking acetaminophen immediately. The possible link between acetaminophen use and reduced ovarian cancer risk 'cannot yet be regarded as one that would prompt a public health recommendation,' noted Bonovas.

He said that the new findings need to be confirmed and much more information should be gathered before officially recommending the drugs.

Ginger could help fight ovarian cancer

Tue, 18 Apr 2006 08:21:00 PST

( from http://www.rxpgnews.com ) Ginger could kill ovarian cancer cells and may help fight the disease, says a new study but researchers warn more work is required to draw a firm conclusion.

Rebecca Liu and other researchers at the University of Michigan used ginger powder, similar to what is sold in shops, which they dissolved in a solution and applied to ovarian cancer cells.

They found it caused the cells to die in all the tests done, reported the online edition of BBC News.

The tests demonstrated two types of death - apoptosis, which is essentially cell suicide, and autophagy, a kind of self-digestion.

"Most ovarian cancer patients develop recurrent disease that eventually becomes resistant to standard chemotherapy, which is associated with apoptosis.

"If ginger can cause autophagic cell death in addition to apoptosis, it may circumvent resistance to conventional chemotherapy," Liu said.

However the researchers warned the results were very preliminary and they plan to test whether they can obtain similar results in animal studies.

"This study doesn't mean that people should dash down to the supermarket and stockpile ginger."

"We still don't know whether ginger, in any form, can prevent or treat cancers in animals or people."

Henry Scowcroft, science information officer for Cancer Research UK, said previous research had shown that ginger extract can stop cancer cell growing so it was possible that ginger could form the basis of a new drug.

Ginger is already known to ease nausea and control inflammation.

Multimarker assay for ovarian cancer most promising to date

Mon, 03 Apr 2006 06:57:00 PST

( from http://www.rxpgnews.com ) The search for a specific protein that could help diagnose ovarian cancer in its early stages has for years eluded researchers who are seeking a reliable and accurate test for the disease. Instead of searching for a single protein, researchers at the University of Pittsburgh School of Medicine used a new technology to analyze a large number of proteins, or potential biomarkers, from a very small sample of serum from women with ovarian cancer. They identified a combination of several biomarkers that could help detect the disease much earlier than it is currently being diagnosed, according to findings presented at the annual meeting of the American Association for Cancer Research, April 1 to 5 at the Washington Convention Center in Washington, D.C.

"One of the most challenging problems with ovarian cancer is that we lack a reliable and accurate test that can detect it early when it is most responsive to treatment," said Anna E. Lokshin, Ph.D., lead investigator and assistant professor of medicine and pathology at the University of Pittsburgh School of Medicine. "By the time women are diagnosed, their cancers have already spread and are extremely difficult to treat successfully. To improve the long-term outcome for women diagnosed with ovarian cancer, we sought to identify a panel of proteins that could signify the presence of early disease."

In the study, Pitt researchers took advantage of a novel technology called LapMAP that is able to analyze multiple proteins in a single drop of blood or serum. They tested 450 serum samples for 46 biomarkers that had previously been correlated with ovarian cancer and were able to identify a multi-marker panel, comprised of 20 proteins that correctly recognized more than 98 percent of serum samples from women with ovarian cancer, offering higher diagnostic power than any other published assay for ovarian cancer.

"Through further examination, our goal is to develop this screening assay into a diagnostic test to improve the early detection of ovarian cancer and to monitor therapeutic response and recurrence in women with the disease," said Dr. Lokshin.

Ovarian cancer will be diagnosed in 22,000 women in the U.S. this year alone. Despite aggressive surgery and chemotherapy approaches, the prognosis for ovarian cancer has been poor since the majority of women have advanced disease at the time it is detected most women have a life expectancy of only three to four years after their diagnoses.

Latest blood testing technology for detecting epithelial ovarian cancer

Thu, 23 Feb 2006 20:45:00 PST

( from http://www.rxpgnews.com ) Yale University Office of Cooperative Research today announced that it has granted an exclusive license agreement with Laboratory Corporation of America Holdings (LabCorp) for the commercialization of the university's blood testing technology for epithelial ovarian cancer (EOC).

In the United States, EOC is the fourth most common cancer in women, and the leading cause of gynecologic cancer death. EOC affects approximately 25,000 women each year, and more than 16,000 will die from the disease.

The Yale technology for EOC is based on a collection of known serum proteins associated with cancer biology. Each protein marker is analyzed using a routine ELISA assay, and the results evaluated using a score system.

Research, led by Gil Mor, MD, associate professor of obstetrics, gynecology and reproductive sciences at Yale, was published on the technology in 2005. Statistical analyses on preliminary sample sets of a population of 206 women, including 24 patients with early stage (I/II) EOC and 76 with later stage (III/IV) EOC, showed a higher sensitivity and specificity than currently available tests, as well as a positive predictive value. Yale expects to conduct additional clinical studies on the test technology prior to its commercial introduction by LabCorp.

"Ovarian cancer is one of the most difficult cancers to detect, especially in the earliest stages when it is more treatable," said Myla P. Lai-Goldman, M.D., Executive Vice President, Chief Scientific Officer and Medical Director of LabCorp. "LabCorp continues to dedicate resources to identifying and commercializing tests to help discriminate earlier between disease-free and cancer patients."

Intraperitoneal chemotherapy improves survival in ovarian cancer patients

Sun, 22 Jan 2006 22:44:00 PST

( from http://www.rxpgnews.com ) 50-year-old method for delivering chemotherapy directly into the abdomen is making a comeback as investigators have found that it increases survival - by more than a year - in some women with advanced ovarian cancer. Results from a seven-year study of more than 400 patients nationwide are published in the January 5 issue of the New England Journal of Medicine.

Investigators randomly grouped women with newly diagnosed stage III ovarian cancer into two categories: those who would get all chemotherapy intravenously or those who would get chemotherapy both intravenously and through a spaghetti-like tube called a catheter that was inserted directly into the abdomen.

"The catheter allows us to bathe the entire abdominal area with a high concentration of chemotherapy for a long period of time, which appears to be better at destroying lingering cancer cells," says Deborah Armstrong, M.D., associate professor at the Johns Hopkins Kimmel Cancer Center and principal investigator for the study, which was conducted by the Gynecologic Oncology Group. While the abdominal area is the main site for ovarian cancer spread, Armstrong says that the intravenous round of chemotherapy is needed to catch cancer cells that may have spread outside the abdomen.

Overall survival for 205 patients receiving abdominal (or intraperitoneal) chemotherapy in the study was an average of 65.6 months, a 25 percent improvement over the intravenous-only group (49.7 months) of 210 patients. Similarly, relapse-free survival for those receiving intraperitoneal chemo was 23.8 months compared with 18.3 months for the intravenous-alone group, a 20 percent improvement.

"This is a significant improvement in survival for women with this disease, which is most often diagnosed at an advanced stage," notes Armstrong.

Side effects, such as suppressed blood counts and neurological problems, were significantly worse for the group receiving intraperitoneal (IP) chemotherapy. They reported poorer quality of life during their treatment. However, investigators noted that, one year later, patients in the IP group were on par with those only getting intravenous chemo. Nine patients died due to complications of the treatments; five from receiving IP chemotherapy and four from intravenous.

With these study results, the team of investigators supported by the national Gynecologic Oncology Group now can recommend IP therapy as the new standard for many women with ovarian cancer. According to Armstrong, many institutions have already adopted this practice.

Armstrong believes that some clinicians might be deterred by cost and lack of familiarity with IP. "We haven't done a cost analysis, but we expect IP therapy to be more expensive than intravenous - more drug and more staff time," she said.

Patients with adhesions or surgical complications, poor kidney function, and those who have had the left side of their colon removed during surgery are not ideal candidates for IP therapy.

It also is not clear whether the procedure has any benefit for recurrent disease or patients with large amounts of residual disease after surgery.

"The first and most important step is good surgery," says Robert Bristow, M.D., director of the Johns Hopkins Ovarian Cancer Center. "If you don't start with a surgeon specializing in gynecologic oncology who can effectively remove most of the tumor, then intraperitoneal chemotherapy may not work."

According to Armstrong, fewer than 50 percent of U.S. women with ovarian cancer seek a gynecologic oncology specialist for their surgery despite research showing better outcomes for this group.

IP chemotherapy was first studied half a century ago for colon cancer but never gained popularity for ovarian cancer despite several studies that hinted at survival benefits. The benefits were overshadowed by the promise of new chemotherapy drugs such as paclitaxel, one of the chemo drugs used in Armstrong's study.

The second chemotherapy agent used in the current study was cisplatin, a drug which most clinicians bypass in favor of carboplatin, a faster and better tolerated drug. But since it does not appear to penetrate tumors as well, most believe that carboplatin is not currently a drug-of-choice for IP therapy.

"Modern dosing techniques may reveal that may not be true, and we're conducting an early study of IP therapy with carboplatin," says Armstrong. Some investigators are also studying ways to add new agents that are highly specific for cancer cells into the IP regimen.

This study was funded by the Gynecologic Oncology Group.

In addition to Armstrong, authors include Brian Bundy, Ph.D., from the Gynecologic Oncology Group and Roswell Park Cancer Institute; Lari Wenzel, M.D., from the University of California at Irvine; Helen Q. Huang, M.D., from the Gynecologic Oncology Group; Rebecca Baergen, M.D., from the New-York Presbyterian Hospital; Shashikant Lele, M.D., from the Roswell Park Cancer Institute; Larry J. Copeland, M.D., from Ohio State University; Joan L. Walker, M.D., from the University of Oklahoma; and Robert A. Burger, M.D., from the University of California, Irvine.

Armstrong DK, Bundy B, Wenzel L, Huang HQ, Baergen R, Lele S, Copeland LJ, Walker JL, Burger RA. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. NEJM, January 5, 2006, Vol. 354, Issue No. 1; pgs.34-43.

Tea Drinking Reduces Risk of Ovarian Cancer

Tue, 13 Dec 2005 06:51:00 PST

( from http://www.rxpgnews.com ) Evidence from laboratory studies indicates that green and black tea preparations may protect against various cancers. But few epidemiological studies have examined the relationship specifically between tea consumption and the risk of ovarian cancer, according to background information in the article.

Women who drank less than one cup of tea per day had an 18 percent lower risk of ovarian cancer than non-drinkers. The risk was 24 percent lower for women who drank one cup of tea per day.

Susanna C. Larsson, M.Sc., and Alicja Wolk, D.M.Sc., of the National Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden, prospectively examined the association between tea consumption and the risk of ovarian cancer in 61,057 women, aged 40 to 76, who were participants in the population-based Swedish Mammography Cohort. Participants completed a validated 67-item food frequency questionnaire at enrollment between 1987 and 1990, and were followed for cancer incidence through December 2004. At baseline, 68 percent of the participants reported drinking tea (mainly black tea) at least once per month. During an average follow-up of 15.1 years, 301 women were diagnosed as having invasive epithelial ovarian cancer.

"We observed a 46 percent lower risk of ovarian cancer in women who drank two or more cups of tea per day compared with non-drinkers," the authors report. "Each additional cup of tea per day was associated with an 18 percent lower risk of ovarian cancer."

"This association does not depend on lower coffee consumption among women with high tea consumption; coffee is not associated with ovarian cancer risk in this cohort," the authors write.

"In summary, our results from a large population-based cohort of Swedish women suggest that tea consumption may lower the risk of ovarian cancer," the authors conclude. "Because prospective data on this relationship are scarce, our findings need confirmation by future studies."

PKCi can be used as a potent predictive test in ovarian cancer

Tue, 23 Aug 2005 20:58:00 PST

( from http://www.rxpgnews.com ) Researchers at The University of Texas M. D. Anderson Cancer Center report they have discovered a potential oncogene in ovarian cancer, which is the leading cause of gynecological cancer death in U.S. women.

They say that levels of the protein produced by this suspected oncogene, known as atypical protein kinase C iota (PKCi), in combination with a second protein, Cyclin E, strongly predict outcome in non-serous ovarian cancer, which accounts for 40 percent of ovarian cancer cases.

They further report PKCi is over-expressed in serous ovarian cancer, which makes up the remaining 60 percent of ovarian cancer cases.

Based on these findings, published in the early edition of the Proceedings of the National Academy of Sciences (PNAS), the week of Aug. 22, 2005, the researchers suggest that PKCi as well as the second protein, Cyclin E, could be used as a powerful predictive test for non-serous ovarian cancer. They also say that an agent that inhibits PKCi might offer a novel therapy for both forms of the cancer, which is difficult to treat in advanced stages.

This study is the first to find that PKCi plays a role in ovarian cancer, says the study's principal investigator Gordon Mills, M.D., Ph.D., a professor and chair of the Department of Molecular Therapeutics.

More than that, he says, "this is the first direct proof that over-expression of PKCi is sufficient to produce proliferation in ovarian cancer, and thus acts as an oncogene."

Mills and the research team, which includes investigators from Lawrence Berkeley National Laboratory and the University of Wisconsin, believe that over-expression of PKCi triggers excess production of Cyclin E, which is known to play a role in cancer growth.

PKCi is a member of a family of PKC kinase proteins that regulates cell-to-cell communication and spatial orientation. While some members of this large family have been associated with cancer, PKCi had not before this study.

Researchers say that PKCi and Cyclin E together contribute to the aggressiveness of ovarian cancer because high levels of the protein are associated with reduced survival. "This is the strongest predictive combination of markers to determine behavior of ovarian cancer yet found," Mills says.

Studying more than 400 tumor biopsies, they found PKCi over-expression in all samples of serous ovarian cancer, and that elevated levels of PKCi and Cyclin E corresponded to a worsening prognosis in women with non-serous ovarian cancer.

Specifically, researchers found that patients with non-serous ovarian cancer whose tumor samples showed low levels of the protein had a chance of long-term survival that was greater than 85 percent. But the chance of long-term survival in patients whose cancer showed high levels of both proteins fell to less than 15 percent.

Mills, who heads M. D. Anderson's Kleberg Center for Molecular Markers, says the findings represent a case in which "the patient's tumor is teaching us what is important.

"Cancer is a disease of genes," he says. "If we can understand what the genetic aberrations are in cancer, and how they work together to cause a cancer or change its progression, then we can develop better ways of identifying a prognosis, predict response to therapy and identify new targets."

To let the tumor "talk," researchers used a technique known as comparative genomic hybridization which measured changes at the DNA level globally in tumors. It reviewed and compared the human genome in normal versus cancerous cells and found an area of constant genomic change in over 200 samples of ovarian cancer. Further probing found an area on chromosome 3 that was abnormal in the majority of ovarian cancer patients, Mills says.

They identified the PKCi gene as potentially contributing to this change and then turned to a "model organism," the fruit fly, to understand why PKCi could contribute to ovarian cancer. Fruit flies are used in this kind of research, Mills says, because "85 percent of all known human cancer genes have a corresponding gene in these organisms."

Researchers found that in fruit flies, PKCi increased the levels of Cyclin E and cell proliferation. "We then went back to our patient samples and found that those with low levels of PKCi and Cyclin E have a remarkably good outcome, while the opposite is true for higher levels," Mills says. "That offers us both a hope that PKCi can be used as a potent predictive test as well as a possible new way to treat the cancer."

Ovarian Cancer: Can We Make the Clinical Diagnosis Earlier?

Mon, 22 Aug 2005 15:21:00 PST

( from http://www.rxpgnews.com ) Many women diagnosed with ovarian cancer actually complained of symptoms of the disease at least four months before they were diagnosed, according to a new study to be published in the October 1, 2005 issue of CANCER (http://www.interscience.wiley.com/cancer-newsroom), a peer-reviewed journal of the American Cancer Society. Although patient complaints of abdominal pain and swelling are not specific for ovarian cancer, the researchers found that only about one quarter of women with these symptoms underwent pelvic imaging, or other tests to diagnose ovarian cancer, in a timely manner.

Ovarian cancer has been thought of as a silent killer, coming to the attention of physicians only at its late stages when prognosis is poor. Adding to ovarian cancer's deadly pattern is that it is a fast growing tumor, progressing from early to advanced disease in as little time as a year. There has been increasing evidence for this poorly studied disease to indicate patients may exhibit symptoms many months before advanced disease and diagnosis occurs.

Lloyd H. Smith, M.D., Ph.D. from the University of California, Davis Medical Center in Sacramento and colleagues compared diagnosis codes and claims for diagnostic procedures among 1,985 elderly women with ovarian cancer, 6,024 elderly women with localized breast cancer, and 10,941 age-matched Medicare-enrolled women without cancer.

As early as 12 months before diagnosis, women with ovarian cancer were at least twice as likely to present to a physician with abdominal swelling or pelvic pain. As early as nine months before diagnosis, women with ovarian cancer were also more likely to complain of abdominal pain. Overall, about 40 percent of these women had physician claims indicating one or more visits for abdominal or pelvic symptoms between 36 and 4 months before their ovarian cancer was diagnosed.

Only 25 percent of ovarian cancer patients had diagnostic pelvic imaging or CA125 serum tests during the period from 36 to 4 months before diagnosis. Most received abdominal imaging or diagnostic gastrointestinal studies, which would be less likely to help establish the correct diagnosis. By contrast, 54 percent of ovarian cancer patients received pelvic imaging or CA125 serum testing within 3 months before their ovarian cancer was diagnosed.

"Our findings suggest that ovarian cancer could be diagnosed earlier in some patients whose diagnosis is currently delayed by at least 4 months because physicians order abdominal imaging or perform gastrointestinal procedures before they order a test more likely to diagnose ovarian cancer, such as pelvic imaging and/or CA125," conclude the authors.

km23 protein may be early warning for ovarian cancer

Sun, 14 Aug 2005 14:24:00 PST

( from http://www.rxpgnews.com ) Penn State College of Medicine researchers have found a signal that could lead to earlier detection and treatment of ovarian cancer.

The Penn State team of scientists led by principal investigator Kathleen M. Mulder, Ph.D., professor of pharmacology, and working in conjunction with a researcher from the Center for Cancer Research, National Cancer Institute in Bethesda, Md., studied "km23," a protein that helps to direct protein traffic in the cell. Mulder's team has found that at least 42 percent of ovarian cancer patient tumor tissues have alterations in km23. No similar alterations in km23 were detectable in normal human tissues, suggesting that it may be both a diagnostic indicator for the development of ovarian cancer and a possible target for cancer therapies. "While only close to half of ovarian cancer patients may have defects in km23, our results are still highly significant because there is no clinically useful screening test available for detection of ovarian cancer," said Mulder.

Additional studies are under way to continue the analyses of km23 abnormalities in specimens from women with ovarian cancer, and to determine whether different km23 alterations exist in other solid tumors, such as breast and colon cancer. "The next step is to develop a screening test for early detection of the km23 alterations in the blood of ovarian cancer patients," Mulder said. In addition, studies are under way to develop drugs that would target km23 and override the defects caused by the km23 alterations in the cancer cells. "The plan is to be able to use the screening test to identify those patients who would benefit from the anti-cancer drugs we will be developing using km23 as the target," Mulder said. "In the pharmaceutical industry, this is often referred to as 'personalized medicine,' meaning that each patient can be checked for alterations in specific genes and their treatment targeted for the alterations specific to their cancer."

Epithelial ovarian cancer is often diagnosed at an advanced stage and accounts for more than 16,000 deaths annually. Despite advances in surgical techniques and chemotherapy, overall survival rates for women with ovarian cancer have not improved significantly because of late detection, often after the disease has already spread to remote organs. The identification of a potential early warning signal and a possible therapeutic target for the disease could lead to improved survival rates.

km23 is responsible, in part, for the movement of cellular proteins along microtubules, the "highways" of the cell. The cellular proteins, or "cargo," are actually driven along the microtubules by "motors" in the cell. km3 helps to connect the right cargo to the motor so that the cargo can reach its appropriate destination.

In a previous study, Mulder and her team found that the process is initiated by the binding of a factor called "TGFß" to receptors on the cell's surface. This, in turn, sends a signal to km23 telling it to attach to the motor and pick up the cargo. When km23 is altered, the cargo doesn't reach the correct destination in the cell. As a result, a traffic jam occurs, which causes chaos in the cell.

This latest study, titled "A TGFß receptor-interacting protein frequently mutated in human ovarian cancer," was published in the Aug. 1 issue of Cancer Research, http://cancerres.aacrjournals.org/.

The initiator of the journey, TGFß, has been the focus of Mulder's research program since 1988.

"TGFß is a critical regulator of cell growth and is present throughout the body," she said. "It is already known to play an important role in suppressing the growth of epithelial cells, the type of cell that gives rise to solid tumors. When the appropriate signals are not sent by TGFß, the growth of epithelial cells will not be controlled and a solid tumor can form. The alterations in km23 appear to disrupt some of the normal signals sent by TGFß."

"The km23 alterations we have identified in human ovarian tumor tissues, described in our recent report, might also be used as prognostic indicators to help physicians decide on the most appropriate treatment for each patient," Mulder said.