Older men with high-risk prostate cancer frequently are offered fewer – and less effective – choices of treatment than younger men, potentially resulting in earlier deaths, according to a new UCSF study.
The scientists found that men above age 75 with high-risk prostate cancer often are under-treated through hormone therapy or watchful waiting alone in lieu of more aggressive treatments such as surgery and radiation therapies. Instead, say the researchers, old age should not be viewed as a barrier to treatments that could lead to potential cures.
"There is a disconnect between risk and treatment decisions among older men," said senior investigator Matthew R. Cooperberg, MD, MPH. "Patient age is strongly influencing treatment decisions, so we sought to understand whether age plays a role in risk of the disease and survival. We found that under-treatment of older-men with high-risk disease might in part explain higher rates of cancer mortality in this group. There is also pervasive over-treatment of low-risk disease in this age group. Overall, treatment needs to be selected more based on disease risk and less based on chronologic age."
The study is published by the "Journal of Clinical Oncology," and is available online here.
Prostate cancer is the most common form of cancer in men and the second most common cause of cancer death after lung cancer. This year, an estimated 217,730 men will be diagnosed with the disease, and 32,050 men will die from it, reports the American Cancer Society. Moreover, prostate cancer is the most common malignancy among older men: 64 percent of new cases in the United States this year were diagnosed in men older than 65, and 23 percent in men above 75.
Yet most studies delving into optimal treatment options focus on men younger than 75. The new UCSF study is among the first to explore the relationship between age, disease risk and survival among prostate cancer patients.
The researchers studied men in the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) database, a longitudinal, observational disease registry of men with prostate cancer who were recruited from urology practices throughout the United States. At the time of the study, the database contained information on 13,805 patients.
The scientists found that older patients are more likely to have high-risk prostate cancer at the point of diagnosis, and less likely to receive potentially curative local therapy. Yet when older, high-risk men received more aggressive treatment, they had a 46 percent lower death rate compared with patients treated more conservatively with hormonal therapy or watchful waiting.
The finding, the researchers say, suggests that underuse of aggressive therapy may in part explain the higher death rates of older men with the disease.
"Age does not independently predict prostate cancer survival," said Peter R. Carroll, MD, MPH, chair of the UCSF Department of Urology and co-leader of the prostate program at the UCSF Helen Diller Family Comprehensive Cancer Center. He is a co-author of the paper. "Our findings support making treatment decisions on the basis of disease risk and life expectancy rather than on chronologic age."
The researchers note that the U.S. Preventive Services Task Force specifically recommends against screening men age 75 or older, but that position is based on studies on younger men, and furthermore does not account for health status or other diseases that the patients may have which would affect life expectancy.
"Older men with high-risk disease frequently die of prostate cancer and under-treatment might be a factor in their deaths," said Cooperberg, a prostate cancer specialist in the UCSF Department of Urology and the Helen Diller cancer center. "The notion of age as a primary determinant should be reconsidered. Patients with aggressive local disease should be offered a chance of aggressive therapy that might cure them regardless of their age."
Traditionally, Cooperberg said, physicians have feared the risks of surgery on their older patients. But for older patients with localized, high-risk disease – and a life expectancy of more than 10 years – the researchers recommend that surgical treatment and radiation be considered.
"Surgery and radiation risks do go up with age, but it may be that we are focusing too much on risk than on benefit," said Cooperberg. "We need a better balance between risk and benefit."
University of California - San Francisco
Tuesday, December 21, 2010
Thursday, December 16, 2010
PSA test better predicts cancer in men taking prostate-shrinking drug
The PSA screening test for prostate cancer is not perfect. It can indicate cancer when none is present and miss life-threatening tumors. But a new study suggests the test is more reliable in men taking dutasteride (Avodart®), a drug widely prescribed to shrink an enlarged prostate gland.
Dutasteride lowers PSA levels by about half within six months. But the researchers found that even a slight rise in PSA levels among men taking the drug was a stronger indicator of prostate cancer, particularly aggressive tumors that require early diagnosis and treatment, than rising PSA levels in men who took a placebo.
"Dutasteride stabilizes the amount of PSA that comes from enlarged prostates and low-grade cancers," says lead author Gerald Andriole, MD, the Robert Killian Royce, MD, Distinguished Professor and chief of urologic surgery at Washington University School of Medicine in St. Louis. "This enhances a rising PSA's ability to detect high-grade cancers that require early diagnosis and treatment, while reducing the discovery of tumors that are unlikely to cause harm if left untreated."
The study is now available online and will be published in January in the Journal of Urology.
The PSA test measures the amount of prostate-specific antigen in the blood. The larger a man's prostate, the more PSA he produces. Elevated levels can point to cancer. But PSA often rises naturally as men age, mainly due to benign prostatic hyperplasia (BPH), a progressive enlargement of the prostate. This leads to many false positive PSA tests for cancer. Indeed, biopsies only find cancer in about one in four men with an elevated PSA.
In the new study, the researchers looked more closely at data from a four-year trial that evaluated whether dutasteride could reduce the risk of detecting prostate cancer in men with an increased risk of the disease. The study involved 8,231 men ages 50-75 who were randomly assigned to receive a placebo or a daily 0.5 mg dose of dutasteride. The men had elevated PSA levels (2.5 ng/ml-10 ng/ml) but no evidence of cancer on biopsies performed within six months of enrolling in the trial.
Results published earlier this year in the New England Journal of Medicine showed that dutasteride reduced the risk of a prostate cancer diagnosis by 23 percent. Dutasteride appears to keep tumors small or shrink them to the point that they are less likely to be detected by a biopsy, says Andriole, who led the steering committee that oversaw the earlier trial.
In the current analysis, the researchers looked at the performance of PSA as a marker for prostate cancer, particularly for aggressive cancer. Among men taking dutasteride, the investigators found that any subsequent rise in PSA levels over the course of the study was more likely to be linked to aggressive, high-grade tumors (Gleason score 7-10), compared to rising PSA levels in men on a placebo.
The Gleason scoring system measures tumor aggressiveness based on biopsy results and can range from 2-10, with 10 being the most aggressive.
"If a man is taking dutastride and his PSA level starts to rise, he has a higher chance of having an aggressive cancer," Andriole says. "This makes PSA a more effective screening tool for prostate cancer but even more importantly for aggressive cancer."
Over four years, PSA levels increased in 72 percent of men taking a placebo and only 29 percent of men taking dutasteride, the data show. However, there was no significant difference in high-grade tumors between the two groups.
Men taking dutasteride were almost twice as likely to have aggressive prostate cancer if their PSA levels rose, compared to men whose PSA levels went up while taking a placebo. In men with any increase in PSA, aggressive, high-grade tumors were diagnosed in 13.2 percent of those on dutasteride and 7.7 percent of those taking a placebo.
Even a slight rise in PSA levels was a more accurate predictor of aggressive tumors. Among men whose PSA levels increased one point or less, 10.3 percent of those taking dutasteride had aggressive cancer, compared with 5.4 percent taking a placebo.
That trend also held for larger increases in PSA levels. Among men whose PSA levels rose two points or more, nearly 20.9 percent of those taking dutasteride had aggressive cancer, compared with 9.8 percent taking a placebo.
In contrast, PSA levels tended to decrease or remain stable in men taking dutasteride who either had low-grade tumors or no cancer at all.
The study's authors do not suggest that men take dutasteride just to get a more accurate readout of PSA levels attributable to cancer. "However, men who are taking dutasteride can be confident that the drug does not weaken the ability of PSA to find cancer if it develops," Andriole says. "Rather, the drug enhances the ability to find cancer if PSA levels are rising."
Washington University School of Medicine
Dutasteride lowers PSA levels by about half within six months. But the researchers found that even a slight rise in PSA levels among men taking the drug was a stronger indicator of prostate cancer, particularly aggressive tumors that require early diagnosis and treatment, than rising PSA levels in men who took a placebo.
"Dutasteride stabilizes the amount of PSA that comes from enlarged prostates and low-grade cancers," says lead author Gerald Andriole, MD, the Robert Killian Royce, MD, Distinguished Professor and chief of urologic surgery at Washington University School of Medicine in St. Louis. "This enhances a rising PSA's ability to detect high-grade cancers that require early diagnosis and treatment, while reducing the discovery of tumors that are unlikely to cause harm if left untreated."
The study is now available online and will be published in January in the Journal of Urology.
The PSA test measures the amount of prostate-specific antigen in the blood. The larger a man's prostate, the more PSA he produces. Elevated levels can point to cancer. But PSA often rises naturally as men age, mainly due to benign prostatic hyperplasia (BPH), a progressive enlargement of the prostate. This leads to many false positive PSA tests for cancer. Indeed, biopsies only find cancer in about one in four men with an elevated PSA.
In the new study, the researchers looked more closely at data from a four-year trial that evaluated whether dutasteride could reduce the risk of detecting prostate cancer in men with an increased risk of the disease. The study involved 8,231 men ages 50-75 who were randomly assigned to receive a placebo or a daily 0.5 mg dose of dutasteride. The men had elevated PSA levels (2.5 ng/ml-10 ng/ml) but no evidence of cancer on biopsies performed within six months of enrolling in the trial.
Results published earlier this year in the New England Journal of Medicine showed that dutasteride reduced the risk of a prostate cancer diagnosis by 23 percent. Dutasteride appears to keep tumors small or shrink them to the point that they are less likely to be detected by a biopsy, says Andriole, who led the steering committee that oversaw the earlier trial.
In the current analysis, the researchers looked at the performance of PSA as a marker for prostate cancer, particularly for aggressive cancer. Among men taking dutasteride, the investigators found that any subsequent rise in PSA levels over the course of the study was more likely to be linked to aggressive, high-grade tumors (Gleason score 7-10), compared to rising PSA levels in men on a placebo.
The Gleason scoring system measures tumor aggressiveness based on biopsy results and can range from 2-10, with 10 being the most aggressive.
"If a man is taking dutastride and his PSA level starts to rise, he has a higher chance of having an aggressive cancer," Andriole says. "This makes PSA a more effective screening tool for prostate cancer but even more importantly for aggressive cancer."
Over four years, PSA levels increased in 72 percent of men taking a placebo and only 29 percent of men taking dutasteride, the data show. However, there was no significant difference in high-grade tumors between the two groups.
Men taking dutasteride were almost twice as likely to have aggressive prostate cancer if their PSA levels rose, compared to men whose PSA levels went up while taking a placebo. In men with any increase in PSA, aggressive, high-grade tumors were diagnosed in 13.2 percent of those on dutasteride and 7.7 percent of those taking a placebo.
Even a slight rise in PSA levels was a more accurate predictor of aggressive tumors. Among men whose PSA levels increased one point or less, 10.3 percent of those taking dutasteride had aggressive cancer, compared with 5.4 percent taking a placebo.
That trend also held for larger increases in PSA levels. Among men whose PSA levels rose two points or more, nearly 20.9 percent of those taking dutasteride had aggressive cancer, compared with 9.8 percent taking a placebo.
In contrast, PSA levels tended to decrease or remain stable in men taking dutasteride who either had low-grade tumors or no cancer at all.
The study's authors do not suggest that men take dutasteride just to get a more accurate readout of PSA levels attributable to cancer. "However, men who are taking dutasteride can be confident that the drug does not weaken the ability of PSA to find cancer if it develops," Andriole says. "Rather, the drug enhances the ability to find cancer if PSA levels are rising."
Washington University School of Medicine
Thursday, December 2, 2010
scientists discover mechanism that turns healthy cells into prostate cancer cells
A protein that is crucial for regulating the self-renewal of normal prostate stem cells, needed to repair injured cells or restore normal cells killed by hormone withdrawal therapy for cancer, also aids the transformation of healthy cells into prostate cancer cells, researchers at UCLA have found.
The findings, by researchers with the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA, may have important implications for controlling cancer growth and progression.
Done in primary cells and in animal models, the findings from the three-year study appear Dec. 2, 2010 in the early online edition of the peer-reviewed journal Cell Stem Cell.
The protein, called Bmi-1, is often up-regulated in prostate cancer, has been associated with higher grade cancers and is predictive of poor prognosis, according to previous studies. However, its functional roles in prostate stem cell maintenance and prostate cancer have been unclear, said Dr. Owen Witte, who is director of the Broad Stem Cell Research Center, a Howard Hughes Medical Institute investigator and senior author of the study.
A study of loss and gain of function in prostate stem cells indicated that Bmi-1 expression was required for self-renewal activity and maintenance of prostate stem cells with highly proliferative abilities. Loss of Bmi-1 expression blocks the self-renewal activity, protecting prostate cells from developing abnormal growth changes which can lead to cancer.
More importantly, Bmi-1 inhibition slowed the growth of an aggressive form of prostate cancer in animal models, in which the PTEN tumor suppressor gene was removed allowing the cancer to run wild, Witte said.
"We conclude by these results that Bmi-1 is a crucial regulator of self-renewal in adult prostate cells and plays important roles in prostate cancer initiation and progression," Witte said. "It was encouraging to see that inhibiting this protein slows the growth of even a very aggressive prostate cancer, because that could give us new ways to attack this disease."
UCLA stem cell researchers have been studying the mechanisms of prostate stem cells for years on the theory that the mechanism that gives the cells their unique ability to self-renew somehow gets high jacked by cancer cells, allowing the malignant cells to grow and spread. If the mechanism for self-renewal could be understood, researchers could find a way to interrupt it once it is taken over by the cancer cells, Witte said.
Rita Lukacs, a doctoral student in Witte's laboratory and first author of the study, found that Bmi-1 inhibition also stops excessive self-renewal driven by other pathways. This suggests that the Bmi-1 pathway may be dominant to other genetic controls that affect the cancer phenotype.
"Prostate cancer can be initiated by so many different mutations, if we can find a key regulator of self-renewal, we can partially control the growth of the cancer no matter what the mutation is," Lukacs said. "We're attacking the process that allows the cancer cells to grow indefinitely. This provides us an alternate way of attacking the cancer by going to the core mechanism for cancer cell self-renewal and proliferation."
Witte said future work will be centered on searching for methods to control these pathways in human prostate cancer cells.
Prostate cancer is the most frequently diagnosed non-skin cancer and the second most common cause of cancer-related deaths in men. This year alone, more than 277,000 men in the United States will be diagnosed with prostate cancer. Of those, 32,000 men will die from the disease.
University of California - Los Angeles
The findings, by researchers with the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA, may have important implications for controlling cancer growth and progression.
Done in primary cells and in animal models, the findings from the three-year study appear Dec. 2, 2010 in the early online edition of the peer-reviewed journal Cell Stem Cell.
The protein, called Bmi-1, is often up-regulated in prostate cancer, has been associated with higher grade cancers and is predictive of poor prognosis, according to previous studies. However, its functional roles in prostate stem cell maintenance and prostate cancer have been unclear, said Dr. Owen Witte, who is director of the Broad Stem Cell Research Center, a Howard Hughes Medical Institute investigator and senior author of the study.
A study of loss and gain of function in prostate stem cells indicated that Bmi-1 expression was required for self-renewal activity and maintenance of prostate stem cells with highly proliferative abilities. Loss of Bmi-1 expression blocks the self-renewal activity, protecting prostate cells from developing abnormal growth changes which can lead to cancer.
More importantly, Bmi-1 inhibition slowed the growth of an aggressive form of prostate cancer in animal models, in which the PTEN tumor suppressor gene was removed allowing the cancer to run wild, Witte said.
"We conclude by these results that Bmi-1 is a crucial regulator of self-renewal in adult prostate cells and plays important roles in prostate cancer initiation and progression," Witte said. "It was encouraging to see that inhibiting this protein slows the growth of even a very aggressive prostate cancer, because that could give us new ways to attack this disease."
UCLA stem cell researchers have been studying the mechanisms of prostate stem cells for years on the theory that the mechanism that gives the cells their unique ability to self-renew somehow gets high jacked by cancer cells, allowing the malignant cells to grow and spread. If the mechanism for self-renewal could be understood, researchers could find a way to interrupt it once it is taken over by the cancer cells, Witte said.
Rita Lukacs, a doctoral student in Witte's laboratory and first author of the study, found that Bmi-1 inhibition also stops excessive self-renewal driven by other pathways. This suggests that the Bmi-1 pathway may be dominant to other genetic controls that affect the cancer phenotype.
"Prostate cancer can be initiated by so many different mutations, if we can find a key regulator of self-renewal, we can partially control the growth of the cancer no matter what the mutation is," Lukacs said. "We're attacking the process that allows the cancer cells to grow indefinitely. This provides us an alternate way of attacking the cancer by going to the core mechanism for cancer cell self-renewal and proliferation."
Witte said future work will be centered on searching for methods to control these pathways in human prostate cancer cells.
Prostate cancer is the most frequently diagnosed non-skin cancer and the second most common cause of cancer-related deaths in men. This year alone, more than 277,000 men in the United States will be diagnosed with prostate cancer. Of those, 32,000 men will die from the disease.
University of California - Los Angeles
Genetic mutations associated with increased PSA and prostate cancer
Austrian researchers have uncovered mutations throughout the mitochondrial genome that are associated with prostate cancer. An exciting aspect of the study, published by Cell Press on December 2 in the American Journal of Human Genetics, is the association of tRNA mutations with elevated levels of prostate-specific antigen (PSA) in Austrian men diagnosed with various stages of prostate cancer.
Prostate cancer is among the most prevalent cancers diagnosed in the United States and Europe. The most common and noninvasive way to detect prostate cancer is to check PSA levels. This is a routine part of men's health checks starting around the age of 50. Elevated PSA levels indicate the possibility of prostate cancer. Prostate biopsies are used for verification of PSA results and cancer diagnosis. Treatment may include surgery, radiation, or chemotherapy. "Identifying genetic variants associated with prostate cancer and its primary biomarker is an exciting accomplishment," says Dr. Anita Kloss-Brandstätter, the lead author of this study.
Recognizing the important role mtDNA mutations have been found to play in development and progression of many types of cancer, Dr. Kloss-Brandstätter and colleagues set out to sequence the entire mitochondrial genome in 30 prostate cancer patients. "The influence of mtDNA on the origin and progression of prostate cancer is still not understood, leaving much to be discovered," says Dr. Kloss-Brandstätter. The group used a high-quality sequencing approach to detect differences in mtDNA sequence between cancerous and noncancerous tissue from the same 30 men. "It is the first study targeting the entire mitochondrial genome in prostate cancer and benign tissue from the same patient with a superior sequencing strategy," notes Dr. Kloss-Brandstätter.
By examining both the frequency and types of somatic mtDNA mutations in prostate cancer patients, Dr. Kloss-Brandstätter and colleagues were able to identify several genetic changes having clinical significance. They suggest that, "sequencing of selected mitochondrial regions will likely result in a mutation spectrum useful for prognosis." Perhaps the most striking finding of the study is the association between somatic tRNA mutations and PSA levels at diagnosis. "Patients with a somatic tRNA mutation had a significantly higher PSA value at diagnosis than did patients without a somatic tRNA mutation," explains Dr. Kloss-Brandstätter. "These findings will potentially help others monitor malignant transformation, tumor progression, and metastasis," she says.
Cell Press
Prostate cancer is among the most prevalent cancers diagnosed in the United States and Europe. The most common and noninvasive way to detect prostate cancer is to check PSA levels. This is a routine part of men's health checks starting around the age of 50. Elevated PSA levels indicate the possibility of prostate cancer. Prostate biopsies are used for verification of PSA results and cancer diagnosis. Treatment may include surgery, radiation, or chemotherapy. "Identifying genetic variants associated with prostate cancer and its primary biomarker is an exciting accomplishment," says Dr. Anita Kloss-Brandstätter, the lead author of this study.
Recognizing the important role mtDNA mutations have been found to play in development and progression of many types of cancer, Dr. Kloss-Brandstätter and colleagues set out to sequence the entire mitochondrial genome in 30 prostate cancer patients. "The influence of mtDNA on the origin and progression of prostate cancer is still not understood, leaving much to be discovered," says Dr. Kloss-Brandstätter. The group used a high-quality sequencing approach to detect differences in mtDNA sequence between cancerous and noncancerous tissue from the same 30 men. "It is the first study targeting the entire mitochondrial genome in prostate cancer and benign tissue from the same patient with a superior sequencing strategy," notes Dr. Kloss-Brandstätter.
By examining both the frequency and types of somatic mtDNA mutations in prostate cancer patients, Dr. Kloss-Brandstätter and colleagues were able to identify several genetic changes having clinical significance. They suggest that, "sequencing of selected mitochondrial regions will likely result in a mutation spectrum useful for prognosis." Perhaps the most striking finding of the study is the association between somatic tRNA mutations and PSA levels at diagnosis. "Patients with a somatic tRNA mutation had a significantly higher PSA value at diagnosis than did patients without a somatic tRNA mutation," explains Dr. Kloss-Brandstätter. "These findings will potentially help others monitor malignant transformation, tumor progression, and metastasis," she says.
Cell Press
'Watchful waiting' has a new set of eyes
A UCSF research collaboration with GE Healthcare has produced the first results in humans of a new technology that promises to rapidly assess the presence and aggressiveness of prostate tumors in real time, by imaging the tumor's metabolism.
This is the first time researchers have used this technology to conduct real-time metabolic imaging in human patients and represents a revolutionary approach to assessing the precise outlines of a tumor, its response to treatment and how quickly it is growing.
Data on the first four patients are being presented today at the Radiology Society of North America's weeklong annual conference.
The initial results validate extensive preclinical research that has linked the speed at which tumors metabolize nutrients to the aggressiveness of their growth. The new imaging technique also has been used to show early biochemical changes in animal tumors in real time as they respond to medication therapy, long before a physical change occurs.
So far, the technology has produced the same response in human patients' tumors as it did in laboratory studies, even at the lowest dose, according to Sarah Nelson, PhD, a professor of Radiology and Biomedical Imaging and a member of the California Institute for Quantitative Biosciences (QB3) at UCSF.
"This is a key milestone that could dramatically change clinical treatment for prostate cancer and many other tumors," Nelson said. "We had shown this worked in animal models and tissues samples. Now, in men, we are seeing exactly the type of results we had hoped for."
For an oncologist, that means immediate feedback on whether a patient should continue in "watchful waiting" or pursue treatment, and also whether a therapy is working, either during standard treatment or in a clinical trial.
"If we can see whether a therapy is effective in real time, we may be able to make early changes in that treatment that could have a very real impact on a patient's outcome and quality of life," said Andrea Harzstark, MD, an oncologist with the UCSF Helen Diller Family Comprehensive Cancer Center who is leading the clinical aspects of the current study.
More than 200,000 men are diagnosed with prostate cancer each year and 28,000 die from it, making it one of the most common cancers in men nationwide and also one of the leading causes of cancer death in men, according to the Centers for Disease Control.
Yet the disease ranges widely in its rate of growth and aggressiveness, according to John Kurhanewicz, PhD, a UCSF expert in prostate cancer imaging. As a result, there is great debate over the ideal strategy for treating the disease, he said, leaving patients with a difficult and potentially life-changing decision over how aggressively to respond to the disease.
"This test could give both physicians and patients the information they need to make that decision," said Kurhanewicz, whose work with Dan Vigneron, PhD, and their colleagues from the UCSF Department of Radiology and Biomedical Imaging first linked a prostate tumor's production of lactate to tumor aggressiveness. Other researchers also have linked that lactate production to tumor aggressiveness and response to therapy in other cancers.
The method uses compounds involved in normal tissue function – in this case, pyruvate, which is a naturally occurring by-product of glucose, and lactate, also known as lactic acid – and uses newly developed equipment to increase the visibility of those compounds by a factor of 50,000 in a magnetic resonance imaging (MRI) scanner.
That process requires pyruvate to be prepared in a strong magnetic field at a temperature of minus 272O C, then rapidly warmed to body temperature and transferred to the patient in an MRI scanner before the polarization decays back to its native state.
The result is a highly defined and clear image of the tumor's outline, as well as a graph of the amount of pyruvate in the tumor and the rate at which the tumor converts the pyruvate into lactate.
The sterile production process requires a dedicated clinical pharmacist with the knowledge of both quality control and of clinical practice. As the birthplace of the field of clinical pharmacy and one of only a handful of schools nationwide with drug production expertise, the UCSF School of Pharmacy and contributions of Marcus Ferrone, PharmD, and his colleagues in the Drug Products Services Laboratory were integral to this process.
The procedure must take place within minutes, which meant integrating a clean room into the scanning facility. QB3 also worked with GE Healthcare in designing Byers Hall, in which the Surbeck Laboratory of Advanced Imaging is housed, to accommodate the extremely strong magnetic field of the MRI scanner and enable time-sensitive experiments.
"All of that insight is why we moved this technology to Northern California," said Jonathan Murray, general manager, Metabolic Imaging at GE Healthcare. "This is a huge accomplishment UCSF and QB3 have achieved. They brought together the best engineering from UC Berkeley and the best bioscience and pharmacy knowledge from UCSF, and are now demonstrating the technology in a world-renowned academic medical center. We are delighted with the speed of progress of this collaboration. The science is very exciting."
The first trial involves men with prostate cancer involved in the "watchful waiting" phase of treatment, Nelson said. Future studies will directly compare these data with the results from surgically removed tumors and will look at how specific therapies change tumor metabolism. UCSF also will be studying the process for use in brain tumor patients.
The project's funding through the National Institute of Biomedical Imaging and Bioengineering, in the National Institutes of Health, was critical in adapting this technology for humans and developing new ways to obtain the MR metabolic imaging data. The project received further support from the American Recovery & Reinvestment Act and the UC Discovery Program.
Initial development of this instrumentation and its demonstration of proof of principle was conducted by Jan Henrik Ardenkjaer-Larsen, Klaes Golman and other colleagues from across GE. UCSF customized that principle and obtained the Investigational New Drug (IND) approval from the Food and Drug Administration to use the hyperpolarized pyruvate in humans.
These concepts are still investigational and not being offered for sale, nor have they been cleared or approved by the FDA for commercial availability.
University of California - San Francisco
This is the first time researchers have used this technology to conduct real-time metabolic imaging in human patients and represents a revolutionary approach to assessing the precise outlines of a tumor, its response to treatment and how quickly it is growing.
Data on the first four patients are being presented today at the Radiology Society of North America's weeklong annual conference.
The initial results validate extensive preclinical research that has linked the speed at which tumors metabolize nutrients to the aggressiveness of their growth. The new imaging technique also has been used to show early biochemical changes in animal tumors in real time as they respond to medication therapy, long before a physical change occurs.
So far, the technology has produced the same response in human patients' tumors as it did in laboratory studies, even at the lowest dose, according to Sarah Nelson, PhD, a professor of Radiology and Biomedical Imaging and a member of the California Institute for Quantitative Biosciences (QB3) at UCSF.
"This is a key milestone that could dramatically change clinical treatment for prostate cancer and many other tumors," Nelson said. "We had shown this worked in animal models and tissues samples. Now, in men, we are seeing exactly the type of results we had hoped for."
For an oncologist, that means immediate feedback on whether a patient should continue in "watchful waiting" or pursue treatment, and also whether a therapy is working, either during standard treatment or in a clinical trial.
"If we can see whether a therapy is effective in real time, we may be able to make early changes in that treatment that could have a very real impact on a patient's outcome and quality of life," said Andrea Harzstark, MD, an oncologist with the UCSF Helen Diller Family Comprehensive Cancer Center who is leading the clinical aspects of the current study.
More than 200,000 men are diagnosed with prostate cancer each year and 28,000 die from it, making it one of the most common cancers in men nationwide and also one of the leading causes of cancer death in men, according to the Centers for Disease Control.
Yet the disease ranges widely in its rate of growth and aggressiveness, according to John Kurhanewicz, PhD, a UCSF expert in prostate cancer imaging. As a result, there is great debate over the ideal strategy for treating the disease, he said, leaving patients with a difficult and potentially life-changing decision over how aggressively to respond to the disease.
"This test could give both physicians and patients the information they need to make that decision," said Kurhanewicz, whose work with Dan Vigneron, PhD, and their colleagues from the UCSF Department of Radiology and Biomedical Imaging first linked a prostate tumor's production of lactate to tumor aggressiveness. Other researchers also have linked that lactate production to tumor aggressiveness and response to therapy in other cancers.
The method uses compounds involved in normal tissue function – in this case, pyruvate, which is a naturally occurring by-product of glucose, and lactate, also known as lactic acid – and uses newly developed equipment to increase the visibility of those compounds by a factor of 50,000 in a magnetic resonance imaging (MRI) scanner.
That process requires pyruvate to be prepared in a strong magnetic field at a temperature of minus 272O C, then rapidly warmed to body temperature and transferred to the patient in an MRI scanner before the polarization decays back to its native state.
The result is a highly defined and clear image of the tumor's outline, as well as a graph of the amount of pyruvate in the tumor and the rate at which the tumor converts the pyruvate into lactate.
The sterile production process requires a dedicated clinical pharmacist with the knowledge of both quality control and of clinical practice. As the birthplace of the field of clinical pharmacy and one of only a handful of schools nationwide with drug production expertise, the UCSF School of Pharmacy and contributions of Marcus Ferrone, PharmD, and his colleagues in the Drug Products Services Laboratory were integral to this process.
The procedure must take place within minutes, which meant integrating a clean room into the scanning facility. QB3 also worked with GE Healthcare in designing Byers Hall, in which the Surbeck Laboratory of Advanced Imaging is housed, to accommodate the extremely strong magnetic field of the MRI scanner and enable time-sensitive experiments.
"All of that insight is why we moved this technology to Northern California," said Jonathan Murray, general manager, Metabolic Imaging at GE Healthcare. "This is a huge accomplishment UCSF and QB3 have achieved. They brought together the best engineering from UC Berkeley and the best bioscience and pharmacy knowledge from UCSF, and are now demonstrating the technology in a world-renowned academic medical center. We are delighted with the speed of progress of this collaboration. The science is very exciting."
The first trial involves men with prostate cancer involved in the "watchful waiting" phase of treatment, Nelson said. Future studies will directly compare these data with the results from surgically removed tumors and will look at how specific therapies change tumor metabolism. UCSF also will be studying the process for use in brain tumor patients.
The project's funding through the National Institute of Biomedical Imaging and Bioengineering, in the National Institutes of Health, was critical in adapting this technology for humans and developing new ways to obtain the MR metabolic imaging data. The project received further support from the American Recovery & Reinvestment Act and the UC Discovery Program.
Initial development of this instrumentation and its demonstration of proof of principle was conducted by Jan Henrik Ardenkjaer-Larsen, Klaes Golman and other colleagues from across GE. UCSF customized that principle and obtained the Investigational New Drug (IND) approval from the Food and Drug Administration to use the hyperpolarized pyruvate in humans.
These concepts are still investigational and not being offered for sale, nor have they been cleared or approved by the FDA for commercial availability.
University of California - San Francisco
Monday, November 29, 2010
New prostate cancer imaging shows real-time tumor metabolism
A UCSF research collaboration with GE Healthcare has produced the first results in humans of a new technology that promises to rapidly assess the presence and aggressiveness of prostate tumors in real time, by imaging the tumor's metabolism.
This is the first time researchers have used this technology to conduct real-time metabolic imaging in a human patient and represents a revolutionary approach to assessing the precise outlines of a tumor, its response to treatment and how quickly it is growing.
Data on the first four patients will be presented on Dec. 2 at the Radiology Society of North America's weeklong annual conference.
The initial results validate extensive preclinical research that has linked the speed at which tumors metabolize nutrients to the aggressiveness of their growth. The new imaging technique also has been used to show early biochemical changes in animal tumors in real time as they respond to medication therapy, long before a physical change occurs.
So far, the technology has produced the same response in human patients' tumors as it did in laboratory studies, even at the lowest dose, according to Sarah Nelson, PhD, a professor of Radiology and Biomedical Imaging and a member of the California Institute for Quantitative Biosciences (QB3) at UCSF.
"This is a key milestone that could dramatically change clinical treatment for prostate cancer and many other tumors," Nelson said. "We had shown this worked in animal models and tissues samples. Now, in men, we are seeing exactly the type of results we had hoped for."
For an oncologist, that means immediate feedback on whether a patient's therapy is working, either during standard treatment or in a clinical trial.
"If we can see whether a therapy is effective in real time, we may be able to make early changes in that treatment that could have a very real impact on a patient's outcome and quality of life," said Andrea Harzstark, MD, an oncologist with the UCSF Helen Diller Family Comprehensive Cancer Center who is leading the clinical aspects of the current study.
More than 200,000 men are diagnosed with prostate cancer each year and 28,000 die from it, making it one of the most common cancer in men nationwide and also one of the leading causes of cancer death in men, according to the Centers for Disease Control.
Yet the disease ranges widely in its rate of growth and aggressiveness, according to John Kurhanewicz, PhD, a UCSF expert in prostate cancer imaging. As a result, there is great debate over the ideal strategy for treating the disease, he said, leaving patients with a difficult and potentially life-changing decision over how aggressively to respond to the disease.
"This test could give both physicians and patients the information they need to make that decision," said Kurhanewicz, whose work with Dan Vigneron, PhD, and their colleagues from the UCSF Department of Radiology and Biomedical Imaging first linked a prostate tumor's production of lactate to tumor aggressiveness. Other researchers also have linked that lactate production to tumor aggressiveness and response to therapy in other cancers.
The method uses compounds involved in normal tissue function – in this case, pyruvate, which is a naturally occurring by-product of glucose, and lactate, also known as lactic acid – and uses newly developed equipment to increase the visibility of those compounds by a factor of 50,000 in a magnetic resonance imaging (MRI) scanner.
That process requires pyruvate to be prepared in a strong magnetic field at a temperature of minus 272O C, then rapidly warmed to body temperature and transferred to the patient in an MRI scanner before the polarization decays back to its native state.
The result is a highly defined and clear image of the tumor's outline, as well as a graph of the amount of pyruvate in the tumor and the rate at which the tumor converts the pyruvate into lactate.
The sterile production process requires a dedicated clinical pharmacist with the knowledge of both quality control and of clinical practice. As the birthplace of the field of clinical pharmacy and one of only a handful of schools nationwide with drug production expertise, the UCSF School of Pharmacy and contributions of Marcus Ferrone, PharmD, and his colleagues in the Drug Products Services Laboratory were integral to this process.
The procedure must take place within minutes, which meant integrating a clean room into the scanning facility. QB3 also worked with GE Healthcare in designing Byers Hall, in which the Surbeck Laboratory of Advanced Imaging is housed, to accommodate the extremely strong magnetic field of the MRI scanner and enable time-sensitive experiments.
"All of that insight is why we moved this technology to Northern California," said Jonathan Murray, general manager, Metabolic Imaging at GE Healthcare. "This is a huge accomplishment UCSF and QB3 have achieved. They brought together the best engineering from UC Berkeley and the best bioscience and pharmacy knowledge from UCSF, and are now demonstrating the technology in a world-renowned academic medical center. We are delighted with the speed of progress of this collaboration. The science is very exciting."
The first trial involves men with prostate cancer involved in the "watchful waiting" phase of treatment, Nelson said. Future studies will directly compare these data with the results from surgically removed tumors and will look at how specific therapies change tumor metabolism. UCSF also will be studying the process for use in brain tumor patients.
The project's funding through the National Institute of Biomedical Imaging and Bioengineering, in the National Institutes of Health, was critical in adapting this technology for humans and developing new ways to obtain the MR metabolic imaging data. The project received further support from the American Recovery & Reinvestment Act and the UC Discovery Program.
Initial development of this instrumentation and its demonstration of proof of principle was conducted by Jan Henrik Ardenkjaer-Larsen, Klaes Golman and other colleagues from across GE. UCSF customized that principle and obtained the Investigational New Drug (IND) approval from the Food and Drug Administration to use the hyperpolarized pyruvate in humans.
University of California - San Francisco
This is the first time researchers have used this technology to conduct real-time metabolic imaging in a human patient and represents a revolutionary approach to assessing the precise outlines of a tumor, its response to treatment and how quickly it is growing.
Data on the first four patients will be presented on Dec. 2 at the Radiology Society of North America's weeklong annual conference.
The initial results validate extensive preclinical research that has linked the speed at which tumors metabolize nutrients to the aggressiveness of their growth. The new imaging technique also has been used to show early biochemical changes in animal tumors in real time as they respond to medication therapy, long before a physical change occurs.
So far, the technology has produced the same response in human patients' tumors as it did in laboratory studies, even at the lowest dose, according to Sarah Nelson, PhD, a professor of Radiology and Biomedical Imaging and a member of the California Institute for Quantitative Biosciences (QB3) at UCSF.
"This is a key milestone that could dramatically change clinical treatment for prostate cancer and many other tumors," Nelson said. "We had shown this worked in animal models and tissues samples. Now, in men, we are seeing exactly the type of results we had hoped for."
For an oncologist, that means immediate feedback on whether a patient's therapy is working, either during standard treatment or in a clinical trial.
"If we can see whether a therapy is effective in real time, we may be able to make early changes in that treatment that could have a very real impact on a patient's outcome and quality of life," said Andrea Harzstark, MD, an oncologist with the UCSF Helen Diller Family Comprehensive Cancer Center who is leading the clinical aspects of the current study.
More than 200,000 men are diagnosed with prostate cancer each year and 28,000 die from it, making it one of the most common cancer in men nationwide and also one of the leading causes of cancer death in men, according to the Centers for Disease Control.
Yet the disease ranges widely in its rate of growth and aggressiveness, according to John Kurhanewicz, PhD, a UCSF expert in prostate cancer imaging. As a result, there is great debate over the ideal strategy for treating the disease, he said, leaving patients with a difficult and potentially life-changing decision over how aggressively to respond to the disease.
"This test could give both physicians and patients the information they need to make that decision," said Kurhanewicz, whose work with Dan Vigneron, PhD, and their colleagues from the UCSF Department of Radiology and Biomedical Imaging first linked a prostate tumor's production of lactate to tumor aggressiveness. Other researchers also have linked that lactate production to tumor aggressiveness and response to therapy in other cancers.
The method uses compounds involved in normal tissue function – in this case, pyruvate, which is a naturally occurring by-product of glucose, and lactate, also known as lactic acid – and uses newly developed equipment to increase the visibility of those compounds by a factor of 50,000 in a magnetic resonance imaging (MRI) scanner.
That process requires pyruvate to be prepared in a strong magnetic field at a temperature of minus 272O C, then rapidly warmed to body temperature and transferred to the patient in an MRI scanner before the polarization decays back to its native state.
The result is a highly defined and clear image of the tumor's outline, as well as a graph of the amount of pyruvate in the tumor and the rate at which the tumor converts the pyruvate into lactate.
The sterile production process requires a dedicated clinical pharmacist with the knowledge of both quality control and of clinical practice. As the birthplace of the field of clinical pharmacy and one of only a handful of schools nationwide with drug production expertise, the UCSF School of Pharmacy and contributions of Marcus Ferrone, PharmD, and his colleagues in the Drug Products Services Laboratory were integral to this process.
The procedure must take place within minutes, which meant integrating a clean room into the scanning facility. QB3 also worked with GE Healthcare in designing Byers Hall, in which the Surbeck Laboratory of Advanced Imaging is housed, to accommodate the extremely strong magnetic field of the MRI scanner and enable time-sensitive experiments.
"All of that insight is why we moved this technology to Northern California," said Jonathan Murray, general manager, Metabolic Imaging at GE Healthcare. "This is a huge accomplishment UCSF and QB3 have achieved. They brought together the best engineering from UC Berkeley and the best bioscience and pharmacy knowledge from UCSF, and are now demonstrating the technology in a world-renowned academic medical center. We are delighted with the speed of progress of this collaboration. The science is very exciting."
The first trial involves men with prostate cancer involved in the "watchful waiting" phase of treatment, Nelson said. Future studies will directly compare these data with the results from surgically removed tumors and will look at how specific therapies change tumor metabolism. UCSF also will be studying the process for use in brain tumor patients.
The project's funding through the National Institute of Biomedical Imaging and Bioengineering, in the National Institutes of Health, was critical in adapting this technology for humans and developing new ways to obtain the MR metabolic imaging data. The project received further support from the American Recovery & Reinvestment Act and the UC Discovery Program.
Initial development of this instrumentation and its demonstration of proof of principle was conducted by Jan Henrik Ardenkjaer-Larsen, Klaes Golman and other colleagues from across GE. UCSF customized that principle and obtained the Investigational New Drug (IND) approval from the Food and Drug Administration to use the hyperpolarized pyruvate in humans.
University of California - San Francisco
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