Popular Diabetes Treatment Could Trigger Pancreatitis, Pancreatic Cancer

A drug widely used to treat Type 2 diabetes may have unintended effects on the pancreas that could lead to a form of low-grade pancreatitis in some patients and a greater risk of pancreatic cancer in long-term users, UCLA researchers have found.

In a study published in the online edition of the journal Diabetes, researchers from the Larry L. Hillblom Islet Research Center at UCLA found that sitagliptin, sold in pill form as Januvia, caused abnormalities in the pancreas that are recognized as risk factors for pancreatitis and, with time, pancreatic cancer in humans. Januvia is marketed by Merck & Co. Inc. Sitagliptin is a member of a new class of drugs that enhance the actions of the gut hormone known as glucagon-like peptide 1 (GLP-1), which has been shown to be effective in lowering blood sugar in people with Type 2 diabetes. The study is available at http://diabetes.diabetesjournals.org/cgi/content/abstract/db09-0058v1. "Type 2 diabetes is a lifelong disease -- people often take the same drugs for many years, so any adverse effect that could over time increase the risk for pancreatic cancer would be a concern," said Dr. Peter Butler, director of the Hillblom Center and the study's lead investigator. "A concern here is that the unwanted effects of this drug on the pancreas would likely not be detected in humans unless the pancreas was removed and examined."

An observed connection between Byetta, a drug used to treat Type 2 diabetes that is related to Januvia in its intended actions, and pancreatitis has already been reported, prompting a Food and Drug Administration warning. Amylin Corp., which markets Byetta, has suggested that since there is no known mechanism linking the cases of pancreatitis with Byetta, the association might be chance. The UCLA study suggests that there may indeed be a link between drugs that enhance the actions of GLP-1 and pancreatitis -- by increasing the rate of formation of cells that line the pancreatic ducts.

In the study, researchers used human IAPP transgenic (HIP) rats to test both sitagliptin and metformin; metformin, a member of an older, different class of diabetes drugs in use since the 1950s, has recently been found to have anti-tumor properties. The researchers sought to determine how the drugs, both singly and in combination, affected islet disease progression in the pancreas -- particularly how they affected beta cells in the pancreas's Islets of Langerhans. Beta cells are responsible for releasing insulin in people with normal metabolism, but they don't produce insulin in sufficient amounts in diabetes patients. HIP rats approximate both the islets and metabolism of people with Type 2 diabetes. The drugs were tested in 40 rats for 12 weeks.

The researchers found that the two drugs in combination had a synergistic effect that helped preserve beta cells, improved their function and enhanced insulin sensitivity in the test rats. With the sitagliptin alone, however, the rats had abnormally high rates of cell production in their pancreatic ducts; a few developed an abnormality known as ductal metaplasia, and one developed pancreatitis.

But the metformin, trade name Glucophage, seems to counteract sitagliptin's adverse effect.

"The apparent protection against the unwanted actions of sitagliptin in the exocrine pancreas are intriguing and may offer a potential way of using the GLP-1 class of drugs safely," Butler said. "The protective effect may have been either by the actions of metformin to decrease blood glucose values or its recently appreciated properties as a tumor suppressive agent."

Butler noted that the present study was undertaken in rats and that it is possible the adverse effects observed would not occur in humans.

"Given these findings, it is probably sensible to use the GLP-1 class of drugs only with metformin until other data is forthcoming," he said.

The National Institutes of Health, the Larry Hillblom Foundation and the Merck Research Foundation funded this study.

In addition to Butler, researchers included Aleksey V. Matveyenko, Heather I. Cox, Artemis Moshtaghian, Tatyana Gurlo, Ryan Galasso and Alexandra E. Butler, all of the Hillblom Center, and Sarah Dry of the department of pathology and laboratory medicine at the David Geffen School of Medicine at UCLA.

The Larry L. Hillblom Islet Research Center at UCLA, established in 2004, is the first center dedicated to the study of the Islets of Langerhans, which include the insulin-producing cells in the pancreas. An understanding of the causes of islet cell destruction is key to finding a cure for diabetes. The center's faculty members, recruited from around the world, provide leadership in the worldwide fight against the disease. The center is funded by a grant from the Larry Hillblom Foundation, which supports medical research in the state of California.

read the full article...

Study Predicts Dramatic Growth in Cancer Rates Among U.S. Elderly, Minorities

Over the next 20 years, the number of new cancer cases diagnosed annually in the United States will increase by 45 percent, from 1.6 million in 2010 to 2.3 million in 2030, with a dramatic spike in incidence predicted in the elderly and minority populations, according to research from The University of Texas M. D. Anderson Cancer Center.

The study, published online today in Journal of Clinical Oncology, is the first to determine such specific long-term cancer incidence projections. It predicts a 67 percent increase in the number of adults age-65-or-older diagnosed with cancer, from 1 million in 2010 to 1.6 million in 2030. In non-white individuals over the same 20-year span, the incidence is expected to increase by 100 percent, from 330,000 to 660,000. According to Ben Smith, M.D., adjunct assistant professor in M. D. Anderson's Department of Radiation Oncology, the study underscores cancer's growing stress on the U.S. health care system.

"In 2030, 70 percent of all cancers will be diagnosed in the elderly and 28 percent in minorities, and the number of older adults diagnosed with cancer will be the same as the total number of Americans diagnosed with cancer in 2010," said Smith, the study's senior author. "Also alarming is that a number of the types of cancers that are expected to increase, such as liver, stomach and pancreas, still have tremendously high mortality rates."

Unless specific prevention and/or treatment strategies are discovered, cancer death rates also will increase dramatically, said Smith, who is currently on active military duty and is stationed at Lackland Air Force Base.

To conduct their research, Smith and his team accessed the United States Census Bureau statistics, updated in 2008 to project population growth through 2050, and the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) registry, the premier population-based cancer registry representing 26 percent of the country's population. Cancer incidence rates were calculated by multiplying the age, sex, race and origin-specific population projections by the age, sex, race and origin-specific cancer incidence rates.

The researchers found that from 2010 to 2030, the population is expected to grow by 19 percent (from 305 to 365 million). The total number of cancer cases will increase by 45 percent (from 1.6 to 2.3 million), with a 67 percent increase in cancer incidence in older Americans (1 to 1.6 million), compared to an 11 percent increase in those under the age of 65 (.63 to .67 million).

With respect to race, a 100 percent increase in cancer is expected for minorities (.33 to .66 million); in contrast, in white Americans, a 31 percent increase is anticipated (1.3 to 1.7 million). The rates of cancer in blacks, American Indian-Alaska Native, multi-racial, Asian-Pacific Islanders and Hispanics will increase by 64 percent, 76 percent, 101 percent, 132 percent and 142 percent, respectively.

Regarding disease-specific findings, Smith and his team found that the leading cancer sites are expected to remain constant - breast, prostate, colon and lung. However, cancer sites with the greatest increase in incidence expected are: stomach (67 percent); liver (59 percent); myeloma (57 percent); pancreas (55 percent); and bladder (54 percent).

Given these statistics, the role of screening and prevention strategies becomes all the more vital and should be strongly encouraged, said Smith. In the study, Smith and his team site: vaccinations for hepatitis B and HPV; the chemoprevention agents tamoxifen and raloxifene; interventions for tobacco and alcohol; and removal of pre-malignant lesions, such as colon polyps.

These findings also highlight two issues that must be addressed simultaneously: clinical trial participation and the increasing cost of cancer care. Historically, both older adults and minorities have been under-represented in such studies, and, therefore, vulnerable to sub-optimal cancer treatment. Simultaneously, over the past decade in particular, the cost of cancer care is growing at a rate that's not sustainable.

"The fact that these two groups have been under-represented in clinical research participation, yet their incidence of cancer is growing so rapidly, reflects the need for therapeutic trials to be more inclusive and address issues that are particularly relevant to both populations," said Smith. "In addition, as we design clinical trials, we need to seek not only the treatment that will prolong survival, but prolong survival at a reasonable cost to patients. These are two issues that oncologists need to be much more concerned about and attuned to."

Another issue that needs to be addressed is the shortage of health care professionals predicted. For example, according to a workforce assessment by American Society for Clinical Oncology (ASCO), the shortage of medical oncologists will impact the health care system by 2020. Smith said ASCO and other professional medical organizations beyond oncology are aware of the problem, and are actively engaged in efforts to try and grow the number of physicians, as well as encourage the careers of nurse practitioners and physician assistants who are part of the continuum of care, to best accommodate the increase in demand forecasted.

"There's no doubt the increasing incidence of cancer is a very important societal issue. There will not be one solution to this problem, but many different issues that need to be addressed to prepare for these changes," said Smith. "I'm afraid if we don't come to grips with this as a society, health care may be the next bubble to burst."

In addition to Smith, other M. D. Anderson authors on the study include: Thomas Buchholz, M.D., professor and chair of the Department of Radiation Oncology and the study's senior author; Gabriel Hortobagyi, M.D., professor and chair of the Department of Breast Medical Oncology; and Grace Smith, M.D., Ph.D., assistant professor in the Department of Radiation Oncology. Arti Hurria, M.D., post-doctoral fellow in the Department of Medical Oncology, City of Hope Cancer Center, also is a contributing author on the study.

About M. D. Anderson
The University of Texas M. D. Anderson Cancer Center in Houston ranks as one of the world's most respected centers focused on cancer patient care, research, education and prevention. M. D. Anderson is one of only 40 comprehensive cancer centers designated by the National Cancer Institute. For four of the past six years, including 2008, M. D. Anderson has ranked No. 1 in cancer care in "America's Best Hospitals," a survey published annually in U.S. News & World Report.

read the full article...

Most Popular: Predicting Breast Cancer Metastasis

Predicting breast cancer metastasis may get easier with a new process called TMEM,  Tumor Microenvironment of Metastasis.

TMEM is determined by measuring cellular activity in a concentrated area of the tumor, identifying three types of cells and how they interact; invasive carcinoma cells, perivascular white blood cells (macrophages), and the endothelial cells that line vessel walls. A higher TMEM density rating was associated with the development of distant organ metastasis via the bloodstream -- the most common cause of death from breast cancer.

"If patients can be better classified as either low risk or high risk for metastasis, therapies can be custom tailored to patients, preventing over-treatment or under-treatment of the disease," adds first author Dr. Brian D. Robinson, resident in Anatomic Pathology at NewYork-Presbyterian Hospital/Weill Cornell Medical Center.

From the article:

Researchers at NewYork-Presbyterian Hospital/Weill Cornell Medical Center have identified a new marker for breast cancer metastasis called TMEM, for Tumor Microenvironment of Metastasis. As reported in the March 24 online edition of the journal Clinical Cancer Research, density of TMEM was associated with the development of distant organ metastasis via the bloodstream -- the most common cause of death from breast cancer.


The National Cancer Institute (NCI)-funded translational study could lead to the first test to predict the likelihood of breast cancer metastasis via the bloodstream -- a development that could change the way breast cancer is treated. An estimated 40 percent of breast cancer patients relapse and develop metastatic disease. About 40,000 women die of metastatic breast cancer every year.


"Currently, anyone with a breast cancer diagnosis fears the worst -- that the cancer will spread and threaten their lives. A tissue test for metastatic risk could alleviate those worries, and prevent toxic and costly measures like radiation and chemotherapy," says senior author Dr. Joan G. Jones, professor of clinical pathology and laboratory medicine at Weill Cornell Medical College and director of Anatomic Pathology at NewYork-Presbyterian Hospital/Weill Cornell Medical Center.


"If patients can be better classified as either low risk or high risk for metastasis, therapies can be custom tailored to patients, preventing over-treatment or under-treatment of the disease," adds first author Dr. Brian D. Robinson, resident in Anatomic Pathology at NewYork-Presbyterian Hospital/Weill Cornell Medical Center.


The Weill Cornell investigators set out to build on previous research by co-author Dr. John S. Condeelis of the Albert Einstein College of Medicine. Working in animal models, he identified a link between blood-borne or systemic metastasis and a three-part association between invasive carcinoma cells, perivascular white blood cells (macrophages) and the endothelial cells that line vessel walls. To confirm this finding in humans, Drs. Jones and Robinson developed a triple immunostain for human breast cancer samples that simultaneously labels the three cell types that together they named TMEM (Tumor Microenvironment of Metastasis).


In a case-control study, they performed a retrospective analysis of tissue samples from 30 patients with invasive ductal carcinoma of the breast who developed systemic, distant-organ metastases. These samples were compared to matched controls that had only localized disease (i.e., invasive ductal carcinoma limited to the breast or with regional lymph node metastasis only). All patients were female and underwent primary resection of their breast cancer at NewYork-Presbyterian Hospital/Weill Cornell Medical Center between 1992 and 2003.


They found that TMEM density was more than double in the group of patients who developed systemic metastases compared with the patients with only localized breast cancer (median of 105 vs. 50, respectively). Offering further evidence in support of the TMEM concept, they found that in well-differentiated tumors, where the outcome is generally good, the TMEM count was low.
Notably, TMEM density was associated with the development of distant-organ metastasis, independent of lymph node status and tumor grade.


"Traditionally, the likelihood of breast cancer metastasis is estimated based on tumor size, tumor differentiation -- how similar or dissimilar the tumor is compared to normal breast tissue -- and whether it has spread to the lymph nodes. While these are useful measures, TMEM density directly reflects the blood-borne mechanism of metastasis, and therefore may prove to be more specific and directly relevant," says Dr. Jones.


The researchers say the next step will be to validate the findings in a larger sample group. Also on the agenda is identifying a threshold TMEM density for metastasis risk, and streamlining the process for measuring TMEM.


Breast cancer is the most prevalent malignant disease of women in the developed world, apart from non-melanoma skin cancers, with approximately one in eight women in the United States being diagnosed with breast cancer at some time in their lives. While an estimated 10 percent to 15 percent of patients have an aggressive form of the disease that metastasizes within three years after initial diagnosis, metastasis can take 10 years or longer to occur. To decrease the risk for the emergence of metastatic tumors, approximately 80 percent of breast cancer patients are treated with adjuvant chemotherapy. The clinical benefit is a 3 percent to 10 percent increase in 15-year survival, depending upon the age of the patient at diagnosis.

read the full article...

Most Popular: Gold Nanoparticles Destroy Cancer

Hollow gold particles called nanospheres, smaller than the finest flecks of dust, can be targeted to search out and "cook" cancer cells.

As a minimally invasive treatment in skin cancer, for example, the hollow gold nanospheres are equipped with a special "peptide" that draws the nanospheres directly to melanoma cells, avoiding healthy skin cells. After collecting inside the cancer, the nanospheres are induced to heat up by exposing them to near-infrared light.

(left: image of the gold nanoparticle as seen through an electron microscope. The darker ring shows the "wall" of the nanosphere, while the lighter area to the right of the ring shows the interior region of the shell.)

"This technique is very promising and exciting," explains study co-author Jin Zhang, Ph.D., a professor of chemistry and biochemistry at the University of California in Santa Cruz. "It's basically like putting a cancer cell in hot water and boiling it to death. The more heat the metal nanospheres generate, the better."

From the article:

Researchers are describing a long-awaited advance toward applying the marvels of nanotechnology in the battle against cancer. They have developed the first hollow gold nanospheres -- smaller than the finest flecks of dust -- that search out and "cook" cancer cells. The cancer-destroying nanospheres show particular promise as a minimally invasive future treatment for malignant melanoma, the most serious form of skin cancer, the researchers say. Melanoma now causes more than 8,000 deaths annually in the United States alone and is on the increase globally.


The topic of a report presented here today at the American Chemical Society's 237th National Meeting, the hollow gold nanospheres are equipped with a special "peptide." That protein fragment draws the nanospheres directly to melanoma cells, while avoiding healthy skin cells. After collecting inside the cancer, the nanospheres heat up when exposed to near-infrared light, which penetrates deeply through the surface of the skin. In recent studies in mice, the hollow gold nanospheres did eight times more damage to skin tumors than the same nanospheres without the targeting peptides, the researchers say. "This technique is very promising and exciting," explains study co-author Jin Zhang, Ph.D., a professor of chemistry and biochemistry at the University of California in Santa Cruz. "It's basically like putting a cancer cell in hot water and boiling it to death. The more heat the metal nanospheres generate, the better."


This form of cancer therapy is actually a variation of photothermal ablation, also known as photoablation therapy (PAT), a technique in which doctors use light to burn tumors. Since the technique can destroy healthy skin cells, doctors must carefully control the duration and intensity of treatment.


Researchers now know that PATs can be greatly enhanced by applying a light absorbing material, such as metal nanoparticles, to the tumor. Although researchers have developed various types of metal nanoparticles to help improve this technique, many materials show poor penetration into cancer cells and limited heat carrying-capacities. These particles include solid gold nanoparticles and nanorods that lack the desired combination of spherical shape and strong near-infrared light absorption for effective PAT, scientists say.


To develop more effective cancer-burning materials, Zhang and colleagues focused on hollow gold nanospheres -- each about 1/50,000th the width of a single human hair. Previous studies by others suggest that gold "nanoshells" have the potential for strong near-infrared light absorption. However, scientists have been largely unable to produce them successfully in the lab, Zhang notes.


After years of research toward this goal, Zhang announced in 2006 that he had finally developed a nanoshell or hollow nanosphere with the "right stuff" for cancer therapy: Gold spheres with an optimal light absorption capacity in the near-infrared region, small size, and spherical shape, perfect for penetrating cancer cells and burning them up.


"Previously developed nanostructures such as nanorods were like chopsticks on the nanoscale," Zhang says. "They can go through the cell membrane, but only at certain angles. Our spheres allow a smoother, more efficient flow through the membranes."


The gold nanoshells, which are nearly perfect spheres, range in size from 30 to 50 nanometers -- thousands of times smaller than the width of a human hair. The shells are also much smaller than other nanoparticles previously designed for photoablation therapy, he says. Another advantages is that gold is also safer and has fewer side effects in the body than other metal nanoparticles, Zhang notes.
In collaboration with Chun Li, Ph.D., a professor at the University of Texas M.D. Anderson Cancer Center in Houston, Zhang and his associates equipped the nanospheres with a peptide to a protein receptor that is abundant in melanoma cells, giving the nanospheres the ability to target and destroy skin cancer. In tests using mice, the resulting nanospheres were found to be significantly more effective than solid gold nanoparticles due to much stronger near infrared-light absorption of the hollow nanospheres, the researchers say.


The next step is to try the nanospheres in humans, Zhang says. This requires extensive preclinical toxicity studies. The mice study is the first step, and there is a long way to go before it can be put into clinical practice, Li says.

read the full article...

Most Clipped: Prostate Screenings Prevent Few Deaths in Older Patients

The prostate cancer screening tests that have become an annual ritual for many men do not appear to reduce deaths from the disease among those with a limited life-expectancy. Study results show six years of aggressive, annual screening for prostate cancer led to more diagnoses of prostate tumors but did not lead to fewer deaths from the disease.

"The important message is that for men with a life expectancy of seven to 10 years or less, it is probably not necessary to be screened for prostate cancer," says the study's lead author and principal investigator Gerald Andriole, M.D., chief urologic surgeon at the Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital.

For younger men with a longer life-expectancy, annual prostate screenings may still be the best way to detect cancer in its earliest, most treatable stages.

"We don't have enough data yet about the youngest men in the study - those in their 50s," Andriole says, "and it may be that over time, we will, in fact, see a benefit from screening."



From the article:

The prostate cancer screening tests that have become an annual ritual for many men don't appear to reduce deaths from the disease among those with a limited life-expectancy, according to early results of a major U.S. study involving 75,000 men.

Results released today from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial show that six years of aggressive, annual screening for prostate cancer led to more diagnoses of prostate tumors but not to fewer deaths from the disease. The study, led by researchers at Washington University School of Medicine in St. Louis and conducted at 10 sites, will appear online March 18 in the New England Journal of Medicine (and in the journal's print edition on March 26).

"The important message is that for men with a life expectancy of seven to 10 years or less, it is probably not necessary to be screened for prostate cancer," says the study's lead author and principal investigator Gerald Andriole, M.D., chief urologic surgeon at the Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital.

But it's too soon, he added, to make broad screening recommendations for all men based on the study's initial findings.

"So far, only a minority of men enrolled in the PLCO study have died, so it may be premature to make generalizations about the ultimate results of the trial," he says. "We don't have enough data yet about the youngest men in the study - those in their 50s - and it may be that over time, we will, in fact, see a benefit from screening."

The PLCO trial began in 1992 with funding from the National Cancer Institute and was designed to determine whether prostate cancer screening reduces deaths from the disease. It involves men ages 55 to 74 who received either annual PSA blood tests and digital rectal exams or "routine care," meaning they had the screening tests only if their physicians recommended them. After seven to 10 years of follow up, deaths from prostate cancer were very low in both groups and did not differ significantly between the groups.

Health guidelines issued last year by the U.S. Preventive Services Task Force recommend against prostate cancer screening for men age 75 or older and concluded there is insufficient evidence to assess the balance of benefits and harms of prostate cancer screening in men younger than 75. However, the American Urological Association and the American Cancer Society recommend annual prostate cancer screening tests beginning at age 50 for most men.

More than 186,000 U.S. men will be diagnosed with prostate cancer this year, and nearly 29,000 will die from the disease, according to the National Cancer Institute. PSA blood tests, introduced in 1988, have increasingly been used as a screening tool for prostate cancer, despite a lack of evidence showing they reduce death rates from disease.

The controversy over prostate cancer screening has arisen because most men who undergo a biopsy for an abnormal PSA test do not have prostate cancer. For those who have cancer, the tumors generally grow so slowly that most men die of other causes. Furthermore, prostate cancer treatment can result in incontinence and impotence. However, some tumors can be aggressive, and the difficulty has been distinguishing aggressive cancers from those that are slow growing.

"We definitely need to find better ways to detect and treat aggressive tumors, those that are truly life-threatening, so that men with slow-growing tumors can avoid unnecessary treatments," says Andriole.

Today's results are the first to detail death rates from prostate cancer among men in the PLCO study and are being released to coincide with the presentation of the data at the European Association of Urology meeting in Stockholm, Sweden.

The PLCO data are being made public now because the study's Data and Safety Monitoring Board, an independent review committee that meets every six months, saw a continuing lack of evidence that screening reduces deaths due to prostate cancer as well as the suggestion that screening may cause men to be treated unnecessarily. The PLCO investigators will continue to follow patients for several more years to see whether annual screening eventually reduces prostate cancer deaths.

The trial involved 76,693 men, who were randomly assigned to receive either annual PSA blood tests for six years and digital rectal exams for four years or routine care, which included physical checkups but no mandate for annual prostate cancer screening.

The new report includes data for all participants seven years after they joined the trial and for 67% percent of participants 10 years after they joined the trial.

At seven years, there were 22 percent more prostate cancer diagnoses in the men screened annually (2,820 men in the screening group vs. 2,322 in the routine-care group). This trend has continued in data collected up to 10 years (currently there are 17 percent more prostate cancer diagnoses in the screening group).

Deaths from prostate cancer did not differ significantly between the groups. Seven years after the start of screening, there were 50 deaths from prostate cancer in the screening group and 44 deaths in the routine-care group. Ten years after the start of screening, there were 92 prostate cancer deaths in the screening group and 82 in the routine-care group.

"My recommendation is that, for now, men with a life expectancy of more than seven to 10 years continue to be screened for prostate cancer," says Andriole.

"On the other hand, screening is probably not necessary for elderly men and men with significant health issues. These men should have a conversation with their doctors to make an individual decision about whether they want to be screened, because clearly there can be harmful side effects related to treatment, while for these men, there has been no demonstration that screening will prolong their lives."

Of the men who received annual screening, 85 percent had PSA tests and 86 percent had digital rectal exams. Men in the routine-care arm sometimes had prostate cancer screening tests: PSA screening ranged from 40 percent of men at the beginning of the study to 52 percent of men by the last screening year, and screening with rectal exams ranged from 41 percent initially to 46 percent by the last screening year. The exam involves a doctor inserting a lubricated, gloved finger into the rectum to feel for anything that is not normal.

Men were referred for follow up testing for prostate cancer if their PSA level was higher than 4.0 ng/ml or if the rectal exam was abnormal.

The researchers noted that the vast majority of men in both groups who developed prostate cancer were diagnosed with stage II disease (out of IV). The number of later-stage cases was similar in the two groups. However, men in the routine-care group had more aggressive tumors (Gleason score 8-10). The reduced number of men with prostate cancer with a Gleason score of 8-10 in the intervention group may eventually lead to a mortality difference, but data analyzed so far have not shown such a benefit.

Additionally, men in both groups received similar treatments for their disease, which was not dictated by being a participant in the PLCO.

Another study reported in this same online issue of the NEJM is the large European Randomized Trial of Screening for Prostate Cancer (ERSPC), which shows a 20 percent reduction in the rate of death from prostate cancer but with a high risk of overdiagnosis. In the ERSPC, unlike the PLCO trial, men were referred for follow-up testing if their PSA level was 3.0 ng/mL or higher and were also screened, on average, every four years as opposed to annually in the PLCO.

Lowering the threshold for what is considered an abnormal PSA to 3.0 ng/ml is likely to diagnose more tumors but not necessarily identify those that are more likely to be aggressive, Andriole says.

read the full article...

Top Story: Good Outcome Possible in Prostate Cancer without Immediate Treatment

Men newly diagnosed with prostate cancer who have a minimal risk of cancer progression or metastases must answer an important question: when to actively treat versus when to observe and closely monitor. A new study recommends that some men diagnosed with low-risk prostate cancer can safely opt out of treatment, if they are closely monitored.

Because radiation therapy and surgery can be associated with serious long-term side effects such as incontinence and erectile dysfunction, some patients are deciding to forego more aggressive treatment and instead choose a path of active surveillance.

From the Article:

A multi-center study of prostate cancer patients appearing in today's Journal of Urology recommends that for some men diagnosed with low-risk prostate cancer, opting not to initially receive treatment can be safe if they are closely monitored.

The study addresses an important question for men newly diagnosed with prostate cancer and at minimal risk of cancer progression or metastases: when to actively treat versus when to observe and closely monitor. Radiation therapy and surgery are effective treatments but can be associated with serious long-term side effects such as incontinence and erectile dysfunction. Investigators in the study show that two separate biopsies are needed to determine optimal selection of patients for active surveillance, also known as "watchful waiting" when patients decide not to undergo immediate treatment.

Study author Scott Eggener, MD, assistant professor of surgery at the University of Chicago Medical Center, notes there are no widely-accepted recommendations on which patients are appropriate candidates for active surveillance or when to perform second or "restaging" biopsies. The authors show that a restaging biopsy provides doctors with additional information regarding the cancer and is the best way to ensure the short-term success of active surveillance.

"When or if to treat men with low-risk prostate cancer has always been a challenging question that faces patients and urologists," Eggener says.

"Some men may be rushing into treatment that won't necessarily benefit them, prevent problems, or prolong life. Close observation in certain patients may provide and maintain quality of life without increasing the chances of the cancer spreading," he says.

The study suggests that before electing active surveillance, it is important for patients to undergo a restaging biopsy following the initial diagnostic biopsy. A similar study released last year by many of the same authors found that approximately 30 percent of patients were no longer appropriate candidates for active surveillance following a restaging biopsy.

Eggener adds that the study was precipitated by the estimated 20-50 percent of men diagnosed with prostate cancer in the U.S. who will eventually die from another cause, but not from their prostate cancer. This represents a large number of men who do not benefit from treatment.

The study conducted between 1991 and 2007 involved 262 men from four hospitals in the U.S. and Canada who met the following criteria: under age 75; prostate-specific antigen (PSA) below 10 ng/ml; clinical stage T1-T2a; Gleason score 6 or below; and 3 or fewer positive cores at diagnostic biopsy. In addition, participants underwent a restaging biopsy and had no treatment for six months following the repeat biopsy. They subsequently underwent physical exams and PSA tests every six months with biopsies recommended every 1-2 years.

Of that initial pool electing surveillance of their cancer, 43 patients eventually chose treatment or had evidence of cancer progression prompting recommendation of treatment by their physician. Following delayed treatment (radiation or surgery,) all but one were cured of their cancer. The remaining 219 patients remained on active surveillance without evidence of metastases.

"Active surveillance with delayed treatment, if necessary, for select patients appears to be safe and associated with a low risk of metastatic spread," the study concludes.

Unlike many past studies on active surveillance that used data before PSA tests were widely available, this multi-center study is based on patients who were screened with the PSA blood test. The PSA test is a widely used cancer screening tool that predicts a man's chances of having prostate cancer.

"Active surveillance is not a total disregard for patients with prostate cancer. Instead, it identifies men unlikely to be affected by their cancer and encourages frequent monitoring, and then starting therapy at a later appropriate time if needed. Cure rates appear to be identical when these men choose immediate treatment or delayed treatment when prompted by new information about their condition," Eggener says.

read the full article...

Dormant Cancer Cells Rely on Cellular Self-Cannibalization to Survive

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.

The 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 Cancer .

"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 ARHI¹s 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.

read the full article...

Hormone Therapy Associated with Reduced Colorectal Cancer Risk

The combination of estrogen plus progestin, which women stopped taking in droves following the news that it may increase their risk of breast cancer, may decrease their risk of colorectal cancer.

"Compared to women who had never taken these hormones, the use of estrogen plus progestin was associated with a reduced risk of colorectal cancer," said Jill R. Johnson, M.P.H., a doctoral student at the University of Minnesota School of Public Health.

The largest risk reduction, approximately 45 percent, was seen among women who had completed use of estrogen plus progestin five or more years previously.

Johnson and her colleagues extracted data from 56,733 postmenopausal women who participated in the Breast Cancer Detection Demonstration Project follow-up study. Hormone therapy use and other risk factors were ascertained through telephone interviews and mailed questionnaires between 1979 and 1998. During an average 15 years of follow-up, Johnson and colleagues identified 960 new cases of colorectal cancer in this population.

Any use of estrogen therapy was associated with a 17 percent reduced risk in colorectal cancer. Among those who used estrogen, the largest reductions were seen among those who were current users (25 percent reduced risk) and users of ten or more years duration (26 percent reduced risk).

Researchers also found a 22 percent reduced risk among those who had ever used estrogen plus progestin in combination. They further found a 36 percent reduction in risk among those who had used progestin sequentially or less than 15 days per month. Past users of estrogen plus progestin, who had stopped at least five years ago, had a 45 percent risk reduction.

Although Johnson's study was not designed to look at biological mechanisms for the protective effect of estrogen therapy, she did say that previous research has suggested that hormones may play a role in decreasing levels of insulin-like growth factors, thereby reducing risk. "The biological mechanism will need to be explored in further studies," said Johnson.

read the full article...

The Essential Role of Protein in Repairing Damaged Cells Revealed

Researchers have discovered a key protein that plays two important roles in the the development of cancer.  It was long known that the protein Mre11 functioned as a "gatekeeper" to signal injury to the cell and prevent damaged cells from proliferating.  But know researchers have observed that the Mre11 protein also serves as a "caretaker," and can repair damaged DNA.

"Most proteins involved in responding to DNA damage that can cause cancer either help detect the damage and warn the rest of the cell, or help repair the damage," says David O. Ferguson, M.D., Ph.D., the study's lead author. Ferguson is an assistant professor of pathology at the U-M Medical School and a member of U-M's Comprehensive Cancer Center.

This research may yield cancer-prevention applications as scientists determine which cancers can cause a mutation in the Mre11 protein, and how to detect and prevent that mutation. 

Prior research has shown that the protein, Mre11, functioned as a "gatekeeper" to signal injury to the cell and prevent damaged cells from proliferating. Now, Ferguson and colleagues have discovered that in mammals, a function of the Mre11 protein also serves as a "caretaker," by repairing DNA.

Their findings, published in the journal Cell, could have important implications for cancer treatment by someday allowing oncologists to predict a tumor's sensitivity to radiation and other therapies, making it more vulnerable to treatment.

Under normal circumstances, the body's cells grow, divide and eventually die. When something damages a healthy cell's DNA -- such as radiation or exposure to a toxin -- a multiprotein complex steps in to repair the breakage and activate other fundamental cellular processes.

The MRN complex, comprised of the Mre11, Rad50 and NBS1 proteins, senses DNA damage, known as double-strand breaks, within the cell. The complex then transmits that information to an enzyme called the ATM (ataxia-telangiectasia mutated) checkpoint kinase.

The ATM kinase controls the cell's response to double-strand breaks, and slows cell growth to give the cell opportunities to repair them, says Ferguson.

When the MRN complex doesn't work properly, inherited human neurological diseases, such as ataxia-telangiectasia-like syndrome and Nijmegen breakage syndrome, result. Both feature MRN mutations and significantly predispose a person to immunodeficiency and cancer.

What Ferguson and colleagues discovered is that Mre11 not only senses and communicates damage, it also repairs DNA double-strand breaks by acting as a nuclease, an enzyme that modifies and processes the broken DNA ends.

Research details The researchers generated mouse models to examine the exact role of Mre11 in the MRN complex. They engineered two mouse strains, one in which Mre11 was disabled completely, and one in which only a single amino acid change was made.

What surprised researchers the most was that making that change to a single amino acid in Mre11 caused consequences as severe as when they eliminated the entire MRN complex.

Taking out the amino acid in Mre11 responsible for nuclease activity caused the mice to develop growth defects, chromosomal abnormalities and sensitivity to DNA-damaging agents. Therefore, researchers could say that the nuclease, or repair, activity of Mre11 proves critical for both MRN function and stability of the genetic material of the organism.

"First, Mre11 signals to the cell by activating the kinase, but it also acts in the repair of double-strand breaks via the nuclease functions. Therefore, it prevents the two individual steps that lead to cancer," Ferguson says.

Implications The work, called "virtuoso cell engineering" in a Cell preview article, holds particular promise for identifying mutations associated with many cancers.

"What's emerging in the literature from large-scale screening studies of human tumors is that Mre11 may be frequently mutated in certain cancers," Ferguson says.

"This may have implications for diagnoses because tumors associated with different mutations may have different prognoses and respond to different therapies," he says. In particular, mutations in Mre11 may predict how sensitive or resistant a particular tumor will be to treatments with DNA-damaging agents.

"The fact that we have now separated the functions of DNA repair from the checkpoint functions means we may have identified a target that can sensitize tumors to radiation and chemotherapeutic agents used in treating cancer."

read the full article...

Chemopreventive Agents in Black Raspberries Identified

Components of black raspberries have been found to potentially have a chemopreventive effect on cancer cells. The substance, a class of compound known as flavonoids, inhibited growth and stimulated apoptosis in the esophagus of rats treated with an esophageal carcinogen. Apoptosis can best be described as the self-cannabalization of a cell.

"Our data provide strong evidence that anthocyanins are important for cancer prevention," said the study's lead author, Gary D. Stoner, Ph.D., a professor in the department of internal medicine at Ohio State University.

Stoner and his team of researchers fed rats an anthocyanin-rich extract of black raspberries and found that the extract was nearly as effective in preventing esophageal cancer in rats as whole black raspberries containing the same concentration of anthocyanins. This study demonstrates the importance of anthocyanins as preventive agents in black raspberries and validated similar in vitro findings. It is among the first to look at the correlation between anthocyanins and cancer prevention in vivo.

Stoner and his colleagues have conducted clinical trials using whole berry powder, which has yielded some promising results, but required patients to take up to 60 grams of powder a day. "Now that we know the anthocyanins in berries are almost as active as whole berries themselves, we hope to be able to prevent cancer in humans using a standardized mixture of anthocyanins," said Stoner.

"The goal is to potentially replace whole berry powder with its active components and then figure out better ways to deliver these components to tissues, to increase their uptake and effectiveness.

Ultimately, we hope to test the anthocyanins for effectiveness in multiple organ sites in humans," said Stoner.

read the full article...

Six Things Women Should Know About the Pap Test

January is Cervical Cancer Awareness Month and The University of Texas M. D. Anderson Cancer Center shares important information about the cervical cancer screening exam, the Pap test.

For many women, their annual Pap test is not something to look forward to; however, this test has the potential to make a huge difference in the lives of women everywhere. The Pap test detects cell changes, which may cause cervical cancer. If these cell changes are found and treated early, cervical cancer may be prevented.


Andrea Milbourne, M.D., associate professor in M. D. Anderson's Department of Gynecologic Oncology, explores six facts women should know about this important test.

1. Increased sexual activity equals increased need for a Pap test.

Increased sexual activity raises a woman¹s risk for acquiring the human papilloma virus (HPV). While HPV can be harmless, it also can cause cervical cancer by changing normal cells in the cervix.

"Because condoms do not provide 100 percent protection against HPV, women who are sexually active and not in a monogamous relationship need to be even more vigilant about following cervical cancer screening guidelines," Milbourne said.

2. The HPV vaccine is a supplement, not a replacement for the Pap test.

Getting the HPV vaccine, or encouraging young female family members to consider it, is a great first step toward cervical cancer prevention. That being said, the vaccine is in no way a substitute for the Pap test.

"The vaccine may give women a false sense of security," Milbourne said. "And because getting a Pap test is not what most women consider a favorite activity, getting the vaccine might cause them to procrastinate even more to make an appointment for their next Pap test."

Because the HPV vaccine does not protect against all types of HPV, or other sexually transmitted diseases, it cannot be the only method of cervical cancer prevention. Women also should remember that cervical cancer doesn¹t have many visible symptoms, which makes the Pap test significantly important in preventing cervical cancer.

3. Women should prepare for an upcoming Pap test.

Milbourne recommends a few tips to help women prepare for an upcoming test: * Avoid douching or using vaginal medicines, spermicidal foams, creams or jellies 48 hours before the test. * Do not have sexual intercourse 48 hours before the test. * Reschedule a Pap test appointment if an unexpected heavy menstrual flow occurs on the day of the exam.

"Lubricants, spermicides, douching and sexual activity can interfere with the interpretation of Pap test results, potentially leading to incorrectly interpreted results or the need for repeat tests," Milbourne said.

4. A woman is never too old to get her Pap test.

Of all the benefits that might come with growing older, skipping a regular Pap test for a sexually active woman over age 65 is not one of them.

As female life expectancy gets longer, many women continue to enjoy sexually active lives throughout their sixties and into their seventies.

"For women over age 65, cervical cancer is rare, but it does happen," Milbourne said. "If you are over age 65, sexually active and not in a monogamous relationship, you should continue your annual Pap test, as you are still susceptible to HPV, which can cause cervical cancer."

5. Women can afford a Pap test.

"Without health insurance or access to affordable health care, a Pap test can be costly," Milbourne said. "For women who can not afford a Pap test, there may be places in your community where you can get one for free."

For information on where to get a free or low-cost Pap test, call the National Cancer Institute¹s Cancer Information Service at 1-800-4-CANCER. Pap tests also are sometimes covered by Medicaid and are covered every two years by Medicare or every year for certain women at higher risk. For more information, call 1-800-MEDICARE.

6. Before the Pap test, cervical cancer was a leading cause of death in American women.


The American Cancer Society estimates that about 3,870 women died from cervical cancer in the United States during 2008. This number is low compared to annual statistics for other more common cancer types, such as breast or lung cancer, but what most people do not know is that cervical cancer was once one of the most common causes of cancer death in American women.

As the Pap test became a standard test for American women, doctors were able to find abnormal changes in the cervix before cancer developed. Between 1955 and 1992, the cervical cancer death rate declined by 74 percent.

"While the cervical cancer death rate continues to decline in the United States, women in countries where Pap tests are not as readily available or affordable still face the challenges, shared by American women more than 50 years ago," Milbourne said.

Cervical cancer is the second largest cause of female cancer deaths worldwide, according to the World Health Organization, with 288,000 deaths each year. About 510,000 cases of cervical cancer are reported each year ­ nearly 80 percent are in developing countries.

For additional information, visit www.mdanderson.org/focused.

read the full article...

Scientists Pull Genetic Tail to Curtail Cancer

>An innovative researcher followed a hunch and encouraged activity in an important cellular tumor-suppressor by grabbing it by the tail.

Inside human cancer cells, the important tumor-suppressing protein often seems to play hooky, lolling around in cellular broth instead of muscling its way out to the cells' membranes, where it can prevent cancer growth. This delinquency puzzled scientists for a long time, until a cell biologist in the Johns Hopkins University School of Medicine felt compelled to genetically grab the protein by the tail and then watched as it got back to work at tamping down disease.

"It was curious that when we removed its tail, the protein suddenly was unhindered and moved out to the membrane and became active," says Meghdad Rahdar, a graduate student in pharmacology.

The discovery, published Dec. 15 online at the Proceedings of the National Academy of Sciences, represents a potential new approach to cancer therapy, according to Peter Devreotes, Ph.D., professor and director of cell biology at Johns Hopkins.

"A long-term goal is to find a drug that does the equivalent of our bit of genetic engineering," he says.

The flexible tail contains a cluster of four amino acids ‹ the building blocks of proteins ‹ that regulate this tumor suppressor known as PTEN. When chemically modified, these amino acids act to ³glue² the tail back to the body of PTEN and prevent the attachment of PTEN to the membrane. By genetically removing PTEN's tail, or manipulating the cluster of four amino acids so that they cannot be modified, the researchers persuaded PTEN to move to the cell membrane where it goes about its tumor-suppressing business of degrading a molecular signal called PIP3 that causes errant cell growth.

"As far as I know, I haven't seen anyone activate a tumor suppressor, but we seem to have done it genetically," Rahdar says.

While genetically engineering cancer cells in the human body is neither practical nor safe, manipulating such unbinding of PTEN with drugs is a viable alternative to guard against cell overgrowth, the hallmark of cancer, the Hopkins scientists say.

In many tumors, PTEN is simply not present. In others, it's there, but a key enzyme that produces PIP3 is over-activated. The Hopkins team already has shown the first evidence that adding the modified PTEN to cells that lack PTEN not only restores normal enzyme levels but ramps up PTEN activity and quells the cell growth signal.

The research was supported by the National Institutes of Health.

In addition to Rahdar and Devreotes, authors on the paper are Takanari Inoue, Tobias Meyer, Jin Zhang and Francisca Vazquez, all of Johns Hopkins.

On the Web:

http://www.hopkinsmedicine.org/cellbio/devreotes http://www.pnas.org

read the full article...

Grape Seed Extract Kills Laboratory Leukemia Cells, Proving Value of Natural Compounds

An extract from grape seeds forces laboratory leukemia cells to commit cell suicide. Within 24 hours of exposure to the naturally occurring compound, 76 percent of leukemia cells had died. The grape seed extract that led to cell death, or apoptosis, by activating JNK, a protein that regulates the apoptotic pathway.

"These results could have implications for the incorporation of agents such as grape seed extract into prevention or treatment of hematological malignancies and possibly other cancers," said the study's lead author, Xianglin Shi, Ph.D., professor in the Graduate Center for Toxicology at the University of Kentucky.

"What everyone seeks is an agent that has an effect on cancer cells but leaves normal cells alone, and this shows that grape seed extract fits into this category," he said.

Shi adds, however, that the research is not far enough along to suggest that people should eat grapes, grape seeds, or grape skin in excess to stave off cancer. "This is very promising research, but it is too early to say this is chemo-protective."

Hematological cancers ­ leukemia, lymphoma and myeloma ­ accounted for an estimated 118,310 new cancer cases and almost 54,000 deaths in 2006, ranking these cancers as the fourth leading cause of cancer incidence and death in the U.S.

Given that epidemiological evidence shows that eating vegetables and fruits helps prevent cancer development, Shi and his colleagues have been studying chemicals known as proanthocyanidins in fruits that contribute to this effect. Shi has found that apple peel extract contains these flavonoids, which have antioxidant activity, and which cause apoptosis in several cancer cell lines but not in normal cells. Based on those studies, and findings from other researchers that grape seed extract reduces breast tumors in rats and skin tumors in mice, they looked at the effect of the compound in leukemia cells.

Using a commercially available grape seed extract, Shi exposed leukemia cells to the extract in different doses and found the marked effect in causing apoptosis in these cells at one of the higher doses.

They also discovered that the extract does not affect normal cells, although they don¹t know why.

The researchers then used pharmacologic and genetic approaches to determine how the extract induced apoptosis. They found that the extract strongly activated the JNK pathway, which then led to up-regulation of Cip/p21, which controls the cell cycle.

They checked this finding by using an agent that inhibited JNK, and found that the extract was ineffective. Using a genetic approach ­ silencing the JNK gene ­ also disarmed grape seed extract's lethal attack in leukemia cells.

"This is a natural compound that appears to have relatively important properties" Shi said.

read the full article...

Why Prostate Cancer Patients Fail Hormone Deprivation

Prostate cancer patients often take hormone deprivation therapy that causes tumors to shrink, sometimes dramatically. In some patients, this therapy gives them only a temporary fix, with tumors usually regaining their hold within a couple of years.

This therapy eventually fails because the androgen receptors on prostate cancer cells become overactive, leading them to survive and causing the tumor to grow aggressively.

In patients who no longer respond to this therapy, a critical differences in the hormone receptors on the prostate cancer cells could lead to a way to track disease progression, as well as new targets to fight prostate cancer.

"We may eventually be able to develop an assay to test for this androgen receptor variant, giving us a way to test which patients are good candidates for hormone deprivation therapy and providing a way to monitor disease progression in patients already on this therapy," Luo says.

The hormone deprivation therapy that prostate cancer patients often take gives them only a temporary fix, with tumors usually regaining their hold within a couple of years. Now, researchers at Johns Hopkins have discovered critical differences in the hormone receptors on prostate cancer cells in patients who no longer respond to this therapy. The findings, reported in the Jan. 1 issue of Cancer Research, could lead to a way to track disease progression, as well as new targets to fight prostate cancer.

Prostate cancer cells rely on androgens, male hormones that include testosterone, to survive and grow, explains Jun Luo, Ph.D., an assistant professor at Johns Hopkins' James Buchanan Brady Urological Institute. Since 1941, doctors have taken advantage of this dependency to battle prostate cancer by depriving patients of androgens, either by castration or chemical methods. For most patients, this hormone deprivation therapy causes tumors to shrink, sometimes dramatically. However, it's never a cure‹tumors eventually regrow into a stronger form, becoming resistant to this and other forms of treatment.

Seeking the reason why this therapy eventually fails, Luo and his colleagues at the Johns Hopkins University School of Medicine, the University of Washington and Puget Sound VA Medical Center looked to a key player: the androgen receptors on prostate cancer cells.

Using a large database, the researchers searched for variations of the nucleic acid RNA that prostate cells use to create androgen receptors, eventually identifying seven RNA sequences different from the "normal" androgen receptor already known to scientists. When they looked for these sequences in cells isolated from 124 prostate cancer patients, they found over-production of these outlaw variants in prostate cancer cells taken from patients whose disease had become resistant to hormone deprivation therapy. One variation‹known as AR-V7, was also prevalent in a select group of patients who had never taken hormone therapy, but whose cancer aggressively regrew after surgery to remove their tumors.

To see how androgen receptors made from AR-V7 differ from others, the researchers forced lab-grown prostate cancer cells to produce only the AR-V7 sequence. Unlike cells with other androgen receptors, those with only AR-V7 receptors acted as if they were continually receiving androgens‹turning on at least 20 genes that rely on androgens for activation‹even though no androgens were present.

The results suggest that hormone therapy might encourage prostate cancer cells to overproduce the AR-V7 receptors over time, leading them to survive and grow aggressively even without androgens, explains Luo. In some patients, he adds, AR-V7 receptors might already be prevalent even without hormone therapy, predisposing them to an already-aggressive form of prostate cancer that won't respond as well to hormone deprivation therapy.

"We may eventually be able to develop an assay to test for this androgen receptor variant, giving us a way to test which patients are good candidates for hormone deprivation therapy and providing a way to monitor disease progression in patients already on this therapy," Luo says.

Examining the differences between AR-V7 and other androgen receptor variants may also provide researchers with new ideas to develop prostate cancer-fighting pharmaceuticals, he adds.

Other researchers who contributed to this study include Rong Hu, Thomas A. Dunn, Shuanzeng Wei, Sumit Isharwal, Robert W. Veltri, Elizabeth Humphreys, Misop Han, Alan W. Partin, William B. Isaacs and G. Steven Bova, all of the Johns Hopkins University School of Medicine; and Robert L. Vessella of the University of Washington and Puget Sound VA Medical Center.

This research was funded by a grant from the David H. Koch Foundation.

For more information, go to: http://urology.jhu.edu/

read the full article...

Medication Errors Common in Outpatient Cancer Treatment

A concerning number of cancer patients taking chemotherapy drugs, either in clinics or at home, were given the wrong dose or suffered from other mistakes in their medications. A recent study found medication errors in 7% of the adult and 19% of the child patients surveyed.

More disturbing still, about 40 percent of the medication errors in children had the potential to cause harm, and several children in the study actually had been harmed by the mistakes. In the adult patients, similar numbers had potential to harm or resulted in actual harm.

The errors included administration of incorrect medication doses due to confusion over conflicting orders and incorrect frequencies of administration. Some consequences of errors included patients being over-hydrated, and complaints of abdominal pain in patients taking narcotics without treatment for constipation. More than 70 percent of the errors in children occurred at home.

Seven percent of adults and 19 percent of children taking chemotherapy drugs in outpatient clinics or at home were given the wrong dose or experienced other mistakes involving their medications, according to a new study supported in part by HHS' Agency for Healthcare Research and Quality through its Centers for Education and Research on Therapeutics program.

Researchers analyzed data on nearly 1,300 patient visits at three adult oncology outpatient clinics and 117 visits at one pediatric facility between September 1, 2005 and May 31, 2006. The study, "Medication Errors among Adults and Children with Cancer in the Outpatient Setting," is in the January 1, 2009 issue of the Journal of Clinical Oncology.

Of the 7 percent of medication errors involving adults, 55 had the potential to harm the patient and 11 did cause harm. The errors included administration of incorrect medication doses due to confusion over conflicting orders ­ one written at the time of diagnosis and the other on the day of administration. Some consequences of errors included patients being over-hydrated prior to administration of chemotherapy and complaints of abdominal pain in patients taking narcotics without treatment for constipation. More than 50 percent of errors involving adults were in clinic administration, 28 percent in ordering of medications, and 7 percent in use of the drugs in patients' homes.

About 40 percent of the 22 medication errors in children had the potential to cause harm and four children were harmed. Examples of pediatric errors included giving the wrong amount or the wrong number of times a day for home medicines because of confusion about instructions. In children more than 70 percent of the errors in children occurred at home.

According to the study's leader, Kathleen E. Walsh, M.D., an assistant professor of pediatrics at the University of Massachusetts School of Medicine and a Robert Wood Johnson Physician Faculty Scholars Award recipient, avoiding prewriting of chemotherapy orders in adults in outpatient clinics may have prevented many of the errors in the adults, whereas most of those involving children could have been avoided by better communication, training, and support for parents of children who use chemotherapy medications at home.

read the full article...

Cancer Drug Arouses Hope for Patients Suffering with Scleroderma

Newswise — A convergence of research has created a great deal of speculation on the far-reaching implications of Gleevec for patients suffering with the autoimmune disease scleroderma. Autoimmune diseases are developed when the body’s immune system attacks healthy cells and tissues, often resulting in devastating chronic pain and organ damage.

First, Novartis brought Gleevec to market in 2001. It was a product originally developed as a treatment for leukemia; but through clinical observations, it was found also to impede inflammation, a chronic symptom of autoimmune diseases such as systemic scleroderma.

Second, researchers at the University of California at San Francisco found evidence that Gleevec could reverse diabetes in mice by blocking a cell component called platelet-derived growth factor receptor (PDGFR). This receptor functions as part of a signaling system that regulates cell growth and inflammation.

Third, a research report in the New England Journal of Medicine reported that PDGFR is a significant factor in the development of scleroderma.

Today, Dr. Daniel Furst, a professor of rheumatology at the University of California at Los Angeles, is currently leading no less than five clinical studies into the safety and efficacy of utilizing Gleevec in the treatment of scleroderma. He believes that the ramifications of this research could have effects not only in scleroderma but amongst other autoimmune diseases.

“This research also helps understand systemic sclerosis and other forms of scleroderma as well as having implications for illnesses such as liver cirrhosis and chronic obstructive lung disease,” says, Dr. Furst. Virginia Ladd, President and Executive Director of the American Autoimmune Related Diseases Association (AARDA), is encouraged by this sequence of events. “This is the first time that patients who suffer from scleroderma have a real possibility for an effective treatment. It is cause for hope for those involved in the fight against autoimmune diseases like scleroderma.”

There is currently no effective treatment for scleroderma. No drug currently can treat the problem at the cellular level however, doctors attempt to treat patients’ discomfort, by treating each symptom individually. Therefore, patients must deal with multiple specialists, multiple pills, and multiple side effects.

Kerri Connolly, Education Manager of the Scleroderma Foundation, a member of the National Coalition of Autoimmune Patient Groups is optimistic about the future, “…At this time, Scleroderma treatment is based only on symptoms/manifestations inflicted on the patients. We will still need time and patience since the "verdict" isn't out yet regarding Gleevec and its efficiency to treat Scleroderma. What this is showing is the progress the research community is making getting to the molecular level of the disease.”

read the full article...

Red Wine May Lower Lung Cancer Risk

Moderate consumption of red wine may decrease the risk of lung cancer in men, according to a report in the October issue of Cancer Epidemiology, Biomarkers and Prevention¸ a journal of the American Association for Cancer Research.

“An antioxidant component in red wine may be protective of lung cancer, particularly among smokers,” said Chun Chao, Ph.D., a research scientist at Kaiser Permanente Department of Research and Evaluation in Pasadena, California.

Chao analyzed data collected through the California Men’s Health Study, which linked clinical data from California’s health system with self-reported data from 84,170 men aged 45 to 69 years. Researchers obtained demographics and lifestyle data from surveys computed between 2000 and 2003, and identified 210 cases of lung cancer.

Researchers measured the effect of beer, red wine, white wine and liquor consumption on the risk of lung cancer. Adjustments were made for age, race/ethnicity, education, income, body mass index, history of chronic obstructive pulmonary disease or emphysema, and smoking history.

Among the study participants, there was on average a two percent lower lung cancer risk associated with each glass of red wine consumed per month. The most substantial risk reduction was among smokers who drank one to two glasses of red wine per day. The researchers reported a 60 percent reduced lung cancer risk in these men. Researchers warned men to stop smoking as the best way to reduce lung cancer risk; noting that even men who drank one to two glasses of red wine per day still face higher lung cancer risk than do non-smokers.

No clear associations with lung cancer were noted for consumption of white wine, beer, or liquor. “Red wine is known to contain high levels of antioxidants. There is a compound called resveratrol that is very rich in red wine because it is derived from the grape skin. This compound has shown significant health benefits in preclinical studies,” Chao said.

Chao said their findings should not be construed to recommend heavy alcohol consumption.

read the full article...

Scientists Find Second Site for Prostate Cancer Gene

Newswise — Scientists at Wake Forest University School of Medicine and colleagues who are studying a prostate cancer gene called HNF1B have found a second independent site within the HNF1B gene on chromosome 17 (17q12) – increasing the number of genetic variants that may contribute to risk of developing the disease.

After comparing the newly-discovered site with a previously discovered site in the same gene among two large groups of patients in Sweden and at Johns Hopkins Hospital in Baltimore, “these data strongly suggest that the two sites are genetically independent,” said Jianfeng Xu, M.D., Dr. Ph.H., senior researcher on the study.

“We found another genetic variant associated with prostate cancer risk,” Xu said. “The more genetic variants we discover, the better off we are. As we find more of these, it improves our ability to predict prostate cancer risk.”

Xu, a professor of epidemiology and cancer biology and Director of the Center for Cancer Genomics, reported the results with 30 colleagues in the current on-line version of Nature Genetics.

The researchers conducted what they termed a “fine-mapping study” in the two groups, one called CAPS, from Sweden, that had 2,899 prostate cancer cases and 1,722 control participants, and the Johns Hopkins study that had 1,527 prostate cancer patients and 482 control participants.

They found two separate clusters of prostate-cancer-associated SNPs (single nucleotide polymorphisms), one in a region previously identified and one in a new region. The researchers then worked to see whether the genetic variants were associated with risk of developing the disease. They looked at the same locations in five other large studies of prostate cancer patients and found that prostate cancer risk was higher among men who had the genetic variants.

Earlier this year, the same research group reported in the New England Journal of Medicine that genetic variants have a strong cumulative effective. A man with four of the five previously discovered variants has a 400 percent increased risk of developing prostate cancer compared to men with none of the variants.

Xu said that as the number of genetic variants associated with prostate cancer risk continues to mount, it improves the precision of risk prediction. But he predicted that prostate cancer will be found to be polygenic, “not dependent on one gene, but a group of genes.”

Prostate cancer risk might be plotted on a bell-shaped curve, with men with a family history of the disease and multiple variants being at the upper end of the curve.

The researchers are exploring another finding, that the HNF1B gene is also associated with diabetes. But if a patient with the HNF1B gene has diabetes, the prostate cancer risk decreases, “We still don’t know how,” Xu said.

Collaborating with Xu were William B. Isaacs, Ph.D., from the Department of Urology at Johns Hopkins Medical Institutions in Baltimore, and Henrik Grönberg, M.D., Ph.Dl, from Karolinska Institute in Stockholm, Sweden.

Jielin Sun, Ph.D., and S. Lilly Zheng, M.D., of the Center for Cancer Genomics and the Center for Human Genomics at Wake Forest, are co-first authors of the paper. Additional co-authors from Wake Forest’s cancer genomics and human genomics centers are Lina D. Purcell, M.S., Zhengrong Gao, B.S., Seong-Tae Kim, Ph.D., Wennuan Liu, Ph.D., Yi Zhu, B.S., Latchezar Dimitrov, M.S., Jishan Sun, Ph.D., Tao Li, M.D., Ph.D., Aubrey R. Turner, M.S., Tamara S. Adams, M.S., and Bao-Li Chang, Ph.D. Fang-Chi Hsu is from the Department of Biostatistical Sciences at Wake Forest.

Wake Forest University Baptist Medical Center (www.wfubmc.edu) is an academic health system comprised of North Carolina Baptist Hospital, Brenner Children’s Hospital, Wake Forest University Physicians, and Wake Forest University Health Sciences, which operates the university’s School of Medicine and Piedmont Triad Research Park. The system comprises 1,154 acute care, rehabilitation and long-term care beds and has been ranked as one of “America’s Best Hospitals” by U.S. News & World Report since 1993. Wake Forest Baptist is ranked 32nd in the nation by America’s Top Doctors for the number of its doctors considered best by their peers. The institution ranks in the top third in funding by the National Institutes of Health and fourth in the Southeast in revenues from its licensed intellectual property.

read the full article...

Common Vitamin Supplement Could Prevent Cancer

Early laboratory research has shown that resveratrol, a common dietary supplement, suppresses the abnormal cell formation that leads to most types of breast cancer, suggesting a potential role for the agent in breast cancer prevention. Resveratrol is a natural substance found in red wine and red grapes. It is sold in extract form as a dietary supplement at most major drug stores.

“Resveratrol has the ability to prevent the first step that occurs when estrogen starts the process that leads to cancer by blocking the formation of the estrogen DNA adducts. We believe that this could stop the whole progression that leads to breast cancer down the road,” said Eleanor G. Rogan, Ph.D., a professor in the Eppley Institute for Research in Cancer and Allied Diseases at the University of Nebraska Medical Center.

read the full article...