NIH to Support Addiction Medicine Education Programs

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Wednesday, October 26, 2011
Contact:NIAAA Press Office 301-443-3860

NIH grant will help translate addiction research into practice

A new grant will help establish a core of post-graduate addiction medicine education programs in academic medical centers throughout the United States. The National Infrastructure for Translating Addiction Research into Clinical Practice grant, awarded last month to the University at Buffalo School of Medicine and Biomedical Sciences, will provide about $900,000 over a two-year period. The grant was awarded by the National Institute on Alcohol Abuse and Alcoholism (NIAAA), part of the National Institutes of Health, and strengthens the foundation for training clinicians in the emerging specialty of addiction medicine.

“We are very excited about this opportunity to help medical students and residents in a variety of specialties who are interested in addiction medicine apply advances in research to real-world practice,” says NIAAA Acting Director Kenneth Warren, Ph.D. “This critical investment in our nation’s health will ultimately improve patient care and reduce the medical, social, and financial burden of the addiction disorders.”

“There is a shortage of academically oriented addiction medicine physicians qualified to conduct clinical research on addictions, to translate this research into practice, and to teach medical students and a wide range of residents about addiction in academic medical centers,” says Co-Principal Investigator Richard D. Blondell, M.D., professor of family medicine at the University at Buffalo, N.Y., and chair of the Residency Training and Accreditation Committee of the American Board of Addiction Medicine (ABAM) Foundation. “This grant will allow established leaders in addiction medicine to help bridge the gap between research and medical education on one hand and clinical practice on the other, and train a new cohort of leaders who will continue to advance the field.”

ABAM Foundation President-Elect Jeffrey Samet, M.D., professor of medicine and community health sciences at Boston University Schools of Medicine and Public Health, is also a co-principal investigator on the grant. In addition to Drs. Blondell and Samet, other key members of the ABAM Foundation will be actively involved in the project.

The goals of the project are to establish a National Addiction Medicine Residency Assistance Council (NAMRAC) that will develop standards of excellence for physician training; identify up to 10 addiction medicine model residency programs; and disseminate curricula and related products and recruit new members to NAMRAC so it can serve as an ongoing resource for development of additional addiction medicine residency programs.

The project is designed to rapidly deploy intensive assistance to the model residencies to help them overcome the barriers that frequently thwart new programs. The model residencies, in turn, will produce educational products, including research-to- practice physician education modules that can be used both in physician training and in helping practicing physicians to incorporate the latest knowledge from alcohol and addictions research into their patient care.

The National Institute on Alcohol Abuse and Alcoholism, part of the National Institutes of Health, is the primary U.S. agency for conducting and supporting research on the causes, consequences, prevention, and treatment of alcohol abuse, alcoholism, and alcohol problems. NIAAA also disseminates research findings to general, professional, and academic audiences. Additional alcohol research information and publications are available at www.niaaa.nih.gov.

Increase in postmastectomy breast reconstruction

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Released: 10/18/2011 11:00 AM EDT

Source: American College of Surgeons (ACS)

New findings show an increase in postmastectomy breast reconstruction, and that TRAM flap reconstruction remains intact with a high degree of patient satisfaction

Newswise — SAN FRANCISCO: Until now, studies looking at trends in cancer care have shown that immediate postmastectomy breast reconstruction has been underutilized. But a pair of studies presented today at the 2011 Annual Clinical Congress of the American College of Surgeons indicate that the number of women undergoing breast reconstruction procedures has almost doubled between 1998 and 2007. Furthermore, the first study points to successful results from a surgical technique called TRAM (Transverse Rectus Abdominis Myocutaneous) flap with a minimum of 15 to 29 years of follow-up after the procedure, while the second study identifies which women were most likely to undergo reconstruction procedures.

Breast reconstruction is a surgical procedure that restores shape to the breast after mastectomy. There are two types of breast reconstruction—autologous and implant-based. A TRAM flap operation is an autologous reconstruction that involves taking abdominal tissue and relocating it to the chest to build a natural-looking breast.

As reported on at the Clinical Congress, Chris D. Tzarnas, MD, FACS, senior author and professor of surgery, Temple University School of Medicine, Philadelphia, and his colleagues reviewed the outcomes of 217 women who underwent TRAM flap breast reconstruction between 1982 and 1996. Most of the women, average age 51, underwent the reconstruction procedure immediately following a mastectomy. The point of the study, Dr. Tzarnas explained “was to assess the long-term outcomes. This is the longest follow-up for this type of reconstruction in the literature to date.” After examining medical records and conducting interviews with the patients 15 to 29 years after the procedures, researchers found that the reconstructions were still intact, and very few women required additional operations, unlike implant-based reconstructions, which often rupture or harden over time. More important, from a quality of life perspective, all of the women felt good about themselves after the TRAM procedure.

“The best reconstructions are those that try to replace everything that is removed. And that has been and, I think, continues to be using the TRAM flap,” Dr. Tzarnas said. “It’s good to show that these reconstructions are doing well and holding up long term.”

On another front, researchers from NorthShore University HealthSystem, Evanston, IL, wanted to look at the reasons breast reconstruction procedures have been underutilized in the past. In their analysis, lead researcher Mark Sisco, MD, a clinical assistant professor of surgery at the University of Chicago Pritzker School of Medicine and his team examined data from the National Cancer Data Base (NCDB) of the American College of Surgeons and the American Cancer Society, a nationwide oncology outcomes database for more than 1,500 Commission on Cancer- accredited cancer programs in the United States and Puerto Rico.

Dr. Sisco and his team sought to conduct a follow-up study of one led by Monica Morrow, MD, FACS, and published in the Journal of the American College of Surgeons in January 2001.*

Dr. Sisco and colleagues found that although the use of breast reconstruction, both autologous and implant-based, actually increased from 12 to 23 percent between 1998 and 2007, some populations of women still are not undergoing reconstructive procedures at the same rate as others.

To identify factors influencing the use of immediate and early breast reconstruction (within 90 days post-mastectomy), they evaluated data on 396,434 women who underwent mastectomy for invasive breast cancer between 1998 and 2007. Then, they compared two cohorts of patients: 134,479 women who had a mastectomy between 1998 and 2000 to 105,114 women who had a mastectomy between 2005 and 2007.

After accounting for tumor characteristics, they found that overall, women who were not African American; had private insurance; were cared for in an academic medical center; resided in large metropolitan communities; and lived in higher-income areas were up to twice as likely to undergo breast reconstruction during both time periods. Despite the overall increase in utilization, none of these disparities have significantly narrowed over both time periods.

“We are doing better at getting reconstruction to women, which is terrific, but it’s clear that we haven’t done a very good job of narrowing the gap in patients who have lower socioeconomic status or live in smaller communities,” Dr. Sisco observed.

Medical guidelines for breast reconstruction are a work in progress, he explained. The guidelines have changed over the years and future change is certain. “Our study really underscores the importance of continuing efforts to improve access to reconstructive surgery, in part by educating both the providers that it’s safe for women to have immediate post mastectomy breast reconstruction and the patients that breast reconstruction is not considered cosmetic surgery,” said Dr. Sisco.
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NOTE: Both of these studies on postmastectomy breast reconstruction were designated as “Posters of Exceptional Merit” at the ACS Clinical Congress.

Dr. Tzarnas’ co-authors included Wendie Grunberg, DO; R. Barrett Noone, MD, FACS; Andres Mascaro, MD; Azra Ashraf, MD; and Emilia Diego, MD. Dr. Tzarnas’ study was not funded and the data analyzed was obtained from medical records.

Dr. Sisco’s co-authors included Hongyan Du, MS; Karol A. Gutowski, MD; David H. Song, MD, FACS; David J. Winchester, MD, FACS; Kathy Yao, MD, FACS; Jeremy P. Warner, MD; and Michael A. Howard, MD. The study was supported by data provided by the division of plastic surgery, NorthShore University HealthSystem and by the American College of Surgeons National Cancer Database access site.

*Morrow, M et al. “Factors influencing the use of breast reconstruction postmastectomy: a national cancer databgase study.” J Am Coll Surg. 2011 Jan:1-8.

Children’s Use of Asthma Controller Drugs Has Doubled

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Released: 10/17/2011 8:00 AM EDT
Source: Agency for Healthcare Research and Quality (AHRQ)

Newswise — The proportion of children who used a prescribed controller drug to treat their asthma doubled from 29 percent in 1997–1998 to 58 percent in 2007–2008, according to the latest News and Numbers from the Agency for Healthcare Research and Quality.

Asthma controller drugs, such as cortisteroids, control inflammation thereby reducing the likelihood of airway spasms; asthma reliever drugs, such as short-acting beta-2-agonists, make breathing easier; and leukotrienes help prevent asthma symptoms from occurring.

AHRQ also found that during the 1997–1998 and 2007–2008 timeframes:

• Use of inhaled corticosteroids, a type of controller drug increased from 15.5 percent to 40 percent. Use of other controller drugs also increased: beta agonists (from 3 percent to 13 percent); and leukotriene (from 3 percent to 34 percent).

• Use of reliever and oral corticosteroid drugs declined from 44 percent to 30 percent and from 17 percent to 9 percent, respectively.

• Average annual total spending for all asthma drugs more than quadrupled from $527 million to $2.5 billion. Specifically, spending for controller drugs grew from $280 million to $2.1 billion and for reliever drugs, the increase was $222 million to $352 million (all in 2008 dollars).

• Spending for oral corticosteroids fell from $25 million to $8 million (2008 dollars).

The data in this AHRQ News and Numbers summary are taken from the Medical Expenditure Panel Survey (MEPS), a detailed source of information on the health services used by Americans, the frequency with which they are used, the cost of those services, and how they are paid. For more information, go to Statistical Brief #341: Changes in Children’s Use and Expenditures for Asthma Medications, United States, 1997–1998 to 2007–2008

Aspirin Desensitization: for Patients with Aspirin & NSAID Allergies; CV Disease

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Released: 10/10/2011 9:00 AM
Source: Thomas Jefferson University

Newswise — (PHILADELPHIA) – Beth Moore can now keep up with her children. The suburban Philadelphia mother of two had suffered from allergies and chronic sinusitis since her teens. With age her symptoms became more severe, turning into bronchitis and eventually asthma, diminishing her ability to breathe and sapping her of her energy. The only complete relief came from aspirin; and the aspirin desensitization that allowed her to overcome her aspirin allergy and end her decades-long battle with sinusitis.

John R. Cohn, MD, head of the Adult Allergy Section at Thomas Jefferson University Hospital and professor of Medicine at Jefferson Medical College of Thomas Jefferson University is one of few allergists to perform the desensitization procedure which trains the body to tolerate aspirin, improving some patients with the triad of sinusitis, asthma, and aspirin-exacerbated respiratory disease (AERD), while allowing others to receive the complete benefits of aspirin for cardiovascular and related disorders.

“Aspirin and nonsteroidal anti-inflammatory drug (NSAID) allergies can cause patients to have life-threatening reactions in the form of asthma, chronic rhinosinusitis or constriction of the upper and lower airways (e.g., nasal congestion and bronchospasm) anywhere from a few minutes to hours after ingestion,” Dr. Cohn explains.

Moore recalls her reaction to aspirin as a teenager, “Within minutes I was short of breath and overheating,” she says.

Unlike conventional allergies, most aspirin “allergies” are caused by an abnormality in the patient’s body chemistry that aspirin aggravates. Desensitization alters the body’s chemistry to allow it to tolerate aspirin. For patients with asthma and nasal symptoms, aspirin desensitization can improve their airway disease substantially. The procedure can also benefit cardiac patients, allowing them to take an important preventative drug, as aspirin is commonly prescribed for heart patients, especially after stents are placed.

Physicians have found in recent years that patients like Moore, who previously did not tolerate aspirin saw significant improvement in their sinus and lung conditions when desensitized to aspirin. “Desensitization alters pathways of leukotriene production, improving the patient’s tolerance to aspirin and often their underlying disease,” says Cohn. Leukotrienes, like histamine, are a family of chemicals made in the body that can cause allergic-like disorders in the nose and chest.

Moore was admitted to Thomas Jefferson University Hospital overnight for the 24-hour desensitization procedure, allowing her to be carefully monitored. She received increasing doses of aspirin at 90-minute intervals beginning with 20.25 mg and working up to 325 mg. Her lung capacity was checked at 90-minute intervals to uncover any adverse reactions. If a dose was not tolerated, she was evaluated and the provoking dose repeated after three hours. “We gradually increase the dose to allow the body to adjust,” explains Cohn.

The procedure was a success. Moore now takes 650 mg of aspirin a day and a stomach coater to protect her stomach lining. Her problems with sinusitis and asthma are much improved. She has not had a single infection in the six months since desensitization and has been able to stop most medication.

“The aspirin desensitization gave me back my health, energy and the ability to run and play with my kids that asthma had taken away,” said Moore. “Dr. Cohn’s aspirin desensitization truly changed my life,” she proudly says. “I only wish I had found it sooner.”

Through-the-Nipple Breast Cancer Therapy Shows Promise in Early Tests

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October 26 2011

Newswise — Delivering anticancer drugs into breast ducts via the nipple is highly effective in animal models of early breast cancer, and has no major side effects in human patients, according to a report by Johns Hopkins Kimmel Cancer Center researchers in Science Translational Medicine on October 26. The results of the study are expected to lead to more advanced clinical trials of so-called intraductal treatment for early breast cancer.

“Our results support the theory that by treating the breast tissue directly we can reach a much more potent drug concentration where it is needed, with far fewer adverse effects on tissues outside the breasts,” says oncologist Vered Stearns, M.D., Ph.D., the Breast Cancer Chair in Oncology and co-director of the Breast Cancer Program at the Kimmel Cancer Center, who supervised the clinical part of the study.

“This has been a classic translational medicine collaboration between a bench researcher and a clinician scientist,” says cancer biologist Saraswati Sukumar, Ph.D., who supervised the animal tests.

Sukumar, the Barbara B. Rubenstein Professor of Oncology at the Kimmel Cancer Center, and co-director with Stearns of the Breast Cancer Program, began intraductal research more than a decade ago, reasoning that because most breast cancers originate from cells lining the milk ducts, early or preventive therapies should be delivered directly to the ducts via the nipple, rather than intravenously. In 2006, in the journal Cancer Research, Sukumar and her colleagues reported on an initial successful test of the technique using the chemotherapy drug doxorubicin against early ductal breast cancers in rats.

For the current study, Stearns set up a small clinical trial to determine the feasibility of Sukumar’s technique in 17 breast cancer patients. Starting first with dextrose — essentially sugar water — and later with escalating doses of the same doxorubicin formulation used on Sukumar’s rats (pegylated liposomal doxorubicin, or PLD), she was able to infuse patients’ breast ducts via a small catheter placed into the nipple. The technique wasn’t used in this case to treat cancer; the patients in the study all had established breast tumors and were awaiting mastectomies. But Stearns was able to establish that single doses of PLD to breast ducts caused only mild side effects including mild nipple pain and breast fullness.

A comparison of 12 patients receiving PLD intraductally with three patients treated with PLD by the standard intravenous route also was revealing, Stearns said. “Intraductal delivery of PLD resulted in much higher concentration in the breast compared to the circulation, whereas in the women with intravenous doses we saw relatively high concentrations in the blood but very little if any in the breast,” she noted.

In the animal portion of the study, Sukumar’s lab examined the intraductal effectiveness of four standard anticancer drugs, 5-fluorouracil (5FU), carboplatin, methotrexate and paclitaxel, all compared with PLD. Of these drugs, intraductal 5FU prevented the most cancers compared to no drug or to intravenous delivery. It also shrank established breast tumors with striking effectiveness, completely eliminating them in 10 of 14 treated rats, she said. “As both a preventive and a therapy, 5FU worked extremely well in these tests,” Sukumar added.

5FU has the additional advantage, she noted, of sparing breast ducts the kind of damage caused by PLD, which at therapeutic doses can destroy large parts of the ductal lining. But perhaps the most intriguing outcome of these tests, she said was that preventive treatment of only four mammary glands in rats — who have a total of twelve — showed a strong effect in preventing tumors in the untreated glands as well. “We think that 5FU, at the high concentration achieved with intraductal delivery, elicits an immune response that can suppress tumor formation in the other ducts,” Sukumar said. “This is an attractive feature, because some breast ducts in women are ‘blind ducts’ that are unconnected to the nipple and therefore unreachable directly with intraductal therapy.”

Sukumar and Stearns say the next step is to set up a further clinical study with 5FU, based on the new findings. The goal is to use intraductal therapy to suppress tumors in patients with a high genetic risk for breast cancer or premalignant lesions in their breast ducts. “In principle, one could do such a procedure every ten years or so to keep one’s breasts tumor-free, as an alternative to having the breasts removed,” Sukumar says.

The study was funded by the National Cancer Institute, Windy Hill Medical Center, the Mary Kay Ash Foundation and the Susan Love Research Foundation.

Other contributors to the study, besides Drs. Sukumar and Stearns, were co-first author Tsuyoshi Mori, currently at the Shiga Institute of Medical Science in Japan; and Lisa K. Jacobs, Nagi F. Khouri, Edward Gabrielson, Takahiro Yoshida, Scott L. Kominsky, David L. Huso, Stacie Jeter, Penny Powers, Karineh Tarpinian, Regina J. Brown, Julie R. Lange, Michelle A. Rudek, Zhe Zhang and Theodore N. Tsangaris, all of Johns Hopkins.

Gene responsible for relapses in young leukemia patients

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One of the causes of resistance to cancer treatment in children is now beginning to be elucidated. Acute lymphoblastic leukemia patients with a particular form of the ATF5 gene are at higher risk of having a relapse when treated with E. coli asparaginase, a key chemotherapy drug for this type of leukemia. This is what a study by Dr. Maja Krajinovic published in the Blood, the journal of the American Society of Hematology, reveals Dr. Krajinovic is an investigator at the Sainte-Justine University Hospital Research Center, which is affiliated with the University of Montreal.

Dr. Krajinovic’s team focused on asparaginase, one of the drugs in a chemotherapy “cocktail” administered to young patients during the intensification phase of their treatment.

They observed that E. coli asparaginase therapy was associated with an increase in relapses when administered to patients who had particular polymorphism (special form) of the ATF5 gene. In fact, this gene regulates asparagine synthetase, an enzyme that produces asparagine, which in turn feeds cancer cells.

“In the presence of this polymorphism that, as we demonstrated, modifies the transcription rate of the ATF5 gene, it is possible that the medication, rather than preventing the proliferation of leukemia cells by reducing the rate of asparagine, does just the opposite by creating feedback that triggers cancer cells to produce asparagine themselves,” explains Dr. Krajinovic.

The discovery of a form of gene associated with high rates of relapse during treatment with E.coli asparaginase opens the door to the possibility of selecting a type of pharmacological treatment based on a patient’s genetic profile, an approach that reflects the shift toward personalized medicine. “If a DNA test detects the implicated polymorphisms in children, it will be possible to predict the risk of relapse or side effects,” exclaimed Dr. Krajinovic. “The clinician can then propose an alternative treatment or adjust the dose accordingly.”

Since the introduction of combination chemotherapy, the rate of pediatric survival without relapse has skyrocketed to about 80%. Yet some patients still resist treatment or present side effects. Pharmacogenetic research strategies involve studying the reaction to each drug used for combined chemotherapy based on various patient genetic profiles so as to design treatment plans that increase efficacy and reduce side effects in patients. Dr. Krajinovic has published a number of similar studies that focus on antifolate, another drug used in combination regimens to treat acute lymphoblastic leukemia.

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Study Details

The study, led by Dr. Maja Krajinovic, an investigator in the Viral and Immune Disorders and Cancers research axis at the Sainte-Justine University Hospital Research Center and the Departments of Pediatrics and Pharmacology at the University of Montreal, was published online on the Oct. 4, 2011 in the scientific journal Blood. Dr. Daniel Sinnett, an investigator working in the same research axis, conducted with Dr. Krajinovic polymorphism-related functional assays. Dr. Sinnett is also an author of many studies on the genetic determinants of acute lymphoblastic leukemia, including a recent study on natural killer cells published in collaboration with Dr. Ali Ahmad as principal author. The study was published in the August 4, 2011, issue of Blood and was reviewed in an editorial that underscored the originality of the work.

The study was funded by the Canadian Institutes of Health Research (CIHR), the Leukemia and Lymphoma Society of Canada, the Charles Bruneau Foundation and the Fondation des Gouverneurs de l’espoir. Drs. Maja Krajinovic and Daniel Sinnett also held National researcher career award from the Fonds de recherche en santé du Québec (FRSQ) in conjunction with this work. The functional studies were conducted in part within the context of one of the projects of Genome Quebec and Genome Canada.

EurekAlert Public release date: 26-Oct-2011

Study finds estrogen may prevent younger menopausal women from strokes

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ROCHESTER, Minn. – Estrogen may prevent strokes in premature or early menopausal women, Mayo Clinic researchers say. Their findings challenge the conventional wisdom that estrogen is a risk factor for stroke at all ages. The study was published in the journal Menopause.

Researchers combined the results from a recent Mayo Clinic study with six other studies from across the world and found that estrogen is protective for stroke before age 50. That is roughly the average age when women go through menopause.

“We were very surprised because these results were unexpected,” says study author Walter Rocca, M.D., an epidemiologist and neurologist at Mayo Clinic. “The old idea that estrogen is always a problem in the brain has to be corrected.” Estrogen can be a problem in older women, he explains, but in younger women, estrogen may be important to protect the brain from strokes.

The study has implications for women who experience premature (before age 40) or early menopause (before age 45) from natural causes or from ovary removal. Women in these groups should consider taking estrogen up to approximately age 50 to prevent stroke, Dr. Rocca says.

Ischemic stroke occurs as a result of an obstruction within a blood vessel supplying blood to the brain. According to the American Stroke Association, these types of strokes account for 87 percent of all stroke cases.

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Co-authors of the study include: Brandon Grossardt, M.S.; Virginia Miller, Ph.D.; Lynne Shuster, M.D.; Robert Brown, Jr., M.D.

Study shows increased prostate cancer risk from vitamin E supplements

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Men who took 400 international units (I.U.) of vitamin E daily had more prostate cancers compared to men who took a placebo, according to an updated review of data from the Selenium and Vitamin E Cancer Prevention Trial (SELECT). The findings showed that, per 1,000 men, there were 76 prostate cancers in men who took only vitamin E supplements, vs. 65 in men on placebo over a seven-year period, or 11 more cases of prostate cancer per 1,000 men. This represents a 17 percent increase in prostate cancers relative to those who took a placebo. This difference was statistically significant and therefore is not likely due to chance. The results of this update appeared Oct. 12, 2011, in the Journal of the American Medical Association.

SWOG, an international network of research institutions, carried out SELECT at more than 400 clinical sites in the United States, Puerto Rico, and Canada. SELECT was funded by the National Cancer Institute (NCI) and other institutes that comprise the National Institutes of Health.

“Based on these results and the results of large cardiovascular studies using vitamin E, there is no reason for men in the general population to take the dose of vitamin E used in SELECT as the supplements have shown no benefit and some very real risks,” said Eric Klein, M.D., a study co-chair for SELECT, and a physician at the Cleveland Clinic. “For now, men who were part of SELECT should continue to see their primary care physician or urologist and bring these results to their attention for further consideration.”

The SELECT study began in 2001 and included over 35,000 men. It was started because earlier research had suggested that selenium or vitamin E might reduce the risk of developing prostate cancer. However, based on an independent safety monitoring review in autumn 2008, participants were told to stop taking their study supplements because it had become clear that the trial would never produce the 25 percent reduction in prostate cancer the study was designed to show with the use of these supplements. In 2010, the study sites were closed and over half of the participants consented to have their health monitored via mail questionnaires. Now, because of this latest finding, researchers are encouraging all participants to consider taking part in long-term study follow-up so investigators can continue to track outcomes.

SELECT was undertaken to substantiate earlier, separate findings from studies in which prostate cancer risk was not the primary outcome. A 1998 study of male smokers in Finland who took 50 I.U. of vitamin E daily to prevent lung cancer, showed 32 percent fewer prostate cancers in men who took the supplement. A 1996 study of men and women with a history of skin cancer who took selenium for prevention of disease recurrence showed that men who took the supplement had 52 percent fewer prostate cancers than men who did not take the supplement.

Based on these and other findings, men were recruited to participate in SELECT. They were randomly assigned to take one of four sets of supplements or placebos, with more than 8,000 men in each group. One group took both selenium and vitamin E; one took selenium and a placebo that looked similar to vitamin E; one took vitamin E and a placebo that looked similar to selenium; and the final group received placebos of both supplements. Men who took selenium alone or vitamin E and selenium together were also more likely to develop prostate cancer than men who took a placebo, but those increases were small and possibly due to chance.

“SELECT has definitively shown a lack of benefit from vitamin E and selenium supplements in the prevention of prostate cancer and has shown there is the potential for harm,” said Lori Minasian, M.D., study co-author and acting director of NCI’s Division of Cancer Prevention. “Nevertheless, this type of research has been critically important to understanding the potential benefits and risks from supplements.”

SELECT researchers are now measuring the amount of vitamin E, selenium, and other nutrients in the blood of participants when they joined the trial, to see if the effect of the supplements depended upon this baseline level of micronutrient. Other researchers are looking at single nucleotide polymorphisms, which are DNA changes known as SNPs, to see if a change in one or more genes could affect cancer risk or perhaps increase a man’s risk of developing prostate cancer while taking vitamin E.

The participant samples come from the study biorepository of blood and toe nail clippings which, when coupled with the extensive clinical information on participants, is a vital resource for further study. “SWOG is soliciting proposals from researchers nationwide to use the SELECT biorepository to help answer the biological question of why vitamin E increased risk instead of decreasing it,” said Laurence Baker, D.O., study co-author and chairman of SWOG. “There are many more questions raised by these study results than we have answers for, and thus the need for further investigation.”

Except for skin cancer, prostate cancer is the most common type of cancer in men in the United States. The current lifetime risk of prostate cancer for American men is 16 percent. In 2011, there will be an estimated 240,890 new cases of prostate cancer and 33,720 deaths from this disease in the United States.

Reference: EA Klein, IM Thompson, CM Tangen, JJ Crowley, MS Lucia, PJ Goodman, L Minasian, LG Ford, HL Parnes, JM Gaziano, DD Karp, MM Lieber, PJ Walther, L Klotz, JK Parsons, JL Chin, A Darke, SM Lippman, GE Goodman, FL Meyskens, and LH Baker. Vitamin E and the Risk of Prostate Cancer: Results of The Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA. October 12, 2011. 306(14) 1549-1556.

Ovarian cancer patients survive longer with BRCA2 mutated in tumors

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HOUSTON – Women with high-grade ovarian cancer live longer and respond better to platinum-based chemotherapy when their tumors have BRCA2 genetic mutations, researchers at The University of Texas MD Anderson Cancer Center and the Institute for Systems Biology report in the Oct. 12 issue of the Journal of the American Medical Association.

“BRCA2-mutated tumors are more vulnerable to these DNA-damaging agents, which is really exciting because there are a number of drugs in clinical trials now that block DNA repair that might prove effective against these tumors in combinations,” said senior author Wei Zhang, Ph.D., professor in MD Anderson’s Department of Pathology.

BRCA2 and its cousin, BRCA1, are tumor-suppressing genes involved in DNA repair that, when mutated, raise a woman’s risk for having breast or ovarian cancer.

“Uncovering the separate potential effects of BRCA1 and BRCA2 mutations takes us a step towards a more personalized approach to treating ovarian cancer, and perhaps other cancers,” Zhang said. “This paper suggests those two genes, and the many others involved in DNA repair, are prime targets for further research.”

Past studies of the possible clinical impact of BRCA1 and BRCA2 mutations tended to look at the two genes together and were limited by small sample sizes.

First author Da Yang, Ph.D., an Odyssey Fellow in MD Anderson’s Department of Pathology, said their in-depth study was made possible by The Cancer Genome Atlas project. TCGA published a study of 489 cases of high-grade serous ovarian cancer, the most common form of the disease, that combined an exhaustive analysis of each tumor’s genome with comprehensive clinical data on each patient.

“TCGA gave us enough analytical power to differentiate between BRCA1 and BRCA2 mutations and conduct a survival analysis,” Yang said.

Improved overall survival

Of 316 cases, 29 tumors had BRCA2 mutations tumors and 37 had BRCA1 mutations. Tumors were similar in grade and stage. Findings include:

  • 61 percent of patients with BRCA2 mutations survived for five years, compared with 25 percent of those with normal BRCA2 in their tumors.
  • 44 percent of those with BRCA2 mutations lived three years after surgery and platinum treatment without disease progression, compared with 16 percent of those with normal BRCA2.
  • BRCA1 mutations in tumors were not associated with survival.
  • All of those with BRCA2 mutations responded to platinum chemotherapy, compared to 82 percent with the normal gene and 80 percent whose tumors had BRCA1 mutations.
  • Their response to chemotherapy lasted 18 months, compared with 11.7 months for normal BRCA2 and 12.5 months for BRCA1 mutations.
  • Tumors with BRCA2 variations also are hypermutants – they had more genetic mutations – with 84 mutations per tumor sample compared to 52 for normal BRCA2

Zhang said this last aspect – called the hypermutator phenotype – might be both a factor in the development and growth of the tumor and a sign of its vulnerability.

BRCA2 is normally involved in the repair of double-strand DNA breaks. Cells with BRCA2 mutants are less capable of repair, allowing other genetic mutations to survive and grow, the type of genomic instability that cancer thrives upon.

However, cancer cells in turn rely on DNA repair to defend themselves against DNA-damaging drugs, such as platinum-based agents. So adding drugs that inhibit DNA repair could increase the effectiveness of chemotherapy, Zhang noted. PARP-inhibitors, a new class of drug in clinical trials, block DNA repair and may also be effective in treating BRCA2 mutated ovarian cancer.

Additional studies of the function of BRCA1 and BRCA2 mutations are needed to more fully understand and exploit their findings to treat cancer, Zhang and colleagues note.

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The Cancer Genome Atlas is a joint project of the National Cancer Institute and the National Human Genome Research Institute, both of the National Institutes of Health, to comprehensively characterize changes in genetic mutation and regulation of various cancers.

Co-authors with Zhang and Yang are Sofia Kahn, Ph.D., and Yan Sun, M.D., Ph.D., of MD Anderson’s Department of Pathology; Kenneth Hess, Ph.D., of MD Anderson’s Department of Biostatistics, Anil Sood, M.D., of MD Anderson Departments of Cancer Biology and Gynecologic Oncology and Reproductive Medicine and the Center for RNAi and Non-Coding RNA; and Ilya Shmulevich, Ph.D., Institute for Systems Biology in Seattle.

This research was funded by the National Cancer Institute; the Blanton-Davis Ovarian Cancer Research Program, MD Anderson’s NCI Specialized Program in Research Excellence in Ovarian Cancer; MD Anderson’s Odyssey Fellows Program; and an ASLA-Fulbright Research Grant.

About MD Anderson

Mushroom compound appears to improve effectiveness of cancer drugs

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AUGUSTA, Ga. – A compound isolated from a wild, poisonous mushroom growing in a Southwest China forest appears to help a cancer killing drug fulfill its promise, researchers report.

The compound, verticillin A, sensitizes cancer cells to TRAIL, a drug which induces cancer cells to self destruct, said Dr. Kebin Liu, cancer immunologist at the Georgia Health Sciences University Cancer Center and corresponding author of the study in the journal Cancer Research.

The compound appears to keep cancer cells from developing resistance to TRAIL, short for tumor necrosis factor-related apoptosis inducing ligand. Drug resistance, intrinsic or acquired, is a major problem for cancer patients, accounting for greater than 90 percent of treatment failures in patients with metastatic disease.

“If we can make drugs work again, more people will survive,” Liu said.

Patient experience has shown cancer’s skill at desensitizing itself to the TRAIL. “It looks as though most cancer cells have found a way to become resistant and evade its action,” said Dr. Wendy Bollag, cell physiologist at GHSU and a study co-author. Tenacious cancer cells also are naturally resistant to cell suicide, which is how TRAIL works.

In mice, they found verticillin A alone was adequate to kill cancer cells, but the required dose made the mice sick, a common problem with many cancer therapies. However, when a lower dose was paired with TRAIL, it became a powerful, more tolerable recipe that killed previously resistant cells.

They also found that the compound improved the efficacy of commonly used cancer drugs etoposide and cisplatin, which also work by promoting cancer cell death but are less targeted than TRAIL. “We believe this could be a good companion drug for a lot of cancer therapies,” Liu said.

One way verticillin A appears to work is by upregulating BN1P3, a gene that promotes cell death, the researchers said. Cancer cells work to silence BN1P3 through a process called DNA methylation; verticillin A appears to modify the same process to turn the gene on.

All cells use DNA methylation but cancer cells use it differently, said Dr. Keith Robertson, cancer epigeneticist and Georgia Cancer Coalition Scholar. “Verticillin A may be working by altering methylation in a way that makes the cancer cells sensitive to TRAIL,” Robertson said.

Their studies were of metastatic human colon cancer cells, which are highly resistant to treatment, including TRAIL, both in culture as well as transplanted into mice. They did similar studies on sarcoma, lung adenocarcinoma and breast cancer.

Additional toxicity studies are needed before moving forward with clinical trials, Bollag said. The researchers also want to pursue the compound’s potential in melanoma and pancreatic cancer.

Verticillin A was isolated from mushrooms in Dr. Ping Wu’s laboratory at the Research Centre of Siyuan Natural Pharmacy and Biotoxicology at China’s Zhejiang University and brought to GHSU by former postdoctoral fellow, Dr. Feiyan Liu, the study’s first author, who studied with Kebin Liu in Augusta for two years. The Chinese university is involved in extensive studies to isolate active compounds from plants to explore their therapeutic potential and both Dr. Lius liked verticillin A’s aggressive response against cancer.

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GHSU and Zhejiang University have a joint use patent on verticillin A and Zhejiang University has a synthesis patent.