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Researchers at Erasmus MC University Medical Centre in The Netherlands found that cyclosporine treatment is a significant risk factor for the development of de novo cancer in liver transplant patients. Full details appear in the July issue of Liver Transplantation, a journal published by Wiley-Blackwell on behalf of the American Association for the Study of Liver Diseases (AASLD).

The 1-year survival rate after liver transplantation has dramatically increased in the past three decades to more than 80%. In contrast, there has been little improvement in long-term outcomes. Malignancy is one of the major leading causes of late death after liver transplant and is reported to be directly related to the intensity and the cumulative dose of immunosuppression.

Calcineurin inhibitors (CNI) such as cyclosporine (CsA) or tacrolimus (TAC) are the cornerstone of immunosuppressive treatment after transplantation. Several studies have yielded conflicting results about the incidence of de novo cancer between CsA- based and TAC-based regimens. Elucidating the role of different CNI regimens in the occurrence of de novo cancer after liver transplant was the goal of this study.

The Dutch team performed retrospective analyses in 385 liver transplant patients who underwent surgery between 1986 and 2007. Analyzed data included age of recipient at time of transplantation, gender of recipient, primary liver transplant indication, type of primary immunosuppressive therapy, de novo malignancy post transplantation, interval from liver transplant to diagnosis of malignancy, interval from liver transplant or diagnosis of cancer to death and interval from liver transplant to diagnosis of the first acute rejection. All patients were followed until December 2008. The primary endpoint was de novo malignancy, which was defined as the development of cancer other than recurrent primary liver cancer. Of the 385 study participants, 50 (13.0%) patients developed at least one de novo cancer.

The researchers observed that CsA in comparison to TAC treatment is the most important risk factor for de novo malignancy after liver transplant. This higher cancer risk was not, however, found in all CsA treated patients, but CsA specifically enhanced development of de novo cancer in patients transplanted in more recent years (2005-2007), and in younger patients (less than 50 years of age). In addition, CsA treatment particularly resulted in more aggressive types of cancer compared to TAC, with a 1-year survival rate less than 30%.

The reason for the increased cancer rates among CsA recipients is believed to be the fact that from January 2005, CsA dosing based on the conventional C0 level monitoring was replaced by dosing based on C2 level monitoring in all liver transplant patients. As this was the only major change in the CsA treatment in the recent study period, the team concludes that the C2 monitoring strategy was the reason for the increased early de novo cancer risk.

“Strikingly, CsA treated patients transplanted from 2005 on showed a 9.9-fold higher de novo cancer risk in the early phase after liver transplant compared to patients treated with TAC. These data indicate that only the specific CsA treatment used in recent years was associated with a higher risk for early development of de novo cancer,” said research team leader Herold Metselaar, M.D., Ph.D. “We also observed that, compared with TAC treated patients, CsA treated patients had a 2.5-times higher risk to develop more aggressive cancer types that do not belong to the non-melanoma skin cancer and post-transplant lymphoproliferative disorder (PTLD) categories, indicating that CsA is not only associated with a higher early de novo cancer risk, but also with cancer types having a worse prognosis.”

In this month’s editorial, Julie Thompson, M.D., suggests that further study is required, stating, “Metselaar and colleagues draw much-needed attention to concerns regarding overall immunosuppressant exposure and its relationship to long-term outcomes after liver transplantation. These data serve as a call to reassess the aggressiveness of current immunosuppressive regimens as a means of reducing risk from de novo malignancy.”

Article: “Increased Incidence of Early de novo Cancer in Liver Graft Recipients Treated with Cyclosporine: An Association with C2 Monitoring and Recipient Age.” Angela S.W. Tjon, Jerome Sint Nicolaas, Jaap Kwekkeboom, Robert A. de Man, Geert Kazemier, Hugo W. Tilanus, Bettina E. Hansen, Luc J.W. van der Laan, Thanyalak Tha-In, Herold J. Metselaar. Liver Transplantation; Published Online: March 8, 2010 (DOI: 10.1002/lt.22064 ); Print Issue Date: July 2010. http://www3.interscience.wiley.com/journal/123313851/abstract

Editorial: “Immunosuppression, Cancer, and the Long-Term Outcomes after Liver Transplantation: Can We Do Better?” James M. Abraham, Julie A. Thompson. Liver Transplantation; Published Online: May 31, 2010 (DOI: 10.1002.lt.22114); Print Issue Date: July 2010.

This study is published in Liver Transplantation. Media wishing to receive a PDF of this article may contact healthnews@wiley.com

Liver Transplantation is published on behalf of The American Association for the Study of Liver Diseases and the International Liver Transplantation Society. Since the first application of Liver Transplantation in a clinical situation was reported more than twenty years ago, there has been a great deal of growth in this field and more is anticipated. As an official publication of the AASLD and the ILTS, Liver Transplantation delivers current, peer-reviewed articles on surgical techniques, clinical investigations and drug research ? the information necessary to keep abreast of this evolving specialty. For more information, please visit http://www3.interscience.wiley.com/journal/106570021/home.

Wiley-Blackwell is the international scientific, technical, medical, and scholarly publishing business of John Wiley & Sons, Inc., with strengths in every major academic and professional field and partnerships with many of the world’s leading societies. Wiley-Blackwell publishes nearly 1,500 peer-reviewed journals and 1,500+ new books annually in print and online, as well as databases, major reference works and laboratory protocols. For more information, please visit www.wileyblackwell.com or www.interscience.wiley.com.

COLLEGE STATION, June 24, 2010 ? Some viruses insert themselves into the host’s DNA during infection in a process called retroviral integration, causing several diseases, including AIDS and cancer, notes a Texas A&M researcher who specializes in fetal diseases. However, stem cells that give rise to the early embryo and yolk sac fight back, inhibiting further infection by aggressively silencing the invading viral DNA, says Michael Golding of the Department of Veterinary Physiology and Pharmacology.

The work of the researcher was recently published in Cell Stem Cell.

Early mammalian embryos actually possess three stem cell lineages: ES (embryonic stem), TS (trophectoderm stem), and XEN (extraembryonic endoderm), which give rise to the fetus, placenta and yolk sac respectively, the Texas A&M researcher explains. Using the mouse as a model organism, Golding and his colleagues demonstrate that the mechanisms silencing gene expression are different between each of the three stem cell types.

“Much like a closed book cannot be read while an open book can, the DNA encoding genes can either be tightly wound up and silent or in a relaxed, open, active state,” Golding explains. “The mechanisms that control this gene packaging are called epigenetic as they represent a level of regulation that is above or ‘epi’ to genetics.”

The study shows “retroviral silencing in XEN cells is epigenetic in origin” and that “the three cell lineages of early mammalian embryo have vastly different viral silencing strategies as well as different capacities to suppress retroviral activity.”

To examine the validity of a common assumption that these stem cells use similar mechanisms to silence retroviruses, Golding infected the mouse embryo stem cells with mouse leukemia virus (MLV) and monitored the virus’ activity.

ES cells showed a progressive decline in virus activity, while TS cells had a constant level of virus activity. XEN cells, however, exhibited extremely aggressive and rapid silencing of virus activity, according to the study.

“Epigenetics is an exciting new field of research which is altering the way we think about fetal nutrition and exposure to environmental chemicals,” Golding adds. “This discovery that all three stem cell types of the early embryo utilize slightly different mechanisms to control gene expression has profound implications for how we diagnose and treat fetal diseases.”

About research at Texas A&M University: As one of the world’s leading research institutions, Texas A&M is in the vanguard in making significant contributions to the storehouse of knowledge, including that of science and technology. Research conducted at Texas A&M represents an annual investment of more than $582 million, which ranks third nationally for universities without a medical school, and underwrites approximately 3,500 sponsored projects. That research creates new knowledge that provides basic, fundamental and applied contributions resulting in many cases in economic benefits to the state, nation and world.

Contact: Keith Randall, News & Information Services, at (979) 845-4644 or keith-randall@tamu.edu; Michael Golding, Department of Veterinary Physiology and Pharmacology, at (979) 862-1332 or mgolding@cvm.tamu.edu; or Miao Jingang, News & Information Services, at miaojingang@tamu.edu.

For more news about Texas A&M University, go to http://tamunews.tamu.edu.

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Simple, automated telephone reminders can increase colon cancer screening rates by 30 percent, according to a Kaiser Permanente Center for Health Research study funded by the National Cancer Institute that appears in the July print edition of Medical Care.

The study ? which is the first to examine whether automated calls can increase screening for colon cancer ? involved nearly 6,000 Kaiser Permanente members in Oregon and Washington who were overdue for screening. Half received up to three reminder calls stressing the importance of screening and offering them an at-home kit to detect blood in the stool. Within six months, 22.5 percent of people who received reminder calls ordered and completed a stool card test, compared to only 16 percent of those who did not receive reminder calls.

“Most Americans who should be screened for colon cancer are not being screened. If everyone who is eligible for screening received reminder calls through a program like this one we could screen millions of additional people,” said study lead author David Mosen, PhD, MPH, an investigator at the Kaiser Permanente Center for Health Research. “And because the calls are automated, they can be delivered to large numbers of people in a short period of time.”

Colon cancer is the second leading cause of cancer death in the United States, claiming more than 52,000 lives a year. The U.S. Preventive Services Task Force urges Americans to start screening at age 50, unless they are at high risk, in which case they should be screened earlier.

There are several screening methods available, including: colonoscopy, where a tube is inserted into the rectum to examine the entire colon; sigmoidoscopy, which examines the lower colon; and Fecal Occult Blood Tests, a non-invasive test to detect blood in the stool. FOBT, which was the test used in this study, is often recommended as a first step, and requires people to place stool samples on cards and then send the cards to a lab.

“The stool test is easy to take, but many people see it as unpleasant. This study shows that simple, automated calls motivate more people to take the test, and that means we will detect more cancers at an early stage when we can still save lives” said Adrianne Feldstein, MD, the study’s principal author and a researcher at the Kaiser Permanente Center for Health Research.

The study, conducted in 2008, was so successful that Kaiser Permanente in Oregon and Washington now is using the automated phone calls to remind all members who are overdue for colon cancer screening.

Other studies have found live phone calls very effective in boosting cancer screening rates, but because those calls require hiring extra people, they are cost-prohibitive for many health care organizations. Other research found that reminder postcards can boost screening rates, but automated phone calls are less expensive than postcards because the cost per call decreases as the number of calls increases. An automated call system could be implemented easily by public and private health care systems, especially those with fewer resources, researchers said.

In this study, people aged 51 to 80 received calls because they had not had a colonoscopy in the last 10 years, a flexible sigmoidoscopy or barium enema in the last five years, an FOBT test in the past 12 months, or a clinician referral for FOBT or barium enema within the last three months. The automated calls in English and Spanish lasted about one minute. Members were told about the importance of screening, and were asked to press a number on their phone if they wanted to order a free at-home kit. If the person did not order and complete the test within six weeks they received a second call, and if they didn’t respond in another six weeks, they received a third call. People in the control group ? who were of similar age, sex, BMI and race ? did not receive automated calls, but may have received reminders from their primary care physician.

A recording of the automated reminder call is available at this link: http://www.kpchr.org/research/public/Audio/CRC_EN.mp3.

Study authors include David M. Mosen, Ph.D., MPH, Adrianne C. Feldstein, MD, MS, Nancy Perrin, PhD, A. Gabriela Rosales, MS, David H. Smith, RPh, Ph.D., Elizabeth G. Liles, MD, Jennifer L. Schneider, MPH, from the Kaiser Permanente Center for Health Research, Portland, Ore.; Michael Kositch MD, Thomas Hickey, MD from Northwest Permanente, Portland, Ore.; Russell E. Glasgow, PhD, from the Kaiser Permanente Institute for Health Research, Denver; Jennifer E. Lafata, PhD, from Henry Ford Health System in Detroit; and Ronald E. Myers, PhD, from Thomas Jefferson University, Philadelphia.

About the Kaiser Permanente Center for Health Research (http://www.kpchr.org):

Kaiser Permanente’s Center for Health Research, founded in 1964, is a nonprofit research institution dedicated to advancing knowledge to improve health. It has research sites in Portland, Ore., Honolulu and Atlanta.

About Kaiser Permanente:

Kaiser Permanente is committed to helping shape the future of health care. We are recognized as one of America’s leading health care providers and not-for-profit health plans. Founded in 1945, our mission is to provide high-quality, affordable health care services and to improve the health of our members and the communities we serve. We currently serve 8.6 million members in nine states and the District of Columbia. Care for members and patients is focused on their total health and guided by their personal physicians, specialists and team of caregivers. Our expert and caring medical teams are empowered and supported by industry-leading technology advances and tools for health promotion, disease prevention, state-of-the art care delivery and world-class chronic disease management. Kaiser Permanente is dedicated to care innovations, clinical research, health education and the support of community health. For more information, go to: www.kp.org/newscenter.

http://www.kaiserpermanente.org

Professor Arto Urtti of Helsinki University (formerly from Kuopio) explains: “When these compounds are in solution and DNA is added, they bind together. The large, loose DNA molecule collapses and tiny particles of about 10-50nm in diameter are formed, composed of both DNA and carrier. When you present this to the cells, the nanoparticles bind to the cell surface, which folds inwards to form a vesicle within the cell. The particles then escape from the vesicle, releasing the DNA.”

Researchers at Helsinki University found that out of all the compounds tested, the most effective were those which succeeded in transferring DNA into the nucleus. The mechanism by which the DNA enters the nucleus is not yet clearly understood, but it is known that gene transfer is more effective in cells which are actively dividing, e.g. cancer cells.

Dr Aiva Plotniece, Dr Arkadijs Sobolevs and their colleagues at the Latvian Institute then set out to synthesise dozens of different DHP derivative compounds. Dr Plotniece comments: “The great advantage of these compounds is the biologically active 1,4-DHP fragment, which with proper substitution, can show certain biological and physico-chemical properties. During the project we have designed different 1,4-DHPs, which allowed us to establish structure-activity relationships.”

The third project partner, the independent Latvian chemical producer Bapeks, contributed its experience of larger-scale synthesis and advised the Latvian Institute researchers on how best to scale up the synthesis methodology. The compounds were then distributed to a number of other research colleagues in Latvia, Finland and Lithuania for further study. At present, project partners feel that the main uses will be in laboratory experiments, and much further research is needed before they can be used for gene transfer in the human body.

Partners in the EUREKA project believe that although more research is needed, the project has been very successful. “It was the first big, important project for us” says Dr Sobolevs. “We have significantly widened the potential uses of self-assembling 1,4-dihydropyridine derivatives into nanomedicine, gene delivery and even into drug delivery systems.” The project team found that EUREKA support helped greatly in preparing, managing and reporting the project. It was also through EUREKA that the other partners were introduced to Bapeks.

E! 3371 GENE TRANSFER AGENT is a EUREKA project.

Founded in 1985, EUREKA now unites 39 member countries promoting together innovation through the support they offer to enterprises, universities and research institutes. Results stemming from EUREKA projects are everywhere: mobile phone technology; navigation systems; smartcards; special effects in movies; state-of-the-art medical devices and technologies to monitor and limit environmental pollution.