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News Article | December 20, 2016
Site: www.eurekalert.org

A new breast cancer model, published today in the Journal of the National Cancer Institute, will help health care providers more accurately predict breast cancer risk in their Hispanic patients. The model, developed by a Kaiser Permanente researcher and his colleagues, is the first to be based exclusively on data from Hispanic women, and will become part of the National Cancer Institute's online tool that helps providers calculate breast cancer risk in individual patients. "Hispanics are the largest racial/ethnic minority group in the U.S., so it's important that the NCI tool include information from these women in determining their risk score. Our model does that because it is based on data from Hispanic women and specifically tailored for them," said Matthew P. Banegas, PhD, MPH, lead author and researcher from the Kaiser Permanente Center for Health Research. NCI's Breast Cancer Risk Assessment Tool asks providers to enter information about the patient's age, race, family history of breast cancer and other risk factors, including: The Breast Cancer Risk Assessment Tool currently includes risk models for non-Hispanic white, African-American and Asian and Pacific Islander women, but no model specific to Hispanic women, and studies show that the tool underestimates breast cancer risk in these women. "Prior studies have shown that Hispanic women born in the U.S. have a higher breast cancer risk than Hispanic women who emigrate here from other countries," said Banegas. "Our model includes data from U.S. and foreign-born women, so providers will be able to more accurately predict risk based on where the woman was born." To build the model, researchers started with data from the San Francisco Bay Area Breast Cancer Study, which included 1,086 Hispanic women who developed breast cancer between 1995 and 2002 and 1,411 women who did not have breast cancer. Nearly 1,000 of the women were born in the United States and 1,500 were born in other countries. The researchers then included breast cancer incidence and mortality data from the California Cancer Registry and NCI's Surveillance, Epidemiology and End Results program. To validate their model, researchers used data from the Women's Health Initiative and the Four-Corners Breast Cancer Study. The new model accurately predicted the number of breast cancers among U.S.-born Hispanic women who participated in the Women's Health Initiative, but slightly overestimated the number of breast cancers among foreign-born Hispanic women in the WHI. "We built the model using data from Hispanic women in California who are mostly of Mexican and Central American descent, so these are the women for whom the model will be most accurate," said Banegas. "As we collect more data on Hispanic women from other regions and countries, we will be able to further refine the model." The new model, like the National Cancer Institute's Breast Cancer Risk Assessment Tool, should not be used for women who already have invasive breast cancer, for women who have an inherited genetic mutation known to cause breast cancer, or for women who received therapeutic radiation of the chest for other types of cancers. This study was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. Other authors include: Esther M. John PhD, MSPH, and Scarlett Lin Gomez, PhD, MPH, Cancer Prevention Institute of California and the Department of Health Research and Policy at the Stanford Cancer Institute; Martha L. Slattery, PhD, MPH, University of Utah Department of Medicine; Mandi Yu, PhD, Division of Cancer Control and Population Sciences, National Cancer Institute; Andrea LaCroix, PhD, Family and Preventive Medicine, University of California, San Diego; David Pee, MPhil, Information Management Services; Rowan T. Chlebowski, MD, PhD, Los Angeles Biomedical Research Institute, Harbor-UCLA Medical Center; Lisa Hines, ScD, Department of Biology, University of Colorado Colorado Springs; Cynthia Thompson, PhD, RD, Mel and Enid Zuckerman College of Public Health, University of Arizona; and Mitchell Gail, MD, PhD, Division of Cancer Epidemiology and Genetics, National Cancer Institute. About the Kaiser Permanente Center for Health Research The Kaiser Permanente 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, Oregon and Honolulu. Visit kpchr.org for more information. 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, Kaiser Permanente has a mission to provide high-quality, affordable health care services and to improve the health of our members and the communities we serve. We currently serve more than 10.6 million members in eight 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: kp.org/share.


News Article | November 10, 2016
Site: www.marketwired.com

Editors: An online press kit is available at www.NCCN.org/justbagit As part of its mission to improve the quality, effectiveness, and efficiency of cancer care so that patients can live better lives, the National Comprehensive Cancer Network® (NCCN®) today announced the launch of Just Bag It: The NCCN Campaign for Safe Vincristine Handling. This campaign encourages health care providers to adopt a policy to always dilute and administer vincristine in a mini IV-drip bag to prevent a deadly medical error. Vincristine is a chemotherapy agent, widely used in patients with Leukemia or Lymphoma, which should be administered intravenously, or directly into the patient's vein. When it enters the blood, it is highly effective at blocking the growth of cancer by preventing cells from separating. However, vincristine is a neurotoxin that causes peripheral neuropathy when given intravenously and profound neurotoxicity if given into the spinal fluid, which flows around the spinal cord and brain. Many patients who receive vincristine have a treatment regimen that includes other chemotherapy drugs that are administered intrathecally, or injected into the spinal fluid with a syringe. If vincristine is mistakenly administered into the spinal fluid, it is uniformly fatal, causing ascending paralysis, neurological defects, and eventually death. In 2005, NCCN Chief Executive Officer Robert W. Carlson, MD, a medical oncologist, witnessed such a tragedy with a 21 year-old patient with Non-Hodgkin's Lymphoma named Christopher Wibeto. Wibeto was transferred to Carlson's care after receiving incorrectly administered vincristine at another hospital. Carlson watched the young man go from having a likely curable condition to deteriorating and dying within four days. Motivated by this tragic experience, Carlson spearheaded a national effort to address this deadly error when he arrived at NCCN, enlisting the help of its Best Practices Committee, which is dedicated to improving cancer treatment protocols. To ensure that vincristine is always administered properly, NCCN has issued guidelines advising health care providers to always dilute and administer vincristine in a mini IV-drip bag and never use a syringe to administer the medication. This precaution renders it impossible to accidentally administer the medication into the spinal fluid and greatly decreases the chances of improper dosage. All 27 NCCN Member Institutions have adopted policies in line with these guidelines, which are also recommended by the Institute for Safe Medication Practices, the Joint Commission, the World Health Organization, and the Oncology Nursing Society. "We are proud of this achievement and grateful for the support and participation of our Member Institutions in reaching this goal," Carlson said. "Our efforts will not stop here. We challenge all medical centers, hospitals, and oncology practices around the nation and the world to implement this medication safety policy so this error never occurs again." Surveys issued by the Institute for Safe Medication Practices (ISMP) show that over time, more hospitals have adopted a policy to always bag vincristine. According to ISMP data, the number of hospitals that have fully implemented the policy across their practice nearly doubled between February 2014 and February 2016. Earlier surveys indicated a similar increase between 2005 and 2012. Still, only about half of all respondents indicated that they have implemented the policy in all treatment settings, indicating that there is a long way to go. With 125 known cases of accidental death in the U.S. and abroad since the inception of vincristine use in the 1960s, this error is relatively rare. Still, it is unique in its level of mortality. Improvements in practice over the years, including manufacturer- and pharmacist-issued warning labels, have reduced the number of deaths, but the error continues to occur. Diluting vincristine into a mini IV-drip bag may entail a change in practice for some providers, but it is well worth the outcome of avoiding preventable deaths, according to Michael Cohen, RPh, MS, FASHP, President of ISMP. "One more life taken is one too many," Cohen said. "We are glad an organization of NCCN's influence has stepped up to bring this issue to national attention. Ending this devastating error should be a priority for all of us who care for and advocate on behalf of patients and their families." Some health care providers may associate the use of an IV bag with a heightened risk of extravasation, or the leaking of a chemotherapy drug into the tissue surrounding the intravenous administration site. But research shows that the risk of extravasation is extremely low. [1] "The Just Bag It campaign is the latest of NCCN's long-standing efforts to improve the safe use of drugs in cancer care," said F. Marc Stewart, MD, Medical Director of the Seattle Cancer Care Alliance and Member of the Fred Hutchinson Cancer Research Center, Professor of Medicine at University of Washington, and Co-Chair of the NCCN Best Practices Committee. "For more than 15 years, the Best Practices Committee has worked to ensure the highest standards of safety for patients." In 2008, the Best Practices Committee led the charge for NCCN to begin publishing Chemotherapy Order Templates (NCCN Templates®), which detail the most common regimens for many cancers and highlight safety parameters. These resources enable practitioners to standardize patient care, reduce medication errors, and anticipate and manage adverse events. There are more than 1,500 NCCN Templates® for 86 cancer types, and they are used by more than 10,000 subscribers. For more information about Just Bag It: The NCCN Campaign for Safe Vincristine Handling, or to report that a medical facility has adopted a vincristine policy, visit www.NCCN.org/JustBagIt. The National Comprehensive Cancer Network® (NCCN®), a not-for-profit alliance of 27 of the world's leading cancer centers devoted to patient care, research, and education, is dedicated to improving the quality, effectiveness, and efficiency of cancer care so that patients can live better lives. Through the leadership and expertise of clinical professionals at NCCN Member Institutions, NCCN develops resources that present valuable information to the numerous stakeholders in the health care delivery system. As the arbiter of high-quality cancer care, NCCN promotes the importance of continuous quality improvement and recognizes the significance of creating clinical practice guidelines appropriate for use by patients, clinicians, and other health care decision-makers. The NCCN Member Institutions are: Fred & Pamela Buffett Cancer Center, Omaha, NE; Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute, Cleveland, OH; City of Hope Comprehensive Cancer Center, Los Angeles, CA; Dana-Farber/Brigham and Women's Cancer Center | Massachusetts General Hospital Cancer Center, Boston, MA; Duke Cancer Institute, Durham, NC; Fox Chase Cancer Center, Philadelphia, PA; Huntsman Cancer Institute at the University of Utah, Salt Lake City, UT; Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance, Seattle, WA; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL; Mayo Clinic Cancer Center, Phoenix/Scottsdale, AZ, Jacksonville, FL, and Rochester, MN; Memorial Sloan Kettering Cancer Center, New York, NY; Moffitt Cancer Center, Tampa, FL; The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute, Columbus, OH; Roswell Park Cancer Institute, Buffalo, NY; Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, St. Louis, MO; St. Jude Children's Research Hospital/The University of Tennessee Health Science Center, Memphis, TN; Stanford Cancer Institute, Stanford, CA; University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, AL; UC San Diego Moores Cancer Center, La Jolla, CA; UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA; University of Colorado Cancer Center, Aurora, CO; University of Michigan Comprehensive Cancer Center, Ann Arbor, MI; The University of Texas MD Anderson Cancer Center, Houston, TX; University of Wisconsin Carbone Cancer Center, Madison, WI; Vanderbilt-Ingram Cancer Center, Nashville, TN; and Yale Cancer Center/Smilow Cancer Hospital, New Haven, CT. [1] ISMP. Death and neurological devastation from intrathecal vinca alkaloids: Prepared in syringes = 120; Prepared in minibags = 0. ISMP Medication Safety Alert! 2013;18(18):3. The following files are available for download:


News Article | November 15, 2016
Site: www.marketwired.com

Providing access to NCCN Templates® through Cerner's PowerChart Oncology™ will help practitioners make informed treatment decisions based on up-to-date, standard protocols FORT WASHINGTON, PA--(Marketwired - November 15, 2016) - The National Comprehensive Cancer Network® (NCCN®) is collaborating with Cerner to integrate the NCCN Chemotherapy Order Templates (NCCN Templates®) into PowerChart Oncology™, the oncology-specific solution within Cerner's electronic health record (EHR), as electronic chemotherapy protocols for use by health care providers. NCCN Templates® will be available for PowerChart Oncology users in 2017. "We are collaborating with Cerner to provide practitioners with access to evidence-based treatment protocols at the point of care to help provide patients with the most up-to-date regimens possible for their specific diagnoses," said Dr. Robert W. Carlson, CEO, NCCN. As part of the integration, Cerner's EHR will link to NCCN.org, providing end-user access to NCCN Templates and the corresponding NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®), helping practitioners make treatment decisions based on up-to-date, evidence-based standard protocols. "At Cerner, we constantly work to provide solutions that support the oncology care team as they make the best treatment decisions possible. Our collaboration with NCCN will further this mission by providing clinicians with direct access to the evidence-based NCCN Chemotherapy Order Templates in their PowerChart Oncology workflow," said Susan Stiles, Oncology solution executive at Cerner. "We have always recommended that clients use NCCN Guidelines® and NCCN Templates and now they will be integrated into PowerChart Oncology. This will help providers follow the most up-to-date treatment plans and be more available to focus on what is most important, their patients." The information contained in the NCCN Templates is based on the NCCN Guidelines. NCCN Templates include chemotherapy and immunotherapy regimens with literature support, supportive care agents, monitoring parameters and safety instructions. A goal of the NCCN Templates is to enhance patient safety by empowering health care providers to standardize patient care, reduce medical errors, and anticipate and manage adverse events. NCCN continues to expand the library of chemotherapy order templates to work toward improved safe and effective use of drugs and biologics in cancer care. For more information about NCCN Templates, visit NCCN.org/templates. Cerner's health information technologies connect people, information and systems at more than 25,000 provider facilities worldwide. Recognized for innovation, Cerner solutions assist clinicians in making care decisions and enable organizations to manage the health of populations. The company also offers an integrated clinical and financial system to help health care organizations manage revenue, as well as a wide range of services to support clients' clinical, financial and operational needs. Cerner's mission is to contribute to the systemic improvement of health care delivery and the health of communities. Nasdaq: CERN. For more information about Cerner, visit cerner.com, read our blog at blogs.cerner.com, connect with us on Twitter at twitter.com/cerner and on Facebook at facebook.com/cerner. Our website, blog, Twitter account and Facebook page contain a significant amount of information about Cerner, including financial and other information for investors. The National Comprehensive Cancer Network® (NCCN®), a not-for-profit alliance of 27 of the world's leading cancer centers devoted to patient care, research, and education, is dedicated to improving the quality, effectiveness, and efficiency of cancer care so that patients can live better lives. Through the leadership and expertise of clinical professionals at NCCN Member Institutions, NCCN develops resources that present valuable information to the numerous stakeholders in the health care delivery system. As the arbiter of high-quality cancer care, NCCN promotes the importance of continuous quality improvement and recognizes the significance of creating clinical practice guidelines appropriate for use by patients, clinicians, and other health care decision-makers. The NCCN Member Institutions are: Fred & Pamela Buffett Cancer Center, Omaha, NE; Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute, Cleveland, OH; City of Hope Comprehensive Cancer Center, Los Angeles, CA; Dana-Farber/Brigham and Women's Cancer Center | Massachusetts General Hospital Cancer Center, Boston, MA; Duke Cancer Institute, Durham, NC; Fox Chase Cancer Center, Philadelphia, PA; Huntsman Cancer Institute at the University of Utah, Salt Lake City, UT; Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance, Seattle, WA; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL; Mayo Clinic Cancer Center, Phoenix/Scottsdale, AZ, Jacksonville, FL, and Rochester, MN; Memorial Sloan Kettering Cancer Center, New York, NY; Moffitt Cancer Center, Tampa, FL; The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute, Columbus, OH; Roswell Park Cancer Institute, Buffalo, NY; Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, St. Louis, MO; St. Jude Children's Research Hospital/The University of Tennessee Health Science Center, Memphis, TN; Stanford Cancer Institute, Stanford, CA; University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, AL; UC San Diego Moores Cancer Center, La Jolla, CA; UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA; University of Colorado Cancer Center, Aurora, CO; University of Michigan Comprehensive Cancer Center, Ann Arbor, MI; The University of Texas MD Anderson Cancer Center, Houston, TX; University of Wisconsin Carbone Cancer Center, Madison, WI; Vanderbilt-Ingram Cancer Center, Nashville, TN; and Yale Cancer Center/Smilow Cancer Hospital, New Haven, CT. The following files are available for download:


As reported in JNCCN, a recent study from McGill University shows that while opioid use increases during treatment in older patients with breast cancer, most do not continue use into survivorship; however, use of anxiolytics and antidepressants remains high in survivors FORT WASHINGTON, PA--(Marketwired - November 21, 2016) - A new McGill University study published in the November issue of JNCCN - Journal of the National Comprehensive Cancer Network found that most patients with breast cancer aged 65 and older use psychotropic and opioid medications during active treatment and often in the first year of survivorship, despite this population's vulnerability to adverse events. According to the authors, this study highlights the need for a multidimensional approach to distress and anxiety that includes comprehensive psychological intervention. The study, "Psychotropic and Opioid Medication Use in Older Patients with Breast Cancer across the Care Trajectory: A Population-Based Cohort Study," is available free-of-charge until February 28, 2017 on JNCCN.org. According to principle investigator, Ari Meguerditchian, MD, MSc, FRCS, Assistant Professor in the Departments of Surgery and Oncology, and member of the Clinical and Health Informatics Research Group at McGill University, "Women over 65 represent the fastest growing segment of breast cancer survivors. The fact that so many of them need mediations for anxiety, depression, and distress even after active cancer care highlights the fact that we know so little about the specific needs of these patients." The researchers followed more than 19,500 women, 65 years or older, diagnosed with incident, non-metastatic breast cancer in Quebec, Canada, and analyzed the use of anxiolytics, antidepressants, antipsychotics, and opioids from precancer baseline through active care and into first-year survivorship. The most prescribed drugs within the population were anxiolytics and antidepressants. Although the percentage of patients on opioids and antipsychotics was lower than the other drugs, with 16.2 percent of patients using antipsychotics and 25 percent using opioids, the authors noted a marked increase in use of opioids and antipsychotics-4.5- and 7-fold, respectively-from baseline to active care. More than 50 percent of women studied used anxiolytics during care-an increase from 36 percent at baseline-and the vast majority of those women (44.4 percent) continued use of the medication into first-year survivorship. Moreover, use of antidepressants among the cohort was 22.4 percent, with 22.3 percent continuing use into survivorship. Dr. Meguerditchian further noted, "Chronic use of these drugs is related to an increased risk of adverse events among these women, notably medication-related falls and injuries. Many studies suggest that this segment of the population is over-medicated." Conversely, the authors saw a notable drop-off in use of antipsychotics and opioids in first-year survivorship. This is likely due, at least in part, to the fact that antipsychotics and opioids are used to treat physical side effects of treatment, such as extreme nausea and pain, which decrease dramatically after treatment. Anxiolytics and antidepressants, on the other hand, are generally prescribed to combat the psychological aspects of diagnosis and treatment such as distress and anxiety, which have an extended effect on the patient. "Our findings raise important questions about the lasting psychological impact of cancer, such as uncertainty of recurrence, family hardships, etc. Are we supporting our older patients as they move to survivorship? How can we best address their needs?" said Dr. Meguerditchian. According to Crystal Denlinger, MD, FACP, Chief, GI Medical Oncology, and Associate Professor in the Department of Hematology/Oncology at Fox Chase Cancer Center, "This study represents an important overview of high-risk medication use in a vulnerable population, namely older breast cancer survivors. The fact that women increase their use of psychotropic and opioid medications during treatment is not surprising due to the current treatment of nonmetastatic breast cancer (ie, surgery and cytotoxic chemotherapy), but the trend toward continued use into survivorship warrants further evaluation as to cause. Given the current campaign to curb opioid abuse in the general population, understanding the reasons for use of these medications and development of better interventions to address underlying causes is critical to ensuring the best outcomes for this, and potentially other, patient populations." About JNCCN - Journal of the National Comprehensive Cancer Network More than 23,000 oncologists and other cancer care professionals across the United States read JNCCN-Journal of the National Comprehensive Cancer Network. This peer-reviewed, indexed medical journal provides the latest information about best clinical practices, health services research, and translational medicine. JNCCN features updates on the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®), review articles elaborating on guidelines recommendations, health services research, and case reports highlighting molecular insights in patient care. JNCCN is published by Harborside Press. Visit JNCCN.org. To inquire if you are eligible for a FREE subscription to JNCCN, visit http://www.nccn.org/jnccn/subscribe.asp About the National Comprehensive Cancer Network The National Comprehensive Cancer Network® (NCCN®), a not-for-profit alliance of 27 of the world's leading cancer centers devoted to patient care, research, and education, is dedicated to improving the quality, effectiveness, and efficiency of cancer care so that patients can live better lives. Through the leadership and expertise of clinical professionals at NCCN Member Institutions, NCCN develops resources that present valuable information to the numerous stakeholders in the health care delivery system. As the arbiter of high-quality cancer care, NCCN promotes the importance of continuous quality improvement and recognizes the significance of creating clinical practice guidelines appropriate for use by patients, clinicians, and other health care decision-makers. The NCCN Member Institutions are: Fred & Pamela Buffett Cancer Center, Omaha, NE; Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute, Cleveland, OH; City of Hope Comprehensive Cancer Center, Los Angeles, CA; Dana-Farber/Brigham and Women's Cancer Center | Massachusetts General Hospital Cancer Center, Boston, MA; Duke Cancer Institute, Durham, NC; Fox Chase Cancer Center, Philadelphia, PA; Huntsman Cancer Institute at the University of Utah, Salt Lake City, UT; Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance, Seattle, WA; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL; Mayo Clinic Cancer Center, Phoenix/Scottsdale, AZ, Jacksonville, FL, and Rochester, MN; Memorial Sloan Kettering Cancer Center, New York, NY; Moffitt Cancer Center, Tampa, FL; The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute, Columbus, OH; Roswell Park Cancer Institute, Buffalo, NY; Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, St. Louis, MO; St. Jude Children's Research Hospital/The University of Tennessee Health Science Center, Memphis, TN; Stanford Cancer Institute, Stanford, CA; University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, AL; UC San Diego Moores Cancer Center, La Jolla, CA; UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA; University of Colorado Cancer Center, Aurora, CO; University of Michigan Comprehensive Cancer Center, Ann Arbor, MI; The University of Texas MD Anderson Cancer Center, Houston, TX; University of Wisconsin Carbone Cancer Center, Madison, WI; Vanderbilt-Ingram Cancer Center, Nashville, TN; and Yale Cancer Center/Smilow Cancer Hospital, New Haven, CT. The following files are available for download:


As published in JNCCN, a recent project out of Canada shows that programs identifying stress and distress in patients with cancer increase health care professionals' confidence and awareness of patient-centeredness; outcomes are influenced by site-based navigators and practice size FORT WASHINGTON, PA--(Marketwired - November 01, 2016) - As many as 60 percent of patients with cancer report distress following a cancer diagnosis, and this stress can have significant impacts on patients' well-being, resulting in psychosocial problems, physical side effects, and dissatisfaction with their health care. To examine the impact of distress on patients and health care professionals (HCPs), Linda Watson, PhD, RN, CancerControl Alberta, Alberta Health Services, led the implementation of screening for distress (SFD) as a new standard of care across 17 provincial cancer care sites. More than 250 HCPs across cancer care facilities in Alberta, Canada, participated in educational sessions and adopted this standard of practice. Dr. Watson and Dr. Rie Tamagawa, a senior researcher in provincial practices, found that HCPs who participated in this educational program and utilized SFD routinely reported improved confidence in detecting patient distress and increased awareness of the importance of a patient-centered approach to care. The study, "The Effects of a Provincial-Wide Implementation of Screening for Distress on Health Care Professionals' Confidence and Understanding of Patient-Centered Care in Oncology", is published in the October issue of JNCCN - Journal of the National Comprehensive Cancer Network. Complimentary access to the article is available until December 15, 2016 at JNCCN.org. "Distress can be caused by a variety of issues, concerns, or symptoms, but how distress is experienced and what underlies a person's distress is unique to each person and changes over time. The SFD helps clinicians identify distressed patients and their issues, concerns, or symptoms driving their distress. This project has demonstrated that through clinical review and targeted response to the patient priority issue, improved clinical outcomes and patient experiences can be achieved," said Dr. Watson. For Dr. Watson's quality improvement project, the SFD intervention was implemented as a standard of care at all cancer care facilities in Alberta over a 10-month period. HCPs at all sites completed educational sessions prior to implementation of this new practice. HCPs also completed surveys before and after implementation. Results of the project illustrated a significant increase in participants' confidence in identifying, assessing, and managing distress, as well as their awareness of person-centered care principles following the implementation. HCPs at smaller community cancer centers reported greater person-centered awareness as compared to HCPs at larger tertiary sites throughout the study. HCPs at those smaller sites identified more benefits from the SFD intervention relative to HCPs at the larger sites. This variance, Dr. Tamagawa reports, is likely because smaller, more remote cancer centers have patient navigation as part of their model of care and physicians are treating multiple tumor types. These are likely to contribute to personable patient-provider relationships. The benefits of the SFD was more salient for HCPs taking care of multiple tumor types, suggesting that such intervention is well adopted by physicians who practice as generalist model of care. On the other hand, physicians from larger centers tend to be single-tumor specialists at hospitals that do not employ patient navigation programs -- these participants reported lower awareness in person-centeredness in general, and the SFD intervention potentially posed an additional workload. Prior to adequate SFD training and with less time for patient relationship-building, physicians often lack confidence in their ability to identify and treat patient distress in a timely manner. The study highlighted that SFD intervention can help build this confidence and awareness of person-centered care delivery regardless of the types of care facilities. In Alberta, Dr. Watson shared, "We have found that utilizing a SFD tool that spans the physical, emotional, social, spiritual, practical, and informational domains has been helpful as it reflects the whole patient experience. It has been our experience that using a tool that helps the patient to specify their particular area of concern facilitates meaningful interventions." "Patient distress has received little attention from clinicians, but can have a large impact on patient quality of life. As such, screening for distress will become increasingly important in clinical practices, so information on its implementation is useful for practitioners," said Jimmie C. Holland, MD, Wayne R. Chapman Chair in Psychiatric Oncology, Memorial Sloan Kettering Cancer Center, and Chair of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Panel for Distress Management. Complimentary access to the article is available until December 15, 2016 at JNCCN.org. About JNCCN - Journal of the National Comprehensive Cancer Network More than 24,000 oncologists and other cancer care professionals across the United States read JNCCN-Journal of the National Comprehensive Cancer Network. This peer-reviewed, indexed medical journal provides the latest information about best clinical practices, health services research, and translational medicine. JNCCN features updates on the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®), review articles elaborating on guidelines recommendations, health services research, and case reports highlighting molecular insights in patient care. JNCCN is published by Harborside Press. Visit JNCCN.org. To inquire if you are eligible for a FREE subscription to JNCCN, visit http://www.nccn.org/jnccn/subscribe.asp About the National Comprehensive Cancer Network The National Comprehensive Cancer Network® (NCCN®), a not-for-profit alliance of 27 of the world's leading cancer centers devoted to patient care, research, and education, is dedicated to improving the quality, effectiveness, and efficiency of cancer care so that patients can live better lives. Through the leadership and expertise of clinical professionals at NCCN Member Institutions, NCCN develops resources that present valuable information to the numerous stakeholders in the health care delivery system. As the arbiter of high-quality cancer care, NCCN promotes the importance of continuous quality improvement and recognizes the significance of creating clinical practice guidelines appropriate for use by patients, clinicians, and other health care decision-makers. The NCCN Member Institutions are: Fred & Pamela Buffett Cancer Center, Omaha, NE; Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute, Cleveland, OH; City of Hope Comprehensive Cancer Center, Los Angeles, CA; Dana-Farber/Brigham and Women's Cancer Center | Massachusetts General Hospital Cancer Center, Boston, MA; Duke Cancer Institute, Durham, NC; Fox Chase Cancer Center, Philadelphia, PA; Huntsman Cancer Institute at the University of Utah, Salt Lake City, UT; Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance, Seattle, WA; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL; Mayo Clinic Cancer Center, Phoenix/Scottsdale, AZ, Jacksonville, FL, and Rochester, MN; Memorial Sloan Kettering Cancer Center, New York, NY; Moffitt Cancer Center, Tampa, FL; The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute, Columbus, OH; Roswell Park Cancer Institute, Buffalo, NY; Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, St. Louis, MO; St. Jude Children's Research Hospital/The University of Tennessee Health Science Center, Memphis, TN; Stanford Cancer Institute, Stanford, CA; University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, AL; UC San Diego Moores Cancer Center, La Jolla, CA; UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA; University of Colorado Cancer Center, Aurora, CO; University of Michigan Comprehensive Cancer Center, Ann Arbor, MI; The University of Texas MD Anderson Cancer Center, Houston, TX; University of Wisconsin Carbone Cancer Center, Madison, WI; Vanderbilt-Ingram Cancer Center, Nashville, TN; and Yale Cancer Center/Smilow Cancer Hospital, New Haven, CT. The following files are available for download:


News Article | February 15, 2017
Site: www.eurekalert.org

Researchers at the Stanford University School of Medicine used heart muscle cells made from stem cells to rank commonly used chemotherapy drugs based on their likelihood of causing lasting heart damage in patients. Drugs known as tyrosine kinase inhibitors can be an effective treatment for many types of cancers, but they also have severe and sometimes fatal side effects. Using lab-grown heart cells, Stanford researchers were able to assess the drugs' various effects on heart muscle cells, including whether the cells survived, were able to beat rhythmically and effectively, responded appropriately to electrophysiological signals and communicated with one another. The researchers found that their assay can accurately identify those tyrosine kinase inhibitors already known to be the most dangerous in patients. In the future, they believe their system may prove useful in the early stages of drug development to screen new compounds for cardiotoxicity. "This type of study represents a critical step forward from the usual process running from initial drug discovery and clinical trials in human patients," said Joseph Wu, MD, PhD, director of the Stanford Cardiovascular Institute and a professor of cardiovascular medicine and of radiology. "It will help pharmaceutical companies better focus their efforts on developing safer drugs, and it will provide patients more effective drugs with fewer side effects." A paper describing the research will be published Feb. 15 in Science Translational Medicine. Wu, who holds the Simon H. Stertzer Professorship, is the senior author. Former graduate student Arun Sharma, PhD, is the lead author. "We used multiple measurements to accurately predict which of the tyrosine kinase inhibitors were the most cardiotoxic," said Sharma. "The drugs with the lowest safety indices in our study were also those identified by the Food and Drug Administration as the most cardiotoxic to patients. Other drugs that are not as cardiotoxic performed much better in our assays." Validating the researchers' cardiac-safety test on drugs with extensive clinical track records is necessary before the assay can be used to predict with confidence the likely clinical outcomes of drugs still under development. Sharma, Wu and their colleagues created heart muscle cells called cardiomyocytes from induced pluripotent stem cells, or iPS cells, from 11 healthy people and two people with kidney cancer. They grew the lab-made cardiomyocytes in a dish and tested the effects of 21 commonly used tyrosine kinase inhibitors on the cells. They found that treatment with drug levels equivalent to those taken by patients often caused the cells to beat irregularly and begin to die. The cells also displayed differences in the electrophysiological signaling that controls their contraction. The researchers used these and other measurements to develop a cardiac safety index for each drug. They found that those drugs known to be particularly dangerous to heart function, such as nilotinib, which is approved for the treatment of chronic myelogenous leukemia, and vandetanib, which is approved for the treatment of some types of thyroid cancer, also had the lowest safety indices based on the assay; conversely, those known to be better tolerated by patients ranked higher on their safety index. Prescribing information for both nilotinib and vandetanib contains warnings from the FDA about the drugs' potential cardiotoxicity. An activity increase in an insulin responsive pathway Six of the 21 tyrosine kinase inhibitors tested were assigned cardiac safety indices at or below 0.1 -- the threshold limit at which the researchers designated a drug highly cardiotoxic. Three of these six are known to inhibit the same two signaling pathways: VEGFR2 and PDGFR. The researchers noticed that cells treated with these three drugs ramped up the activity of a cellular signaling pathway that responds to insulin or IGF1, an insulinlike growth factor. This discovery, coupled with the fact that treatment with insulin or IGF1 is known to enhance heart function during adverse cardiac events such as heart attacks, led the researchers to experiment further. They found that exposing the cells to insulin or IGF1 made it less likely they would die due to tyrosine kinase inhibitors blocking the VEGFR2 and PDGFR pathways. Although more research is needed, these findings suggest it may be possible to alleviate some of the heart damage in patients receiving these chemotherapies. The current study mirrors another by Wu's lab that was published in April 2016 in Nature Medicine. That research focused on the toxic effect of a chemotherapy drug called doxorubicin on iPS cell-derived cardiomyocytes. Doxorubicin, which indiscriminately kills any replicating cells, is increasingly being replaced by more targeted, cancer-specific therapies such as the tyrosine kinase inhibitors tested in the current study. "The switch from doxorubicin is a result of the paradigm shift in cancer treatment to personalized, precise treatment as emphasized by President Obama's 2015 Precision Medicine Initiative," said Wu. "Moving even further, we're discovering that many tyrosine kinase inhibitors are themselves significantly cardiotoxic, and some have been withdrawn from the market. There is a critical need for a way to 'safety test' all drugs earlier in development before they are administered to patients. Our drug safety index is a step in that direction." Other Stanford co-authors are Paul Burridge, PhD, a former instructor at the Cardiovascular Institute; graduate student Wesley McKeithan; postdoctoral scholars Praveen Shukla, PhD, Tomoya Kitani, MD, Haodi Wu, PhD, and Alexandra Holmström, PhD; instructors Nazish Sayed, MD, PhD, Elena Matsa, PhD, and Jared Churko, PhD; medical student Anusha Kumar; undergraduate student Yuan Zhang; assistant professor of medicine Alice Fan, MD; associate professor of medicine Sean Wu, MD, PhD; and professor of medicine Mark Mercola, PhD. The research was funded by the American Heart Association, the National Science Foundation, the National Institutes of Health (a Director's Pioneer Award and grants R01HL113006, R01HL130020, R01HL128170, R01HL123968 and R24HL117756), the Lucile Packard Foundation for Children's Health, the Stanford Child Health Research Institute and the Burroughs Wellcome Foundation. Wu is a member of the Stanford Cancer Institute, Bio-X and the Child Health Research Institute. Mercola is on the scientific advisory board for Vala Sciences, a company offering high-content screening services, and Wu is on the scientific advisory board of Stem Cell Theranostics, a company using patient-specific iPS cells for drug discovery. The Stanford University School of Medicine consistently ranks among the nation's top medical schools, integrating research, medical education, patient care and community service. For more news about the school, please visit http://med. . The medical school is part of Stanford Medicine, which includes Stanford Health Care and Stanford Children's Health. For information about all three, please visit http://med. .


News Article | February 22, 2017
Site: www.eurekalert.org

Cells within our bodies divide and change over time, with thousands of chemical reactions occurring within each cell daily. This makes it difficult for scientists to understand what's happening inside. Now, tiny nanostraws developed by Stanford researchers offer a method of sampling cell contents without disrupting its natural processes. A problem with the current method of cell sampling, called lysing, is that it ruptures the cell. Once the cell is destroyed, it can't be sampled from again. This new sampling system relies on tiny tubes 600 times smaller than a strand of hair that allow researchers to sample a single cell at a time. The nanostraws penetrate a cell's outer membrane, without damaging it, and draw out proteins and genetic material from the cell's salty interior. "It's like a blood draw for the cell," said Nicholas Melosh, an associate professor of materials science and engineering and senior author on a paper describing the work published recently in Proceedings of the National Academy of Sciences. The nanostraw sampling technique, according to Melosh, will significantly impact our understanding of cell development and could lead to much safer and effective medical therapies because the technique allows for long term, non-destructive monitoring. "What we hope to do, using this technology, is to watch as these cells change over time and be able to infer how different environmental conditions and 'chemical cocktails' influence their development - to help optimize the therapy process," Melosh said. If researchers can fully understand how a cell works, then they can develop treatments that will address those processes directly. For example, in the case of stem cells, researchers are uncovering ways of growing entire, patient-specific organs. The trick is, scientists don't really know how stem cells develop. "For stem cells, we know that they can turn into many other cell types, but we do not know the evolution - how do they go from stem cells to, say, cardiac cells? There is always a mystery. This sampling technique will give us a clearer idea of how it's done," said Yuhong Cao, a graduate student and first author on the paper. The sampling technique could also inform cancer treatments and answer questions about why some cancer cells are resistant to chemotherapy while others are not. "With chemotherapy, there are always cells that are resistant," said Cao. "If we can follow the intercellular mechanism of the surviving cells, we can know, genetically, its response to the drug." The sampling platform on which the nanostraws are grown is tiny - about the size of a gumball. It's called the Nanostraw Extraction (NEX) sampling system, and it was designed to mimic biology itself. In our bodies, cells are connected by a system of "gates" through which they send each other nutrients and molecules, like rooms in a house connected by doorways. These intercellular gates, called gap junctions, are what inspired Melosh six years ago, when he was trying to determine a non-destructive way of delivering substances, like DNA or medicines, inside cells. The new NEX sampling system is the reverse, observing what's happening within rather than delivering something new. "It's a super exciting time for nanotechnology," Melosh said. "We're really getting to a scale where what we can make controllably is the same size as biological systems." Building the NEX sampling system took years to perfect. Not only did Melosh and his team need to ensure cell sampling with this method was possible, they needed to see that the samples were actually a reliable measure of the cell content, and that samples, when taken over time, remained consistent. When the team compared their cell samples from the NEX with cell samples taken by breaking the cells open, they found that 90 percent of the samples were congruous. Melosh's team also found that when they sampled from a group of cells day after day, certain molecules that should be present at constant levels remained the same, indicating that their sampling accurately reflected the cell's interior. With help from collaborators Sergiu P. Pasca, assistant professor of psychiatry and behavioral sciences, and Joseph Wu, professor of radiology, Melosh and co-workers tested the NEX sampling method not only with generic cell lines, but also with human heart tissue and brain cells grown from stem cells. In each case, the nanostraw sampling reflected the same cellular contents as lysing the cells. The goal of developing this technology, according to Melosh, was to make an impact in medical biology by providing a platform that any lab could build. Only a few labs across the globe, so far, are employing nanostraws in cellular research, but Melosh expects that number to grow dramatically. "We want as many people to use this technology as possible," he said. "We're trying to help advance science and technology to benefit mankind." Melosh is also a professor in the photon science directorate at SLAC National Accelerator Laboratory, a member of Stanford Bio-X, the Child Health Research Institute, the Stanford Neurosciences Institute, Stanford ChEM-H and the Precourt Institute for Energy. Wu is also the Simon H. Stertzer, MD, Professor; he is director of the Stanford Cardiovascular Institute and a member of Stanford Bio-X, the Child Health Research Institute, Stanford ChEM-H and the Stanford Cancer Institute. Pasca is also a member of Stanford Bio-X, the Child Health Research Institute, the Stanford Neurosciences Institute and Stanford ChEM-H. The work was funded by the National Institute of Standards and Technology, the Knut and Alice Wallenberg Foundation, the National Institutes of Health, Stanford Bio-X, the Progenitor Cell Biology Consortium, the National Institute of Mental Health, an MQ Fellow award, the Donald E. and Delia B. Baxter Foundation and the Child Health Research Institute.


News Article | February 16, 2017
Site: www.eurekalert.org

Alpha cells in the pancreas can be induced in living mice to quickly and efficiently become insulin-producing beta cells when the expression of just two genes is blocked, according to a study led by researchers at the Stanford University School of Medicine. Studies of human pancreases from diabetic cadaver donors suggest that the alpha cells' "career change" also occurs naturally in diabetic humans, but on a much smaller and slower scale. The research suggests that scientists may one day be able to take advantage of this natural flexibility in cell fate to coax alpha cells to convert to beta cells in humans to alleviate the symptoms of diabetes. "It is important to carefully evaluate any and all potential sources of new beta cells for people with diabetes," said Seung Kim, MD, PhD, professor of developmental biology and of medicine. "Now we've discovered what keeps an alpha cell as an alpha cell, and found a way to efficiently convert them in living animals into cells that are nearly indistinguishable from beta cells. It's very exciting." Kim is the senior author of the study, which will be published online Feb. 16 in Cell Metabolism. Postdoctoral scholar Harini Chakravarthy, PhD, is the lead author. "Transdifferentiation of alpha cells into insulin-producing beta cells is a very attractive therapeutic approach for restoring beta cell function in established Type 1 diabetes," said Andrew Rakeman, PhD, the director of discovery research at JDRF, an organization that funds research into Type 1 diabetes. "By identifying the pathways regulating alpha to beta cell conversion and showing that these same mechanisms are active in human islets from patients with Type 1 diabetes, Chakravarthy and her colleagues have made an important step toward realizing the therapeutic potential of alpha cell transdifferentiation." Rakeman was not involved in the study. Cells in the pancreas called beta cells and alpha cells are responsible for modulating the body's response to the rise and fall of blood glucose levels after a meal. When glucose levels rise, beta cells release insulin to cue cells throughout the body to squirrel away the sugar for later use. When levels fall, alpha cells release glucagon to stimulate the release of stored glucose. Although both Type 1 and Type 2 diabetes are primarily linked to reductions in the number of insulin-producing beta cells, there are signs that alpha cells may also be dysfunctional in these disorders. "In some cases, alpha cells may actually be secreting too much glucagon," said Kim. "When there is already not enough insulin, excess glucagon is like adding gas to a fire." Because humans have a large reservoir of alpha cells, and because the alpha cells sometimes secrete too much glucagon, converting some alpha cells to beta cells should be well-tolerated, the researchers believe. The researchers built on a previous study in mice several years ago that was conducted in a Swiss laboratory, which also collaborated on the current study. It showed that when beta cells are destroyed, about 1 percent of alpha cells in the pancreas begin to look and act like beta cells. But this happened very slowly. "What was lacking in that initial index study was any sort of understanding of the mechanism of this conversion," said Kim. "But we had some ideas based on our own work as to what the master regulators might be." Chakravarthy and her colleagues targeted two main candidates: a protein called Arx known to be important during the development of alpha cells and another called DNMT1 that may help alpha cells "remember" how to be alpha cells by maintaining chemical tags on its DNA. The researchers painstakingly generated a strain of laboratory mice unable to make either Arx or DNMT1 in pancreatic alpha cells when the animals were administered a certain chemical compound in their drinking water. They observed a rapid conversion of alpha cells into what appeared to be beta cells in the mice within seven weeks of blocking the production of both these proteins. To confirm the change, the researchers collaborated with colleagues in the laboratory of Stephen Quake, PhD, a co-author and professor of bioengineering and of applied physics at Stanford, to study the gene expression patterns of the former alpha cells. They also shipped the cells to collaborators in Alberta, Canada, and at the University of Illinois to test the electrophysiological characteristics of the cells and whether and how they responded to glucose. "Through these rigorous studies by our colleagues and collaborators, we found that these former alpha cells were -- in every way -- remarkably similar to native beta cells," said Kim. The researchers then turned their attention to human pancreatic tissue from diabetic and nondiabetic cadaver donors. They found that samples of tissue from children with Type 1 diabetes diagnosed within a year or two of their death include a proportion of bi-hormonal cells -- individual cells that produce both glucagon and insulin. Kim and his colleagues believe they may have caught the cells in the act of converting from alpha cells to beta cells in response to the development of diabetes. They also saw that the human alpha cell samples from the diabetic donors had lost the expression of the very genes -- ARX and DNMT1 -- they had blocked in the mice to convert alpha cells into beta cells. "So the same basic changes may be happening in humans with Type 1 diabetes," said Kim. "This indicates that it might be possible to use targeted methods to block these genes or the signals controlling them in the pancreatic islets of people with diabetes to enhance the proportion of alpha cells that convert into beta cells." Kim is a member of Stanford Bio-X, the Stanford Cardiovascular Institute, the Stanford Cancer Institute and the Stanford Child Health Research Institute. Researchers from the University of Alberta, the University of Illinois, the University of Geneva and the University of Bergen are also co-authors of the study. The research was supported by the National Institutes of Health (grants U01HL099999, U01HL099995, UO1DK089532, UO1DK089572 and UC4DK104211), the California Institute for Regenerative Medicine, the Juvenile Diabetes Research Foundation, the Center of Excellence for Stem Cell Genomics, the Wallenberg Foundation, the Swiss National Science Foundation, the NIH Beta-Cell Biology Consortium, the European Union, the Howard Hughes Medical Institute, the H.L. Snyder Foundation, the Elser Trust and the NIH Human Islet Resource Network. Stanford's Department of Developmental Biology also supported the work. The Stanford University School of Medicine consistently ranks among the nation's top medical schools, integrating research, medical education, patient care and community service. For more news about the school, please visit http://med. . The medical school is part of Stanford Medicine, which includes Stanford Health Care and Stanford Children's Health. For information about all three, please visit http://med. .


News Article | February 16, 2017
Site: www.eurekalert.org

Timothy Blake, a postdoctoral fellow in the Waymouth lab, was hard at work on a fantastical interdisciplinary experiment. He and his fellow researchers were refining compounds that would carry instructions for assembling the protein that makes fireflies light up and deliver them into the cells of an anesthetized mouse. If their technique worked, the mouse would glow in the dark. Not only did the mouse glow, but it also later woke up and ran around, completely unaware of the complex series of events that had just taken place within its body. Blake said it was the most exciting day of his life. This success, the topic of a recent paper in Proceedings of the National Academy of Sciences, could mark a significant step forward for gene therapy. It's hard enough getting these protein instructions, called messenger RNA (mRNA), physically into a cell. It's another hurdle altogether for the cell to actually use them to make a protein. If the technique works in people, it could provide a new way of inserting therapeutic proteins into diseased cells. "It's almost a childlike enthusiasm we have for this," said chemistry Professor Robert Waymouth. "The code for an insect protein is put into an animal and that protein is not only synthesized in the cells but it's folded and it becomes fully functional, capable of emitting light." Although the results are impressive, this technique is remarkably simple and fast. And unlike traditional gene therapy that permanently alters the genetic makeup of the cell, mRNA is short-lived and its effects are temporary. The transient nature of mRNA transmission opens up special opportunities, such as using these compounds for vaccination or cancer immunotherapy. Gene therapy is a decades-old field of research that usually focuses on modifying DNA, the fundamental genetic code. That modified DNA then produces a modified mRNA, which directs the creation of a modified protein. The current work skips the DNA and instead just delivers the protein's instructions. Previous work has been successful at delivering a different form of RNA - called short interfering RNA, or siRNA - but sending mRNA through a cell membrane is a much bigger problem. While both siRNA and mRNA have many negative charges - so-called polyanions - mRNA is considerably more negatively charged, and therefore more difficult to sneak through the positively charged cell membrane. What the researchers needed was a positively charged delivery method - a polycation - to complex, protect and shuttle the polyanions. However, this alone would only assure that the mRNA made it through the cell membrane. Once inside, the mRNA needed to detach from the transporter compound in order to make proteins. The researchers addressed this twofold challenge with a novel, deceptively straightforward creation, which they call charge-altering releasable transporters (CARTs). "What distinguishes this polycation approach from the others, which often fail, is the others don't change from polycations to anything else," said chemistry Professor Paul Wender, co-author of the paper. "Whereas, the ones that we're working with will change from polycations to neutral small molecules. That mechanism is really unprecedented." As part of their change from polycations to polyneutrals, CARTs biodegrade and are eventually excreted from the body. This research was made possible through coordination between the chemists and experts in imaging molecules in live animals, who rarely work together directly. With this partnership, the synthesis, characterization and testing of compounds could take as little as a week. "We are so fortunate to engage in this kind of collaborative project between chemistry and our clinical colleagues. It allowed us to see our compounds go from very basic building blocks - all the way from chemicals we buy in a bottle - to putting a firefly gene into a mouse," said Colin McKinlay, a graduate student in the Wender lab and co-lead author of the study. Not only did this enhanced ability to test and re-test new molecules lead to the discovery of their charge-altering behavior, it allowed for quick optimization of their properties and applications. As different challenges arise in the future, the researchers believe they will be able to respond with the same rapid flexibility. After showing that the CARTs could deliver a glowing jellyfish protein to cells in a lab dish, the group wanted to find out if they worked in living mice, which was made possible through the expertise of the Contag lab, run by Christopher Contag, professor of pediatrics and of microbiology and immunology. Together, the multidisciplinary team showed that the CARTs could effectively deliver mRNA that produced glowing proteins in the thigh muscle or in the spleen and liver, depending on where the injection was made. The researchers said CARTs could move the field of gene therapy forward dramatically in several directions. "Gene therapy has been held up as a silver bullet because the idea that you could pick any gene you want is so alluring," said Jessica Vargas, co-lead author of the study, who was a PhD student in the Wender lab during this research. "With mRNA, there are more limitations because the protein expression is transient, but that opens up other applications where you wouldn't use other types of gene therapy." One especially appropriate application of this technology is vaccination. At present, vaccines require introducing part of a virus or an inactive virus into the body in order to elicit an immune response. CARTs could potentially cut out the middleman, directly instructing the body to produce its own antigens. Once the CART dissolves, the immunity remains without any leftover foreign material present. The team is also working on applying their technique to another genetic messenger that would produce permanent effects, making it a complementary option to the temporary mRNA therapies. With the progress already made using mRNA and the potential of their ongoing research, they and others could be closer than ever to making individualized therapeutics using a person's own cells. "Creating a firefly protein in a mouse is amazing but, more than that, this research is part of a new era in medicine," said Wender. Additional co-authors of this study, "Charge-altering releasable transporters (CARTs) for the delivery and release of mRNA in living animals," include Timothy Blake, Jonathan Hardy, Masamitsu Kanada and Christopher Contag. Waymouth is also a professor, by courtesy, of chemical engineering, a member of Stanford Bio-X, a faculty fellow of Stanford ChEM-H and an affiliate of the Stanford Woods Institute for the Environment. Wender is also a professor, by courtesy, of chemical and systems biology, a member of Stanford Bio-X, a member of the Stanford Cancer Institute and a faculty fellow of Stanford ChEM-H. Contag is also a professor, by courtesy, of radiology and of bioengineering, a member of Stanford Bio-X, a member of the Child Health Research Institute and a member of the Stanford Cancer Institute. This work was funded by the Department of Energy, the National Science Foundation, the National Institutes of Health, the Chambers Family Foundation for Excellence in Pediatric Research, the Child Health Research Institute, the Stanford Center for Molecular Analysis and Design and the National Center for Research Resources.


News Article | January 22, 2016
Site: www.biosciencetechnology.com

Some stage-2 colon cancer patients may benefit from the use of chemotherapy after surgery, according to a retrospective study by researchers at the Stanford University School of Medicine. Previous studies have suggested that chemotherapy given to such patients had limited benefit. The study was published Jan. 21 in The New England Journal of Medicine along with two editorials describing its significance. The researchers first categorized colon cancer patients based on the presence or absence of a protein called CDX2, which is found in mature colon cells. In these cells, CDX2 helps to control the expression of other genes that drive colon cell specialization. The researchers found that about 4 percent of people with colon cancer have tumors that don’t express CDX2. In an initial study of 466 patients with any stage of colon cancer, only about 41 percent of those with cells lacking CDX2 lived disease-free for five years after treatment, compared to 74 percent of those with CDX2 in their cancer cells.   CDX2-negative cancers respond well to chemo But the researchers identified another important distinction between the two groups, particularly in those with stage-2 disease: Patients whose tumor cells didn’t express CDX2 were much more likely to benefit from chemotherapy in addition to surgery than were people with CDX2-positive tumors. About 91 percent of patients with CDX2-negative cancers treated with chemotherapy in addition to surgery lived disease-free for five years versus about 56 percent of those who did not receive chemotherapy. Previous studies that did not distinguish between CDX2-positive and CDX2-negative cancers suggested that chemotherapy provided little additional benefit to stage-2 colon cancer patients. “We’ve learned that a patient group that formerly was not known to need adjuvant chemotherapy may, in fact, benefit from this treatment. Conversely, it may be possible to identify those patients who could avoid the toxic side effects of chemotherapy,” said Michael Clarke, M.D., professor of medicine and the Karel H. and Avice Beekhuis Professor in Cancer Biology. The retrospective study looked at gene expression in cancer cells and tissues from over 2,000 patients whose treatment courses and outcomes were known. The researchers emphasize that a randomized, prospective clinical trial is necessary to further confirm the results before clinical changes are codified. Clarke, who is also a member of the Stanford Cancer Institute and the associate director of the Stanford Institute for Stem Cell Biology and Regenerative Medicine, is the senior author of the study. Former instructors and Siebel fellows Piero Dalerba, M.D., and Debashis Sahoo, Ph.D., share lead authorship of the study. Dalerba is now an assistant professor of pathology and cell biology and of medicine (Division of Digestive and Liver Diseases) at Columbia University, and Sahoo is an assistant professor of pediatrics and of computer science at the University of California-San Diego. Stem cell, cancer connection Clarke and his colleagues have been studying the connection between stem cells and cancer for several years. For this study, Dalerba and Sahoo sought to devise a way to identify colon cancers that were more stem-cell-like, and thus likely to be more aggressive. They looked for a gene that was expressed in more mature cells but not in stem or progenitor cells. They did this by using a novel bioinformatics approach that drew on their knowledge of stem cell biology to identify developmentally regulated genes important in colon tissue maturation. Because they knew from previous research by Dalerba in the Clarke laboratory that stem and immature colon cells express a protein called ALCAM, Dalerba and Sahoo looked for genes whose protein product was negatively correlated with ALCAM expression. “We reasoned that those proteins would likely be involved in the maturation of colon tissue and might not be found in more aggressive, immature cancers,” Sahoo said. Finally, to ensure their results would be useful to doctors, the researchers added another criterion: The gene had to make a protein that was easily detectable by an existing, clinical-grade test. The screening technique identified a promising candidate: the CDX2 protein. “We chose CDX2 because it was the only candidate that was already used as a diagnostic biomarker in the clinic,” Dalerba said. “However, we were also intrigued by the fact that CDX2 is a master transcription factor controlling the expression of many differentiation genes in colon epithelial cells.” When they separated colon cancer cases into those with cells that either did or did not express CDX2, they found a marked difference in both five-year, disease-free survival rates and in response to chemotherapy. Data sharing and collaboration “The CDX2 protein plays a role in the differentiation of the intestinal epithelium,” said Clarke, who is also deputy director of the Ludwig Center for Cancer Stem Cell Research and Medicine at Stanford. “The novel bioinformatics analyses used in this paper links its expression to more differentiated cells in colon cancers. We found that patients whose cancers lacked CDX2 expression, which suggests that their tumors have a high proportion of cancer stem and progenitor cells, had a much worse prognosis. However, their outcomes improved significantly if they had received chemotherapy as part of their treatment.” The study is hailed in an accompanying editorial in the journal as an endorsement of data sharing and collaboration among many different research groups. The Stanford researchers used information stored in the National Center for Biotechnology Information’s Gene Expression Omnibus database to identify CDX2. Tissue samples were provided by the Cancer Diagnosis Program of the National Cancer Institute, the National Surgical Adjuvant Breast and Bowel Project and the Stanford Tissue Microarray Database. “A major question in the cancer field is whether the study of cancer stem cells can lead to increases in survival for cancer patients. This research is one of the first examples of how we can use our growing knowledge of stem cell biology to improve patient outcomes,” Clarke said.

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