Prevention of Complications in Thalassemia

描述（由申请人提供）：在开展和解决地中海贫血并发症预防研究倡议的研究和规划目标方面的先前工作经验：自17年前成立以来，NCTC已经开发了一个不断发展的全州项目，致力于提供全面的多学科护理、亚专业服务、社区外展和参与研究试验的机会。NCTC的主要站点是儿童医院和奥克兰研究中心（CHRCO）以及遍布加利福尼亚州的七个卫星医疗中心网络。作为全国为数不多的综合性地中海贫血中心之一，国家中心在许多与地中海贫血相关的问题上是一个罕见的资源和权威。它是世界上一些最有经验的地中海贫血研究人员和卫生保健提供者的所在地，拥有积极和广泛的外展计划，并拥有良好的基础设施和堪称典范的研究和传播记录。自2002年以来，NCTC参与了CDC拨款U27/CCU92210，为整个加利福尼亚州的患者提供全面的多学科护理，为患者和社区提供外展和教育，在地中海贫血的国家研究试验中发挥主导作用，并将CHRCO的患者纳入CDC地中海贫血通用数据收集计划和血清转化和可疑血源性病原体的调查。除了持续参与疾病预防控制中心的地中海贫血并发症试验外，我们还协调了多中心研究试验，在地中海贫血临床研究网络中发挥主导作用，并开展了大量基础、临床和转化研究。

DESCRIPTION (provided by applicant): Prior work experience in conducting and addressing the research and programmatic objectives of the Research Initiative for the Prevention of Complications of Thalassemia: Since its establishment 17 years ago, the NCTC has developed a growing statewide program dedicated to delivering comprehensive multidisciplinary care, subspecialty services, community outreach, and opportunities to participate in research trials. The primary site of the NCTC is Children's Hospital and Research Center Oakland (CHRCO) and a network of seven satellite medical centers throughout the state of California. As one of only a handful of comprehensive thalassemia centers in the nation, the NCTC is a rare resource and authority on many issues related to thalassemia. It is home to some of the most experienced thalassemia researchers and healthcare providers in the world, has an active and wide-reaching outreach program, and boasts an excellent infrastructure and an exemplary record of research and dissemination. Since 2002, the NCTC has participated in CDC grant U27/CCU92210, offering comprehensive multi-disciplinary care to patients throughout California, providing outreach and education to patients and communities, playing a lead role in national research trials in thalassemia, and enrolling patients from CHRCO in the CDC Thalassemia Universal Data Collection Program and investigations of sero-conversions and suspected blood borne pathogens. In addition to its ongoing participation in the CDC trial Prevention of the Complications of Thalassemia, we have coordinated multi-center research trials, assumed a leading role in the Thalassemia Clinical Research Network, and undertaken numerous basic, clinical, and translational research studies. A clear description of the populations to be reached and how they will be identified, enrolled and made part of all research initiatives: In 2006, the NCTC provided comprehensive care to 140 thalassemia patients at Children's Hospital and Research Center at Oakland (CHRCO), a 12% increase in the number of patients seen in the previous year. Of these 140, 42% have beta thalassemia and 43% are transfusion dependent. Approximately 51% are women and 75% are of Asian descent. Within the entire network of CHRCO and its satellites, nearly 400 patients across California receive care through the NCTC. In 2006, 91% of the patients in the NCTC received a comprehensive annual visit. During these comprehensive annual visits, and via widely disseminated research flyers and outreach efforts (including over 60 activities in 2006), patients are educated about ongoing research initiatives at the NCTC. More than 300 NCTC patients have consented to participate in research studies through the TCRN alone. Outreach to both the identified thalassemia community and the at-risk population has been a top priority and continues to be a mainstay of the NCTC's work. The tremendous influx in the Asian population and growing awareness of thalassemia and its complications have created an increased demand for patient services, education, and counseling statewide. Recently, the NCTC expanded efforts into new Asian communities within the Stockton, Fresno, and San Jose areas and to the Middle Eastern and Indian communities. The NCTC website continues to offer updated information about thalassemia, new research and clinical trial opportunities, and allows individuals to email questions to NCTC. An outline of the surveillance data collection systems in place and how they will be employed and expanded to support and underpin the programs to be implemented under this new project: Infections are the second most common cause of death in thalassemia major. Pathogens are transmitted by blood transfusion, and altered host immunity from hypersplenism and iron overload contribute to the morbidity. Specific transfusion protocols are followed and all transfused patients are screened annually for hepatitis B surface antibody, surface antigen and core antibody and HIV. Transfused patients are also screened annually for hepatitis C surface antibody and if positive, PCR for hepatitis C is measured. Liver function tests are obtained every 3 months and if elevated, patients are again screened for hepatitis B, C, and A; CMV, EBV, Parvovirus, and HIV. These protocols and infrastructure have supported the enrollment of 55 patients from NCTC on CDC U27/CCU922110. Continued funding will allow us to follow these patients annually with ongoing specimen collection and shipping to the CDC and completion of annual data forms. We will also be able to enroll an additional 30 patients over the next funding cycle. A full range of services and screening for complications are available for thalassemia patients at the NCTC. The Hemoglobinopathy Reference Laboratory at NCTC is the reference laboratory for the State of California Newborn Screening Program. We are the only program in North America to universally screen all births for both beta-thalassemia and alpha-thalassemia. Patients are referred to the center through newborn screening and outreach activities. We have been successful in providing annual comprehensive exams to over 90% of patients with the goal of providing annual screening, surveillance and treatment for iron overload, heart disease, liver disease, endocrine dysfunction, nutritional deficiencies and disorders of bone metabolism. Our future goals include expanded screening for cardiac iron deposition using newly available MRI technology and pulmonary hypertension. Indications of research hypotheses and research questions to be addressed and answered throughout the life of this new award cycle Indications of research hypotheses and research questions to be addressed and answered throughout the life of this new award cycle: The NCTC continues to take a leading role as PI or Co-Pi on almost all of the protocols for the TCRN. In addition, several investigators at the NCTC are recipients of K and other research awards and are coordinating independent studies in thalassemia. Examples of current research hypotheses under investigation include: 1) Deferoxamine (DFO) and deferiprone (L1) combination therapy improves left ventricular function more rapidly than DFO/placebo therapy among transfusion dependent beta-thalassemia patients with abnormal resting ejection fractions, 2) Arginine and sidenafil will both show clinical efficacy in the treatment of pulmonary hypertension, 3) Nine months of administration of low-dose subcutaneous decitabine can produce clinically significant (2-3g/dl) increases in total hemoglobin in patients with thalassemia intermedia, 4) Antioxidant therapy with a combination of RS-Alpha-Lipoic Acid (LA) and L-Carnitine (ALCAR) will produce a measurable decline in oxidative stress in patients with thalassemia, 5) Increased platelet activation and hypercoagulability is the primary cause of the development of pulmonary hypertension, and 6) Zinc supplementation can improve bone health as measured by bone mineral density, bone strength, and markers of bone formation and resorption in beta-thalassemia patients. Presentation of completed and in-process studies undertaken with an indication of how new data and research will contribute to enhanced outcome-based initiatives for patient identification, clinical care and follow-up, including family and caregiver dynamics: A major focus of the NCTC is to undertake outcome-based research that will result in improved diagnosis and treatment of patients with thalassemia and assistance for their families. Our multi-disciplinary approach to outcome-based research addresses the wide spectrum of problems facing this disease that range from cultural obstacles affecting immigrants to new iron chelators, nutrition, management of medical complications, and experimental therapy. These subjects are briefly summarized here and are referred to throughout the text. We are California's Reference Hemoglobinopathy Center for newborn screening and the NIH-sponsored central Hemoglobin Diagnosis Laboratory for North America. This has given us the opportunity to prospectively monitor the epidemiology of thalassemia. Long-term, prospective follow-up of newborns who have undergone DNA and genetic modifier diagnosis has enabled us to better understand the genotype/phenotype correlations. Information from these studies has led to the establishment of North America's only universal alpha-thalassemia screening program, defined the clinical importance of Hb H Constant Spring, Hb E Thalassemia and other new variants. In addition, there is ongoing research to understand the cultural and social impact of thalassemia on the changing ethnic groups. Iron overload and its management: The NCTC is the principal investigator on several approaches to improve iron chelation and monitor their toxicity. This includes the development of new chelators, including long-acting starch Desferal, and combination therapy with deferasirox and Desferal. In addition, we are the co-investigator on several prospective trials evaluating deferiprone, deferasirox, continuous desferal for cardiac disease or cardiac hemosiderosis. Linked to the new chelators is a comprehensive program addressing non-invasive technology to diagnosis iron overload including new studies measuring pituitary, gonadal, and cardiac iron with SQUID and MR. Management of complications: Treatment of thalassemia requires evidence-based information. Our program focuses on prospective studies to prevent and improve the diagnosis and treatment of complications. Complications and therapy under study include aspirin, arginine, sildenafil for pulmonary hypertension, antioxidant supplementation, combination therapy for hepatitis surveillance programs of blood safety, new approaches to cardiac disease, preimplantation therapy for pregnancy and the problem of transitioning patients into adulthood. New therapy: Our approach to therapy has focused on fetal hemoglobin F modulator trials, including hydroxyurea, darbepoietin, and recently Decitabine. In addition, we have been prospectively evaluating new approaches to stem cell transplantation in order to decrease morbidity and increase access for patients without allogeneic matches.