MINUTES OF THE NINETY-THIRD MEETING OF THE SICKLE CELL DISEASE ADVISORY COMMITTEE

Bethesda, Maryland

October 29, 2007


COMMITTEE MEMBERS PRESENT

F. Daniel Armstrong PhD., (Chair), University of Miami, M.A. Bender,MD., Ph.D., Fred Hutchinson Cancer Research Center, Frans Kuypers, MD., CHORI, Punam Malik, MD., Cincinnati Children’s Hospital Medical Center, Ms. Shirley Miller, Southwestern Comprehensive Sickle Cell Center, Eugene Orringer MD., University of North Carolina, Prospective members pending confirmation. Susan Perrine, MD., (Boston University School of Medicine, Yogen Saunthararajah, MD., Cleveland Clinic/Case Western Reserve, Wally Smith, MD., Virginia Commonwealth University

Ex- Officio Members Present

Joseph DeSimone, PhD., Veterans Administration, ILL, Dr. Marie Earley, MD, CDC

Ex-. Officio Members Absent

Marie Mann, MD., HRSA, David McCune, MD, MPH, Madigan Army Medical Center, Tacoma, WA

NIH Staff Present:

(NHLBI) R.Blaine Moore PhD, Greg Evans PhD, Ellen Werner PhD, Harvey Luksenurg MD, Charles Peterson MD MBA, Susan Shurin MD, (NHLBI) Terry Bishop PhD., (NIDDK), Ms. Annie Joseph, Committee Management, Kathryn Hassell, MD (NHLBI), Mammah Borbor, (NHLBI), Liz Wagner, (NHLBI),

Other Persons Present:

Willarda Edwards MD MBA, (SCDAA), Ms. Sonja Ross, (SCDAA), William Woods MD, (invited presenter), William Winter, PhD., (Howard University), Garei Pahuja, PSI, Inc.

The meeting was held in room 9112/9116 of 6701 Rockledge Dr. Dr. Moore opened the meeting at 8:30 am. He welcomed all of the participants and commented that it was an exciting time for advances in sickle cell research. Yet, there are challenges that will face the research community in the near future due to the continued limitations in NIH funding. Dr. Moore turned the meeting over to Dr. Armstrong, the Chair.

Dr. Armstrong also extended his welcome to everyone. Following his brief comments, everyone introduced themselves. The minutes for the previous meeting, June 4 2007, were raised for discussion. A motion to approve the minutes was put forward, seconded and passed unanimously. Dr. Susan Shurin, the Deputy Director of NHLBI was introduced and invited to make comments.

Dr. Susan Shurin welcomed everyone on behalf of Dr. Betsy Nabel, the Institute Director. Dr. Shurin informed the committee that the NHLBI Strategic Plan is completed and will be available soon. The plan is purposefully generic so that it is pertinent to all interests of the institute including heart, vascular, lung, blood and sleep. However, a retreat is planned to assess how the overall plan will apply to each of the divisions and branches. The Institute is very excited about the real advances that are being made in sickle cell research and the ways in which they are impacting our health care for this population. In addition to the ongoing studies that are to be presented later in the meeting, there have been exciting new frontiers as demonstrated by the workshop on Neurobiology of Pain in Sickle Cell Disease held in 2007. Discussions regarding future directions in research and health care for sickle cell disease have been held in conjunction with an American Society of Hematology Workshop and a Summit meeting with the American Society of Pediatric Hematology/Oncology. NHLBI continues to collaborate with other institutes within NIH on sickle cell disease programs including NIDDK, NICHD, NIA and NINDS. Our partnerships with other agencies such as HRSA and CDC continue and we hope will be increased in the near future.

PRESENTATION

The first presenter, Dr. William Woods was introduced by Dr. Blaine Moore. Dr. Woods talk was entitled, “Improving Research and Health Care for Patients with Sickle Cell Disease – Discussions from the ASPHO Summit.”

Dr. Woods is currently the President of the American Society of Pediatric Hematology/Oncology, a 1300 member association whose primary emphasis is pediatric oncology. In 2007, the main focus of their summit was sickle cell disease. Dr. Woods explained that the Children’s Oncology Group developed out of grass roots interest among physician scientists and that such a model program would be worth considering for sickle cell disease. The vision of the Summit was to consider developing an adequately funded coordinated comprehensive and integrated national model for care of persons with SCD; one that would involve all stakeholders. Among the topics discussed were: the opportunities, threats, gaps, and actions required to implement such a vision. The areas that need to be addressed were: Access to Care; a Medical Home; Best Practices; Surveillance Research; Developing a single unified voice; and Fund Raising. A White Paper or Summary of the Findings of the ASPHO summit is being written to increase public awareness.

Following the presentation there was considerable discussion from the SCDAC members. It was felt that, while the oncology group model is meritorious and may be helpful in developing a nationwide program for sickle cell disease, it may not be as applicable for several reasons. First, there needs to be a revenue stream in which to initiate and maintain such a national program and this has proved difficult to acquire for SCD. Second, unlike childhood cancer, a group of diseases that are life-threatening and affect all racial and ethnic populations, sickle cell disease is limited predominantly to the African American population and does not attract a comparable level of the public interest as cancer. Third, iIt was acknowledged that public awareness and completing the vision would occur only if the program was designed by all of the stakeholders, NIH, other DHHS agencies such as CDC, HRSA, AHRQ and CMS and patient advocacy groups, most importantly, the Sickle Cell Disease Association of America. Involvement of the community organizations across the country would be a key component. What is required is a small group or organization to spearhead such a coordinating committee of the major stakeholders. The recent meetings with ASH and ASPHO are good starts but a more centralized working group is needed.

It was decided that the SCD Advisory Committee would compose a letter to the Institute commending the NHLBI on their successes in advancing sickle cell research and improving health care for sickle cell patients in the United States. The letter will encourage the Institute to continue its leadership in this field and to participate in or help initiate a national program to further improve our research plan and the way in which we provide care for sickle cell patients in the U.S.

I. CHAIRMAN’S REPORT (Dr. Daniel Armstrong)
Dr. Armstrong expressed his thanks on behalf of the committee regarding the recent joint SCDAA and NHLBI Sickle Cell Meeting. It was one of the best that has been organized. Both the science and the social events were outstanding.

II. AGENCY REPORTS

Newborn Screening Branch/CDC (Dr. Mary Early)
A Newborn Screening and quality insurance program has been implemented for the screening of sickle cell disease.  In addition to the 49 US sites there are a limited number (26) of international sites.  Improvements in technologies are being made for better testing.  The Branch will be merging with the Biology and Molecular Medicine Branch at CDC.

HRSA                                                                                                                                     
No report at this meeting.  A representative from HRSA was unable to attend due to a conflict.

VETERANS ADMINISTRATON (Dr. Joseph DeSimone)
We are very concerned about veterans with SCD or trait who are not receiving appropriate attention and follow-up.  Better reviews are needed for research in this area.  There have been no reports regarding adverse events of sickle cell trait among soldiers in Iraq or Afghanistan. 

Dr. Armstrong reported on a case of a sickle cell trait teenager who died from being beaten and that the death was attributed to vaso-occlusion – the guards were exonerated.  This occurred in Florida. It is very unfortunate that mistakes of this kind are still made due to lack of knowledge about the disease.

III. DBDR DIRECTOR’S REPORT   (Dr. Charles Peterson)

Division Strategy – When Dr. Peterson arrived NHLBI had an abundant SCD program but it was not a coordinated program with a pipeline and a direction.  Pharmaceuticals for this disease have been very hard to develop because companies are not interested in a limited cohort, so desired achievements have not been attained.    A plan to harness the health care community and provide them with a financial pipeline would go a long way toward improving access to improved therapies and better health outcomes.

Dr. Armstrong announced that Dr. Peterson would be leaving in the near future:  The SCDAC expressed there debt of gratitude for the service that he has provided to the Division of Blood Diseases and Resources and to the National Heart, Lung and Blood Institute over the last 10 years.

IV. UPDATE ON PROGRAM ACTIVITIES       

A.        Comprehensive Sickle Cell Centers (Drs. Ellen Werner & Greg Evans)
           
The Comprehensive Sickle Cell Centers (CSCC) program began in 1972, with a mandate from Congress for 10 centers to be funded beginning in 1983.  At this time, the CSCC include the following components:  (1) Clinical, basic, translational, and patient services research projects; (2) Clinical, Administrative, and Patient Services Cores; and (3) a Scholars Program, as well as a high school summer program.  Multi-institutional Phase II clinical trials are conducted by the CSCC, with support for all programs provided by a Statistics and Data Management Center.  There is a link to the CSCC on the NHLBI website.

There are currently nine multi-center phase II studies (Dr. Evans distributed a timeline for these studies to SCDAC members).  These include:

  • Oral Arginine supplementation (no benefit in the pediatric arm)
  • Neurocognitive/neuroimaging study (seen a real neurocognitive deficit and are now working towards transfusion therapy to correct this)
  • Collaborative-Data
  • Epidemiology of priapism (recruited 1200 of the 1600 patients)
  • Hydroxyurea plus magnesium
  • Oral Dexamethasone for acute chest syndrome (in its early stages)
  • Decitabine for fetal Hemoglobin induction
  • Genotype/phenotype study (3500 patients for the C-data study)
  • DNA protocol to go with the C-data program

 

The centers are being re-competed.  The Review Meeting was held on September 5-7, 2007 and the summary statements are now out. Dr. Orringer expressed his opinion at how well the CSCCs do in enrolling patients for there Phase I/II studies.  Centers ought to be commended.   Dr. Malik commented that the creation of the CTC within the centers has been very good.  This was an excellent vision.  She expressed her concern about the time required to get the trials up and started. Drs. Smith and Malik commented that there need to be observational studies and they are just as important as clinical drug interventional trials. Dr. Armstrong commented that it is common to see patients that come in for one clinical study have participated in many other previous studies and trials. He also noted that it is apparent that we have limited patient outcomes research. This could be addressed by partnering with HRSA, CDC and AHRQ for an RFA on Health Economics Research.  Several members of SCDAC noted that, at the clinical level, patients are not being provided with the research results.

B. Sickle Cell Disease Clinical Research Network                          Dr. Harvey Luksenburg

The SCD CRN is composed of 8 clinical sites, 2 Patient Outcomes Cores and one Data Coordinating Center (NERI).  Funding of the program began in October 2005.  The purpose of the network is to translate results from basic and Phase I/II studies in sickle cell disease to Phase III clinical trials.  The network was to include Patient Outcomes Cores to conducts studies in epidemiology, health economic studies and psychosocial, behavioral and QoL studies.  The network has 36 million dollars committed to it over 5 years.  At this time four protocols have been approved by the Steering Committee to proceed towards activation.  This process involves protocol development, PRC, DSMB and IRB approvals, investigator/coordinator training and site activations.  Two clinical studies are among those proposed within the network.  PROACTIVE is entitled, “Preventing Acute Chest Syndrome by Transfusion”.  The PI for this trial is Dr. Lori Styles at Oakland, CA.  The study will investigate whether or not transfusion therapy can be used to prevent impending episodes of ACS.  The Losartan study will determine whether an angiotensin receptor blocker will decrease the rate of progression of renal disease in SCD patients with albuminuria.  The TAPS study is one initiated in the UK to determine if transfusion for sickle cell patients is required or even harmful pre-operatively.  Partial funding is available for this protocol from the UK study.  Finally a Bone Marrow Transplant protocol is being considered to study a reduced intensity conditioning regimen in unrelated donors.  This is a phase II  study involving children between the ages of 3 and 16 who have severe sickle cell disease. Within the last year, protocol subcommittees within the network were formed to review potential protocols submitted from within the network and from outside the network.  The DSMB and PRC for this network have been created.  The PRC has reviewed the first protocol PROACTIVE.  The manual of procedures for this protocol has been completed.  The TAPS and BMT studies were approved by the Steering committee in September 2007.  The next meeting of the Steering Committee to approve protocols is in November 2007
                       
A comment was made that the network will have difficulty doing many of the clinical studies because there are not enough centers that have sufficient patients for their mission.  No network or trial has been successful in completing trials/studies without involving satellite sites.  The average successful multi-center trial involving a single protocol recruits 15-25 clinical sites.  At present the SCD CRN only has 8 funded centers and four of them are associated with Comprehensive Sickle Cell Centers who have many patients already enrolled in their phase I/II studies.  This issue is currently being reviewed by NHLBI.

C.        Sickle Cell Health-Related QOL Questionnaire Project            Dr. Ellen Werner
           
            ASCQ-Me stands for Adult Sickle Cell Quality of Life Measurement and Information system.  The concept for this program was initiated from a conference held in 2002.  The RFP was released and a contract was awarded in 2005.  The purpose of the contract is to develop a validated instrument that will assess health related quality of life in adult sickle cell subjects (ages 18 and above). The contract was awarded to the American Institute of Research;  Dr. San Keller is the Principal Investigator.  Considerable progress has been made in creating the initial Instrument which is expected to be ready for field tests in Spring 2008.  According to the schedule, the final version will be ready for implementation in September 2008.  NHLBI will be encouraging future clinical studies to use this instrument to capture information on quality of life issues.

D.        Surveillance System for Hemoglobinopathies: Initiative         Dr. Ellen Werner
           
            Federal health data systems provide researchers, policy-makers, and the U.S. public with information on the general population and specific patient groups.  These systems are part of the public health function of NIH and the Centers for Disease Control and Prevention (CDC). 

            From November 2006 to June 2007, DBDR/NHLBI participated in meetings at the invitation of the Sickle Cell Disease Association of America, and with CDC, HRSA, professional organizations and consumers, to discuss a national patient registry for sickle cell disease.  Discussions focused on a potential registry’s purpose; utility; feasibility; HIPAA issues, confidentiality, and privacy; data linkage; and data quality.  In consultation with the NHLBI’s Sickle Cell Disease Advisory Committee (SCDAC), at its June 2007 meeting, stakeholders and DHHS agencies concluded that a federal surveillance system would be a more useful and feasible data collection system to characterize the USA sickle cell patient population’s clinical, epidemiologic, health care utilization, provider practice patterns, and community organization involvement.

            A report is being prepared in response to the SCDAC’s deliberations at its June 2007 meeting.  This report  will describe preliminary plans to develop, pilot test, evaluate, and implement a trans-DHHS collaborative, state-specific Hemoglobinopathies Surveillance System that can be used for research, information dissemination, policy decisions, and health care planning and provider training at the local, state, and national levels.

The purposes of a Hemoglobinopathies Surveillance System are to systematically collect, analyze, interpret, and disseminate state-specific data on the epidemiology, clinical correlates, health care utilization, and community resources of patients with sickle cell disease, thalassemias (α and β), and hemoglobin E disease.

E.         Assessing guidelines for SCD Management                            Dr. Ellen Werner

Objectives:

  • Extract sickle cell-specific guidelines from documents on the websites of NIH, AHRQ, and other agencies, and through paper or electronic means of state departments of health and health insurance companies, and the ACMG action sheets
  • Compile sickle cell-specific guidelines in one document, and organize them by organ system and age (i.e., infancy, childhood, adolescence, adult); and convene expert panels to evaluate the type and strength of evidence, and validity of the guidelines.

Purpose and Rationale of the Initiative:  The purposes of this initiative are to evaluate existing guidelines for sickle cell management, determine gaps in evidence that can be used to generate guidelines (i.e., for primary, secondary, or tertiary prevention among all affected age groups), and to enable dissemination of validated guidelines to the health care community and consumers.         

  • NIH Consensus Development Conference: HU in SCD   Dr. Ellen Werner

 

In the 1990’s, Hydroxyurea was considered a hopeful drug for sickle cell patients to ameliorate the many clinical symptoms, primarily a reduction in the frequency and severity of pain episodes.  Hydroxyurea has been used as an anti-cancer drug and may have adverse long term side effects including carcinogenesis.  In 1998, the FDA approved hydroxyurea for use in sickle cell adults.  Since that time there have been unresolved issues about its use. 
 
In order to take a closer look at this important topic, the National Heart, Lung, and Blood Institute and the Office of Medical Applications of Research of the National Institutes of Health will convene a Consensus Development Conference from February 25–27, 2008, to assess the available scientific evidence related to the following questions:

  • What is the efficacy (results from clinical studies) of hydroxyurea treatment for patients who have sickle cell disease in three groups: infants, preadolescents, and adolescents/adults?
  • What is the effectiveness (in everyday practice) of hydroxyurea treatment for patients who have sickle cell disease?
  • What are the short- and long-term harms of hydroxyurea treatment?
  • What are the barriers to hydroxyurea treatment (i.e., health care system factors, and patient-related factors) for patients who have sickle cell disease and what are the potential solutions?
  • What are the future research needs?

A fuller description of the conference including the agenda and speakers can be found at the following URL address:   http://consensus.nih.gov/2008/2008sicklecellcdc119main.htm
           
G.        Best Practices in Transfusion Medicine                                   Dr. Kathy Hassell

Dr. Kathy Hassell spoke as representative of the Sickle Cell Adult Provider Network (SCAPN).  The network is evaluating the best practices for assessing and treating adult sickle cell disease.  The first conference was held in September, 2006 and focused on pain management in the emergency department, inpatient and outpatients settings.  SCAPN holds an annual symposium to discuss many of these issues.  The most recent meeting was held during the 35th sickle cell meeting in September 2007 in Washington, DC and addressed transfusion practices and chelation therapy in adults with sickle cell disease.  The network is in the process of preparing a best guidelines document that should be completed within 6 months to 1 year.

H.        BABY HUG Phase 3 Clinical Trial                                        Dr. Charles Peterson

The Baby HUG trial is nearing the end.  All 193 patients have now been enrolled and all data will be entered by 2009.  Funding has been identified for a contract to do a follow-up study.   

I.          SWiTCH Phase 3 Clinical Trial                                         Dr. Harvey Luksenburg

SWiTCH is a Phase III clinical trial designed to test the hypothesis that hydroxyurea and phlebotomy can maintain an acceptable stroke recurrence rate and significantly reduce hepatic iron burden in comparison to transfusion plus chelation in children who have had a prior overt stroke.

This trial is expected to accrue 130 subjects.  Sixty-five subjects will be randomized to continue to receive periodic transfusion therapy and chelation, and 65 to receive hydroxyurea and undergo phlebotomy.  There are two primary endpoints:  the occurrence of secondary stroke during the 30 month treatment period, and change in liver iron level between baseline and the end of therapy. 

There are 23 clinical sites; all have been activated.  Enrollment began at the end of October, 2006.  As of November 1, 2007, 80 subjects have been enrolled (consented), and 55 have been randomized.  These accrual rates are within 80% of their projected targets.

J.         MSH Patients Follow-up Cohort Trial                                        Dr. Blaine Moore

The original Multi -center study for hydroxyurea was conducted between1993 and1998 and was followed up by a 10 year study to determine the long term benefits and possible adverse events of this drug.  The follow-up study will finish December 31, 2007.  Currently, there are 5 topics with either draft manuscripts completed or analyses completed and waiting for a first draft. In addition, Data Coordinating Center is progressing with renewed efforts to complete the HU usage data from the clinical sites.  The topics being addressed in these manuscripts are:

  • Treatment effects on daily pain
  • Analgesia usage in sickle cell patients
  • Long term mortality in sickle cell patients using hydroxyurea
  • Reproductive outcomes in sickle cell patients using hydroxyurea
  • Career and Employment in SS before and after HU treatment

                                                                                                                                   
K.        Pulmonary Complications of SCD                      Drs Greg Evans & Ellen Werner
           
            In July, 2006,  the NHLBI funded 5 grants to address major complications of pulmonary disease in SCD.  Four of the applications were in DBDR and one was in DLD.  All of the protocols have obtained DSMB approval and are active.  The third investigator’s meeting was held in Washington DC in late September.

The group from Howard University reported preliminary data showing that pulmonary arterial pressure as estimated by TRV is significantly higher in children and adolescents with SCD at steady state than age-matched control participants. Among children with SCD, TRV elevation is independently associated with systolic blood pressure and LDH concentration. Impairment of exercise capacity as assessed by the six minute walk test was not found. In children with SCD, relative systemic hypertension and degree of hemolysis may both contribute to the development of mild pulmonary hypertension, but related symptoms may be delayed until adulthood.

The group from Duke reported evidence of association of pulmonary hypertension with genes in the TGFβ superfamily, including activin A receptor, type II-like 1 (ACVRL), bone morphogenetic protein receptor 2 (BMPR2), and bone morphogenetic protein 6 (BMP6).  SCD patients with pHTN have higher levels of markers of endothelial activation and other markers of inflammation than those patients without pHTN. The TGFβ superfamily was the primary biological pathway associated with the occurrence of pHTN in our sickle cell patients. Interestingly, this has also been true thus far for genes identified for primary pHTN (ACVRL1 and BMPR2). That is, the TGFβ pathway may be an excellent candidate pathway for targeting treatments that may prevent or ameliorate this condition.

The group from Washington University in St. Louis is studying the physiological basis for the association of asthma and nocturnal oxygen desaturation to SCA-related morbidity. They have enrolled 120 out of a desired 300 participants that have received longitudinal assessment of full pulmonary function tests and sleep studies. They are also performing a case-control study evaluating whether genes associated with asthma increase the risk of pain and ACS episodes (n ~ 700). Lastly, they are using a compound murine model of asthma and SCD to study the effect of asthma on lung pathology in the sickle cell setting.

The group from Children’s Hospital Cincinnati reported data that erythroid cells release PLGF that likely contributes to both pulmonary inflammation and asthma in SCD.  PLGF likely contributes to pulmonary vasoconstriction via ET-1 release from pulmonary endothelium and this effect is mediated via HIF1. A clinical study to determine the role of PLGF as a biomarker for acute chest syndrome is underway.

The group from Children’s Hospital of Philadelphia summarized its plans to study the role of oxyhemoglobin desaturation in pulmonary complications and vasculopathy in children with SCD. The epidemiology protocol entitled “Oxyhemoglobin Desaturation and Vasculopathy in Sickle Cell Disease” is just beginning.

There was some discussion about the general delays in getting clinical studies up and running and how this affects the completion of the studies.

L.         Sildenafil Trial: Treatment of Pulmonary Hypertension in SCD Dr. Greg Evans

Contracts for this trial were issued to 9 clinical sites and a Data Coordinating sender in September 2006.  Among the 9 clinical sites are the NHLBI intramural program, and one in the UK, a site that involves 3 hospitals in London.
There are 2 phases to the trial.   Phase I involves screening patients and obtaining repository samples.  The projected target enrollment is 132 patients half of which will receive sildenafil and half will receive placebo.  The primary endpoint for the trial is cardiac function.  Patient age range is from 12 to adult.

  • Working Group in Standardized Terminology for Hematology Research

            March 2008                                                                            Dr. Ellen Werner                                

As DBDR representative to HLB-STAT, Dr. Werner will work with
Barry Coller, MD, proposed chair, to organize a Working Group that will review, discuss and make recommendations for standardized terminology in blood diseases and resources.  Working Group members will include some representatives from NHLBI’s May 2007 “Kick-Off” meeting, and others recommended by Dr. Coller, for a total of 8-12.  Based on Dr. Coller’s availability, this Working Group will be held in January or March, 2008.  A report will be produced, and will be used to facilitate further discussions at the trans-NHLBI Working Group on interoperability and harmonization of standards.

Sickle Cell Disease Association of America (SCDAA) REPORT
Community organizations want to be more aware of the clinical trials and be able to make patients more interested.  The SCDAA wants clinical sites to interface more with the community organizations and to be included in their budgets. They would also like to push the SCD Control Act to be expanded and to increase the budget to $20M.  New born screening should continue to be housed in HRSA.  The next SCDAA annual meeting will be held September 24-27th in New Orleans.

V.         OPEN DISCUSSION & ADVICE TO NHLBI

RECOMMENDATIONS TO NHLBI

  • The SCDAC would like to commend the NHLBI for their success of previous studies in sickle cell disease.  However, the NHLBI can still do better and the SCDAC wishes them to do so.  This will require a better infrastructure for sickle cell centers and a viable clinical research network.
  • There is a need to develop academic institutions and medical care facilities that value sickle cell disease as an important disease.  There needs to be institutional support and perhaps State or private support because federal support is so tenuous.
  • There needs to be a robust basic science program to set the foundation for translational and future clinical research.
  • The NHLBI needs to find ways of improving the regulatory bureaucracy of getting clinical studies up and running (e.g., PRC, DSMB, FDA and IRB’s)
  • The NHLBI needs to develop partnerships with other institutes, agencies, foundations and industry to provide better health care to sickle cell patients through research.

 

VI.        FUTURE MEETING DATES (June 2, 2008 & November 3, 2008)

 

                                                                        /s/                                                                               
                                                            R. Blaine Moore, PhD
                                                      SCDAC Executive Secretary

 

                                                                        /s/                                                                               
                                                    F. Daniel Armstrong, PhD
                                                            SCDAC  Chair

Last updated: April 22, 2007

 
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