Views from the Bench Rob Squires, MD, FAAP Clinical Director, - PDF document

4/2/2012 Views from the Bench Rob Squires, MD, FAAP Clinical Director, Children’s Hospital of Pittsburgh Professor of Pediatrics, University of Pittsburgh Dream Job: General Pediatrician in El Paso, Texas Observations Residency Dr. Larry Nicky UT Galveston Galveston Associate • If the coach isn’t coaching you, you are not a priority • Success can breed arrogance; all glory is fleeting • Standing or sitting next to the coach doesn’t help • For some, the best year in their life was the senior F h b i h i lif h i year. • Talent and hard work are often not aligned, but when they are, sparks fly • If you get an opportunity to play, take it; even if it is not your position 1

4/2/2012 Dream Job: Dream Job: General Pediatrician in El Paso, Texas General Pediatrician in El Paso, Texas Residency Dr. Larry Nicky Residency Dr. Larry Nicky UT Galveston UT Galveston Galveston Associate Galveston Associate Bill Daeschner, MD Bill Daeschner, MD Where can I do a pediatric Where can I do a pediatric neurology externship? neurology externship? St. Louis Children’s Hospital 1977 Dream Job: Dream Job: General Pediatrician in El Paso, Texas General Pediatrician in El Paso, Texas Residency Dr. Larry Nicky Residency Dr. Larry Nicky UT Galveston UT Galveston Galveston Associate Galveston Associate St. Louis Children’s Hospital 1977 St. Louis Children’s Hospital 1977 Jim Keating, MD Jim Keating, MD Janet Endress 1979 Dream Job: Dream Job: General Pediatrician in El Paso, Texas General Pediatrician in El Paso, Texas Residency Dr. Larry Nicky Residency Dr. Larry Nicky UT Galveston UT Galveston Galveston Associate Galveston Associate St. Louis Children’s Hospital 1977 St. Louis Children’s Hospital 1977 Jim Keating, MD Jim Keating, MD Janet Endress 1979, Greg 1980 Janet Endress 1979, Greg 1980, Jim 1982 2

4/2/2012 Dream Job: Dream Job: General Pediatrician in El Paso, Texas General Pediatrician in El Paso, Texas Residency Dr. Larry Nicky Residency Dr. Larry Nicky UT Galveston UT Galveston Galveston Associate Galveston Associate Private GI Practice Private GI Practice Ft. Worth, Texas 1982 Ft. Worth, Texas 1982 Beth 1983 St. Louis Children’s Hospital 1977 St. Louis Children’s Hospital 1977 Jim Keating, MD Jim Keating, MD Janet Endress 1979, Greg 1980, Jim 1982 Janet Endress 1979, Greg 1980, Jim 1982 Dream Job: Dream Job: General Pediatrician in El Paso, Texas General Pediatrician in El Paso, Texas Residency Dr. Larry Nicky Residency Dr. Larry Nicky UT Galveston UT Galveston Galveston Associate Galveston Associate Private GI Practice Private GI Practice Ft. Worth, Texas 1982 Ft. Worth, Texas 1982 Beth 1983 Beth 1983 St. Louis Children’s Hospital 1977 St. Louis Children’s Hospital 1977 Janet Endress 1979, Greg 1980, Jim 1982 Janet Endress 1979, Greg 1980, Jim 1982 Bill Belknap, MD Bill Belknap MD UT Southwestern 1987 UT Southwestern 1987 Clinical Program Clinical Program Charles Ginsburg, MD Development Development Will Lee, MD PALF Consortium 1999 Pat Robuck, PhD NIH/NIDDK 2005 ‐ 15 Dream Job: General Pediatrician in El Paso, Texas Residency Dr. Larry Nicky UT Galveston Galveston Associate Private GI Practice Ft. Worth, Texas 1982 Beth 1983 St. Louis Children’s Hospital 1977 Janet Endress 1979, Greg 1980, Jim 1982 UT Southwestern 1987 Clinical Program Development PALF Consortium 1999 David Perlmutter, MD NIH/NIDDK 2005 ‐ 15 Mark Lowe, MD, PhD. Children’s Hospital of Pittsburgh 2003 Clinical Program Pediatric Intestinal Failure Consortium Development NIH/NIDDK 2006 ‐ 08 3

4/2/2012 Pediatric Intestinal Failure Consortium PIFCon’s Inception June 3,2006 (PIFCon) • Single site studies requires decades to achieve sufficient numbers of patients • Medical, surgical, nutritional, and transplant options vary depending upon the era options vary depending upon the era • National, multi ‐ center collaborative is the only mechanism to achieve sufficient numbers in a contemporary era. PIFCon Site Principal Invest Other Support Personnel Specific Aims Rob Squires (GI) Nucci (D), Burns (PS), Mazariegos (TX) Pittsburgh Kamin (GI), Jaksic (PS), Kim (TX) Chris Duggan (GI) Boston Brown (GI), Johnson (D) Dan Teitelbaum (Ped Surg) Ann Arbor* • To identify demographic, clinical, and nutritional risk Ric Superina (Transplant) Cohran (GI), Superina (PS), Kazermski (D) Chicago factors within a contemporary cohort of infants and Valentine (D), Teich (PS) Jane Balint (GI) children with intestinal failure that will predict the need Columbus* Reichman (PS, TX), Wessel (D), Jeff Rudolph (CO) for long ‐ term TPN (< 60 days), weaning from total Sam Kocoshis (GI) Cincinnati parenteral nutrition, development of cholestasis, Antonson (GI), Raynor (PS), Sunderman (D) D. Sudan/D.Mercer (Transplant) Omaha intestinal transplant and death. (PS), Ballew (D), Brent Polk (CO) Andres Martinez (GI) Vanderbilt* Brandt (PS), Phillips (D) Beth Carter (GI) Houston* • To identify practice pattern variability and outcomes (PS), Brown/Fidanza (D) Jason Soden (GI) Denver* Beckwith (D), Dunn (PS), Farmer (TX) Rob Venick (GI) UCLA • To initiate planning and feasibility for a prospective, Susan Rhee (GI) Farmer (PS), Kang (TX), Bower (D) UCSF multi ‐ center consortium Villanueva (D), Reyes (TX), Healey (PS) Simon Horslen (GI) Seattle Pencharz (GI), Fecetau (TX), Courtney ‐ Martin (D) Paul Wales (Ped Surg) Toronto * = not an intestinal transplant site Not everything that is good will succeed Proposed Model of the Natural Course and Outcome of Acute Liver failure in Children • 2006.6.3: Breakfast meeting • 2007.6.14: Submitted R21 application • 2008.6.3: R21 DK 081059 awarded • 2008.6.15: Funding for R21 begins; retrospective study with 12 + 2 sites • 2009.2.20: Efforts to incorporate a GLP ‐ 2 trial into the UO1 fell through Alive • 2009.3.27: First letter to NIH requesting application for U34 proposal – Aim 1: Longitudinal Study urse – Aim 2: Microbiome Project – Aim 3: Ethanol Lock Trial Disease Co Sudden event that • 2009.4.10: Application to apply rejected alters expected • 2009.4.30: Second letter to the NIH submitted course: bleeding, – Aim 1: Longitudinal Study sepsis, SIRS, etc – Aim 2: Assess markers of adaptation – Aim 3: Markers of oxidative stress • 2009.5.10: Approval to submit a U34 Application • 2009.6.23: U34 proposal submitted to the NIH • 2009.11.13: Grant reviewed Dead • 2009.12.16: Summary statement received – Scored “Good”…not good enough Prodrome TIME Hours, Days, Weeks 4

4/2/2012 Proposed Model of the Natural Course and Proposed Model of the Natural Course and Outcome of Acute Liver failure in Children Outcome of Acute Liver Failure in Children Patient characteristics and management Cytokine profile/SIRS markers Liver regenerative markers Alive Alive Genetic polymorphisms First Encounter A Immunologic profile urse urse Metabolomics Event alters Proteomics Proteomics expected expected Disease Co Sudden event that Disease Co B Diagnosis course: bleeding, alters expected sepsis, renal failure course: bleeding, C sepsis, SIRS, etc D Dead Dead Liver Transplant Prodrome Prodrome TIME TIME Hours, Days, Weeks Hours, Days, Weeks Contributing PALF Investigators Pediatric Acute Liver Failure (PALF) Study Group Mike Leonis/John Bucuvalas ‐ Cincinnati Rob Squires/Ben Shneider ‐ Pittsburgh David Rudnick ‐ St. Louis (Wash U) Mike Narkewicz ‐ Denver • PALF Study Group (NIH/NIDDK 1 UO1 DK 072146 ‐ 01) Estella Alonso ‐ Chicago (Children’s Memorial) Kathy Loomes/Liz Rand ‐ Philadelphia (CHOP) – Began in 2000; Independently funded 2005 ‐ 2010 Norberto Rodriguez ‐ Dallas Simon Horslen/Karen Murray ‐ Seattle Rene Romero ‐ Atlanta (Emory) – Multi ‐ center, multi ‐ national study Phil Rosenthal ‐ San Francisco Vicky Ng ‐ Toronto, Canada • United States = 17 Girish Subbarao ‐ Indianapolis Anil Dhawan ‐ London, UK (Kings) • Canada (Toronto)= 1 Nanda Kerkar ‐ New York (Mt. Sinai) Saul Karpen ‐ Houston (Baylor) Jim Lopez Ann Arbor Jim Lopez ‐ Ann Arbor • United Kingdom (London, Birmingham) = 2 • United Kingdom (London Birmingham) = 2 D Dominic DelOlio, Deirdre Kelly ‐ i i D lOli D i d K ll Scott Elisofon ‐ Boston (Harvard) Birmingham, UK – Data Kathy Schwarz ‐ Baltimore DCC • Clinical and Laboratory data, plus serum, daily for 7 days Steve Lobritto ‐ New York (Columbia) Steve Belle • End points: death, transplant, discharge Sharon Lawlor • Biological samples: DNA, bile, liver, fibroblasts, urine NIH ‐ NIDDK Song Zhang Pat Robuck, PhD, MPH Joy Bowen • Treatment trial Stephanie Kelly Edward Doo, MD – N ‐ acetylcysteine for non ‐ acetaminophen ALF (completed) Denise Vandersal Jay Hoofnagle, MD • Core and Ancillary studies Thank you to the participating children and their families Results Passion versus Equipoise Primary Outcome: 1 Year Survival • NAC was used routinely in the UK, Canada and 100% Placebo age Survival 82% many sites in the US in non ‐ acetaminophen 80% ALF NAC 73% 60% • No prospective data • No prospective data Cum. Percenta P • Sites committed to test the hypothesis that IV 40% NAC in non ‐ acetaminophen ALF improved 1 p-value =0.20 20% year outcome 0% 0 100 200 300 400 Days Following Randomization 5