Welcome to the Clinical Center Grand Rounds, a weekly series of educational lectures for physicians and health care professionals broadcast from the Clinical Center at the National Institutes of Health in Bethesda, MD. The NIH Clinical Center is the world's largest hospital totally dedicated to investigational research and leads the global effort in training today's investigators and discovering tomorrow's cures. Learn more by visiting us online at http://clinicalcenter.nih.gov >> LET'S GET STARTED. I'M A CLINICAL INVESTIGATOR IN NIAID. IT'S MY PLEASURE TO WELCOME YOU HERE AT OUR CLINICALICAL PATHOLOGIC, THE THIRD AND LAST OF THIS FISCAL YEAR. A SERIES OF GRAND ROUNDS THAT HAVE TWO IMPORTANT MISSIONS, ONE, EDUCATIONAL THROUGH PRESENTATION OF INTERESTING CASES. AT THE SAME TIME, AN IMPORTANT MISSION OF THIS FORUM IS TO PRESENT AND SHOWCASE PROGRAMS THAT HAVE BEEN ESTABLISHED HERE AT THE NIH, SHOWING THE SUBURB CLINICAL CARE AND TRANSLATIONAL RESEARCH. SO TODAY'S CASE IS A GREAT EXAMPLE OF THAT AND YOU'LL SEE THROUGHOUT. IT'S TITLE REVERSAL OF CHRONIC COMPLICATION OF SICKLE CELL ANBEMIA ARE HEMATOPOIETIC STEM CELL TRANSPLANTATION. FIRST DR. MICHAEL HSIEH. DR. KLEINER WILL SHOW US THE PATHOLOGY, AND THEN DR. CO WILL PRESENT THE LIVER ASPECT. DOCTOR WE'RE. WITH NO FURTHER ADO. >> GOOD AFTERNOON. SO WE DON'T HAVE ANY FINANCIAL DISCLOSURES TO REPORT. DR. NEIL [TECHNICAL DIFFICULTIES] HERE ARE THE LEARNING OBJECTIVE OBJECTIVES. THE FIRST PATIENT WAS 22-YEAR OLD AFRICAN AMERICAN GENTLEMEN WITH HISTORY OF HOMOZYGOUS SICKLE CELL DISEASE. HIS PAST MEDICAL HISTORY INCLUDED SEVERE CONJUGATED HYPER BILL RIRUB PEOPLIA, [SEE SLIDE] >> HE HAD BEEN TRANSFUSED 20-30 TIMES. HOSPITALIZED ONE-3 TIMES PER YEAR. ACUTE CHEST SYNDROME. HIS MEDICATIONS AT THE TIME ARE HYDROXY RIA A GOOD DOSE OF 30-MILLIGRAMS PER KILOGRAM, ALSO FOLK ACID. NO FAMILY HISTORY OF SICKLE CELL DISEASED. HE WAS LIVING IN NEW YORK. HIS PARENTS WERE FROM JAMAICA. HE WAS ON DISABILITY, DID NOT REPORT TOBACCO OR ALCOHOL OR RECREATIONAL DRUG USE. ON PHYSICAL EXAMINATION, HIS BLOOD PRESSURE WAS ELEVATED FOR SOMEONE WITH SICKLE CELL DISEASE. HE HAD SIGNIFICANT CLEARERAL ICTERUS. HE DID NOT HAVE ANY HEMATOMEGLY. HIS LIFE BLOOD CELL COUNT WAS ELEVATED AT 9. HEMATOCRIT 21%. PLATELET WAS LOW, 213,000. AND ARC, 234,000. PH, SLIGHTLY ELEVATED, AST, AND AST, MINIMALLY ELEVATED AT 35. TOTAL BILIRUBIN WAS SIGNIFICANT, 10.2, WITH A DIRECT BILIRUBIN OF 3.7 AND LOW ALBUMIN OF 2.6. LDH, ELEVATED 250 WITH A FERTEN, OVER 1,000. AND NTPROBNP, ELEVATED AT 133. HIS ECHO CARDIOGRAM SHOWED A LEFT VENTRICLE MILD LIDILATED. LEFT ATRIUM, NORMAL. RIGHT WAS NORMAL IN SIZE AND FUNCTION. HE HAD MILD PULL MONIC REJUDGERTATION. TRV WAS ELEVATED. 3, WITH THE RIGHT VENTRICULAR SYSTOLIC PRESSURE, ELEVATED AT 41. INDICATION FOR TRANSPLANT WAS SICKLE HOPE TOPTHY AND ELEVATED TRV. HE WAS CONDITIONED WITH [INDISCERNIBLE] AND 300 TOTAL BODY RADIATION. DONOR WAS HL.MATCHED BROTHER. HE UNDERWENT TRANSPLANT MAY 28, 2009. STARTED ON SIR SIR ONE DAY -- SIRO LIMES, AND HIS TRANSPLANT WAS ONLY COMPLICATED BY FEVER AND NEUTROPENIA. HE DID NOT HAVE ANY GRAPH VERSES HOST DISEASE. MOST RECENT CHIMERISM, FOUR YEARS POST YEAR, 55% DONOR CD3. BASE HIS DONOR CD3 WAS GREATER THAN 50%, THE PROTOCOL ALLOWED US TO WEAN HIS SIRO LIMES AND IT WAS DISCONTINUED. THESE TWO FIGURES SHOW HIS -- THE -- THIS FIGURE SHOWED THE TOTAL BILLI RUBIN. THIS IS DIRECT. MAXED ABOUT 25. DIRECT AT 20. OWNED THAT THEY BOTH DECREASED TO NORMAL AFTER THE TRANSPLANT. THIS WAS THE TIME HE GOT HIS TRANSPLANT AND THESE ARE THE TIMES OF THE LIVER BIOPSY. WITHIN WAS DONE BEFORE, ONE AFTER. DR. KLEINER WILL SHOW THE RESULTS OF THE LIVER BIOPSIES. >> THANK YOU. SO THE FIRST LIVER BIOPSY WAS 3 MONTHS PRIOR TO TRANSPLANT. AND WHAT YOU CAN SEE -- HERE IS THE PROFILE OF THE CORE OF LIVER. IT HAS A VERY NODULE APPEARANCE, ABNORMAL FOR LIVER. IT SHOULD LOOK NICE AND STRAIGHT ALONG THE SIDES. YOU HAVE A NODULE RIGHT HERE. ON THIS SIDE, THE CENTRAL VAIN WITH SOME INFLAMMATORY. THESE LITTLE BLUE CELLS HERE ARE LYMPHOCYTES. THE SINUSES OF THE LIVER ARE VERY CONGESTED. AND DILATED WITH RED CELLS AND HERE YOU CAN SEE THE RED CELLS HAVE WASHED OUT AND THEN BIG OPEN SINUSES. THE PORTAL AREAS WERE A LITTLE BIT IF I BROUGHTIC. RELATIVELY NORM 8. VERY MILD INFLAMMATION. THIS IS THE CENTRAL VAIN. NOW, PATHOCITES SHOULD COME UP TO THE EDGE OF THE CENTRAL VAIN. YOU CAN SEE THESE ARE THE HEPATOCITES. THERE IS PINK STUFF IN BETWEEN, COLLAGEN OR FIBROSIS. AND SO WE'RE NOT GETTING -- WE LOST A NUMBER OF HEMATOPOIETIC SITES AND REPLEASED BY FIBROUS TOUCH. HERE IS THE INFLAMMATION. THIS IS A CLOSEUP PICTURE OF THAT CONGESTION. SO IN SICKLE CELL DISEASE WHAT HAPPENS, YOU GET CLUMPING OF THE RED CELLS IN THE SINUSES. LIVER. AND YOU CAN SEE ACTUALLY THESE POINTED CELLS OFF HERE WHERE THEY'RE ALL BY THEMSELVES. HERE YOU CAN'T MAKE IT OUT BUT THERE YOU CAN SEE THE SICKLE SHAPE. SO THEY GET HUNG UP IN THE SINUSES OF LIVER, IMPEDING BLOOD FLOW THROUGH THE LIVER. YOU CAN GET BACKWARD FLOW FROM HEART PROBLEMS OR FROM PULMONARY HYPER TENSION. AND BOTH OF THESE TOGETHER CAN CAUSE THE DAMAGE THAT I SHOWED. THIS IS A STAIN THAT SHOWS THE FIBROSIS IN THE LIVER. SO AGAIN, NORMALLY YOU SHOULDN'T SEE ALL THIS BLUE. IT SHOULD BE BLUE RIGHT THERE THE PORTAL AREAS ARE. HERE WE'VE GOT BLUE FIBROSIS EXTENDING BETWEEN PORTAL AREAS AND BETWEEN CENTRAL VEINS. SO IT'S NEARLY SURE ROTIC. AT THIS POINT. AND HERE A VERY CLOSE PICTURE AROUND THE CENTRAL VAIN, YOU CAN SEE THAT ALL THAT MATERIAL, THAT PINK MATERIAL WAS COLLAGEN AND IT'S TRAPPING THE HEPATOSITES. THE FINAL DIAGNOSIS, THIS IS A FAIRLY CHARACTERISTIC CHANGE. ONE OF THE POSSIBLE OUTCOMES. LIVER BIOPSY IN THIS DISEASE. THERE WAS SEVERE CONGESTION OF THE RED CELLS, BRICKING FIBROSIS AND RELATIVELY MILD INFLAMMATION IN IRON. NOW, CONTRAST TO THAT, 17 MONTHS AFTER TRANSPLANT, WE HAVE THIS BIOPSY. AND IT'S CURVED BUT THAT'S JUST AN ARTIFACT. WHAT I WANT YOU TO SEE IS THAT THESE SLIDES ARE STRAIGHT NOW. YOU DON'T SEE THOSE NODULES THAT I SHOWED YOU BEFORE. THERE ISN'T LARGE AREAS OF PINK MATERIAL THAT WOULD INDICATE FIBROSIS. SO AGAIN, A PORTAL AREA HERE, STILL WITH SOME MILD INFLAMMATION. THIS IS ACTUALLY A CENTRAL VAIN AREA, SO THE VAIN IS RIGHT THERE. THERE IS CONGESTION. BUT THESE ARE NOT SICKLE RED CELLS. THIS IS JOUST RESIDUAL, LITTLE BIT OF RESIDUAL COLLAGEN FROM WHAT WE HAD BEFORE. DEFINITELY MUCH BETTER LOOKING THAN THE PRIOR BIOPSY. THERE WAS A LITTLE BIT OF IRON, STILL PRESENT IN THE BIOPSY. THIS IS THE STAIN, SO I'M SHOWING YOU THE WORST AREA OF THE BIOPSY. THERE WERE OTHER CENTRAL VEINS WERE THAT BASICALLY NORMAL. STILL A LITTLE BIT OF LOOSE COLLAGEN HERE. I EXPECT THAT AS TIME GOES BY, THIS WILL ACTUALLY HEAL AND RESOLVE. THIS IS ANOTHER CONNECTIVE TISSUE STAIN, AND THIS HIGHLIGHTS SOME OF THE STRUCTURE THAT SOMETIMES IS NOT ABLE TO BE SEEN ON AN H AND E. IT IS NODULAR BUT WE EXPECT THAT THIS WILL PROBABLY GO AWAY WITH TIME. SO IN CONCLUSION, THERE WAS STILL A LITTLE BIT OF PERISIGN YOU SIGHTAL BY MUCH LESS THAN PRIOR. THERE WAS IRON ACCUMULATION, IN ENDOTHELIAL CELLS. THAT WILL GO AWAY, TOO, IF TRANSFUSIONS AND MILD FROM FROMATION MILD CONGESTION BUT WITHOUT THE SICKLE RED CELLS WE SAW BEFORE. AND NOW DR. COE WILL TELL YOU ABOUT THE LIVER DISEASE. DR. KOH. >> THANK YOU. SO FIRST WE'RE GOING TO DO A BRIEF OVERVIEW OF SICKLE CELL DISEASE BEFORE WE DIVE INTO LIVER DISEASE PORTION OF THIS. SICKLE CELL DISEASE, VERY COMMON DISORDER, EFFECTS 100,000 INDIVIDUALS IN THE U.S. IT EFFECTS ABOUT ONE OUT OF EVERY 500 BLACK OR AFRICAN AMERICANS BIRTHS, ONE OUT OF EVERY 37 HOUR HISPANIC AMERICAN BIRTHS. ON THE FIGURE ON THE RIGHT YOU CAN SEE A WORLDWIDE SCHEME SHOWING PREVALENCE OF SICKLE CELL PATIENTS. YOU CAN SEE THAT AREAS OFF RED AND PURPOSERAL THE HIGHEST, AND TYPICALLY, THIS IS FOUND IN AFRICA AND SOUTH AMERICA. SO WHAT HAPPENS IN SICKLE CELL DISEASE? WELL, IT'S A HEMOGLOBINOPATHY, CAUSED BY A SICKLE AMINO ACID SUBSTITUTION IN THE BETA GLOBIN CHAIN. THERE IS A SINGLE NUCLEOTIDE REPLACEMENT WHERE VALIEN REPLACES GLUE TAMIC ACID. YOU SEE NORMAL HEMOGLOBIN. IN SICKLE CELL. CELLS ARE STIFF, AND THEY CLUMP TOGETHER. ON THE RIGHT, ANOTHER FIGURE SHOWING RED BLOOD CELLS GOING THROUGH BLOOD VESSELS. LEFT IS NORMAL, RIGHT IS SICKLE CELL. YOU CAN SEE AS IT GETS INTO SMALLER BLOOD VESSELS, THEY GET STUCK. SO DURING PERIODS OF LOWERED OXYGEN SATURATION, WE TEND TO SEE HEMOGLOBIN POLY MERIZATION. DEFERMATION OF RED BLOOD CELLS, LEADING TO VASSAL OCCLUSION. DOWN STREAM, WE SEE -- WE CAN SEE ISCHEMIA AND INFARCT AND HE MOLSIS. HERE YOU CAN SEE THE CELLS CLUMPING AND BROKING BLOOD FLOW. SO WHAT ARE THE COUNCIL MANIFESTATIONS? -- CLINICAL MAP FESSTATIONS? THEY SUFFER DOCTOR CHRONIC ANEMIA. INFECTIONS, AND DEATH FROM MUTCH ORGAN SYSTEM FAILURE. ON THE RIGHT IS A PICTURE THAT SHOWS DIFFERENT ORGANS THAT CAN BE EFFECTED, INCLUDING THE LUNGS, THE HEART, BONE, AND MANY OTHERS. SO IN THE UNITED STATES, HEALTHCARE COSTS RELATED TO SICKLE CELL DISEASE EXCEEDS ABOUT $1.1 BILLION ANNUALLY. THE AVERAGE COST OF CARE PER MONTH PER PATIENT IS ALMOST $2,000. AND THIS INCREASES WITH INCREASING AGE. SO FOR AN AVERAGE PATIENT WITH SICKLE CELL DISEASE REACHING AGE 45 THEIR ESTIMATES COSTS OF HEALTHCARE HAVE BEEN ESTIMATED TO BE OVER 950,000. SO YOU CAN SEE FROM BOTH THE HUMAN TARRIAN ASPECT AND FINANCIAL, IT'S VERY COSTLY. AND NOW FOR THE REMAINDER OF MY TALK, WE'LL TALK BRIEFLY ABOUT SICKLE CELL LIVER DISEASE. SO I SHOWED YOU THE SLIDE A COUPLE OF SLIDES -- SHOWED YOU THIS PICTURE A COUPLE SLIDES AGO. WHAT'S MISSING HERE? THERE ISN'T MUCH IN TERMS OF DESCRIPTION OF LIVER DISEASE AS IT RELATES TO SICKLE CELL DISEASE. SO ONE OF THE THINGS I WOULD -- IT'S IMPORTANT TO DISCUSS IS, FIRST, DEFINE WHAT IS LIVER DISEASE AND SICKLE CELL DISEASE? DOES IT MATTER, HAVING LIVER DISEASE REALLY MATTER IN THE SETTING OF SICKLE CELL DISEASE? HOW DO WE KNOW IF SOMEONE WITH SICKLE CELL DISEASE HAS LIVER DISEASE AND WHAT'S NEEDED TO FURTHER DEFINE LIVER DISEASE IN SICKLE CELL DISEASE? SO FIRST, SICKLE CELL DISEASE LIVER DISEASE IS DEFINED ASTELY DAMAGE OF END ORGAN DAMAGE. ESTIMATED TO OCCUR IN 10-39% OF PATIENTS WITH SICKLE CELL DISEASE BUT THERE IS A LOT WE DON'T KNOW. A LOT INCLUDES THE DYSFUNCTION, NATURAL HISTORY, HOW AND WHEN TO MONITOR PATIENTS AND WHO TO TREAT. SO THE TERM SICKLE CELL HOPE TOPTHY HAVE BEEN USED BROADLY TO DESCRIBE LIVER DISEASE. AND I'D LIKE TO SHOW YOU HERE, THIS IS JUST A BRIEF SPECTRUM OF CITIES THAT CAN BE SEEN WITH SICKLE CELL DISEASE. THEY'RE VERY DIFFERENT. ACUTE SICKLE HEPATIC CRISIS, INFARCTION, IRON OVERLOAD AND EVEN NODU LARRY GENERATIVE HYPERPLASIA. WHAT I PROPOSE, WE SHOULD NOT CALL EVERYTHING WE SAY RELATED TO LIVER DISEASE AS SICKLE CELL HOPE TOP THAT BUT CALM IT WHAT IT IS. DOES HAVING LIVER DISEASE, DOES IT REALLY MATTER? WELL, OUR GROUP MERE IN COLLABORATION WITH THE NHLBI EVALUATED PATIENTS IN ACUTE CRISIS, IDENTIFIED PATIENTS AND WE IDENTIFIED THAT THESE PATIENTS, THEY ENDED UP HAVING STIFFER LIVERS. BUT IN THOSE PATIENTS THAT WERE FOUND TO HAVE HEPATIC INVOLVEMENT, THEY HAD AN INCREASED LENGTH OF HOSPITAL STAY. SO THIS POTENTIALLY DESCRIBES THESE PATIENTS ARE SICKER. AND WHAT ABOUT LIVER DISEASE IN SICKLE CELL DISEASE AND MORTALITY? AT THE NIH WE FOLLOWED OVER ABOUT 250 PATIENTS. FOR MEDIAN OF 30 MONTHS. WITHOUT GOING TOO INDEPTH INTO THE STUDY, WE'VE IDENTIFIED THAT BILIRUBIN WAS ASSOCIATED WITH MORTALITY. HERE IS A KAPLAN MEIER CURVE LOOKING AT FERTEN AND SURVIVAL. THE SOLID LINE IS FOR PATIENTS WITH FERTEN, LESS THAN 1,000. IN PATIENTS WITH HIGHER FERRITIN, THEY HAVE LOWER SURVIVAL. WE LOOKED AT DIRECT BILIRUBIN IN SURVIVAL. SOLID LINE SHOWS PATIENTS WITH LOW DIRECT BILIRUBIN. THE DOTTED LINE, SHOWS HIGHER DIRECT BILIRUBINS GREATER THAN O OWE 4. YOU CAN SEE PATIENTS BEA HIGH DIRECT BILIRUBIN HAVE A DECREASED SURVIVAL. SO TO BRING THIS BACK TO OUR PATIENT THAT WAS PRESENTED, HE HAS AN ELEVATED DIRECT BILIRUBIN AND ALSO INCREASED FERRITIN. SO THE PATIENT SHOULD HAVE FIT IN THE DOTTED LINE. TO HAVE A -- AND WOULD BE PREDICTED TO HAVE WORSE SURVIVAL. BUT WITH THE TRANSPLANTATION THAT HAPPENED WE HOPE WE HAVE MODIFIED THIS PERSON'S COURSE, AND ULTIMATELY, WE HOPE AND AS EVIDENCED BY DR. KLEINER AS WELL, THE LIVER DISEASE HAS IMPROVED. WE THINK WE MADE A DIFFERENCE. NEXT HOW DO WE DIAGNOSE PATIENTS WITH LIVER DISEASE AND SICKLE CELL DISEASE? A LOT OF LABS WE USED ARE ALTERED AS A RESULT OF SICKLE CELL ANBEMIA. AND FOR EXAMPLE, WE TYPICALLY LOOK AT A RATIO, SUGGESTING CIRRHOSIS. IN SICKLE CELL THE AC IS ALWAYS ELEVATED SO THIS WOULD MAKE IT DIFFICULT FOR US TO DIAGNOSIS. BILLI RUBINS ARE INCREASED, ALSO INCREASED AS A RESULT OF HE MOLSIS. ALBUT MINUTE IS DECREED. IN SICKLE CELL, THERE IS ILLNESSES. IN ELEVATED ALKALINE, IT CAN SUGGEST LIVER DISEASE. IN SICKLE CELL DISEASE IT CAN BE DUE TO BONE DISEASE. PATIENTS WITH CIRRHOSIS HAVE COMPANY AGENCIES, BUT WITH PATIENTS WHO HAVE PULMONARY HYPER TENSION, THEY MAY BE ANTICOAGULATED. FINALLY, HEPATOLOGIES LOOK AT PLATELETS AS A MARKER OF CIRRHOSIS. PLATELET COUNTS ARE OFTEN ALTERED. SO WHAT ABOUT THE GOLD STANDARD OF DIAGNOSISING LIVER DISEASE, LIVER BIOPSIES? IN 2003, THE KING'S COLLEGE PUBLISHED THEIR EXPERIENCE PERFORMING BIOPSIES IN PATIENTS DURING ACUTE CRISIS. WHAT THEY DESCRIBED WAS A COMP PUBLICATION UP TO 80% INCLUDING DEATH. MANY HAVE REFRAINED FROM PERFORMING LIFE BOKO HARAMS, AND IT'S A RELATIVE CONTRAINDICATION. SO AS A RESULT OF THIS, THERE HAS BEEN INSUFFICIENT DATA LOOKING AT LIVER HISTOLOGY IN PATIENTS WITH SICKLE CELL DISEASE. BUT I WOULD LIKE TO REPORT THAT HERE AT THE NIH, WE HAVE PERFORMED OVER 120 BIOPSIES IN PATIENTS NOT IN CRISIS, ALSO VIA DIFFERENT ROUTE, WITH YOU WE'VE HAD VERY GOOD SUCCESS AND MINIMAL COMPLICATION. SO IN SUMMARY, LIVER DISEASE AND SICKLE CELL DISEASE MATTERS. WE NEED TO FIND BETTER WAYS TO ASSESS PATIENTS. TYPES OF LIVER DISEASE AND HOW 250 STAGE THEIR LIVER DISEASE. WE NEED TO BETTER UNDERSTAND THE MECHANISM OF EFFECT AND EFFECT ON LIVER DISEASE AND MORTALITY IN SICKLE CELLING. WE NEED NEW THERAPY, AND AS WE HAVE DESCRIBED, BONE MARROW TRANSPLANTATION SEEMS TO BE A GOOD OPTION FOR BOTH SICKLE CELL DISEASE AND AT LEAST FOR LIVER DISEASE RELATED TO SICKLE CELL DISEASE AS WELL. SO IN TERMS OF SICKLE CELL LIVER DISEASE WE'RE AT THE TIP OF THE ICEBERG. THERE IS A LOT TO DO. WE HOPE THROUGH RESEARCH, CONTINUED RESEARCH WE'LL BE ABLE TO DEFINE MORE OF THE SICKLE CELL LIVER DISEASE AND HELP PATIENTS. WITH THAT I'D LIKE TO RETURN THIS BACK TO YOU FOR THE SECOND PATIENT. >> OKAY, SO OUR SECOND PATIENT WAS A 30 YEAR AFRICAN AMERICAN WOMAN WITH HISTORY OF HOMOZYGOUS SICKLE CELL DISEASE, EVALUATED FOR [TECHNICAL DIFFICULTIES]. SHE REPORT SHE HAD CHEST PAIN WITH EXERTION. PALPITATIONS ABOUT ONCE WEEKLY. LASTED A FEW MINUTES, WITH NO ASSOCIATED SYMPTOMS, BUT NO HISTORY OF SYNCOPE. THIS IS AN ABBREVIATED LIST OF HER PAST MEDICAL HISTORY. THE DISEASE WAS NOT RESPONSIVE TO HYDROX RIA. SHE HAD TRANSFUSION ASSOCIATED IRON OVERLOAD, GREATER THAN 50 UNITS TRANSFUSED IN HER LIFE. SHE HAD A LIVER BIOPSY, SHOWED MARKED HEMO SIDE ROSIS, MILD INFLAMMATION. HER LIVER IRON CONCENTRATION WAS ELEVATED, 19. SHOULD HAVE BEEN CLOSER TO 5 TO 7 IN SOMEONE WHO WAS APPROPRIATELY KEY LATED. SHE HAD RECURRENT VASO OCLUSIVE CRISIS. SHE HAD 16 HOSPITALIZATIONS WITHIN THE PAST YEAR, AND 27 HOSPITALIZATIONS IN THE PREVIOUS 3 YEARS. SHE HAD CHRONIC BACK PAIN, RECURRENT ACUTE CHEST SYNDROME, HYPER TENSION,. HER MAIN PULMONARY PRESSURE WAS 30, AND 12. SHE WAS STARTED ON MEDICATION. [SEE SLIDE] SHE HAD NO FAMILY HISTORY OF SICKLE CELL DISEASE. SHE MOVED FROM THE UNITED STATES TO NIGERIA IN 1999. SHE WAS LIVING WITH HER MOTHER AND 2-YEAR OLD SON. SHE WAS ON DISABILITY, BUT USED DO WORK RETAIL. SHE DID NOT REPORT ANY SMOKING. HAD OCCASIONAL ALCOHOL, NO RECREATIONAL DRUG USE. PHYSICAL EXAM, TACKY CARDIC, HEART RATE OF 107. SHE HAD GRADE 2 OUT OF 6 MURMUR. HUNG WERE CAREER. HAD MILD TENDERNESS. SHE HAD NO SINUS OR EDEMA. SO HER WHITE CELL COUNT WAS 11. HEMOGLOBIN OF 9.7. PLATELET COUNT ELEVATED, 482,000. ARC, 441,000. CREATININE, 0.67. A BILLI RUBIN OF 0.9. LDH ELEVATED, 281. NTPROBNP ELEVATED. 154. FERRITIN, CLOSE TO 3,000. SO HER INDICATION FOR THE TRANSPLANT WAS [SEE SLIDE] >> SO WE WANTED TO REPEAT OUR -- SHE WAS IN A CRISIS SO WE COULDN'T WE PETE THIS. [SEE SLIDE] HOAR -- HER DONOR WAS HER SISTER. UNDER WENT TRANSPLANT, AUGUST 9, 2013. STARTED ON SIROLIMUS, FIVE DAYS POST TRANSPLANT BEA GOAL LEVEL OF 10-15. SHE HAD A COMPLICATED TRANSPLANT COURSE. SHE WAS DIAGNOSED WITH CMV COLITIS. TREATED SUCCESSFULLY. SHE ALSO HAD MALNUTRITION REQUIRING TPN. NEFF TROTIC SYNDROME. WAS CONSISTENT [INDISCERNIBLE]. IT RESOLVED WITH DISCONTINUATION OF THE SIROLIMUS. SHE HAD DIABETES, ALSO [INDISCERNIBLE] RESOLVED. REMAINED ON A HYDROMORPHONE PCA DUE TO PAIN. AND SHE WAS DISCHARGED FROM THE HOSPITAL ON SEPTEMBER 23, 2013. WHICH IS 45 DAYS POST TRANSPLANT. SHE DID NOT HAVE GRAPH VERSES HOST DISEASE. HER MOST RECENT CHIMERISM WAS 87% DONOR MYELOID, 36% DONOR CD3. HEMOGLOBIN 10. SLIGHTLY SHOW. SHE'S UNDERGOING THERAPEUTIC PHLEBOTOMY. SO DR.WARE WILL TALK ABOUT HYPER TENSION, MORE ABOUT OUR PATIENT. >> I'M GOING TO REVIEW PULMONARY HYPER TENSION THIS AFTERNOON WITH YOU. EVERY FIVE YEARS, THE WORLD HEALTH ORGANIZATION GETS TOGETHER AND EITHER REFINES OUCHEDS THE CLASSIFICATION OF -- UPDATES THE CLASSIFICATION OF PULMONARY HYPER TENSION. THE LAST MEETING WAS IN 2013 IN FRANCE. THEY DID NOT CHANGE THE DEFINITION OF PULMONARY HYPER TENSION, IT REMAINS A PULMONARY MEAN PRESSURE OF 25-METERS OF MERCURY OR GREATER. THIS IS A DISEASE THAT IS PROGRESSIVE. IT IS OBSTRUCTIVE, INVOLVES ONLY THE LUNGS. SUPER IMPOSED YOU HAVE VASO SPASMS AND THROMBOSIS. THIS IS A NICE CARTOON. SHOWS A PROGRESSION OF THIS CITIES STARTING WITH MUSCULARIZATION OF THE PULMONARY ARTERIES PROCEEDING WITH MEDIAL HIPPER TROPHY. AND YOU DEVELOP THIS INTERRUPTION AND YOU END UP WITH A HALLMARK LESION WHICH IS A PLEXI FORMED LESION THAT YOU CAN SEE OBSTRUCTS THE ENTIRE LUMEN. THIS IS A LIGHT MICROSCOPE, A VIEW OF THE SAME THING THAT I JUST SHOWED YOU IN CARTOON FORM. THIS IS THE SMOOTH MUSCLE, THE PRESCRIPTION DRUG OF THAT -- DRUGS OF THAT LAMINA. IT'S COMPLETELY OBSTRUCTED. SO THE WORLD HEALTH ORGANIZATION HAS FIVE CLASSIFICATIONS, FIVE GROUP CLASSIFICATIONS OF PULMONARY HYPER TENSION. ARTERIAL IS GROUP ONE. TO HAVE THE DIAGNOSIS OF PULMONARY ARTERIAL, YOU NEED A PRESSURE OF 25 MILLIMETERS OF MURKY OR MORE, BUT LOW LEFT SIDED PRESSURES, ON RIGHT HEART CATHETERIZATION YOU NEED A PULMONARY ARTERY WEDGE PRESSURE NO GREATER THAN 15-MILLIMETERS OF MURKY. IN 2013 THEY ADDED A PULMONARY RESISTANCE GREATER THAN 3. NOW, IN 2012 WHEN WE STARTED DIAGNOSING AND MONTHLING THIS PATIENT PULMONARY HYPER TENSION, SICKLE CELL DISEASE WAS CONSIDERED A GROUP ONE PULMONARY HYPER TENSION DISEASE. AT THAT TIME WE GAVE HER FDA APPROVED MEDICATIONS FOR PULMONARY HYPER TENSION. IN 2013 THE WORLD HEALTH ORGANIZATION RECLASSIFIED SECURELING 2008 DISEASE AND GROUP 5. I WANT TO MAKE THIS VERY CLEAR BECAUSE THE MEDICATIONS WE'RE GOING TO DISCUSS THIS AFTERNOON ARE NO LONGER CONSIDERED FDA APPROVED PAUSE SECURAL CELL IS NOW GROUP 5 PULL MON NARY HYPER TENSION. THESE ARE JUST SOME OF THE GROUP 1 PULMONARY HYPER TENSION -- THESE ARE SOME OF THE DESIGNATION DIAGNOSIS IN THE GROUP ONE. GROUP TWO IS ONLY RELATED TO LEFT HEART DISEASE. GROUP 3 IS ONLY RELATED TO LUNG DISEASE, HYPOXIC DISEASES OR SLEEP DISORDER. GROUP 4 HAS ONLY TO DO WITH CHRONIC TROM BOW EMBOLIC DISEASE. THAT LEADS US WITH GROUP 5, A MISCELLANEOUS GROUP. SUBCATEGORIZED 250 INCLUDE COMMON CITIES. THIS GROUP, LUMPED IN ANEMIAS. THIS IS WHERE SICKLE CELL PULMONARY HYPER TENSION LIVES. THERE ARE THREE WAYS THIS CAN HAPPEN. THEY CAN HAVE HIGH OUTPUT LEFT HEART DISEASE. SYSTOLIC OR DIASTOLLIC LEFT HEART DYSFUNCTION. THAT CAN GIVE YOU A GROUP TWO DYSFUNCTION. BE KNOW SICKLE CELL PATIENTS HAVE A HIGH RISK OF PULMONARY THROMBOEMBOLIC DISEASE. IN THE ABSENCE OF LEFT HEART DISEASE OR CHRONIC THROMBOBOLIC DISEASE, YOU CAN HAVE ANALYTICKY MEANNIA. THAT IS NOW CONSIDERED GROUP FIVE. HOW SYMPTOMATIC YOU ARE AT PRESENTATION GREATLY IMPACTS YOUR SURVIVAL. AND ONE OF THE WAYS WE MEASURE SYMPTOMS IS BY CLASSIFICATION. SO IF YOU'RE A [INDISCERNIBLE] CLASS ONE THAT MEANS YOU'RE NOT SYMPTOMATIC WITH JUST ABOUT ANYTHING. BUT IF YOU'RE A FUNCTIONAL CLASS TWO, YOU GET BREATHLESS WITH MODERATE EXERTION. IF YOU'RE CLASS 3, YOU'RE SMALLIC WITH MINIMAL EXERTION. CLASS 4, I GET SYMPIC AT REST. FROM THIS GRAPH IF YOU'RE FUNCTIONAL CLASS ONE OR TWO AT PRESENTATION, YOU HAVE A SIGNIFICANTLY BETTER OUTCOME REGARDLESS OF YOUR INTERVENTION COMPARED WITH FUNCTIONAL CLASS 3 OR 4. OUR PATIENT WAS A FUNCTIONAL CLASS 3 ON PRESENTATION. NOW, THIS IS GROUP ONE PILL MON NARY HYPERTENSION. WHAT ABOUT SICKLE CELL PH? IN SICKLE CELL DISEASE WE TEND TO DO A LOT OF SCREENING ECHO CARDIOGRAPHY AS A NON INVASIVE INDIRECT MEASUREMENT OF RIGHT HEART DISEASE. THE TR JET VELOCITY WHEN IT'S LOSS IS CONSIDERED TO BE A GOOD SIGN. WHEN YOU PRESENT WITH PULMONARY HYPERTENSION, IF IT'S LOW, YOU HAVE A FAR BETTER OUTCOME THAN WHEN IT'S MODERATELY ELEVATED OR SIGNIFICANTLY. SO A TR JET VELOCITY GREATER THAN 2.9 WAS ASSOCIATED WITH A FAR WORSE OUTCOME. OUR PATIENTS TR JET VELOCITY WAS 3.9. BUT ANY PULL MONOLOGIST OR CARDIOLOGISTS WILL TELL YOU ECHO IS INDIRECT. WE ALL WANT RIGHT HEART CATHETERIZATION DATA. THIS IS DATA FROM OUR COHORT HERE AT THE NIH. THIS IS DATA LOOKING AT WHETHER PATIENTS HAD ANY TYPE OF PULL MONEY HYPERTENSION, GROUP 2, 4 OR 5. VERSES NO TYPE OF PULMONARY HYPERTENSION. YOU CAN SEE THIS IS A TRAFFIC DIFFERENCE IN SURVIVAL BETWEEN THOSE PATIENTS WHO HAD SICKLE CELL RELATED PULMONARY HYPERTENSION AND THOSE WHO DID NOT. IN 2015 THERE ARE STILL 3 DIFFERENT MECHANISMS THAT WE USE TO TREAT THIS DISEASE. THE CORNER STONE OF OUR THERAPY, THE KNITRIC OXIDE WE'RE VERY FAMILIAR WITH AT THE NIH, STILL IS A SURROUNDMENTAL PATHWAY WE USE. THE ENDOTHELIAL PATHWAY IS REMARKABLY CHANGED HOW WE MANAGE ALL OUR PATIENTS. WHAT ABOUT OUR PATIENT? SHE UNDERWENT TRANSPLANT IN AUGUST, 2013. BUT IN 2012 SHE PRESENTED WITH PROGRESSIVE DECLINE IN FUNCTIONING. SHE WAS DIZZY, HAD EXERTIONAL CHEST PAIN, DYSENEIA. WE PROCEEDED WITH DOING A VENTILATION PROFUSION SCAN TO LOOK FOR VENUS THROMBBOLIC DISEASE. WE DIDN'T FIND ANY. WE DID DOPPLERS OF HER LEGS TO LOOK FOR DVT AND THOSE WERE NEGATIVE. WE PROCEEDED WITH DOING PULMONARY FUNCTION TESTING. THIS SHOWED SEVERE DIFFUSION IMPAIRMENT, ONLY MILD RESTRICTION. WE EXCLUDED SIGNIFICANT LUNG DISEASE. WE DID SERLOGIC TESTING. AND THIS WAS NEGATIVE AS WELL. SO WE PROCEEDED WITH RIGHT HEART CATHETERIZATION IN MAY, 2012. AND HER PULMONARY MEAN PRESSURE WAS 30. WEDGE PRESSURE WAS 12. ERR CARDIAC INDEX, 5.3. ELEVATED. OUR SICKLE CELL PATIENTS TEND TO HAVE HIGH CARDIAC OUTPUTS LIKE I MENTIONED EARLIER. A NORMAL INDEX IS ON AVERAGE 3. SHE WAS VERY SYMPTOMATIC AS I MENTIONED, A FUNCTIONAL CLASS OF 3. 6 MINUTE WALK DISTANCE WAS SIGNIFICANTLY REDOSED AT 252-METERS, HALF OF WHAT IT SHOULD BE. SHE WAS HYPOXIC. HAD A RESTING SATURATION OF 90%. AND SHE HAD AN ELEVATED NTMP OF 287. WAS AT HER BASELINE WITH A HEMOGLOBIN OF 7.4. WE STARTED HER ON A RECEPTOR ANTAGONIST, INCREASED TO THE MAXIMAL DOSE OVER SEVERAL WEEKS TO MONTHS. AND IN ONE YEAR, AFTER SHE HAD BEEN ON THAT THERAPY, WE NOTED THAT SHE HAD HAD A SIGNIFICANT IMPROVEMENT IN HER FUNCTIONAL CLASS. GREATER THAN 100-METER IMPROVEMENT IN HER 6 MINUTE WALK. THAT'S CLINICALLY RELEVANT. SHE HAD A SIGNIFICANT IMPROVEMENT IN HER SATURATION, NORMALIZATION OF HER BMP. SHE WAS STILL EQUALLY ANEMIC. IF YOU LOOK AT THE ECHO CARDIOGRAM SHE HAD DONE AT THE EXACT SAME DATES, AT THE TIME OF HER BASELINE CATHETERIZATION, OFF THERAPY, DILATED RIGHT ATRIUM AND RIGHT VENTRICLE. SHE HAT EXCEPTIONAL BOWING. A SIGN OF SIGNIFICANT RIGHT HEART STRAIN. SHE HAD A RIGHT VENTRICULAR SEC TOLLIC PRESSURE OF 67. A YEAR AFTER THAT, ON THERAPY, SHE HAD NORMALIZED RIGHT SIDED CHAMBERS, NO FURTHER POING WITH A NORMALIZED PRESSURE. SHE UNDERWENT HER TRANSPLANT. AND AFTER HER TRANSPLANT SHE FELT REMARKABLY BETTER. SO WE ACTUALLY DECIDED TO TRY TO DECREASE THE DOSE OF HER RECEPTOR ANTAGONIST. 8 MONTHS AFTER HER TRANSPLANT, WE -- AT ONE OF HER VISITS, WE NOTED SHE WAS ON 50-MILLIGRAMS. SHE WAS NOT SMALLIC ANY LONGER. FUNCTIONAL CLASS OF ONE. HER 6 MINUTE WALK CONTINUED TO IMPROVE. SHE HAD 100% OXYGEN NATION ON ROOM AIR AND NTMB WAS NORMAL AND HEMOGLOBIN NORMAL. WE CONTINUED TO WEAN HER OFF THERAPY, SO OFF VASO DILATER THERAPY. MANY WEEKS LATER. IN AUGUST, 2014 WE REPEATED HER RIGHT HEART CATHETERIZATION. HER PULMONARY MEAN PRESSURE WAS 17 COMPARED WITH 30 PRIOR TO TRANSPLANT. HER PULMONARY WEDGE PRESSURE WAS 6 COMPARED TO 12 BEFORE TRANSPLANT. HER CARDIAC INDEX, 2.8, WHICH IS NORMAL COMPARED WITH 5.1 BEFORE TRANSPLANT. SHE WAS ASYMPTOMATIC. HER 6 MINUTE WALK DISTANCE CONTINUED TO IMPROVE. SHE WAS [INDISCERNIBLE], NORMAL BMP AND MORE ANEMIC BECAUSE WE WERE FROM BOTMIZING HER. THE YOU LOOK AT THE ECHO CARDIUMS DONE, WHEN SHE WAS ON FIVE MILLIGRAMS SHE HAD NORMAL RIGHT SIDED CHAMBERS, NORMAL LEFT SIDE. NORMAL PRESSURE. OFF THE DRUG AT THE TIME OF THE RIGHT HEART CATHETERIZATION. SHE HAD NORMAL RIGHT SIDED CHAMBERS. NORMAL LEFT SIDED FUNCTION. AND NORMAL RIGHT VENTRICK CAN YOU LAR SYSTOLIC PRESSURE. WHAT CAN WE CONCLUDED ABOUT THIS? WE CAN SAY THAT SICKLE CELL RELATED -- CAN CAUSE 3 TYPES OF PULMONARY HYPER HYPERTENSION, RELATED TO HIGH OUTPUT HEARTED DISEASE OR JUST RELATED TO HEMOLYTIC ANEMIA. REGARDLESS OF WHICH TYPE, THE PRESENCE OF PULMONARY HYPER HYPERTENSION IN SICKLE SELL DISEASE WITH ASSOCIATED WITH WORST SURVIVAL. IN THIS PATIENT, RIVER BLOOD STEM CELL TRANSPLANT RESULTED IN A CURE OF SMALLIC PULMONARY HYPERTENSION. IT RESOLVED HER STATE. WE NORMALIZED HER FUNCTIONAL CLASS AND 6 MINUTE WALK TEST. NORMALIZED HER HEMODYNAMICS, OFF AN EFFECTIVE VASODILATOR THERAPY. I'M GOING TO TURN THIS OVER NOW DO HEAR MORE ABOUT THE TRANSPLANTS. >> I HOPE IN THE NEXT TEN MINUTES OR SO, I'LL TELL YOU ABOUT THE BENEFITS THAT STEM CELL TRANSPLANT CAN OFFER TO PATIENTS WITH SICKLE CELL DISEASE. YOU HEARD FROM THE PREVIOUS PRESENTERS THAT LIVER DISEASE ASSOCIATED WITH SICKLE CELL FOR PULMONARY HYPERTENSION IS ASSOCIATED WITH WORSE MORTALITY. THIS IS WORK DONE BY TWO DOCTORS, WHERE THIS -- THEY STRATIFIED TWO SETS OF PATIENTS. ONE SET OF PATIENT WITH NO EMERGENCY ROOM VISITS OR HOSPITALIZATION COMPARED 250 THOSE THAT HAD ONE OF THOSE. AND YOU CAN SEE THAT IS THE CURVE WITH PERCENT SURVIVAL. DESPERATE NICELY -- THIS SEPARATES NICELY AS THE PATIENTS GET OLDER. YOU GET THE IMPRESSION THAT IF YOU HAVE ANY SICKLE RELATED MORBIDITY, THAT'S ASSOCIATED WITH EARLY DEATH. AND THAT IS TRUE. AND I DON'T WANT YOU TO THINK SICKLE CELL DISEASE IS BENIGN HEMOGLOBINOPATHY. IT'S NOT THAT BENIGN OF A DISEASE. THE SHAPE OF THIS CURVE, I KNOW THAT AS WE GET OLDER, WE -- THERE IS AN AGE INCREASED RELATED DEATH AND THE CURVE TYPICALLY LOOKS MORE FLAT. BUT AS YOU CAN SEE THE SHAPE OF THIS CURVE, IS THAT IT DROPS RAPIDLY. IT TELLS US THAT SICKLE CELL DISEASE, WHILE DESIGNATED OR UNDESIGNATED, THIS IS ACCUMULATE AND PATIENTS DO DIE EARLY. SO IF YOU WERE TO LOOK AT THE MORTALITY ESTIMATES, YOU HAVE HEARD A LITTLE BIT FROM DR. KOH, THE PREVALENCE RANGE FROM 10-25%, DEPENDING HOW YOU DEFINE IT. YOU HEARD FROM DR. WEIR, THE SEVERITY. AMONG 2 COHORTS AT THE NIH, THERE IS OVERLAP SYNDROME WITH PULMONARY HYPER HYPERTENSION. AND I JUST SHOWED YOU, SOMETIMES ACUTE CHEST SYNDROME. THIS CAN PROGRESS TO PROTEIN YOU ARIA, TO NEF ROTIC SYNDROME IN OUR SECOND PATIENT. SOME OF THE PATIENTS CAN PROGRESS TO END STAGE RENAL DISEASE. WHAT ABOUT OTHER ORGANS? ABOUT 10% OF THE CHILDREN, THEY CAN HAVE STROKE. NEUROLOGIC DEFICIT. ANOTHER 10% GET EYE DISEASE IN THE RETINA. AND THIS EYE DISEASE IS MORE PREVALENT IN THOSE WITH HEMOGLOBIN SC OR COMPOUND HETEROZYGOUS DISEASE. AN ADDITIONAL THIRD OF THE CHILDREN CAN HAVE WHAT'S CALLED SILENT STROKE, THEY -- THE CHILDREN AS THEY GROW UP ARE FEELING FINE, BUT SUDDENLY, IMAGING, YOU CAN PICK UP A STROKE OR STROKES, AND THAT'S ASSOCIATED WITH COGNITIVE DEFECTS. THIS SILENT STROKE RISK CONTINUES EVEN WHEN THEY BECOME ADULTS. YOU LOOK AT THESE MORTALITY ESTIMATES AND THINK ARE THESE [INDISCERNIBLE], THE ANSWER IS YES. THEY'RE ADDITIVE. THAT'S WHY THE MEDIAN AGE OF DEATH FOR AN AVERAGE PERSON IS ABOUT 45 YEARS OLD. SO BASED ON THE ORGAN INJURY THAT I HAVE SHOWED YOU, WE ADDED THESE ORGAN DAMAGE 250 THE LIST OF -- TO THE LIST OF TRANSPLANT INDICATIONS. SO YOU SEE HERE IN THE BLACK LETTERS, THESE ARE THE TRADITIONAL INDICATIONS FOR TRANSPLANT. FOR CHILDREN. AND WE EXPANDED THAT 250 INCOLLIDE ELIGIBLE ADULTS. SO I WANT TO GO OVER A LITTLE BIT OF THE TRANSPLANT DEVELOPMENT IN THE FULL OR MILO AREA PLATIVE TRANSPLANTS, STARTED 3 DECADES AGO WITH A VERY SUCCESSFUL CASE REPORT IN 1984, FOLLOWED BY SUCCESSFUL CASE SERIES IN THE COUSIN DISEASE, AND THIS REALLY PROMPTED MULTICENTER EFFORTS TO TRANSPLANT CHILDREN IN SICKLE CELL. AND IN THE NEXT DECADE, REALLY, THERE IS A GOOD EXPLOSION OF PATIENTS BEING TRANSPLANTED. AND REALLY ESTABLISHING THAT SICKLE CELL DISEASE IS SEVERE AND NEEDS TRANSPLANT AS A CURATIVE OPTION. AND THE LAST DECADE, THIS NUMBER, THE NUMBER OF PATIENTS TRANSPLANTED HAS CONTINUED TO INCEDES. OWNED NOW WE'RE IN THE THIS CURRENT DECADE, CLOSE TO 500 CHILDREN AND IF YOU WERE TO COUNT CHILDREN NOT PUBLISHED IN THE LITERATURE, THERE IS MORE THAN FIVE CHILDREN THAT HAVE BEEN TRANSPLANTED. REALLY, THE DISEASE SURVIVAL IS TRAFFIC, GREATER THAN 95% CAN SURVIVE A FULL TRANSPLANT. THAT'S REMARKABLE. AND VERY LOW TRANSPLANTED RELATED COMPLICATIONS. BUT WHAT ABOUT THE NON ABLATIVE TRANSPLANTS? THE EFFORTS STARTED ABOUT 2 DECADES LATER BUT IN CONTRAST TO THE ABLATIVE OR THE FULL TRANSPLANT. EXPERIENCE IN THE FIRST CASE SERIES WERE QUITE DISATE POINTING. THERE WERE DEATHS, GRAPH REJECTIONS. THE TRANSPLANT TOOK THAT AS A CHALLENGE TO REDESIGN AND REWORK ON WHAT'S A GOOD CONDITION REGIMENT FOR PATIENTS WITH SICKLE CELL DISEASE. WE'RE HAPPY TO TELL YOU IN THE LAST DECADE WE MADE REALLY GOOD PROGRESS. CAME UP WITH A REGIMENT BOTH IN THE FIRST PATIENT AND WE BUILT UPON THAT FOR THE HAPLOTRANSPLANT REGIMENT FOR THE SECOND PATIENT NOW PRESENTED. WE'RE IN THE CURRENT DECADE WHERE THE NUMBER OF PATIENTS ARE UNDERGOING TRANSPLANT HAS INCREASED. AND AS WE HAVE MADE THE FOCUS TO TRANSPLANT ADULTS, WE'RE HAPPY TO SAY THAT THE DISEASE-FREE SURVIVAL IS APPROACHING THAT OF THE FULL TRANSPLANT. AND I'D LIKE TO SAY THAT OUR TRANSPLANT RELATED COMPLICATION IS PROBABLY JUST AS LOW AS THE FULL TRANSPLANT. WHAT ABOUT THE BENEFITS? THESE ARE THE PUBLISHED LITERATURE ON THE BENEFITS OF ABLATIVE TRANSPLANTS IN CHILDREN. YOU CAN SEE THAT IN THE DIFFERENT ORGAN SYSTEMS, IN TERMS OF BRAIN WAVES WITH AVERAGE OF 3-5 YEARS OF POST FOLLOW-UP, STABLE BRAIN IMAGING. IN ONE STUDY THERE IS STABILITY IN IQ, IN ANOTHER TREND IN IMPROVEMENT. AWE ALL SHOWED THAT THERE IS SPEED WHERE THE PROCESSING INFORMATION THROUGH COGNITIVE TESTING AND THAT SPEED HAS INCREASED. OTHER COGNITIVE TESTING IN TERMS OF VERBAL, REASONING, MEMORY, STABLE. IN TERMS OF CARDIAC AND PULL MON NARY TESTING, ALSO STABLE. REDUCTION IN HEPATIC IRON. TRANSPLANT WERE TO BE DONE EARLIER, SLEEP FUNCTION CAN BE IMPROVED. IN THE MAJORITY THEY REMAIN DISABLE. WHAT ABOUT OUR TRANSPLANT? OUR NON ABLATIVE TRANSPLANT ACHIEVED WHAT'S CALLED A MIX THE CHAMBERISM. THAT MEANS NO -- THE PERFECTLY BLOOD, YOU DON'T -- PERIPHERAL BLOOD, WE LEARNED QUICKLY, YOU DON'T NEED TO COMPLETELY REPLACE THE BONE MARROW. THIS MILLILLOYD CURVE HERE, I NEED 20% TO KEEP SICKLE CELL AWAY. WITH THE MIXED CLIMBISM THAT WE HAVE SEEN, YOU CAN SEE THAT ANEMIA GRADUALLY RESOLVES AT THE TIME OF TRANSPLANT AND THE HEMOGLOBIN INCREASES IN A GENDER SPECIFIC WAY. IN TERMS OF THE TYPICAL MARKERS OF HE MOLSIS, THE COUNTED HERE OR TOTAL BILLI RUNEN, THESE MARKERS GRADUALLY IMPROVE TO THE NORMAL RANGE. AND WITH THE -- RESOLUTION OF THEIR SICKLE CELL DISEASE, THERE IS A LOWER HOSPITAL ADMISSION RATE FROM THE MEDIAN OF 3 TO LESS THAN 1. A GRADUAL REDUCTION IN NARCOTIC USE. YOU CAN SEE THAT 24 IS A WEEKLY EQUIVALENT OF MORPHINE, DECREASE IN THE FIRST 3-4 MONTHS AFTER TRANSPLANT. SO WHAT ABOUT THE BENEFITS? THE ORGAN STATUS WHEN YOU COMPARE THEM TO THE ABLATIVE? SO THESE ARE THE RESULTS IN OUR PATIENTS THAT WE FOLLOW AT THE NIH. IN 9 PATIENTS THAT HAVE PREVIOUS CNS DISEASE, WE SAW STILT IN THEIR IMAGING. IN COLLABORATION WITH PAEDIATRIC ONCOLOGY BRANCH NCI, WE HAVE PERFORMED NEURO COGNITIVE TESTING IN MORE THAN 25 PATIENTS. AND WE'RE HAPPY TO SO YOU THAT -- SHOW YOU, WE SEE STABILITY IN THE VERBAL PERFORMANCE AND ATTENTION MEMORY TESTING. JUST HIKE THE ABLATIVE STUDY, WE SAW IMPROVEMENT. THERE IS A TREND IN IMPROVEMENT IN FUNCTIONING MOSTLY IN REDUCTION OF PAIN AND QUALITY OF LIFE. WHAT ABOUT THE LUNGS AND HEART? IN 14 PATIENTS WITH TRICUSPID, WE SAW REDUCTION IN THE TRV, AS WELL AS INCREASE IN THE 6 MINUTE WALK TEST, JUST LIKE YOU SAW IN THE SECOND PATIENTS. AND WITH THAT, OUR PATIENTS TELL US THAT THEY FEEL BETTER. THEY CAN DO MORE. AND THEY HAVE BETTER STAMINA. ECHO PARAMETERS, WE SAW THAT THERE IS A PRESERVATION OF THE EJECTION FRACTION, HOW MUCH BLOOD CAN BE -- FLOW FROM EACH CHAMBER. WE SAW THIS NUMBER QUITE STABLE AFTER TRAN PLANT. THIS LEFT, WE SAW THIS NUMBER DECREASE IN THE NORMAL RANGE. THIS IMPROVEMENT CORRESPOND WITH INCREASE IN HEMOGLOBIN. WHAT ABOUT THE LUNGS? OTHER THAN THE TRV AND 6 MINUTE WALK TEST. WHEN WE PERFORM THE PULMONARY FUNCTION TEST ALONG THE TYPICAL PARAMETERS THAT WE FOLLOW, YOU CAN SEE MOSS OF THESE LINES ARE FLAT WITH THE EXCEPTION OF THIS RV. AND DR. WEIR TELLS ME THAT THIS IS WHAT YOU WANT TO SEE. SO I'M ALSO HAPPY TO TELL YOU THAT WITH -- YOU KNOW, GOOD AMOUNT OF FOLLOW-UP, AND AFTER 300-RADIATION, OUR PATIENTS LUNG STATUS REMAINED STABLE. ALSO TELLS US THAT THE TRANSPLANT OF FOLKS, THAT THERE IS GO UNDERLYING UNDIAGNOSED LUNG CHRONIC HOST DISEASE. WHAT ABOUT THE LIVER? DR. KOH MENTIONED RELATED LIVER DISEASE. IN 14 PATIENTS THAT WE HAD ELEVATED, IN TEN THEY UNDERWENT LIVER BIOPSIES. MOST HAD CONFIRMED IRON OVERLOADS. YOU SAW WITH DR. KLEINER, A LOT HAD DISTORTED LIVER ARCHITECTS WITH BRIDGING GUBERNATORIAL ROSIS IN SOME. ALL THOSE THESE PATIENTS HANDLED THE REGIMENT BREATHY WELL, THEY HAD -- PRETTY WELL. THEY EVENTUAL -- IN 7 OF 14, AS WELL AS THE SECOND PATIENTS HAVE COMPLETED LARGE VOLUMES FE BOTMY. THEIR LIFE IS AT LEAST MUCH BERT. SO I WANT TO LEAVE YOU WITH THE LAST TWO SLIDES, A QUICK SUMMARY. WHEN I COMPARE THE NON ABLATIVE VERSES ABLATIVE IN TERMS OF TRANSPLANT OUTCOME, QUALITY OF LIFE IN THE DIFFERENT ORGAN STATUS, I'D LIKE TO SEE THAT THE NON ABLATIVE REGIMENT THAT WE HAVE STARTED HERE AND CONTINUE IS REALLY QUITE SIMILAR OUTCOME AS THE FULL ABLATIVE. AND WHILE THE ABLATIVE TRANSPLANT IS STANDARD FOR CHILDREN, I I LIKE TO SAY THE NON APLATIVE CAN BE CONSIDERED STANDARD FOR ADULTS. NOT ONLY LESS TOXIC, BUT DEFINITELY APPLICABLE FOR THOSE WITH AN ORGAN INJURY. THERE IS EXTRA BENEFIT THAT THIS APPROACH DOESN'T OFFER, THAT IS, THE PRESERVATION. THIS IS MY LAST SLIDE. JUST WANTED TO IMPRESS ON YOU THAT WHILE SICKLE CELL DISEASE IS CONSIDERED [INDISCERNIBLE] IT'S ASSOCIATED WITH EXTENSIVE MORBIDITY. CHRONIC COMPLICATIONS DOES REALLY LEAD TO EARLY MORTALITY. TRANSPLANT IS A FEASIBLE OPTION, EVEN FOR THOSE WITH CHRONIC COMPLICATIONS. SOME OF THE COMPLICATIONS CAN BE REVERSED BY SICKLE CELL TRANSPLANTATION. SO WE HAVE ONE SURPRISE. >> OUR SECOND PATIENT, THIS IS GOING TO COME -- SHE IS GOING TO COME UP. SHE'S A GRAPHIC DESIGNER. SHE PAINTED THIS PICTURE AND SUBMITTED IT DO A CONTEST AND WON SECOND PRIZE. SO CAN YOU TELL US WHAT YOUR PAIN WAS LIKE BEFORE AND AFTER THE TRANSPLANT? >> BEFORE THE TRANSPLANT, I WAS IN CONSTANT PAIN AND WAS ALWAYS A STRUGGLE [INDISCERNIBLE] BECAUSE IT WAS JUST CONSTANT PAIN. ALL THE TIME. BUT NOW, WHEN I WAKE UP, ABSOLUTELY NO PAIN. OTHER THAN THE NORMAL CHRONIC PAINS AT WHICH TRYING MY POSSIBLE BEST, TO WEAN MYSELF OFF THE DRUGS. I'M GOING AUTOMATICALLY REACHING OUT TO THE DRUGS WHICH I'M TRYING TO CHANGE NOW. SO IT'S A BIG CHANGE. DEFINITELY. >> WHAT ABOUT YOUR PULMONARY HYPERTENSION SYMPTOMS? HOW HAVE THEY CHANGED SINCE THE TRANSPLANT. >> LET'S SAY I WALKED FROM HERE AND I WAS NOT OUT OF BREATH, WHICH IS UNUSUAL FOR ME. ABOUT THREE YEARS AGO, I WOULD HAVE BEEN OUT OF -- HARD TO STAND THERE, CATCH MY BREATH FIRST. COME DOWN HERE, SIT DOWN, CATCH MY BREATH AGAIN. BUT I WAS ABLE TO DO THAT, NORMAL, SIT DOWN AND HAVE A CHAT. I COULD NOT DO THAT BEFORE. THAT WAS -- EVEN RUNNING UP THE T STAIRS, I COULD NOT DO THAT. I HAD TO TAKE THEM ONE AT A TIME. TAKE A BREATH AND KEEP GOING. I TRIED DO HAVE A CONVERSATION AFTER THAT. >> TELL US, HOW HAS YOUR LIFE CHANGED NOW SINCE YOU HAD THE TRANSPLANT? >> WELL, MY [INDISCERNIBLE] BECAUSE I'M NOT IN THE HOSPITAL. SO I CAN ACTUALLY, YOU KNOW, PLAY WITH MY SON, GO TO THE PLAY GROUND, MORE THINGS. AND HE PRETTY MUCH DOESN'T KNOW ME WHEN I HAD SICKLE CELL. HE KNOWS ME AS A HEALTHIER MOTHER. AND MY FAMILY ABLE TO KEEP MY PROMISES [INDISCERNIBLE] I CAN BE THERE. SO THAT'S ALSO ANOTHER CHANGE, TOO. [APPLAUSE] >> THANK YOU FOR A GREAT PRESENTATION. THANK YOU FOR BEING HERE. AND WE HAVE A FEW MINUTES FOR QUESTIONS, SO YOU PLEASE STAND TO THE MICROPHONE AND ADDRESS YOUR QUESTION TO THE SPEAKER THAT YOU WOULD LIKE AN ANSWER FROM, THAT WOULD BE GREAT. >> THERE WAS A STUDY DONE IN THE STATE OF MARYLAND OF ASTHMA DEATHS FROM 1988 TO 1992. AND WITHIN THAT STUDY WAS INCLUDED SOME SUDDEN DEATHS DUE TO SICKLE CELL SQUEEZE, THIS WAS A STUDY BASED OUT OF THE MEDICAL EXAMINER OF THE STATE OF MARYLAND WITH THE UNIVERSITY OF MARYLAND. I WAS FIRST AUTHOR ON THE PAPER, I PUT THE PROJECT TOGETHER. IT WAS PUBLISHED IN THE ARCHIVES OF PATHOLOGY AND LABORATORY MEDICINE IN 1998. WE HAD 60 PATIENTS OR 60 DEATHS. AND THERE WAS SOME SUGGESTION THAT SICKLE CELL WAS ASSOCIATED WITH ASTHMA AND SUDDEN DEATH. I NOTICED YOU DIDN'T SAY ANYTHING WHATSOEVER ABOUT ASTHMA HERE IN TERMS OF SUDDEN DEATHS. I WAS KIND OF SURIOUS IF YOU FOUND THAT TO BE A SIGNIFICANT FACTOR. >> OUR PATIENT DIDN'T HAVE ASTHMA BUT YOU'RE RIGHT. THERE IS AN INCREASED INCIDENCE OF ASTHMA IN SICKLE CELL PATIENTS AND SOME BELIEVE THERE IS ACTUALLY A COEXISTENCE OF ASTHMA WITH THE PULMONARY HYPERTENSION, AND THERE IS SOME RESEARCH GOING ON INTO THAT. I'LL LEAVE IT AT THAT. >> THANK YOU. >> ANY OTHER QUESTIONS? >> WELL, THANK YOU ALL FOR BEING HERE. OUR NEXT CBC IS COMING IN THE FALL. IF YOU HAVE GREAT CASES FROM A CLINICAL AND RESEARCH STANDPOINT PLEASE SEND E-MAIL AND WE'LL MAKE SURE THAT GETS DISCUSSED AND PRESENTED HERE. THANK YOU SO MUCH.