OKAY. LET'S GO AHEAD AND GET
STARTED. THANK YOU ALL FOR BEING
HERE AND ALSO FOR ALL OF YOU WHO
ARE ATTENDING VIRTUALLY. WELCOME
TO THE CLINICO PATHOLOGIC GRAND
ROUNDS OF THE 9TH CLINICAL
CENTER. A SERIES THAT IS MEANT
TO REALLY HIGHLIGHT VERY
INTERESTING CLINICAL CASES AS
YOU WILL SEE TODAY BUT ALSO IN
THE BROADER SCHEME, VERY
INTERESTING AND MONUMENT
CHANGING, I DON'T THINK THAT'S
ANYTHING WRONG YET. BUT MIND
CHANGING RESEARCH CLINICAL
RESEARCH PROGRAMS THAT I THINK
THIS CASE TODAY HIGHLIGHTS BOTH
AT THE HIGHEST LEVEL. WE WILL
HEAR TODAY ABOUT
HYPERPHOSPHATEMIC FAMILIAL
TUMORAL CALCINOSIS AND DEFINING
PATHOMECHANISMS FOR TREATMENT.
WE HAVE A GREAT ROSTER OF
SPEAKERS, MIKE COLLINS HEAD OF
THE SKELETAL DISORDERS AND
MINERAL HOMEOSTASIS SECTION
NIDCR. DR. ROSZKO, A RESEARCH
PHYSICIAN AT THE SAME SECTION AT
NIDCR. WE WILL SEE RADIOLOGY
FROM DR. SABOURY FROM THE
RADIOLOGY AND IMAGING SCIENCES
AT THE NIH CLINICAL CENTER. WE
WILL HEAR FROM DR. KLEINER, HEAD
OF THE HISTOPATHOLOGY AND
AUTOPSY PATHOLOGY SECTION AT THE
NCI FOR THE PATHOLOGY FINDINGS.
AND THEN WE WILL ALSO HEAR FROM
DR. GOURH, ASSISTANT CLINICAL
INVESTIGATOR HEAD OF SCLERODERMA
GENOME EX AND HEALTH DISPARITIES
UNIT AT NATIONAL INSTITUTE OF
MINORITY HEALTH AND HEALTH
DISPARITIES. THE LAST THING I
WILL SAY BEFORE WE START YOU
WILL SEE ON THE SCREEN THE PHONE
CALL -- PHONE NUMBER NEEDED IN
ORDER TO OBTAIN CME FOR TODAY
AND THE CME CODE IS 50533.
50533. WE HAVE ALSO DONE
THOROUGH EVALUATION OF THE
LIGHTS IN ROOM AND WE ARE READY
TO GET STARTED. MIKE.
>> THANK YOU FOR YOUR
INTRODUCTION. I HAVE BEEN
CHARGED WITH PRESENTING THE CASE
WHICH I WILL GO RIGHT INTO. SO
THIS NOW 42-YEAR-OLD MAN FIRST
CAME TO THE NIH IN 2011 AT THE
AGE OF 21. HE WAS ONE OF THE
FIRST PATIENTS WITH THIS
CONDITION THAT WE SAW. HIS
PERTINENT MEDICAL HISTORY
STARTED AROUND AGE 10 WHEN HE
DEVELOPED BILATERAL SHIN PAIN
AND ON X-RAY HAD DIAPHYSEAL
THICKENING SUGGESTIVE OF OSTEO
MYELITIS. AT 14 HE NOTICE AD 2
BY 2 SOFT PAINFUL RED WATCH
LUNCH OVER HIS HIP, THIS GREW 6
MONTHS TO 17-CENTIMETERS
RESECTED AT AGE 15, IT
IMMEDIATELY RECURRED AND HAD
MULTIPLE RESECTIONS SINCE. HE
DEVELOPED MULTIPLE LARGE PAINFUL
LEAGUES THAT YOU SEE HERE ON HIS
SHOULDERS, HANDS, HE ELBOWS AN
HIPS.S. LESIONS WOULD LEAK A
THICK WHITE LIQUIDITY CALLED
MILK OF CALCIUM. THE BIGGEST
PROBLEM WAS CHRONIC DEBILITATING
PAIN AND PROGRESSIVE LOSS OF
FUNCTIFUNCTION. SO THIS CAN BE A
DEVASTATING DISEASE AND HE HAD A
VERY DIFFICULT COURSE WITH THIS
HIS PERTINENT FAMILY HISTORY,
HIS PARENTS ARE FIRST COUSINS,
NOT INFECTED. THREE OF SEVEN
SIBLINGS HAVE SIMILAR BUT LESS
SEVERE FINDINGS AS DOES HE. HE
RESIDES IN SAUDI ARABIA BUT IS
NOT A CITIZEN AND HAS NO HEALTH
INSURANCE UNFORTUNATELY. HIS
PERTINENT LABORATORY VALUES AT
PRESENTATION ARE THAT HE HAD AN
ELEVATED BLOOD PHOSPHATE, HIS
BLOOD CALCIUM WAS UPPER LIMIT
NORMAL ELEVATED CALCIUM TIMES
PHOSPHATE PRODUCT. HIS KIDNEY
FUNCTION WAS NORMAL WHEN HE
FIRST CAME. HIS 125 DIHYDROXY
VITAMIN D, THE ACTIVE FORM WAS
ELEVATED, PARATHYROID HORMONE
LOW NORMAL. C REACTIVE PROTEIN A
MEASURE OF INFLAMMATION WAS
ELEVATED. YOU WILL LEARN MORE
ABOUT THE LOW INTACT FGF 23 AND
HIGH C TERMINAL FGF 23 IN A
LITTLE BIT FROM DR. ROSZKO WHEN
SHE GOES OVER THE
PATHOMECHANISM. HE UNDERWENT
GENETIC TESTS AND SHOWS A
HOMOZYGOUS LOSS OF FUNCTION
VARIANT IN GALLANT T 3 A SERE
ANINE AND 3 ANINE
GALACTOTRANSFERASE AND THE NAME
IS SHOWN THERE. SO THE HOSPITAL
COURSE YOU HAVE SEEN HERE, HE'S
BEEN HERE SEVERAL TIMES OVER THE
YEARS FROM HIS HOSPITAL STAYS
QUITE LENGTHY. HE'S HAD
RESECTIONS OF HIP, SHOULDER AND
BUTTOCKS LEAGUES AND HE HAD --
LESIONS AND DRAINAGE OF THE
LARGE FLUID COLLECTION THAT WAS
OVER THE CHEST, YOU CAN SEE THAT
THERE WAS A FLUID, FLUID LEVEL
THERE IDENTIFIED BY THESE
ARROWS. THIS IS A ONE LITER
BOTTLE, THIS WAS DRAINED OFF OF
THERE. AND THIS CHALKY SUBSTANCE
IN THE BOTTOM IS SHOWN HERE. HE
ALSO AT PRESENTATION YOU WILL
SEE THIS ON THE X-RAYS FROM DR.
SABOURY, HAD THESE LESIONS OR
CALCIFICATIONS ON X-RAY AND AT
FIRST WE SAID DID HE HAVE ORAL
CONTRAST? I DIDN'T GIVE HIM, DID
YOU? I SAID SURE LOOKED LIKE HE
HAD ORAL CONTRAST IN THE BOWEL.
BUT ON ENDOSCOPY THESE WERE
COLLECTIONS OF CALCIFICATION
THAT WERE SUB MUCOSAL AND
AMAZINGLY EVEN WITH THIS DEGREE
OF ALMOST OBSTRUCTION OF THE
BOWEL HE HAD NO GI SYMPTOMS BUT
THIS IS REMARKABLE FINDING, I
HAVE NEVER SEEN ANYTHING LIKE IT
SINCE. WE DID TRY AND TREAT HIM
AND OTHER PATIENTS WITH
MULTIPLE, MULTIPLE MEDICATIONS
AS YOU CAN SEE HERE. WE TRIED TO
INHIBIT ABSORPTION OF PHOSPHATE
FROM THE GUT AND HE WAS ON TWO
MEDICATIONS FOR THAT. WE TRIED
TO PROMOTE EXCRETION OF
PHOSPHATE INTO THE URINE. WE
USED THESE THREE MEDICATIONS
SHOWN HERE. WE TRIED TO REDUCE
CALCIFICATIONS WITH TOPICAL
DISULFATE. THIS IS A GRAPH OF A
RATHER LENGTHY COURSE THAT HE
HAD HERE. SHOWN IN THE TOP IS
THE TUBULAR REABSORPTION OF
PHOSPHORUS AND YOU CAN SEE HIS
TUBULAR REABSORPTION OF
PHOSPHORUS IS QUITE HIGH. SO IN
SPITE OF HAVING HIGH BLOOD
PHOSPHATE HIS KIDNEY WAS
INAPPROPRIATELY REABSORBING OR
HOLDING ON TO AS MUCH PHOSPHATE
AS IT COULD. THE SEQUENTIAL
THERAPIES THAT WE GAVE HIM ARE
SHOWN DOWN HERE. SO THESE WERE
TO INHIBIT PHOSPHATE ABSORPTION
TO PROMOTE EXCRETI EXCRETI EXCRT
OOH PROMOTE ABSORPTION AND
SECRETION AND THIOSULFATE WITH
NO EFFICACY AT ALL FOR THIS
PATIENT. SO THIS WAS A
THERAPEUTIC FAILURE. AS MANY OF
THESE HAVE BEEN. IT WAS CLEAR WE
NEEDED TO DO BETTER AND YOU WILL
SEE WHAT WE HAVE BEEN TRYING TO
DO SINCE THEN. WITH THAT NOW I
WILL INTRODUCE MY COLLEAGUE, DR.
KELLY ROSZKO WHO IS A STAFF
CLINICIAN IN THE UNIT, AND SHE
WILL TALK TO YOU ABOUT THE
PATHOMECHANISM OF DISEASE.
>> THANK YOU. SO AS YOU HAVE
SEEN HYPERPHOSPHATEMIC FAMILIAL
TUMORAL CALCINOSIS OR ATEFTC IS
A DISORDER WHICH PRESENTS WITH
LARGE TUMOR LIKE GROWTHS OF
ABOUT NORMAL CALCIUM DEPOSIT DE
DEBILITATING CALCIFICATION
AROUND THE SHOULDER AND
CALCIFICATION AROUND THE
BILATERAL HIPS IN THIS 3-D
RECONSTRUCTED CT PHOTO HERE.
HFTC IS INHERITED IN AUTOSOME
A.M. RECESSIVE PATTERN AND
PATIENTS HAVE HIGH BLOOD
PHOSPHATE LEVELS.
MECHANISTICALLY HFTC IS PA
DISORDER OF DEFICIENT FGF 23
SIGNALING. SO FGF 23 IS A
HORMONE WHICH IS MADE BY BONE
CELLS, IT CIRCULATES THROUGH THE
BODY AND ACT AS THE KIDNEY WHERE
IT BINDS TO FGF 1 RECEPTOR AND
CORECEPTOR P. UPON SIGNALING IT
DECREASES NAPY 28 EXPRESSION AND
EXPRESSION OF 1 ALPHA
HYDROXYLASE. THIS LEADS TO A
DECREASED FORM OF -- SORRY THIS
LEADS TO DECREASED PHOSPHATE IN
THE URINE. INCREASED PHOSPHATE
IN THE URINE AND DECREASED BLOOD
PHOSPHATE. ONE OF THE
HYDROXYLASES IS IMPORTANT
BECAUSE IT HYDROXYLATES 25
HYDROXY VITAMIN D, ACTIVE FORM
OF VITAMIN D, 125 DIHYDROXY
VITAMIN D. IT INCREASES CALCIUM
AND PHOSPHATE ABSORPTION FROM
THE INTESTINE. SO FGF 23 ACTS IN
TOTAL TO DECREASE SERUM
PHOSPHATE AND DECREASE ACTIVE
VITAMIN D. SO AS I SAID FGF 23
IS MADE IN BONE CELLS WHERE
UNDERGOES POST TRANSLATIONAL
REGULATION. FGF 23 IS
GLYCOSYLATED BY GALLIN T 3 AND
UPON GLYCOSYLATION FGF 23 IS
STABILIZED AND SECRETED AND
ACTED IN INTACT FORM. IN THE
ABSENCE OF GALNT 3 FGF 23 CAN BE
CLEAVED BY A CONVERTASE CALLED
FERINNIN. INACTIVE C AND END
TERMINAL FRAGMENTS HERE AND NO
BINDING AND INCREASE IN SERUM
PHOSPHATE AND ACTIVE VITAMIN D.
SO IN THE CASE OF FGF 23
DEFICIENCY NAPI 2A AND ONE ALPHA
HYDROXY ALREADY EXPRESSED WITH
INCREASE IN SERUM PHOSPHATE AND
ACTIVE VITAMIN D. THE CALCIUM
TENDS TO BE IN THE HIGH NORMAL
RANGE AND THE CALCIUM PHOSPHATE
PRODUCT TENDS TO BE QUITE
ELEVATED YOU CAN SEE HERE. IN
MANY OF OUR PATIENTS THE PATTERN
OF FGF 23 FOLLOWS WHAT YOU CAN
SEE IN THIS GRAPH HERE, WITH THE
INTACT ACTIVE FGF 23 BEING QUITE
LOW BUT THE TOTAL FGF 23 WHICH
INCLUDES THE INACTIVE BREAK DOWN
PRODUCTS IS QUITE HIGH. SO THE
LOSS OF FGF 23 ACTION IS MOST
COMMONLY CAUSED BY PATHOGENIC
VARIANTS IN GALNT 3, THIS LEADS
TO LACK OF GLYCOSYLATION AND A
BREAKDOWN OF FGF 23 INTO ITS
INACTIVE FRAGMENTS. THIS CAN BE
DO YOU KNOW TO PATHOGEN -- DUE
TO PATHOGENIC VARIANTS ITSELF.
THIS LEADS TO LOW INTACT FGF 23
AND ELEVATED C TERMINAL FGF 23
THE PATTERN I DESCRIBED IN MOST
PATIENTS. ADDITIONALLY, THERE'S
BEEN ONE CASE DESCRIBED OF A
PATHOGENIC VARIANT IN THE
CORECEPTOR CLOCO AND ONE
PATHOGENIC VARIANT IN THE FGF 1
RECEPTOR ITSELF. IN THESE
PATIENTS IT LEADS TO PATTERN OF
HIGH INTACT FGF 23 BE HIGH C
TERMINAL FGF 23 BREAKDOWN
PRODUCTS. WE HAVE DESCRIBED ONE
CASE OF AUTOANTIBODIES TO FGF 23
WHICH LEAD TO THAT SAME PATTERN
WITH HIGH INTACT FGF 23. SO OUR
TEAM AT THE NIH HERE INCLUDES
DR. RACHEL AND DR. IRIS HEARTLY,
WE HAVE SEEN A TOTAL OF 21
PATIENTS IN OUR COHORT. SO THE
WORK THAT I'M GOING TO TELL YOU
ABOUT REPRESENTS AN ANALYSIS OF
17 PATIENTS, THE MAJORITY HAD
PATHOGENIC VARIANTS IN GANT 3.
WE ALSO HAVE SINGLE PATIENTS
WITH VARIANTS IN FGF 23 ITSELF,
ONE PATIENT WITH A CLOTHO
TRIPLICATION AND ONE FGF 23
AUTOANTIBODIES AND ONE WITH
UNKNOWN GENETICS. SO DENTAL
CALCIFICATION AND SHORT ROOTS IN
THE TEETH WERE PRESENT IN 92% OF
OUR PATIENTS. THAT MAKES THIS
THE MOST PENETRANT PHENOTYPE OF
THIS DISORDER. WE SAW SOFT
TISSUE CALCIFICATION IN 82% OF
THE PATIENTS, 59% OF THE
PATIENTS WERE FOUND TO HAVE
VASCULAR CALCIFICATION, 44% HAD
INFLAMMATION, YOU WILL HEAR MORE
FROM DR. KLEINER WHO LOGO OVER
THE PATHOLOGY. IDEAS SO WE HAVE
BEEN CHARACTERIZING LOCATION OF
THESE SOFT TISSUE CALCIFICATIONS
WITH THE MOST COMMON BEING AT
THE HIPS, FOLLOWED BY THE
SHOULDERS AND THEN THE ELBOWS.
SO INTERESTINGLY ONE OF OUR
PATIENTS DEVELOPED THESE VERY
PRONOUNCED CALCIFICATIONS OF THE
THUMB AND THEN WE FOUND OUT THAT
SHE WAS AN AVID BOWELLER. THUS
THE CURRENT HYPOTHESIS IS THE
CALCIFICATIONS OCCUR IN AREAS OF
PRESSURE OR REPEATED TRAUMA. AND
WE THINK INFLAMMATION AND
HYPOXIA MIGHT BE A MAJOR FACTOR
IN THIS. SO WE ARE CURRENTLY
WORKING WITH OUR MOUSE MODEL TO
TRY TO ELUCIDATE THE MECHANISM
OF CALCIFICATION FORMATION. SO
THROUGH OUR OBSERVATIONS WITH
THE PATIENT COHORT, WE HAVE
DEVISED THIS WORKING MECHANISTIC
HYPOTHESIS. SO WE BELIEVE THAT
AN ELEVATED CALCIUM PHOSPHATE
PRODUCT IS NECESSARY BUT NOT
SUFFICIENT TO CAUSE THOSE
CALCIFICATIONS. IN THE SETTING
OF THIS ELEVATED CALCIUM
PHOSPHATE PRODUCT WE BELIEVE
THERE ARE OTHER FACTORS SUCH AS
PRESSURE, HYPOXIA, AND
INFLAMMATION THAT ARE THE
TRIGGERS FOR CALCIFICATION. WE
ALSO HYPOTHESIZED THAT THERE ARE
INSUFFICIENT INHIBITORS OF
MINERALIZATION SUCH AS
PYELOPHOSPHATE, THAT PERMIT THIS
CALCIFICATION TO FORM. THEN
AFTER CALCIFICATION IS TRIGGERED
WE BELIEVE THERE IS A VICIOUS
CYCLE WHERE CALCIFICATION
TRIGGER ES INFLAMMATION AND
INFLAMMATION TRIGGERS FURTHER
CALCIFICATION. THAT CAN BE SHOWN
HERE. SO NOW I WOULD LIKE TO
INTRODUCE DR. SABOURY, A
DIAGNOSTIC RADIOLOGIST AND
NUCLEAR MEDICINE PHYSICIAN, A
SPECIAL VOLUNTEER IN SKELETAL
DISORDERS IN MINERAL HOMEOSTASIS
SECTION IN THE NIDCR.
>> HELLO, EVERYBODY. AFTER THESE
TWO GREAT PRESENTATIONS I ONLY
NEED TO REPEAT WHATEVER YOU
HEARD. BUT THAT IS EXACTLY MY
JOB. AND I START WITH THE PLAIN
RAID YES GRAPH AND CALCIUM AND
CALCIFICATION IN GENERAL IS THE
FRIEND OF THE RADIOLOGIST
BECAUSE OF THE ELECTRON DENSITY
OF CALCIUM SO IT IS NOT VERY
SURPRISING TO YOU TO SEE THESE
PLAIN RADIOGRAPHS IN THE LEFT
SIDE, YOU SEE FRONTAL X-RAY OF
THE RIGHT SHOULDER AND ALSO
ELBOW. I WANT TO BRING YOUR
ATTENTION TO TWO DIFFERENT TYPE
OF CALCIFICATION PATTERN. ONE IS
COURSE, DENSE, WITH SOME LUCENT
LINES BETWEEN THEM. AND THE
OTHER IS VERY FINE. IT IS JUST
LIKE A LINEAR AS IF MOVE THROUGH
THE FASCIA. IN ADDITION, IN THIS
IMAGE ON THE RIGHT SIDE YOU SEE
TUBULAR AND CALCIFICATION THAT
MOVES BEHIND THECALCA INHIUS AND
SUBSEQUENTLY YOU WILL SEE THIS
IS CORRESPOND TO THE POSTERIOR
TIBIAL ARTERY. ONE OTHER POINT
TO MENTION IS LOCATIONS THAT WE
SEE THE CALCIFICATION. SO
SURROUNDING THE JOINTS AS WE
DISCUSSED BEFORE, SUBCUTANEOUS
DEEP MUSCULAR AND ALSO VASCU VA.
GOING TO MORE THREE DIMENSIONAL
IMAGING, ON THE LEFT SIDE YOU
SEE MAXIMUM INTENSITY PROJECTION
OF THE CT. BY THAT YOU MAY HAVE
A VERY GOOD GRASP OF DIFFERENT
TYPE OF CALCIFICATIONS. THE
COURSE CALCIFICATIONS THAT WE
TALKED ABOUT AROUND THE
SHOULDERS, THIS THICK SHAPE
HYPERDENSE LESION THAT DR.
KLEINER LATER TALK ABOUT IT, AND
IN ADDITION TO THAT, THESE BOWEL
RELATED HYPERDENSE MATERIAL AND
OF COURSE THE SURROUNDING THE
HIP JOINT ON THE LEFT SIDE. BUT
THE THING THAT I WANT TO BRING
OUR ATTENTION TO IS THE IMAGE ON
THE RIGHT SIDE. BONE HAS CORTEX
AND MEDULLA.ND USUALLY WHEN WE
HAVE NORMAL CORTEX WE HAVE A
CONTINUE MITY OF THESE DENSE
LINE. AS WE SEE HERE WE HAVE THE
CORTICAL EROSION. WHEN WE HAVE
CORTICAL EROSION WITHOUT A DOUBT
THERE SHOULD BE SOME
INFLAMMATORY PROCESS IN THE
REGION. AND THIS IS ONE OF THE
HALLMARKS THAT WE LATER SEE, HOW
PLAY THE ROLE HERE. BUT THE NAME
OF THE GAME IS QUANTIFICATION OF
THESE DISEASE BURDEN AS A
HOLISTIC ASPECT OF THE PATIENT
IN GENERAL. EARLY EFFORTS WERE
BASED ON EITHER DUAL X RAY
ABSORBOMETRY OR DEXA WHICH SHOWS
THE GROWTH IN THE GLOBAL BURDEN
OF DISEASE FOR THAT MATTER OR
USING MVP MY THEY WILL DIPHOS
DIPHOSPHANATE SINGLE PHOTON
IMAGING. THESE ARE DECENT FIRST
LEVEL OF QUANTIFICATION BUT AS
YOU CAN IMAGINE THEY LACK THE
ACCURACY AND PRECISION WE NEED.
SO HOW WE CAN DO A BETTER JOB?
GOING BACK TO THE MOLECULAR
MECHANISM OF THESE
CALCIFICATIONS YOU SEE THE
DEPOSITED MOLECULES ARE A
COMBINATION OF CALCIUM YOU SEE
IN THIS ORANGE SCHEMATIC DRAWING
AND THE PHOSPHATE. AND HYDROXYL
GROUPS OVER THERE. THE IMAGE
THAT I SHOWED YOU BEFORE MVP,
THAT MOLECULE IS A BIPHOSPHANATE
THAT EXCHANGE WITH PHOSPHATE.
WHAT IF WE CAN HAVE A MOLECULE
THAT OR ATOM THAT CAN EXCHANGE
WITH THE DIHYDROXY GROUP AND
THEN WE CAN IMAGE IT? AND WE
HAVE THAT P. FLOOR RENNE 18 IS
ONE RADIO TRACERS. ONE OF THE
FIRST RADIO TRAITSERS BEFORE ANY
OTHER PET TRACER COMES OUT THAT
CAN DO THAT. IF WE DO THAT WE
HAVE A SODIUM FLUORIDE PATH THAT
CAN DEMONSTRATE THE POSITION OF
THESE EXPOSED HYDROXYAPATITE
MOLECULES. NOT ONLY CAN WE SEE
THE AREAS OF ACTIVE AND MACRO
CALCIFICATION BUT ALSO YOU CAN
POTENTIALLY FIND THE LOCATIONS
THAT MICROCALCIFICATION HAPPEN
SINCE THE SENSITIVITY OF THE
PATH IS IN THE ORDER OF
NANOMOLAR IN COMPARISON TO THE
CT WHICH IS MILLIMOLAR FOR
DETECTION. SO GOING THERE YOU
SEE THE DEVICES OF THIS KIT IS
ALSO ACTIVE, A NORMAL ACTIVITY.
YOU SEE SOME ACTIVITY IN THE
KIDNEYS AND ALSO BLADDER. BUT
THING THAT I WANT TO BRING OUR
ATTENTION TO IS THE VASCULAR
CALCIFICATION. THE REASON FOR
THAT, AS YOU HEARD, BY MY
COLLEAGUES, THIS DISEASE IS
SPATIALLY HETEROGENOUS. WHEN YOU
ARE DEALING WITH THE SPATIALLY
HETEROGENOUS PROCESS YOU SHOULD
THINK HOW YOU CAN QUANTIFY
BURDEN OF DISEASE TO CAPTURE
THIS HETEROGENEITY IN ONE HAND
AND GLOBAL BURDEN OF DISEASE ON
THE OTHER HAND. THAT IS THE
DILEMMA WE WANTED TO SOLVE. FOR
THAT WE WANTED TO QUANTIFY THE
CALCIFICATION MICROSCOPY
CALCIFICATION IN EACH LOCATION
OF THE AORTA. BUT AT THE SAME
TIME WE WANTED TO BRING ALL THE
DATA IN A COMMON SPACE THAT WE
CAN DO STATISTICAL ANALYSIS ON.
OTHERWISE WE COULDN'T COMPARE
THE PATTERNS WITH EACH OTHER. TO
DO THAT WE HAD -- CREATED THESE
VASCULAR ATLAS METHOD. THAT IS
WITH GREAT COLLABORATION BETWEEN
THE CLINICIANS AND RADIOLOGY AND
BASIC SCIENTISTS, ONE OF THE
HALLMARK OF THIS PROJECT IS THAT
HOW DISCLOSE -- THIS CLOSE
COLLABORATION RESULTED IN THE
DEVELOPMENT OF THIS METHOD. FOR
THAT WE CREATE A LINE THAT GOES
THROUGH THE CENTER OF THE
VESSELS AND EACH LOCATION WE
HAVE A PLATE THAT IS
PERPENDICULAR TO THE AXIS OF THE
VESSEL AND WE MEASURED THE
AMOUNT OF ACTIVITY IN EACH
LOCATION. IMAGINE THIS LOCATION
IS THE POINT OF ZERO AND IT GOES
ON TO LET'S SAY THIS LOCATION.
SO THE DISTANCE OF ZERO AND
HUNDRED FOR EXAMPLE. AND THEN
YOU MAP IT FROM HERE TO HERE.
THEN IN EACH LOCATION FOR EACH
PARENT YOU SEE HOW MUCH ACTIVITY
WAS THERE AND YOU DEPICT THAT
OVER THERE. BY THAT YOU BRING IN
ALL THE DATA IN A COMMON SPACE
WHICH WE CALL THE VASCULAR
ATLAS. THAT GIVES YOU A
CAPACITY TO COMPARE DIFFERENT
PATTERNS WITH EACH OTHER.
TESTING YOUR HYPOTHESIS
MECHANISTIC HYPOTHESIS THAT HOW
DIFFERENT HYDRO DYNAMIC IN
ADDITION TO THE BACKGROUND COULD
RESULT IN DIFFERENT -- I JUST
WANT TO SHOW YOU A COUPLE OF
EXAMPLES TO EMPHASIZE THAT MACRO
CALCIFY QUAILINGS AS WE SEE ON
CT AND MICROCALCIFICATION AS WE
SEE ON SODIUM FLUORIDE PET, THEY
ARE NOT SHOWING THE SAME
INFORMATION. THERE IS SOME
DISCREPANCY BETWEEN INFORMATION
BECAUSE THEY ARE TALKING ABOUT
DIFFERENT SCALE OF THE
PATHOGENESIS. ONE IS AT THE
MICROSCALE AND THE OTHER IS AT
THE MACRO SCALE. AND GOING FROM
ONE TO THE OTHER IS EXTREMELY
IMPORTANT. SOMETIMES YOU HAVE A
CALCIFICATION AND CORRESPONDING
HIGH ACTIVITY. SOMETIMES YOU
HAVE MICROSCOPY CALCIFICATION
WITHOUT VERY HIGH MICROSCOPY
ACTIVITY. AND THE OTHER
LOCATIONS YOU MAY SEE
HYPERACTIVITY IN A MICROSCOPY
MICROCALCIFICATION, WHILE YOU
HAVE NOT SEEN YET THE MICROSCOPY
CALCIFICATION. THAT IS THE POINT
THAT CAN BE USED AS A BIOMARKER
FOR SHOWING EFFICACY OF THE
TREATMENT BEFORE YOU WAIT FOR
LONG PERIOD OF TIME TO SEE
MICROSCOPY CHANGES. BY THIS I
WANT TO CONCLUDES AND ASK THE
DISTINGUISHED PATHOLOGISTS AND
SENIOR RESEARCH CLINICIAN DR.
DAVID KLEINER TO TEACH US HOW
THE LOOK AT THE SLIDES.
>> IT IS MY JOB TO SHOW YOU
PATHOLOGY OF THESE PATIENTS
WHICH IS IN SOME WAYS MORE
COLORFUL AND SOME WAYS LESS
COLORFUL THAN WHAT YOU HAVE
ALREADY SEEN. SO THIS PATIENT
HAD MULTIPLE PROCEDURES OVER THE
TIME THAT HE SPENT AT THE NIH.
FOUR SEPARATE PROCEDURES IN 2011
ALONE THREE WHICH TOOK PLACE IN
ONE MONTH. THEN TWO PROCEDURES
LATER ON, YOU CAN SEE THAT SOME
OF THESE REPEATED PROCEDURES AT
SAME LOCATION. SO TWO RESECTIONS
OF THE RIGHT SHOULDER MASS, AND
OTHER MASSES THAT RECURRED AND
REQUIRED RETREATMENT. HERE IS
THIS FIG SHAPED MASS THAT YOU
PRESENT, ONCE IT WAS REMOVEDDED
IN THIS PARTICULAR INSTANCE IT
WAS QUITE WELL CIRCUMSCRIBED SO
YOU CAN SEE THE WHOLE THING
COULD BE REMOVED, BIG TEAR
DROPPED SHAPE THING, YOU CAN SEE
THE EXTERNAL SURFACE BUT WHEN WE
CUT INTO IT WHAT WE SAW WAS NOT
NORMAL TISSUE SO THE NORMAL
TISSUE IN THIS AREA LOOK THE
SAME AS EXTERNAL SURFACE. BUT
WHAT WE SAW INSIDE WAS THIS
CHALKY MATERIAL VERY THICK AND
GRANULAR IN CONSISTENCY TO LOOK
AT SOME OF THESE LESIONS YOU CAN
SEE THE X-RAYS OF THESE COURSE
DEPOSITS. THIS IS WHAT THEY
LOOKED LIKE MICROSCOPEICALLY SO
THIS WAS TAKEN IN THE PRE-SINGLE
MASS, YOU CAN SEE SURFACE HERE,
THE EPIDERMIS, DERMIS, AND THIS
LESION WHICH IS REALLY NOT A
SINGLE LESION BUT MULTIPLE
CYSTIC SPACES EACH IRREGULAR IN
SHAPE AND PROBABLY WITH SOME
COMMUNICATION BETWEEN BUT YOU
CAN SEE THIS IS NOT SOMETHING TO
DRAIN VERY EASILY. WHEN WE STAIN
THIS TISSUE SECTION FOR CALCIUM
USING A STAIN, THE CALCIUM WILL
STAIN BLACK. SO CONFIRMING THE
APPEARANCE OR THE CALCIFICATION
OF THIS LESION. IT DOES ERODE
THROUGH THE SURFACE WHICH I WILL
SHOW YOU THE NEXT SLIDE. SO HERE
AGAIN IS THE EPIDERMIS UP HERE,
COMING DOWN INTO THIS ALLS
SOREATION WHERE IT DISAPPEARS
AND THE DERMIS DISAPPEARING INTO
THIS MASS. YOU CAN SEE THE
INDIVIDUAL CYSTIC SPACES
SEPARATED BY FIBER INFLAMMATORY
TISSUE AND THIS ULCERATED
SURFACE. YOU CAN IMAGINE THE
CAUSE SEEMIC DEBRIS FLOWS OUT OF
LEAGUES UNDER THE SKIN SURFA SU
SO WE LOOK CLOSELY AT THE
INDIVIDUAL CYSTIC SPACES THE
DEBRIS IS GRANULAR AND
ACELLULAR, NO CELLS WITHIN HERE
BUT YOU HAVE INFLAMMATORY EDGE
TO ALL THESE SPACES, THIS IS
SOMETHING THE BODY TRIES TO DO
WHEN IT ENCOUNTERS A FOREIGN
SUBSTANCE CREATES A GRAIN LOMA
THUS THERE'S FEW SITES IN THIS
INFLAMMATORY INFILTRATE, THEY
ARE ALL ACTIVATED SO
EOSINOPHILIC CYTOPLASM, THEY ARE
ENLARGED AND THEY ALSO FORM
GIANT CELLS WHICH YOU CAN SEE ON
THIS VERY HIGH MAGNIFICATION
PICTURE YOU CAN SEE THE
MULTI-NUCLEATED GIANT CELLS,
VEINLY TRYING TO ENGULF THIS
CALCIFIC DEBRIS AT THE EDGE OF
THE LESION. HERE IS ANOTHER
IMAGE TAKEN FROM A DIFFERENT
PART WHERE YOU CAN SEE THEM
TRYING TO ENGULF THIS DEBRIS.
THEY JUST CAN'T KEEP UP, AS YOU
SAW BEFORE FEEDS INTO THIS LOOP
OF INFLAMMATION, AND REPEATED
CALCIFICATION. IT GOES ON AND ON
AND NEVER ACTUALLY HEALS. ONE
OF THE OTHER THINGS YOU SEE IN
THESE DEPOSITS IS NEW BONE
FORMATION, SO WHENEVER YOU GET
CALCIUM DEPOSITED IN THE BODY NO
MATTER WHERE IT MIGHT BE THERE
IS A CHANCE THAT IT WILL BECOME
BONE. . YOU CAN SEE BONEY
TRABECULAE IN A MARROW SPACE
HERE NOT FILLED WITH
HEMATOPOIETIC STEM CELLS BUT
FIBROUS TISSUE IN HISTIOCYTES.
THAT IS SHOWN AT HIGHER
MAGNIFICATION HERE. I HAVE TAKEN
ONE OUT ONE OF THE TREABECULAE
AND YOU CAN SEE OSTEOBLASTS
LINING THIS AND A OSTEOCLAST UP
THERE AND MATURE OSTEO SITES IN
THE TRABECULAE. THE MARROW SPACE
ITSELF IS NOT CELLULAR IN THIS
PARTICULAR EXAMPLE,S BUT CAN BE
FILLED WITH FIBROBLASTS AND
HISTIOCYTES. ONE THING WE DID
WITH ONE OF THESE SPECIMENS WAS
TO TAKE A SMALL PIECE OF TISSUE
AND LOOK AT IT UNDER ELECTRON
MICROSCOPY. SO YOU CAN SEE THE
MACROPHAGES HERE, THESE ARE
THREE MACROPHAGES SOME OF THEM
ARE VACULATED BUT WITHIN THESE
MACROPHAGES YOU CAN SEE THE DARK
SPICULATED MASSES THAT ARE THESE
CALCIUM DEPOSITS THAT HAVE BEEN
ENGULFED BY THE MACROPHAGES. NOW
I WILL TURN THIS OVER TO DR.
GOUHR WHO WILL CONTINUE THE
ADVENTURE.
>> THANK YOU, DR. KLEINER. SO AS
WE ALL HEARD ONE OF THE MAJOR
PROBLEMS IN THESE PATIENTS BE
FAMILIAR TUMORAL CALCINOSIS HAS
BEEN HYDROXYAPATITE CHRISALS.
DR. KLEINER NICELY SHOWED
MACROPHAGES ENGULFING THEM.
WHERE I GOT INVOLVED AS A
RHEUMATOLOGIST, WE HAVE VERY
MANY SCRIESAL ASSOCIATED
DISEASES INCLUDING -- MANY
CRYSTAL, BUT HYDROXYAPATITE
ASSOCIATED AIRLOPOTHYS ARE KNOWN
IN RHEUMATOLOGY. MORE COMMONLY A
DISEASE CALLED OSTEOARTHRITIS,
MOST OF US KNOW WEAR AND TEAR
ARTHRITIS IS SHOWN WITH
DEPOSITION OF HYDROXYAPATITE
CRYSTALS AROUND THE JOINT. THEY
CAN SOMETHING CALLED CALCIFIC
OSTEOARTHRITIS ALONG THE TENDONS
AND TUMORAL CALCINOSIS,
SOMETHING I STUDY CLOSE, THE
CALCIUM DEPOSITS ALSO MORE SO
UNDER THE SENSE OF -- UNDER THE
SKIN SUBCUTANEOUS LEAGUES
PRIMARILY HYDROXYAPATITE
CRYSTALS AS WELL. SO WHAT DO WE
KNOW ABOUT THIS? SO THE SOME
STUDIES HAVE BEEN DONE IN THE
PAST COUPLE OF DECADES THAT HAVE
SUGGESTED THESE HYDROXYAPATITE
CRYSTALS THAT ARE HERE CAN BE
ENGULFED BY THE THE MACROPHAGES
AS WE HAVE SHOWN ELECTRON
MICROSCOPY AND BEING ENGULFED
ACTIVATE THE NLRP 3 INFLAMMASOME
WHICH IS COMPOSED OF THE NLRP 3,
C COMPLEX AN PRO CASPASE 1. WHEN
THIS COMES TOGETHER IT FORMS NLR
BETWEEN INFLAMMASOME, RELEASES
ACTIVE CASPASE ON ENZYME, THIS
CLEAVES THIS PRO INTERLEUKIN 1
BETA MOLECULE TO THE ACTIVE FORM
OF THE INTERLEUKIN 1 BETA. THIS
IS A PRO-INFLAMMATORY CYTOKINE.
SO THIS IS THE IDEA THAT THESE
CRYSTALS WHEN PRESENT IN TISSUE
CAN LEAD TO ACTIVATION AND
RELEASE OF INFLAMMATORY
MOLECULE. ALMOST I THINK 11
YEARS AGO STUDY PUBLISHED IN
PNAS WHERE THEY LOOK AT A MOUSE
MODEL AND IN THIS STUDY IT WAS
THEY INJECTED MICE WITH PBS, OR
THEY INJECTED THE MICE WITH
HYDROXYAPATITE CRYSTALS. AND
THEN THEY WERE INJECTING MICE
WITH HYDROXYAPATITE CRYSTALS
THERE WAS A NEUTROPHILIC
INFILTRATE OBSERVED AND NOT SEEN
WITH PBS INJECTION. NOW THEY
ALSO USE GENETICALLY MODIFIED
MICE WHERE THEY KNOCKED DOWN
NLRP 3 OR THE ASC COMPLEX OR
CASPASE 1. THESE ARE THE THREE
DIFFERENT COMPONENTS OF THE
INFLAMMASOME AND KNOCKING THEM
OUT AND STIMULATING WITH
HYDROXYAPATITE CRYSTALS NO
TISSUE INFLAMMATION WAS OBSERVED
AT THIS POINT AND THESE MICE
DEVELOPED JOINT ARTHRITIS AND
THEY HAD HYDROXYAPATITE
CRYSTALS. THUS THE IDEA WAS THE
HYDROXYAPATITE CHRISALS LEAD TO
INFLAMMASOME IN THE MACROPHAGES
AND SECRETION OF ACTIVE
INTERLEUKIN 1 BETA MOLECULE.
THIS IS A PRO CYTOKINE AND LEADS
TO C REACTIVE PROTEIN AS WE CAN
MEASURE IN A PATIENT. SO WITH
THAT KNOWLEDGE, WE THOUGHT ABOUT
THIS AND THIS IS ALMOST A DECADE
AGO WHEN WE FIRST STARTED, IS
COULD WE USE IL 1 INHIBITORS IN
THIS PATIENT OR THESE PATIENTS?
SO THE IL 1B MOLECULE BINDS TO
THE IL 1 RECEPTOR AND CAUSES
SIGNAL TRANSDUCTION AND
ACTIVATION OF A FEW INFLAMMATORY
PATHWAYS. AT THAT TIME THREE
DRUGS WERE AVAILABLE TO BLOCK
THIS PATHWAY IN THREE WAYS. ONE
COMMONLY KNOWN AS ANNA KIN DR.
IS A RECOMBINANT PROTEIN OF
INTERLEUKIN 1 REACCEPT TOKER
ANTAGONIST SHOWN HERE. IT BLOCKS
THE INTERLEUKIN ONE RECEPTOR SO
THE ALPHA OR BETA MOLECULES BIND
TO RECEPTOR THUS INHIBITING THE
SIGNIFICANT DOWNSTREAM. ANOTHER
ONE CALLED RELONACEPT IS A DECOY
RECEPTOR WHICH CAPTURES IL 1
ALPHA OR BETA IN CIRCULATION.
ONCE YOU REMOVE THE IL 1 ALPHA
AND BETA INFLAMMATORY CYTOKINES
NOTHING REMAINS TO BIND TO
RECEPTOR AND THUS THERE'S NO
SIGNIFICANT INFLAMMATION
DOWNSTREAM. ANOTHER THIRD ONE IS
KANAKINAMAD, A MONOCLONAL
INTERLEUKIN 1 ANTIBODIES THIS
BINDS TO THE INTERLEUKIN 1 BETA
IN CIRCULATION AND THUS NO
INTERLEUKIN 1 REMAINING TO BIND
RECEPTORS AND PREVENTS
DOWNSTREAM SIGNALING. SO LEE
WAYS OF -- AT THAT TIME THREE
DIFFERENT WAYS OF BLOCKING
INTERLEUKIN 1 SIGNALING. WE
DECIDED TO PURSUE WITH ANAKINRA
FOR A COUPLE OF REASONS. ONE
HAD A SHORT LAUGH LIFE OF FIVER
HOURS SO YOU CAN SEE RESPONSE
QUICKLY BUT IN CASE OF CONCERNS
OF SIDE EFFECTS WE CAN STOP IT
ALSO. SECONDLY IT WAS AT THAT
TIME AVAILABLE IN THE CLINICAL
CENTER AS WELL. SO COMES UNDER
THE BRAND NAME KINARED AND
PATIENT STARTED AT 100
MILLIGRAMS SUBCUTANEOUS
INJECTIONS DAILY. BESIDES HAVING
THE LOCALIZED INJECTION SITE
ERYTHEMA THE PATIENT TOLERATED
THE DRUG WELL. AND THE C
REACTIVE PROTEIN LEVELS OF
PATIENTS WERE MONITORED DURING
THE DURATION OF THE THERAPY. SO
HERE WE HAVE A PLOT SHOWING THE
C REACTIVE PROTEIN LEVELS AS
MEASURED IN MILLIGRAMS PER
LITTERS AND Y AXIS IN OUR
PATIENT AND YOU CAN SEE A HIGH
LEVELS OF THE C REACTIVE PROTEIN
BETWEEN 200 TO 300 MILLIGRAMS
PER LITTER AND ON THE X AXIS IS
THE TIME DURATION OF THERAPY. SO
HERE THE POINT ANAKINRA WAS
INITIATED, THERE WAS DRAMATIC
DECLINE IN THE C REACTIVE
PROTEIN AND THIS PERSISTED
DURING THE DURATION OF THERAPY.
THE PATIENT MISSED ONE DOSE AND
YOU SAW THAT THERE WAS A
DRAMATIC INCREASE THE NEXT DAY
IN THE C REACTIVE PROTEIN LEVEL
BUT ON RESTARTING THERAPY, C
REACTIVE PROTEIN LEVELS DECLINED
FURTHER AGAIN. SO WHAT WE
OBSERVED IN THIS PATIENT WAS
THAT USING ANAKINRA WE WERE ABLE
TO REDUCE THE C REACTIVE PROTEIN
LEVELS, THIS LED TO INCREASE IN
THE ENERGY LEVEL THE PATIENT
COULD EASILY TELL US ABOUT.
THERE WAS AN INCREASE IN
APPETITE AND THIS INCREASED
APPETITE OVER PERIOD OF TIME LED
TO THE PATIENT GAINING WEIGHT
WHICH WAS AN ISSUE. AND THERE
WAS A GENERAL FEELING OF WELL
BEING. ALONG WITH AN IMPROVEMENT
IN ANEMIA, NOW THERE ARE CERTAIN
ANEMIAS ASSOCIATED WITH HAVING
PERSISTENT OR CHRONIC SYSTEMIC
INFLAMMATION THAT GOES WITH THE
PATHWAY AND PERHAPS IT WAS
BECAUSE OF THAT AS WELL. I WOULD
ALSO LIKE TO PRESENT ANOTHER
PATIENT WITH THE SAME PHENOTYPE,
BUT PEDIATRIC CASE WHERE WE USED
ANOTHER FORM OF IL 1 INHIBITOR,
THE KANAKINAMAB, AUTOANTIBODY.
THE C REACTIVE PROTEIN SHOWN
HERE IN MILLIGRAMS PER LITTER LR
AND THE PATIENT HAD 80
MILLIGRAMS HIGHEST LEVEL OF CRP.
HERE IS WHEN KANA CAN,INAMAB
STARTED, SUN CUTANEOUS INJECTION
ONCE A MONTH EVERY 28 DAYS. YOU
CAN SEE DECLINE IN THE C
REACTIVE PROTEIN TO
NORMALIZATION OF CRP IN THIS
PATIENT. BUT WHAT WAS REALLY
DRAMATIC AND REMARKABLE, BEFORE
THE CANAKINUMAB ON THE HUMOROUS
YOU CAN SEE THE LESION HERE
THERE WAS CALCIUM DEPOSIT THAT
WAS THERE AND ALSO THE LEVEL
LEFT SIDE OF THE NECK OF THE
PATIENT YOU CAN SEE THIS
CUTANEOUS LESION. AFTER A YEAR
OF THERAPY ON CANAKINUMAB THIS
LESION COMPLETELY RESOLVED AND
DISAPPEARED. ALONG WITH THAT
THERE WAS ALSO A DRAMATIC
RESOLUTION OF THIS CALCIFICATION
THAT IS SEEN ON THE NECK. NOW,
THIS -- WE HAVE TO KEEP IN MIND
THE PATIENTS ARE ON AGGRESSIVE
PHOSPHATE LOWERING THERAPY AT
THIS TIME BUT BEFORE THE
PATIENTS WERE ON THESE THERAPIES
THEY DIDN'T HAVE THIS KIND OF
RESOLUTION SO IT IS A COPY
NATION OF THIS INTERRUPTION OF
THE INFLAMMATORY SIGNAL ALONG
WITH THE AGGRESSIVE PHOSP
PHOSPHOLOWERRING THERAPY. WITH
THAT I WILL HAND IT OVER TO DR.
ROSZKO.
>> THANK YOU. SO IN OUR ONGOING
WORK WE ARE CONTINUING TO
CHARACTERIZE THE NATURAL HISTORY
OF HFTC. AND WHILE WE DOING THIS
WE ARE PLACING A SPECIAL
EMPHASIS ON UNCOVERING POTENTIAL
END POINTS FOR FUTURE CLINICAL
TRIAL. SO THIS IS AN EXCITING
PROJECT, THIS IS A COLLABORATION
WITH DR. SABOURY WHO YOU JUST
HEARD FROM AND OUR SKILLS
MEDICAL MRST STUDENT AARON
SHEPHERD LED THIS PROJECT AND
DID MUCH OF THIS WORK. SO WE ARE
USING SODIUM FLUORIDE PET SCANS
TO QUANTIFY CALCIFICATION
BURDEN. YOU CAN SEE HERE OUR TWO
SODIUM FLUORIDE PET SCANS OF
THIS PATIENT ONE AT AGE 11 AND
TWO YEARS LATER AT AGE 13. YOU
CAN SO E THIS LARGE DEBILITATING
SHOULDER LESION THAT SHE HAD
HERE. WHAT WE DID WAS WE GRAPHED
THE SUB, METABOLIC ACTIVITY OF
THE LESION, VERSUS HANS FIELD
UNITS THE DENSITY OF THAT LESION
ON CT PORTION. AND YOU CAN SEE
THAT AT THE ORIGINAL TIME POINT
5.2% OF THE LESION WAS SHOWING A
HIGHER METABOLIC ACTIVITY AND
LESS OF THE LESION WAS SHOWING
AN INCREASE DENSITY HERE. YOU
CAN SEE TWO YEARS LATER LESS OF
THE LESION WAS HIGHLY METABOLIC
ACTIVE BUT MUCH MORE OF LESION
HERE HAD CALCIFIED AND WAS MORE
DENSE. SO WE THINK HERE THAT WE
ARE ACTUALLY SEEING A VERSUS
SELL BY VOX SELL ANALYSIS
SHOWING THE LESION PROGRESSION
OVER TIME. WE ARE GOING TO USE
THIS TO LEARN MORE ABOUT THE
NATURAL HISTORY OF THIS DISEASE
BUT ALSO TO DEVELOP END POINTS
THAT CAN POSSIBLY BE USED IN A
CLINICAL TRIAL TO LOOK FOR
IMPROVEMENT WHEN PATIENTS ARE
TREATED WITH MEDICATION. SO WE
HAVE ALSO WORKED TOGETHER WITH
DR. SABOURY TO EVALUATE THIS
VASCULAR CALCIFICATION IN
PATIENTS WITH HFTC AND AS YOU
HEARD FROM HIS PRESENTATION HE
GAVE YOU A LOT OF THE TECHNIQUE
THAT WE HAVE USED. WE HAVE USED
SODIUM FLUORIDE PET SCANS TO GET
A MICROCALCIFICATION SCORE
LISTED HERE ON THE Y AXIS. AND
THEN ON THE X AXIS WE HAVE A
VASCULAR ATLAS WHICH IS THE
STANDARD ACCESS WHERE WE MAP THE
PATIENT GOING FROM THE AORTA,
HERE IS THE ARCH OF THE AORTA TO
THE DISTAL EXTREMITIES AS IF THE
PATIENT WERE LYING DOWN HERE ON
THE GRAPH. EACH DOTTED LINE
REPRESENTS A TRANSITION BETWEEN
DIFFERENT VASCULAR SEGMENTS. YOU
CAN SEE THAT WE WERE SURPRISED
TO SEE MANY OF OUR FTC PATIENTS
HAD VASCULAR CALCIFICATION OVER
THAT OF THE CONTROL. SO WE HAVE
SIX PATIENTS MAPPED HERE AND THE
CONTROL IS THIS DOTTED LINE
BELOW. WE WERE VERY SURPRISED TO
SEE THAT EVEN OUR YOUNGER
PATIENTS YOU CAN SEE AGE 11
THROUGH 20 ON THIS GRAPH HAD
GREATER VASCULAR CALCIFICATION.
THAT WAS SURPRISING TO US AND
HAS LED US TO SCREEN THESE
PATIENTS MORE AND WATCH THEM
CAREFULLY. ADDITIONALLY I WILL
DRAW YOUR ATTENTION TO THE
YELLOW LINE, THE 11-YEAR-OLD
PATIENT, SEEMS TO BE AROUND THE
AREA OF THE CONTROL, BUT THAT
MEANS THAT THAT 1 # 1-YEAR-OLD
HAS THE SAME AMOUNT OF
MICROCALCIFICATION AS A
46-YEAR-OLD WHO IS THE CONTROL
HERE. SO AS WE ASSESS MORE
PATIENTS WE ARE GOING TO
CONTINUE TO LOOK FOR PATTERNS,
IN WHICH CERTAIN SEGMENTS MIGHT
HAVE A GREATER TENDENCY TO
DEVELOP VASCULAR CALCIFICATION
IN HFTC AND ALSO WE WILL STUDY
THESE PATIENTS PROSPECTIVELY TO
DETERMINE THE TENDENCY OF
VASCULAR CALCIFICATION TO CHANGE
OVER TIME. BUT WE WERE VERY
EXCITED TO SEE THAT WE CAN
ACTUALLY INDEED USE SODIUM
FLUORIDE PET SCANNING TECHNOLOGY
TO MONITOR AND QUANTIFY THE
RESPONSE TREATMENT IN BUN OF OUR
PATIENTS. . . SO THIS IS A
53-YEAR-OLD WOMAN WITH HFTC WITH
EXTENSIVE VASCULAR AND SOFT
TISSUE CALCIFICATION AND
INFLAMMATION AS YOU JUST HEARD
ABOUT FROM DR. GOUHR. HER CRP
WAS EXTREMELY ELEVATED AT 44. SO
SHE WAS TREATED WITH ANAKINRA
FOR A TOTAL OF 15 MONTHS. AND
HER CRP DECREASED DURING THAT
TIME 44 TO 5.9. PHOSPHATE
REMAINED UNCHANGED AT 5.8 AND
6.7 PRE AND POST TREATMENT. SO
HER BASELINE SODIUM FLUORIDE PET
SCAN IS THE RED LINE HERE. WHICH
IS THE UPPER GRAPH. AND YOU CAN
SEE THERE IS A MARKED ELEVATION
IN THE MICROCALCIFICATION SCORE.
THIS BLUE LINE HERE REPRESENTS
HER POST TREATMENT SCAN WHICH
YOU CAN SEE HERE BELOW ACTUALLY
DOES LOOK IMPROVEMENT --
IMPROVED. SO THE FINDING THAT
MICROCALCIFICATION COULD RESPOND
TO TREATMENT IN THIS PATIENT IS
PROMISING. AND AGAIN WE ARE
LOOKING TO DEFINE THESE FUTURE
POTENTIAL END POINTS FOR
CLINICAL TRIAL THAT COULD CHANGE
WITH INTERVENTION. SO WE ARE
VERY EXCITED OF THESE RESULTS
GOING FORWARD. ONE OF THE MAJOR
UNANSWERED QUESTIONS ABOUT HFTC
IS WHAT CAUSES THE HUGE DEGREE
OF PHENOTYPIC VARIATION BETWEEN
PATIENTSS. AS I MENTIONED WEED T
LOCATION OF CALCIFICATION IN OUR
PATIENTS AND WE CALCULATED THE
TOTAL LESION VOLUME PER LESION
AT EACH LOCATION AND TOTAL
LESION VOLUME OF CALCIFICATION
PER PATIENT. AS YOU CAN SEE
HERE, THERE IS HUGE VARIATIONS
OF LESION VOLUME BOTH BETWEEN
LESIONS AND ACROSS PATIENTS.
THESE ARE EACH INDIVIDUAL
PATIENTS AND SOME HAVE A PRETTY
LOW BURDEN OF DISEASE WHILE
OTHERS HAVE EXTREME AMOUNTS OF
CALCIFICATION. SO A MAJOR
QUESTION IN THIS FIELD IS WHY
SOME OF THESE PATIENTS DEVELOPED
THOSE DEBILITATING CALCIFY CASES
WHILE OTHERS ARE ALMOST
ASYMPTOMATIC. THIS IS FURTHER
EXEMPLIFIED BY THE BROTHER OF
THE PATIENT WHO WE HAVE JUST
DISCUSSED IN THIS CASE. SO THE
PATIENT'S BROTHER WAS
ASYMPTOMATIC. WE ENROLLED HIM TO
OUR PROTOCOL AND WE MEASURED HIS
PHOSPHATE. AND WE FOUND THAT IT
WAS ELEVATED. ON GENETIC TESTING
HE HAD THE SAME GENETIC VARIANT
IN GALNT 3 AS HIS SEVERELY
AFFECTED BROTHER. IN FACT, THE
ASYMPTOMATIC BROTHER HAD HIGHER
ELEVATION IN PHOSPHATE AND
CALCIUM PHOSPHATE PRODUCT. YOU
CAN SEE HERE AT 6.3 AND 62.
HOWEVER, AS I SAID OUR PATIENT
YOU SAW HAD THESE MASSIVE
CALCIFICATIONS AND THIS PATIENT,
THE ONLY THING WE COULD FIND HE
WAS ASYMPTOMATIC BUT ON DENTAL
X-RAYS WE WERE ABLE TO FIND THE
DENTAL FINDINGS OF DENTAL
CALCIFICATION AN SHORT BULBUS
ROOTS. SO HE HAS HIGHER WANT FGF
23 WHICH MAYBE PROTECTIVE BUT
SURPRISING BECAUSE THE PHOSPHATE
LEVEL ARE ACTUALLY HIGHER.
THEREFORE WE KNOW THE ELEVATED
CALCIUM PHOSPHATE PRODUCT IS
NECESSARY FOR CALCIFICATION BUT
NOT SUFFICIENT TO CAUSE
CALCIFICATCALCIFICATION. SO A LT
OF THE FUTURE WORK IN OUR
LABORATORY WILL BE AIMED AT
UNDERSTANDING THE MECHANISM OF
CALCIFICATIONS AND THE REASONING
FOR THIS VARIABILITY. TO FURTHER
EXPLORE THE PATHOMECHANISM OF
OUR DISEASE, IN CONJUNCTION WITH
OUR WORK ON THE PATIENTS WE HAVE
BEEN WORKING WITH THE GALNT 3
KNOCK-OUT MICE. HERE YOU CAN
SEE THE BIOCHEMICAL PROFILE OF
THESE MICE. WE HAVE WILD TYPE
MICE AND HOMOZYGOUS MICE. AT
TWO DIFFERENT AGE POINTS, 12 TO
13 WEEKS. AND AT 19 TO 20 WEEKS.
YOU CAN SEE THAT IN THE
HOMOZYGOUS MICE THERE IS
SIGNIFICANT ELEVATIONS IN
PHOSPHATE, THERE'S LOWER INTACT
FGF 23 LEVELS AND REALLY
STRIKING ELEVATIONS IN C
TERMINAL FGF 23 LEVELS. THIS
MOUSE WORK IS CARRIED OUT BY
SKILLED LABORATORY MANAGER
REBECCA GALISTEO. TO FURTHER
EXPLORE THE CALCIFICATIONS WE
ESTABLISHED A COLLABORATION WITH
DR. (INDISCERNIBLE) IN THE NIBIB
TO IMAGE THE MICE WITH PET
SCANS. FOR THIS I WILL FOCUS ON
THIS LESION WHICH APPEARS TO BE
A LARGE TONGUE LESION. SO WE
WERE ABLE TO SEE THE LESION ON
SODIUM FLUORIDE PET SCANS AND
ALSO ABLE TO SEE THE LESION HERE
ON X-RAY. AND FINALLY WE ARE
ABLE TO LOOK ON HISTOLOGY AND
SEE THIS LARGE CALCIFICATION IN
THE TONGUE OF THAT MOUSE. SO WE
HAVE ALSO FOUND THAT WE CAN
DETECT MUCH SMALLER LESIONS WHEN
LOOKING THROUGH MICRO-CT
ANALYSIS. THIS WORK IS DONE
WITH THE HELP OF THE MOUSE
IMAGING FACILITY WHERE WE HAVE
BEEN ABLE TO DO IN VIVO MICRO-CT
ON OUR MICE. SO ON THE LEFT YOU
CAN SEE THIS MOUSE, IT HAS
SEVERAL CALCIFICATIONS AND THESE
HAVE BEEN SEGMENTED WITH MIM
SOFTWARE TO DETERMINE THE SIZE
OF THE CALCIFICATIONS. AND THEN
THE GRAPHS ON THE RIGHT HERE
SHOW THE TOTAL CALCIUM VOLUME
PER CALCIFICATION. AND THE
INTEGRAL DENSITY HERE. YOU CAN
SEE THAT -- SORRY THIS IS NOT
WORKING. ANYWAYS YOU CAN SEE
CALCIFICATION BURDEN IS INDEED
HIGHER IN THE HOMOZYGOUS MICE
AND INTEGRAL DENSITY OF THESE
LESIONS IS HIGHER IN THE
HOMOZYGOUS MICE. SO WE WERE
ALSO HAPPY TO SEE WE WERE ABLE
TO TRACK THE CALCIFICATION
CHANGES OVER TIME USING THE
MOUSE MODEL. ON THE LEFT HERE
YOU CAN SEE THE LESION, THIS IS
WHEN THE MOUSE IS 11 WEEKS OLD
AND HOW IT CHANGED AND DEVELOPED
AT AGE 16 WEEKS SO OVER THE FIVE
WEEKS. WE WERE ALSO ABLE TO
GRAPH EACH LESION AND SHOW
INCREASE IN MAXIMUM HANS FIELD
UNITS OVER FIVE WEEKS ON THIS
GRAPH AND THIS IS SIX CALCIFY
CASES IN ONE SINGLE MOUSE AND
YOU CAN SEE EACH LINE
REPRESENTING CALCIFICATION HAS
HAD A BIT OF INCREASE OVER THAT
TIME PERIOD. FINALLY HERE YOU
CAN SEE A 3-D SURFACE MODEL OF
ONE CALCIFICATIONS AT TWO TIME
POINTS. THE TIME POINT 1 IS IN
BLUE AND TIME POINT 2 IN RED RE
YOU ARE SEEING A SPATIAL GROWTH
OF CALCIFICATION OVER THOSE FIVE
WEEKS. SO WE HAVE A MOUSE MODEL
WHICH SHOWS CALCIFICATION AND WE
ARE CHARACTERIZING HOW THESE
LESIONS GROW AND HOW THEY CHANGE
OVER TIME. WE ARE GOING TO BE
USING THIS MOUSE MODEL IN
PRE-CLINICAL STUDIES WITH THE
GOAL OF FINDING A TREATMENT THAT
CAN ACTUALLY DECREASE
CALCIFICATION THAT THEN WE CAN
APPLY TO OUR PATIENTS. A BRIEF
NOTE ON THE TREATMENT OF HFTC.
UNFORTUNATELY THERE'S NO
DEDICATED THERAPY FOR THIS
DISEASE. AS YOU SAW IN THE CASE
WE HAVE TRIED NUMEROUS AGENTS
WITH GOAL OF DECREASING
PHOSPHATE AND INFLAMMATION BUT
THE SUCCESS HAS BEEN VARIED AND
IN GENERAL PRETTY LIMITED. SO
HERE I'M MENTIONING ONE PATIENT
YOU SAW FROM DR. GOUHR WHERE THE
CRP WAS LOWERED WITH ANAKINRA
ASSOCIATED WITH RESOLUTION OF
HER SKIN AND ELBOW LESIONS.
HOWEVER, THIS IS GRAPH ON THE
PATIENT IN THE CASE WE DESCRIBED
TODAY. YOU CAN SO E THE
TREATMENT THE PHOSPHATE LEVELS
WHICH ARE THOSE BLUE DIAMONDS
ACTUALLY GO UP OVER TIME AND
CONTINUED ADDITION OF THERAPIES
GOING ACROSS THE GRAPH HERE AS
IS HOSPITAL STAY PROGRESSES.
YOU CAN ALSO SEE THE RED SQUARES
WHICH ARE TUBULAR REABSORPTION
OF PHOSPHATE DON'T CHANGE
SHOWING THAT WE ARE REALLY NOT
MAKING MUCH PROGRESS WITH HIM.
ANOTHER QUESTION HAS ALWAYS BEEN
WHETHER THESE LESIONS SHOULD BE
SURGICALLY RESECTED. WE ALSO
PLAN TO USE OUR MOUSE MODEL TO
DETERMINE THE AFFECTS OF SURGERY
ON THESE LESIONS. SO THIS IS
GRAPH OF THE PATIENT WE
DESCRIBED HERE SHOWING THE
LESION VOLUME OVER SEVEN YEARS
TIME WE HAVE BEEN FOLLOWING HIM.
THE ASTERISK HERE SHOW TWO
POINTS HE HAD SURGERY ON THESE
LESIONS. AS YOU CAN SEE, THE
LESION VOLUME INCREASES
EXPONENTIALLY AFTER SURGICAL
INTERVENTION. SO THEREFORE FOR
THIS REASON OUR CURRENT
RECOMMENDATION HAS BEEN TO
PATIENTS THAT WE SHOULD HOLD
SURGICAL INTERVENTION UNLESS
CALCIFICATION IS LOCATED IN A
PLACE THAT REALLY REQUIRES
DEBULKING TO PREVENT LOSS OF
FUNCTION FOR THESE PATIENTS. SO
WE ARE OPTIMISTIC THAT THERE ARE
FUTURE POTENTIAL THERAPIES, THAT
CAN BE EXPLORED, THAT CAN HELP
CORRECT THE BIOCHEMICAL
ABNORMALITIES IN THIS DISORDER
AND TO IDEALLY DECREASE
CALCIFICATION. SO NHE 3
INHIBITORS COULD FURTHER
DECREASE ABSORPTION OF CALCIUM
FROM THE INTESTINE. NAPI 2A
INHIBITORS HAVE POTENTIAL TO
INCREASE RENAL PHOSPHATE
EXCRETION. AND FGF 23
REPLACEMENT THERAPY WOULD BE A
PROMISING FUTURE TREATMENT. SO
TO END I WILL GIVE BRIEF
FOLLOW-UP ABOUT OUR PATIENT.
UNFORTUNATELY THE PATIENT WAS
USING CHRONIC NSAIDS BECAUSE OF
ALL PAIN HE WAS EXPERIENCING AND
HE ENDED UP DEVELOPING CHRONIC
RENAL FAILURE DUE TO NSAID USE
HIS DISEASE CONTINUED TO
PROGRESS AND HIS CALCIFICATIONS
CONTINUED TO GROW AND FORM. YOU
CAN SEE HERE ON CT THIS IS A
SHOULDER PROGRESSION -- SHOULDER
LESION PROGRESSING OVER SIX
YEARS TIME HERE ON CT. IT WAS
INCREASINGLY DIFFICULT TO GET
HIM ACCESS TO THESE MEDICATIONS,
AS HE LIVED OUTSIDE THE U.S. AND
DID NOT HAVE INSURANCE ACCESS.
SO UNFORTUNATELY A DIFFICULT
CASE FROM THE STANDPOINT OF OUR
PATIENT. BUT WE DO REMAIN
OPTIMISTIC AS I SAID, WE HAVE
NEW MEDICATIONS ON THE HORIZON
AND WE ARE HOPING THROUGH THE
PROGRAM HERE THAT WE WILL BE
ABLE TO TEST THESE AND IDEALLY
BRING A NEW TREATMENT TO THESE
PATIENTS. THANK YOU ALL ALL FORR
TIME.
[APPLAUSE]
>> THANK YOU FOR THIS PHENOMENAL
PRESENTATIONS. SO FIRST TO
REMIND THOSE WHO ARE VIRTUALLY,
THAT YOU CAN CLICK THE BUTTON
AND ASK A QUESTION VIRTUALLY AND
ALSO FOR EVERYBODY WHO IS HERE
IN THE ROOM TO COME TO THE
MICROPHONE. WHILE WE ARE WAITING
FOR OTHER QUESTIONS, I WAS
WONDERING ABOUT THE IL 1 BETA
ASPECT. I THINK THE CRYSTALS
PROMOTING IL 1 BETA IS AS YOU
DESCRIBED KNOWN AND EXPECTED THE
CRP WILL COME DOWN BUT IT IS
VERY IMPRESSIVE THAT YOU COVER
REVERSAL OF INFLAMMATION THAT
THEN LEADS TO REVERSAL OF
CALCIUM. MY QUESTION, IS THAT AN
OUTLIER OF THE PATIENT OR IS
THAT GENERALIZABLE FINDING? IF
THE LATTER, IT SOUNDS LIKE IT,
IS THIS THEN CONSISTENT WITH THE
MODAL BY WHICHEVER TIME YOU HAVE
SOME INFLAMMATORY INSULT THAT
THEN IS REALLY ONE OF THE
REASONS IL 1 BETA DRIVEN THAT
YOU HAVE MORE CALCIUM. SO WHAT
ARE THE SPECULATIONS OF THE
MECHANISM? SECOND WHEN THE
PATIENTS GO FOR SURGE ARE I
SHOULD THEY BE ON ANAKINRA TO
PREVENT THE WORSENING?
>> GREAT QUESTION. DEFINITELY
NOT ONE PATIENT ALONE, THERE'S
MULTIPLE PATIENTS WITH THIS
DISORDER THAT HAVE BEEN TREATED
WITH EITHER ANAKINRA OR
CANAFINAMAB MONOCLONAL ANTIBODY
AND RESPONDED WELL. THESE ARE
PATIENTS WITH ELEVATED CRP
LEVELS. I THINK DR. ROSZKO IN
INITIATE SLIDE SHOWED THAT THERE
WERE I THINK ABOUT 47% OF THE
PATIENTS IN THE COHORT OF 21
PATIENTS WHO HAVE ELEVATED CRP
LEVELS SO WE DON'T KNOW WHAT
WOULD HAPPEN IN PATIENTS WHO
DON'T HAVE ELEVATED CRP LEVEL. I
DON'T THINK IT IS -- JUST
REDUCTION OF INFLAMMATION
OBVIOUSLY THERE IS PRIMARY
PATHOLOGY THAT IS PERSISTING AND
STILL THERE BUT I THINK IT
CREATES A FEET FORWARD MECHANISM
THIS INFLAMMATION LEADS TO
TISSUE INJURY AND THE HEALING
MECHANISM OF BODY FORMING A
SCAR, FIBROSIS OR CALCIFICATION
THEY HAVE. SINCE THEY HAVE A
PROPENSITY TO HAVE A HIGHER
CALCIUM PHOSPHATE PRODUCT MORE
LIKELY THEY END OF DEPOSITING AT
SITE OF INJURY AND PERPETUATES
THE CYCLE, INTERRUPTING THAT
WITH IL 1 PERHAPS LEADS TO
IMPROVEMENT IN THIS PATHOLOGY
AND CAN LEAD TO NORMAL HEALING.
I HAVE TRIED THIS IN OTHER
PATIENTS WITH SYSTEMIC SCLEROSIS
AS WELL. LARGE CALCINOSIS AND
ELEVATED CRP LEVELS AND WE HAVE
HAD GOOD RESULTS OF THAT. WHERE
WE HAVE BEEN ABLE TO REDUCE THE
CRP LEVELS AS EXPECTED BUT ALSO
THERE IS SOME REDUCTION IN THE
CALCIUM, IT IS NOT DRAMATIC
RESULTS LIKE YOU SAW IN THIS
PATIENT HERE THE NUMBER 2. BUT
WE DO SEE THAT IMPROVEMENT IN
OTHER DISEASES AS WELL.
>> WE HAVE A QUESTION FROM
ONLINE. WHAT IS THE STATUS OF
THE FGF 23 AS A THERAPEUTIC
AGENT, HOW LONG BEFORE IT WILL
BE AVAILABLE TO TRY?
THAT IS A GOOD QUESTION.
THERE IS -- THERE ARE SEVERAL
GROUPS WITHIN A COMPANY WORKING
TO DEVELOP THAT, IT IS IN THE
PIPELINE, IT IS NOT IN HUMAN
STUDIES YET BUT TO GIVE IT A
TIME LINE COUPLE OF YEARS MAYBE,
I WOULD SAY.
>> LET ME REPEAT THE CME CODE
BECAUSE I THINK THERE MIGHT BE
AN ERROR ON THE SCREEN THERE SO
THE CORRECT ONE IS 50533. I
WOULD LIKE TO THANK ALL OF YOU
FOR BEING HERE AND VIRTUALLY.
THANK YOU FOR THIS GREAT
PRESENTATION. WELCOME TO THE NIH
CLINICAL CENTER.
[APPLAUSE]