EMERGING TECHNOLOGY AND LTCI

1
EMERGING TECHNOLOGYAND LTCI

• Session 16 February 27, 2006
• Session Producer
• Margaret Czellecz, HIA
• LTCI Consultant

2
Panelists

• Patricia Bomba, MD, FACP, Vice President and
  Medical Director, Geriatrics
• MedAmerica
• Gus Alva, MD, Medical Director, ATP Clinical
  Research, Associate Clinical Professor of
  Psychiatry, University of California Irvine

3
Emerging Technology and LTCIAdvances in Medical
Technology,Non-invasive Imaging, Biology,
Genomics

• Patricia A. Bomba M.D., F.A.C.P.
• Vice President and Medical Director, Geriatrics
• Patricia.Bomba_at_lifethc.com

4
Objectives

• Review examples of advances in medical technology
• Describe clinical utility of current non-invasive
  imaging
• Examine new genetic tests for specific diseases
• Discuss genotypic analysis for drug metabolism

5
Advances in Medical Technology

• Inflammatory Markers of Coronary Artery Disease
  Risk
• High Sensitivity C-Reactive Protein
• Lipoprotein-Associated Phospholipase A2
• Biochemical Markers of Bone Turnover

6
Inflammatory Markers of Coronary Artery Disease
(CAD) Risk

• High Sensitivity C-Reactive Protein (hs-CRP)
• Nonspecific acute phase reactant produced by
  liver
• Marker of inflammatory process
• Studies suggest association of low-level chronic
  inflammation during atherogenesis
• Enzyme linked immunoabsorbent assays (ELISA) and
  techniques using monoclonal antibodies detect
  lower levels of CRP

7
Inflammatory Markers of Coronary Artery Disease
(CAD) Risk

• High Sensitivity C-Reactive Protein (hs-CRP)
• Studies indicate correlation between hs-CRP
  levels and CAD
• Primary prevention for individuals at
  intermediate risk (10-20) of heart disease over
  the next 10 years, based on standard, accepted
  risk stratification approaches
• Cholesterol/LDL levels, diet, smoking, family and
  personal history
• American Heart Association and Centers for
  Disease Control and Prevention, January 2003
• Strong and independent marker for future heart
  events in these high-risk patients

8
Inflammatory Markers of Coronary Artery Disease
(CAD) Risk

• Lipoprotein-Associated Phospholipase A2 (Lp-PLA2)
• Platelet-activating factor acetylhydrolase
• Enzyme that hydrolyzes phospholipids
• Primarily associated with low-density
  lipoproteins
• May have a proinflammatory role in progression of
  atherosclerosis
• Two large-scale observational studies suggest
  Lp-PLA2 is an independent risk factor for CAD in
  men but no correlation with improved health
  outcomes
• Not a component of National Cholesterol Education
  Program Adult Treatment Panel III guidelines

9
Biochemical Markers of Bone Turnover

• Bone remodeling (or turnover)
• Constant state of remodeling
• Initial absorption of bone by osteoclasts
• Deposition of new bone matrix by osteoblasts
• Critical to overall bone growth
• May reflect fracture risk still unclear
• Current fracture risk based primarily on bone
  mineral density plus factors such as family
  history of osteoporosis, history of smoking, and
  weight
• Assessed by measurement of surrogate markers of
  bone turnover in blood and urine
• Sensitivity and specificity too low to be useful
  in identifying patient for treatment of
  osteoporosis

National Institutes of Health and Agency for
Healthcare Research and Quality
10
Biochemical Markers of Bone Turnover

• Formation Markers
• Serum osteocalcin (OC)
• Serum total alkaline phosphatase (ALP)
• Serum bone specific alkaline phosphatase (BSAP)
• Serum procollagen I carboxyterminal propeptide
  (PICP)
• Serum procollagen type I N-terminal propeptide
  (PINP)
• Bone sialoprotein

11
Biochemical Markers of Bone Turnover

• Resorption Markers
• Serum and urinary hydroxyproline (Hyp)
• Urinary total pyridinoline (Pyr)
• Urinary total deoxypyridinoline (dPyr)
• Urinary free pyridinoline (f-Pyr or Pyrilink)
• Urinary free deoxypyridinoline (f-dPyr or
  Pyrilink-D)
• Urinary collagen type I cross-linked
  N-telopeptide A
• (NTx or Osteomarks NTx test)
• Urinary collagen type I cross-linked
  C-telopeptide
• Serum carboxyterminal telopeptide or I collagen
  (ITCP)

12
Non-invasive Imaging

• Non-invasive Imaging
• Magnetic Resonance Imaging
• Positron Emission Tomography (PET)
• Oncologic applications
• Non-Oncologic applications
• Spiral Computed Tomography (CT) for Lung Cancer
  Screening
• Mammography Digital, Direct, Full-Field
• Review of Indications
• Medically appropriate indications
• Peer-reviewed literature shows medically proven
  effectiveness
• Investigational
• Peer-reviewed literature does not show medically
  proven effectiveness

13
Magnetic Resonance Imaging (MRI)

• Magnetic Resonance Imaging (MRI)
• Diagnostic imaging modality that uses magnetic
  and radio frequency fields
• Two-dimensional view and tomographic image of
  organ and surrounding tissues
• Identify anatomic abnormalities
• Provide information on the characteristics of the
  tissue

14
Magnetic Resonance Imaging (MRI)

• Configuration
• Whole-body, circumferential MRI
• Mid or high field strength magnet
• Whole-body, open MRI
• Low, mid or high field strength magnet
• Dedicated extremity MRI
• Low field strength magnet
• Standing and sitting position MRI
• Low field strength magnet
• High field strength better quality image, less
  time
• Low field adequate claustrophobic or obese
  patients, patients with metallic implants

15
Magnetic Resonance Imaging (MRI)

• Medically appropriate indications
• head (brain), orbit, face, neck, spine, breast,
  cardiac, chest, extremities, abdomen, pelvis,
  temporomandibular joint, bone marrow blood supply
• Investigational
• Breast cancer screening in equivocal physical
  exam, mammography and ultrasound and high risk
  women other than those at genetic risk
• Evaluation of coronary arteries
• Evaluation of cardiomyopathy
• Detecting and grading diffuse hepatic diseases
• Extremity MRI of hip
• Whole body/dedicated extremity MRI in evaluation
  of symptomatic Rheumatoid Arthritis

Peer-reviewed literature does not show medically
proven effectiveness
16
Positron Emission Tomography (PET)

• Positron Emission Tomography (PET)
• Imaging technology can reveal both metabolic and
  anatomical information
• Metabolic info distinguishes PET from MRI and CT
• Measures concentrations of radioactive chemicals
  partially metabolized in the body region
• Clinical value related to the ability to image
  the relative metabolic activity of target tissues
  and resolution associated with PET scanners
• Multiple detectors in full or partial ring permit
  detection of photons emitted at 180o from one
  another
• Variety of tracers used IV or inhaled

17
Positron Emission Tomography (PET)

• Molecular Coincidence Detection (MCD)
• PET using a gamma camera
• Imaging techniques in which SPECT gamma camera is
  used to detect photons emitted from decaying
  positrons associated with the metabolism of
  labeled fluoreodeoxyglucose (FDG)
• metabolism related to glucose
• Referred to as FDG-SPECT, metabolic SPECT,
  FDG-collimated SPECT or dual-head-coincidence or
  dual-head-coincidence (FDG-DHC-SPECT)

18
Positron Emission Tomography (PET)

• Oncologic Medically appropriate indications
• Brain tumors radiation necrosis vs recurrence
• Breast cancer restaging
• Cervical cancer staging for invasive ca
• Colorectal cancer metastases, resectability
• Esophageal cancer post-chemo, resectability
• Head and neck cancer staging, residual/recurrent
  ca
• Lung cancer staging, restaging, solitary nodule
• Unknown primary (occult primary tumor)

When conventional imaging techniques are
inconclusive
19
Positron Emission Tomography (PET)

• Oncologic Investigational
• Breast neoplasms initial diagnosis and staging,
  evaluation response and surveillance
• Cervical cancer primary diagnosis
• Esophageal cancer primary diagnosis and staging
• Gastric cancer detection, recurrence, monitoring
• Melanoma regional metastases in candidates for
  sentinel biopsy
• Ovarian cancer detection, recurrence, monitoring
• Pancreatic cancer evaluation
• Prostate cancer diagnosis, staging
• Soft tissue sarcoma, testicular cancer, unknown
  primary, others

Peer-reviewed literature does not show medically
proven effectiveness
20
Positron Emission Tomography (PET)

• Non-Oncologic Medically appropriate
  indications
• Epileptic seizures
• Complex partial seizures, failed medical therapy,
  pre-surgical evaluation
• Cardiac Applications
• Determination of myocardial viability prior to
  revascularization in patients with LV dysfunction
  
• Suspected CAD for evaluation of myocardial
  perfusion

When conventional imaging techniques are
inconclusive
21
Positron Emission Tomography (PET)

• Non-Oncologic Medically appropriate
  indications
• Dementia and Neurodegenerative Diseases
• Differential diagnosis of fronto-temporal
  dementia (FTD) and Alzheimers Disease (AD)
• Documented cognitive decline for at least 6
  months
• Meet criteria for both FTD and AD
• SPECT test with inconclusive results
• Comprehensive clinical exam
• Evaluation by experienced physician
• Clarification of diagnosis will guide treatment

22
Spiral Computed Tomography (CT)

• Lung Cancer Screening
• Routine screening of asymptomatic individuals at
  elevated risk for lung ca not medically proven
  to be effective in reducing mortality
• Coronary Artery Calcification Screening
• Routine screening of asymptomatic patients at
  either normal or high risk has not demonstrated
  a benefit to patient outcomes by improving
  prognostic information

Cochrane Database Systematic Review
Agency for Healthcare Research and Quality
23
Mammography Digital, Direct, Full-Field

• Direct, full-field digital mammogram (FFDM)
• Generated as a digital image initially
• Conventional film (FSM) converted to digital
  image
• Can alter orientation, magnification, brightness,
  contrast to highlight lesion
• Large randomized study (49,500 patients)
  comparing SFM and FFDM National Cancer Institute
• Comparative diagnostic performance
• Impact of false positives on health-related
  quality of life and cost-effectiveness
• Initial results 2006

http//www.cancer.gov/dmist
24
Genetic Testing vs Family History

• Genetic testing
• Single gene conditions
• Very significant risk but few policyholders
• Multifactorial conditions
• One of many risk factors influencing major causes
  of claim
• Family history
• Important and well proven risk factor for many
  major conditions
• Indicator of both genetic and environmental
  factors

25
Genetic Tests for Specific Diseases

• Utilization of Genetic tests
• Carrier screening identifying unaffected
  individuals who carry a copy of a gene that
  requires 2 copies to be expressed
• Presymptomatic testing for predicting adult-onset
  disorders e.g. Huntingtons
• Presymptomatic testing for estimating the risk of
  developing adult-onset diseases
• Confirmational diagnosis of a symptomatic
  individual
• Prenatal diagnostic testing
• Newborn screening such as Phenylketonuria (PKU)

26
Genetic Tests for Specific Diseases

• Medically appropriate indications
• Patients whose family history indicates a
  significant risk for genetic defect for whom
  therapeutic measures, instituted as a result of
  knowledge of a particular defect, can prevent or
  mitigate future morbidity
• Symptomatic patients who may have genetic disease
  or asymptomatic individuals who may have a
  genetic disease or strong family history of
  genetic disease where early diagnosis is important

27
Genetic Tests for Alzheimers Disease

• Alzheimers Disease (AD)
• 50-75 of cases of dementia
• Estimated lifetime risk of AD is 15
• More than 90 occurs after age 65
• 4 genes associated with Alzheimer's
• Susceptibility polymorphism at the Apolipoprotein
  E (APOE) Gene
• 3 alleles-epsilon 2, 3, 4 3 most common
• Every person carries 2 alleles
• Presence of 1 ?4 associated with 1.2 to 3 fold
  increased risk of AD
• Higher risk for homozygous ?4 -2 of population
• ?4 not sufficiently sensitive or specific for
  diagnosis of AD

28
Genetic Tests for Alzheimers Disease

• Early-onset AD
• Before age 65, as early as 30 year 2-10 of AD
• Autosomal dominant pattern of inheritance
• 3 genes identified by linkage analysis
• Amyloid-beta precursor protein gene (APP)
• Presenilin 1 (PS1)gene
• Presenilin 2 (PS2) gene
• Nearly 100 penetrance
• Variety of genetic mutations in 30-50 PS1 most
  common
• Mutations are rare causes of AD

29
Genetic Tests for Alzheimers Disease

• Clinical criteria for diagnosis of AD
• Multiple cognitive deficits including memory
  impairment and at least 1
• Aphasia, apraxia, agnosia, disturbance in
  executive function
• Definitive diagnosis
• Pathologic criteria
• Presence of senile plaques, neurofibrillary
  tangles, neuronal loss, accumulation of
  beta-amyloid protein
• Genetic testing not proven risk assessment tool
  nor diagnostic test

30
Genetic Testing for BRICA1 or BRICA2

• Cancer risk
• General population breast cancer
• 1 for women up to age 40
• 12.5 lifetime risk
• Inherited risk
• 5 to 10 of population breast cancer
• 10 of population ovarian cancer
• Alterations in BRICA1 and BRICA2 genes explain
  majority, but not all, inherited breast and
  ovarian cancer
• BRICA1 and BRICA2
• 60 to 85 lifetime risk of breast cancer
• 15 to 40 lifetime risk of ovarian cancer
• Prevalence of BRICA mutations 0.1 -0.2
  population

31
Genetic Testing for BRICA1 or BRICA2

• High risk individuals
• Three affected close relatives with breast cancer
  on same side of family including patient
• Early age at breast cancer diagnosis (especially
  before age 45) in patient and/or close relative
• One or more individuals with ovarian cancer at
  any age, in addition to one or more individuals
  on the same side of family with breast cancer at
  any age
• Multiple primary breast or bilateral breast
  cancers in patient and/or one close relative
• Breast cancer in male patient or male close
  relative
• Women at high risk due to ethnic background
  (Ashkenazi Jewish descent) and with family
  history of one or more cases of breast cancer or
  ovarian cancer at any age

Close relative first and/or second degree
relatives on the same side of family
32
Oncotype Dx

• Genetic assay of tumor tissue to determine
  prognosis of breast cancer
• Prognosis is based on patient age, tumor size,
  histology, status of the axillary lymph nodes,
  histologic type, and hormone receptor status
• Patients with same set of risk factors can have
  markedly different prognoses
• More sensitive and specific risk factors would
  improve patient selection for adjuvant therapy
• Gene expression in tumor tissue as prognostic
  factor

33
Oncotype Dx

• Genetic assay of tumor tissue to determine
  prognosis of breast cancer
• Patterns of genetic expression compared to
  outcome databases
• Literature validation studies to identify the
  optimal set of cancer-related genes
• No prospective studies that used this information
  in the management of the patients
• No data showing this technology is useful to
  select or deselect patients for adjuvant therapy

34
Genotypic Analysis for Drug Metabolism

• Pharmacogenomics
• Study of how an individuals genetic inheritance
  affects the bodys response to drugs
• Testing for important DNA sequence variations or
  polymorphisms (genotyping) in key
  drug-metabolizing enzymes, receptors,
  transporters
• Results assist in choice of drug or dose to
  increase efficacy and/or avoid toxicity
• Other factors influence variability of drug
  effects age, liver function, concomitant
  diseases, nutrition, smoking, and drug-drug
  interactions

35
Genotypic Analysis for Drug Metabolism

• Pharmacogenomics - Observations
• Assay need only be performed once relevance of
  information must be validated for each drug
• Not all drug prescribing will benefit from
  pharmacogenetic approach
• Good retrospective evidence to support clinical
  validity
• Clinical utility of retrospective data remains
  unproved
• No prospective studies on drug choice, dose,
  outcomes
• Reduced activity in a particular CYP450 enzyme
  because of genotype may not affect outcomes when
  other metabolic pathways are available

36
Genotypic Analysis for Drug Metabolism

• AmpliChip CYP450 genotyping testing kit
• Tests white blood cells for 29 polymorphisms and
  mutations for CYP2D6 gene and 2 polymorphisms for
  the CYP2C19 gene
• CYP2D6 metabolizes 25 of all clinically used
  medications (e.g. dextromethorphan, beta
  blockers, antiarrhythmics, antidepressants,
  morphine derivatives)
• CYP2C19 metabolizes others (e.g. proton pump
  inhibitors diazepam, propanolol, imipramine and
  amitryptiline)

37
Other Genetic Testing Kits

• Invader UGT1A1 Molecular Assay test
• Detects genetic variation in UGT1A1 gene that
  produces enzyme active in metabolism of colon
  cancer drug irinotecan
• Trugene HIV-1 Genotyping Kit
• Detects variations in the genome of the human
  immunodeficiency virus associated with
  anti-retroviral drug resistance
• PRO-Predict TPMT
• Identify TPMT gene mutation in patients receiving
  AZA/6-MP at risk for bone marrow suppression

38

• Questions?
• Patricia.Bomba_at_lifethc.com

Knowing is not enough we must apply. Willing
is not enough we must do. Goethe