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					  Emerging Technology and
Women’s Health: Contemporary
  Screening and Diagnostic
         Strategies

        Barbara Winkler, MD
  Associate Director for Gynecologic
   Pathology and Women’s Health
      Quest Diagnostics, NY/NJ
      Evidence Based Screening
• Disease common
   – Effects duration &/or quality of life
• Acceptable & effective therapy available
• Asymptomatic period
  – Intervention (detection & therapy) → improved
     outcome
• Rx asymptomatic > symptomatic Rx
• Test
   – Safe, affordable
   – Adequate sensitivity and specificity
           Diagnostic Strategies
• Screening = Risk stratification = early intervention
• Accurate targeting of follow-up/therapy to level of
  risk
    – Minimize morbidity/toxicity
    – Maximize benefit and cost efficacy
•   Annual screening visit
•   Monitoring
•   Compliance                   ⇌ EMR & Informatics
•   Counseling
Integrated Patient Summary
Customizable Flowsheet
Graphic Monitoring
ACS
USPSTF Recommendations for
         Women
– Strongly recommends (A)
  •   Blood pressure (A) 18+
  •   Lipid disorders (A ) 45+
  •   Cervical cancer (A) – Sexually active, have cx
  •   Colorectal cancer (A) – 50+
– Recommends (B)
  • Lipid disorders –20 – 45 yo if other risk
  • Osteoporosis – 65+
       – 60+ in high risk
  • Breast cancer – 40+
                            US Preventive Services Task Force
CARDIOVASCULAR
    DISEASE
          Traditional Coronary Risk
                   Factors
                                         Framingham Study, 1957-1966
•    Age
•    Hypertension
•    Smoking
•    Diabetes
•    Hyperlipidemia
    *Does not incorporate modern concepts of the pathophysiology of
    atherothrombosis and CAD (hemostasis, thrombosis, inflammation, endothelial
    dysfunction, plaque instability)
         Cardiovascular Disease in
            Women - Factoids
• Leading cause of mortality in women – 38% of all
  deaths
• Women living with CVD in US – 34%
• 70% of CV events occur in patients defined as
  intermediate risk
• 4 out of 10 patients no prior symptoms
• 50% of all heart attack & stroke patients have
  “normal” cholesterol (Greenland et al, JAMA. 2003; 290)
• 10 – 20% no major risk factors (Khot et al, JAMA. 2003;
  290)
     AHA Screening Guidelines
• Screening in general population
   – Adults over age 20
   – Fasting lipoprotein profile q 5 years
      •   Total cholesterol
      •   HDL cholesterol
      •   LDL
      •   Triglycerides
• LDL › 130 mg/dl – more frequent monitoring
• Patients on cholesterol-reducing medications
   – Post 4-6 wks & at 3 mos
   – Then q 4 mos
        New Lipid Target Goals


•   Total cholesterol - < 200
•   LDL - < 100 (↓from 130)
•   HDL - > 40 (↑from 35)
•   Triglycerides - <150
      The Reynolds Risk Score
          www.reynoldsriskscore.org



• More predictive than Framingham or ATP
  III scoring
• Re-classified 40-50% of intermediate risk
  women into higher or lower categories



                        Ridker et al, JAMA. 2007; 297
            Reynolds Risk Score
          Clinical Risk Algorithms
                                  Clinically Simplified
     Best Fitting Model A                 Model B
•   Age                      •   Age
•   HbA1c (diabetic)         •   HbA1c (diabetic)
•   BP                       •   BP
•   Current smoking          •   Current smoking
•   hsCRP                    •   hsCRP
•   Parental Hx < 60 yo      •   Parental Hx < 60 yo
•   ApoB100                  •   Non-HDL-C
•   Apo A-1                  •   HDL-C
•   Lp(a) if Apo B100 >100
              Cardio CRP
(high sensitivity C-reactive Protein)
• Independent marker for CVD
• Non-specific acute-phase liver protein
  produced with tissue injury/inflammation
• < 1 – Low risk
• 1-3 mg/L – Average risk
• > 3 mg/L – High risk
• > 10 – Non-CV inflammation
       Osteoporosis - Factoids
• Osteoporotic fracture
  – 40-50% of women
  – 700,000 vertebral fractures & 300,000 hip
    fractures annually
     • < half recover fully
  – In ♀, lifetime risk of death following hip
    fracture = risk of death from breast cancer
Traditional Risk Factors for Fracture

•   Low BMD
•   Advanced age
•   Hx of fracture over age 50
•   Corticosteroid use
•   Family hx
•   Smoker
•   Rheumatoid arthritis
             Osteoporosis
              Screening

• BMD ↔ DXA ( dual energy x-ray
  absorpitometry)
  – Bone size & bone volume
• Bone markers → surrogate markers of
  fracture efficacy
                    Vitamin D
• Vitamin D deficiency – Epidemic in US
   – 50% of women with osteoporosis are Vit D deficient or
     insufficient
• Skeletal health & neuromuscular function
   – Positive association between 25(OH) D & Total BMD
   – Direct effect on muscles (type 2 fibers) and proximal
     musculature
• Cancers, immune competence, diabetes …
• Critical level = 30 ng/ml (70-80 nmol/ml) or less
  → 2o hyperparathyroidism

                    Holick, MF NEJM 357: 266- 81, July 2007
                      Vitamin D
• 25-Hydroxyvitamin D (25OHD) – major
  circulating form of Vit D
   – Precursor of active form (1,5-dihydroxyvitamin D)
• 2 forms of Vit D
   – Vitamin D3 - Cholecalciferol
      • Foods of animal origin, Conversion of 7-dehydrocholesterol in
        skin (UV light)
   – Vitamin D 2 – Ergocalciferol
      • Foods of plant origin
             Vitamin D
      Insufficiency/Deficiency
• Deficiency - < 20 ng/ml (50 nmol/l)
• Insufficiency – Range 21 – 29 ng/ml
• Critical to assess Vit D level:
  – Low BMD
  – Osteoporosis, osteomalacia
  – Subclinical myopathy - Muscle pain &
    weakness
  Clinical Targets for Vitamin D
              Testing
• Vitamin D deficiency
  –   Elderly
  –   Housebound & nursing home
  –   Asian
  –   Light restricting clothing
       • Orthodox Jewish & Muslim women
  – Bariatric surgery/malabsorption
• Patients under treatment
• Suspected toxicity
                 Prevention

Sun Exposure & Vit D
• Sunscreen
  – SPF 8 ↓Vit D 95%
• 5-15 minutes sunlight 2-3 X week (arms &
  legs)

Rx – 1000 IU +
   Advanced Methodology for
      Vitamin D Testing
• LC/MS/MS
  – Liquid chromatography, tandem mass
    spectrometry
  – Accurate, Sensitive, Specific for Vitamin D3 &
    D2
  – Reference Range 20-100 ng/ml
     • Correlate with levels of parathyroid hormone &
       calcium
Clinical Applications of Vitamin
           D Testing
• Identify Vitamin D deficiency
  – Yearly monitoring in high risk & older
• Monitor therapeutic response & compliance

• Diagnose intestinal malabsorption
• Identify Vitamin D intoxication
       Cancer in Women – ACS
          Statistics for 2007
        New Cases                    Deaths
•   Breast                •   Lung & Bronchus
•   Lung & Bronchus       •   Breast
•   Colon & rectum        •   Colon & rectum
•   Uterine corpus (Em)   •   Pancreas
         Breast Carcinoma
           ACS - 2007
• New cases – 178,480
• Deaths – 40, 460
        ACS Guidelines - Breast
• 20 – 39 yo – CBE at least q 3 yrs
   – Breast self examination
• 40 + - Annual CBE at minimum
   – Annual Mammography
       • Reduces mortality by 35% in women over 50 yo
       • Reduces mortality by 25-35% in women 40-50 yo
• High risk
   – Earlier initiation, screening at shorter intervals
   – Digital mammography
   – Screening MRI
       • ~ 20%-25% or greater lifetime risk of breast cancer
       • Strong family history of breast or ovarian cancer or Rx for
         Hodgkins disease
  Mammogram Prevalence (%), by Educational
Attainment and Health Insurance Status, Women
         40 and Older, US, 1991-2006
                     70                                   All women 40 and older

                     60


                     50                                           Women with less than a high school education
    Prevalence (%)




                     40
                                                                      Women with no health insurance
                     30


                     20


                     10


                      0
                       1991   1992   1993   1994   1995    1996    1997   1998   1999   2000   2002   2004   2006
                                                             Year
                     *A mammogram within the past year. Note: Data from participating states and the District of Columbia were
                     aggregated to represent the United States.
                     Source: Behavior Risk Factor Surveillance System CD-ROM (1984-1995, 1996-1997, 1998, 1999) and Public Use Data
                     Tape (2000, 2002, 2004, 2006), National Centers for Chronic Disease Prevention and Health Promotion, Centers for
                     Disease Control and Prevention, 1997, 1999, 2000, 2000, 2001, 2003, 2005, 2007.
         Breast Cancer – Risk
             Recognition
• Prior history of breast cancer or pre-
  malignant breast changes
• Familial clustering
• Inherited syndromes
  – BRCA1, BRCA2
    Limitations of Mammography
• Sensitivity = 83-97%
    – Most sensitive in 50-70 yo
•   High false positive rate
•   Expensive & resource intensive
•   Quality variable
•   Early Detection ≠ Cure
•   500%↑detection of DCIS
•   Not cost effective in women < 50 yo
 Breast Masses & Breast Cancer
           Diagnosis
• All breast masses should be evaluated!
  – Young age
  – Negative imaging
  – FNA or open biopsy
      New Technologies in Breast
          Cancer Screening
• Digital mammography
  –   Computer assisted triage
  –   Remote consultation
  –   ↓recall rate
  –   ↑efficiency
  –   Improved retention & storage
• MRI
  – Expensive, low specificity
  – Hi risk women & women with dense breast tissue
       Colorectal Carcinoma
           ACS - 2007
• New cases – 57,050
• Deaths – 26,180
             Colon Cancer

• Third leading cause of cancer death
• 30% → Familial clustering
• 3-5% → High risk inherited syndromes
  – FAP (familial adenomatous polyposis) ,
    HNPCC (hereditary nonpolyposis cancer)
• 1% → Inflammatory bowel disease
    Colon Cancer - Risk Recognition
• Colon cancer < 45 yo
• Adenomas > 2 cm dx at < 40 yo
• Multiple colonic malignancies
• Multiple primary cancers
• 10 or more adenomas with + family hx
• Multiple closely related family members with
  colon carcinoma
• Colon cancer in more than one generation
• Clustering of extracolonic cancers in family (esp
  gastric, breast, thyroid and endometrium)
   ACS Guidelines - Colorectal
• 50 + yo
• Options
  –   Flexible sigmoidoscopy q 5 yrs
  –   Colonoscopy q 10 yrs
  –   DCBE q 5 yrs
  –   CT colonography q 5 yrs
  –   Annual FIT or FOBT
       • FIT > FOBT
  – Stool DNA test (interval uncertain)
                         *Moderate or high risk - different testing schedule
     Testing for Occult Blood
• Single digital FOBT – poor performance, no
  longer recommended
• At home guaiac FOBT x3 – Poor
  compliance, lower sensitivity than FIT
• FIT – fecal immunochemistry test
  – Detects globin protein of hemoglobin molecule
  – Improved patient compliance & accuracy
 Fecal Globin, Immunochemistry
   (Insure® ) – FDA Approved
• Does not react with non-human hemoglobin
  or heme peroxidase
  – Food restrictions not required
• Specific for lower GI bleeding
  – Target the globin portion of hemoglobin
• Improved sensitivity and specificity
  – 88.9% sensitivity for ca
• Improved patient compliance (↑66%)
      History of Pap Smear Screening
                          • 1928 – First scientific
                            paper
                          • 1943 – Atlas
                          • 1945 – ACS
                          • 1963 – ↓ deaths from
                            cervical cancer
Dr. George Papanicolaou
                          • 2007 – death from
      1883-1962             cervical cancer ↓ 80%
        Cervical Carcinoma
           ACS - 2007
• New cases – 11,150
• Deaths – 3,670
   Prevalence of HPV Infection
• Overall prevalence – 26.8% in women aged
  14 – 59 yrs (n=1921)
• Highest prevalence – 44.8% in women aged
  20 – 24 years
• Independent risk factors – age, marital
  status, increasing numbers of lifetime and
  recent sex partners
                              JAMA Vol 297, Feb 2007
                              Dunne et al
    HPV Prevalence and Incidence of
       Cervical Cancer by Age




Sources: Sellors et al. CMAJ. 2000;163:503. Ries et al. Surveillance, Epidemiology
and End Results (SEER) Cancer Stats NCI, 1973-1997. 2000.
        ACS Guidelines - Cervix
• 3 yrs post sexual debut or at age 21 then q 2 yrs
  with LBC
• 30 +
   – Annual until 3 normals then q 2-3 yrs with LBC or q 3
     yrs with HR HPV
• 70 +
       • Consider D/C if 3 neg w/in past 10 yrs
• S/P total hyst - not necessary
• *Exceptions = Hx of SIL/Ca, DES, or immunosuppressed
     2006 ASCCP Guidelines
         www.asccp.org
• Incorporate HR HPV screening in
  women over 30 yo into official
  guidelines
• HR HPV testing ↔ Standard of
  care
 HPV DNA Testing and Cervical
      Cancer Prevention
• Digene hc2
  – Cocktail of the 13 most frequent HR HPV types
     • Includes HR HPV’s 16 & 18 identified in 70% of cx cancers
• DNAwithPap – Combines Pap test & HR HPV for
  screening in women › 30 yo
  – Sensitivity approaching 100% for HSIL & CxCa
  – NPV = 99.2%
  – 4-6% of women with neg Pap are HR HPV +
• Recommended by ASCCP, ACS, ACOG & SGO
  Sensitivity & Predictive Value –
 Double Blinded Controlled Studies
• HPV DNA vs Pap - Mayrand et al, NEJM, 10/2007 (Canada)
   – 10,154 women
   – HPV DNA Sensitivity = 94.6% (Spec 94.1%)
   – Pap Sensitivity = 55.4%% (Spec 96.8)
• HPV & Pap to Screen for Cx Ca – Naucler et al, NEJM,
  10/2007 (Sweden)
   – 12, 527 women followed for 4 yrs
   – At enrollment detection by HPV was 51% greater than
     Pap
   – Subsequent screening exams – 40% reduction in risk
     for CIN 2/3
   – Persistent HR HPV positivity – 24% developed CIN
     2/3
        Trends in STD – 2006
           www.CDC.gov

• Chlamydia, Gonorrhea, Syphilis
• 19 million new cases annually
• 50% in young, 15-24 yo
               CDC Trends
• CT
  – Estimated 2.8 million new cases per year
  – Increased 5.6% from 2005
• GC
  – Increased 5.5% from 2005
• Syphilis
  – Increased 13.8% from 2005, esp MSM
  – Increased 11.1 % in women
 CDC Screening Recommendations
• Annual CT for all sexually active women < 26 yo
  (inc GC if prev > 1%)
   – Estimate 56% reduction in PID if compliant
• Older women with new or multiple partners, hx
  unprotected sex
   – High risk – GC, CT, syphilis, HIV, Hep, HSV 2)
• Pregnancy (esp Syphilis)
• Diagnose and treat partner
• Test of cure 3 months following therapy

• HEDIS – <40% of eligible are screened
                  NAATS
• Critical tools
• Substantially improved sensitivity
• Can substitute non-invasive testing (urine)
  – Expand venues for testing
• Can detect CT & GC in same specimen
• Can be performed “OTV”
           NAATS Platforms
• Roche Amplicor – PCR
• Abbot LCx – Ligase CR (LCR)
• BD ProbeTec* – Strand displacement
  amplification
  – CT target = Cryptic plasmid
  – GC target = Pillin protein homologue
• GenProbe APTIMA** – transcription mediated
  amplification (TMA)
  – Target = Ribosomal RNA
Autoimmune & Allergic Disease
• “Mystery” illnesses, subclinical, quality of
  life
• Thyroid disease
• Celiac disease (Sprue)
• Allergies
  – Respiratory
  – Food
  – Skin (eczema & urticaria)
 Epidemiology of Primary Thyroid
            Disease
• Incidence of Hashimoto’s and
  hypothyroidism increase with age
• Overt: 0.6-5% of elderly, 7% over 80 yo
• Subclinical:
  – Age 30 3-5%
  – Age 50 7-8%
  – Age 80 14-20%
           Thyroid Screening
           Recommendations

• ATA         Women over 35 yo
• ACP         Women over 50 yo,
              geriatric**



• USPSTF      Insufficient evidence
    Screening for Hypothyroidism
• High Risk
    – Hx of thyroid or autoimmune disease
    – Family hx of thyroid disease

•   TSH
•   T4
•   Thyroid antibodies
•   Peroxidase antibodies
             ImmunoCAP
        Specific IgE Blood Test
•   Simple blood test
•   Objective laboratory results
•   Sensitive, accurate, reproducible
•   Respiratory & Food Allergens
    – Profiles for Adults & Children
• Avoidance, immunotherapy
• Adjust medication to exposure
      ImmunoCAP Indications
• Eczema & chronic urticaria
• Asthma
  – Allergic asthma – 60%
• Recurrent ear infection
• Rhinitis
• GI distress
  Malabsorption & Osteoporosis
• Celiac disease
  – Osteoporotic individuals – Prevalence = 3.4%
  – Non-osteoporotic individuals – Prevalence =
    0.2%
  – Infertility



                   Stenson et al, Increased prevalence of celiac disease
                   and need for routine screening among patients with
                   osteoporosis. Arch Int Med 2005; 165.
       Summary of Discussion
• Electronics & Computerization
  – EMR & informatics
  – Mammography
• Cardiovascular Disease
  – Redefining risk in women using updated markers &
    Reynolds Risk Score
     • Cardio CRP
• Bone & Musculoskeletal Health
  – Vitamin D
       Summary of Discussion
• Cancer screening
  – Breast
     • Digital imaging, MRI, Genetic testing
  – Colon
     • Epidemiology, FIT
  – Cervix
     • HR HPV
• STD screening
  – Annual in < 26 yo & high risk, NAATS
• Autoimmune Disease & Allergy
  – Hypothyroidism
  – ImmunoCAP
 Screening & Diagnostic Testing
• Not standardized
• Define & stratify risk
• Emphasize health maintenance in the
  context of evidence-based guidelines
  – Keeping the annual visit annual !!!
• Coordinate with personal & family history
  – Behavioral, social & occupational factors
• Coordinate with physical exam
ACS

				
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