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Flashcards in Unit IV: Clinical Vignettes Deck (20)
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1

Prostate Cancer - Demographics

In the US, 240,000 men are diagnosed with prostate cancer every year (29% of all new cancer cases in men) and 30,000 men die

2

Sources of systemic testosterone

Tesis - 90-95%
Adrenal Glands - 5-10%
Intracrine androgen production in the prostate cancer cells themselves

3

AR Mechanism

The AR normally resides in the cytoplasm when not bound to an androgen agonist (most commonly testosterone); upon ligand binding, inhibitory HSP chaperones dissociate from AR and it moves to the nucleus; there, it undergoes homo-dimerization and binds to the androgen-responsive elements of the DNA where it promotes gene expression

4

AR Antagonist

Ex: Flutamide, bicalutamide

Compete with agonists to block androge binding to the AR ligand binding domain & interferes with co-activator binding

5

Mechanisms of resistance to hormone therapy in PCA

1. AR activation via non-gonadal testosterone (i.e. adrenal)
2. Overexpression of AR
3. AR mutation leading to promiscuous AR activation
4. Truncated form of AR with constitutive activation of the ligand-binding domain

6

Abiraterone

A specific inhibitor of the enzyme CYP17, which plays an important role in androgen production; blocks testosterone production from all 3 sources; offers significant survival improvement for men with castration-resistant prostate cancer

Side effects: Hypokalemia, Edema, and Hypertension due to accumulation of testosterone precursor mineralcorticoids

7

Enzalutamide

Second generation anti-androgen; blocks binding of testosterone to AR, which inhibits nuclear translocation of AR, inhibits co-activator recruitment, and inhibits DNA binding of AR

Side effects: Hot flashes, loss of secondary sex hair features

8

Genetics of Cystic Fibrosis

Autosomal recessive condition caused by mutation in the CFTR protein on chromosome 7; CF exibits genetic heterogeneity although the most common mutation is F508del; failure of the CFTR to extrude Cl- ions from the apical membrane diminishes serous secretion leading to diminished mucociliary clearance, infection, & inflammation

9

Clinical features of CF

Greasy, malodorous stools
Failure to thrive due to pancreatic insufficiency
Chronic sinus infections
Digital clubbing
Bronchiectasis
Sweat Chloride > 60mmol/L
Dehydration & Hyponatremia
Deficiency of fat-soluble vitamens A, D, E, K due to steatorrhea
Nasal polyps

10

CF Treatment

Pancreatic enzyme supplementation, high calorie/protein/fat/vitamin/salt diet

Airway clearance treatment - daily percussive therapy, inhaled hypertonic saline, bronchodilators

Antibiotic therapy - inhaled tobramycin (TOBI)

Anti-inflammatory treatment

11

Classes of CFTR mutations

I. No synthesis of CFTR (i.e. nonsense or frameshift mutation)
II. Block in processing & localization of CFTR - CFTR is produced but is not present in the apical membrane; delF508
III. Improper regulation - CFTR is localized to the apical membrane but does not function properly
IV. Altered Conductance - CFTR is present at normal amounts but has reduced activity
V. Reduced synethesis - Normal CFTR is produced at lesser amounts

12

Diagnosing CF

Sweat chloride > 60 mmol/L
2 CF mutation genotype

13

Predictive vs. Prognostic Biomarkers

Prognostic biomarkers give information about the likelihood of certain outcomes (i.e. survival) based on the natural course of the disease, without any therapeutic intervention

Predictive biomarkers give information about the likelihood of an outcome (i.e. survival) related to a specific treatment - "who will benefit from therapy?"

14

Small Cell Lung Cancer (SCLC)

Accounts for 15% of all lung cancers and is most often seen in heavy smokers; characterized by aggressive growth, frequent metastases, and poor 5-year survival; combined chemotherapy is SOC and no targeted agents have yet shown clinical activity

15

Non Small Cell Lung Cancer (NSCLC)

Accounts for 85% of all lung cancer diagnoses; standard treatment is platinum-based chemotherapy and multiple targeted treatment options are available

Includes adenocarcinoma, squamous lung cancer (almost exclusively smokers), and large cell carcinoma

16

EGFR / HER1 / ErbB-1

EGFR/HER is frequently over-expressed in early stages of lung cancer development; may be targeted for molecular therapy by antibodies or TKIs in patients with EGFR mut (+) tumors

17

EGFR TKIs

Ex: Gefitinib; interact with the intracellular tyrosine kinase domain of EGFR, blocking it's downstream phosphorylation cascade

Sensitive tumor characterization: EGFR mut (+)

18

EGFR Antibodies

Ex: Cetuximab; block the extracellular, ligand-binding domain of EGFR, inhibiting it's activity;

Sensitive tumor characterization: EGFR overexpression or high gene copy number (per FISH)

19

ALK-EML4 Fusion

Fusion gene resulting from translocation or inversion of ALK and EML-4, identified by FISH; the fusion protein has constitutive kinase activity and can be targeted by ALK inhibitors

3% of lung cancer patients

20

Lung Cancer Screening

Yields a 20% reduction in lung cancer mortality and a 6.7% reduction in all cause mortality,

BUT, the screen also detects lung nodules, yielding a 95% false positive rate