Block 5 Case 6

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Paget's Disease: incidence, problem in determining: 3% adults > 40yo
Hard to tell because often asymptomatic.
Paget's Disease: etiology: Cause unknown, theory that paramyxovirus may be involved.
Paget's Disease: pathophysiology: Increased bone resorption AND formation... often at same rate.
Paget's Disease: stages: Osteoporotic/osteolytic phase: excessive resorption, calcium temporarily low... leads to...

Osteoplastic/sclerotic phase:
Ratio of resorption to formation moves towards 1:1... Hard dense less vascular bone formed.
Paget's Disease: histologic changes: 20x bone turnover rate --> deeply scalloped lacunae with larger than normal osteoclasts and many osteoblasts.
Normal marrow --> highly vascular loose stroma...
Paget's Disease: labs: VERY high alkphos.
Calcium usually normal (formation = destruction)
Paget's Disease: clinical: Often asymptomatic .
Gradual swelling and deformity of long bone or gait disturbance. Increasing hat size.
Paget's Disease: treatment: Usually none.

Some may require NSAIDS, joint replacement.

Drugs: calcitonin (increased deposition), bisphosphanates (inhibits bone resorption/formation), gallium nitrate (treats hypocalcemia)
Paget's Disease: other name: Osteitis deformans
Osteomalacia: definition: problem with mineralization of new organic bone matrix (osteoid), results in rickets in children.
Osteomalacia: causes: Vit.D deficency
Hypophosphatemia
Bone matrix disorder
Mineralization inhibitors (bisphosphonates etc)
Squamous cell carcinoma: epidemiology: 30-40% of bronchogenic ca.
More common in men, closely related to smoking.
Squamous cell carcinoma: general features: Usually centrally located (2/3), most likely to cavitate.
Only 20% chance to met, usually direct extension.
Associated with hypercalcemia, (PTH secretion by tumors).
Squamous cell carcinoma: histo changes: Keratin pearls.
Intercellular bridging.
Squamous cell carcinoma: genetic changes: High frequency of p53 mutation.
15% tumor suppressor RB lost
65% cdk inhibtor p16 lost.
General locations of each major type of lung ca:: "LA is on the coast"

Adeno, large cell are periphreal.
Small cell, squamous are central.
Osteoporosis: define: Skeletal disorder with 2 elements: low bone mass, microarchitectural disruption.
Osteoporosis: epidemiology, risk factors: 10 million: 2m men, 8m women.
Risk factors: age, women, family hx, estrogen deficiency, low body weight, low Ca intake, inactivity
Osteoporosis: labs: Ca, Phosphate, PTH NORMAL!
Alkphos usually normal.
Vitamin D deficency common.
Osteoporosis: WHO DEXA scan T scores for normal, osteopenia, osteoporosis, and severe osteoporosis: normal = >1
osteopenia 1 to -2.5
osteoporosis less than -2.5
severe osteoporosis less than -2.5 with a fracture
Osteoporosis: pathogenesis: Mismatch between bone resorption and bone formation
Osteoporosis: 2 types of Primary disease and causes: Type I: menopause related -- "high turnover". Osteoclast overactivity, can be prevented by estrogen therapy
Type II: age related -- "low turnover". Osteoblast inactivity.
Osteoporosis: causes of secondary disease: Pregnancy
PTH excess
VitD deficency
Decreased CA
Androgen deficiency
Hypercortisolism
Osteoporosis: treatment: Bisphosphonates
Sex hormones
Selective estrogen receptor modulators (SERMS)
Calcitonin
Vit D and Calcium
Exercise
Diffuse parenchymal lung disease (DPLD): definition, characteristics: Heterogeneous group of ~180 diseases with these features:
Dyspnea, hypoxemia, restrictive pattern on PFT, bilateral infiltrates on CXR.

Result of inflammation and sometimes fibrosis of parenchyma.
Diffuse parenchymal lung disease (DPLD): other terms: interstitial lung disease
diffuse lung disease
pulmonary fibrosis
Diffuse parenchymal lung disease (DPLD): cause categories: Infectious disease
"Dust" related
Autoimmune
Drug-induced
Idiopathic
Miscellanous (sarcoid, amyloidosis etc)
Diffuse parenchymal lung disease (DPLD): PFTs: restrictive pattern with low volumes, low FVC, low FEV1.
Reduced DLCO common.
Diffuse parenchymal lung disease (DPLD): on imaging: CXR shows bilateral diffuse pulmonary infiltrates with ground glass appearance.
Dequamative interstitial pneumonia (DIP): definition and category: Idiopathic form of DPLD, almost exclusively in smokers.
Dequamative interstitial pneumonia (DIP): histology: accumulation of large, pigment laden (hemosiderin + cig smoke pigment) macrophages in alveoli.
Dequamative interstitial pneumonia (DIP): symptoms, treatment: Chronic dyspnea and cough.
Restrictive PFT pattern.
Usualy resolved by quitting smoking, may need steroids for 3mo.
SCLC: Common mutations: Tumor supressors (80%): Rb, p53
Oncogenes (90%): telomerase, myc, bcl-2 overexpression
SCLC: hormones released: ACTN, ADH, IGF-I, GRP (gastrin releasing peptide)
SCLC: common mets: Bone liver brain adrenals

And obviously lymph nodes.

Aggressive, metastsizes widley.
SCLC: paraneoplastic syndromes: SIADH --> hyponatremia
ACTH: hypokalemia, electrolyte disturbances
SCLC: morphology: Small, high N/C ratio, basophilic, high mitotic count.
SCLC: staging: Limited (30-40%): ipsilateral disease + ipsi nodes.
Extensive (60-70%): mets outside ipsilateral

MUST DO BIOPSY TO CONFIRM DX.
SCLC: treatment for limited stage: Combination chemo: etoposide + cis/carboplatin.
Radiation therapy.
Supportive care (!emetics)
SCLC: treatment for extensive stage: Chemotherapy: etoposide + cis/carboplatin
Maybe radiotherapy
SCLC: mortality with and without treatment at each stage: Extensive w/treat: 10-12mo
Limited w/treat: 14-18mo
Untreated: 2-4mo
SCLC: % of all lung cancer: 20-25%
Large cell carcinoma: % of all cancer: 10-15%
Large cell carcinoma: morphology, location: Mostly peripheral.
Large cells, large nuclei with prominent nucleoli. Moderate cytoplasm. No glands/pearls/bridging.
NSCLC: prognosis: 5 year survival:
IA: 75%
IIIB: 5%

Overall: 10-15%
ECOG performance status grades:: 0: Fully active
1: Restricted in strenuous activity
2: Self-care but no work, up and about >50% waking hours.
3: Limited self care, up and about <50% waking hours.
4: Disabled. No self care, confined to bed/chair.
5: Dead
NSCLC: stages of treatment: Stage tumor
PFTs
Neoadjuvant therapy
Pneumectomy/Lobectomy
Adjuvant therapy
NSCLC: chemotherapy agents: Old: carboplatin, cisplatin
New: gemcitabine, paclitaxel, docetaxel, vinorelbine

Combine 1 old, 1 new.
NSCLC: biologic therapy agents: Gefitinib, erlotinib.

EGFR pathway blockage. EGFR increases mitotic activity.
NSCLC: treatment by stage: 0: limited surgery
1: surgery
2: surgery
3a: surgery if can get nodes
3b: radiation, unless can get nodes, then surgery
4: chemotherapy
NSCLC: staging: I: No nodal involvement
II: Local invasion or nodal involvement
IIIA: Invasion and nodal involvement
IIIB: Distant nodal involvement
IV: Mets
Lung adenocarcinoma: % of Lung ca, epidemiology: 25-40%
Most common lung ca in women and nonsmokers.
Lung adenocarcinoma: mutations: K-RAS, p53, RB, p16
Lung adenocarcinoma: histology: Must have neoplastic gland formation or mucin.
Bronchioloalveolar Carcinoma (BAC): by definition...: DOES NOT METASTASIZE. Kills by suffocation.... grows along alveolar architecture without destroying it.
Bronchioloalveolar Carcinoma (BAC): subtypes: Nonmucinous
Mucinous
Tumor lysis syndrome: common abnormalities: Hyperuricemia: purine metabolism by xanthene oxidase (give allopurinol)
Hyperkalemia, hyperphosphatemia: from cell cytoplasm
Hypocalcemia: calcium phosphate precipitates in soft tissue
ARF: most often by uric acid crystal deposition --> mechanical obstruction.
3 types of pain:: Somatic
Visceral
Neuropathic
WHO's pain relief ladder: Start with NSAID.
If insufficent
Move to weak opiod (codeine)
If insufficent
Move to stronger opiod (morphine)
Adjuvant pain drugs and indications:: Analgesic adjuvants: less opiod side effects.
Tricyclics, clonidine: neuropathic pain
Carbamazepine: anticonvulsant
Corticosteroids: inflammation
Benzodiazepines: anxiety
Colace (Docusate): class, MOA, adverse effects: laxative
Decreases surface tension at oil-water interface of feces... makes them more watery and oily.
Diarrhea, abdominal cramping.
5 stages associated with major change or loss:: DABDA:
Denial
Anger
Bargaining
Depression
Acceptance
5 types of advanced directives:: Health care proxy: DPA
Living will
Instructional directive: more specific living will
Values history: extrapolation from prior statements
Combined directive: uses all components.
Cisplastin: class, MOA, adverse effects... solution to adverse effect.: Platinum chemotherapy agent
Enters cell via copper transporter, reacts with guanine in DNA, crosslinks DNA strands inhibing replication and leading to p53 mediated apoptosis.
Nephrotoxic!! Mannitol, an osmotic diuretic, flushes kidneys out and reduces toxicity.
Gemcitabine: class, MOA, adverse effects: Cytidine chemotherapeutic agent
Inhibits DNA synthesis... enters cell by nucleoside transporters, inhibits ribonucleotide reductase (less deoxy nucleutides) and is incorporated into DNA resulting in chain termination.
Myelosuppresion major side effect.
Allopurinol: class, MOA, adverse effects: Treat hyperuricemia.
Inhibits xanthine oxidase, which converts hypoxanthine to xanthine.
Well tollerated... occasional hypersensitivity rx.
Prochlorperazine: class, use, MOA, adverse effects: Phenothiazine antiemetic
Administer before starting chemo.
Antagonizes neurotransmitter receptors in chemoreceptor trigger zone of brain. D2, H1, 5HT(serotonin) receptors.
Side effect: Sedation
4 phases of drug trials: I: healthy ppl, to assess safety.
II: test efficacy in sick people
III: large, double blind. Compares to standard of care.
IV: Post-launch studies.
Patient vs doctor in treatment limitation:: Courts do not recognize physician right to end treatment.
Courts DO recognize right of patient to request OR deny treatment.
Osteoblast actions:: Secretes collagen fibrils... osteoid. Calcium phosphate is layed on this framework --> bone.
Osteoclast actions:: Secrete collagenase and lytic enzymes to break up bone and release Ca, phosphate, and amino acids.
Calcium: distribution: 40% albumin bounds
60% ultra filtrate...(50% of total calcium is free, the biologically active form.)
Calcium: regulation organs: Intestine brings in 200mg/day
Bone remodeling cycles Ca.
Kidney eliminates excess Ca, 200mg/day.
Calcium: regulation hormones: PTH: Increase bone resorption (bone), decrease phosphate reabsorption (kidney), increase Ca reabsorption (kidney).
Vitamin D: promote mineralization of bone by increasing Ca and Phosphate levels in blood. Increases absorption of BOTH in kidney, intestine. Promotes osteoclast activity in bone.
Calcitonin: inhibits osteoclasts, reducing serum Ca.
Overall, bone formation stimulated by and inhibited by what compounds?: Stim: GH, insulin, androgens, Vita D.
Inhib: Cortisol
Overall, bone resorbtion stimulated by and inhibited by what compounds?: Stim: PTH, VitaD, Thyroid hormone, cortisol, prostaglandins
Inhib: estrogens.

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