Understand 2nd year medicine

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Basic Pharmacology

Administration, Distribution, Metabolism, Excretion


I-I-I Can't Possibly Enjoy Slow Sloppy Sex
Quickest route

Changes in old people
"Crumbly Old Fasted People Remember Horrible Wars"

  • Cardiac Output decreased
  • Fat content increased
  • Protein binding decreased
  • Renal function decreased
  • Hepatic BF (& enzyme activity) decreased
  • Water (TBW) decreased

cAMP (all the H’s)
  • FSH (follicular stimulating hormone), LH luteinizing hormone, ACTH acth adrenocorticotropic hormone, TSH thyroid stimulating hormone , CRH crh corticotropin releasing hormone, hcg human chorionic gonadotropin , ADH antidiuretic hormone, MSH melanocyte stimulating hormone, PTH Parathyroid hormone

cGMP (all the vasodilators)
  • ANP atrial natriuretic peptide
  • NO (nitric oxide)

Steroid receptors
  • Progesterone, Estrogen, Testosterone, Cortisol, Aldosterone, Thyroxine and T3

RTK (all the GF’s)
  • Insulin, PDGF platelet derived growth factor

Pain Pathway


*** ALL descending pathways are INHIBITORY for pain!
C (slow) and A-delta (fast) to lamina of dorsal horn
  • C: 1, 2
  • A-delta: 1, 5

  • Inhibit COX cyclooxygenase (esp. COX-2)
  • Block prostaandin synthesis (hyperalgesia, mucosal production → ulcers)

Opioid analgesic
Binds to receptors on PAG periaqueductal gray, inhibitory interneurone of dorsal horn, nociceptor
Stimulate descending inhibitory pathway (locus coeruleus, PAG →  Raphe)


mu: Most common, euphoria (morphine)
delta: Enkephalin
kappa: dynorphin, dysphoria (depression)
Endogenous opioid peptides
  • Endorphin
  • Dynorphin: Binds to inhibitory interneurone → GABA release to dorsal horn → Hyperpolarize so no pain
  • Enkephalin

Reduced cAMP --> Closing of Ca2+ ion channels an dopen K+ -> Hyperpolarize

NE from locus coeruleus

Analgesic ladder
  1. NSAID, paracetamol (not NSAID - as it is not antiinflammatory, COX-1 inhibitor...)
  2. Codeine, dihydrocodeine
    1. less potent
    2. thus more higher dosage needed to achieve the effect (can't be given in equinalegesic dose due to adverse fx) -> restriction of dose unlikely sfx
  3. Morphine, diamorphine (heroin), methadone, pethidine, fentanyle, buprenophine
    1. diamorphine: more lipid soluble thus rapid onset
    2. Fentanyl: Given transdermal as patches for chronic pain
    3. Pethidine: Rapid onset but short duration (preg)
    4. Methadone: Long duration and less sedating (treat addiction)

Sfx of morphine
MD cares
Respiratory depression

Pharmacology of anesthesia
Bases administered as hydrochloride (B.HCl)
  • e.g. Lidocaine hydrochloride: most commonly 0.5% to 1%, 2% lidocaine in dentistry

Most local anesthetics vasodilates. Adrenaline (1/200,000) helps limits the local spread.
  • Adrenaline vasoconstricts arteries and hence delays the resorption into systemic circulation, almost doubling the duration of local anaesthesia.
  • Side effects of adrenaline use - Tissue ischemia and necrosis due to constriction
  • DO NOT use adrenaline in dirty wounds (risk infection) or distal organs (fingers nose hose toes)
    • fingers, toes, nose, penis

After injection of B.HCl, B is liberated by the relatively alkaline pH of tissue fluids: B.HCl + HCO3 <--> B + H2CO3 + Cl-

pH of the tissue: Acidic (e.g. pyogenic abscess)
  • Reduces the availability of unionized base (B reacts with H+)
  • So less B through neuronal membrane → less potent

Unionised base B diffuses through neuronal membrane into nerve axoplasm and ionizes due to the acidity: B + H+ ←→ BH+ depending on the pH of the solution and the pKa of the drug.

BH+ diffuses through the nerve sheath, perineuronal tissues and the neuronal membrane, to reach the axoplasm where it partially ionises again: B + H+ <--> BH+

Ionised form BH+ enters voltage gated sodium channel and reversibly inhibits it →  threshold potential not reached → no propagation

Pharmocology of anesthesia
  1. Lipid solubility: The greater, the greater potency due to 90% of neuron membrane is lipid (thus can diffuse across and block sodium channels)
  2. Protein binding: The greater affinity to the sodium channel, the longer fx
  3. Ionization depends on pH of environment

  • If unionized, diffuse across membrane and block sodium channel
  • More unionized, strong potency
  • Sodium bicarbonate
  • Reduces the amount of H+

  • Increase amount of unionized drug
  • Reduce initial sting of infiltration (H+)

  1. Physiologic activity of local anesthetics is a function of their lipid solubility, diffusibility, affinity for protein binding, percent ionization at physiologic pH, and vasodilating properties.
  2. All local anesthetics (except cocaine) are vasodilators → faster absorption and, thus, shorter duration of action
    1. counteract using epinephrine included in local anesthetic solutions

Side effects due to excitable membranes
  • CNS: neurotoxicity
  • CV: myotoxicity (decrease rate of depolarization - treat ventricular arrythmia, but had higher doses: inotropic - bradycardia, asystole)
  • Hypotension

Immunohistochemistry (IHC)

Immunohistochemistry (IHC) shows how much HER2 protein is expressed, graded from from 0 to 3+.
  • 0–1+ normal amount expressed; HER2-negative
  • 2+ moderate amount expressed; Further testing REQUIRED (e.g. FISH to give definite result)
  • 3+ higher than normal expressed; HER2-positive.

Fluorescence in-situ hybridisation (FISH) test

Identify specific parts of a chromosome (translocation? if none - one signal as it hybridizes to only one place; if yes - two signals)
  • Make a DNA probe complementary to the known sequence and label it with fluorescent marker
  • Put the chromosomes on a microscope slide , arrest in metaphase and denature DNA into single strands.
  • Add DNA probe to the microscope slide, letting the probe hybridize to its complementary site.
  • Wash off the excess probe and look at the chromosomes in a fluorescence microscope. The probe will show as one or more fluorescent signals in the microscope, depending on how many sites it can hybridize to.

Anti-HER2 Antibodies labelled with a fluorescent dye. Wash. Emits.
  • FISH-negative – normal levels of the gene are present, or
  • FISH-positive – excessive amounts of the gene are present.

ELISA (enzyme-linked immuno-sorbent assay)

y axis = response, x axis = [drug]
Vmax = Maximum reaction velocity
Km is the [drug] needed for ½ Vmax to occur



Competitive inhibitor
  • Greater [substrate] to produce ½ Vmax → Greater Km
  • Will eventually reach Vmax if keep adding [substrate] → same Vmax as normal

Non-competitive inhibitor
  • Substrate changes shape of enzyme so adding more [substrate] will not help Vmax → lower Vmax
  • Same Km as normal



Potassium-sparing diuretics are diuretic drugs that do not promote the secretion of potassium into the urine

K+ sparing diuretic affects principal cell of collecting duct
Aldosterone antagonist (Blocks aldosterone-induced synthesis of Na/K ATPase pump) → Less Na/K+ ATPase in basolateral to blood thus less Na+ absorbed (and less K+ secreted) → Less water absorbedheart failure, ascites in patients with liver disease, low-renin hypertension, hypokalemia, secondary hyperaldosteronism (such as occurs with hepatic cirrhosis), and Conn's syndrome (primary hyperaldosteronism)It can also cause gynecomastia in males and should never be given with potassium supplementation for fear of the development of hyperkalemia.

LactuloseSynthetic dissacharide that is osmotic laxative - poorly absorbed so osmotic pressureTreat constipation, hepatic encephalopathy
Thiazideinhibiting reabsorption of sodium (Na+) and chloride (Cl−) ions from the distal convoluted tubules in the kidneys by blocking the thiazide-sensitive Na+-Cl− symporter

FurosemideInhibit na/k/2cl- cotransporter in thick ascending
Like many diuretics - may cause hypo, hypoca, hypona and mg. Excessive can also cause metabolic alkalosis due to hypochloremia and hypokalemia.
Paracetamol - NOT nsaid (no anti-inflammatory)

aka tylenol/acetaminophen
COX inhibitorFever, headache
MorphineAgonist at opiod receptor (mu)

MetaclopramideDopamine antagonist - Blocks dopamine receptor in CTZ → AntimeticNausea, vomiting
CarbimazoleInhibit thyroid peroxidase: Less T3/4 synthesisHyperthyroidism

Long regiment as it takes time for stores to decrease in colloid

PropanololB1 antagonist Tachycardia, tremor in hyperthyroidism
LevothyroxineProdrug to T3 (active!)HypothyroidismArrythmia, weight loss, sweating
Metformin (Biguanide)Decreases gluconeogenesis, increase insulin sensitivityHyperglycemia in DM2 (The "average" person with type 2 diabetes has three times the normal rate of gluconeogenesis; metformin treatment reduces this by over one third)Lactic acidosis
SulfonylureaCloses ATP-sensitive K+ channel → No k+ efflux → Depolarization → INsulin release from B-cellType 2 DM Only - still has B-cells
Ramipril (ACE inhibitor)

ACE breaks down kinin
Less AT2 and aldosterone (less blood volume!)

More kinin so vasodilation
Hypertension, heart failure
SimvastatinUpregulate LDLR → Less LDL

HMG CoA reductase inhibitor → Less cholesterol synthesis (Arteries may insist sucking cholesterol - 3xacetylcoa (HMGcOA reductase) mevalonate isoprene squalene cholesterol)

DMARD (Disease modifying anti-rheumatic disease)
Gold salt
Depress immune
Slow onset (6 months)

Antibiotic vs Enterobacteria in urine

Glucocorticoid (induce annexin/lipocortin -> inhibit PLA2), more iKB transcription

DiclofenacNSAID, preferential COX-2 inhibitor

Prednisolone (oral glucocorticoid): Given up to 3 weeksAct on glucocorticoid receptor (altered gene prescription - less cytokine prodxn and produce lipocortin aka annexin (inhibits PLA2)

Glucocorticoid - induce lipocortin which inhibits PLA2 (so less A’A)

NSAID - inhibit COX cyclooxygenase

Cycloph    osphamideProdrug into metabolite phosphoramide mustard - an alkylating agent: Irreversibly crosslinks DNA to cause apoptosisLymphoma

CyclosporineBind to cyclophillin -> calcineurin inhibited (phosphatase!)-> Inactive NFAT (TF) -> Less IL2 made

Phosphatase - removal of phosphate
Immunosupressant to prevent organ rejection

calcium calmodulin calcineurin (ca!)
T cell activation requires intracellular calcium levels to increase. When an antigen-presenting cell interacts with a T cell receptor on T cells, there is an increase in the cytoplasmic level of calcium Calcium x Calmodulin activates calcineurin. Calcineurin (calcium-sensitive phosphatase ) dephosphorylates TF NF-AT (nuclear factor of activated T cell). NF-AT then goes to T cell nucleus to increase expression of genes coding for IL2.

When Calmodulin binds to calcineurin it gets ACTIVATED!

Tacrolimus (FK506)Bind to immunophilin -> calcineurin inhibited (phosphatase!)-> Inactive NFAT (TF) -> Less IL2 made Immunosuppressant

MycophenolatePurine synthesis antagonist - inhibits inosine monophosphate dehydrogenase in B and T lymphocytesImmunosupressant to prevent organ rejection
Triple therapy (oral corticosteroid, ciclosporin, azathioprine)

Nystatin (Macrolide - drugs whose activity stems from the presence of a macrolide ring)Antifungal - Have both polar and nonpolar structures, thus binds with ergosterol (cholesterol in human, ergosterol in fungi) in fungal membrane to form pores to disrupt membrane permeabilityCandida (fungal) infection

Compete with PABA, thus inhibiting DHPS, thus, no functional folic acid madeAntimicrobial
Trimethoprim Analog of folic acid that inhibits DHFRAntimicrobial
Co-trimoxazoleSulfamethazole (Sulfonamide inhibit folate synthesis) + trimethoprim (inhibit DHFR)Antimicrobial
Colomycin (in=antimicrobial?)poly-cationic regions interact with the bacterial outer membrane while the hydrophobic/hydrophillic regions interact with the cytoplasmic membrane just like a detergentAntimicrobial
Amphotericin B ( PolyeneMacrolide)Same activity as nystatin - binds to ergosterol in fungal membrane and create poresAntifungal

Beclometasone (Inhaler/nasal spray)Glucocorticoid - reduce mucosal edema, mucosal production, PG & Leukotriene synthesisAsthma, rhinitis

Rest cardiac output - 5l/min
exercise - 25l/min (greatest gain is skeletal muscle) - Adrenaline
- Central nervous system: Less parasympathetic, more sympathetic
- Muscular: metabolite dilates muscle arteriole,

Increase in Heart rate (β1)
Constriction of arterioles (α1)
Non essential organs (viscera & skin)
Dilation of arterioles (β2) to Skeletal muscle
Dilation of airways (β2)
Zafirlukast (oral leukotriene receptor antagonist)Antagonist at CysLT1 receptor (Leukotriene receptors) in bronchiolar muscle -> BronchodilationAsthma
SalmeterolLong-acting B2 agonistAsthma
SalbutamolShort-acting B2-agonistAsthma

(Anticholinergic-muscarinic) … high tech..
Block M3 (Gq coupled - PLC) receptor which responds to PS, causing bronchoconstrictionAsthma

A bolus dose is when the drug is injected all at one shot into the vein. Drip is when the drug is connected to a tubing and allowed to flow slowly into the vein. Bolus furosemide (Na/K/2Cl- symporter antagonist) used in CHF to create immedate diuretic effect or glucose for a diabetic who is unresponsive from severe hypoglycemia.

cAMP -PDE (Phosphodiesterase)-> AMP (Asthma!) -> Bronchoconstriction
cAMP -> PKA -> PKA phosphorylates MLCK -> MLCK can’t phosphorylate myosin light chain in head-> Myosin head can’t form crossbridge with actin  -> Muscle can’t contract -> Bronchodilation

Theophylline (Xanthine)Increase cAMP in bronchial SM by inhibiting phosphodiesterase (hydrolyzes cAMP to AMP) -> Increased cAMP relaxes SM -> BronchodilationAsthma
tPa (Serine protease on endothelium)Tissue plasminogen activator (e.g. alteplase: Plasminogen -> Plasmin)PE, MI, Stroke
Fibrinolytic therapy: tPa, urokinase, streptokinase (basically plasminogen activators)

Atenolol B1 receptor antagonist

Methacholinenon-selective muscarinic receptor agonistdiagnose bronchial hyperreactivity

Cholesterol synthesis: Arteries may insist sucking cholesterol
  • 3x Acetyl CoA -(HMG CoA Reductase)-> Mevalonate -> Isoprene -> Squalene -> Cholesterol

2 functions
Thromboxane synthase inhibitor - lowers TXA2 levels and thus no platelet aggregation

Inhibit phosphodiesterase (hydrolyze cAMP and cGMP into AMP ) -> Increased cAMP -> Less calcium and paltelet aggreggation
Used with warfarin in prophylaxis against thrombosis in patients with prosthetic heart valve
Clopidogrel Irreversibly binds to p2y12 (ADP receptor) so no gp2b3a expressed -> no cross linking with fibrinogen

Simvastatin  (Statin)HMG coa reductase inhibitor (sfx - hepatotoxicity, myositis) and upregulate LDLR to increase uptake from systemic circulation

Rampipril ACE inhibitor

Methyldopaalpha2 (Gi!) -adrenergic agonist
Competitive inhibitor of DOPA decarboxylase that converts L-Dopa into dopamine thus... preventing dopamine into NE --> NE

stimualtes central inhibitory alpha-adrenergic receptors, leading to a reduction in sympathetic tone
Warfarin Inhibit vitamin K epoxide reductase -> inhibit carboxylation (activation) of platelets


COX-1 is protective.. so if it gets inhibited -> gastric ulcers

-anti-inflam therapeutic effect due mainly to inhibition of cox-2
Acetylates (irreversibly inhibiting) COX -> Less TXA2 (->PLC->Ca+) made -> less platelet aggregation

NSAID - COX inhibitor

Amlodipine - Dihydropyridine (L-type calcium channel blockers i.e. DHP receptor: End in -pine e.g. Amlodipine)Calcium ion channel blocker -> Prevent influx of calcium into VSM and Heart muscleHypertension

Tyrosine + Tyrosine hydroxylase  --> L-DOPA + dopa decarboxylase --> Dopamine + Dopamine hydroxylase --> NE → EP


ALPHA1 (Gq) (norepinephrine)= CONSTRICTION
BETA 2(epineprhine - epipen...) = DILATION  (Gs)

Vasodilation mechanisms
  1. cAMP-mediated: e.g. Prostacyclin, histamine, noradrenaline, prostagnaldin
    1. ↑Gs activity --> ↑AC activity --> ↑cAMP --> ↑PKA activity --> phosphorylation of MLCK --> ↓MLCK activity --> dephosphorylation of MLC
  2. cGMP (Nitrovasodilator) e.g. Nitric oxide
    1. ↑cGMP --> ↑PKG activity → phosphorylation of MLCK --> ↓MLCK activity --> dephosphorylation of MLC and ↑SERCA (--> ↓intracellular Ca)
  3. Hyperpolarization mediated (Calcium channel blocker)
    1. ↑ATP-sensitive K+ channel --> hyperpolarization --> close VDCC --> ↓intracellular Ca2+

Adrenaline reacts with both α- (constriction) and β-adrenoreceptors (dilation), causing vasoconstriction and vasodilation, respectively.

high levels of EP epinephrine-> alpha adrenoceptor -> vasoconstriction
low levels of EP -> b adrenoceptor -> vasodilation

In coronary vessels it is the opposite.
Transient vasoconstriction (alpha1) → vasodilation due to active hyperemia and b1-adrenoceptor

Vasoconstriction mechanisms
increased concentration of calcium (Ca2+ ions) within vascular smooth muscle cells (e.g. circulating epinephrine  and sympathetic release of NE - IP3 cacium release and calcium release from SR -> Ca x calmodulin -> MLCK activated

Aqueous flow: Produced by ciliary body (located behind iris) and controls lens shape -> Fills up posterior chamber (between iris and lens) and flows forward through pupil into anterior chamber and drains out the trabecular meshwork into canal of schlmem

Sphincter pupillae: Innervated by M4
Dilator pupillae: Innervated by alpha-1
symp is to dilate pupil (antimuscarinic e.g. tropicamide and sympathomimetic e.g. phenylephrine)
ps is to constrict
Tropicamide (m4 antagonist)Antagonist of M4 receptor (Block constrictor pupillae) thus allow mydriasis (pupil dilation)Shorrt half-life, thus, used for eye examination to see better insidesfx: Glaucoma
Phenyllephrine (ephrine...alpha1 adreno agonist) Alpha-1 agonist (-> dilator pupillae) -> Mydriasisused with tropicamide to dilate pupilGlaucoma

non-selective muscarinic agonist... two functions -
Nonselective muscarinic receptor agonist - cause ciliary muscle to contract, opening the trabecular meshwork for drainage through schlemm.

It also causes sphincter pupillae M4 to contract (miosis)
Phenoxybenzamine Irreversible alpha1 antagonist (by forming permanent covalent bond with adrenergic receptor) prevent catecholamine binding thus vasodilationpheochromocytoma

(hyperplasia of chromaffin cell!)

Atenolol B1 receptor antagonist

Nifedipine  (Dihydropyridine) Ca2+ channell blocker

CarbimazoleProdrug -> Methimazole

Inhibit thyroid peroxidase thus inhibit iodine uptake and coupling
Long-term steroid sfxCushings syndrome

Central Obesity + peripheral wasting
U - Unusual brUising
S - Straiae
H - Hypertension + Hyperglycemia
I - Impotence
N - Nothing
G - Growth retardation

Unit 4

Antimetabolite: masquerade as purine/pyrmidine thus preventing the actual substances incorporated during S phase
Methotrexate (meFO)Antimetabolite: Inhibit DHFR (S phase)Leukemia
Cyclophosphamide (pro...agent)Alkylating agent - attack guanineNon-hodgkins
Cisplastin (blast...)Alkylating agent - cross-link DNATesticular, ovarian cancer
DoxorubicinInhibit topoisomeraseHodgkin
6-MercaptopurinePurine antimetabolite (S phase) bioactivated by HGPR transferaseALL, immunosupression (azathioprine forms 6M-P)
Vincristine and vinblastineLessens microtubular polymerization (M phase)

Bleomycin (break...)Complex with Fe and oxygen to cause DNA scission (g2)Hodgkin’s
Procarbazine (pro..agent)Alkylating agentHodgkin
5-fluorouracilPyrimidine antimetabolite bioactivated to inhibit thymidylate synthetaseBreast ovarian cancer
Inflixmab (inflict...)Binds to TNFRA and Crohns


Overexpression of the HER2 protein by tumour cells has been found in 25 of women with breast cancer and is generally due to amplification of the HER2 gene. This phenomenon is also observed in other cancers.

Gene amplication (presence of more than 2 copies of a gene; normaly 2 genes in total from parents) of HER2 gene - codes for Human Epidermal growth factor Receptor 2, a protooncogene.

HER2 protein
- Increased risk of aggressive course of disease -> poor prognosis
- Respond less well to therapy
DexamethasoneGlucocorticoid (induce annexin/lipocortin -> inhibit PLA2), and expression of iKb

Trastuzumab (Herceptin)Binds to her2 receptor. No mitogen can bind -> no dimerization -> No tyrosine kinase (e.g. MAPK for angiogenesis, invasion etc.) - arrest G1, ADCC too!


CeftriaxoneCephalosporin: B-lactam antibiotic, less susceptible to penicillinase made by bacteriaMeningitis



Types of Necrosis (Fatty cheese (coagulate) -> Liquid)

  • Fat Necrosis: Caused by pancreatic enzymes or by trauma to fat
    • Lipase releases ffa -> combines with calcium to form soap (Calcium deposits)
  • Caseous (Cheese): A distinct form of coagulative necrosis seen in mycobacterial infections
  • Coagulative (cardiac..): Caused by ischemia (reversible if oxygen is restored; if continues, cytoplasm becomes eosinophilic and nuclei pyknotic [fragment]. Cell ghost; polys -> Granulation tissue)-> Less ATP
    • Less Na/K activity -> Na+ accumulate in cell -> Cell swell, mitochondria, ER swell
    • Less Na/Ca exchange -> More Ca2+ in cell -> Activate enzymes
    • Less ATP -> Anaerobic glycolysis -> Lactic acid -> Decrease pH
    • The archietecture is OK because lysosymes are denatured (HYPOXIC!!)
    • If dead, fibrosis... (e.g. MI!)
  • Liquefactive: Bacterial infections -> PMN (polymorphonuclear neutrophil) > Dissolve nearbly tissue → Liquify and pus  (e.g. abscess, brain ischemia, pneumonia)

Nomenclature for cancer

Epithelial (think basal cell....papillary)
- Benign: Adenoma (glandular) or other cell type + papilloma (e.g. squamous cell papilloma)
- Malignant: + Carcinoma

Connective Tissue (think lipo..)
- Benign: Fibroma (just add +oma)
- Malignant: + Sarcoma


Skeletal muscle
Squamous cell papilloma
Transitional cell papilloma
Basal cell papilloma
Adenoma (e.g. breast adenoma)

Rhabdomyoma (sounds cooler...)
Benign Mesothelioma
Squamous cell carcinoma
Transitional cell carcinoma
Basal cell carcinoma
Adenocarcinoma (e.g. adenocarcinoma of breast)

Malignant mesothelioma
*Synovial sarcoma

Nomenclature exceptions
* Benign mesothelioma or malignant mesothelioma
* Synovioma or synovial sarcoma

Benign (-oma only)
- Of epithelial origin: From ectoderm or endoderm (e.g. adenomatous polyps: from colon glands - endoderm)
- Of CT connective tissue origin: From mesoderm (e.g. lipoma from adipose tissue)

Tumors that tend to be benign
- Teratoma: Encapsulated mass (-> benign), containing all 3 germ layers (e.g. mesoderm - cartilage, ectoderm -epidermis, endoderm - endoderm)
- Reproductive system (ovary, testes); though in men: tend to be malignant
- Pineal gland
- Mediastinum


- Of epithelial origin (squamous, glandular, transitional, basal): CARCINOMA
- e.g. Squamous: Squamous cell carcinoma of cervix
- e.g. Glandular: Adenocarcinoma of lung
- e.g. Transitional: Transitional cell carcinoma of ureter
- e.g. Basal: Basal cell carcinoma (skin)
- Of CT origin: SARCOMA
- e.g. Osteosarcoma - bone

Hamartoma (similar to teratoma - contain mixture of tissues)
- NON-neoplastic (stops growing when becomes an adult)
-  e.g. Bronchial hamartoma: cartilage, SM, bronchial epithelium

Staging - Severity - Better measure of PROGNOSIS than grading
  • TNM staging: Tumor size (esp. if >2cm), nodal involvement, metastasis
  • T ((0),1-4): size or direct extent of the primary tumour
  • N (0-3): spread to regional lymph nodes
  • M (0/1): distant metastasis
  • G (1-4): grade of cancer cells ("low grade" if similar to normal, “high grade” if poorly differentiated)
  • R (0/1/2): the completeness of the operation (resection-boundaries free of cancer cells or not)
  • Small, low grade cancer, no metastasis, no spread to regional lymph nodes, cancer completely removed, resection material seen by pathologist - pT1 pN0 M0 R0 G1; this grouping of T, N, and M would be considered Stage I
  • Large, high grade cancer, with spread to regional lymph nodes and other organs, not completely removed, seen by pathologist - pT4 pN2 M1 R1 G3; this grouping of T, N, and M would be considered Stage IV

RAS activates a number of pathways but an especially important one seems to be the mitogen-activated protein (MAP) kinases, which themselves transmit signals downstream to other protein kinases and gene regulatory proteins.[2] Constitutively active Ras (RasD) is one which contains mutations that prevent GTP hydrolysis, thus locking Ras in a permanently 'On' state.

  • Grading - Histology (remember low, high grade): Looking @ DEGREE OF DIFFERENTIATION, invasivness, nuclear features (e.g. N:C ratio, nucleolus)
  • Duke’s grading: A (confined to wall: good prognosis), B, C (lymph node metastasis: poor prognosis)

Normal -> Hyperplasia + Dysplasia -> Carcinoma in situ (preinvasive) -> Invasive carcinoma (BM broken by collagenase)

Carcinoma in situ
- Shows all features of malignancy (e.g. high N:C ratio.. see above), BUT
- Not invasive yet!

Hyperplasia is NOT neoplasia
  • Hyperplasia still has cell control
  • Neoplasia: Lose brakes for cell control

Can be divided into quadrants
Lateral: UOQ (Upper outer quadrant) Medial: UIQ

Breast cancer
1. Freq. of distribution: UOQ -> Nipple -> Others.
2. Risk factors
- + Age
- Genetics
- Esp. if first generation
- Autosomal dominant BRCA 1&2 mutation: DNA mismatch repair genes (MSH and ?)
- Li Fraumeni Syndrome: Inactivated TP53 gene
- Amplified HER2 gene -> + gene product of HER2 receptor tyrosine kinase receptor
- Smoking
- Prolonged estrogen exposure: e.g. HRT, early menarche and late menopause

3. Factors decreasing risk
- Breast feed: Lowers estrogen
- Exercise/weight reduction: Same as lowering estrogen?

4. Findings in breast cancer
- Painless lump
- Retracted nipple
- If metastasis: BONE pain (2bs, 2ls), hepatomegaly

5. Mammography
- Screening: ANNUALLY at age 40; earlier if high risk
- Does not tell whether benign or malignant but can tell MICROCALCIFICATION (malignant calcification? necrosis i.e. low grade malignancy?)

6. Staging
- Sentinal node biopsy
- Sampling of node that drains tumor (If -’ve, usually other nodes also negative)

Axillary lymph node levels (in relation to pec minor!)
I: Lateral border of pec minor
II: Beneath pec minor
III: Medial to pec minor

7. Treatment
- Surgery: Mastectomy (complication: dmg lateral thoracic nerve - serratus anterior - winged scapula)

Lung cancer

10% Small cell lung carcinoma (SCLC): Not as common as N-SCLC
darkly staining cells with prominent nuclei and little cytoplasm
Highly related to smoking
Highly malignant cancer
undifferentiated neoplasm
Responsive to chemo

90% Non-small-cell lung carcinoma (NSCLC): The more common one!

Any type of lung cancer other than small cell lung carcinoma
squamous cell carcinoma, large cell carcinoma, adenocarcinoma
If lung cancer in non-smoker, almost always NSCLC-adenocarcinoma
Not as responsive to chemotherapy

Lung adenocarcinoma
most common type of lung cancer in non-smokers
often seen peripherally in the lungs

Squamous cell carcinoma

Closely related to smoking
often seen centrally in the lungs (e.g. bronchi)
Malignant cells derived from epithelium (contain keratin, desmosomes etc.)
most common cancer
begins as a small nodule → metaplasia/dysplasia → carcinoma in situ → enlarges with center becoming necrotic (forming cavitation) and nodule turning to ulcer

If the tumour grows too large for its blood supply then the central areas can become deprived of oxygen and nutrients and will undergo necrosis, they die.

Squamous-cell carcinoma in situ identified via sputum cyto/BAL/bronchoscopy biopsy
arises centrally in bronchi then metastasize to nearby lymph nodes (e.g. hilar). Asymptomatic until mass obstructs lumen of major bronchus → atelectasis and infection

lung: ectopic production of parathyroid hormone-related protein (PTHrP) → hypercalcemia (PARANEOPLASTIC PHENOMENON)

PTHrP ParaThyroid Hormone related Protein: Same N-terminal as PTH → binds to PTH receptor
  • increased bone resorption
  • increased calcium reabsorption
  • inhibit phosphate reabsorption

Paraneoplastic syndrome
  • Consequence of cancer in body
    • Cancer cells release hormone/cytokine
    • Cancer cells initiate immune response

Large cell carcinoma
often seen centrally in the lungs (e.g. bronchi)
larger size of the anaplastic cells, a higher cytoplasmic-to-nuclear size ratio, and a lack of "salt-and-pepper" chromatin.

undifferentiated malignant neoplasms originating from transformed epithelial cells in the lung.

Combined SCLC squamous cell lung cancer = SCLC (small-cell) + NSCLC (non-small cell lung cancer)