Heme/onc

Front 1

one word for each phase of hemostasis

Back 1

primary - platelets
secondary - fibrin
tertiary - plasmin

Front 2

primary screening test for platelet function

if abnormal...

Back 2

bleeding time

everyone with thrombocytopenia will have long bleedings times

next step: platelet aggregation studies with ADP, epinephrine, collagen, ristocetin as agonists

Front 3

dense granules in platelets contain

Back 3

calcium, serotonin, other small molecule mediators of platelet function

Front 4

alpha granules in platelets contain

Back 4

protein mediators of platelet function

(fibrinectin, platelet factor 5, thrombospondin, vWF)

Front 5

can have prolonged bleeding times (platelet function test) due to

Back 5

congenital
drugs
alcohol
uremia
hyperglobulinemias
fibrin/fibrinogen split products
thrombocythemia
cardiac surgery

Front 6

a congenital platelet adhesion disorder

inheritance
problem
test

Back 6

Bernard Soulier disease

AR
abnormal GPIb-IX complex (receptor on platelets for vWF) so the monolayer of platelets doesn't form

test: ability to aggregate platelets in presence of ristocetin

Front 7

delta-storage pool disease

Back 7

normal platelet adhesion, but you don't release dense granules (ADP, serotonin, calcium) on activation to aggregate more platelets

--> MILD bleeding disorder

Front 8

Gray platelet syndrome

Back 8

alpha granules are leaky, so you don't get release of protein mediators of platelet aggregation (thrombospondin, vWF, fibronectin, etc)

--> MILD bleeding disorder

Front 9

problems with platelet aggregation that lead to mild bleeding disorder

Back 9

delta-storage pool disease
Gray platelet syndrome

Front 10

Glanzmann's thrombasthenia

inheritance

consequence

Back 10

lack of GP IIb/IIIa (fibrinogen receptor) on platelets...platelets cannot aggregate in response to usual stimuli

AR

SEVERE bleeding

Front 11

Scott syndrome

Back 11

loss of shufflase enzyme that flips PM inside out...so the acidic phosphilipid that form receptors for Factor 5a and 8a aren't produced...can't localize the clotting cascade to right place

Front 12

drug induced platelet function defects cause by

Back 12

alcohol
prostaglandin synthetase inhibitors (aspirin, NSAIDs, phenylbutzone)
ADP receptor inhibitors clopidogrel, ticlopidine, prasugrel)

Front 13

causes of decreased platelet production

tx?

Back 13

leukemia**
aplastic anemia
metastatic carcinoma
drugs
radiotherapy
primary marrow disorders

--> decreased megakaryotes, but life span of the platelets is normal

tx: good response to transfusion

Front 14

causes of increased destruction of platelets

Back 14

immune mediated:
ITP
lymphoma
lupus
drugs

note: platelet life span 12-24 hrs instead of 7-10 days; often see increased megakaryocytes and macroplatelets
*poor response to transfusion

consumption:
DIC
TTP
HUS

septicemia

Front 15

ITP pathogenesis

Back 15

IgG autoantibodies opsonize platelets for removal by macrophages

no good dx test...it's a dx of exclusion

Front 16

ITP tx

Back 16

steroids - first line
splenectomy - second line

Front 17

HIV-associated thrombocytopenia:
pathogenesis
tx

Back 17

early HIV: immune complexes sit on platelet and get destroyed in innocent bystander reaction
late HIV: marrow infiltration by fungus/TB/mycobacteria and pancytopenia

ART, esp. AZT

Front 18

if more than one clotting factor is abnormal, get a

Back 18

inhibitor screen

Front 19

how are clotting tests prepared

Back 19

blood collected in sodium citrate, a weak calcium chelator; amount designed to drop calcium to a level where spontaneous clot will not occur

RBCs and platelets centrifuged off, leaving plasma

PT: 50% patient plasma, 25% TF and phospholipid species, 25% calcium chloride (to activate clotting process) --> time to clot measured (10-14 s normal)

aPTT: 50% patient plasma, 25% phospholipid and surface active agent, 25% calcium chloride --> time to clot measured (normally 25-35)

Front 20

clotting factor deficiency tests done only

how is it done

Back 20

if aPTT or PT abnormal

50% patient plasma with 50% plasma deficient in a single clotting protein

Front 21

PT abnormal implicates factors

Back 21

2, 5, 7, or 10

Front 22

aPTT abnormal implicates factors

Back 22

12, 11, 9, 8 abnormal

Front 23

von Willebrand disease

prevalence

inheritance

Back 23

lack of vWF --> decreased factor VIII activity, defect in platelet adhesion;
most common congenital bleeding disorder; variable severity, even within one family; mild bleeding

0.8-2%

AD

Front 24

vWF made in

stored in

secretion

Back 24

endothelial cells and megakaryocytes

multimers stored in Weibel-Palade bodies in endothelial cells

constitutive and stimulated secretion

Front 25

vWF will have a prolonged ___

Back 25

aPTT (b/c of low Factor VIII activity)

also low ristocetin cofactor activity, increased bleeding time

but 20% of the time all of these will be normal in heterozygotes, so you have to test multiple times

Front 26

types of vW disease

Back 26

Type I: most common; quantitative defect; defect due to non-sense mutation; 50% normal levels

Type II: qualitative defect
IIa - no multimer formation (normal levels of factor VIII but adhesion defect)
IIb - decreased multimers, decreased platelets
IIc - hundred of defects in multimerization
IIn - defect in factor VIII binding - looks a lot like hemophilia

Type III: severe quantitative defect (double heterozygotes or homozygotes) - usually lack factor VIII and platelet adhesion properties

Front 27

Hemophilia __ is more common

tx:

Back 27

A (85%)

A = Factor 8
B = Factor 9
(clinically indistinguishable except by factor analysis)

tx: lethal without replacement therapy

incidence hasn't changed over time, so many mutations are new

Front 28

strata of hemophilia severity

Back 28

mild: >5% factor - bleeding with significant trauma

moderate: 1-5% factor - bleeding with mild trauma, occaional spontaneous hemarthroses

severe: <1% factor level - spontaneous hemarthroses and soft tissue bleeding

**within each kindred, similar severity in disease (unlike vWF)
**thousands of different mutations

Front 29

vWF are __ in hemophiliacs

Back 29

normal

if you add hemophiliac's blood to vWD patient, factor VIII levels go up b/c the vWF stabilizes what VIII they are making

Front 30

in hemophilia A, bleeding time is __, aPTT is ___

Back 30

normal (initially, but then plug breaks and they rebleed)

prolonged

Front 31

in vW disease, bleeding time is ___ and aPTT is ___

Back 31

prolonged

prolonged

Front 32

Factor XI deficiency

tx:

Back 32

Hemophilia C aka Jewish hemophilia

90% ashkenazi

mild bleeding (usually with procedures); #1 cause of lawsuits

AR

tx: fresh frozen plasma good for one week

Front 33

causes of acquired clotting disorders

Back 33

Vitamin K deficiency
liver disease
DIC
coumadin
heparin

Front 34

Vitamin K deficiency bleeding almost always seen in __ because ___

lab abnormality

tx

Back 34

hospital patients

need malnutrition and reduced gut flora

PT prolonged first due to factor VII's short half-life

tx: replace Vitamin K (response in 1-2 days)

Front 35

liver disease and abnormal hemostasis

tx:

Back 35

decr. synthesis of vitamin K dependent proteins

decr. clearance of activated proteins

incr. fibrinolysis secondary to decr. antiplasmin

dysfibrinogenemia secondary to synthesis of abnormal fibrinogen

increased fibrin split product

increased PT, aPTT
decreased platelets (hypersplenism)

Tx: replacement only if they are having a procedure or an active problem

Front 36

Tissue Factor Pathway Inhibitor (TFPI) complexes with ___

function:

Back 36

7a/10a/TF

inactivates 10a

Front 37

antithrombin III is a classic serine protease inhibitor; it inactivates ___

this is normally a very slow reaction, but it's sped up by ___

Back 37

9a, 10a, 11a, thrombin

heparin (which floats away and continues working after the reaction, as a true catalyst)

Front 38

in addition to leading to fibrin formation/inactivating 5a and 8a/activating platelets, thrombin but it also binds to ___ on the surface of ___

this activates ___

Back 38

thrombomodulin

endothelial cells

protein C

Front 39

Protein S function

Back 39

cofactor for Protein C...together they inactivate Va and VIIIa

Front 40

though you usually need <10% of clotting factor to start having clinical problems, deficiencies of <__% of ATIII, Protein C, Protein S, thrombomodulin, plasminogen can

heterozygous protein deficiency -->

homozygous protein deficiency -->

Back 40

50

increased venous thrombosis, occasional increased arterial thrombosis

neonatal purpura fulminans, fibrinogenolysis, chronic DIC (most don't survive first year of life; luckily it's rare)

Front 41

dominant phenotype of anticoagulant protein deficiency

Back 41

increased venous thrombosis
young age of thrombosis
no predisposing factors
increased thrombin generation in all patients
positive family history

Front 42

recessive phenotype of anticoagulant protein deficiency

Back 42

no family history
neonatal purpura fulminans in offspring
increased thrombin generation (similar to that seen in dominant)

Front 43

why is it that the same mutation in anticoagulant protein can cause a dominant phenotype in one person and recessive in another

Back 43

Activated Protein C resistance

failure of activated Protein C to prolong aPTT

98% of the time it's due to Factor V Leiden mutation

Front 44

Factor VIIIa is inactivated by ...

Back 44

APC
Protein S
Factor V ******
phospholipid

thus, Factor V Leiden deficiency leads to problems inactivating factor VIII as well

Front 45

acquired hypercoagulable states

Back 45

1. inflammatory diseases
2. nephrotic syndrome
3. anticardiolipin antibody syndrome
4. malignancy
5. immobilization
6. TTP
7. DIC
8. OCT
9. prosthetic valves
10. PNH
11. myeloproliferative diseases
12. atherosclerosis
13. surgery
14. diabetes mellitus

Front 46

Factor V Leiden mutation

Back 46

Arg 506 --> Gln

(this is at a cleavage site, so activated Protein C can't inactivate 5a properly)

found in >98% of patients with activated protein C resistance

5-20% of caucasians are carriers

increases risk of venous thromboembolism....4x in heterozygotes, 10x in homozygotes

in combination with other deficiencies (protein C, protein S, ATIII, plasminogen) has a synergistic effect

so in 50% of patients with dominant phenotype, they have both a mutation in the protein and a factor V Leiden mutation

Front 47

Prothrombin G20210 --> A mutations leads to

Back 47

increased prothrombin production, higher risk of thrombosis during pregnancy or venous thromboembolic disease

1-3% of Northern European population

Front 48

one of the most potent prothrombotic disorders

Back 48

anticardiolipin antibody syndrome (lupus anticoagulant)

Front 49

why is inflammatory disease a hypercoagulable state?

Back 49

increased C4b binding protein binds Protein S and removes it as a cofactor for Protein C

increased IL-1 and TNF downregulate thrombomodulin (via endocytosis and decreased transcription) so that thrombin becomes procoagulant

Front 50

in nephrotic syndrome, ___ proteins are lost, but ___ is big enough to not get through

Back 50

Protein C, protein S, ATIII

C4b (which binds any remaining protein S)

thus, nephrotic syndrome (and protein-losing enteropathy) are pro-thrombotic states!

Front 51

someone with anticardiolipin antibody may have

Back 51

lupus (only 30% of the time)

false + RPR (measures antiphospholipid antibodies)

spontaneous abortions

bleeding in vitro, thrombosis in vivo (try using different phospholipid source in vitro, e.g. platelets)
-true antigen is source of controversy
-no good assay to test...it's a clinical diagnosis

Front 52

dx of anticardiolipid antibody syndrome

Back 52

at least 2 abnormal tests more than 12 weeks apart
+ clinical syndrome of either:

3 1st trimester abortion, 1 2nd/3rd trimester abortion, or unexplained venous/arterial thrombotic event

Front 53

causes of subacute/chronic DIC

Back 53

acute leukemia
carcinomas (probably release of TF from tumor)
hemangiomata
aortic aneurysm
?liver disease

Front 54

plasmin activation

Back 54

12a --> kallikrein --> plasmin

urokinase --> plasmin

tPA --> plasmin

Front 55

vitamin K dependent co-factors

Back 55

2, 7, 9, 10
protein C and S

Front 56

Fibrinogen split products (elevated in ___) include___

besides freeing up the lumen, they also

Back 56

DIC

Fragment X (big core, largely insoluble)
Fragment D (<50% of end, soluble)
Fragment Y (>50% of end, soluble)
Fragment E (disulfide knot, soluble)

inhibit further fibrin polymerization

Front 57

defibrination mechanisms

Back 57

release of tissue procoagulants:
-tumor
-fetus/placenta
-prostatic cancer
-pancreatic cancer
-WBC
-RBC
-shock

damage to vascular tree:
-septicemia
-aortic aneurysm
-hemangioma
-tumor emboli

decreased clearance
-liver disease

brain tissue is very high in TF

Front 58

lab values in acute DIC

1. PT
2. aPTT
3. fibrinogen
4. thrombin time
5. factor levels
6. platelet count
7. RBC fragmentation
8. fibrin split products

Back 58

labs

1. slightly to grossly prolonged
2. usually prolonged
3. usually low (consumption)
4. usually prolonged (b/c fibrinogen is low)
5. variable
6. usually low (platelets consumed in clots)
7. sometimes present (fibrin strands clothesline them)
8. usually present (D-dimer assay measures cross-linked fragment D)

Front 59

DIC therapy

Back 59

depends on primary manifestation
1. thrombosis --> anticoagulant therapy
2. bleed --> replacement therapy
--cryoprecipitate (give fibrinogen)
--fresh frozen plasma (gives other factors)
--platelets

TREAT UNDERLYING DISEASE WHEN POSSIBLE (DIC will almost always go away if you can...of course something like pancreatic cancer will be hard to treat)

heparin is rarely indicated, unless the underlying disease requires you to shut off the thrombotic process

Front 60

lupus anticoagulant is a bad name for __ because ___

Back 60

anticardiolipin antibody

only 30% have lupus, and it's not associated with bleeding except in rare cases...mostly associated with arterial or venous thrombosis (mechanism unknown)

Front 61

cause of acute DIC

Back 61

shock
sepsis (esp. Gram negative)
allergic reactions
mismatched transfusion
obstetrical problems (*always DIC until misproven*)
trauma
burns
extracorporeal circulation
acidosis
purpura fulminans

Front 62

generally, subacute DIC --> __; tx with ___

acute DIC --> __ because ___;

Back 62

clotting problems (DVT, PE, arterial)
anticoagulants

bleeding
DIC leads to consumptive coagulopathy...when you rev up the system to this extent by damage or exposure to large amounts of endotoxin, you cause thrombotic problems but you also consume your clotting factors in the process

Front 63

in acute DIC you see decreases in both

Back 63

coagulants and anticoagulants

(severity may relate to levels of anticoagulants)

Front 64

the first mutation in most men with prostate cancer

others that may occur subsequently

Back 64

GSTP1 (protects against oxidative damage) - normal part of aging for men, and a clear player in almost every case

RNASEL, MSR1 (germline mutations)

Front 65

the mutation that marks the transition from normal prostate epithelium to prostatic intraepithelial neoplasia

Back 65

decrease in NKX3.1 (tumor suppressor)

--> predisposes to DNA damage and increases cell survival

Front 66

mutation present in 60% of prostate cancer, marking transition from PIN to localized prostate cancer (invasive cancer)

transition from localized to metastatic?

Back 66

ETS translocation (AR-dependent), P27

PTEN, P53, RB, MYC

Front 67

single clear driver of castration-resistant cancer

Back 67

mutation in AR gene

Front 68

between the ages of 50 and 75, risk of prostate cancer increases __ fold

Back 68

7

(colon cancer only 4 fold)

Front 69

who has most prostate cancer?

Back 69

blacks (earlier and steeper slope for incidence and mortality)

Front 70

risk factors for prostate cancer

Back 70

clearly a disease of aging

also, western diet --> earlier onset, higher risk

Front 71

incidence of prostate cancer has been going ___

mortality has been going __, and this is due to ___

Back 71

up (and a bump is due to PSA screening)

down

something, but NOT screening

Front 72

PSA is a

why is it an imperfect test?

Back 72

serine protease that liquifies seminal coagulum

there is an age-dependent leakage of PSA, and can also see increases in BPH and prostatitis

Front 73

PSA is a good indicator of

Back 73

cancer recurrence post-tx

Front 74

refinements in PSA test

Back 74

PSA density (amt. in blood, size of prostate via ultrasound)

free vs bound PSA

PSA velocity (how fast it rises - this is completely useless in an undiagnosed male, but in a dx man, rapid rise is worse)

Front 75

for prostate cancer, 10-yr survival with:
organ confined disease___
regional extension ___
distant metastases ___

Back 75

69%
38.5%
15%

Front 76

screening has picked up significant prostate cancer, but has not significantly improved cause-specific death at __

Back 76

10 years out

(European study has shown benefit 13 years out for 50-59 and 65-69 y.o.)

Front 77

most powerful prognostic index for newly diagnosed prostate cancer

Back 77

Gleason score

a 1cm prostate cancer can be incredibly diverse in severity

Front 78

Gleason grade of 1 =

5 =

Back 78

well formed, well circumscribed glands with nice nuclei

almost no glandular architecture, palisading, pleiomorphic nuclei, cells that invade the stroma

not until you get to the higher grades that prostate cancer has <50% impact on mortality

Front 79

whether we should even tx Gleason grade __ is still a major question

Back 79

6

Front 80

in prostate cancer (and in normal aging), you have multiple loci that are microscopically malignant, but

Back 80

usually only one clone is the bad one
-there is therefore sampling error in the biopsy

if a 90-yr-old male dies of other causes, he has a 90% chance of having cancer in the prostate

Front 81

prostate cancer staging:
T1a =
T1b =
T1c =

T2a =
T2b =
T2c =

T3, T4

N0, N1

M0
M1a
M1b
M1c

Back 81

T1's are incidental histology findings
T1a = <5% of tissue
T1b = >5% of tissue
T1c = PSA detection (70-75% of diagnosis these days)

T2 is abnormal rectal exam
T2a = <half lobe
T2b = >half lobe
T2c = both lobes

T3, T4 = invasive local disease (firmness in seminal vesicles would indicate T3 disease)

N0, N1 = +/- regional nodes

M1a = distant mets
M1b = bone mets

Front 82

if you feel a nodule on rectal exam, it has a __% chance of being malignant

Back 82

50%

Front 83

treatment of primary prostate cancer, locally invasive

Back 83

Watchful waiting
Radical prostatectomy (highest rate in low-grade cancer)
External beam radiation (highest in high-grade cancer...becoming less popular)
Radiation seed implantation (Brachy...becoming more popular)

Front 84

in prostate cancer, increased __ rates result from lead time bias

Back 84

survival

Front 85

a neurovascular bundle runs ___ to the prostate and supplies the ___

Back 85

posterior

erectile mechanism

Front 86

men undergoing radical prostatectomy have 30 year survival that matches the general population; is that because the surgery is really good or because it didn't make a difference

Back 86

we don't know

one european study showed that watchful waiting was worse that prostatectomy, but that was in symptomatic patients, not screen-detected patients; the surgery was especially beneficial in those <65, but no difference for >65

Front 87

confined prostate cancer > __ > __ > __

Back 87

extracapsular extension > seminal vesicle invasion > LN+

Front 88

estimate that __% of screen-detected cancers are unnecessarily found

Back 88

47

Front 89

after prostatectomy, get PSA every

cancer recurrence if

salvage radiotherapy...

Back 89

6 months

2 consecutive rises

can be done but it markedly increases incontinence and GUARANTEES impotence

Front 90

urinary incompetence post prostatectomy is more common in

Back 90

1. older pts
2. comorbidity
3. less prolific centers (slightly)

Front 91

all radiation for prostate cancer is given with a small margin, so you get some

Back 91

bladder, rectum, proximal urethra, seminal vesicles

Front 92

what is IMRT

Back 92

intensity modulated radiation therapy

(a strategies to improve the risk benefit ratio...if MR can identify regions of more cancer, IMRT can tailor the dose accordingly)

Front 93

advantage of brachytherapy over external beam radiation in prostate cancer

problems?

Back 93

external beam is 6-8 wks, half hour every day

brachy is a 1 time implantation

proctatitis, obstruction, works in a small gland, but not done in a large gland

not shown to be any more effective than external beam

Front 94

major complication of radical prostatectomy?

radiation therapy?

Back 94

urinary strictures (17%)

radiation proctitis (18%)

Front 95

in terms of physical composite score, there is a long-term cost to ___therapy

Back 95

brachy

Front 96

worst prostate cancer tx in terms of incontinence

all have a pretty bad effect on erectile function, but __ is the worst

Back 96

RP (10% vs 4%)

RP (79.6% vs 61.5%)

Front 97

tx of locally advanced prostate cancer

Back 97

GnRH agonist (leuprolide, goserelin) + radiation
orchiectomy
finasteride (propecia...doesn't work)
adrenal blockade (ketoconazole)
antiandrogens (bicalutamide, flutamide)

Front 98

when you give a GnRH agonist, there is a

Back 98

brief spike in testosterone, then the pituitary production of LH shuts off, then you have chemical castration

these are injections that you have to keep getting

Front 99

__% of circulating androgens come from the adrenal gland

Back 99

10%

Front 100

__ is responsible for male pattern baldness

Back 100

5HT (a prostate-specific androgen)

Front 101

finasteride works for __ but not __

Back 101

BPH, baldness

prosate cancer

Front 102

can you make more people candidates for prostatectomy by shrinking it with hormonal therapies?

Back 102

no

Front 103

greatest advance in tx of prostate cancer

Back 103

addition of hormonal therapy to simultaneous radiation therapy for locally advanced disease

makes a huge difference! on any parameter

Front 104

90% of the time, prostate cancer metastasizes to the __ first

Back 104

bone

Front 105

tx of metastatic prostate cancer

mean disease-free survival is

Back 105

hormonal therapy (it's hormone sensitivity is retained for some period of time...study shows big benefit of early androgen ablation)

2-2.5 years

Front 106

morbidity of androgen ablation

Back 106

osteoporosis and fractures
fatigue
diabetes
cardiovascular risk

Front 107

the hormone therapy used in metastatic disease

second-line hormonal therapy

management of mets

Back 107

anti-androgen + GnRH agonist
(it's worth it)

-anti-androgen withdrawal (in case it's agonistic
-ketoconazole (adrenal blockade)
-adrenal blockade with steroids, aminoglutethimide

-prophylactic radiation in weight-bearing bones
-pain management (narcotics, NSAIDs, radioactive nuclides that are calcium analogs)
-second line hormonal therapy
-chemotherapy - last line...doesn't really help except maybe docetaxel)

Front 108

androgen ablation is beneficial to __ prostate cancer but harmful for ___

Back 108

poorly differentiated

moderately differentiated

Front 109

in metastatic prostate cancer, androgen ablation should not be discontinued, even after

Back 109

progression on a GnRH agonist

(there is a component of the tumor that clearly benefits from that therapy b/c prostate cancer will always, until death, depend on androgen receptor activity)

Front 110

androgen receptor has these domains

Back 110

DNA binding (Zn fingers)
steroid binding
transcription regulation

assembly of transcriptional complexes in front of genes that have androgen response elements

Front 111

castration resistant prostate cancer is characterized by

Back 111

1. AR gene amplification (ligand independence)
2. AR mutations (tunr anti-androgens into androgens)
3. AR phosphorylation (allows activation)
4. AR coactivator over expression
5. incr. expression fo androgen synthetic enzymes
6. alternate splicing to generate ligand independence

tells us that prostate cancer is always dependent on AR

Front 112

what waste does the blood remove

Back 112

CO2
nitrogenous waste
cellular toxins

Front 113

normal RBC volume

diameter

thickness

Back 113

80-100 femtoliters

8 microns (about the size of lymphocyte nucleus)

2 microns

Front 114

automated counters measure __ using ___

Back 114

size, number

impedance

Front 115

*anisocytosis =

Back 115

variable size of RBCs

Front 116

term for variable sizes of RBCs

Back 116

anisocytosis

Front 117

*poikilocytosis =

Back 117

variability in the shape of RBCs

Front 118

variability in shape of RBCs

Back 118

poikilocytosis

Front 119

smaller RBCs are thinner and therefore look __ colorful

Back 119

less

Front 120

normal hemoglobin ranges

Back 120

female: 12-16

male: 13.5-17.5

(androgens tend to stimulate hemoglobin production)

Front 121

red cell counts and __ levels are often related to each other

Back 121

hemoglobin

Front 122

normal reticulocyte count

Back 122

0.2-2.0%

(retics are the 1st day of a red cell's life)

Front 123

normal platelet count

Back 123

150,000-400,000

Front 124

*definition of anemia

Back 124

decrease in the number of circulating red blood cells

(most common hematologic disorder by far...more common than all of the others put together...for the most part it's a secondary disorder...usually not a problem with their blood cells)

Front 125

*most common hematologic disorder

Back 125

anemia

(by far)

Front 126

*causes of anemia

Back 126

1. blood loss
2. decreased RBC production (marrow failure)
3. increased RBC destruction (hemolysis)

Front 127

how can you distinguish between hemolytic anemia and marrow failure

Back 127

reticulocyte count
(decreased in marrow failure, increased in hemolysis)

Front 128

*single most important marker of RBC production

Back 128

retic count

(absolute value more accurate than percentage)

Front 129

reticulocytes still have small amounts of __ present in them

tend to stain somewhat __er

slightly smaller/larger?

can be detected using

Back 129

RNA (undergo removal of RNA on passing through spleen in 1st day of life)

blue

larger

supravital stain which stains the RNA directly

Front 130

*how to calculate the absolute value of reticulocytes

Back 130

retic % x RBC count

*more accurate way to assess body's response to anemia, rather than percentage
normal up to 100,000/ microleter

Front 131

*if the anemia is a marrow failure due to cytoplasmic protein production problem, the anemia is usually __cytic

if a problem in nuclear division/maturation, it's usually __cytic

Back 131

normo or micro

macro

Front 132

anemia due to cytoplasmic protein production problems...name the types of disorders

Back 132

disorders of globin synthesis
disorders of heme synthesis

Front 133

causes of disorder in heme synthesis

Back 133

1. decreased iron (if you don't have iron, in a utilizable form, you can't make RBCs)

2. iron not in utilizable form (anemia of chronic disease...iron can't get into the cells that produce RBCs)

Front 134

most common cause of anemia

2nd most

Back 134

anemia of chronic disease

iron deficiency

Front 135

active form of iron

in __ conditions it's easy to maintain this state

Back 135

Fe2+ (ferrous)

Fe3+ (ferric) cannot trasnport electrons or bind O2

anaerobic (but iron donates electrons readily to oxygen --> ROS)...green plants wiped out 95% of species and the ones that survive were the ones that could limit their exposure to iron

Front 136

*iron compartments:

hemoglobin iron __%
storage iron (ferritin, hemosiderin) __%
myoglobin rion (critical for muscle metabolism) __%
labile pool and other tissue iron (important for electron transport and cytochrome sstem) __%
transport iron __%

Back 136

Hb 67%
storage 27%
myoglobin 3.5%
labile/other tissue 2.5%
transport 0.08%

Front 137

*senescent RBCs are eaten by macrophages in reticuloendothelial system, and the iron can either be:

Back 137

1. bound to ferritin (IC storage)
2. bind transport molecule, go across membrane, bind transferrin in circulation (very tightly); transferrin transports iron back to bone marrow to RBC precursor where it binds to a specific transferrin receptor; complex is internalized, iron is released and incorporated into heme, heme into hemoglobin

the transferrin + receptor is taken back to membrane and transferrin released back into circulation

Front 138

how is iron released from transferrin intracellularly

Back 138

vacuole fuses with lysosome, acidified, which releases iron from lysosome into cytoplasm

Front 139

most comon cause of anemia in men and post-menopausal women

Back 139

GI bleed

Front 140

*causes of iron deficiency anemia

Back 140

GI bleed
menstrual blood loss

pregnancy
infancy (rapid growth rate)
adolescence (rapid growth rate)
polycythemia vera (increased production of red cells)

tropical sprue (malabsorption)
gastrectomy or bariatric surgery (absorption of iron requires an acid environment)
chronic atrophic gastritis (loss of parietal cells and acid production)

diertary inadequacy (rarely sole cause)

Front 141

__ of iron in diet is soluble; __ of that actually gets taken up into intestinal cells; about __ of that is absorbed into system

Back 141

1/2

1/2

1/4

Front 142

how does iron get from lumen into GI cells? via __

how does iron get from intestinal cells to blood stream? via __

Back 142

DMT-1

ferroportin

Front 143

*__ measures the amount of iron present in the crypt cells and either stimulates production of more __ which leads to increased iron absorption or down-regulates production of those while up-regulating ___

Back 143

HFE

DMT-1, ferroportin

ferritin (which leads to iron being bound in GI cell, which then gets sloughed into the lumen of the intestines)

Front 144

iron production is regulated at the _NA level

Back 144

RNA

(based on iron binding to an iron regulatory protein)

the IRP, in a low iron state with 3 irons attached, binds the stem loop of ferritin so that translation cannot occur or binds the stem loops of transferrin and DMT-1 such that it stabilizes those mRNAs

in a high iron state, 4 Fe's are attached to IRP and it can't bind the loops

Front 145

can't be iron deficient until your __ is used up

Back 145

storage pool

Front 146

*progression of findings in iron deficiency anemia

Back 146

1. stainable iron, bone marrow aspirate (loss of storage pool)
2. serum ferritin low
3. desaturation of transferrin
4. low serum iron
5. transferrin production increases
6. microcytosis/hypochromic/anisocytosis/poikilocytosis
7. anemia

reverse in same order

Front 147

changes in iron compartments in anemia

Back 147

hemoglobin iron is low, but now 87% of iron

storage iron is now 0%

rest is the same

Front 148

*sx of iron deficiency

Back 148

1. fatigue (can be out of proportion)
2. atrophic glossitis
3. pica
4. koilonychia (nail spooning)
5. esophageal web (Plummer Vinson syndrome, rare)

Front 149

**tx iron deficiency anemia

side effects

Back 149

oral iron replacement (100-900 mg)
+/- Vitamin C (Fe requires acid environment for absorption)

(takes a long time, at least 2-3 months, to replace since iron is poorly absorbed)

side effects: constipation, nausea, GI cramps

parenteral iron possible but problematic to allergic reactions...may have to do it if they had gastrectomy

Front 150

response to iron replacement therapy

Back 150

initial response takes 7-14 days (have to synthesize RBCs from earliest precursor)
modest reticulocytosis (7-10%) - modest b/c of difficulty in getting enough iron into the body

need 6 months of therapy beyond correction of anemia (which usually takes 2-3 months) b/c you need to replete stores, assuming no further loss of blood/iron in which case you need to be treated longer

Front 151

__% of population has hemochromatosis

inheritance

defects in

Back 151

2%

AD (varying degrees of penetrance)

HFE, sometime in DMT-1

(the HFE sensor is messed up, reads like you have constantly low levels...defect in HFE --> decreased iron uptake by crypt enterocytes --> decreased IC iron --> increased DMT-1 and increased absorption)

Front 152

sequence of events in hemochromatosis

Back 152

1. increased ferritin
2. increased transferrin saturation (normal 33%, >60% is a marker of disease, >95% can lead to free iron

albumin does buffer free iron a little bit

Front 153

**IRREVERSIBLE diseases of iron deposition in tissues:

Back 153

1. skin darkening
2. endocrinopathies (diabetes, hypothyroid, hypopituitarism)
3. liver damage (cirrhosis, HCC)
4. cardiac damage (cardiomyopathies --> CHF)

Front 154

*when do you use iron chelation in iron overload?

Back 154

generally for transfusion-induced iron overload (can't phlebotomize them)

Front 155

**anemia of chronic disease is generally:

Hb:
Hct:

usually __cytic

retic count is

bilirubin is

EPO levels

Back 155

mild

10
30%

normocytic (30% microcytic) with mild anisocytosis or poikilocytosis

normal (inappropriately low...also somewhat shortened RBC lifespan)

normal (b/c destruction is relatively normal)

increased but blunted for degree of anemia

Front 156

*anemia of chronic diseass diseases:

Back 156

thyroid disease

collage vascular disease (RA, SLE, polymyositis, polyarteritis nodosa)

IBD

malignancy

chronic infectious disease (osteomyelitis, tubercuosis)

Familial mediterranean fever

Front 157

iron compartment profile in anemia of chronic disease

Back 157

Hb is 40% (normal amt)
storage is 54%

can't get it to where it needs to go

decrease in transport iron b/c it's stuck in the storage pool

Front 158

*what's the pathogenesis of anemia of chronic disease

Back 158

TNF and IL-1 --> increased ferritin and decreased transferrin

also have decreased iron absorption in gut b/c hepcidin (upregulated in ACD) binds to and causes internalization of ferroportin leading to decreased iron uptake

iron stays trapped in the macrophage with ferritin, so it can't get back to bone marrow to red cell precursors

Front 159

hepcidin

Back 159

antimicrobial polypeptide produced in the liver

binds to and causes internalization of ferroportin --> decreased iron uptake from GI tract

upregulated in inflammation, down-regulated in iron deficiency

part of decreased iron absorption in anemia of chronic disease

Front 160

*in iron deficiency:
serum iron is __
transferrin is __
ferritin is __

in anemia of chronic disease:
serum iron is __
transferrin is __
ferritin is __

Back 160

low
increased (compensatory)
low

low
low
increased

Front 161

in iron metabolism disorders, the problem is with RBCs and

Back 161

no other cell types, really

Front 162

tx for anemia of chronic disease

Back 162

replacement therapy
correction of underlying cause

Front 163

which is more dangerous, iron excess or iron deficiency?

Back 163

iron excess

(in treating iron deficiency, you really can't overshoot unless you give it IV)

Front 164

*most important cause of iron deficiency in men and post-menopausal women is

Back 164

colon cancer! (in the US)

(b/c of blood loss)

Front 165

white cell life span

Back 165

12-24 hrs

Front 166

platelet life span

Back 166

7 days

Front 167

__ is one of the most highly active organs in the body

Back 167

bone marrow

any slowing of DNA production leads to bone marrow failure

Front 168

any slowing of __ leads to bone marrow failure

Back 168

DNA production

Front 169

hallmark disease for marrow failure

Back 169

megaloblastic anemia

Front 170

in megaloblastic anemia,
hemoglobin production is __
defect is in __
affects __ cells
LDH is __
serum Fe is __
serum B12 or folate __

Back 170

normal

nuclear replication and division(--> anemia)

all marrow derivatives (-->anemia, leukopenia, thrombocytopenia, reticulocytopenia) = pancytopenia

elevated (RBCs don't have mitochondria, make lactate, have LDH to detoxify)

normal or elevated (defect in utilization b/c of block in nuclear maturation and division)

low

Front 171

trademark cells in megaloblastic anemia

Back 171

oval macrocyte > 100 fl
hypersegmented neutrophil

Front 172

structure of folic acid

bridge is

Back 172

pteridine ring --> PABA --> glutamic acid tail

N-C-C-N b/w pteridine and PABA

Front 173

all organisms need folic acid; bacteria in particular utilize folic acid for DNA production, and some abx work at this part

Back 173

the N-C-C-N bridge between pteridine and PABA

prevent bacteria from growing, which kills them

mammals don't have the mechanisms to synthesize this

Front 174

*folate's major role is to

Back 174

transfer 1-carbon fragments to things

Front 175

if you take methenyl THF and oxidize it, you get

if you take methenyl THF and reduce it, you get

if you then break a bond you get

Back 175

formyl THF - one important for purine biosynthesis (not the most important one)

methylene THF - one important for thymine synthesis...major one for DNA synthesis (inhibited by cancer drugs)

methyl THF - the primary transport form of folic acid...what's in your blood

Front 176

folate is readily absorbed from diet in methyl THF form...when that gets into cells its converted to THF by ...

then ...

Back 176

an enzyme that uses B12

you can add the polyglutamate tail which traps it inside the cell; that then goes to methylene THF

Front 177

***methotrexate (chemo agent) blocks

Back 177

dihydrofolate reductase
(which converts DHF polyglutamate back to THF polyglutamate)

so does trimethoprim

Front 178

*causes of folate deficiency

Back 178

folate poor diet
--alcoholism
--severe poverty

increased folate requirement
--pregnancy
--severe hemolytic anemia
--severe psoriasis (increased skin cell production)

drug therapy (that's actually how chemo works, so you don't want to give folic acid b/c that could block the effect of the drug)

malabsorption
--tropical sprue
--celiac

Front 179

manifestations of folate deficiency

Back 179

megaloblastic anemia
glossitis/stomatitis (often lose their taste buds as a result)
GI malabsorption secondary to impaired GI epithelium (rare)...since turnover is rapid, it's susceptible

Front 180

*B12 functions

Back 180

1. cofactor for conversion of methyl-THF to THF
2. methylation of myelin
3. cofactor for conversion of methylmalonyl CoA to succinyl CoA (important in maximizing ox-phos)

Front 181

*cobalamin structure

what are the different beta groups

Back 181

4 pyrrole rings (like heme), except it has one straight C-C bond
-cobalamin is the coordinating metal instead of Fe

CN (inactive; can be converted)
OH (inactive; can be converted)
methyl (folate metabolism)
adenosyl (mutase activity - important for methyl malonyl CoA conversion to succinyl CoA)

Front 182

when __ cobalamin converts methyl THF to THF, __ is converted to __

Back 182

methyl

homocysteine

methionine

Front 183

a more sensitive way to measure B12

Back 183

homocysteine levels
methylmalonic acid levels

(caveat, everyone with renal insufficiency will have high levels of these b/c they're excreted by the kidney)

Front 184

if you're deficient in B12 OR folate, you inhibit

if you're B12 deficient but not folate deficient, you'll have high levels of

Back 184

conversion of homocysteine to methionine

methylmalonic acid

Front 185

*high levels of methylmalonic acid can be seen in

Back 185

B12 deficiency
renal insufficiency
maple syrup urine disease

Front 186

*__ is only present in animal proteins, so vegans are prone to deficiency and should be supplemented

Back 186

B12

Front 187

*GI absorption of cobalamin

Back 187

GI mucosa makes an R protein that binds B12 and gets it through stomach; as B12 goes into duodenum, R is stripped off, IF (made by parietal cells) binds; in terminal ileum, the IF-B12 complex goes into cell; complex splits, transcobalamin II binds B12; that complex circulates then goes into hematopoietic precursor cells where they split

there's another transport protein called transcobalamin I that isn't able to get into the hematopoietic precursors...we don't know what it does other than screw up our assays

Front 188

*causes of cobalamin deficiency

Back 188

gastric failure
--pernicious anemia (loss of parietal cells)
--total gastrectomy

ileal failure
--regional enteritis (Crohn's)
--ileal resection (due to Crohn's)
--tropical sprue (infection of ileum)

competing organisms
--bacterial overgrowth (blind loop...they love eating B12)
--diphyllobothrium latum (gefilte fish parasite)

Front 189

*pernicious anemia is ___ destruction of ___

particularly associated with this disease

Back 189

autoimmune

parietal cells

(antibodies against parietal cells, IF...achlorhydria is universal)

hashimoto's thyroiditis

Front 190

increased incidence of pernicious anemia in

Back 190

American blacks, northern europeans

Front 191

*why does B12 deficiency lead to megaloblastic anemia

Back 191

really it's the deficiency in intracellular folate...because you can't get to polyglutamate THF (folate) so the methyl THF leaves the cell freely

Front 192

*manifestations of cobalamin deficiency

Back 192

much like folate deficiency:
-megaloblastic anemia
-stomatitis/glossitis
-GI mucosa alterations

BUT there are also the demyelination effects (dementia, psychological disturbance, loss of posterior and lateral columns (combined system disease...lose vibration and position sense first)), so you can't just treat it with folate, which would correct the others...treat with B12

neurological disease is stabilized with treatment but usually not reversed

Front 193

in subacute combined degeneration they lose

Back 193

position sense and vibration sense

Front 194

*sequence of events in cobalamin deficiency

is this process fast or slow

Back 194

1. rise in homocysteine and methylmalonic acid
2. cobalamin decrease
3. MCV rises, neutrophil hypersegmentation
4. MCV is macrocytic
5. anemia
6. symptoms

slow process...have about 10 years worth in storage pool if you're not a vegan...so if you destroy my parietal cells now, it will take 10 years to get anemia

Front 195

*where is folic acid absorbed

Back 195

duodenum/jejunum

Front 196

*how long will your storage supply of folate last?

Back 196

4-5 months

Front 197

*dietary deficiency of B12 is

Back 197

unheard of

(folate is possible, though not as common since fortification)

can supplement either o fthese as much as you want...no side effects

Front 198

*folic acid is found in __ foods, cobalamin found in __

which is water soluble?

Back 198

all

animal proteins

both

Front 199

*in megaloblastic anemia, you have to draw a level before...

Back 199

they eat (b/c one meal can replace folate levels)

after you draw blood, can feed them both; when you get the test result, only have to supplement the deficient one

don't transfuse!!! just give the vitamin and all the stuff stuck in the bone marrow can divide

Front 200

*correction of megaloblastic anemia takes about

Back 200

2 months

retic count peaks at about a week and a half

Front 201

*pts with megaloblastic anemia also have a defect in __ metabolism; __ in particular leads to ~ absorption problems

Back 201

iron

B12 deficiency (so when you start treating with B12, improvement will stop after a point, and you've unmasked the iron deficiency, so you have to work that up now)

Front 202

*macrocytic anemia develops __ly, responds to tx __ly

Back 202

slowly

quickly

Front 203

oxygen binds to the __ in hemoglobin

Back 203

the ferrous atom

Front 204

the 4 globin chains normally have a __ association

Back 204

loose

Front 205

*at __ oxygen tensions, there's significant unloading into tissues

Back 205

low

sigmoid shaped oxygen dissociation curve b/c of cooperative binding

Front 206

*Epo function

Back 206

1. stimulate proliferation of committed RBC precursors
2. stimulate maturation of those

Front 207

nucleus is extruded from RBC __ it leaves the bone marrow

Back 207

before

Front 208

what causes Epo to be released from kidneys

Back 208

oxygen sensing apparatus in the kidneys

Front 209

*alpha like globin genes

on chromosome

promoter

Back 209

zeta (fetal, though alpha turned on way early then stays constant)
2 identical alphas

16

HS-40

Front 210

*beta like globin genes

chromosome

promoter

Back 210

epsilon (embryonic)
2 gammas (each slightly different)
delta (dysfunctional beta - 1% of adult)
beta

11

beta-LCR (essential for developmental expression...through looping, it's intimately associated with gamma during fetal life and with beta and delta during adult life)

Front 211

*gamma globin levels fall

Back 211

pretty much at birth, though you don't get more beta than gamma until about 6 mo.

1% of adult is still gamma though

Front 212

*important region for beta-LCR switiching from fetal to adult globins

Back 212

PYR complex (pyrimidine rich region) in intergenic region b/w A-gamma and delta loci

Front 213

***what is BCL11A

Back 213

transcription regulator protein that is necessary for Sox 6 binding; without it, fetal gamma globin remains active

(trying to make drugs that are Ab to BCL11A)

Front 214

globin genes contain __ exons and __ introns (spliced out)

Back 214

3

2

Front 215

hemoglobinopathy is a ___itative change

thalassemia is a ___ change

Back 215

qualitative

quantitive (decreased or absent production of an otherwise normal globin chain)

heterozygotes of either have increased survival advantage over malaria (homozygotes do not)

Front 216

*second most common Hb disorder

seen in

severity

Back 216

HbE

SE asia

generally mild unless you have a sickle gene or thal gene (synergistic)

Front 217

*Hb C seen in

Back 217

West africa

Front 218

thalassemias seen in

Back 218

mediterranean, S. asia, SE asia

Front 219

*Hb D seen in

important because

Back 219

India

when inherited with a sickle gene --> sickling disorder

Front 220

*beta thalassemia is due to __ gene defects

Back 220

a number of (several hundreds)

usually involve splice sites (ineffective splicing) or defect in 5' regulation

Front 221

*beta+ thal is a __zygous condition

difference b/w that and beta0 thal

Back 221

homo

beta+ makes 10-30% beta chains
beta0 makes none

(both make 100% alpha)

Front 222

*why are you anemic in beta thal

Back 222

excess alpha globin aggregates and precipitates on RBC membrane, causing those developing RBCs to be hemolyzed IN THE BONE MARROW...they don't make it to circulation

gamma globin is insufficiently increased to compensate

Front 223

***profile of beta thal trait

Back 223

mild anemia (Hct 10.8) +
low MCV (60 fl)

in iron deficiency, if MCV were this low, the Hct would be <10

Front 224

*in beta+ thal you see __ Hb F

in beta0?

Back 224

slightly increased

slightly increased

(Hb A2 is variable in both)

Front 225

*in beta+ thal, the anemia is __

in beta0 thal?

Back 225

severe

severe

Front 226

*δβ thal, HPFH and Corfu are deletion abnormalities at

Back 226

the intergenic region b/w gamma and delta

impairs the binding of BCL11A, so fetal Hb is expressed

Front 227

*δβ thal is a __ anemia with __ HbA and __ HbF

Back 227

mild

absent

modestly increased

Front 228

*HPFH is __ anemia with __ HbA and __ HbF

Back 228

absence of

0%

100%

Front 229

*corfu is a __ anemia with __ HbA and __ HbF

Back 229

mild

10%

90%

Front 230

*in __ bone marrow expands, and there's an attempt to make blood in extramedullary sites like spleen (site of blood production in fetal life) and liver/spine

Back 230

beta thal major

but it's not sufficient --> poor growth and development

Front 231

*tx of beta thal

Back 231

chronic transfusions - will extend life significantly, but problems accompany this, including iron overload (complications e.g. cardiomyopathy = most common cause of death, usually happens in 30s)

chelation has problems of compliance, local skin reaction

(improvements like guidelines, leukodepletion filters, testing of blood, venous access, chelation improvements)

Front 232

*alpha thal silent carrier

alpha thal trait

HbH disease

hydrops fetalis

Back 232

deletion of one alpha locus (black)

deletion of two loci (on same or different chromosomes...two blacks or one oriental)

deletion of three alpha genes (oriental and one black)

deletion of all alpha genes (two oriental)

Front 233

*HbH disease

Back 233

tetramer of 4 beta chains

deletion of 3 alpha globin genes (one black, two asian)

moderate/manageable hemolytic anemia (unstable Hb, tends to precipitate and hemolyze)...most live through adult life

Front 234

*hydrops fetalis

Back 234

deletion of all four alpha globin genes

Front 235

*single alpha globin deletion seen in

double deletions in

Back 235

20% of blacks (--> silent carrier)

orientals (alpha thal trait)

two "black mutations" would also be alpha thal trait

Front 236

*profile of alpha thal trait

Back 236

like beta thal in that MCV is low, anemia is mild, but you don't see elevated Hb A2

Front 237

*acquired gene defect in alpha thalassemia myelodysplasia

Back 237

ATRX chromatin remodeling protein --> clumps of Hb H

Front 238

*sickle mutation

Back 238

codon 6 on beta globin (glu-->val)

Front 239

*if you inherit one HbC and one HbS, you get

homozygous HbC -->

Back 239

a sickling disease

mild anemia, target cells

Front 240

*mutations that cause polycythemias

why?

Back 240

Yakima, Chesapeake

Hb doesn't release oxygen well, so more Epo is produced thanks to oxygen sensor

Front 241

*mutations that cause oxidation of hemoglobin --> cyanosis

Back 241

M Boston, M milwaukee

Front 242

*Hb mutations that causes instability --> hemolysis (alone or with drug stimulation)

Back 242

Zurich,
Koln,
Hammersmith

Front 243

*sickling shape does not occur when the __ form is present

Back 243

oxy

(when deoxy happens, it starts to sickle; but if you're a sickle trait, you have one beta S and one beta A, so the reaction is too slow/dilute to sickle)

Front 244

*Hb __ is favorable with a sickle trait

Back 244

A or F

(C is synergistic --> sickling)

Front 245

*sickle cell patients have an ONGOING ___

Back 245

hemolytic anemia

(vaso-occlusive crisis is episodic, and what brings them to the hospital)

Front 246

*why is sickle crisis episodic

Back 246

there's only sometimes slowing down of flow or constriction in post-capillary venule --> vaso-occlusive crisis

Front 247

folks with SS trait can get

Back 247

hematuria (renal papillae can slough if they're dehydrated or high altitude)

Front 248

*SC sickling is __ in severity; prediliction for __ damage

Back 248

moderate

bone, eye

Front 249

the worst sickle cell syndromes

Back 249

SS and Sbeta0

Sbeta+ is less trouble

SF is mild

SC is moderate

Front 250

*dx of sickle cell disease

Back 250

hemoglobin electrophoresis
+
sickling test

Front 251

**in sickle cell, hemolysis --> consumption of NO, reduced NO -->

Back 251

leg ulceration
childhood stroke
priapism
PE

so the complications of SS are due to both physical plugging up and endothelial problems

Front 252

*tx for SS?

Back 252

1. hydroxyurea allows a little more HbF production (by shifting to stem cells that divide less) --> some improvement

also reduces risk of stroke by decreasing flow velocity in cranial vessels (increased flow is a warning sign of stroke)...stroke happens b/c of accumulation of debris, inflammation, interaction of RBC/WBC/damaged endothelial cells

2. exchange transfusion - but you have to keep it constant, and there is risk of iron overload; has been shown to help avoid stroke

3. BM Transplant - works in the right setting; more successful the younger you are

Front 253

can you diagnose SS disease antenatally?

Back 253

yes
can counsel, abort

Front 254

*features of hemolytic anemia:
__cytic
__RBC survival
__retic count

Back 254

normo
shortened
increased

Front 255

*bone marrow has the capacity to increase production of retics by __fold; so you don't become anemic from hemolytic anemia until your RBC survival is < __ days

Back 255

6

20

Front 256

*findings CONSISTENT with hemolysis:
bilirubin __
LDH __
haptoglobin __
urine Hb __
urine hemosiderin __
urine urobilinogen __

Back 256

up (unconjugated)
up
decreased/absent
present
present in chronic hemolysis

but these are not sensitive or specifc

Front 257

**what is haptoglobin?

Back 257

protein that binds and removes Hb from circulation, b/c free Hb is nephrotoxic

Front 258

*most common blood smear finding in hemolytic anemia is

Back 258

normal blood smear!

Front 259

*tests to define the CAUSE of hemolysis (but do not demonstrate the presence of hemolysis)

Back 259

Hb electrophoresis
RBC enzymes (G6PD, PK, etc)
antiglobulin tests (immune-mediated hemolysis)
cold agglutinins (some immune hemolysis)
osmotic fragility (spherocytosis)
CD55/CD59 (PNH)
clotting profile (DIC)

Front 260

*categories of causes of hemolytic anemia

Back 260

INTRAcorpuscular
--membrane abnormalities (e.g. hereditary spherocytosis)
--metabolic abnormalities
--hemoglobinopathies

EXTRAcorpuscular
--immune
--nonimmune

Front 261

*when red cells develop and increased sensitivity to complement, you have __

Back 261

paroxysmal nocturnal hemoglobinuria

Front 262

possible membrane defects in hemolytic anemia

Back 262

microskeletal defects (spherocytosis, elliptocytosis)
membrane permeability (stomatocytosis)
increased sensitivity to complement (PNH)

Front 263

*what gives RBC its nice shape?

in hereditary spherocytosis, __ is defective or absent

where is the hemolysis

Back 263

spectrin lattice, with actin wound between it, all anchored by glycophroin C

spectrin

spleen (extravascular)

Front 264

*describe splenic hemolysis in hereditary spherocytosis

Back 264

low oxygen tension in spleen b/c cells sit around longer; lower tension --> build-up of metabolites, swelling, of cells, which they don't tolerate well b/c they have less membrane --> rupture

Front 265

in spherocytosis, you start to get hemolysis at __% normal saline; in normal person, it's at __%

Back 265

0.6

0.55

Front 266

*in PNH, the hemolysis is

Back 266

intravascular and extravascular

Front 267

PNH is an acquired deficit of __ protein; which does what?

Back 267

GPI-associated, including Decay Activating factor (CD 59)...or could be lack of GPI anchor (located on X chromosome)

if complement binds to RBC, which it generally shouldn't, DAF is there to degrade it. no DAF --> assembly or membrane attack complex --> poking holes in membrane

more active when pH is lower, which happens at night when CO2 is high; but it occurs through the day and night

Front 268

*G6PD leads to ___ because ___

Back 268

hemolytic anemia

it regenerates NADPH, which is necessary to make glutathione from its oxidized form; glutathione protects against oxidative stress in RBCs

without it, oxidative Hb forms and precipitates on RBC membrane as Heinz bodies, which get picked off in spleen --> loss of membrane --> eventual lysis during oxidative stress

(causes of oxidative stress = infection, medications, fava beans)

Front 269

*causes of oxidative stress

oxidative stress in G6PD deficiency leasd to __ formation and __vascular hemolysis

Back 269

Infection

Meds
--antimalarials
--aspirin
--nitroglycerin

Fava beans

Heinz body

extra

Front 270

*normal G6PD falls off over the life span of the cell, but not to a dangerous level; the __ variant is worse and the __variant is worst

Back 270

African (unstable enzyme) - poops out at 50 days, so older cells are susceptible

Mediterranean (really unstable, almost all cells susceptible)

Front 271

*non immune types of extracorpuscular hemolysis

Back 271

mechanical
infectious
chemicla
thermal
osmotic

Front 272

*causes of microangiopathic hemolytic anemia

Back 272

vascular abnormalities (no coag abnormalities)
--TTP
--renal lesions
--vasculitis
--AV fistula

intravascular coagulation predominant (activation of clotting system)
--abruptio placentae
--DIC

Front 273

**clinical diagnosis of TTP

Back 273

Fever
Anemia (microangiopathic hemolytic)
Thrombocytopenia
Renal dysfunction (mild)
Neuro (variable severity)

need to have the A and T

Front 274

causes of TTP

Back 274

HIV, SLE, SS, drugs (plavix, cyclosporine, tacrolimus)

Front 275

*pathophys of TTP

test?

Back 275

autoantibody to vWF cleaving factor (ADAMTS13); usually preceded by viral infection

there is also a rare congenital form (relapsing)

no good test; clinical dx; could check level of ADAMTS13, but could be too late

Front 276

*TTP tx

Back 276

95% fatal without tx

plasmapharesis
steroids
retuximab, vincristine, splenectomy (resistant disease)

could be like a month that they're hooked up to this every day before they get better; ADH decreases, Bili, decreases, platelets go up

Front 277

*immune hemolytic anemia --> __vascular hemolysis

Back 277

intra or extra
(destroyed in vascular tree if complement is activated vs tagged for destruction by macrophages via opsonization with Fc or C3b)

the antigen-Ab rxn depends on class of antibody, number and spacing of antigenic sites, availability of complement, environment tmemperature, functional status of RE system

Front 278

*Direct Coombs test

Back 278

test for immune hemolytic anemia

looks for Ig and/or complement on surface of RBC (red cells don't have Fc receptors, so they'd be bound via antigen combining site)

Coombs reagent = anti-human Ig and anti-human complement + patient's cells ... if Ig or complement is on surface, coombs reagent will link cells together and cause agglutination of RBCs

if negative, the cells stay in suspension

any positive test is abnormal

Front 279

*serum is

Back 279

plasma that has been clotted (no clotting factors)

Front 280

*Indirect coombs test

Back 280

add patients SERUM to a panel of RBCs with known antigens; add coombs reagent; if there were Abs in the patient serum, agglutination occurs

Front 281

*types of immune hemolytic anemia

Back 281

drug-related hemolysis
--immune complex mechanism
--haptenic mechanism
--true autoimmune

alloimmune hemolysis
--transfusion reaction
--hemolytic disease of newborn

autoimune hemolysis
--warm
--cold

Front 282

drug-related immune hemolysis:

immune complex mechanim drugs?
haptenic mechanism?
true autoimmune mechanism?

tx?

Back 282

1. quinidine, quinine, isoniazid - drug and Ab bind in plasma and either activate complement in plasma or sit on RBC...RBC gets hemolyzed in innocent bystander reaction

2. penicillins, cephalosporins - these alter the RBC membrane, creating a neoantigen

3. L-DOPA, procaineamide, ibuprofen - alters RBC membrane that leads to Ab formation...cause Abs that react with normal antigens on RBC surface; you don't need the drug to be in the system!!! for the other two you do

stop the drug!

Front 283

*type of alluimmune hemolysis from hemolytic transfusion reaction

Back 283

immediate intravascular hemolysis - within 5-10 minutes, life-threatening due to nephrotoxicity of Hb - preformed Ab's that can fix complement

slow extravacular hemolysis - days - usually due to repeat exposure to a foreign antigen - more commonly seen - reactivation of memory B cells pretty quickly

delayed sensitization - weeks - usually due to 1st exposure to foreign antigen - asx - normal rate of hemolysis until you get enough Ab to form a complex, then it drops off

Front 284

*testing of blood before transfusion

Back 284

ABO and Rh type of both people

antibody screen, indirect coombs of both people

major cross-match (recipient serum and donor red cells) - looks for minor Ab's

Front 285

*scenario where you get hemolytic disease of newborn

tx?

Back 285

mom is Rh-, first baby is Rh+...some baby blood spills into mom at birth; subsequent baby, she revs up antibodies against Rh, which go to baby; if baby is Rh+ --> hemolysis

can cause severe anemia, hyperbilirubinemia (kernicterus)

Tx with RhoGam after EACH pregnancy...can totally prevent this reaction

Front 286

*autoimmune hemolysis often associated with either

Back 286

lymphoproliferative disease
-CLL

collagen vascular disease
-SLE

Front 287

*types of autoimmune hemolysis

Back 287

Warm type
-IgG
-Ab's bind at all temps
-don't fix much complement
-Fc receptors/C3b recognized by macrophages, therefore...
-EXTRAvascular hemolysis
-70% associated with other illnesses

Cold type
-IgM
-antibodies bind best at 30 degrees or lower (so you typically see only complement on cells)
-fix entire complement cascade
-membrane attack complex
-INTRAvascular hemolysis
-90% associated with other illnesses

Front 288

***tx warm type autoimmune hemolysis

cold type?

Back 288

steroids, splenectomy - responds well

plasmapheresis (not steroids or splenectomy) b/c IgM is very large and only in plasma

Front 289

*in hemolytic anemia, marrow function is usually

often require extra __ to maintain hematopoiesis

Back 289

normal

folic acid

(they depend on bone marrow being hyperfuncitonal, so anything that decreases marrow function will be life-threatening

Front 290

pediatric cancers are 1/__ the rate of breast cancer or prostate cancer

Back 290

10

1/330 children gets one
1/750 20-year olds is a survivor

Front 291

overall survival for childhood cancer is

Back 291

80%

Front 292

*most curable child cancers

~50% curable

least curable

Back 292

RB
hodgkin's
wilm's tumor

brain tumors, neuroblastoma

AML

Front 293

*most common pediatric cancers

Back 293

Leukemia > brain tumors > lymphoma > neuroblastoma

Front 294

*cancers that are primarily in 1-2 y.o. then drop off dramatically

Back 294

RB
Neuroblastoma
Wilm's tumor

Front 295

*pediatric cancer that's seen increasingly with adolescents than with younger kids

Back 295

lymphoma

Front 296

*___ (cancer) has a peak at 3-4 y.o. but has pretty high rates at other ages

Back 296

ALL

Front 297

*retinoblastoma (primitive neuroectodermal tumor) exists in three forms:

mutation is the __ gene

Back 297

1. familial - 10% - almost complete penetrance; increased risk of other cancers
2. sporadic hereditable - 30% - new germline mutation - increased risk of other cancers
3. sporadic non-herditable - 60% - two hits occur after conception - always unilateral

tumor suppressor RB1

Front 298

*bilateral RB appears ___er; __ hit

Back 298

earlier

one (familial form leads to bilateral in 90% of cases - second hit occurs after conception)

Front 299

*non-heritable RB is always

Back 299

unilateral

Front 300

variation occurs in the incidence of __ retinoblastoma

Back 300

unilateral (more in poor living conditions)

Front 301

*most common presenting sx of RB

Back 301

leukocoria
(often visible only with electric light or camera flash) - often not visible until tumor is large enough to have affected vision

usually painless

more advanced disease - proptosis, erythema, pain

Front 302

*RB 5 year survival

tx

Back 302

97%

enucleation --> chemo/radiation

local therapy (laser and cryo) could treat less affected eye in bilateral disease

Front 303

*secondary malignancies often see after retinoblastoma (36% in those with germline mutations)

Back 303

bone (esp. orbits), nasal cavity, soft tissue, pineal

later increased risk of melanoma, breast, lung, bladder cancer

limit radiation exposure in these kids!

Front 304

*Wilm's tumor makes up 95% of

Back 304

child renal tumors

(others are rhabdoid, clear cell, RCC)

Front 305

*Wilms tumor is associated with weird __ in 15% of patients

Back 305

congenital anomalies like:

aniridia
hemihypertrophy
cryptorchidism
hypospadias

can be divided into syndromes with or without overgrowth features

Front 306

*WT1 gene (a __) is mutated in __% of wilms tumor

Back 306

zinc finger transcription factor

5-20%

Front 307

*what is WAGR?

Back 307

Wilms tumor with Aniridia, GU anomalies, and Retardation

without overgrowth features

Front 308

*aniridia alone is a mutation in

with new onset, look to see if

Back 308

PAX6

WT1 is also mutated (nearby), they're at risk for developing wilm's tumor

Front 309

*syndrome of Wilm's tumor with overgrowth features

what is the mutations

Back 309

Beckwith-Wiedemann (but Wilms tumor occurs in only 5-7% of B-W) - this is an imprinting disorder

visceromegaly, macroglossia, omphalocele, microcephaly, gigantism; increased risk of adrenal carcinoma, hepatoblastoma, gonadoblastoma

WT2 - region of IGF2 and H19...oppositely imprinted - IGF-2 is doubly expressed and H19 (which normally balances IGF-2) is turned off...so too much insulin-like growth factor...don't know why it only occurs in half of body

Front 310

Wilm's tumor has a lot of histological diversity, but has varying proportions of 3 cell types

Back 310

stromal, epithelial, blastemal...trying to recreate a kidney, but doesn't do it well

Front 311

*Favorable histology (FH) of wilms tumor

in non-favorable histology there is a high incidence of __ mutation

Back 311

no anaplasia

(anaplasia more likely in patients >5 y.o.)

p53 (86% vs 0.8 in FH)

Front 312

*most common presentation of Wilms tumor

Back 312

palpable mass in abdomen - slow growing so may not be noticed by parent

also hypertension and hematuria sometimes

**usually asx

Front 313

Wilms tumor staging

Back 313

1 - limited to kidney and excised
2 - not limited to kidney but all excised
3 - residual non-hematogenous tumor in abdomen
4 - hematogenous metastases
5 - bilateral renal involvement at dx

Front 314

***tx Wilms tumor

survival rate

Back 314

radical nephrectomy
+ radiation
+ chemo (dactinomycin)

90%

Front 315

most common pediatric abdominal tumor

Back 315

neuroblastoma

Front 316

*neuroblastoma arises from __ cells

Back 316

neural crest (which give rise to adrenal gland and symp. ganglia)

Front 317

*this pediatric cancer (___) can have widely varying outcomes, including __

Back 317

neuroblastoma

spontaneously regress
differentiate into benign
metastasize with high mortality rate (2/3)

among the metastatics, one group is young infants who do well, another is children 2-3 who do not

Front 318

*most common cancer of infancy

Back 318

NB

Front 319

*why have we seen in increase in NB in infants, but not 1 year olds?

Back 319

prenatal diagnosis of cases that spontaneously regress

Front 320

genetic defect in NB

Back 320

deletion at 1p often seen, LOH

sometimes see MYCN amplification (more often in advanced disease, rapid progression, poor outcome)

Front 321

benign NB

Back 321

ganglioneuroma

Front 322

*NBs can originate from

at presentation __ have metastatic disease, often in __-

Back 322

any site in SNS (cervical and thoracic common in infants, adrenal common in older)

1/2-2/3
bone marrow 70%
bone 55%
lymph nodes 30%
liver 29%
cranial 18%
lung, skin

Front 323

*opsoclonus-myoclonus

tx?

Back 323

paraneoplastic syndrome associated with NB (or EBV or coxsackie B)
dancing eye and dancing feet - acute cerebellar encephalopaty, truncal ataxia, rapid and random eye movements - can lead to permanent neuro deficits, decreased IQ, behavioral problems

kids can be nervous, irritable, lethargic

tx: ACTH, IVIG, chemo

Front 324

*work-up for NB

Back 324

urinary catecholamine metabolites HVA and VMA

CT/MRI

bone scan, bone marrow aspirate to assess for mets

Front 325

NB staging

Back 325

1 - localized and excised
2A - localized, incomplete resection, ipsilateral LN-
2B - ipsilateral LN+
3 - unresectable or contralateral LN+
4 - eissemination

*4S - localized primary tumor, dissemination limited to skin, liver (big mets), and/or bone marrow; children <1 year - DO NOTHING, usually regress spontaneously

Front 326

*tx of low grade NB

Back 326

just take out tumor (no chemo) --> 90% survival

high risk is another story

Front 327

***tx of 4S neuroblastoma

Back 327

supportive care in 55% (good prognosis)

symptomatic 45% - cyclophosphamide +/- hepatic RT (babies <2 mo who don't have enough space in abdomen for everything) - some of these die from organ failure, hepatomegaly

Front 328

*genetic/histo features of 4S NB

Back 328

96% FH
no MYC amplification

Front 329

*NB survival much better in children __1 year old and without ___

Back 329

less than

MYC amplification

even if you're non-MYC amplified, outcome is poor if you're 3 y.o.

Front 330

***best therapy for high grade NB

Back 330

BMT+ retinoic acid > BMT > chemo + retinoic acid > chemo

Front 331

*pathophys of ALL (most common pediatric cancer)

Back 331

single lymphocyte loses ability to apoptose --> accumulation of abnormal lymphocytes in marrow, crowding out normal elements

--> varying degrees of anemia, granulocytopenia, thrombocytopenia

Front 332

*epidemiology of ALL

Back 332

boys > girls
more whites

Front 333

*common symptoms of ALL

Back 333

1. fatigue (90%) - often secondary to
2. anemia (80%)
3. thrombocytopenia (50%) - petechiae
4. splenomegaly (65%)
5. bleeding (50%)

fever, bone pain, chest mass
6. LAD (50%)

Front 334

*dx of ALL

Back 334

CBC
smear
bone marrow aspirate
flow cytometry
cytogenetics
CXR (look for chest mass)
chemistries for hemolysis
LP to see if it went to CSF
D-dimer
infectious disease profile

Front 335

*many leukemias have a "signature" which can be appreciated by __ but not __

Back 335

flow cytometry

morphology alone

(useful for monitoring disease, stratifying patient, targeting therapy in future)

Front 336

***the clonal cell of ALL: ___

has flow cytometry positive for

Back 336

precursor B cells

HLA-DR
CD19
CD10

Front 337

***cytogenetics in ALL: hyperdiploidy is ___; hypodiploidy is __


philadelphia chromosome (___) is ___

TEL/AML (t12,21) is

Back 337

good

bad
(near haploid is very bad)

t(9,22)

bad

good

Front 338

*leukemia standard risk:
age ___
initial WBC count __
no __ disease
disease of __ cells

high risk:
age ___
initial WBC count __
presence of __ disease
disease of __ cells

Back 338

1-10
<50,000
CNS
precursor B

<1 year or >10 years
>50,000
CNS
T cells

Front 339

*typical ALL tx is __ years of chemo

if Philadelphia chromosome, tx is

if MLL

if hypodiploidy

Back 339

3-3.5

immediate BMT after initial induction

additional consolidation therapy

additional consolidation therapy

Front 340

*minimal residual disease in __ can be detected by __

Back 340

ALL

flow cytometry
PCR

(can detect 1K - 100K cells)

MRD > 0.001 after 30 days of tx suggests poor prognosis; give more intensive therapy, but don't know if that works

Front 341

***general scheme of ALL tx

Back 341

1. steroid prophase
2. remission induction (4 wk inpatient)
3. consolidation (inpatient)
4. CNS (cranial radiation or intrathecal; outpatient)
5. consolidation II (30 wks outpatient)
6. continuation/maintenance (70 wks outpatient)

Front 342

*what fraction of people get cancer before they die

Back 342

1/3-1/4

Front 343

*lung cancer is going __ in men, __ in women

Back 343

down

up

Front 344

*colon cancer is gradually ___ing

Back 344

decreasing

(probably because of awareness)

Front 345

men have more cancer b/c of

Back 345

prostate cancer

Front 346

all cancer incidence is ___ing

all cancer mortality is __ing

Back 346

increasing

decreasing

(so something good is happening...screening and tx)

Front 347

virtually all colon cancer is due to

Back 347

diet

Front 348

non-hodgkin lympoma is #__ cancer; it is kind of __ing

Back 348

6

rising

Front 349

prostate/breast > lung > __

Back 349

colorectal

Front 350

by far the most common cause of cancer

Back 350

smoking

Front 351

*cigarettes cause these cancers

Back 351

lung (90% of them)
pancreas (very high correlation)
esophageal
bladder (very strong dose-response correlation...stronger than for lung...the more you smoke, the more likely you are to get bladder cancer)

Front 352

most cancer deaths

Back 352

lung > prostate/breast > colon > pancreas

Front 353

increased cup size and breast cancer in Japan attributed to

Back 353

Western diet

combination of fat and hormones

Front 354

*cancers that can be caused by diet

Back 354

prostate (meat and fat intake)
breast (fat intake)
colorectal (grilled meat has carcinogens)

Front 355

*direct link between benzene and

Back 355

leukemia

Front 356

HPV is a _NA virus

makes proteins that can bind __ proteins and immortalize cells

Back 356

DNA

tumor suppressors (p53, RB...act as ubiquitin e3 ligase)

Front 357

*why does EBV make more Burkitt's lymphoma (non-hodgkin lymphoma) in Africa

Back 357

children are infected younger, when B cells are at a different stage of development (more Ig gene rearrangement and higher chance for genetic errors)

<50% of Burkitt's lymphoma in west is due to EBV

Front 358

*HTLV is indigenous to ___ and causes this cancer

Back 358

Japan, Caribbean

T-cell leukemia (a lot in Brooklyn where there are caribbean immigrants)

Front 359

*cancers caused by infectious agents

Back 359

HCC (hepatitis)
cervical
non-Hodgkin lymphoma (EBV)
leukemias (HTLV)
gastric (H. pylori)

Front 360

3-legged stool of cancer causation

Back 360

epidemiologic evidence - observation

mutation potential

animal model (recapitulates with no cofounders)

Front 361

how does asbestos cause mutations

Back 361

crocidolite fibers disrupt mitotic spindel (b/c they are so small)

inject a mouse intraperitoneally with crocidolite and it will get peritoneal mesothelioma

Front 362

mutagenesis in cancer:

__% are sporadic mutations
__% are inherited
__% are exposure to mutagens and hereditary predisposition

Back 362

15% - e.g. childhood leukemia
5% - high penetrance, low incidence
80% - why only 10% of smokers get lung cancer

MZ twins only have 10-20% concordance...something stochastic is going on

Front 363

only __% of colon cancers are APC or MSH/MLH

__% of breast is BRCA

Back 363

1-2%

1-%

Front 364

*ATM mutation increases RR of __ cancer by 1.5-5x

Back 364

breast

Front 365

one cancer can provide and produce hundreds to thousands of cells with metastatic potential (independent, can intravasate, attach to endothelium, extravasate, set up an new colony) but

Back 365

very few ever result in macroscopic metastases

Front 366

***progression of mutations in colon cancer

Back 366

1. APC
2. KRAS
3. p53

Front 367

most cancers have ___ mutations, but not all are important

Back 367

60-100

Front 368

*tumor suppressor genes are __

oncogenes are __

cancer can also be caused by gene __

Back 368

recessive

dominant (good targets so far)

methylation (changes levels of expression)...cancers as a group have different patterns of gene methylation than adjacent normal tissue

Front 369

*cancer genes fall into 4 categories

Back 369

signal transduction
cell cycle/checkpoints
DNA damage or repair
apoptosis

Front 370

***some cell cycle/checkpoint cancer genes are recessive (e.g. ___), some are dominant (e.g. ___)

they are mutated in most cancers

Back 370

p53, RB

CDKs

Front 371

***DNA damage or repair genes

Back 371

BRCA
MSH/MLH (mismatch repair; HNPCC)
ATM (DNA damage recognition)
XP (DNA repair)

Front 372

*apoptosis mutations (least prevalent class)

Back 372

BAX - colon cancer
BCL2 - leukemias

Front 373

*high salt diet --> __ cancer

Back 373

gastric

Front 374

*single most carcinogenic thing we eat

Back 374

aphyllotoxin - aspergillus fungus, grows in grain silos

solution? fresh food

Front 375

*aphyllotoxin --> __ cancer

Back 375

HCC

Front 376

the offending hormone in breast cancer is

Back 376

progesterone

(estrogen + progesterone replacement in post-menopausal women --> cancer)

earlier periods, fewer children increase breast cancer

Front 377

*baby aspirin and COX-2 inhibitors can help prevent __ cancer

Back 377

colon

(unfortunately COX-2 has toxicity, so only give if APC mutation)

Front 378

which are specific, kinases or phosphatases?

Back 378

kinases...many more of those are cancer genes

Front 379

first proof of cancer kinase

Back 379

Raus sarcoma virus, under a certain temp, would phosphorylate and cause malignancy...raise temp and things are hypophosphorylated and benign

Front 380

*receptor tyrosine kinases -->

Back 380

Ras or PI3K

Ras can --> PI3K

both can activate mTOR

Front 381

cancer will never mutate 2 steps in the same pathway; what is hierarchical activation?

reactivation after resistance arises via

Back 381

have to activate some pathways before they activate others

reactivation of the same pathway you shot with your arrow - the cancer has to have that pathway!!!

Front 382

cancer kinases are often tyrosine kinases, but they could be

Back 382

serine/threonine kinases

Front 383

*human genome has __ tyrosine kinases and __ total kinases

Back 383

90

518

(you can tell b/c they have common sequences)

Front 384

*Ret receptor mutated in

Back 384

thyroid cancer

Front 385

IGFR is very important in cancer, but drugs have a side effect of hypoglycemia

Back 385

t

Front 386

*Her2 is in the __ family

Back 386

EGFR

it is ErbB2

Front 387

*each tyrosine in the EGFR tail

Back 387

when phosphorylated --> downstream effectors

different between cells and at stages in development

Front 388

*the 4 members of EGFR family can make lots of dimer combos, and each combo has preferred ligand; but the rules are that

Back 388

Her2 has no ligand binding domain

Her 3 has no active kinase domain

(so don't put two of those together)

Front 389

***the kinase domain of the EGFR is mutated in 10% of __ cancers

the drug that blocks this effect is

how does resistance develop

Back 389

lung

erlotinib - blocks ATP binding - causes regression of the lung cancer in weeks


RESISTANCE:
1. Thr790 then becomes mutated, which is in the binding pocket for erlotinib, and it decreases affinity; knowing this, can make drugs that target that

2. could also develop increased phosphoHer3 --> increased Akt --> activated EGFR

3. Met amplification; Met transphosphorylates Her3, reactivates that pathway

Front 390

***cetuximab is an antibody to

Back 390

EGFR, but it's not as effective as erlotinib at regressing lung cancer

Front 391

***a cancer where you have an EGFR variant III, deletion in first 5 exons makes it constitutively active

tx?

Back 391

glioma

also responds to erlotinib

Front 392

***Her2 is amplified in 25% of breast cancers, and is essential for growth in those (when breast cancer is diagnosed, you do IHC or FISH for Her2 amplification)

in these patients, there is indication for higher dose ___

the drug that targets Her2 is ___

Back 392

doxorubicin

trastuzumab (which also sensitizes to taxanes) - not great as a single drug, but VERY dramatic improvement as adjuvant therapy

Front 393

***trastuzumab MOA

toxicity

Back 393

targets Her2 (in breast cancers where Her2 is amplified...which is 25%)

CHF, anaphylaxis, rash

Front 394

Ras is bound to

Back 394

inner plasma membrane

mutated in 90% of pancreas, 80% of lung, 45% of colon cancers

Front 395

***DBL

Back 395

a GEF

oncogene deleted in B-cell lymphoma

Front 396

*neurofibromin

Back 396

a GAP

oncogene of NF

Front 397

*N-RAS (non-essential) mutated in

H-RAS (non-essential) mutated in

Back 397

rare melanomas

salivary, Spitz nevi (innocent melanoma)

Front 398

***the cancer mutations that arise in Ras are

Back 398

12,13, 61 - such that GAP can't bind, so Ras is constitutively active

Front 399

*lovostatin was shown to inhibit

Back 399

the FA addition to RAS, which anchors it to PM...however that hasn't been an effective drug for pancreatic cancer yet...too much toxicity, not enough efficacy

Front 400

***a big intracellular tyrosine kinase

mutated form does what

drug that targets it

Back 400

ABL

has an mRNA with BCR and ABL sequences that makes an abnormal tyrosine kinase, constitutively active in CML (it lacks the autoinhibitory cap) --> cancer in neutrophils

imatinib

Front 401

***imatinib blocks:

corresponding cancers:

resistance?

Back 401

ABL - CML
KIT - GIST
PDGFR-A -hypereosinophilic syndrome
PDGFR-B -myeloproliferative syndrome

all inhibited by imatinib

1. most commonly, see mutation in imatinib binding pocket (can be targeted if we know the sequence)
2. can also see gene amplification, which stops if you stop imatinib (b/c it can)

Front 402

GIST is in young adults, generally doesn't metastasize, but kills by

Back 402

occupying abdomen

Front 403

*CML in natural history transforms into a more aggressive leukemia that kills in a matter of months (blast crisis), even then, imatinib extends survival to a year in __oid types

Back 403

myeloid

Front 404

*1/__ chance of getting a spontaneous mutation in any cell in the body at any time

Back 404

10 million

use 2 drugs at same time and chances of both mutations is 1/10^14

Front 405

*lessons for therapeutic strategies

Back 405

1. target dominant oncogenes (they drive the malignant phenotype)

2. pathway blockade DOWNstream of activation

3. resistance mechanisms reactive the SAME pathway; you know where to look, use multiple drugs on that pathway

Front 406

*Shh pathway activated in __ cancer

tx?

Back 406

BCC

mutation either disrupts Patched inhibition or causes Smoothened activation

can use derivatives of the rocky mountain thing that blocked Shh and --> cycloptic sheep (cyclopamine)

showed response in 85% of metastatic BCC

Front 407

*what is the phenotype in each:
acute leukemia
chronic leukemia
lymphoma
myeloma

Back 407

precursor cells
differentiated cells
differentiated cells
differentiated cells

Front 408

*myeloma is a disease of __ cells

Back 408

terminally differentiated B cells

Front 409

*WBC profile for each:

1. leukemoid reaction:
2. acute leukemia:
3. CML
4. CLL

Back 409

1. 82% neutrophils, 13% bands
2. 82% blasts (or promyelocytes in APL)
3. whole spectrum of differentiation
4. 98% lymphocytes

Front 410

*what is ANLL

Back 410

acute non-lymphocytic leukemia

= acute myeloid leukemia
(includes granulocytic, erythroid and megakaryocyte lineages)

Front 411

*acute leukemia is basically and imbalance between __ and __

the majority of cells are not __

Back 411

proliferation and differentiation

dividing (presents a therapeutic challenge)

Front 412

***majority of leukemias have visible chromosomal abnormalities; some tumor-specific translocations:

acute promyelocytic leukemia ___
CML ___
Burkitt's lymphoma/leukemia

Back 412

t(15,17) -- almost always
t(9,22)
t(8,14)

Front 413

deletions of tumor suppressor genes are typically more __

Back 413

aggressive, difficult to treat

Front 414

***in Burkitt's lymphoma, ___ is overactive

Back 414

myc (a TF)

Front 415

*causes of leukemia

Back 415

radiation
chemo
combination of two (like in treating hodgkin's lymphoma)
benzene
hereditary
HTLV-1

Front 416

lymphohematopoietic stem cell -->

Back 416

1. hematopoietic stem cell
2. lymphoid stem cell

Front 417

*hematopoietic stem cell -->

Back 417

1. erythroid progenitor
2. megakaryocyte progenitor
3. granulocyte monocyte progenitor --> all white cells other than B and T lymphocytes

if a chromosomal abnormality arises in a progenitor, everything downstream will have that

Front 418

*in CML you often see the philadelphia chromosome as far back as

Back 418

granulocyte monocyte progenitor, hematopoietic stem cell, or lymphohematopoietic stem cel

Front 419

*myelodysplastic syndrome, seen in ___, is a precursor to ___

can commonly see __cytic anemia

other morphologic abnormalities

Back 419

elderly (often)

ANLL

macro (without B12 or folate deficiency)

pancytopenia (can happen) with aniso~, poikilo~, neutrophil hypogranularity/hyposegmentation, macroplatelets, hypolobated/smallmegakaryocytes, increased blast count

Front 420

*tx of MDS

Back 420

Epo, GCSF, hypomethylating agents (doesn't respond well to tx...just have to stabilize)

Front 421

*Auer rods =

Back 421

APL

distorted primary granules

Front 422

***DIC is common with __ leukemia

Back 422

APL

Front 423

*tx of APL

Back 423

arsenic, retinoic acid + chemo

(cells mature to PMNs)

80% cure

Front 424

*t(15,17) is __ genes

Back 424

RA receptor (with RA promotes differentiation) and PML (apoptosis gene)

with the translocation you get no apoptosis or differentation

Front 425

***features of ALL vs ANLL wrt
age
myeloperoxidase stain
auer rods
terminal transferase
cell surface Ag
Ig or T cel receptor gene rearrangement

Back 425

ALL:
-kids
-no (neutrophils contain)
-no (derived from myeloid precursor granules)
-yes TdT
-B or T
-yes (Ig if B, T cell if T)

ANLL
-adults
-yes
-yes
-no TdT
-myeloid
-no

Front 426

*manifestations of acute leukemia

Back 426

marrow failure (neutrophenia, anemia, thrombocytopenia) --> infections, fatigue, bleeding

hyperuricemia (high turnover of purines) --> acute renal failure

DIC (especially in APL; decreased platelets, abnormal clotting) - purpura, intracranial hemorrhage

Front 427

***in acute leukemia, you can get bone pain (b/c of expansion of medullary cavity, esp. in children)

enlarged liver, spleen, nodes (more in __)

hypertrophied gums (esp. in ___)

meningeal infiltratino (esp. ___) --> cranial nerve palsies, headache

Back 427

ALL

AML

ALL

Front 428

*blast leukocytosis is an emergency because

Back 428

rising number of blasts can --> leukostasis in small vessels of brain/lungs/kidneys --> tachypnea, tinnitus, lethargy, stupor, death

Front 429

***tx of acute leukemia

Back 429

aggressive (except APL)
CNS prophylaxis
BMT if relapse
allopurinol (uric acid builds up from purine breakdown)
transfusions
3-4 broad spectrum abx if infection

Front 430

*median survival of child ALL?
adult ALL or adult ANLL?

5 year survival for child ALL?
adult ALL?
adult ANLL?

Back 430

6+ years
1-2 years

70%
30%
15% (except APL) - elderly have more resistant form, usually in background of MDS

Front 431

***in addition to CML, many patients with ___ have the philly chromosome

Back 431

adult ALL

Front 432

*two phases of CML

Back 432

chronic phase (stable)
blastic phase (terminal phase)

transition is accelerated phase

Front 433

***symptoms of CML chronic phase

median duration if untreated

Back 433

weakness, weight loss
purpura (related to platelets)
thrombocytosis (2-4 million)
leukocytosis
normocytic anemia
splenomegaly 80%)
priapism
can see eos and basophils too
but low alk phos

3-4 years

Front 434

*CML test in non-developed countries

if you can't see Ph chromosome on cytogenetics,

Back 434

alk phos

can see in FISH or PCR

Front 435

*ABL is on chromosome

BCR is on

both end up on

BCR ABL activates __

Back 435

9
22

little 22

Ras

Front 436

*if CML is going to affect lymphoid cells, they will more often be

Back 436

B cells

Front 437

***tx of CML chronic phase

Back 437

-hydroxyurea stabilizes blood counts, but disease progresses

-interferon leads to cure in 10-15% (cure = Ph-negative)

imatinib (60% become Ph negative)

allogeneic BMT for those who don't respond to TK inhibitors

Front 438

*myeloablative conditioning used in patients getting

Back 438

autologous stem cells

(also in allogeneic, but not as important b/c of graft v malignancy effect)

Front 439

*transplant related mortality is __ in autologous tx, __ in allogeneic

Back 439

2-4%

10-30% (mostly GVHD)

Front 440

***autologous stem cell tx has highest curative potential for __

Back 440

hodgkin's lymphoma (40-50%) or diffuse large B-cell lymphoma when it relapses

Front 441

*how can you get stem cells from peripheral blood for transplant

Back 441

give GCSF and they will proliferate into blood, then you can do leukopharesis

Front 442

*GVHD is associated with __ damage

Back 442

skin, liver, gut

Front 443

*increasing incidence of GVHD

Back 443

unrelated donor who is HLA identical (considerable risk) > HLA-identical sibling (ideal) > T cell depleted sample from HLA sibling > identical twin (no GVHD)

but there is an inverse risk of relapse (GVM effect)

Front 444

* in pts whose CML relapses after alloSCT, trasfusion of __ from donor WITHOUT additional chemoradiotherapy can induce complete remission

Back 444

lymphocytes only

(but you do risk GVHD again)

Front 445

*blastic phase of CML presents like

Back 445

acute leukemia almost...

weight loss, fever, sweats, bone pain
worsening splenomegaly, anemia, platelet counts low or high

death in weeks/month from leukostasis

Front 446

*adult ALL has __ prognosis

__% are Ph positive

Back 446

poor

30-40%
(BCR-ABL or an even stronger mutation)

Front 447

***all chronic myeloproliferative disorders will respond to ___, but only one is curable (CML)

Back 447

hydroxyurea

Front 448

***chronic myeloproliferative disorders

least aggressive is __

hematocrit high in __

anemia in __

primarily platelets elevated in __

tendency to bleed in all, but also to clot it ___

Back 448

1. CML
2. Myelofibrosis with myeloid metaplasia
3. polycythemia vera
4. essential thrombocythemia

ET is least aggressive
Hct high in PV (everything elevated)
anemia in MMM
platelets elevated in ET
can clot in PV

splenomegaly seen in all 4
all can convert to acute leukemia
last 3 are Ph negative

Front 449

*JAK2 mutation common in

Back 449

myeloproliferative d/o's, esp. P. vera

Front 450

*polyclonal B cell disorder will have surface ___

monoclonal B cell disorder will have

Back 450

kappa and lambda light chains, innumberable kappa and lambda gene rearrangement bands

either kappa or lambda surface light chains, and a single kappa or lambda gene rearrangement band

Front 451

*Hodgkin's age distribution

nodes seen

cause?

Back 451

20-30 yrs. and >50 yrs

cervical >mediastinal>paraaortic
(tends to be asymmetric, starting in neck)

familial
HLA association
geographic clustering ("epidemics") sometimes
weak assoc with EBV

Front 452

***tx of Hodgkin's lymphoma

Back 452

radiation +/- multiagent chemo with different MOAs and non-overlapping toxicities
---prototype MOPP


if this is unsuccessful, intensify chemotherapy

then go to autologous SCT with leukapharesis and myeloablation-rescue...recovers in 2 weeks

(single agent is good for nothing)

Front 453

*incidence of non-Hodgkin's is ___

mortality is ___

Back 453

increasing

increasing

(both are decreasing for hodgkin's)

Front 454

***Hodgkin's tends to be in __ patients

cell of origin is

usual stage at presentation

extranodal sites are __

Reed-Sternberg cells are __

architecture is ___

Back 454

young or old (NHL is middle-aged)

B cell (also most of NHL)

I or II (vs III or IV in NHL)

follicular (diffuse in NHL)

uncommon (common in NHL)

present in HL, absent in NHL

Front 455

***follicular lymphoma is most common indolent NHL; age usually __

stage usually __

translocation __ -->

33% transform to

prognosis

Back 455

50-60 years

III-IV

t(14,18)

overexpression of BCL-2 (an anti-apoptosis protein) with IgH juxtaposition

aggressive large cell lymphoma

incurable but treatable (median survival 7-8 years)

Front 456

***tx indolent lymphoma

Back 456

asx - observe

radiation for localized cancer

alkylators and purine analogs are very helpful

rituximab (anti-CD20) +/- chemo: high response rate

rituximab with radioactive label

alloSCT sometimes in younger people (generally not helpful)

Front 457

***rituximab MOA

treats

toxicity

Back 457

anti-CD20 monoclonal Ab

treat indolent and aggressive NHL and CLL;
1. binds B cell then promotes apoptosis
2. binds complement to promote lysis
3. leads to antibody-dependent cytotoxicity

fatal infusion rxn, HepB reactivation w/ fulminant hepatitis
tumor lysis syndrome w/ severe renal toxicity
cardiac dysrhythmias

Front 458

*difference b/w indolent and aggressive NHL

Back 458

aggressive commonly has CNS involvement, survival is months (not years) but it's potentially curable (30-60%)

Front 459

***tx of diffuse large B-cell lymphoma

Back 459

Stage I or II:
RCHOP and radiation
(rituximab, cclophosphamide, etc, prednisone)

Stage III, IV
more RCHOP +/- radiation
30-60% cure rate

relapse
salve chemo and rituximab followed by SCT

Front 460

***Burkitt's lymphoma tx

Back 460

cyclophosphamide in CHOP like regimen

Front 461

*cutaneous T cell lymphoma is a malignancy of __ T cells

Back 461

Helper CD4+

Front 462

***difference b/w adult T cell leukemia and Sezary syndrome (cutaneous T cell lymphoma)

geography:
skin:
lytic bone:
nuclei:
pathogenesis:
which is more malignant?
leukemic phase
TCR clonality

Back 462

ATL has clusters in Japan, Caribbean (Sezary, none)

Sezary ALWAYS has skin changes (ATL often does)

ATL has lytic bone lesions (Sezary does not)

ATL has flower cells, Sezary has cerebriform

ATL from HTLV-1; Sezary unknown

ATL is v. malignant; high IL-2 expression

both have leukemic phase

both have TCR clonality

Front 463

*myeloma is a disease of

produces

Back 463

plasma cells (terminally differentiated B cells)

monoclonal Ig or light chain

Front 464

*pre-B-cell malignancy:
B-cell malignancy:
transformed B cell ~:

Back 464

B-ALL
CLL (decreased gamma globulins)
macroglobulinemia (monoclonal IgM)

Front 465

***most common leukemia

Back 465

CLL (B cell origin)

(also least dramatic)

age >50 yrs

Front 466

*signs of CLL

labs

prognosis

Back 466

LAD
splenomegaly
hepatomegaly
asx or vague complaints
recurrent pneumococcus infection

kappa or lambda light chain
single Ig gene rearrangement
hypoimmunoglobulinemia
lymphocytosis

few months to >20 years...mean is 5 years

Front 467

***CLL tx

Back 467

Stage 0 or 1 - no evidence for tx
Asx - watch and wait
sx - radiation good for local
chemo
rituximab - best of drugs

SCT is the only curative tx

Front 468

*multiple myeloma more common in __s

Back 468

blacks

any adult, but mostly older people

increasing incidence, unknown cause

Front 469

***diagnostic features of multiple myeloma

Back 469

1. almost always plasmacytosis (much >10% where there should be <5%)

2. monoclonal Ig and/or light chain in serum or urine (spike on electrophoresis) - other causes include CLL, lymphoma, benign monoclonal gammopathy in elderly

3. lytic disease of bone

other causes of plasmacytosis - inflamm, cirrhosis, AIDS, infection

Front 470

*biggest problem in dx myeloma

Back 470

benign monoclonal gammopathy is more common, only 10% progress to myeloma; most remain stable and have no bone disease or kidney disease

but most patients have sx at diagnosis...bone pain, pneumococcal infections, anemia sx

Front 471

*hyperviscosity syndrome in ___ is due to ___

Back 471

myeloma

aggregating paraprotein; circulatory insufficency, abnormal hemostasis; brain/lung/kidney manifestions like bleeding, dyspnea, encephalopathy and visual disturbances

Front 472

*bacterial infections in myeloma

why?

Back 472

early: s. pneumoniae
late: staph aureus or Gram negative rods

normal Ig levels are reduced; TGF beta and other causes

Front 473

*amyloidosis in myeloma

Back 473

due to light chain deposition in tissue

lambda > kappa

skin, tongue, heart, peripheral nerves, kidneys, soft tissues

no effective therapy

Front 474

***tx for multiple myeloma

Back 474

radiotherapy - most sensitive malignancy

thalidomide - anti angiogenesis
lenalidomide - anti angiogenesis
bortezomib - proteosome inhibitor
+corticosteroids

SCT for control, not cure

Front 475

***thalidomide MOA

treats

toxicity

Back 475

antiangiogenesis

tx multiple myeloma

teratogen, peripheral neuropathy

Front 476

***lenalidomide MOA

treats

toxicity

Back 476

anti angiogenesis

tx multiple myeloma

increased DVT risk, myelosuppression

Front 477

***bortezomib MOA

treats

Back 477

proteasome inhibitor - very active

tx multiple myeloma

GI, cardiac, all the ~penias

Front 478

*sarcomas arise from __ cells (<1% of all cancers)

Back 478

mesenchymal - bone, cartilage, muscle, fat

fleshy tumors

chondrosarcomas
liposarcomas
leiomyosarcomas
rhabdomyosarcomas
fibrosarcomas
osteosarcomas

Front 479

classes of sarcomas

Back 479

pediatric vs adult

translocation-related vs complex karyotype (most are complex)

bone vs soft tissue

origin known vs origin unknown

Front 480

*pediatric sarcomas - 10% of childhood cancers: ___

Back 480

rhabdomyosarcoma (most common)
--embryonal (better prognosis)
--alveolar (translocation related)
osteosarcoma
Ewing's sarcoma
--small round blue cell tumor (neuorectoderm?); translocation related

Front 481

*osteosarcoma

Back 481

pleiomorphic high grade tumor composed of fibroblasts, myofibrobalsts, histiocytes

in long bones usually

painless mass of several months duration

lesions are destructive

cslerosis is either from tumor or reactive

Codman's triangle of bone
sunburst patterns

Front 482

adult sarcoma presentation age

Back 482

40-50s

Front 483

*difference in tx of pediatric vs adult sarcomas

Back 483

peds: LOT of chemo +/- surgery
adult: LOT of surgery +/- chemo

Front 484

***genetic syndromes associated with sarcomas

Back 484

NF - von Recklinghausen's disease
Li-Fraumeni syndrom - p53 - osteosarcomas
RB - sarcomas
Gardner's (FAP) - desmoids

Front 485

***translocation associated sarcomas

Back 485

1. alveolar RMS (PAX)
2. Ewing's (EWS-Fli)
3. synovial
4. clear cell

rest are complex

Front 486

*chondrosarcoma occurs in this age group

Back 486

80s

Front 487

*chemo efficacy for following:
Ewing's
osteosarcoma
chondrosarcoma

Back 487

ewings = good
osteosarcoma = moderate (need surgery too)
chondro = bad (chemo really doesn't work)

Front 488

*sarcomas of unknown origin

Back 488

Ewing's sarcoma
clear cell sarcoma (looks likemelanoma of soft tissue parts)
synovial sarcoma

we think MFH comes from mesenchymal cells

Front 489

***side effect of imatinib (oral)

Back 489

puffy eyes
some swelling
can't drink grapefruit juice (increases metabolism)

Front 490

*about __ of cancer pts are cured with local surgery and/or local radiation

Back 490

1/3

only 10% of cancers curable by chemo (70% of childhood cancers)

Front 491

*neoadjuvant therapy

Back 491

for inoperable cancer; tx of locally advanced disease

maybe reduce from stage 3 or 2b to stage 2a (operable)

Front 492

***curable cancers

Back 492

ALL, AML
Hodgkin's and non-Hodgkin's
germ cell cancer
small cell lung cancer
chriocarcinoma
GIST
CML

Front 493

cell kill in follows __ kinetics

Back 493

first order (constant % every time)

our natural immune system can only handle 100 million cells, but cancer may have 10^12...so that's why you need so much chemo

Front 494

***___ are the only drugs that kill non-growing cells

Back 494

lipophilic alkylators

(temazolamide, BCNU, CCNU)

Front 495

growth fraction of tumor (% of cells actively progressing through cell cycle) is maximal when it is about __ maximum size

Back 495

37%

this is when it's most responsive to chemo

another reason why advanced cancer is hard to tx

some drugs are cell-cycle non-specific, so cells don't have to be in active cell cycle

Front 496

***what phase does each attack:
antimetabolites
taxanes
vinca alkaloids (vincristine)
antitumor abx (e.g. bleomycin)

Back 496

S
M
M
G2/M

Front 497

***all nature-derived chemo drugs are ___ metabolized except ___

all synthetics (antimetabolites, platinum agents, alkylators) are __ metabolized

except

Back 497

hepatically

BET - bleomycin, etoposide, topotecam

renally excreted

cyclophosphamide which must be hepatically metabolized first

Front 498

***cell cycle non-specific agents

Back 498

1. alkylating agents (looks for electron dense parts of DNA to add alkyl and inhibit)

2. anthracyclines (e.g. doxorubicin; topoisomerase II inhibitors, doesn't allow reannealment --> apoptosis)

3. camptothecins (e.g. irinotecan; topoisomerase 1 inhibitor)

4. platinum analogs - atypical alkylators; all have chlorines which come off at physiological pH, loosk for electron dense region to alkylate

Front 499

chemotherapy doesn't kill cell, it makes cell kill itself

Back 499

t

Front 500

about __% of drug cures occur in __% of cancer types

Back 500

90

10

Front 501

drugs known to be partially active against tumor when used alone should be

Back 501

used in combination

Front 502

tumor resistance can be

Back 502

intrinsic (the more genetically unstable the tumor is, the more mutations will occur before you even expose it to chemo) - p53, mismatch repair defect, Bcl-2, NF-kappaB

or

acquired (pumps that kick stuff out, phosphorylases that inactivate drug, decreased conversion of drug like cyclophosphamide to active form, reduced affinity of target enzyme for drug like in methotrexate/DHFR, enhanced DNA repair, increased expression of target enzyme like DHFR)

Front 503

normal tissues never become resistant to drugs...why?

Back 503

b/c of wild type p53...many times resistance requires gene amplification, which you need mutatnt p53 for

Front 504

probably could cure cancer with high doses, but toxicity is

Back 504

just too high

Front 505

in general liquid/solid tumors are more amenable to high dose chemo

Back 505

liquid

Front 506

why has chemo + small molecules not worked

Back 506

small molecules are cytostatic, chemo works at level of DNA to be cytocidal and requires active cells

Front 507

***ways to target VEGF pathway

Back 507

1. Ab to VEGF
2. decoy receptor to bind VEGF
3. Ab to VEGFR
4. ribozymes that degrade VEGFR
5. TKI of VEGFR

Front 508

***ER_ breast cancer is eligible for hormonal therapy

Back 508

+

Front 509

1/__ compounds screened make it to market

Back 509

10K

20 year patent protection

takes about 16 years to get through pipeline, 1 billion dollars

(and antineoplastic agents have lowest success rate)

2x as many developing than abx or cv drugs

Front 510

clinical trial phases

Back 510

I:
safety and tolerability
pharmacokinetics
normal and targeted pops (in cancer, mostly just cancer pts)

II:
single arm, single institution
proof of concept - efficacy in different tumor types - look for 1 in 12-15 (1 in 5 has a good chance of approval)
dose ranging
safety and pharmacokinetics refined in special population

III:
large, multi-center
placebo-controlled
often replicated

IV:
after approval
adverse event reporting
new indications and uses
average 4-5 years

Front 511

endpoints for FDA

Back 511

time to progression
survival
relief of symptoms
delay of event

Front 512

***phase I metabolism most often by

Back 512

CYP3A4/5/7

UGTs

Front 513

***5FU metabolism can be affected by

irinotecan?

Back 513

DPD polymorphism

UGT polymorphism

Front 514

***sorafenib MOA

treats

toxicity

Back 514

inhibits b-RAF and c-RAF (kinases)

RCC

bleeding, rash, hypertensions
**monitor BP

Front 515

***sunitinib MOA

treats

Back 515

TKI - antiangiogenesis

RCC, GIST

Front 516

***methotrexate class

MOA


toxcitiy

Back 516

anti-metabolite (for cancer)

folic acid analog that blocks S phase

teratogen; myelosuppression, reversible with leucovorin

Front 517

***5-FU class

MOA

toxicity

Back 517

anti-metabolite (for cancer)

act on S phase; pyrimidine analog that complexes folic acid, inhibits thymidylate

cerebellar toxicity!!!
myelosuppression reversible with thymidine
photosensitivity

Front 518

***cyclophosphamide class

MOA

toxicity

Back 518

alkylating agent

alkylates at guanines

requires bioactivation by liver

hemorrhagic cystritis

Front 519

***paclitaxel MOA

toxicity

Back 519

taxane

acts on M phase; inhibits microtubule disassembly

allergy to castor oil in formulation
infertility
rash, flushing, chest pain

Front 520

***docetaxotere MOA

toxicity

Back 520

taxane

acts on M phase; inhibits microtubule disassembly

allergy to castor oil in formulation
infertility
rash, flushing, chest pain

Front 521

***vincristine class

MOA

toxicity

Back 521

vinca alkaloids

acts on M phase; inhibits microtubule formation by binding MTs

neurotoxicity
paralytic ileus

Front 522

***irinotecan class

MOA

toxicity

Back 522

camptothecins

topoisomerase I inhibitor

alopecia!!!
GI

Front 523

***doxorubicin class

MOA

toxicity

Back 523

anthracyclines

topoisomerase II inhibitor (DNA intercalation)

cardiotoxicity

Front 524

***bleomycin class

MOA

skin changes

Back 524

antibiotic

acts on G2; induces free radical damage

pulmonary fibrosis, skin changes

Front 525

***carboplatin MOA

toxicity

Back 525

cross links DNA --> apoptosis

**nephrotoxicity, acoustic nerve damage

Front 526

***cisplatin MOA

toxicity

Back 526

cross links DNA --> apoptosis

**nephrotoxicity, acoustic nerve damage

Front 527

***oxaliplatin MOA

toxicity

Back 527

alkylating agent --> evenutal apoptosis

does not cause alopecia;
irreversible neurotoxicity (cold intolerance, paresthesias)

Front 528

***bevacizumab MOA

toxicity

Back 528

Ab against VEGF

bleeding, thrombosis, wound healing problems...wait 6 weeks until surgery!

Front 529

***cetuximab MOA

toxicity

Back 529

Ab against EGFReceptor; prevents dimerization

full body rash...but this is a good sign! good efficacy, better prognosis

efficacy blocked by downstream Ras mutations

Front 530

***tamoxifen MOA

treats

toxicity

Back 530

SERM - blocks binding of estrogen to receptor

ER+ breast ca

may increase endometrial Ca b/c of partial agonist effects
hot flashes

Front 531

***leuprolide MOA

treats

toxicities

Back 531

GnRH agonist - shuts down estrogen/androgen production

ER+ breast cancer, prostate cancer

hot flashes, vaginal bleeding, amenorrhea, AVOID preganancy

gynecomastia, impotence, transient rise in testosterone, alopecia, weight gain

Front 532

***anastrazole MOA

treats

toxicity

Back 532

aromatase inhibitor; interferes with estrogen production in peripheral tissues

ER+ breast cancer

hot flashes, osteoporosis

Front 533

***bicalutamide MOA

treats

toxicity

Back 533

non-steroidal anti-androgen that binds to cytosoal ARs

prostate cancer

hot flashes, gynecomastia

Front 534

***arsenic trioxide treats

Back 534

APL - induces morphological changes and DNA fragmentation in NB4

Front 535

*benign adult renal tumors

malignant

Back 535

renal papillary adenoma
angiomyolipoma
oncocytoma

RCC
urothelial carcinoma (pelvis)

Front 536

*__% of renal cancers are RCC

Back 536

85% (others are urothelial Ca)

(usually older people, 2:1 M:F)

3% of all new cancers

it's an adenocarcinoma

Front 537

*RCC risk factors

Back 537

smoking
obesity (esp in women)
hypertension
unopposed estrogen
metal exposure
CRF
tuberous sclerosis

Front 538

*most RCCs are ___

Back 538

sporadic

familial 4%, occur in younger age group

vonHippel Lindau
hereditary clear cell
hereditary papillary carcinoma

Front 539

*types of RCC

Back 539

clear cell Ca (most common - proximal tuule)
papillary Ca
chromophobe RCC
collecting duct Ca (1% but most aggressive...associated with medullary carcinoma, SS disease...can become sarcamoid)

Front 540

urothelial carcinoma stratification

Back 540

80% in situ
20% invasive (all malignant)

in situ could be:
papillary (benign papilloma, low malignant potential, malignant)
or flat urothelial CIS (malignant)

Front 541

presentation of bladder tumors

Back 541

painless hematuria

tend to recur and progress

60% are single
70% are localized

Front 542

urothelial carcinoma variants

Back 542

squamous cell
adeno
mixed
small cell

all worse prognosis

Front 543

mesenchymal tumors of bladder

Back 543

leiomyoma (benign)

rhabdomyosarcoma (child, malignant)
leiomyosarcoma (adult, malignant)

Front 544

familial melanoma caused by

Back 544

CDK inhibitor mutation (p16 mutation)

Front 545

when RB is active, it is a ___

Back 545

brake on the cell cycle

Front 546

either CDKs gain function or __ lose function...not both

Back 546

CDKi's or RB

Front 547

***overall, p53 mutated in __% of cancers

Back 547

50

Front 548

can inactivated p53 by activating __ (degrades it)

Back 548

MDM2

maybe you can block this with Nutlin?

Front 549

Cyclin D1 is overexpressed in a lot of breast cancers; if the cancer is ER-, the prognosis is __; if ER+, __

if D1+ and Her2+,

Back 549

worse

better

worse prognosis

thus limited predictive value...complex issue

Front 550

***p27 loss leads to __ cancer

Back 550

prostate, breast

(enhanced proteolysis, mislocalization)

Front 551

***RB inhibits proliferation through formation of __ that inhibit __ phase

RB is inhibited by ___

that complex is inhibited by __

Back 551

transcriptional repressor complexes

S

CyclinD1-CDK4 complex (which phosphorylates RB)

p16 (so p16 allows RB to put on its brake)

Front 552

p27 is degraded by

Back 552

Skp2

increased Skp2 is bad

Front 553

MDM2 ubiquitination of p53...

Back 553

targets it for degradation