Justin Practice Questions 2022 Flashcards
Which pathway is TGF-beta part of
SMAD or PI3K/AKT or RAS/RAF/MEK
Apoptosis
Which is not in a proliferation pathway?
BAX (apoptosis gene)
What are G coupled receptors
7 membrane spanning proteins that are activated with GTP then self hydrolyze to GDP and turn off
Transmembrane cell signalling proteins
Proposed mechanism of synergy b/t chemo and angiogenesis inhibitors
Normalization theory - anti-angiogenic agent restores normal blood flow and reduces tumor interstitial fluid pressure favoring the penetration of cytotoxic agents
Most common mechanism of oncogene activation
1) mutation (in promoter)
2) gene amplification (probably this one)
3) chromosome rearrangement
TL: Lit search suggests that gene amplification is the correct answer
Mechanism by which tumor suppressor genes are deactivated
Methylation (think MLH1)
Genes related to apoptosis
- “bcl (b cell lymphoma) - anti-apoptosis
- caspase - programmed cell death including apoptosis (fas pathway), pro apoptosis
- BAX (bcel-2 like protein 4) encoded by BAX gene - pro apoptosis
- TP53
Important: NOT VEGF
Best way to amplify DNA
PCR
Best way to quantitate protein
Mass Spec or ELISA
What are static cells?
Well-differentiated that rarely undergo division as adults (ie neurons, oocytes, striated m, nephrons)
What are expanding cells?
Normally quiescent but grow under stress/injury (ie hepatocytes, vascular endothelium
What are renewing cells
Constantly replicating (ie BM, epidermis, GI
Mechanism of apoptosis (3 phases)
initiation/induction:
—intrinsic pathway = response to internal pro-apoptotic stimuli such as DNA damage
–extrinsic pathway = activated by the binding of ligands
effector: caspase portion
degradation
Morphologically, apoptosis characterized by: condensation of chromatin, nuclear and cytoplasmic blebbing, and cellular shrinkage followed by phagocytic destruction
Oncogene associated with EMCA/lynch syndrome
c-myc… we found kras (maybe wasn’t option?)
Think: M for MMR
diff to find/confirm but looks like similar question last year so trusting their answer (AW)
AS: could be KRAS?
PTEN, MSH2, and TP53 are what type of gene
Tumor suppressor gene
Molecular pathway responsible for epithelial to mesechymal transformation
Wnt/beta-catenin pathway
What is the PD-1 effect on T cells?
PD-1 (expressed on T and B cells) is the negative regulator of T-cell activation.
On T cells, it promotes apopotosis of effector T cells and reduces apoptosis of Treg cells
T cells exhausted and unable to proliferate/secrete IL-2 or kill target cells
PD-1 expressed on: CD4 & CD8 T cells, B cells, monocytes, NK cells, and dendritic cells. Highly expressed on tumor-specific T cells
IL-2 stimulates which cells?
T cells: helper T cells (CD4), cytotoxic T cells (CD8) and Tregs (CD4)
NK cells (in combo with IL-12)
MHC and T cells - which go with which?
Tc/Cytotoxic = MHC1 = CD8 = apoptosis (From beginning to end = MHC1 & CD8)
Th/helper = MHC2 = CD4 (helpers are middle men = MHC2 and CD4)
Both add to 8:
1x8=8
2x4=8
Where are B cells made?
Produced in bone marrow then migrate to lymphoid organs (spleen, LN follicles, GI tract) to mature
What cells are included in innate immunity?
Present at birth. NK, macrophages, dendritic cells
What cells are included in acquired immunity?
T cells and B cells
What cells secrete histamine?
Basophils and Mast cells
What cell / cell line do dendritic cells and macrophages originate from?
Monocytes (myeloid stem cell origin)
Where is MHC I expressed?
MHC class I molecules are ubiquitously expressed on all nucleated mammalian cells including cells of epithelial origin. Platelets too (AW)
(All cells except erythrocytes)
they also had: trophoblast, germ cells ?, neurons?
-expressed on neurons (AW)
-not expressed on spermatogenic cells (AW)
-expression on some types of trophoblasts (AW)…too much to know
Where is MHC II expressed?
MHC class II molecules are selectively expressed on antigen-presenting cells (APC) including dendritic cells (DC), macrophages, and B cells.
Which cells are MHC restricted?
Restrict = T cells
MHC restriction= T cells will only recognize specific Ag on “self” MHC molecule subtype (HLA type) with the correct Ag in combination with it
Prior card had: MHC restriction means that different T cells are restricted to either Class I or Class II MHC antigens. Cytotoxic T cells are restricted to Class I antigens present on nucleated body cells, thus play a role in protecting against virus-infected cells or cancerous cells.
What immune cell secretes IL-1?
Macrophages
(+ monocytes, dendritic cells) (AW)
What does IL-1 do?
Mediates inflammation, fever
Stimulates T cells (cell mediated response)- to make IL-2
Stimulates proliferation of B cells and increase Ab production (Ab mediated response/humoral immunity).
? stimulates Macrophages (inflammatory response) -released by activated macrophage, not sure if it also then acts to further stimulat macrophage (AW)
What do dendritic cells do?
Professional Antigen presenting cells
What do natural killer cells do?
Lymphocyte that destroy tumor cells and cells infected by viruses. Respond to cytokines and interferons. Do not require activation w/receptor (i.e., with MHC1)
Which are the first immune cells to respond?
Polymorphonuclear neutrophils (PMNs)
PMNs=Neutrophils, eosinophils, and basophils
What do CD4 cells do?
recognize MHC II;
Th1 cells stimulate CTLs and macrophages (cellular immune responses)
Th2 cells stimulate antibody responses
Th17 cells mediate autoimmune diseases
What do CD8 cells do
recognize MHC1; secrete cytokines and can defend against tumors by directly killing transformed cells (granuloeoxytosis) or induction of extrinsic apoptosis by activating Fas molecules
What is the function of Immunoglobulins A, D, E, G, M
A = first response: defends mucosal surfaces
D = B cell receptors prior to Ag exposure. Signals B cell activation and is initially coreleased with IgM. Activates basophils and mast cells to produce antimicrobial factors (respiratory immune defense)
E = binds allergans/parasites. Trigger histamine release from mast cell and basophils. involved in hypersensitivity
G = 2nd line Ab; opsonization and neutralization. Crosses placenta
M = 1st line Ab; activates complement. B cell receptor. Used for non-protein Ag. Pentamer
What is the MOA of ipilimumab?
TEST QUESTION
mAb; CTLA4 blockade.
CTLA4 is a receptor on T cells that receives inhibitory signal from dendritic cells/APC (CD80/86 aka B7 molecule).
Ultimately results in Activation of CD4 and CD8 + effector T cells by removing an inhibitory checkpoint on proliferation and function, inhibits Treg activity
Currently used in melanoma
what makes a tumor antigen a good immune (antibody) target?
(Duplicate)
expression on cell surface
What are interleukins?
Interleukins (IL) are a type of cytokine first thought to be expressed by leukocytes alone but have later been found to be produced by many other body cells. They play essential roles in the activation and differentiation of immune cells, as well as proliferation, maturation, migration, and adhesion.
How do you make monoclonal antibodies?
Fuse antibody secreting B cells (spleen cells from mouse immunized with antigen of interest) and myeloma cells —> hybridoma cells.
Select immortal hybridoma that makes specific antibody for antigen of interest
What is a significant limitation of using retroviruses for gene therapy?
Retroviruses (RNA viruses) only infect dividing cells and depend on reverse transcriptive (RNA to DNA) to allow the virus to integrate into the host genome and be continuously produced.
Disadvantage: The ability of retroviruses to integrate into the host cell chromosome also raises the possibility of insertional mutagenesis and oncogene activation. this can lead to leukemia
Which chemo drugs are vesicants?
(Duplicate Q)
Doxorubicin/ Epirubicin/ idarubicin/ daunorubicin
ActinomycinD
Mitomycin C
Nitrogen mustard
Trabectinib
Vinblastine, vincristine, vinorelbine (all vincas)
DAMN TV
Which chemos are S phase specific?
Antimetabolites, Topo 1 (topotecan, irinotecan)
Doxorubicin most cytotoxic in S
“HI 5 The Good Man”= Hydroxyurea,** I**rinotecan, 5-FU, Topotecan, Gem, MTX
Which chemos are M phase specific?
Vinca alkaloids & taxanes: pure M phase
- taxanes: promotes assembly of microtubules and stabilizes them, preventing depolymerization
- vincas: interacts with tubulin w/resulting inhibition of microtubule assembly and cellular division
(Mitotic spindle poisons)
Eribulin, ixabepilone: arrest at G2/M
-Eribulin: inhibitor of microtubule dynamics, binding a small number of high affinity sites at the plus ends of existing microtubules
-Ixabepilone: semi-synthetic analog of epothilone B, like taxol=stabilizes microtubules
Which chemos are G2 phase specific?
- Bleomycin: G2 phase
- Etoposide: G2 (max kill) and S phase
- Eribulin, ixabepilone: causes arrest at G2/M
G2 BE2 or G2 BEE= bleo, etopo, eribulin/ixabepilone
Which Chemos G1 phase specific?
No Chemos specifically act at G1;
MTOR inhibitors, ActD, Tamoxifen - = agree, hormones cited as G1 frequently
Act-D is cell cycle nonspecific with max kill in G1
Which chemos are non-cell cycle specific?
Alkylating: Cyclophosph/ifosf, Altretamine/hexamethylmelamine, ecteinascidin
Platinums
Anti-tumor abx: Doxorubicin, Mitomycin-C, Actinomycin-D
Nitrogen mustards/alk: Melphalan, Chlorambucil
Which chemo leads to amenorrhea in young women?
A. vincristine
B. etoposide
C. mtx
D. cisplatin
Cisplatin
NON CELL CYCLE SPECIFIC ARE MORE LIKELY TO BE GONADAL TOXIC
Chemo induced amenorrhea risk:
Highest risk: Alkylating agents (cyclophosphamide, ifos, busulphan, chlorambucil, melphalan, chlormerthin, procarbazine:
Medium: platinum (cis, carbo); anthracyclines (doxorubicin), taxanes
Low: vincas, bleo, antimetabolites (mtx, 5-FU)
When short-term intensive chemotherapy is used, particularly with antimetabolites, vinca alkaloids, or antitumor antibiotics, injury to the reproductive system is less common. For example, men treated for testicular cancer, children with acute leukemia, and women cured of GTD or ovarian germ cell malignancies usually recover reproductive capacity after therapy
Which chemo don’t have to renally dose?
A Cytoxan
B topo
C gem
D methotrexate
**TEST QUESTION **
Gemcitabine
A BICCC THEMM (ones to renally dose)
ActD
bleo,
ifos,
cis/carbo,
cytoxan,
Capecitabine
topotecan,
hydroxyurea,
etoposide,
mtx/pemetrexed
Melphalan
Which chemos are pro-drugs?
Capecitabine, cyclophosphamide, ifosfamide, gemcitabine
Also the following:
- Oxaliplatin: extensive non-enzymati c conversion to its active metabolize
- Irinotecan: converted to active metabolite SN-38
- MitomycinC
- Cytarabine requires intracellular activation to its phosphorylated derivative
- Temsirolimus
Which of the following agents are cell cycle specific?
A. mtx
B. Taxol
C. Cisplatin
D. carboplatin
E. cyclophosphamide
taxol: M only
- anti-folates (i.e., mtx, pemetrexed): S and G1
Not cell cycle specific:
Alkylating compounds (G1,G2,S): direct DNA damage, DNA adduct formation, free radical production; i.e., radiation, platinum, bleomycin; cyclophosphamide, carboplatin
BAD QUESTION
When is bev held?
Proteinuria >/= 2g in 24h urine (Nephrotic syndrome cutoff is 3.5 g/day) or hypertensive crisis > 180/120 or hypertensive encephalopathy.
package insert says DC not just hold if HTN encephalopathy/PRES or nephrotic range proteinuria (AW)
What toxicity does mtx not have?
A. Cardiotoxicity
B. hepatotoxicity
C. nephrotoxocity
D. hematologic toxicity
Cardiotoxicity
What “rescue” med is available for methotrexate?
Leucovorin - derivative of folic acid (to overcome high dose mtx BM toxicity)
Derivative of tetrahydrofolic acid (reduced by MTX) that is readily converted to other reduced folic acid derivatives which have vitamin activity equivalent to that of folic acid. “rescues” cells by replenishing intracellular reduced folate pools (give within 48 hours of mtx)
FYI can also be used to potentiate anti-tumor activity of 5-FU
What is the most common side effect of amifostine?
(Duplicate)
Hypotension (62%);
Used to protect the kidneys from cisplatin, reduce carbo thrombocytopenia and reduce renal/BM SE from cisplatin and cyclophosphamide
protects salivary glands during radiation tx (decrease dryness in the mouth)
What is the dose limiting toxicity of irinotecan?
Diarrhea > myelosupression
Diarrhea Occuring during infusion- responsive to atropine (anti-cholinergic)
Diarrhea Occuring subacute 2-3 weeks after is not responsive to that, so use anti-motility
Diarrhea Can be life-threatening
What drug characteristics are associated with better IP chemo administration?
ideal IP:
- large molecular weight size
- hydrophilic, ionized compounds.
- high conc in peritoneum
- no need for liver activation
- high volume IP dialysate (low vol increases IP clearance rate rapidly, which is bad)
drugs enter the tumor nodules by passive diffusion
What drug is PPE associated with?
Capecitabine > 5-FU, Doxil, docetaxol (SGO chemo handbook)
(old card had pemetrexed per Chi)
Also Multitargeted tyrosine kinase inhibitors sorafenib, sunitinib
PPE=painful erythema, scaling, swelling, ulceration involving hands/feet
prolonged oral etoposide, weekly and continuous-infusion 5-fluorouracil, capecitabine, PEG-liposomal doxorubicin, prolonged vinorelbine infusions (AW)
What chemo most associated with constipation
Vincristine
Due to autonomic neuropathy: Impaired intestinal motility constipation and upper colon fecal impaction, paralytic ileus
What chemo is primarily renally cleared
**TEST QUESTION ***
Bleomycin (bleo blows out those kidneys)
Bleomycin is eliminated predominantly by the kidney, with 50% of the dose eliminated within 24 hours after administration.
Pemetrexed: About 90% of the drug is excreted unchanged in the urine within 24 hours.
Cisplatin, Carboplatin, oxaliplatin, and Mtx also renally cleared
What chemo causes polymerization of tubulins
Taxol
Unlike other tubulin targeting drugs such as colchicine that inhibits microtubule assembly, paclitaxel stabilizes the microtubule polymers and protects them from disassembly.
What chemo cannot be given IP?
Cyclophosphamide and ifosfamide (are prodrugs that require activation in the liver!)
Capecitabine (oral drug…), cyclophosphamide, ifosfamide
gemcitabine CAN be used as IP chemo (and has been used in pancreatic cancer!)
Some agents are excessively toxic given this route: doxorubicin, mitoxantrone
What are the parameters for carbo calculator
Calvert formula:
Dose (mg) = target AUC (mg/mL x min) x [GFR (mL/min) + 25 (mL/min)]
GFR /CrCl calculated using: Age, creatinine, weight/height, gender
- [(140-age)(wt)(0.85)]/(72xCr)
Use of amifostine
Decrease nephrotox of cisplatin and cytoxan. Prodrug that acts as a free radical scavenger and tends to be selective to non-malignant tissues
Taxol 24 vs. 3 hours
Less neurotoxicity for 24 hours but more BM toxicity
AKA: 3hr= more neurotoxic, 24hr= more myelosuppressive (AW)
Target for aprepitant
**TEST QUESTION **
NK1 receptor (central NS); dominant ligand is substance P
Aprepitant prevents acute and delayed vomiting by inhibiting the substance P/neurokinin 1 (NK1) receptor; augments the antiemetic activity of 5-HT3 receptor antagonists and corticosteroids to inhibit acute and delayed phases of chemotherapy-induced emesis.
Aprepitant is a potent and selective NK-1 tachykinin receptor antagonist that blocks the effects of substance P (SP) in the central nervous system.
Strategies to reduce nephrotoxicity of chemo
Dose reduce, hydration, eliminate other nephrotoxic drugs
Side effect LEAST likely to be minimized when choosing aromatase inhibitor over tamoxifen
**TEST QUESTION **
AI will not Reduce osteoporosis fractures, MSK pain.
Tamox SE: endometrial cancer, vag bleeding, VTE/CVA, hot flashes - anti-est in breast, pro everywhere else (uterus, bone, liver, coagulation system), fatty liver, increased triglycerides, lower LDL, cataracts
AI: hot flashes, osteopenia or osteoporosis, bone pain, diarrhea, heart disease, increase LDL/decrease HDL
Both: hot flashes, sexual dysfunction
Pt on BEP with pulm sx, what do you do first
Stop bleo
Prodrugs: which is not (and list which are common prodrugs)?
A gemzar
B 5FU
C taxotere
D cyclophosphamide
taxotere is not.
True Prodrugs: cyclophosphamide, ifosfamide, capecitabine
Require activation:
- irinotecan - reversible equilibrium with reactive intermediates (SN-38)
- cisplatin, carbo: require activation through irreversible aquation
- others: gemcitabine, 5-FU
Others:
Oxaliplatin: extensive non-enzymatic conversion to its active metabolize
Cytarabine requires intracellular activation to its phosphorylated derivative
Peak level IP vs. IV bioavailability for carbo
A 1:5
B 1:20
C 1:200
D 1:500
(Duplicate)
1:20
Barakat - 18:1 IP vs IV concentration in peritoneal cavity
20:1 cisplatin
1000:1 paclitaxel
Virtually all commonly used drugs administered IP in patients with ovarian cancer have peak or concentration x time product ratio of more than 20.
Most unlikely side effect of bev
A Hypotension
B GI perf
C bleeding
D headache
Hypotension not complication
Hypertension (24% to 42%)
headache (22% to 49%)
Hemorrhage (grades ≥3: ≤7%; including major hemorrhage)
gastrointestinal perforation (≤3%)
Most common sx of GCSF
bone pain
Filgrastin:
Neuromuscular & skeletal: Back pain (15%), ostealgia (3% to 30%)
Pegfilgraststim:
Neuromuscular & skeletal: Ostealgia (31%)
Most emetogenic Chemos
**TEST QUESTION **
Highly emetic (>90%, B&H)
- Cisplatin
- Anthracycline and cyclophosphamide
- Cyclophosphamide >=1500 mg/m²
Most common side effect of megace
A breast tenderness
B weight gain
C hyperglycemia
D hypercholesteremia
weight gain
Hyperglycemia (6%)
gynecomastia (1% to 3%),
weight gain (not attributed to edema or fluid retention)
Most common acute tox of IP chemo
Abdominal pain
Mechanisms of platinum resistance
1) Decreased uptake: Downregulation of CTR1 (Copper transporter 1)
2) Inactivation by glutathione: Elevated levels of enzymes involved in GSH synthesis (gamma-glutamylcystein synthestase) and glutathione S transferase (binds to platinum inactivating it)
3) ** Nuclear excision repair (NER) pathway** : expression of ERCC1 leads to increased repair of platinum-DNA adducts (THIS most common)
4) DNA MMR: loss of function of MMR contributes to developing DNA damage tolerance
5) loss of pro apoptotic factors or over expression of anti-apoptotic factors
Mechanisms of nausea and receptors drugs target/act on
**TEST QUESTION **
Muscarinic - scopolamine
H1 - benadryl, dramamine
D2 - prochlorperazine (compazine, metoclopramie (reglan)
5HT3- zofran, palonsetron
NK-1- aprepitant
GABA - benzos
Mechanism of cisplatin with radiation
Cell repair inhibited.
Cisplatin binds with DNA causing INTRAstand cross-links and DNA adducts that are primarily repaired via NER. Radiation causes single and double strand breaks that are primarily repaired via NHEJ. When these DNA breaks are attempted to be repaired by DNA-protein kinase dependent NHEJ, presence of cisplatin-adducts prevents the repair and leads to cell death.
Increased oxidative stress.
Mechanism of action: topotecan
TEST QUESTION
- Inhibit TOPO-I (a nuclear enzyme that induces reversible SINGLE STAND DNA BREAKS during DNA replication)
- forms topotecan-TOPO-I-DNA complex, preventing religation of ssDNA BREAKS
- Interaction between complex and replication enzymes results in dsDNA breaks and cellular death
S phase
Mechanism of action: methotrexate
Mtx binds to DHF (dihydrofolate reductase) blocking DHF –>THF (tetrahydro-folic acid, active form of folic acid). As a result, thymidylate synthetase and other steps in de novo purine synthesis that require 1-carbon transfer rxn are halted. This arrests DNA, RNA and protein synthesis
S phase specific
Mechanism of action: gemcitabine
**TEST QUESTION **
—> Prodrug metabolized inside cells!!
Metabolized into triphosphate and diphosphate metabolites.
Triphosphate metabolite incorporated into DNA as fradulent base pair, leading to addtl deoxynucleotide at end of DNA.
Replication is terminated (called “MASKED CHAIN TERMINATION) which prevents exonucleases from excising fradulent base pair.
Diphosphate metabolite inhibits ribonucleotide reductase, which depletes deoxynucleotide pools necessary for DNA synth/repair
Primarily S-phase, but also blocks progression through G1 to S.
Gems for short 💎. Gem can be found on a chain around the neck. So it does masked chain termination.
Gems are found in pyramids, so gem-triphosphate is a pyrimidine analog
Mechanism of action: etoposide
Inhibits TOPO-II enzymes (does NOT bind directly to DNA) rather stabilizes transition form of DNA-TOPII.
by stabilizing this it “poisons” TOPOII enzymes which usually helps cells progress out of G2
Cell cycle: S/G2 checkpoint (think more G2)
(JS) also decatenation
Mechanism of action: doxorubicin
Anthracycline antibiotic from Streptomyces peucetius
1) DNA binding and intercalating, inhibiting DNA synthesis (S phase most potent, but not cell cycle specific)
2) Free radical formation - this may be related to the cardiotoxicity (iron chelation)
3) Inhibition of DNA topoisomerase II by inhibiting strand-passing activity of topo-II (acts in G2 phase)
topo II, free radicals (yes), intercalating (yes), DNA adducts
Doxorubicin Limit lifetime dose to what?
Limit dose to 550 mg/m2 cumulative life dose due to cardiac toxicity
From PharmD: Risk for cardiomyopathy increases at cumulative dose 550 over age 18.
Test answer on pharmacy exams is usually 550 but no one ever pushes that high since the recommendation to start dexrazoxane is at 300mg/m2 which is probably why you’re seeing that range!
Cumulative incidence Cardiomyopathy:
450 mg/m2- 3%
550 mg/m2 - 7%
600 mg/m2 - 15%
700 mg/m2 - 40%
Which of the following is the Most leukemogenic chemo?
A etopsoside
B platin
C 5FU
D melphalan
melphalan - 10% risk
Etoposide- 1%
Cisplatin- even less
cyclophos- <1%
Least protein bound chemo?
A doxorubicin
B topotecan
C gem
D carbo
E ifos
Gem / but maybe actually carbo
Chemos low protein bound
gem negligible
Carbo 0%
Ifos negligible
Highly protein bound ie to albumin:
active metab of irinotecan SN-38: ~95%
mtx: 50%
doxorubicin 75%
topotecan 35%
Taxol, docetaxel 90s%
Etoposide 97%
Cis 90%
BIG-CT (least protein bound)
Bleo
Ifos
Gem
Carbo
Topo
Least leukemogenic chemo:
A Cisplatin
B melphalan
C cytoxan
D 5-FU
5-FU
Most leukemogenic: melphalan, cyclophosphamide, etoposide, cisplatin
What are advanced colon adenomas that increase colon cancer risk?
villous or tubulovillous histology (this is the answer), high-grade dysplasia, >/= 1 cm
Changes in apoptosis (two questions)
“not cause inflammation, does cause chromatin condensation (this is the answer)
1) cell shrinkage and rounding due to caspase
2) cytoplasm dense and organelles tightly packed
3) chromatin undergoes condensation against the nuclear envelop (PYKNOSIS)
4) nuclear envelope becomes discontinuous and DNA is fragmented (KARYORRHEXIS)
5) cell membrane buds into blebs
6) cell breaks apart into multiple vesicles called apoptotic bodies - these are phagocytosed”
Least emetogenic chemo?
A Vinca
B carbo
C doxorubicin
D dactinomycin
**TEST QUESTION **
Vinca (vincas don’t vom)
Minimally emetic (<10%)
- Bev
- Bleo
- Nivo, pembro, dostar, durva, ipi
- Trastuzumab
- Vinblastine, vincristine, vinorelbine
Least bone marrow suprresive chemo
Bleomycin (main dose-limiting side effect is pulm tox, 10%; nephrotoxicity)
IP chemo pharmacokinetics
Generally - IP chemo should be LARGER, HYDROPHILIC, IONIZED - b/c clear more slowly from peritoneal cavity and cancer, maintain concentration; penetrate tumor nodules through PASSIVE diffusion (up to 2-3 mm) but that’s why we cytoreduce
Cancer with elevated CA-125 (ovary not a choice)?
Pancreatic, breast, lung cancer), colon, gastric
How does cisplatin augment radiation? (repeat)
Inhibit repair of sublethal damage
Cisplatin sensitizes cancer cells to ionizing radiation via inhibition of non-homologous end joining
Cisplatin pre-treatment increases the number of radiation-induced DNA double-strand breaks
Cellular irradiation induces various forms of DNA damage, with DNA double-strand breaks forming the main cytotoxic lesions.
Most common mutation in mucinous ovarian cancer (p53, KRAS, BRAF, Her2/neu)?
KRAS
Doxil versus doxorubicin
(Duplicate questions)
** TEST QUESTION **
Liposomal bound (aka pegylated) with MPEG methoxypolyethylene glycol to avoid detection by the mononuclear phagocyte system
Results in:
- longer plasma life
- slower plasma clearance,
- reduced volume of distribution
- higher tumor-tissue drug concentrations
- NOT a vesicant
- associated with minimal cardiotox, alopecia, nausea/vomiting
But increased rates of PPE (dose limiting in 25%) and stomatitis
MOA P53 as tumor suppressor
can activate DNA repair, cause G1/S arrest to allow time for repair of DNA damage, maintains genomic stability, initiate apoptosis
Mutation associated with mucinous epithelial ovarian cancer
KRAS, tp53
Mucinous ovarian cancer most common tumor suppressor? Oncogene?
Tumor suppressor: TP53
Oncogene: KRAS
Which pathway is responsible for the Epithelial to mesenchymal transition
WNT/Beta-catenin
Telomerase
Telomeres are “caps” at ends of chromosomes and keep chromosomes from being degraded. Every time cell divides, a few base pairs lost and eventually these “caps” are gone. Telomerase is a protein/DNA complex that lengthens the 3’ telomere end so the cell can divide forever (and thus be immortalized)
Aromatase inhibitors most common side effect
(Duplicate)
**TEST QUESTION **
—> Arthralgia (15-36%) , ? asthenia actually more
vasodilation (25% to 36%)
Endocrine & metabolic: Hot flash (12% to 36%)
Gastrointestinal: Gastrointestinal distress (29% to 34%)
When p53 is activated - what stage of cell cycle does it arrest?
G1 (p53 is the first O.G.) - or apoptosis if defects are large
Relative risk of raloxifene and thrombosis
RR 2.1 (grady 2004, RCT of 7700+ women)
The risk of venous thromboembolic disease (deep venous thrombosis or pulmonary embolism) was 3.1 times higher (95% CI, 1.5-6.2) in women assigned to the raloxifene group than to the placebo group. (Cummings 1999, RCT of 7700+ women)
JS- still lower risk for VTE on raloxifene than tamoxifen
Are psammoma bodies in high grade serous ovary good or bad?
Good/favorable prognosis
What cells make hCG?
Syncytiotrophoblast
What makes up OVA1
CA-125, transthyretin (pre-albumin), Apo A-1, β2 microglobulin, transferrin (5 things)
What stain is used for melanoma?
S100
additionally: SOX10, MelanA, HMB45
What is function of gemzar prodrug
substitutes cytosine that stops replication by “masked chain termination”
anticancer nucleoside is an analog of deoxycytidine. Gemcitabine inhibits thymidylate synthatase, leading to inhibition of DNA synthesis and cell death. Gemcitabine is a prodrug, and once transported into cell, must be phosphorylated by deoxycytidine kinase to an active form. Both gemcitabine diphosphate and gemcitabine triphosphate inhibit processes required for DNA synthesis. Incorporation of gemcitabine triphosphate into DNA is most likely the major mechanism by which gemcitabine causes cell death. After incorporation of gemcitabine nucleotide on the end of the elongating DNA strand, one more deoxynucleotide is added, and thereafter, the DNA polymerases are unable to proceed. This action “masked termination” apparently locks the drug into DNA as the proofreading enzymes are unable to remove gemcitabine from this position
What is least leukomegenic chemo
bleo
Topo vs etoposide (does etopo or topotecan bind topo I or II)
topo – topo I
etop – topo II
(topo t one, etop second letter t two)
Which chemos require adjustment for renal compromise
(Duplicate)
TEST QUESTION
A BICCC THEMM (ones to renally dose)
ActD
bleo,
ifos,
cis/carbo,
cytoxan,
Capecitabine
topotecan,
hydroxyurea,
etoposide,
mtx/pemetrexed
Melphalan
Alkylating
Topoisomerase
Act-D/Bleo
Platinums
Anti-metabolites (excluding 5-FU, gem)
Which chemos requires adjustment for liver compromise?
(Duplicate)
TEST QUESTION
MTV ME 5 CD
methotrexate
Taxanes (docetaxel/ paclitaxel/nab-paclitaxel)
vinkas (vincristine, vinblastine, vinorelbine)
Mitoxantrone
Epirubicin
5-FU
cyclophosphamide
doxorubicin/doxil
Does 3 hr vs 24 hr administration of taxol lead to increase neurotoxicity or decrease in neurotoxicity?
3 hour more neurotoxic, 24 hour more neutropenia
Most common serious side effect of tamoxifen?
A thrombosis
B ut cancer
C vasomotor
D colon cancer
(Duplicate)
Endometrial cancer
Notes say VTE, but…
UTD:
Serious, life-threatening, and fatal events include uterine malignancies, stroke, and pulmonary embolism.
Incidence rates per 1,000 woman-years:
Endometrial adenocarcinoma: 2.20 versus 0.71 for placebo
Stroke: 1.43 for tamoxifen versus 1.00 for placebo.
PE: 0.75 for tamoxifen versus 0.25 for placebo
I confirmed with drug package insert from FDA - jv
Most common overall side effect of tamoxifen?
A thrombosis
B ut cancer
C vasomotor
D colon cancer
Overall: vasomotor (>90%)
What’s the mechanism of action for Topotecan
Traps topoisomerase I on DNA causing unrepaired ssDNA break
Stabilizes the cleavage complex
Acts in G2 phase, but also has some activity in S phase
Pertuzumab mechanism of action
Block HER2 heterodimerization
Pertuzumab is a recombinant humanized monoclonal antibody which targets the extracellular human epidermal growth factor receptor 2 protein (HER2) dimerization domain. Inhibits HER2 dimerization and blocks HER downstream signaling halting cell growth and initiating apoptosis. Pertuzumab binds to a different HER2 epitope than trastuzumab so that when pertuzumab is combined with trastuzumab, a more complete inhibition of HER2 signaling occurs
Which needs renal dosing more (etoposide vs. bleo) - since both are renally cleared
TEST QUESTION
Bleo
Bleo BLOWS out the kidneys
What is Calvert’s formula?
Dose (mg) = target AUC (mg/mL × min) × [GFR (mL/min) + 25 (mL/min)]
The Calvert formula is used to calculate the carboplatin dose accurately in order to obtain a target Area Under the Curve (AUC) by using only the GFR
Crockroft-Gault
Equation used to estimate creatinine clearance
Used in carboplatin dosing calculations
CrCl = 0.85 for female * [(140-age)(weight kg) / (72Cr)]
Unreliable in patients who are at the extremes of body weight or have an abnormally low serum creatinine
Tamoxifen vs. raloxifene
Both anti-est in breast (tamox more effective in breast cancer prevention than raloxifene, but raloxifene less serious side effects [VTE, ut cancer, cataracts])
Both pro-est in the bone
Tamox pro-est in endometrium, but raloxifene is not.
Which is least emetogenic?
A Carbo
B vinca
C doxorubicin
D ifos
**TEST QUESTION **
Vincas
Highly emetic (>90%)
- Cisplatin
- Anthracycline and cyclophosphamide
- Cyclophosphamide >=1500 mg/m²
Minimally emetic (<10%)
- Bev
- Bleo
- Nivo, pembro
- Trastuzumab
- Vinblastine, vincristine, vinorelbine
Which chemo is activated within a tumor cell?
** TEST QUESTION **
Capecitabine
AS: and Gemcitabine
Ideal ROC (receiver operating curve) - AUC
Higher AUC, the more accurate
There are several scales for AUC value interpretation but, in general, ROC curves with an AUC ≤0.75 are not clinically useful and an AUC of 0.97 has a very high clinical value, correlating with likelihood ratios of approximately 10 and 0.1.
AUC varies from 0 to 1. Closer to 1, the higher sensitivity and higher specificity.
What are highly emetogentic chemos
Cisplatin, carbo AUC 4+, doxorubicin >60, Ifos >2
NCCN (>90%)
AC combination defined as any chemotherapy regimen that contains an anthracycline and cyclophosphamide
• Carboplatin AUC ≥4 • Carmustine >250 mg/m2
Cisplatin • Cyclophosphamide >1500 mg/m2 • Dacarbazine • Doxorubicin ≥60 mg/m2 • Epirubicin >90 mg/m2 • Fam-trastuzumab deruxtecan-nxki
Ifosfamide ≥2 g/m2 per dose
• Mechlorethamine • Melphalan ≥140 mg/m2 • Sacituzumab govitecan-hziy • Streptozocin
What are moderately emetogenic chemos
Carbo AUC <4, doxorubicin <60, ifos, oxaliplatin
NCCN (30-90%)
Minimally emetogentic chemos
**TEST QUESTION **
Vincristine, Nivolumab, Bev, Bleo, MTX <50, Pembro
NCCN. <10%:
mAb with emetogenic potential
Olaratumab (anti-platelet derived growth factor)
Withdrawn from the market and used for sarcoma
Anastrozole mechanism
reversible binding to aromatase, blocking extragonadal conversion of androgens to estrogens
inhibiting aromatase thus, the conversion of androstenedione to estrone, and testosterone to estradiol, is prevented. Anastrozole causes an 85% decrease in estrone sulfate levels.
Abraxane (nab-paclitaxel) compared to paclitaxel
Same terminal half life, larger clearance, larger Vd, less allergenic
Paclitaxel is solvent-based and formulated in a mixture of polyoxyethylated castor oil and dehydrated alcohol, while nab-paclitaxel is an albumin-bound nanoparticle formulation of paclitaxel and is free of solvents
Advantage of liposomal doxorubicin over standard
tumor-tissue drug concentration is 4x-16x higher in liposomal formulation
Less cardiotox
gemcitabine mechanism of actions (2)
- Structurally similar to deoxycytidine, gets phosphorylated x3, then incorporated as fradulent base pair, then additional deoxynucleotide added–masked chain termination preventing excision of fradulent base pair–irreparable error that stops synthesis
- Diphosphate version inhibits the enzymeribonucleotide reductase(RNR), which is needed to create new nucleotides. The lack of nucleotides drives the cell to uptake more of the components it needs to make nucleotides from outside the cell, which increases uptake of gemcitabine as well
Chemotx that need dose reduction for hepatic impairment (bili or transaminitis)
TEST QUESTION
MTV ME CD
Mtx
Taxanes
Vinkas
Mitoxantrone
Epirubicin
cyclophosphamide
Doxil/doxorubicin
Doxorubicin MOA
Intercalates DNA inhibiting Topo-II,
Chelates iron
Forms free radicals, active during entire cell cycle, but most active in S
Chemotx causing alopecia
Taxol, ifos, Act-D, etoposide, bleo
alkylating agents (IV cyclophosphamide, ifosfamide, busulfan, thiotepa),
antitumor antibiotics (dactinomycin, doxorubicin, epirubicin, idarubicin),
antimicrotubule agents (paclitaxel, docetaxel, ixabepilone, eribulin),
topoisomerase inhibitors (etoposide, irinotecan at higher doses)
Alopecia is less common or incomplete with:
bleomycin,
low-dose epirubicin or doxorubicin (especially <30 mg/m2),
oral cyclophosphamide,
fluorouracil,
capecitabine,
gemcitabine,
melphalan,
methotrexate,
mitomycin,
mitoxantrone,
platinum agents (oxaliplatin, cisplatin, and carboplatin),
topotecan
weekly low-dose irinotecan
vinca alkaloids (vinorelbine, vincristine, vinblastine).
Most Common side effect of anastrozole
A asthenia
B headache
C increased bone density
D decreased fractures
E Arthralgia
**TEST QUESTION **
Asthenia
AS: Package insert Asthenia 19%, arthralgia 15%, headache 14%, hot flash
Chemo associated with ovarian failure
(Duplicate)
Cyclophosphamide > melphalan, cisplatin, etoposide
Biggest ones are alkylating agents and procarbazine
Also cisplatin, doxorubicin
Drug that will stay in the intraperitoneal cavity the longest?
paclitaxel (large molecule, water insoluble, high cavity to plasma AUC ratio[1000:1])
Not renally cleared chemotherapy
A topotecan
B gemcitabine
C Cyclophosphamide
D methotrexate
TEST QUESTION
Cyclophosphamide: hepatic inactivation appears to be the major mechanism of active drug elimination
Carboplatin, oxaliplatin, Pemetrexed, Bleomycin, Topotecan, gemcitabine, and Mtx also renally cleared
Mechanism of chemotherapy related nausea/vomiting?
** TEST QUESTION **
Acute: Related to 5-HT3
Delayed: substance P
acute CINV, free radicals generated by toxic chemotherapeutic agents stimulate enterochromaffin cells in the gastrointestinal tract, causing the release of serotonin. Subsequently, serotonin binds to intestinal vagal afferent nerves via 5-HT3 receptors, which trigger the vomiting reflex via the nucleus of the solitary tract (NTS) and chemoreceptor trigger zone (CTZ) in the CNS.
delayed CINV. Substance P is principal neurotransmitter. Chemotherapy drugs trigger the release of substance P from neurons in the central and peripheral nervous systems, which then binds to neurokinin-1 (NK1) receptors mainly in the NTS to induce vomiting.
Amongst the agents known to cause secondary leukemia, which is the least likely?
A Ifosfamide
B cyclophosphamide
C altretamine
D carbo/cis
E melphalan
F etoposide
Carbo/cis? (I believe this is wrong, cisplatin has been associated with leukemia)…
Notes said “Ifosfamide (THIS ONE we think)”
But literature review suggests platinum agents are least likely in this list.
- Leukemogenic agents: cyclophosphamide, cisplatin, etoposide, melphalan, cytoxan. Others: chlorambucil, CCNU (Lomustine), BCNU (carmustine), DTIC (dacarbazine), altretamine
AS: B&H -alkylating agents, procarbazine and nutrosoureas are major offenders. Prolonged Etoposide as well
A, B, C, E are alkylating agents + F etoposide
Amongst the agents known to cause secondary leukemia, which is the least likely?
A Ifosfamide
B cyclophosphamide
C altretamine
D carbo/cis
E melphalan
F etoposide
Lowest risk likely platinum agents
- Ifosfamide: listed in UTD
- cyclophosphamide: bolded in UTD
- altretamine discontinued; not listed as AE though is alkylating
- carbo: not listed in UTD
- cis: listed in UTD
- melphalan: listed in UTD
- etoposide: listed in UTD
Most leukemogenic: melphalan > cyclophosphamide > etoposide, cisplatin, procarbazine, and the nitrosoureas
two well defined groups
1) alkylating agents or
2) drugs binding to the enzyme DNA-topoisomerase II.
Call Exner bodies
Granulosa cell tumors
(Call your Granny)
Schiller-Duval
Endodermal sinus tumor (ESS)
its a papillary structure that grows into a cystic space. The papilla is covered by tumor cells and HAS A CENTRAL CAPILLARY region.
Multinucleated giant cells
Dysgerminoma
What cells make hCG?
Syncytiotrophoblast
What makes up OVA1?
CA-125 (upregulated)
transthyretin (pre-albumin)
transferrin
Apo A-1
Beta2 microglobulin (upregulated)
5 things!
*OVA1 is also known as multivariate index assay.
The score ranges from 0 to 10 and interpreted as follows:
Premenopausal patients:
*Low probability of malignancy: OVA1 <5
*High probability of malignancy: OVA1 ≥5
Postmenopausal patients:
*Low probability of malignancy: OVA1 <4.4
*High probability of malignancy: OVA1 ≥4.4
What tumor marker is elevated for PSTT
HPL
- extravillous (intermediate) trophoblast cells, most PSTTs are female and diploid.
- Surgery (hysterectomy with salpingectomy +/- pelvic lymph node biopsy if non metastatic with low risk findings vs. hysterectomy with salpingectomy and excision of mestastic disease + EMA-EP, EP/EMA or BEP for metastatic disease).
Where is Breslow’s depth measured from for melanoma?
From granular layer of surface epithelium to the deepest melanoma
(Background: Breslow is a measure of how deeply a melanoma tumor has grown into the skin)
*Layers of the skin from most superficial to deeper: stratum corneum, stratum lucidum, stratum granulosum, strutum spinosum, stratum basase > dermis.
What are the levels of Breslow?
“Level 1 = in situ
Level 2 = through BM
Level 3 = through papillary dermis
Level 4 = through reticular dermis (survival starts to drop off from 90% or higher to 67%)
Level 5 = through subcutaneous fat (33%)”
Measured from the granular layer of the epidermis to the deepest point of invasion
Tamox least likely to be associated with what benign growth?
answer: ovarian cysts
most likely to be associated with in order of highest association:
benign endometrial polyps
hyperplasia
fibroids/adenomyosis
*also sarcomas and carcinosarcomas
What subunit of HCG is shared with other hormones
Alpha same as LH, FSH, TSH; beta is distinct
- Thyroid work up should be obtained in patients with molar pregnancy or GTD with bHCG > 100,000.
- If features of thyroid storm or impending storm begin immediate treatment with:
Beta blocker – Propranolol preferred.
Thionamide – Propylthiouracil (PTU) preferred.
Iodine – Saturated solution of potassium iodide (SSKI) or Lugol’s solution.
Consider Hydrocortisone if confirmed clinic storm.
Cholestyramine is an additional adjunctive therapy, especially if the patient is allergic to thionamides.
Most common tumor in dysgenetic gonads
Gonadoblastoma (benign)
Most common malignant tumor in dysgenetic gonads
Dysgerminoma
Which growth factors bind to serine-threonine kinase receptor?
Peptide growth factors
*Receptor serine/threonine kinases such as transforming growth factor beta (TGF-beta) receptors contain a single transmembrane domain.
*Hypersignaling via the TGF-β pathway is associated with increased tumor dissemination (immune evasion, promotion of angiogenesis, increased epithelial to mesenchymal transformation) and has been well studied in ovarian cancer.
Location of estrogen receptor and of action mechanism
** TEST QUESTION **
cytosol —> nucleus.
MOA: transcription factor
ERs are ligand-dependent transcription factors
Cancer related to fusion protein
Endometrial stromal sarcomas
(uptodate said: JAZF1-SUZ12 and EPC1/PHF1gene fusion)
*JAZF1-SUZ12 is a carcinogenic fusion related to low-grade ESS. Its fusion frequency is reported to be 75% in endometrial stromal nodule, 50% in low grade ESS, and 15% in high grade ESS, and can be used to distinguish LG-ESS from HG-ESS.
*EPC1-PHF1 is associated with the morphology and clinical features of low-grade ESS.
FOXL2 and ovarian cancer subtypes
adult granulosa cell tumor
EBRT vs brachytherapy: which symptom is shared?
FATIGUE (answer)
-wrong answers: vaginal stenosis, 2 other
Which is a direct (rather than indirect) effect of radiation?
LET (answer)
wrong answers:
photons, gamma rays, hypoxia, chemosens
What radiation is used to treat superficial lesions (aka skin)?
Electrons (answer)
wrong choices: gamma ray, orthovoltage
What is the elemental source for brachytherapy/interstitial?
Iridium-192 (answer)
wrong choice: cesium
What is the depth of dose for 12 MeV in radiation?
4 cm (R90 where beyond <90% of dose is administered)
What is the definition of linear energy transfer (LET)?
The rate of deposition of energy along the path of the radiation beam. Amount of energy transferred to local environment in form of ionizations and excitations. Average energy for a given path length traveled. Average path length for a given deposited energy.
Unit = kEV/um
What is high LET radiation?
OPTIONS:
1. neutrons
2. protons
3. photons
4. Gamma rays
5. alpha particles (I added this option but not in justine’s) “
High LET: alpha particles, neutrons
What is low LET radiation?
electrons, gamma rays, xrays
(both electromagnetic radiation)
What is % dose of XRT 1 cm vs 2 cm from source?
400% because dose is = 1/r squared
*Repeated question
How do you manage severe carboplatin sensitivity if patient is responding to the drug?
Desensitization protocol
We do not recommend rechallenging patients with platinum agents, even with additional premedications. Instead, we advocate referral to an allergist for skin testing. If skin testing is positive, the patient should either avoid any future exposure to the drug or receive it only through a desensitization protocol.
Chemotherapy agents associated with PPE?
Chi: Capecitabine > 5-FU, Doxil, Docetaxol
Also Multitargeted tyrosine kinase inhibitors sorafenib, sunitinib
Factors that increase the rate of PPE with doxil administration?
Higher dose infusion and prior neuropathy
initial doses greater than 40 mg/m2
higher dose and more cycles increased the incidence of several toxicities, including PPE. The use of cooling mechanisms, higher number of PLD cycles, and occurrence of mucositis, neutropenia, and peripheral neuropathy are possible predictors of PPE.
Dose limiting toxicity of Gemcitabine
**TEST QUESTION **
Myelosuppression
Chemo causing ovarian failure
A. cyclophosphamide
B. 5-FU
C. MTX
Cyclophosphamide
EXACTLY why we give taxol before cisplatin/ Carboplatin
( duplicate)
Carboplatinum, cisplatin, cyclophosphamide decrease its clearance and therefore increase myelosuppression so these drugs should be administered after paclitaxel (to decrease myelosuppression)
Mechanism and dose limiting toxicity vinorelbine
Vinka alkaloid derived from vinblastine. It inhibits tubular polymerization, disrupting the formation of tubules during mitosis.
Most of the drug is metabolized in the liver and excreted in the bile.
Dose-limiting toxicity is myelosuppression.
Loss of MSH2 & MSH6 in tumor MMR testing, what next step?
A Tumor genetics
B germline genetics
C methylation testing
**TEST QUESTION **
germline genetics
methylation testing is for Loss of MLH1 and PMS2 —> MLH1 promoter methylation
Which is more important for dosing methotraxate: biliary obstruction or poor renal function, both were choices
Poor renal function
(table 13.11 and 13.9 in Principles and Practice Chi)
confirmed (AW)
Complication with giving carbo as 3rd line for ovary cancer
hypersensitivity
Different side effect between SERM and aromatase inhibitors
** TEST QUESTION **
Tamox SE: endometrial cancer, VTE/CVA, hot flashes
- anti-est in breast, pro everywhere else (uterus, bone, liver, coagulation system) , fatty liver, cataracts, decreased LDL
Ralox: fewer serious side effects than tamoxifen. No increased UtCa risk
AI: hot flashes, osteopenia or osteoporosis, bone pain, diarrhea, heart disease
Both: hot flashes, sexual dysfunction
Which is mTOR inhibitor?
(Duplicate Qs)
the -olimuses not an option.
metformin also inhibits mTOR
Rapalogs:
Rapamycin
Temsirolimus
Everolimus
Deforolimus
Zotarolimus
Diet Derived:
Curcumin
Resveratrol
epigallocatechin gallate (EGCG)
3,3-Diindolylmethane (DIM)
Genistein
Caffeine
Bevacizumab MOA
binds to, and neutralizes, extracellular vascular endothelial growth factor (VEGF) A , preventing its association with endothelial receptors VEGFR1&2
ERBB2 gene encodes
ERBB2 also known as HER2/neu is a gene that encodes for the receptor tyrosine-protein kinase erbB-2.
How is mTOR related to pertuzumab?
Pertuzumab is a monoclonal antibody that binds to her2.
mTOR is downstream from this receptor
Her2 —> PI3K —> PIP3 —> PDK —> AKT —> mTOR
VEGF roles
Causative factor in blood vessel permeability and development
VEGFRs are predominantly found on endothelial cells and bone marrow derived cells
PI3K/AKT/mTOR pathway
PI3K-AKT-mTOR pathway promotes cell growth/survival and inhibits apoptosis and autophagy
- PI3K (phosphatidylinositol-3-kinase) is activated by Growth factor receptor or RAS
- Activated PI3K generates PIP3 (phosphatidylinositol-3-4-5-triphosphate)
- PIP3 activates PDK (phosphoinositide-dependent-kinase)
3.5. [PTEN inhibits PIP3]. - PDK phosphorylates AKT.
- phosphorylated AKT:
6a. Activates mTOR —> synthesis of proteins, needed for cell growth and cell cycle progression
6b. Inhibits Foxo family of transcription factors, responsible for transcription of genes needed for apoptosis and apoptosis cell cycle arrest
How does the HPV vaccine work
Recombinant L1 capsid protein (1 of 2 viral capsid proteins). Forms virus like particles (VLPs) which are combined with adjuvants. Adjuvants stimulate the immune system (aluminum based). VLPs induce humoral response with antbiotides and some cell-mediated immune response
What are HAMAs (human anti-mouse antibodies)?
When patients react to mouse antibodies as if they were a foreign substance, and create a new set of antibodies against the mouse antibodies
A single dose of mouse monoclonal antibodies has the potential to induce an immune response initiating the production on anti-mouse antibodies. However it has been shown that the concentration and IgG isotype of murine antibody used does not influence the production of HAMA [2]. Circulating HAMA has the capability to bind to mouse antibodies that are used in subsequent procedures or treatments. This diminishes the efficacy of the antibody based treatments. The presence of HAMA in patient samples can also be a cause of false positive or false negative immunoassay results, depending on the assay principles and the type of monoclonal antibodies used in the test
Estrogen isoforms created by
Alternative splicing vs. Alternate promoter usage
Pre-mRNA contains both coding regions (exons) that specify the protein sequence and introns that are removed during a process called splicing.
Alternative splicing allows for different combinations of exons to be included in the final mature mRNA, leading to mRNA transcripts that exclude or include specific exons, resulting in isoforms with variations in their protein structure and function.
genes may also have multiple promoters to create different isoforms
Endometrial cancer mutation associated with good prognosis
POLE
Excellent prognosis regardless of grade - high tumor mutation burden, tumor neoantigen production, and tumor infiltrating T cells
Endometrioisis related marker
CA125 is the most common tumor marker associated with endometriosis
ARID1A is the most frequently mutated in gene in endometriosis related ovarian cancer
EGFR (epidermal growth factor receptor) (how it works)
Cell membrane receptors that bind peptide growth factors are composed of an extra cellular ligand-binding domain, a membrane spanning region, and a cytoplasmic tyrosine kinase domain
Binding of a growth factor to the extracellular domain results in dimerization and confirmational shifts in the receptors and activation of the inner tyrosine kinase
The kinase transfers a phosphate group from ATP to a specific tyrosine residue on the growth factor receptor itself (auto phosphorylation) and on molecular targets inside the cell
Describe VEGF proteins and receptors
7 glycoproteins in the family: VEGF A-E and placental growth factor 1-2
- secreted by tumor cells, endothelial cells, stromal cells, leukocytes, platelets
VEGF-A,B,E stimulate angiogenesis via VEGFR1 (A/B) and VEGFR2 (A/E)
VEGFR-C,D activate VEGFR3 and stimulate lymphangiogenesis
ABE12 and CD3
—> high VEGF-D expression is independent poor prognostic factor for epithelial ovarian cancer
Describe HPV cancer pathway
E6/E7 are viral oncogene proteins:
- E6 inactivates p53 leading to its proteosomal degradation,
- E7 inactivates pRb by competing for binding and then frees transcription factor E2F —> expression of S phase genes, uncontrolled cell cycle progression
Cancer vaccines general mechanism
designed to induce antitumor immune responses against specific tumor-associated antigens (TAA). TAAs may be
(i) antigens that are overexpressed in cancers, (ex: Her2/Neu, or mesothelin)
(ii) cancer/germline antigens that are only expressed in germline cells, but can be reexpressed in cancer cells, (ex: MAGE-A1 (melanoma associated antigen), NY-ESO-1, New York esophageal squamous cell carcinoma 1)
(iii) cell lineage differentiation antigens, (ex: tyrosinase and gp100.
Delivery classifications:
i) peptide/protein-based, (ii) cell-based, (iii) DNA/RNA-based, or (iv) glycan-based.
Sipuleucel-T (Provenge) is first therapeutic cancer vaccine for prostate (autologous APCs exposed to cancer antigen, then returned to pt
Cancer risk with Peutz-Jeghers
Also gene?
(Duplicate)
- breast (32 to 54 percent)
- Colorectal – 39 percent
- Stomach – 29 percent
- Small bowel – 13 percent
- Pancreas – >15%
- SCTAT - >10%
**cervix (10 percent) adenoma malignum (minimal deviation adenocarcinoma)
Stk11 (tumor suppressor), autosomal dominant
multiple hamartomatous polyps in the gastrointestinal tract, mucocutaneous pigmentation
Cancer risk with MEN2
Parathyroid hyperplasia (10-25%),
medullary thyroid ca (almost all will get this, avg age 30s),
pheo (~50% will get this),
RET protooncogene
Describe the WNT/beta-catenin pathway
Beta-catenin (CTNNB1 gene) involved with cadherins in cell-cell adhesion junctions and plays a role in inhibiting excessive growth when cells contact one another (cytoplasmic function)
Nuclear target genes promote cell proliferation such as c-myc, cyclin D1 (nuclear function)
Beta-catenin regulated by the WNT pathway:
WNT extracellular ligands bind frizzled cell surface receptor –> Frizzled activates intracellular dishevelled which breaks up destruction complex —> increased accumulation of beta -catenin. Saturates cytoplasmic sites first then translocates to the nucleus.
Disheveled accomplishes this by inhibiting protein complex (axin, GSK-3 beta, APC) that normally proteolyticly degrades beta-catenin
Describe epithelial to mesenchymal transition
A series of events that progress epithelial tumor cells along a mesenchymal like continuum and up regulates survival and invasion signals promoting single cell autonomy
- down regulation of proteins that promotes homotypic cell attachment, such as E-cadherin.
- Upregulation proteins that promote heterotypic cell adhesion, such as P and N cadherin
An epithelial-mesenchymal transition (EMT) is a biologic process that allows a polarized epithelial cell, which normally interacts with basement membrane via its basal surface, to undergo multiple biochemical changes that enable it to assume a mesenchymal cell phenotype, which includes enhanced migratory capacity, invasiveness, elevated resistance to apoptosis, and greatly increased production of ECM components (1). The completion of an EMT is signaled by the degradation of underlying basement membrane and the formation of a mesenchymal cell that can migrate away from the epithelial layer in which it originated.
Cervical cancer pt s/p RT presents with fever, diarrhea, imaging with collapsed bowel, thick walls, dilated bowel
Thumb printing (thickening of haustral folds) = cdiff due to edema
UTD: findings consistent with toxic megacolon include small bowel dilatation, air-fluid levels (mimicking an intestinal obstruction or ischemia), and “thumb printing” (scalloping of the bowel wall) due to submucosal edema
What does the shoulder of the cell survival curve represent?
Sublethal damage that is repaired
What is Gompertzian tumor growth?
Doubling time increases as the tumor size increases
y axis: tumor size log scale
x axis: time
What shifts the cell survival curve to the left?
Left = less radiation needed
Oxygen and higher energy radiation
(JS) Increased temp, decreased pH, increased 2,3-DPG (enzyme that helps release O2 to tissue)
^isn’t this for RBC’s? JD -yes it’s for both. Whatever shifts O2 curve right shifts cell survival curve left
Which has highest LET?
alpha particle
Order of highest to lowest:
alpha, neutron, proton
MLH: Think it’s alpha then neutron
(Hi! LET the APrN do the work! (alpha, proton, neutron))
What is the advantage of protons over electrons in radiation?
Dose stops at precise place due to Bragg peak
(electrons are less precise; most of the dose is delivered 0.5-3 cm from patient’s skin and then gradually loses energy until reaches its target; affecting the non-target tissues)
The Bragg peak is a pronounced peak on the Bragg curve which plots the energy loss of ionizing radiation during its travel through matter.
What is refeeding syndrome?
Glu load leads to insulin productions with cells shifting P and K into cells > can lead to life threatening hypoP and hypoK
*malnourished patients receiving artificial refeeding (whether enterally or parenterally) are high risk for refeeding syndrome
Most common complication continent ileal conduit?
A stone formation
B leaking
C Can’t cath
Stones (5-35%) based on UTD
notes say: Can’t cath aka stomal stricture (2-14%, THIS ONE)
leaking (short term 2-10%)
stone formation (3% upper tract, 5-35% pouch calculi).
infection 5%.
Mgmt of ureteral injury at ureterovesical junction?
A ureteroneocystotomy
B Boari flap
C ureteroureterostomy
D transureterureterostomy
E nephrostomy
F nephrectomy
Ureteroneocystotomy
Lower ureter 90% (ureteroneocystotomy), psoas hitch ureteral reimplantation helps if cannot do either of the prior w/o tension).
Middle ureter 7% (Boari flap, transureterureterostomy).
Upper ureter 2% (nephrostomy, nephrectomy, autotransplation, ileal or appendiceal interposition graft)
Least thermal injury
A pure coag
B blend cut & coag
C pure cut
D spray
pure unblend cut
Highest risk for VRAM flap complications?
A Prior surgery
B smoking
C obesity
Obesity per lit review (AW-agree)
preop RT, obesity increase risk of wound complications/ deep SSI.
https://pubmed.ncbi.nlm.nih.gov/30113449/ says no risk in failure for pts w proper abdominal surgery
Notes said: Prior surgery (this one - prior Maylard?), smoking, obesity
What nerve injury is associated with numbness over the thigh after a pelvic LND?
genfem
What are the phases of wound healing?
Wound healing is classically divided into 4 stages:
(A) hemostasis / coagulation (mast cells, histamines, fibrin clot, vasoconstriction)
(B) inflammation: release of PMNs, macrophages
(C) proliferation / Fibroplasia (collagen deposition)
(D) remodeling
Tensile strength at 10% for PDS
56 days / 8w
Tensile strength at 10% for polyglycolic acid (vicryl)
28 days / 4w
Tensile strength at 10% for chromic catgut
14 days / 2w
also seen 21-28 days listed (excel detroit sheet says 28d, Justin says 14d)
Tensile strength at 10% for catgut
5 days / 1w
Tx for lidocaine tox
Duplicate
Usually supportive - use benzos for seizures
Dialysis is not useful
Pseudomonas UTI - which does NOT cover?
A zosyn
B Amox
C cipro
D meropenem
E aztreonam
Amox (this one).
Pseudomonas coverage: zosyn, ceftazidime or cefepime, aztreonam, cipro (not as much other fluroquinolones), levo, meropenem/doripenem (not as much imipenem), aminoglycosides
AG but need dual therapy (except for tx of UTI).
Oral: pick cipro (or levofloxacin but levo’s additional spectrum of coverage is usually unnecessary)
Which of the following is Inappropriate abx for neutropenic fever?
A Meropenem
B Piperacillin/tazobactam
C Ciprofloxacin plus amoxicillin/clavulanate
D Ceftriaxone
E Levofloxacin
Ceftriaxone (3rd gen without pseudomonas coverage)
Ceftazidine only 3rd generation with P. aeruginosa coverage
4th Generation - Adds Pseudomonas Coverage
NCCN 6/24:
Inpatient therapy:
- Cefepime (category 1)
- Imipenem/cilastatin (category 1)
- Meropenem (category 1)
- Piperacillin/tazobactam (category 1)
- Ceftazidime (category 2B)
Outpatient PO options:
- Ciprofloxacin plus amoxicillin/clavulanate (category 1)
- Levofloxacin
- Moxifloxacin (category 1)
Euvolemic Hyponatremia with high urine sodium (>40)
High urine Na >40, high urine osmolality >300 = SIADH
Euvolemic Hyponatremia with low urine sodium (<25)
Low urine Na <25, low urine osm <100 = primary polydipsia, malnutrition, potomania, or surreptitious diuretic use
Best abx for Klebsiella
Notes say: Ceftazidime (this one), imipenem and clinda, vanc and gent
From emedicine: 3rd gen cephalosporins, carbapenemas (ie: imipenem), AG (gent), quinolones
Lit review:
- third or fourth-generation cephalosporin as monotherapy
- respiratory quinolone as monotherapy
- either 3/4 G cephalosporin or respiratory quinolone + aminoglycoside.
- If penicillin-allergic: aztreonam or a respiratory quinolone
- If nosocomial: carbapenem monotherapy
Appearance of radiation enteritis on imaging
Diffuse bowel wall thickening
The ileum is the most frequently injured segment of the small intestine because of its location in the pelvis. Submucosal edema and fibrosis are seen at barium examinations as thickening and straightening of small-bowel folds and separation of adjacent loops. CT can directly reveal bowel wall thickening related to submucosal edema (Fig. 4A,4B). Fluoroscopic evaluation may show single or multiple areas of stenosis and small-bowel obstruction. Altered peristalsis may also be encountered. Fibrotic changes in the mesentery may cause fixation of bowel loops; in this condition, the loops appear angulated and tethered at small-bowel follow-through examination. Increased density in the mesentery may be evident at CT [5].
When placing Swan ganz- where are you if you see dicrotic notch
Past the PULMONARY VALVE and into the pulmonary artery
the location of the catheter can be determined by viewing the pressure measured from the tip of the catheter.
- right atrium (RA), the pressure usually averages <5 mmHg and fluctuates a few mmHg.
- right ventricle (RV), the systolic pressure increases to ~25 mmHg and the diastolic pressure remains similar to right atrial diastolic pressure.
- pulmonary artery (PA), the systolic pressure normally is similar to the right ventricular systolic pressure, but the diastolic pressure increases to about 10 mmHg because of pulmonic valve closure at the beginning of diastole.
- balloon Inflated occludes the PA branch. the pressure in the distal port rapidly falls, reaches a stable lower value that is similar to left atrial pressure (mean pressure normally 8-10 mmHg). The pressure recorded during balloon inflation approximates left atrial pressure because the occluded vessel and its distal branches that eventually form the pulmonary veins act as an extension of the catheter.
See: https://cvphysiology.com/heart-failure/hf008
Which component of the clotting cascade does PTT measure?
Intrinsic
“PTT=play table tennis, Inside”
Intrinsic
Which component of the clotting cascade does PT measure?
Extrinsic \
“PT= play tennis, outside”
JS- the only way out of the hospital is after PT eval (exit via PT)
What is the goal of phase I, II, III, IV trials?
I = defines max tolerated dose
*Ia trials will provide a single dose of the drug to each participant to determine the MTD within one treatment arm.
*Phase Ib trials run multiple arms simultaneously to test more than one dose of the drug.
II = defined biologic activity > effectiveness in a certain type of cancer and side effects
*Phase 2A studies are typically more preliminary and can address issues such as dosing and safety, while phase 2B studies are generally ‘mini-phase 3’ studies that provide data on efficacy.
III = usually RCT > confirm efficacy compared to standard treatments
*3a studies take place before FDA approval.
*3b studies are conducted after. Post-approval studies may further research how the treatment impacts quality of life, for example.
IV = large scale to see if can translate to larger population, post market studies.
What is smaller than the standard deviation? How do you calculate it?
Standard error of the mean
standard error of the mean = SD / square root of n
Doing multiple t-tests results in more of what type of error?
Type I (false positive aka erroneously rejecting null hypothesis)
What is the heparin induced thrombocytopenia 4 T score?
Scoring system consisted of four criteria, each of which was worth 0, 1, or 2 points. Study used ≤3 points to define low probability group (≤5%) for HIT, 4-5 points for intermediate and 6-8 points for high.
*The 4 Ts score should be used as a guide for clinicians and should not substitute for clinical judgment.
*Based on UTD, HIT antibody testing or presumptive treatment for HIT is not pursued with scores ≤3 (eg, we do not discontinue heparin or start a non-heparin anticoagulant) because the risk of HIT is low and presumptive treatment carries risks (eg, bleeding).
See pic
What is timing of HIT
Occurs 5-10 days after heparin exposure, or within 24hrs if antibodies already present
If Swan-ganz will not wedge, what value most closely corresponds?
PA diastolic pressure
pulmonary artery (PA) diastolic pressure is similar to the pulmonary artery wedge pressure and is similar to left atrial pressure (mean pressure normally 8-10 mmHg).
- accurate as long as no pulmonary HTN exists
See: https://cvphysiology.com/heart-failure/hf008
Best predictor of weaning off vent
Rapid shallow breathing index (RR/TV);
Successful weaning predicted if RSBI <105
Weaning failure predicted if >=105
For transureteroureterostomy - where should it run in relation to IMA
and great vessels
In front of great vessels can be in front of or behind IMA
“This is achieved by tunneling the donor ureter through the sigmoid colon mesentery superior to the inferior mesenteric artery to avoid kinking.”
BB: online textbook says inferior to IMA
MLH: Also saw pics of this above IMA online
Bottom line: IMA relationship probably depends on ureter length
JD: “ preferably cephalad to the IMA. If there is enough ureteral length that the ureter can be readily passed caudal to the IMA across to the contralateral side, then the patient is likely a candidate for ureteroneocystostomy.” Hinmans atlas of urologic surgery
