Justin Practice Questions 2022 Flashcards
Which pathway is TNF-beta part of
Extrinsic pathway of apoptosis
The mechanism of apoptosis mainly consist of two core pathways involved in inducing apoptosis; extrinsic pathway and intrinsic pathway. Extrinsic pathway refers to death receptor-mediated pathway, and the intrinsic pathway is a mitochondrial-mediated pathway
TNF-induced apoptosis is mediated primarily through the activation of type I receptors, the death domain of which recruits more than a dozen different signaling proteins, which together are considered part of an apoptotic cascade
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
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) - regulate apoptosis
- caspase - programmed cell death including apoptosis
- BAX (bcel-2 like protein 4) encoded by BAX gene - regulate apoptosis
Important: NOT VEGF
Best way to amplify DNA
PCR (polymerase chain reaction)
Best way to amplify DNA
PCR
Best way to quantitate protein
Western blot
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, effector, degradation
Oncogene associated with EMCA/lynch syndrome
c-myc
Think: M for MMR
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 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
IL-2 stimulates which cells?
T cells, including Cytotoxic (Tc) and helper (Th) cells
MHC and T cells - which go with which?
Tc = MHC1 = CD8 = apoptosis (From beginning to end = MHC1 & CD8)
Th = MHC2 = CD4 (helpers are middle men = MHC2 and CD4)
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 origin)
Where is MHC I expressed?
MHC class I molecules are ubiquitously expressed on all nucleated mammalian cells including cells of epithelial origin
(Most normal tissue except erythrocytes, plt, trophoblast, germ cells ?, neurons?)
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 = cytotoxic T cells
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
What does IL-1 do?
Mediates inflammation
Stimulates Th (cell mediated response).
Stimulates maturation of B cells (antibody mediated response or humoral immunity).
stimulates Macrophages (inflammatory response)
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. Do not require activation (i.e., with MHC1)
Which are the first immune cells to respond?
Polymorphonuclear neutrophils (PMNs)
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
What is the function of Immunoglobulins A, D, E, G, M
A = first response: defends mucosal surfaces
D = B cell receptors; stimulates release of IgM
E = allergy/parasites
G = 2nd line Ab; opsonization and neutralization. Crosses placenta
M = 1st line Ab; fizzes complement. B cell receptor
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 (CD80/86).
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?
Just S
Anthracyclines (doxorubicin, daunomycin, epirubicin, idarubicin)
Campthotecans (Irinotecan, topotecan)
S + G1
Antifolates (mtx, pemetrexed)
Nucleoside analogs (cytarabine, 5-FU/capecitabine, gemcitabine, 6-MP, fludarabine)
Hydroxyurea
Which chemos are M phase specific?
- Vinca alkaloids, taxanes: M phase
- taxanes
(Mitotic spindle poisons) - Eribulin, ixabepilone: causes arrest at G2/M
Which chemos are G2 phase specific?
- Bleomycin, topotecan: G2 phase
- Etoposide: G2 and S phase
- Eribulin, ixabepilone: causes arrest at G2/M
GEE 2 BET
G2, etoposide, eribulin, bleomycin, (redundant e), topotecan
Which Chemos G1 phase specific?
No Chemos specifically act at G1; however,
gemcitabine: S phase specific, also blocks progression of cells through G1 to S
(I think the answer is MTOR inhibitors, ActD, Tamoxifen - jv)
Which chemos are non-cell cycle specific?
G1, G2, S
- Alkylating agents (cyclophosphamide, ifos, melphalan, etc)
- platinum
- bleo
- mitoC
- nitrosoureas
- nitrogen mustard
- ecteinascidin
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 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
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
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.
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
Substitute for endogenous reduced-folate cofactor Tetrahydro folic acid that is Decreased by mtx, “rescues” cells by replenishing intracellular reduced folate pools and preventing mtx toxicity via blockade of thymidine synthesis (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 and BM from cisplatin and cyclophosphamide, protects salivary glands during radiation tx
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
- high conc in peritoneum
- no need for liver activation
- high volume IP dialysate (low vol increases IP clearance rate rapidly, which is bad)
- hydrophilic, ionized compounds.
What drug is PPE associated with?
Chi: Capecitabine > 5-FU, Doxil, pemetrexed
Also Multitargeted tyrosine kinase inhibitors sorafenib, sunitinib
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 metabolized in the kidney, with 50% of the dose eliminated within 4 hours after administration.
Pemetrexed: About 90% of the drug is excreted unchanged in the urine within 24 hours.
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
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
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, cataracts
AI: hot flashes, osteopenia or osteoporosis, bone pain, diarrhea, heart disease
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
Per NCCN: high risk
- 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
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) Downregulation of CTR1 (Copper transporter 1) transporter (reduced intracellular accumulation of platinum)
2) Elevated levels of cellular glutathione (GSH) inhibits gamma-glutamylcystein synthestase (basically, intracellular inactivation) which reduces GSH trying to restore drug sensitivity
3) Nuclear excision repair (NER) pathway which repairs platinum-DNA adducts through ERCC1 protein (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. Mechiansm of action: binding with DNA causing INTRAstand cross-links and DNA adducts
cisplatin-IR synergistic interaction requires the DNA-protein kinase dependent NHEJ pathway for joining of DNA DSBs, and the presence of a cisplatin lesion on the DNA blocks this pathway.
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.
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 cycles: S phase
Mechanism of action: doxorubicin
Anthracycline antibiotic from Streptomyces peucetius
1) DNA binding and intercalating, inhibiting DNA synthesis (S phase, though not completely specific)
2) Free radical formation - this may be related to the cardiotoxicity
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.
Incidence is 1 to 20% from 300mg/m2 to 500mg/‘m2 if given every 3 weeks.
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!
Which of the following is the Most leukemogenic chemo?
A etopsoside
B platin
C 5FU
D melphalan
melphalan
Alkylating agents (especially melphalan), procarbazine, and the nitrosoureas seem to be the major offenders. Prolonged use of etoposide has been associated with the development of leukemia.
The cumulative 7-year risk of developing acute nonlymphocytic leukemia in patients treated primarily with oral melphalan for ovarian cancer has been reported to be as high as 9.6% in patients receiving therapy for more than 1 year. Although cisplatin has been associated with the development of acute leukemia, the risk is lower than with the alkylating agents
“Women receiving melphalan were two to three times as likely to develop leukemic disorders than were women receiving cyclophosphamide.”
Least protein bound chemo?
A doxorubicin
B topotecan
C gem
D carbo
E ifos
Gem
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%
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
Minimally emetic (<10%)
- Bev
- Bleo
- Nivo, pembro, dostar, durva, ipi
- Trastuzumab
- Vinblastine, vincristine, vinorelbine
NCCN <10%:
Alemtuzumab • Asparaginasee • Atezolizumab • Avelumab • Belantamab mafodotin-blmf • Bevacizumab • Bleomycin • Blinatumomab • Bortezomib • Cemiplimab-rwlc • Cetuximab • Cladribine
Cytarabine <100 mg/m2 • Daratumumab • Daratumumab and hyaluronidase-fihj
• Decitabine • Dexrazoxane • Dostarlimab-gxly • Durvalumab • Elotuzumab • Fludarabine • Ipilimumab • Luspatercept-aamt
Margetuximab-cmkb • Methotrexate ≤50 mg/m2 • Nelarabine • Nivolumab • Nivolumab/relatlimabrmbw
• Obinutuzumab • Ofatumumab • Panitumumab • Pembrolizumab • Pertuzumab • Pertuzumab/trastuzumab
and hyaluronidase-zzxf • Ramucirumab
• Rituximab • Rituximab and hyaluronidase • Siltuximab • Sirolimus-albumin • Teclistamab-cqyv • Temsirolimus • Trastuzumab • Trastuzumab and hyaluronidaseoysk
• Tremelimumab-actl • Valrubicin • Vinblastine • Vincristine • Vincristine (liposomal) • 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, HYDROPHILIS, 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 (THIS ONE per Sjovall 2002, 2nd is lung cancer), colon, gastric
How does cisplatin augment radiation?
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 (abby becomes muscular)
Telomerase
Telomeres are at “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%)
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)
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
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
Which chemos requires adjustment for liver compromise?
(Duplicate)
TEST QUESTION
MTV ME CD
methotrexate
Taxanes (docetaxel/ paclitaxel/nab-paclitaxel)
vinkas (vincristine, vinblastine, vinorelbine)
Mitoxantrone
Epirubicin
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
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
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
Moderate (30-90%)
- doxorubicin
- Azacytidine
- Carboplatin / Oxaliplatin
- Cyclophosphamide <1,500 mg/m2
- Doxorubicin/Epirubicin
- Ifosfamide
- Irinotecan /liposomal irinotecan
- Temozolomide
- Thiotepa
- Trabectedin
Minimally emetic (<10%)
- Bev
- Bleo
- Nivo, pembro
- Trastuzumab
- Vinblastine, vincristine, vinorelbine
Which chemo is activated within a tumor cell?
** TEST QUESTION **
Capecitabine
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%)
Aldesleukin >12–15 million IU/m2 • Amifostine >300 mg/m2 • Bendamustine • Busulfan • Carboplatin AUC <4 • Carmustine ≤250 mg/m2 • Clofarabine • Cyclophosphamide ≤1500 mg/m2 • Cytarabine >200 mg/m2 • Dactinomycin • Daunorubicin
Dinutuximab • Doxorubicin <60 mg/m2 • Dual-drug liposomal encapsulation of cytarabine and daunorubicin
• Epirubicin ≤90 mg/m2 • Idarubicin • Ifosfamide <2 g/m2
per dose
• Irinotecanb • Irinotecan (liposomal) • Lurbinectedin • Melphalan <140 mg/m2
Methotrexateb ≥250 mg/m2 • Naxitamab-gqgk • Oxaliplatin • Romidepsin • Temozolomide • Trabectedinb
Minimally emetogentic chemos
**TEST QUESTION **
Vincristine, Nivolumab, Bev, Bleo, MTX <50, Pembro
NCCN. <10%:
Alemtuzumab • Asparaginasee • Atezolizumab • Avelumab • Belantamab mafodotin-blmf • Bevacizumab • Bleomycin • Blinatumomab • Bortezomib • Cemiplimab-rwlc • Cetuximab • Cladribine
Cytarabine <100 mg/m2 • Daratumumab • Daratumumab and hyaluronidase-fihj
• Decitabine • Dexrazoxane • Dostarlimab-gxly • Durvalumab • Elotuzumab • Fludarabine • Ipilimumab • Luspatercept-aamt
Margetuximab-cmkb • Methotrexate ≤50 mg/m2 • Nelarabine • Nivolumab • Nivolumab/relatlimabrmbw
• Obinutuzumab • Ofatumumab • Panitumumab • Pembrolizumab • Pertuzumab • Pertuzumab/trastuzumab
and hyaluronidase-zzxf • Ramucirumab
Rituximab • Rituximab and hyaluronidase • Siltuximab • Sirolimus-albumin • Teclistamab-cqyv • Temsirolimus • Trastuzumab • Trastuzumab and hyaluronidaseoysk
• Tremelimumab-actl • Valrubicin • Vinblastine • Vincristine • Vincristine (liposomal) • Vinorelbine
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 5 CD
Mtx
Taxanes
Vinkas
Mitoxantrone
Epirubicin
5FU
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 **
Arthralgia
Cell cycle specific chemo
S only
- Anthracyclines (doxorubicin, daunomycin, idarubicin, epirubicin)
- Mitoxantrone
- Etoposide
- ActD
- Campthothecins (Topotecan, Irinotecan)
M only
- Vinca alkaloids
- taxanes
- colchicine
G1 + S
- Antifolates (mtx, pemetrexed)
- nucleoside analogs (5-FU/capecitabine, gemcitabine, cytarabine, fludarabine, 6-MP)
- Hydroxyurea
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?
Notes said “Ifosfamide (THIS ONE we think)”
But literature review suggests platinum agents are least likely in this list.
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
Granulose cell
(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.
Multinucleated giant cells
Dysgerminoma
What cells make hCG?
Syncytiotrophoblast
What makes up OVA1?
CA-125
transthyretin (pre-albumin)
Apo A-1
Beta2 microglobulin
transferrin
5 things!
This is a repeated question
What tumor marker is elevated for PSTT
HPL
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)
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%)”
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%)
Levels of Breslow: Prognostic for Melanoma
Tamox least likely to be associated with what benign growth?
answer: ovarian cysts
most likely to be associated with in order of highest association:
polyps
hyperplasia
fibroids
*also sarcomas
What subunit of HCG is shared with other hormones
Alpha same as LH, FSH, TSH; beta is distinct
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
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)
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?
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, pemetrexed
Also Multitargeted tyrosine kinase inhibitors sorafenib, sunitinib,
—
Notes say:
Docetaxel - not mentioned in Chi, but skin toxicity
Chi doesn’t discuss: Vinorelbine, cytarabine (neither listed in UTD)
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)
Paclitaxel: carboplatinum, cisplatin, cyclophosphamide decrease its clearance and increase myelosuppression so these drugs should be administered after paclitaxel
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 when methotraxate, biliary obstruction or poor renal function, both were choices
Poor renal function
(table 13.11 and 13.9 in Principles and Practice Chi)
Complication with giving carbo as 3rd line for ovary cancer
hypersensitivity
Different side effect between SERM and aromatase inhibitors
** TEST QUESTION **
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, cataracts
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 and 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 (THIS ONE), amplification, 2 other choices
Endometrial cancer mutation associated with good prognosis
Excellent prognosis regardless of grade POLE (why? 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)
●Colorectal – 39 percent
●Stomach – 29 percent
●Small bowel – 13 percent
●Pancreas – 11 to 36 percent
breast (32 to 54 percent),
ovary (21 percent),
**cervix (10 percent) adenoma malignum;
Also benign sex cord stromal with annular tubules ovary tumors
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),
cutaneous lichen amyloidosis
hirschsprung disease
Describe the WNT/beta-catenin pathway
Beta-catenin (CTNNB1) is involved with cadherins in cell-cell adhesion junctions and plays a role in inhibiting excessive growth when cells contact one another
Beta-catenin activity is regulated by the WNT pathway.
WNT extracellular ligands bind frizzled cell surface receptor.
Frizzled activates intracellular disheveled —> increased beta -catenin translocated 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.
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
Which has highest LET?
alpha particle
Order of highest to lowest:
alpha, proton, neutron
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 Bragg peak?
Hint: associated with protons
Bragg peak: rapid deposition of most of their energy at a depth, with a steep falloff in dose to near zero shortly after the peak.
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, cells shift P and K into cells, can lead to life threatening hypoP and hypoK
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
Options: ureteroneocystotomy (this one), Boari, uretero-uretero.
Lower ureter 90% (ureteroureterostomy vs 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
What nerve injury is associated with numbness over the thigh after a pelvic LND?
genfem
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
Tensile strength at 10% for catgut
5 days / 1w
Tx for lidocaine tox
Duplicate
Usually supportive - use benzos for seizures
Dialysis is not useful
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
4th Generation - Adds Pseudomonas Coverage
NCCN 6/23:
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 clothing cascade does PTT measure?
Intrinsic
Notes say: (PITT like pittsburgh) (?)
Which component of the clothing cascade does PT measure?
Extrinsic (PET like pets!)
What is the goal of phase I, II, III, IV trials?
I = max tolerated dose
II = biologic activity
III = usually RCT
IV = large scale to see if can translate to larger population”
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.
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
