Ther III Exam 4 combined

What organs can be transplanted? (6)

1. heart

2. lung

3. kidney

4. liver

5. pancreas

6. intestine

CAUSES OF END STAGE ORGAN DYSFUNCTION

1. Kidney

2. Liver

3. Heart

4. Lung

5. Pancreas

6. Small bowel

1. HTN, DM

2. alcoholic cirrhosis, Hep B/C

3. ventricular failure, viral infxns

4. COPD, idiopathic pulmonary fibrosis

5. DM

6. short bowel syndrome, fx disorders

Living donors are only for ______ and ______ transplants

liver, kidney

IMMUNE SYSTEM

1. Innate →

2. Adaptive →

1. rapid, 1st line of defense

2. develop highly specific response, “immune memory”

INNATE IMMUNE SYSTEM

1. Physical → 3

2. Mechanical → 4

3. Cells (leukocytes) → 5

1. skin, GI tract, resp tract

2. urine flow, tears, saliva, normal flora

3. macrophages, neutrophils, mast cells, eosinophils, basophil

ADAPTIVE IMMUNE SYSTEM

Things that differentiate the adaptive immune

1. -

2. -

3. ability to _______ via cytokines

4. ________ w each subsequent infxn

1. specificity

2. memory

3. amplify

4. evolves

ADAPTIVE IMMUNE SYSTEM

1. 2 major arms →

2. →

1. Humoral → ABs, complement

2. cell-mediated → T lymphocytes

CELLS OF THE ADAPTIVE IMMUNE SYSTEM

1. _________ → specific for individual antigens, initiates T cell activation

2. _________ → antigen recognition and production of antibodies

1. T lympho

2. B lympho

B CELLS CAN DIFFERENTIATE INTO →

1. plasma cells → AB factories

2. memory B cells → long term immunity

______________ →

cell surface antigens expressed on all nucleated cells in the body

plays an important role in transplantation, cell interxns, self-recognition

human leukocyte antigens (HLA)

ANTIGEN PRESENTING CELLS → 3

1. macrophages

2. dendritic cells

3. B cells

T CELL ACTIVATION

Requires 3 SIGNALS for activation →

1. antigen presentation w MHC

2. co-stim signal CD 80/86

3. Interxn of IL2 w IL2 receptor

B CELL ACTIVATION →

1. T cell dependent / independent activation

2. B cell proliferation + maturation

3. B cell differentiation → plasma or memory

IMMUNOGLOBULINS (Antibody)

Glycoprotein contains 4 peptide chains

1. →

2. →

3. chains held together by _______ bonds

1. 2 identical heavy chains

2. 2 identical light chains

3. disulfide

INITIALLY, plasma cells secrete ________

IgM

On SECOND EXPOSURE, memory B lymphocytes predominately produce _______

IgG

IMMUNOGLOBULINS

1. _____ → long-term immunity

2. _____ → first antibody secreted post antigen exposure

3. _____ → in fluid secretions, GI, GU, resp tract

4. _____ → on mast cells (asthma, hay fever)

5. _____ → many immune fx, not completely understood

1. IgG

2. IgM

3. IgA

4. IgE

5. IgD

TYPES OF IMMUNOSUPPRESSIVE AGENTS

1. Induction

2. Maintenance

1. basiliximab OR thymoglobulin OR alemtuzumab

2. CNI, antimetabolites, steroids

INDUCTION: Antithymocyte globulin (rATG, Thymo)

1. Brand →

2. ______ antibodies, directed against ___________

3. ______ agent

4. Dose: 1.5 mg/kg ___________

5. Immunosuppressive effects last _______

6. PREMEDICATION before every dose →

1. Thymoglobulin

2. rabbit, T cell surf antigen CD3

3. depleting

4. IVPB per dose over a couple of days

5. months

6. APAP, diphenhydramine, methylpred

ANTITHYMOCYTE GLOBULIN (rATG, Thymo) ADEs

1. Cytokine release syndrome →

2. →

3. →

4. →

5. MONITORING → 4

1. fever, chills, malaise

2. leukopenia, TC

3. skin rash, serum sickness

4. infxn

5. CBC w diff, efficacy via ALC, toxicity via WBC & platelets, vital signs during admin

INDUCTION: ALEMTUZUMAB

1. Brand name →

2. Monoclonal antibody against _____

3. ______ agent

4. Dose (off-label) 30 mg __________

5. t1/2 = 12 days → prolonged _______

1. Campath

2. CD52

3. depleting

4. IV/SQ during surg

5. lymphopenia

ALEMTUZUMAB (CAMPATH) ADES

Treatment

1. Infusion reactions (fever, chill, hypotension, rash, NVD, dyspnea) →

2. Neutropenia →

3. Anemia →

4. Thrombocytopenia →

1. premed w APAP, diphenhydramine, methylpred

2. filgrastim

3. erythropoetin

4. transfusion

INDUCTION: BASILIXIMAB

1. Brand name →

2. Chimerized MAb, ________

3. __________ agent

4. Dose: 20 mg __________

5. ADEs →

1. Simulect

2. IL2 receptor antag

3. non-depleting

4. IVPB on POD0 + POD4

5. fewer/less sev, NO CYTOKINE RELEASE SYNDROME

Which induction agent is non-depleting and doesn’t cause cytokine release syndrome?

basiliximab (Simulect)

METHYLPREDNISOLONE

1. MOA: down regulate cytokine gene expression (in particular, ____) → -T cell proliferation

2. Redistribution of _______ = -antigen presentation

3. ________ effect

1. IL2

2. monocytes (APC)

3. antiinflam

MAINTENANCE IMMUNOSUPPRESION

1. Calcineurin inhibitors →

2. Antiproliferative agents →

3. Corticosteroids →

4. mTOR inhibitors →

5. Costimulation blockers →

1. tacrolimus, cyclosporine

2. mycophenolate, azathioprine

3. prednisone

4. sirolimus, everolimus

5. belatacept

CALCINEURIN INHIBITORS (CNIs)

1. Tacrolimus PO 0.05-1 mg/kg/dose q12h → conversion to IV, SL

2. Cyclosporine PO 3-5 mg/kg/dose q12h → conversion to IV

3. Which brand of cyclosporine is non modified form (NOT INTERCHANGEABLE)?

4. *Dose medications based on _______! (NTI)

1. IV = ¼ PO, SL = ½ PO

2. IV = 50% PO over 2-6h cont inf

3. Sandimmune

4. levels

CALCINEURIN INHIBITORS ADES

1. →

2. →

3. →

4. Metabolism →

1. tacrolimus → hyperglycemia, alopecia, neurotox

2. both → NEPHROTOX, HTN, infxn, EL abnormalities

3. cyclosporine → gingival hyperplasia, hyperlipidemia, hirsutism, gout

4. CYP3A4, Pgp

CYP3A4 INHIBITORS → 6

1. clarithromycin, erythromycin

2. azoles

3. diltiazem, verapamil

4. protease inhib (-navirs)

5. grapefruit

6. CBD products

CYP3A4 / PGP INDUCERS → 4

1. rifampin

2. phenytoin

3. carbamazepine

4. St john wort

PGP INHIBITORS → 5

1. clarithromycin, erythromycin

2. azole

3. verapamil

4. amiodarone, dronedarone, propafenone

5. carvedilol

3A4 / Pgb inhibitors will _____ CNI concentations

inc

3A4 / Pgb inducers will ______ CNI concentrations

dec

ANTIMETABOLITES

1. Agents =

2. MOA: inhibit _________

3. *Dose adjust medications based on _______!

1. mycophenolate (Myfortic, CellCept), azathioprine (Imuran)

2. cell cycle prolif

3. side effects

MYCOPHENOLATE

1. ADEs → 5

2. DDIs →

1. GI upset, leukopenia, anemia, TC, TERATOGENIC

2. birth control

AZATHIOPRINE

1. ADEs → 6

2. DDIs →

1. leukopenia, anemia, TC, pancreatitis, hepatotox, squamous skin cell CA

2. allopurinol

MAINTENANCE: STEROIDS

1. Dose →

2. ADEs → 4

1. prednisone 5-10 mg daily

2. hyperglycemia, HTN, insomnia, +weight

mTOR INHIBITORS

MOA: regulates synthesis of proteins necessary for cell cycle progression from G1 → S phase, blocks IL2 signal transduction → regulates cell growth & proliferation

1. Agent 1 + dosing →

2. Agent 2 + dosing →

3. *Dose medications based on _______!

4. ADEs → 5

5. *BBW: +risk of ________ in first 30 days post transplant

6. DDIs →

1. sirolimus (Rapamune) → 2 mg PO daily

2. everolimus (Zortress) → 0.75 mg q12h

3. levels

4. TC, anemia, proteinuria, hyperlipidemia, -wound healing

5. hepatic artery/renal artery thrombosis

6. CYP3A4, Pgp

What 2 classes are CYP3A4 / Pgp substrates?

CNIs, mTOR

Which class should NOT be used within the 1st month of transplant?

mTOR

BELATACEPT

1. MOA:

2. Dosage form:

3. Frequency: month 0-3 on days 1,5 + weeks 2,4,8 → Month 4-12 ______

4. **may be used in _________ patients only!!

5. BBW

1. costim blocker

2. IV inf

3. q 4w

4. EBV+

5. lymphomas & other infxns

Which 2 classes has low rejection risk?

CNIs, antimetabolites

Which drug can you not use if you are EBV negative?

belatacept

COMMON IMS REGIMEN

1. →

2. →

3. →

4. _____ tablets/capsules per day

1. tacrolimus 3 mg q12h (goal level 8-10) → 3 cap

2. mycophenolate 1000 mg q12h → 4 tab

3. prednisone 5 mg daily → 1 tab

4. 15

Consequences of medication noncompliance → 3

1. acute rejection episodes

2. organ loss

3. death

HYPERACUTE REJECTION
within few min - few hours

1. Result of destruction of transplant by preformed _____ antibodies to donor vascular endothelium

2. Tissue damage occurs through → 2

1. IgG

2. AB-depend cytotox, complement cascade

ACUTE CELLULAR REJECTION
in first few months

1. Caused by infiltration of allograft by _____

2. _____ and ______ effect on graft

3. Gold standard of dx →

4. Relatively easy to treat →

1. T cells

2. inflam, cytotoxic

3. biopsy of graft

4. methylpred 500 mg IV daily x3, steroid resistant = thymoglobulin

ANTIBODY MEDIATED REJECTION

more difficult to treat → 4

1. plasmapheresis

2. IVIG

3. rituximab

4. bortezomib

Pneumocystis jiroveci (PJP OR PCP) PROPHYLAXIS

1. *Drug of choice to prevent PCP pneumonia →

2. Doses usually given for ________

3. Alternatives for prophylaxis → 3

1. SMX/TMP

2. 6-12m

3. dapsone, atovaquone, pentamidine

PCP PROPHYLAXIS ALTERNATIVES comments

1. Dapsone

2. Atovaquone

3. Pentamidine

1. check G6PD def (hemolysis dose related), monitor CBC weekly x6m then q6m

2. take w high fat meal, anemia/neutropenia

3. bitter/metallic taste

1. DRUG OF CHOICE TO TREAT PCP →

2. Alt tx choices →

1. SMX/TMP → add prednisone if pAO2<70

2. dapsone, atovaquone

VIRAL RISK STATUS FOR CYTOMEGALOVIRUS (CMV)

In Donor / Recipient format

1. High risk

2. intermediate risk

3. low risk

1. (+/-)

2. (+/+), (-/+)

3. (-/-)

CYTOMEGALOVIRUS (CMV)

1. Prophylaxis agent 1 + risk use →

2. Prophylaxis agent 2 + risk use →

1. valganciclovir → high + intermed

2. letermovir → high

Letermovir is ineffective against HSV, must co-administer with _______

acyclovir

CYTOMEGALOVIRUS (CMV) TREATMENT

1. Preferred for severe tissue invasive CMV →

2. Preferred for CMV viremia →

3. Refractory CMV → PO → special note

4. Refractory CMV → IV → special note

1. ganciclovir

2. valganciclovir (V for viremia)

3. maribavir → drug assoc dysgeusia

4. cidofovir, foscarnet → avoid if possible due to nephrotox

FUNGAL PROPHYLAXIS

Center specific based on risk

1. _________ 5 mL swish & swallow TID → preventing oral and esophageal candidiasis

2. _________ 200 mg daily → risk of invasive fungal infxns, must account for DDIs

1. nystatin

2. fluconazole

Which class do you dose based on side effects?

antimetabolites (mycophenolate, azathioprine)

Which type of rejection episode is treated with IV methylprednisone?

A. hyperacute

B. acute cellular

C. antibody mediated

B

ETIOLOGY OF CANCER

Carcinogenesis → the 4 steps

1. initiation → irrevers

2. promotion → REVERSIBLE

3. conversion → irrevers

4. progression → irrevers

which step of carcinogenesis is reversible?

promotion

CARCINOGENS

1. Lifestyle → 4

2. Environmental → 2

3. Chemical → 3

4. Infectious agents → 4

1. smoking, alc, UV light, high fat diet

2. UV radiation, ionizing radiation

3. immunosupp drugs, certain antineoplastics, coal tar

4. hep B/C, HIV, HPV, H pylori

6 HALLMARKS OF CARCINOGENESIS

1. _________ sustaining proliferative signaling

2. _________ evading growth suppressors

3. _________ activating invasion & metastasis

4. _________ enabling replicative immortality

5. _________ inducing angiogenesis

6. _________ resisting cell death

1. oncogenes

2. tumor supp genes

3. hematogenous & lymphatic spread

4. telomerase & senescence

5. VEGF

6. oncogenes & tumor supp genes

Protooncogenes (precursor of oncogene)

Examples → 4

RAS, EGFR, HER2, VEGF

Tumor suppressor genes

Examples → 2

retinoblastoma (Rb), BRCA1/2

__________ → location of tumor is not specified

agnostic

1. ________ intent: long term remission, no recurrence

2. ________ intent: improve symptoms, QoL, and overall survival

1. curative

2. palliative

Following applies to SOLID tumors (eg breast, lung, colon)

1. __________ therapy: given BEFORE definitive tx (usually surgery) → purpose

2. __________ therapy: given AFTER definitive tx → purpose

3. These terms generally apply to __________ (ie. resectable) disease only

1. neoadjuvant → shrink tumor

2. adjuvant → prevent recurrence

3. non-metastatic

Following apply to HEMATOLOGIC malignancies

1. ________ therapy (given first) → induce remission w no visible evidence of cancer

2. ________ therapy (start after ^) → eradicate any remaining cancer cells

3. ________ therapy → prevent recurrence

1. induction

2. consolidation

3. maint

WHICH IS TRUE OF THE NCCN GUIDELINES?

A. They are strictly evidence-based

B. They are updated frequently

C. They only contain guidelines for treatment of cancer

D. They require a paid subscription

B

T or F:

THE NCCN GUIDELINES ARE THE ONLY GUIDELINES AVAILABLE FOR THE ONCOLOGY SETTING.

F

WHICH CLASS OF DRUGS IS NOT AN IMMUNE CHECKPOINT INHIBITOR (ICI)?

A. CTLA-4 inhibitor

B. CD-19 inhibitor

C. PD-1 inhibitor

D. PD-L1 inhibitor

B

WHICH IS MOST CORRECT REGARDING THE ONSET OF ICI-INDUCED IRAES?

A. During IV infusion

B. Within weeks after starting therapy

C. 1-2 days after starting therapy

B

WHICH ORGAN SYSTEM MAY BE AFFECTED BY IRAES?

A. Hepatic

B. Dermatologic

C. Endocrine

D. All of the above

D

STEROIDS MAY BE USED FOR TREATMENT OF WHICH IRAE?

A. Hypothyroidism

B. Hyperglycemia

C. Dermatitis

C

WHICH IS TRUE REGARDING STEROID TAPERING IN PATIENTS WITH ICI-INDUCED IRAES?

A. Taper should begin after one week of therapy, regardless of symptom control

B. Taper may be rapid (over 1-2 weeks)

C. Taper should be slow (over at least 4 weeks)

C

WHICH IS NOT A CHRONIC STEROID TOXICITY?

A. Osteoporosis

B. Infection

C. Leukocytosis

D. Cataracts

C

1. 2 most commonly used PD-1 inhibitors →

2. Type

1. nivolumab (Opdivo), pembrolizumab (Keytruda)

2. IgG

CHECKPOINT INHIBITORS: ADEs

1. IrAEs →

2. Onset: within _______ of starting therapy, sometimes delayed up to 1 year

3. May affect _____ organ systems

4. _______ associated with more severe IrAEs than PD-1 or PD-L1 inhibitors

5. ^ _____ inhibitor

1. immune-related AEs

2. weeks-3m

3. multiple

4. ipilimumab

5. CTLA4

IRAEs SYSTEMS INVOLVED (most common)

1. Pulmonary

2. Endocrine

3. GI

4. Skin

5. Liver

1. pneumonitis

2. hypothyroid, hypophysitis, hypopituitarism, adrenal insuff

3. colitis

4. pruritus, rash

5. transaminitis, hepatitis

IRAES MANAGEMENT

1. IrAEs may require treatment with _________

2. DO NOT USE FOR …

1. corticosteroids

2. hypothyroid, hyperthyroid, hyperglycemia

IRAES MANAGEMENT

1. Grade 1 mild

2. Grade 2 moderate

3. Grade ¾ sev-life threatening

1. consider holding immunotherapy, loperamide, Lomotil, hydration, close monitor

2. HOLD, pred/methylpred

3. HOLD, consider DC, methylpred, if no improv add infliximab or vedolizumab

TUMOR GROWTH MODELS

1. __________ model is the most established

2. Caveat: assumes all cancers are _________ to treatment and that resistance to treatment & metastases do not occur

3. __________ = proportion of actively dividing cells

4. __________ = amount of time it takes for 1 cell or group to divide / double in size

5. __________ = certain % of cancer cells that will be killed with each course of chemo

6. Tumor growth is _______

1. Gompertz

2. equally responsive

3. growth fraction

4. doubling time

5. cell kill hypothesis

6. exponential

TUMOR GROWTH MODEL SUMMARY

1. Green oval

2. Blue oval

3. Red oval

4. Downward zig zag → chemo is often continued after tumor is undetectable to ensure a maximal # of cells are killed and to prevent recurrence

1. high GF + short DT → chemo most effective, tumor less likely dx

2. clinically detectable → ideally dx tumors before they reach this size

3. -GF + longer DT → chemo less effective

4. cell kill hypothesis

Patient with acute leukemia achieves a complete remission after his first cycle of chemo. Which term describes this chemotherapy?

A. adjuvant

B. induction

C. consolidation

B
(leukemia = hematologic

first cycle = induction)

Patient with metastatic breast cancer receives her first line of chemotherapy. Which term describes this chemotherapy?

A. adjuvant

B. induction

C. consolidation

D. none of the above

D

(neoadjuvant)

Which occurs the EARLIEST in the process of carcinogenesis?

A. conversion

B. promotion

C. progression

B

LUNG CANCER COMPARISON

NON-small cell lung cancer (NSCLC)

1. Proportion of lung cancers

2. Natural history

3. Therapy response

4. Pathology

5. Smokers

6. Actionable molecular alterations?

1. 85-95%

2. slower, 50% metastases

3. mod sens to radiation, low sens to chemo

4. adenocarcinoma > squamous cell > large cell

5. +incidence of squamous cell

6. YES

LUNG CANCER COMPARISON

Small cell lung cancer (SCLC)

1. Proportion of lung cancers

2. Natural history

3. Therapy response

4. Pathology

5. Smokers

6. Actionable molecular alterations?

1. 10-15%

2. faster, 60-70% metastases, death in 2-4m w/o tx

3. high sens to radiation/chemo (but responses do not last)

4. classical SCLC

5. higher incidence > NSCLC

6. NO

LUNG CANCER RISK FACTORS

1. _________ exposure

2. _________

3. _________
   Occupational/environmental exposure (petroleum, nickel, arsenic, etc)

4. _________ disease (PF, COPD, asthma)

5. _________

1. tobacco

2. asbestos

3. ionizing radiation

4. lung

5. genetics

UNITED STATES PREVENTIVE SERVICES TASK FORCE (2021)

Screening Guidelines

1. ______

2. ______

3. ______

1. age 50-80

2. >20 pack yr hx

3. current smoker or quit w/in 15 yrs

NO

(15 pack year hx, quit 20 yrs ago)

LUNG CANCER S/S

1. 6 →

2. Laboratory abnormalities → 4

3. SCLC →

4. ____________ syndrome (tumors pressing on/blocking the vein causing swelling in face/neck/upper body + breathing difficulties)

1. cough, -weight, dyspnea, chest pain, hemoptysis (coughing up blood), hoarseness

2. hyperCa, anemia, leukocytosis, TC

3. SIADH, cushing’s

4. superior vena cava

TREATMENT MODALITIES FOR NSCLC/SCLC

1. ________

2. ________ (RT)

3. Systemic therapy →

4. Systemic therapy →

5. Systemic therapy →

1. surgery

2. radiation therapy

3. chemo → plat doublet (cisplatin/carboplatin + another chemo agent)

4. Checkpoint inhib (CPI)

5. Targeted therapy → NSCLC ONLY

NSCLC TREATMENT (NON-SMALL)

Stage I, II, III (resectable)

1. Treatment of choice =

2. Higher risk patients will also receive neoadjuvant and/or adjuvant therapy →

3. Higher risk patients will also receive neoadjuvant and/or adjuvant therapy → if EGFR +

4. Higher risk patients will also receive neoadjuvant and/or adjuvant therapy → if ALK +

1. surgery

2. plat doublet ± CPI, or CPI

3. osimertinib ± plat doublet

4. alectinib

NSCLC TREATMENT (NON-SMALL)

Stage III (unresectable) →

Plat doublet + RT followed by durvalumab or osimertinib x 1yr

NSCLC TREATMENT PEARLS

1. DO NOT USE … for SQUAMOUS non-small cell lung cancer → why?

2. DO NOT USE … for SQUAMOUS non-small cell lung cancer → why?

1. pemetrexed (Alimta) → not effective

2. bevacizumab (Avastin & biosimilars) → pulm hemorrhage

NSCLC TREATMENT PEARLS

For metastatic disease + PD-L1 expression > 50%, _______________ is an option

prolongs survival and is less toxic compared to platinum doublet chemo

CPI monotherapy (eg. pembrolizumab / Keytruda)

PLATINUM AGENTS

Higher incidence of … ADEs (dose-limiting side effect)

→ 3

1. cisplatin → ototox, nephrotox, NV

2. carboplatin → myelosupp

3. oxaliplatin → PN

CISPLATIN-INDUCED NEPHROTOXICITY

1. Risk factors → 2

2. PREVENTION → 3

3. TREATMENT →

1. concomitant nephrotoxins (NSAIDS!), lack of adequate hydration

2. avoid cisplatin, hydration (pre + post cisplatin), avoid nephrotoxins

3. DC cisplatin, supp care

PEMETREXED

1. Brand name =

2. MOA: __________ targets TS, DHFR, GARFT

3. EFFECTIVE FOR __________ ONLY (eg. adenocarcinoma)

4. ADEs + prevention →

5. →

1. Alimta

2. antifolate

3. NON squamous

4. hematologic, vomiting/diarrhea → folic acid, vit B12

5. skin rash → dexamethasone