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IHO > Exam 4 > Flashcards

Exam 4 Flashcards

1
Q

Major clinical uses for immunosuppressiveagents

A
  1. Transplantation induction and maintenance
  2. autoimmune disorders
  3. hypersensitivity- pathological antigen antibody reaction
  • they dampen the immune response
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2
Q

Which immune responses are more effectively suppressed?

A

Primary, more than secondary

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3
Q

Limitations of immunosuppressive therapy:

A
  1. increased risk of infections of all types
  2. increased risk of lymphomas and related malignancies
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4
Q

Induction therapy: Depleting agents

A
  • used to get rid of T cells
    1. Lymphocyte immune globulin (ALG and ATG)
    2. Anti-CD3 antibodies
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5
Q

Induction therapy: Modulators

A
  • do not deplete T cells
  • blocks IL2 mediated T cell activation, takes advantage of the fact that resting T cells don’t have IL2R
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6
Q

ALG

A

anti-lymphocyte globulin

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7
Q

ATG

A

anti-thymocyte globulin

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8
Q

Major classes of immunosuppressive therapy

A
  1. Calcineurin inhibitors (cyclosporine, tacrolimus)
  2. anti-proliferative/antimetabolic drugs (sirolimus, myco. mofetil)
  3. antibodies (ATG, ALG, Anti-CD3: muromonab, teplizumab. Anti-IL2R modulators: Daclizumab, Basiliximab)
  4. glucocorticoids: Anti-inflammatory steroids (predisone, dexamethasone, etc)
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9
Q

Calcineurin inhibitors: cyclosporine

A

-binds to a cytoplasmic receptor protein called cyclophilin, resulting in the inhibition of calcineurin activity
- this blocks dephosphorylation events required for cytokine gene expression/T cell activation

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10
Q

How is cyclosporine metabolized?

A
  • in the liver, can lead to numerous Drug-drug interactions
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11
Q

Major adverse effects of cyclosporine

A
  • renal toxicity/nephrotoxicity
  • may appear as a similar reaction for graft rejection
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12
Q

Calcineurin inhibitors: Tacrolimus (FK506)

A
  • binds to a cytoplasmic receptor protein (FKBP) resulting in the inhibition of calcineurin activity which blocks dephosphorylation critical for cytokine gene expression and T cell activation
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13
Q

Major adverse effects of Tacrolimus

A
  • 100x more potent than cyclosporine
  • nephrotoxicity/renal tox
  • drug drug interactions
  • glucose intolerance
  • diabetes
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14
Q

Antiproliferative/antimetabolic drugs

A
  • prevent the clonal expansion of both B and T lymphocytes
  • Sirolimus
  • mycophenolate mofetil
  • other (azathioprine, methotrexate, cyclophosphamide)
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15
Q

Sirolimus

A
  • Rapamycin
  • Mech: binds to FKBP to inhibit key enzyme in cell cycle progression (mTOR), blocking progression from G1 to S phase in IL2 driven T cell proliferation
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16
Q

Sirolimus toxicity

A
  • dose dependent increase in cholesterol and triglycerides
  • nephrotoxicity
  • increased risk of lymphomas and infections
  • drug drug interactions with CYP3A4
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17
Q

Mycophenolate mofetil (MMF)

A
  • organ transplantation drug
  • Mech: a metabolite of MMF is an inhibitor of inosine monophosphate dehydrogenase (IMPDH), important for guanine nucleotide synthesis required for B and T cells
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18
Q

Toxicity of mycophenolate mofetil (MMF)

A
  • hematologic (leukopenia)
  • gastrointestinal (diarrhea, vomiting)
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19
Q

Antibodies for immunosuppressive therapy

A
  • Depleting agents eliminate lymphocytes
  • anti-thymocyte globulin
  • anti-CD3 antibodies
  • Muromonab-CD3 mAb
  • Teplizumab-CD3 mAb
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20
Q

Antibody modulators that affect cell function

A
  • anti-IL2R mAb including:
  • daclizumab
  • basiliximab
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21
Q

Anti-thymocyte globulin

A
  • purified Igs prepared commercially from hyperimmune serum of animals following immunization with human thymocytes
  • Igs bind to thymocytes in circulation, resulting in lymphopenia and impaired T cell immune responses
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22
Q

Toxicity of Anti-thymocyte globulin

A
  • Ig being recognized as foreign resulting in serum sickness and nephritis
  • anaphylaxis (rare)
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23
Q

Anti-CD3

A
  • Muromonab Cd3
  • a mouse monoclonal antibody that binds to the alpha chain of the Cd3 glycoprotein that is part of the T cell receptor complex on T cells –> T cell receptor complex is internalized and it prevents antigen recognition
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24
Q

Cytokine release syndrome

A
  • Mild flu-like illness to life threatening shock
  • occurs with Anti-CD3 as an initial interaction of Muromonab-CD3 with T cells combined with the Fc mediated crosslinking
  • Frequent, negative side effect
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25
Q

Administration of what before anti-Cd3 can reduce the risk of cytokine release syndrome?

A
  • glucocorticoids. It reduces the symptoms considerably
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26
Q

Newer Anti-CD3 antibodies:

A
  • teplizumab CD3 mAb
  • delays onset of Type 1 diabetes (autoimmune disease)
  • does not bind Fc receptors, minimal mouse antibody structure (it is humainzed)
  • very expensive
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27
Q

Daclizumab and Basiliximab

A
  • Anti-CD25
  • mouse antibody made to the IL2 receptor (CD25)
  • Mech: binds IL2 receptor present on activated but not rested T cells to block IL2 mediated events
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28
Q

Daclizumab and Basiliximab, anti-CD25 toxicity

A
  • no cytokine release syndrome
  • lower incidence of lymphoproliferative disroders and infection
  • However, anaphylactic reactions can occur
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29
Q

Steroids produced in the body

A

Corticosteroids (21C)
- mineralcorticosteroids (electrolyte balance)
- glucocorticoids (carb metabolism, anti-inflam)

Androgens (19C)
- body building steroids

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30
Q

Sodium retention

A
  • ability of the steroid to reduce sodium excretion by the kidney in an adrenalectomized animal
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31
Q

Liver glycogen deposition

A
  • ability of the steroid to cause hepatic deposition of glycogen in a fasted adrenal adrenalectomized animal
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32
Q

Why do we use anti-inflammatory steroid drug therapy?

A
  • exogenous glucocorticoids will turn off the immune system. The endogenous ones are not doing enough
  • we want to: minimized the drug action on mineralcorticosteroids and maximize drug action on the glucocorticoid receptor
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33
Q

Metabolism of the anti-inflammatory steroids

A
  • administered orally, parenterally, or topically
  • metabolized in the liver and excreted by kidneys
  • inhaled glucocorticoids: enhanced uptake and prolonged tissue binding in the airway (also GI first pass inactivation)
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34
Q

Glucocorticoid effect on neutrophils

A
  • more circulating neutrophils
  • release from bone marrow is accelerated
  • half time in circulation is increased
  • blockage of neutrophil migration to inflammatory sites (decrease in adherence capabilities)
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35
Q

Glucocorticoid effect on lymphocytes

A
  • profound transient lymphopenia
  • cells are not lysed, but move to extravascular compartments like spleen, lymph nodes, thoracic duct, and bone marrow
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36
Q

Glucocorticoid effects on Monocytes and eosinophils

A
  • decreased in peripheral blood
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37
Q

Systemic administration of anti-inflammatory therapy can cause:

A
  • life-threatening effects (suppresses infection/inflammation reaction –> unknown causes result)
  • host resistance to microbial and fungal infection is lowered
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38
Q

What can cause toxicity when using glucocorticoids?

A
  • systemic administration
  • continued use of large doses
  • withdrawal or discontinuation of long term use
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39
Q

Continued use of large dose corticosteroids can cause:

A
  • increased infection
  • peptic ulceration
  • behavioral disturbances
  • cataracts
  • osteoporosis and vertebral compression fractures
  • inhibition of growth
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40
Q

withdrawal or discontinuation from long term corticosteroid use can cause:

A
  • symptoms of acute adrenal insufficiency (fever, myalgia, arthralgia, malaise)
  • death can occur with hypotension and shock
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41
Q

Immune checkpoint inhibitors attack what aspect of cancer hallmarks?

A

Avoiding immune destruction

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42
Q

Which protein-protein interactions (Co-stimulatory molecules) inhibit the activation of T cells?

A
  1. PD1 and PD1L
  2. CTLA4 and CD80/86
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43
Q

During tumor development, what types of cell receptors are selected for?

A
  • decreased expression of MHC 1 (makes tumor cells less immunogenic)
    2. increased expression of PD1L (to inhibit T cell activation)
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44
Q

Activating signals from the T cell receptor and co-receptors result in activation of what?

A
  • AP-1
  • NFAT
  • NF-kB
  • transcription factors
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45
Q

PD1 interaction with PDL1 or PDL2 does what?

A
  • blunts the T cell receptor signal and serves as a checkpoint on T cell activation
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46
Q

Increased expression of PDL1/PDL2 on cancer calls can be the result of:

A
  1. oncogene activation
  2. IFN signaling from the T cell
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47
Q

Mechanisms of resistance for immune checkpoint therapies

A
  1. Increased expression of other immune checkpoint proteins (TIGIT, TIM3)
  2. Tumor infiltration of immune suppressive cells (Tregs, M2 macrophages)
  3. Increased cytokine signaling within the tumor microenvironment
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48
Q

Pembrolizumab

A
  • Monoclonal antibody against human PD1
  • checkpoint inhibitor
  • Indicated in lung, breast, and melanoma cancers
  • Acts by blocking the PD1, allowing cytotoxic T cells to kill tumor cells
  • given via IV
  • Side effects include: GI, colitis, dyspnea, and cough
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49
Q

Atezolizumab

A
  • monoclonal antibody against human PDL1
  • checkpoint inhibitor
  • indicated in lung, breast, urothelial cancers
  • Acts by blocking the PDL1, allowing cytotoxic T cells to kill tumor cells
  • given via IV
  • side effects include: GI, colitis, dyspnea, cough
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50
Q

Ipilimumab

A
  • monoclonal antibody against human CTLA-4
  • checkpoint inhibitor
  • indicated in lung, breast, and urothelial cancers
  • Acts by blocking the CTLA-4 interaction with CD80/86. allowing cytotoxic T cells to kill tumor cells
  • given via IV
  • side effects include: GI, colitis, fatigue, and anorexia
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51
Q

What hallmark of cancer is attacked by CDK4/6 inhibitors?

A

Sustaining proliferative signaling

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52
Q

The G1/S phase checkpoint is controlled by the activity of:

A

cyclin dependent kinase 4 and 6 (CDK4/6), which become hyperactive in cancer and contribute to uncontrolled proliferation

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53
Q

In a healthy cell without mitogenic signaling, E2F gene transcription is inhibited by:

A

the retinoblastoma protein (Rb)

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54
Q

Pathway of mitogenic signaling

A

Mitogen signal –> increased cyclin D1 –> formation of CDK4/6 –> phosphorylation of Rb –> activating E2F –> gene expression –> cell cycle progresses to S phase

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55
Q

Cyclin dependent kinase inhibitors:

A

block the activity of CdK4/6 and arrest cells in G1 – tumor suppressors

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56
Q

E2F regulates the activity of:

A

Cyclin E –> activates CDK2 –> phosphorylates Rb –> increased progression through S phase

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57
Q

Breast cancer diverse changes in molecules/receptors and their effects:

A
  1. p16 - loss of CDKIs
  2. p21 - loss of p53
  3. ER/PR/AR - estrogen receptor signaling
  4. MAPK/PI3K/AKT - Her2, EGFR signaling
  5. Cyclin D1 - CDND1 gene amplification
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58
Q

How do CDK4/6 inhibitors work?

A

they keep Rb in its unphosphorylated state

  • resistance occurs via loss of Rb protein and aberrant activity of p27
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59
Q

Ribociclib/palbociclib

A
  • CDK4/6 inhibitor works by inhibiting CDK4/6 complexes (keep Rb unphosphorylated) preventing transition through the G1 checkpoint into S phase
  • given orally
  • Metabolized via CYP3A4
  • side effects include: neutropenia, fatigue, increased risk of upper respiratory infections
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60
Q

Oxygen can be reduced to water through:

A
  • four single electron transfers
  • intermediates include superoxide, hydrogen peroxide, and hydroxyl radicals which are highly reactive
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61
Q

What are the 3 main sources of ROS?

A
  1. Coenzyme Q on the electron transport chain
  2. oxidases, peroxidases, and oxygenases
  3. ionizing radiation
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62
Q

Coenzyme Q reaction:

A
  • accepts 2 electrons from NADH dehydrogenase, and transfers them to cytochrome b-c complex (cytochrome c reductase)
  • semiquinone intermediate can leak single electrons to molecular O2, forming SUPEROXIDE
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63
Q

When is superoxide a signaling molecule?

A

During hypoxia/ low O2 levels

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64
Q

How does the cardiomyopathy occur from Doxorubicin?

A
  • it can accept single electrons to form a semiquinone and undergo redox cycling like CoQ –> the oxidative damage to mitochondria causes the cardiomyopathy
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65
Q

Sulfamethoxazole gets metabolized by what?

A
  1. CYP2C9
  2. myeloperoxidase (MPO)
  3. cyclooxygenase (COX)

– forms sulfamethoxazole hydroxylamine –> reduces O2 to superoxide and bonds sulfhydryl groups on proteins to form adducts

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66
Q

CYP2E1 oxidizes what?

A

Ethanol –> acteylaldehyde in the MEOS reaction

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67
Q

Ethanol metabolism by CYP2E1 contributes to oxidative stress by:

A
  1. Generation of superoxide
  2. depletion of NADPH
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68
Q

Monoamine oxidase catalyzes the conversion of an amino group containing carbon –> aldehyde, this reaction produces what?

A

Hydrogen peroxide

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69
Q

What is the rate limiting step in converting purine nucleotides to uric acid?

A
  • Xanthine oxidase
  • this pathway produces ROS and plays a key role in reperfusion injury after tissue ischemia
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70
Q

Without oxygen, what accumulates?

A

Hypoxanthine and xanthine (O2 is a substrate for both of them to move along)

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71
Q

Low versus high concentrations of O2 and what gets produced by xanthine oxidase:

A

LOW: hydrogen peroxide
HIGH: superoxide

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72
Q

Where are VLCFAs oxidized?

A
  • Peroxisomes, unlike regular FA beta-oxidation, which is in the mitochondria
  • this forms hydrogen peroxide
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73
Q

Ionizing radiation splits water into:

A
  • hydrogen atoms and a hydroxyl radical
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74
Q

Where does ionizing radiation come from?

A
  1. Radon and cosmic
  2. nuclear power generation
  3. nuclear weapons
  4. materials testing equipment
  5. medical diagnostics/treatment
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75
Q

The Haber-Weiss reaction

A

Superoxide + hydrogen peroxide –> oxygen, water, hydroxyl radical

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76
Q

The Fenton reaction

A

H2O2 (hydrogen peroxide) + Fe2+ –> Hydroxyl radical + hydroxyl ion + Fe3+

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77
Q

Superoxide dismutase

A

superoxide –> hydrogen peroxide + O2

  • has 3 isoforms (SOD1, 2, 3)
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78
Q

SOD1

A
  • cytosolic
  • uses copper and zinc
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79
Q

SOD2

A
  • mitochondrial
  • uses manganese
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80
Q

SOD3

A
  • extracellular
  • used copper and zinc
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81
Q

What does reactive oxygen and reactive nitrogen species damage?

A
  1. Cell membranes (lipids- targets unsaturated FAs)
  2. DNA
  3. proteins
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82
Q

Initiation and propagation of lipid cell membrane destruction via ROS

A

Initiation: hydroxyl radical takes electron from carbon on unsaturated fatty acid forming LIPID RADICAL

Propagation: lipid radical reacts with O2 to form LIPID PEROXYL RADICAL –> lipid peroxyl radical takes single electron from adjacent FA forming LIPID PEROXIDE and a new LIPID RADICAL

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83
Q

What is a breakdown product of lipid peroxides that can be measured?

A

Malondialdehyde, measured in the blood

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84
Q

What is a marker of oxidative stress in tissues?

A

8-hydroxyguanine (an oxidation mutation of guanine that base pairs with adenine resulting in G–>T mutations)

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85
Q

Oxidative damage to proteins:

A
  1. oxidized side chains form cross links with other side chains –> aggregates of misfolded proteins
  2. Iron sulfur cluster proteins in the ETC –> loses iron –> non-functional protein AND ROS generation
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86
Q

What does Nitric oxide synthase (NOS) do?

A
  • catalyzes the cleavage of nitric oxide from the amino acid arginine
  • 3 isoforms (iNOS, eNOS, nNOS)
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87
Q

nNOS

A

neuronal

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88
Q

eNOS

A

endothelial

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89
Q

iNOS

A

inducible NOS in immune cells (intentional)

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90
Q

Nitric oxide’s physiological function is to:

A
  • bind iron in heme in soluble guanylyl cyclase, activating it. cGMP is produced, leading to activation of protein kinase G and promotion of VASODILATION
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91
Q

What happens when NO binds ferrous iron in heme in guanylyl cyclase and other enzymes?

A
  • it changes the enzyme activity to depend on NO concentration (biphasic effect)
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92
Q

Derivatives of NO can:

A

Form adducts on amino acid side chains in proteins, interfering with protein function

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93
Q

When neutrophils encounter pathogens:

A

they undergo a respiratory burst, producing NADPH to power the generation of ROS and RNOS

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94
Q

Chronic granulomatous disease:

A
  • inherited deficiency of NADPH oxidase causing deficient production of superoxide in the phagosome
  • engulfs pathogens but cannot kill them
  • characterized by recurrent infections
  • mutations in transmembrane or cytoplasmic subunits can cause CGD
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95
Q

What are secreted into phagocytic vacuoles?

A

Myeloperoxidase (MPO) containing granules

  • they convert hydrogen peroxide and chloride ion to hypochlorous acid (HOCl- bleach) which damages pathogen
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96
Q

Inducible nitric oxide synthase (iNOS)

A
  • produces NO and combines with superoxide to form PEROXYNITRITE (ONOO-) which decays into nitrogen dioxide radical
  • this destroys pathogen via oxygenation and peroxidation of lipids, DNA, and protein
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97
Q

In peroxisomes, hydrogen peroxide is neutralized by:

A

Catalase

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98
Q

Intracellularly, hydrogen peroxide is neutralized by:

A
  • accepting electrons from reduced glutathione
  • selenium dependent enzyme (selenocysteine acid in active site)
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99
Q

Which vitamins can accept single electron transfers to neutralize free radicals and limit oxidative damage?

A
  • vitamin E (vegetable oil, liver, egg yolks)
  • vitamin A (carrots- beta-carotene)
  • vitamin C (citrus fruits)- scavenger, accepts 2 single electrons
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100
Q

What hallmark of cancer is attacked by CAR-T therapy?

A

avoiding immune destruction

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101
Q

Cancer cells evade the immune system by:

A
  1. downregulating MHC 1
  2. upregulated PDL1
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102
Q

Chimeric antigen receptors (CAR)

A

genetically engineered hybrid receptors that bind specific tumor antigen domains, has constructs with:

  1. an extracellular ligand binding domain with specificity for a tumor antigen (cloned from scFV fragment of a monoclonal antibody gene)
  2. Cytoplasmic domains that contain elements of TCR co-stimulatory domains (ex: from the zeta chain of the TCR— requires tyrosine kinase)
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103
Q

Tisaganlecleucal

A
  • derives its extracellular domain form a monoclonal antibody that binds CD19
  • CD19 marks the B cell lineage and is retained in B cell leukemia/lymphoma
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104
Q

Current CAR-T therapy utilizes:

A
  • autologous transplant
  • T cells isolated from patients –> transduced with CAR-T gene via lentiviral vector –> expanded in vitro –> lymphodepleting chemo –> infusion of T cells back into patient
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105
Q

Chimeric antigen receptor interacting with tumor antigen activates the CAR-T cell and:

A

target cells are killed through granzyme and Fas:FasL mediated apoptosis

106
Q

Problems with initial CAR-T therapy:

A
  • fatal neurotoxicity
  • cerebral edema
107
Q

Common toxicity of CAR-T therapy:

A

Cytokine release syndrome
- can cause breakdown of BBB and loss of endothelial integrity

108
Q

Tocilizumab

A
  • anti-IL6 monoclonal antibody that is used as treatment for cytokine release syndrome in CAR-T treated patients
109
Q

TRUCKs:

A
  • T cell redirected for universal cytokine mediated killing
  • these consist of CAR-T cells with chimeric antigen receptors and domains that induce cytokines like IL-12
110
Q

What does IL12 do in a tumor?

A
  • makes an immunologically COLD tumor, HOT by:
    1. activation of CD8 T cells
    2. inhibition of Tregs
    3. recruitment of NK cells
    4. increases Fas:FasL expression on tumor cells
111
Q

Tisagenlecleucel

A
  • chimeric antigen receptor T cell based therapy (CAR-T) that works by chimeric antigen receptor binds CD19 on ALL cells causing Fas:FasL and granzyme killing
  • indicated for pediatric and young adults with refractory or relapsed B cell ALL
  • used with fludarabine and cyclophosphamide usually
  • given via infusion IV
  • side effects include: cytokine release syndrome, neurotoxicity
112
Q

Axicabtagene ciloleucel

A
  • chimeric antigen receptor T cell based therapy (CAR-T) that works by chimeric antigen receptor binds CD19 on ALL cells causing Fas:FasL and granzyme killing
  • indicated for refractory of relapsed large B cell lymphoma
  • used with fludarabine and cyclophosphamide usually
  • given via infusion IV
  • side effects include: cytokine release syndrome, neurotoxicity
113
Q

Radioactivity

A

energy emitted from a source (Becquerel or Curie)

114
Q

Exposure

A

energy traveling through air (Roentgen or Coulomb/Kg)

115
Q

Absorbed dose

A

energy absorbed by a person or object (rad or gray)

116
Q

Dose equivalent

A

normalizes biologic effects of absorbed dose to reference x-rays (roentgen equivalent man (rem) or Sievert)

117
Q

Electromagnetic radiation

A
  • spectrum from radio waves to cosmic waves
  • photons with 33ev or greater energy can ionize water (high energy UV and above)
  • radioactive isotopes can also emit particles such as alpha or beta particles and high energy photons
118
Q

Diagnostic X-ray energy is:

A

10keV to 50keV

119
Q

Therapeutic X-ray energy is:

120
Q

When does ionizing radiation begin to ionize water?

121
Q

Sources of radiation in modern life

A
  1. environmental (altitude, flights, radon)
  2. medical (imaging, therapeutic)
  3. occupational
122
Q

Most common radiation exposures

A
  • Radon and thoron (37%)
  • Computed tomography (CT) (24%)
  • nuclear medicine (12%)
  • interventional fluoroscopy (7%)
  • conventional radiography/fluoroscopy (5%)
    -space (5%)
  • internal (5%)
123
Q

Average annual dose of radiation per person in the USA is:

124
Q

Effects of radiation on tissue:

A

Direct: ionization of biochemicals

Indirect: ionization of water to form superoxide and peroxides that go on to cause further damage. Indirect effects are much more coommon

125
Q

Biologic effects of radiation

A
  • similar to endogenous ROS, but stronger
  • typically exceeds the anti-oxidant capacity of the body
126
Q

Targets of radiation in tissue

A
  1. proteins
  2. membranes
  3. nucleic acids
  4. endothelial cell injury leads to vascular injury, hypoperfusion, and secondary damage to exposed tissues
127
Q

When using radiation as treatment,

A

occasionally it can cause secondary malignancy. The most common is breast cancer, and this usually happens after of an avg latency of 4 years

128
Q

What is the increase of cancer incidence with CT exposure?

129
Q

Linear no threshold model

A
  • high dose exposure leads to more cancers that low dose exposure in a population
  • linear relationship between dose and cancer formation
130
Q

ALARA

A
  • As low as reasonably achievable
  • safety revolves around procedures to keep exposure minimized
  • reduce time and increase distance from exposure
131
Q

Radioactive cures:

A
  • radioactive isotopes (radium) first used to treat cancer 1890
  • cured Hodgkins in 1960s
  • 60% of cancer patients undergo radiotherapy
132
Q

Radiotherapy

A
  • X-rays
  • electrons
  • protons
  • isotopes (oral/injectable- permanent or temporary implant)
133
Q

Fractionation

A
  • at low doses, radiation is preferentially toxic to rapidly proliferating tissue
  • repeating multiple small doses amplifies these differences, leading to large differences in toxicity in cancer vs normal tissue
134
Q

CML arises from:

A

defects in normal neutrophil differentiation pathway

135
Q

What is the basis of CML?

A

BCR-ABL transfusion gene creating a constitutively active tyrosine kinase

136
Q

What happens to neutrophils in CML?

A
  1. differentiation of the neutrophil lineage during normal development
  2. changes in neutrophil differentiation during chronic phase of CML
  3. changes in neutrophil differentiation during the accelerated/blast phase of CML
137
Q

What are neutrophils?

A
  • first responders of innate immune response– most abundant white blood cell circulation
  • generated in the bone marrow, release and migrate to site of infection
  • can kill microbes by multiple mechanisms
  • short lived, generated continuously
138
Q

Neutrophils: Stem cells

A
  • HSC, multipotential progenitor
  • undergo self renewal, pluripotent capable of generating all lineages, capable of proliferation
139
Q

Neutrophils: Progenitor cells

A
  • Common myeloid progenitor, granulocyte macrophage progenitor
  • primarily undergo proliferation and differentiation multipotent, can generate more than one lineage
  • capacity becomes narrower as progress down pathway
140
Q

Neutrophils: committed cells

A
  • do not proliferate
  • only one fate, to differentiate to the next step in the path to the mature neutrophil
141
Q

BCR-ABL genomic translocation leads to:

A
  • genetic chimera of parts of BCR (breakpoint cluster region) gene and ABL1 (ableson tyrosine kinase) gene
  • it is a constitutively active tyrosine kinase that activates proliferation and blocks apoptosis in absence of extracellular signals
  • dysregulates normal neutrophil proliferation
142
Q

Why is having the BCR-ABL transfusion of a selective advantage for progenitor cells

A
  1. BCR-ABL progenitor cells proliferate more, survive longer
  2. they have the opportunity to acquire more mutations which can make cells more oncogenic
143
Q

BCR-ABL cells DO NOT:

A

Self renew (but they do continue to differentiate)

144
Q

Chronic phase of CML (first phase)

A
  • BCR-ABL translocation in HSC
  • increased proliferation and survival of progenitor cells
  • opportunity to acquire more mutations
145
Q

Blast phase of CML (second phase)

A
  • GMP requires ability to self renew
  • acquires block to differentiation
  • huge expansion of blasts. 30% extramedullary
146
Q

GMP acquired self renewal capability in BCR-ABL

A

1.) wnt-beta catenin signaling is activated
2.) differentiation is blocked- translation of CEBP-alpha inhibited

147
Q

What is a known oncogene?

A

V-ABL, works like the mutant version of c-ABL

148
Q

Two most common breakpoints in BCR generate two different proteins:

A
  • p210 found in CML (most common)
  • p190 found in some ALL (less common)
  • “recombination hot spots”
149
Q

Common DNA repair mechanism:

A
  • non-homologous end joining (NHEJ):
    1. it does not require extensive homology
    2. generates mutations at the site of the joint
150
Q

Key functional domains for oncogenic fusion protein from BCR:

A
  1. coiled-coil
  2. tyrosine 177
    Normal function: role in inhibition of some inflammatory rsponses
151
Q

Key functional domains for oncogenic fusion protein from ABL1:

A
  • N-terminal long fatty acid myristate maintains inhibition
  • normally, kinase is held inactive unless activated by external signals
    Normal function: role in DNA repair, cytoskeletal organization
152
Q

Important differences between ABL1 and BCR-ABL:

A
  1. ABL1 is inactivated unless activated by external signaling, while BCR-ABL is constitutively active
  2. ABL1 mainly nuclear, BCR-ABL mainly cytoplasmic
  3. ABL1 and BCR-ABL activate different intracellular signaling pathways
153
Q

Structural changes in BCR-ABL1

A
  1. coil-coiled domain is added from BCR promotes dimerization which is necessary for activation of the tyrosine kinase
  2. Tyrosine-177 (Y-177) is added from BCR phosphorylation of Y-177 creates a new binding site for intracellular signaling proteins
  3. Myristate attachment lost, which is normally necessary for autoinhibition of ABL1 tyrosine kinase activity
154
Q

BCR-ABL transcription is independent of:

A
  • JAK2, RAS, and PI3K
155
Q

What is activated independently of external signaling in BCR-ABL fusion gene?

A

STAT5
- therefore progenitor cells proliferate independently of external signaling

156
Q

Imatinib

A
  • inactivates ABL1 kinase by blocking ATP binding
  • prevents selective advantage that comes from activated oncogenic signaling pathways
  • causes apoptosis in BCR-ABL cells and allows the growth of normal cells
157
Q

Limitations of BCR-ABL tyrosine kinase inhibitors

A
  1. Secondary resistance to imantinib due to mutations of BCR-ABL
  2. not effective against blast phase –> no longer requires BCR-ABL because of genetic changes
  3. Hematopoietic stem cells are quiescent so not strongly affected by inhibitors block proliferation (any stem cells left after treatment can repopulate into cancer again)
158
Q

Hodgkin Lymphoma

A
  • Characterized by Reed-Sternberg cells
  • arises from a single lymph node or chain of lymph nodes
  • spreads in a stepwise fashion to anatomically contiguous nodes (unlike most NHLs)
  • Mesenteric nodes and Waldeyer ring rarely involved
159
Q

What age does Hodgkin lymphoma occur?

A
  • 15-34 years and >50 years, genetic susceptibility in children
160
Q

What is the most common site of involvement for Hodgkin lymphoma

A

Neck region

161
Q

Subtypes of Hodgkin lymphoma

A
  1. Nodular sclerosis
  2. Mixed cellularity
  3. lymphocyte rich
  4. lymphocyte depletion
  5. lymphocyte predominance (non-classical)
162
Q

Reed-sternberg cell

A
  • derived from germinal center or post-germinal center B cells
  • very large
  • Two mirror-image nuclei or nuclear lobes containing acidophilic nucleolus surrounded by a clear zone (Owl-eye appearance)
  • nuclear membrane is distinct
  • EXPRESSES CD15 and CD30 !
163
Q
  1. Nodular sclerosing Hodgkin lymphoma
A
  • most common Hodgkin lymphoma
  • mostly adolescents or young adults
  • good prognosis
  • commonly involves the lower cervical, supraclavicular, and mediastinal lymph nodes
  • Lacunar cell
164
Q
  1. Mixed cellularity Hodgkin lymphoma
A
  • 25% of cases, mostly men (>55%), good prognosis
  • EBV association in 60-70% of cases
  • most common HL that occurs in HIV+ patients
  • MANY Reed-Sternberg cells
  • heterogenous inflammatory infiltrate
  • lymph nodes and spleen affected
165
Q
  1. Lymphocyte rich Hodgkin lymphoma
A
  • uncommon, males > females, older adults
  • EBV association in 40%
  • good prognosis
166
Q
  1. Lymphocyte depletion Hodgkin lymphoma
A
  • least common HL (<1%)
  • EBV associated, especially with HIV+
  • Poorest prognosis, usually advanced stage with low survival rates
167
Q
  1. Lymphocyte predominance Hodgkin lymphoma
A
  • 5% of HL cases, good prognosis
  • Lympho-histiocytic variant Reed-Sternberg cells with delicate multilobed, puffy nucleus resembling popcorn
  • NO EBV association
  • Expresses CD20, BCL6,
  • DOES NOT express CD15, CD30
168
Q

Lacunar cell

A
  • found in nodular sclerosis HL
  • single, multi-lobate nucleus, multiple small nucleoli
  • abundant, pale staining cytoplasm
  • cytoplasm often torn away with formalin-fixed (nucleus lying in an empty space)
  • Immunophenotype: CD15, CD30
169
Q

What divides lymphoid tissue into circumscribed nodules in nodular sclerosing HL?

A
  • Collagen bands
  • cellular infiltrate contains: varying proportions of lymphocytes, eosinophils, histiocytes, and lacunar cells
170
Q

Pathogenesis of HL

A

• arises from germinal center B cells
• EBV in RS cells (70% cases of mixed cellularity subtype)
• non-neoplastic inflammatory cell in infiltrate
• IL5 (attracts and activates eosinophils)
• activation of transcription factor NFkB by EBV/other factors— once activated it turns on genes that promote B cell proliferation

171
Q

Clinical findings of Hodgkins lymphoma

A
  1. Fever, unexplained weightloss, night sweats
  2. Pruritus.
  3. Pel- Ebstein fever
  4. Painless enlargement of the single groups of lymph nodes in the neck region (becomes painful with alcohol)
  5. Normocytic anemia (ACD)
172
Q

People with Hodgkin’s lymphoma have an increased risk of developing what?

A

Second malignancies, usually acute myeloblastic leukemia, or non-Hodgkin’s lymphoma

173
Q

Staging of clinical features of Hodgkin lymphoma

A

Stage one: 1 node above the diaphragm

Stage two : 2 nodes above the diaphragm

stage three: 1+ node above, 1+ node below the diaphragm

Stage four : multi organ involvement

174
Q

What is the treatment for patients with refractory Hodgkin lymphoma?

175
Q

What is an M spike?

A

Increased Ig protein found on gel electrophoresis — secondary to albumin spike

176
Q

What are ways to describe plasma cells seen in multiple myeloma?

A

1.) clock face.
2.) fried egg.

— both talk about the nucleus off to the side, and the HOF area (large golgi area in the cytoplasm)

177
Q

What types of cells are present in multiple myeloma?

A
  1. Overabundance of plasma cells
  2. Flame cells
  3. Russell bodies (large vacuoles, full of Ig)
  4. Mott cell (multiple cytoplasmic inclusions)
  5. Dutcher body (inclusion in the nucleus- light color)
178
Q

What is multiple myeloma?

A

• malignant neoplasm of plasma cells, bone marrow with greater than 10 to 20% of plasma cells
• most common primary malignancy of bone
• 65 years of age= mean
• bone pain in 80% of patients, anemia, elevated total protein, elevated calcium
• increased risk for infection

179
Q

What interleukin is increased in the serum of multiple myeloma patients?

A

IL-6 (stimulates plasma cell growth and Ig production)

180
Q

What immunoglobulins are produced in multiple myeloma?

A
  1. IgG (60%)
  2. IgA (40%)
  • never IgM
  • Does not differentiate (decreased level of normal immunoglobulins)
181
Q

What are lytic bone lesions in multiple myeloma?

A

• punched out lesions on x-ray
• due to osteoclastic activating factor
• bone pain, high calcium, fracture

182
Q

What are bone results that would be inconsistent with multiple myeloma?

A
  • a positive bone scan (indicates blastic activity)
  • Increased alkaline phosphatase (indicates blastic activity)
183
Q

Increased plasma proteins creates:

A

• hyperviscosity
• turbulent blood flow
• symptoms such as blurry vision and Raynaud’s

184
Q

What pattern do red blood cells require during multiple myeloma?

185
Q

What stains indicates amyloidosis?

A

Apple green birefringence (this can indicate multiple myeloma in a lymph node biopsy)

186
Q

What is the multiple myeloma triad?

A
  1. Anemia
  2. Bone pain
  3. Renal failure (caused by high levels of protein, hypercalcemia, amyloidosis)
187
Q

What symptoms does hypercalcemia cause?

A

• Neuro symptoms (weakness, confusion, lethargy)
• constipation
• polyuria

188
Q

What can multiple myeloma be associated with?

A

• primary amyloidosis
• systemic disorder due to diffuse amyloid deposits
• nephrotic syndrome/hepatomegaly
• restrictive cardiomyopathy (MOST COMMON)
• panhypopituitarism

189
Q

CRAB stands for what?

A
  • Hypercalcemia
  • Renal failure
  • anemia
  • bone lytic lesion/back pain
190
Q

What is the criteria for diagnosis of multiple myeloma?

A
  1. Clonal bone marrow plasma cells >10% OR biopsy proven bony or soft tissue plasmacytoma
  2. One of the following:
    - end organ damage
    - Hypercalcemia (>11)
    - Renal insufficiency (cr>2)
    - Anemia (hgb<10)
    - Bone lesions (1+ that is >5mm)
191
Q

MGUS (monoclonal gammopathy of undetermined significance)

A

• serum IgM is found to be very high
• pts usually older than 50 years
• can develop plasma cell dyscrasia (MM) (increases by 1-2% per year)
• may also evolve into Waldenstrom’s macroglobulinemia, primary amyloidosis, B cell lymphoma, or CLL

192
Q

Waldenstrom’s macroglobulinemia (lymphoplasmacytic lymphoma)

A

• small lymphocytic lymphoma with plasmacytic differentiation
• cross between MM & SLL
• IgM causes M spike
• NO CRAB
• no lytic lesions
• Russell bodies, and Dutcher bodies may be present

193
Q

Symptoms of lymphoplasmacytic lymphoma

A

• visual abnormalities due to vascular, dilations and hemorrhages
• neurological symptoms, headache/confusion
• bleeding, and cryoglobulinemia
• raynauds

194
Q

Solitary plasmacytoma

A

• plasma cell dyscrasia
• soft tissue or axial skeleton affected
• skeletal —> MM frequently

Distinctions: only one lesion, BM plasma cell level <5%, protein levels normal, no end organ damage

195
Q

Dexamethasone

A

• treatment of multiple myeloma
• steroid, decreases interleukins (IL6)

196
Q

Melphalan

A

• alkylating agent
• interferes with DNA and RNA synthesis (alkylates and cross-links DNA)
• treatment of multiple myeloma

197
Q

Cyclophosphamide

A

• alkylating agent (G7)
• interferes with DNA synthesis
• SE: BMS, HEMORRHAGIC CYSTITIS
• treatment of multiple myeloma

198
Q

Bortezomib

A

• treatment of multiple myeloma
• inhibits proteasome (prevents degradation of pro-apoptotic factors)

199
Q

Thalidomide

A

• treatment of multiple myeloma
• inhibits TNF-alpha, IL6, IL100, IL12
• enhances production of IL2, IL4 and IL5
• extreme teratogen (Amelia, phocomelia)

200
Q

Lenalidomide

A

• newer agent to treat multiple myeloma
• antiangiogenic agent (antibody)
• inhibits traffic signals to angiogenic factors in cells (decreases disease activity)

201
Q

What are the most common causes of death for multiple myeloma?

A

• renal failure
• sepsis/ infection

202
Q

Multiple myeloma

A

• 70+, African-American males
• CRAB
• Bence Jones protein: free, kappa, or Lambda light chains that are excreted in the urine
• IL-6
• punched out lytic lesions
• clock/fried egg plasma cells

203
Q

Solitary plasmacytoma

A

• skeletal plasmacytoma can progressed to multiple myeloma
• soft tissue plasmacytoma is in the upper respiratory tract
• low or no serum and urine M protein spike
• no malignant plasma, cells in bone marrow

204
Q

Lymphoplasmacytic lymphoma (Waldenstrom’s macroglobulinemia)

A

• acquired mutation of MYD88
• tumor cells, secrete IgM
• mixture of B cells ranging from small lymphocytes —> plasmacytic lymphocytes —> plasma, cells
• behaves like indolent B cell lymphoma involving lymph nodes, bone marrow and spleen

205
Q

What do myeloma cells secrete?

A

• IL6
• IL-1beta
• TNF

—> RANK ligand —> osteoclast activity increases —> bone resorption —> osteolytic lesions, pathological fractures, and hypercalcemia

206
Q

What are the common infections of multiple myeloma?

A
  1. Staphylococcus aureus
  2. Streptococcus pneumonia
  3. E. coli
207
Q

Renal findings in multiple myeloma

A

• renal insufficiency
• proteinaceous tubular casts
• nephrocalcinosis from hypercalcemia
• AL-type amyloidosis

208
Q

Immunophenotype for multiple myeloma

A
  • CD38 +
  • CD138 +
  • CD56 +
  • syndecan1 +
  • high serum immunoglobin (IgA or IgG)
209
Q

Urine immunofixation electrophoresis

A

Characterizes whether Bence Jones protein is kappa or lambda. More sensitive and detecting BJ protein than the standard urine protein electrophoresis

210
Q

Serum for free light chains

A
  • detects and quantitates kappa in lambda light chain in serum
  • More sensitive for detecting light chain than any of the other urine methodologies
211
Q

Waldenstrom macroglobulinemia

A

• visual: tortuosity and distention of retinal veins, retinal, hemorrhages, and exudates
• neurologic: HA/dizzy, tinnitus/deafness
• bleeding: formation of complexes between macroglobulins, and clotting factors that interfere with platelet function (Rouleax)
• cryoglobulinemia: precipitation of macroglobulins at low temp- Raynaud’s

212
Q

What treatment removes macroglobulins?

A

Plasmapheresis— used for WM

213
Q

Monoclonal gammopathy of undetermined significance

A

• asymptomatic, monoclonal, gammopathy
• <3 g/dL monoclonal protein in serum
• precursor lesion with a tendency to evolve to MM (single lesion)

214
Q

POEMS syndrome

A

• paraneoplastic syndrome, including:

P- polyneuropathy
O- organomegaly
E- endocrinopathy
M- monoclonal gammopathy
S- skin changes (hypertrichosis)

215
Q

What do Langerhans cells express?

A
  • CD1a, Langerin
216
Q

What is Langerin?

A

• transmembrane protein in Birbeck granules
• cytoplasmic pentalaminar rodlike tubular structures (tennis racket appearance on EM)

217
Q

Three distinctive clinical pathological entities of Langerhans cell histiocytosis

A
  1. Multisystem LCH: Lederer-Siwe disease
  2. Unifocal unit system LCH: eosinophilic granuloma
  3. Multifocal Unisystem LCH: hand-Shuller-Christian disease

— all have CD1a marker and coffee bean nucleus

218
Q

What mutation is found in Langerhans cell histiocytosis?

A

BRAF— acquired mutation in serine/threonine kinase (a valine to glutamate substitution in residue 600)

219
Q

Letterer-Siwe disease

A

• children younger than two years
• multifocal cutaneous lesions
• hepatosplenomegaly, lymphadenopathy, pulmonary and osteolytic lesions
• pancytopenia
• rapidly fatal if untreated
• eczematous type of rash, due to malignant histiocytes infiltrating skin and dermis

220
Q

Unisystem Langerhans cell histiocytosis

A

• unifocal, or multifocal
• erosive accumulations of Langerhans cells within medullary cavities of bones or skin, lungs, stomach
• variable cell types— eosinophils may be prominent

221
Q

Unifocal Unisystem disease (eosinophilic granuloma)

A

• benign, histiocytosis, mainly and adolescents and young adults
• unifocal lytic lesion in bone (skull, ribs, femur)
• typically seen in young smokers, resolves when smoking cessation occurs

222
Q

Hand-Schuller-Christian disease

A

• malignant histiocytosis, mainly affecting children
• multiple bony masses that may extend into soft tissues

HSC TRIAD:
1. Lytic lesions in skull.
2. Diabetes insipidus
3. Exophthalmos

223
Q

What are the most common TKI therapies for CML?

A
  1. Imatinib
  2. Dasatinib
  • Second generation TKIs (bosutinib, nilotinib) may produce faster and deeper responses, then imatinib
224
Q

What is the mechanism of imatinib in CML?

A

Binds to the ATP binding site of the BCR-ABL tyrosine kinase fusion protein

225
Q

CML therapy goals

A
  1. Hematologic response (normalization of CBC)
  2. Cytogenic response (resolution of the Philadelphia chromosome)
  3. Molecular response (resolution of the BCR – ABL gene)
226
Q

What should you check before assuming a BCR-ABL mutation that makes CML unresponsive to TKI treatment?

A

Adherence by the patient

227
Q

When is ponatinib used?

A

In CML when there is a BCR-ABL T315I mutation

  • however, this causes arterial thrombosis, and hepatic toxicity as a side effect
228
Q

If a patient that has CML gets pregnant, what should you do?

A

Immediately stop imatinib or any TKI, they are teratogens

229
Q

What’s a unique feature of B cell lymphoma?

A
  1. Rash and/or exaggerated response to insect bites
  2. Pruritus and/or alcohol intolerance (also seen in Hodgkin lymphoma)
230
Q

What are B symptoms?

A
  1. Fever
  2. Weight loss, unexplained >10% of body weight over the past six months
  3. Drenching night sweats
231
Q

Which lymphomas are aggressive and symptomatic?

A

• diffuse large B cell lymphoma (DLBCL)
• mantle cell lymphoma
• Burkitt lymphoma
• peripheral T cell lymphomas
• HIV associated lymphomas
• Hodgkin lymphoma

232
Q

Which lymphomas are typically indolent and asymptomatic?

A

• follicular lymphoma
• splenic marginal zone lymphoma
• MALT lymphoma (mucosal associated lymphoid tissue)
• extranodal marginal zone lymphoma

233
Q

If a patient with lymphoma has a GI bleed, which diagnosis should be on the differential?

A

Mantle cell lymphoma

234
Q

What type of diagnostic biopsies are done for lymphomas?

A
  1. Excisional biopsy- best, but invasive
  2. Incisional biopsy
  3. Core-needle biopsy- least invasive for the best results
  4. Fine needle aspiration (not great for lymph node architecture)
  5. Bone marrow biopsy— unilateral, and >3cm
235
Q

What are the problems with flow cytometry for lymphomas?

A
  1. DLBCL can often come back negative, but it does not rule out the diagnosis
  2. Hodgkin lymphoma: RS cells are so few, but it will not pick them up
236
Q

What is seen on diagnostic pathologic evaluation for lymphomas?

A

Double/triple hit:
• MYC and BCL2 and/or BCL6 gene rearrangement

237
Q

Gene expression profiling:

A

1.) germinal center B cell type (GCB), more indolent
2.) activated B cell type (ABC), more aggressive

238
Q

Which cancers are FDG-avid lymphomas on PET scan?

A

• DLBCL
• follicular
• mantle cell
• T cell
• Hodgkin

239
Q

Which cancers are poorly FDG-avid on PET scan?

A

• CLL/SLL
• lymphoplasmacytic lymphoma/ Waldenstrom’s macroglobulinemia
• mycosis fungoides
• marginal zone
• extranodal marginal zone

240
Q

What is a first line treatment for a lot of lymphomas?

A

Bendamustine + rituximab

241
Q

What is CLL?

A

• An uncontrolled clonal accumulation of mature lymphocytes
• lymphocytosis: >5000/mL required
• CD5+, CD23+ (flow cytometry)
• CD19/20+
• SMUDGE CELLS

242
Q

What are poor prognostic factors of CLL?

A

• advanced age at diagnosis
• 11q- and 17p-
• elevated b2-macroglobulin
• unmutated IGVH (no somatic, hypermutation in B cells)

243
Q

What tests should you always get in CLL?

A
  1. WBC
  2. IGVH mutational status
  3. Always get FISH
244
Q

Best to worst prognosis for CLL

A
  1. 13q-
  2. Normal karyotype.
  3. Trisomy 12
  4. 11q-
  5. 17p- (worst— almost always seen with p53)
  6. p53
245
Q

Frequent therapy choices for CLL

A
  1. Bruton tyrosine kinase inhibitors (ibrutinib, acalabrutinib, zanubrutinib)
  2. BCL-2 inhibitors (venetoclax)
  3. Monoclonal antibodies (anti-CD20, rituximab)
    4.) chemotherapy
    5.) CAR-T therapy
    6.) allogenic stem cell transplantation
246
Q

What can a horse voice indicate in patients?

A

Problems with the recurrent laryngeal nerve— maybe from lymph node tumor pressing on it

247
Q

What points you to autoimmune hemolytic anemia?

A
  • Spherocytes
  • high reticulocyte count
  • Nucleated red blood cells
  • Coomb’s +
248
Q

Monoclonal lymphocytosis of unknown significance (MBL, MLUS)

A

• clonal lymphocytes with ALC <5000
• absence of other signs or symptoms of lymphoproliferative disorder
• progression to CLL is around 1-2% per year
• follow up is clinical with occasional CBC monitoring

249
Q

What test do you not order in multiple myeloma and why?

A

Do not order a BONE SCAN, it shows you blastic activity, not lytic.

250
Q

What tests DO you order in multiple myeloma?

A

• H&P
• SIELP, serum free light chains, UPEP, CBC, CMP, beta-2 microglobulin, LDH
• bone marrow biopsy with cytogenetics, and FISH
• bone survey (full body CT, PET if plasmacytoma)

251
Q

Smoldering myeloma

A

• asymptomatic
• serum monoclonal protein >3 g/dL
• Bence Jones protein >500 mg/24hr
• clonal, bone marrow plasma, cells 10-59%
• absence of myeloma-defining events (CRAB) or amyloidosis

252
Q

Paraprotein

A

• a monoclonal immunoglobulin or immunoglobulin light chain in the blood or urine resulting from a clonal proliferation of plasma, cells, or B lymphocytes (synonyms: M-band, M-spike, monoclonal Band, monoclonal spike, monoclonal protein)

253
Q

How do you identify paraproteins?

A

• serum protein electrophoresis
• immunofixation
• urine protein electrophoresis

254
Q

Multiple myeloma staging

A
  1. Stage one: serum beta-2 microglobulin <3.5 g/dL
  2. Stage two: not stage 1 or 3
  3. Stage three: serum beta-2 microglobulin >5.5 g/dL

— staging is weighted heavily by FISH

255
Q

How do you define treatment goals of multiple myeloma?

A

Performance status: who is the patient?

256
Q

What is common treatment for multiple myeloma?

A

RVD: lenalidomide, bortezomib, dexamethasone

257
Q

What makes a multiple myeloma patient high risk genetically?

A

• t(14;16)
• t(14;20)
• 17p- deletion
• t(4;14)
• 1q+ gain

258
Q

What is maintenance therapy post transplant in multiple myeloma?

A
  • lenalidomide
  • bortezomib
259
Q

What do bisphosphonates do?

A

• pamidronate, zoledronic acid
• block osteoclastic activity
• pamidronate < zoledronic acid for hypercalcemia
** however, good renal function needed for zoledronic acid

260
Q

What treatment is used for multiple myeloma when patients have a renal failure?

A

• CyBorD
• cyclophosphamide, bortezomib, dexamethasone

261
Q

What is key to improving outcomes in cancer medicine?

A

Clinical trials

IHO (6 decks)

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