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IHO > Exam 3 > Flashcards

Exam 3 Flashcards

1
Q

Cancer is:

A

• a disease of uncontrolled cell proliferation
• the accumulation of mutations that activate proto-oncogenes and inactivate tumor suppressor genes
• cell growth becomes uncoupled from the hormonal and metabolic conditions that normally maintain homeostasis

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2
Q

Colorectal cancer gene alterations

A

(normal epithelium) Loss of APC—> (hyper proliferative epithelium, early adenoma) activation of Ras—> (intermediate adenoma) loss of tumor suppressor gene—> (late adenoma) loss of p53 activity—> (carcinoma) additional alterations—> metastases

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3
Q

Which cancers have the fewest mutations, and are driven by only single changes typically?

A

• blood cancers
• pediatric cancers

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4
Q

Causes of DNA mutations:

A

• DNA replication errors, chromosome segregation errors
• chemical damage to DNA
• oxidative stress, pathological and physiological
• radiation
• virus infection
• infidelity in DNA repair

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5
Q

Proto-oncogenes normally function to:

A

Promote cell proliferation, and physiologically there expression an activity are tightly regulated

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6
Q

What are the types of mutations that convert proto-oncogenes to oncogenes?

A

• point mutation
• gene rearrangement
• gene amplification

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7
Q

Single base changes within a coding sequence leading to overactive enzymes, or enzymes with different substrates/products

A
  1. Phosphatidylinositol-4,5-bisphosphate-3-kinase (PI3K) activating mutations in breast cancer
  2. Isocitrate dehydrogenase (IDH2) mutations in glioblastoma
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8
Q

Example of mutations in promoters that cause hyperactive expression of genes

A

• telomerase (TERT) promoter activating mutations in urothelial cancer

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9
Q

The fusion of chromosomes 9 and 22

A

• chronic myelogenous leukemia
• Proto oncogene becoming activated through rearrangements of short DNA fragments or large pieces of chromosomes— more common in blood cancer

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10
Q

What gene is amplified in human breast cancer?

A

• Cyclin D1
• increases their copy number and expression amount

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11
Q

Tumor suppressor gene RB1

A

• retinoblastoma protein (Rb) encoded tumor suppressor gene
• it’s normal function is to bind and inactivate E2F transcription factors
• when myogenic signal increases cyclin D1, Rb is phosphorylated, and that releases E2F causing increased transcription of genes that promote DNA replication

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12
Q

For a tumor suppressor to become inactivated:

A

Both alleles must be lost

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13
Q

What is the most frequently mutated tumor suppressor in human cancers?

A

p53 encoded by TP53 gene

• it’s normal function is to respond to DNA damage by halting the replication fork, initiating DNA repair, arresting the cell cycle at G1-S checkpoint, and increasing apoptosis

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14
Q

Log kill model

A

• assumes that cancer cells have the same rate in proliferation at all stages of disease
• example: if a given drug can reduce cancer burden from 10^10 to 10^7, I can also reduce the cancer burden from 10^18 to 10^15, and so on

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15
Q

What does debulking the tumor do?

A

This is a surgical procedure before chemotherapy in order to lower the tumor burden and decrease the number of chemotherapy cycles required

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16
Q

Gompertzian growth model

A

• human tumors follow this rather than a logarithmic growth
• early stages of tumorigenesis: Cancer cell proliferation is limited by the ability of the vasculature and supply of oxygen/nutrients
• later stage of tumorigenesis: Cancer cell proliferation is limited by the accumulation of lethal mutations
• the cell cycle is most active right in the middle, during the angiogenic switch

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17
Q

G1 phase:

A

• a checkpoint, in which signals from the extracellular environment, are integrated into a decision whether to proliferate or not (40% of time)

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18
Q

S phase

A

• when genomic DNA is duplicated (DNA synthesis) (39% of time)

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19
Q

G2 phase

A

• a checkpoint in which the integrity of DNA replication is assessed
• synthesis of cellular components for mitosis (19% of time)

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20
Q

M phase

A

• mitosis, in which replicated, chromosomes, segregate, and the cell divides into two daughter cells (2% of time)

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21
Q

G0 phase

A

• Quiescent, or non-replicative state
• metabolism still occurs, but replication and division is not active

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22
Q

Cell cycle specific drugs

A

• cytotoxic chemotherapy drugs. Their target only exists for a discreet period In the cell cycle.
• Taxane/paclitaxel
• 5-fluorouracil

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23
Q

Taxane/paclitaxel

A

Cell cycle specific drug that stabilizes mitotic spindles in the M phase, preventing division into two daughter cells

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24
Q

5-fluorouracil

A

Cell cycle specific chemotherapy that inhibits thymidine synthase, an enzyme expressed during S phase

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25
Q

Which part of the cell cycle do alkylating agents work?

A

G1

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26
Q

Which part of the cell cycle do vinca alkaloids work?

A

M phase, G1

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27
Q

Which part of the cell cycle do taxoids work?

A

G2-M

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28
Q

Which part of the cell cycle do Anti-metabolites work?

A

S phase

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29
Q

Which part of the cell cycle do antitumor antibiotics work?

A

G1, S phase

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30
Q

Cell cycle nonspecific drugs

A

• the targets of these drugs, exist throughout the cell cycle and in G0.
• their toxicity may be manifested as cells progress through a specific phase
• anthracycline doxorubicin
• platinum analog cisplatin

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31
Q

Anthracycline doxorubicin

A

• a cell cycle nonspecific chemotherapy drug that intercalates double stranded DNA throughout the cell cycle. This causes double stranded DNA breaks and cell death, mainly in S phase

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32
Q

Platinum analog cisplatin

A

• a cell cycle non-specific chemotherapy drug that causes intrastrand cross-links in DNA throughout the cell cycle. This causes DNA breaks and cell death, mainly in S phase

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33
Q

What is a common strategy for sequencing, chemotherapy agents?

A
  1. Cell cycle non-specific drug first.
  2. Cell cycle specific drug second

• the CCNS reduces tumor burden into a phase of high cell cycle turnover— this is where the CCS will work better

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34
Q

Traditional view of cancer pharmacology

A

The dominant feature of cancer is uncontrolled cell proliferation, and cancer cells are the most rapidly dividing cells in the body. Using agents that kill cells as they progress through the cell cycle, we can adjust the dosing so that cancer cells are killed while sparing healthy tissues that are not rapidly dividing.

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35
Q

Problems with the traditional view of cancer pharmacology

A
  1. There are some tissues that divide rapidly (hematopoietic, GI)
  2. Some cancer cells can survive in a quiescent or nondividing state, and therefore will not be affected by the drug
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36
Q

Emerging view of cancer pharmacology

A

Proliferation in cancer cells is driven by a Hallmark phenotype/phenotypes. By targeting the drivers of cell proliferation in cancer cells, off target affects will be minimized.

Problems: we do not know the drivers of all cancers, target agents do have off target effects still, and target agents are very expensive

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37
Q

Hallmarks of cancer 2000-2022

A

• Description of general features that were required for cancer progression. This paper was used to find vulnerabilities that could be therapeutically exploited to improve Cancer care.

• divisions:
1. Resisting cell death.
2. Inducing angiogenesis.
3. Sustaining proliferative signaling
4. Enabling replicative immortality.
5. Activating invasion and metastasis.
6. Evading growth suppressors

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38
Q

Antigen processing is:

A
  • the conversion of native proteins into Major Histocompatibility Complex (MHC)-associated peptides
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39
Q

Antigen presentation is:

A
  • the display of self and foregin peptides by the MHC on antigen presenting cells (APCs- dendritic cells, macrophages, B cells, vascular endothelial cells, and thymic epithelial cells) to T cells
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40
Q

What are the common routes of antigen entry?

A
  1. Antigens from epithelial and connective tissues collected in lymph node
  2. Blood-borne antigens collected in the spleen
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41
Q

What is a part of T cell recognition of Peptide:MHC complexes?

A
  • T cell contact residue of antigen peptide
  • Polymorphic residue of MHC
  • Anchor residue of peptide in MHC complex
  • Peptide
  • T cell receptor
  • MHC complex
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42
Q

Dendritic cells and antigen presenting

A
  • constitutive expression of MHC class 2
  • increased with maturation, and increased by IFN-gamma, and T cell CD40L:CD40 interaction
  • constitutive co-stimulator activation, increased with TLR singaling, IFN-gamma, and CD40L:CD40 interaction,
  • principle function: antigen presentation to naive T cells
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43
Q

Macrophages and antigen presenting

A
  • Low/negative expression of MHC class 2
  • increased by IFN-gamma, cells CD40L:40 interaction
  • expression of co-stimulators is increased w/TLR signaling, IFN-gamma, and T cell CD40L:40
  • principle function: antigen presentation to effector CD4+ T cells in effector phase of cell-mediated killing of microbes (CD8+)
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44
Q

B cells and antigen presenting

A
  • Expression of MHC class 2 is constitutively active, increased by IL4, antigen receptor cross-linking, and T cell CD40L:CD40 interaction
  • co-stimulator expression is increased by CD40L:CD40 interaction and antigen receptor cross linking
  • principle function: antigen presentation to effector CD4+ cells in humoral immune response (T helper-B cell interactions)
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45
Q

Vascular endothelial cell and antigen presentation

A
  • Expression of MHC class 2 is increased by IFN-gamma, and constitutive in some blood vessels
  • Co-stimulators are low, possibly inducible
  • principle function: may promote activation of antigen specific T ells at antigen exposure site and in organ grafts
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46
Q

Thymic endothelial cells and antigen presentation

A
  • Expression of MHC class 2 is constitutive
  • There are no known co stimulators
  • Principle function: positive and negative selection of developing T cells
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47
Q

Langerhans cells

A

tissue-resident dendritic cells in epidermis

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48
Q

Trogocytosis

A

The transfer of functional membrane fragments and their associated molecules directly from one cell to another cell – macrophages sample the antigen and keep it on the outside of their membranes (not intracellular)

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49
Q

Cytosolic pathogens

A
  • degraded in the cytosol
  • peptides bind to MHC class 1
  • presented to effector CD8 T cells
  • effect on presenting cell: death
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50
Q

Intravesicular pathogens

A
  • degraded in endocytic vesicle (low pH)
  • peptides bind to MHC class 2
  • presented to effector CD4 T cells
  • effect on presenting cell: activation of macrophage to kill intravesicular bacteria and parasites
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51
Q

Extracellular pathogens and toxins

A
  • degraded in endocytic vesicles (low pH)
  • peptides bind to MHC class 2
  • presented to effector CD4 T cells
  • effect on presenting cells: activation of B cells to secrete Ig to eliminate extracellular bacteria/toxins/viruses
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52
Q

MHC Class 1 (self/non-self)

A
  • expressed on ALL nucleated cells of the body
  • Bind and present ENDOGENOUS (within the cell) antigens
  • Cytosolic pathway: intracellular protein synthesis of endogenous proteins
  • proteasome (required)
  • 8-10 amino acids
  • presents to CD8 T cells –> cell lysis
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53
Q

MHC class 2

A
  • expressed on antigen presenting cells (APCs)
  • Bind and present EXOGENOUS (ingested) antigens
  • Endocytic pathway: endocytic uptake of exogenous proteins
  • Endolysosome
  • 13-18 amino acids
  • Present to CD4 T cells –> B cell response –> antibodies (plasma cell creation)
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54
Q

Cross presentation

A

Process by which anitgens of other cells (ex. virally infected or tumor cells) are presented by dendritic cells. These extracellular antigens are taken up by dendritic cells (phagocytosis), processed, and presented by MHC class 1

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55
Q

Beta-2 microglobulin

A

Soluble subunit on all MHC Class 1 cells

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56
Q

TAP

A

transports peptides from cytosol to ER Lumen

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57
Q

Calnexin

A

assists in folding of heavy chain of MHC class 1. Stabilizing MHC class 1 and preventing aggregation (aggregation would cause conformational change, and binding could not occur)

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58
Q

ERp57

A

catalyzes formation of disulfide bonds

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59
Q

Calreticulin

A

replaces calnexin and binds ERp57

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60
Q

Tapasin

A

Binds to ERp57 and Calreticulin, stabilizing the peptide loading complex. Acts as a bridge between MHC class 1 and TAP to keep MHC class 1 close to incoming peptides. Stabilized TAP, increasing flow of peptides into ER lumen.

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61
Q

Peptide loading complex

A

facilitates translocation and loading of peptides onto MHC class 1. Compromised of MHC class 1, TAP, ERp57, Tapasin, and calreticulin

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62
Q

MHC 2 antigen processing and presentation:

A

Synthesis of class 2 MHC in ER –> transport of class 2 MHC and Ii to vesicle –> binding of processed peptides to class 2 MHC –> transport of peptide:MHC2 complex to cell surface –> expression of peptide:MHC complex on cell surface

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63
Q

MHC 1 antigen processing and presentation:

A

Production of proteins in or delivery to the cytosol –> proteolytic degradation of proteins –> peptide transport from cytosol to ER –> assembly of peptide:MHC1 complexes in ER –> surface expression of peptide:MHC1 complexes

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64
Q

Invariant chain (Ii)

A

associated with newly synthesized MHC class 2. Facilitates transport of MHC class 2 to the endolysosome

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65
Q

Class 2-associated Ii chain polypeptide (CLIP)

A

proteasome-cleaved remnant of the Ii chain occupying the peptide binding groove of MHC class 2 until removed by HLA-DM

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66
Q

HLA-DM

A

Catalyzes removal of CLIP and the loading of antigenic peptides into the peptide binding groove on MHC class 2

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67
Q

Innate and adaptive working together:

A

Production of IFN-gamma –> cytokine-mediated MHC2 expression on APCs –> enhanced antigen presentation –> enhanced T cell response

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68
Q

Development of T cells

A

Multipotent HSC –> common lymphoid progenitor –> T cell, ILC precursor–NOTCH/GATA3–> Pro-T cell –> alpha/beta or gamma/delta T cells

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69
Q

Thymic involution

A
  • thymic production is greatest before puberty
  • as we age, hematopoietic stem cells reduce lymphoid and increase myeloid differentiation capacity
  • thymic involution is the loss of thymic mass with age
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70
Q

Double negative

A

Cells that do not express CD4 or CD8. These cells are the first before CD3 takes place

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71
Q

Double positive

A

Cells that express both CD4 and CD8. Prospective alpha-beta T cells proceed through development this way

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72
Q

c-kit (CD117)

A

expressed early in T cell development, aids in early lymphocyte development

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73
Q

What is the role of CD44?

A

Homing precursor cells to the thymus

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74
Q

Stages of Double negative T cells in the Thymic cortex

A
  1. ETP (DN1): C-kit ++, Cd44 +, CD25 -
  2. Pro-T (DN2): C-kit ++, CD44 +, CD25 +
  3. Small pre-T (DN3): C-kit +, CD44 -, CD25 +, pre-TCR bound
  4. Large pre-T (DN4): C-kit low/-, Cd44 -, Cd25 -, proliferation occurs here
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75
Q

Stages of double positive T cells

A
  • before this occurs, the TCR-alpha locus rearrangement occurs to have double +
    1. Cortex: CD4 and CD8
    2. Medulla: CD4 and CD8 and TCR
    3. progresses to single positive (Cd4 or CD8) with TCR
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76
Q

Gene rearrangement with alpha-beta T cells

A
  • V gene rearranges with DJ
  • rearranged beta chain associates with surrogate alpha chain to form complex CD3 (forming pre-TCR)
  • beta rearrangement stops, initiates proliferation
  • now double + thymocyte and alpha chain undergo rearrangements followed by positive and negative selection
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77
Q

Positive selection

A
  • only T cell receptors that bind with sufficient strength (low avidity) to self peptide presented by MHC on thymic epithelium receive survival signals. Other cells die due to neglect (no TCR signals) via apoptosis
  • this process determines if surviving thymocyte becomes CD4 or Cd8
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78
Q

Negative selection

A
  • Thymocytes that react strongly (high avidity) to antigens presented by self-MHC are deleted (prevents autoreactivity)
  • AIRE
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79
Q

What is responsible for non-thymic peptide presentation to developing T cells?

A

Autoimmune regulator (AIRE) that express antigen from all over the body

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80
Q

NOTCH signaling is required for what?

A

Initial signaling instruction and guidance through the cortex

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81
Q

Chemokines regulate thymocytes migration through various regions of the thymus via:

A
  • initially through CXCR4 and CCR7
  • further outward migration via CCR9
  • single positive thymocytes gain expression of CCR7 and return to medulla (AIRE and central tolerance)
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82
Q

T cell activation requires:

A

2 SIGNALS:

  1. MHC antigen presentation
  2. co-receptor signal

signal 3: supports T cell differentiation. cytokines support further subset differentiation

  • without these two signals the T cell becomes anergic
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83
Q

Examples of co-receptor signaling:

A

CD40:CD40L
PD-1L:PD-1
ICOS-L:ICOS
CD80/86:CD28 CS80/86:CTLA4

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84
Q

T helper differentiation (polarization)

A

following interaction with their cognate antigen, naive Cd4 T cells are driven by cytokines in the micro-environment and transcription factors to further develop into specific CD4 T helper subsets

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85
Q

Promoter of differentiation: IFN-gamma

A
  • Cell: Th1
  • transcription factor: Tbet
  • signature cytokines: IFN-gamma
  • stability of phenotype: yes
  • cytotoxic potential: yes
  • disease involvement: intracellular pathogens (viral, bacterial)
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86
Q

Promoter of differentiation: IL-4

A
  • Cell: Th2
  • transcription factor: GATA3
  • signature cytokines: IL4, 5, 13, 9
  • stability of phenotype: yes
  • cytotoxic potential: yes
  • disease involvement: allergies, helminth infections
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87
Q

Promoter of differentiation: IL-21

A
  • Cell: Th17
  • transcription factor: RORyt
  • signature cytokines: IL17, IL22
  • stability of phenotype: yes
  • cytotoxic potential: yes
  • disease involvement: extracellular bacterial infections, celiac, auto-immune (IL17)
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88
Q

Promoter of differentiation: TGF-beta

A
  • Cell: Treg
  • transcription factor: Foxp3
  • signature cytokines: TGF-beta
  • stability of phenotype: yes
  • cytotoxic potential: yes
  • disease involvement: immune suppression, homeostasis, tolerance
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89
Q

Promoter of differentiation: IL-21

A
  • Cell: Tfh (follicular helper, secondary lymphoid ONLY)
  • transcription factor: Bcl-6
  • signature cytokines: IL-21
  • stability of phenotype: yes
  • cytotoxic potential: ND
  • disease involvement: B cell maturation in germinal center
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90
Q

Superantigen

A
  • recognized by T cells without being processed into peptides presented by MHC molecules
  • bind independently to MHC class 2 and the T cell receptor (to coreceptor area)
  • does NOT prime pathogen-specific adaptive immune response
  • massive cytokine production by CD4 T cells that result in system toxicity, and suppression of adaptive immune system
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91
Q

Common bacterial superantigens

A
  1. staphylococcal enterotoxins (SEs)
  2. toxic shock syndrome toxin-1 (TSST-1)
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92
Q

What are the chain types in T cells receptors?

A
  • alpha-beta
  • delta-gamma
  • each has a constant and a variable portion
  • V(D)J, takes place in the thymus
  • both alpha and beta have transmembrane domains
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93
Q

alpha chain of T cell receptors

A
  • encoded by VJ and Constant gene segments
  • rearrangement –> VJ combo + single C segment
  • alpha chain has a transmembrane cytoplasmic tail making the TCR alpha receptor a membrane bound chain
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94
Q

beta chain of T cell receptors

A
  • encoded by VDJ and constant gene segments
  • rearrangement –> VDJ combo + one of 2 constant gene segments
  • beta chain has a transmembrane cytoplasmic tail making the TCR alpha receptor a membrane bound chain
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95
Q

Pre-T cells express:

A

RAG1 and RAG2: to recognize conserved recombination signal sequences flanking the regions of the V, D, and J coding sequences in the DNA

TdT: somatic mutation to add/deletion 0-6 nucleotide bases between the V and D and between the D and J

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96
Q

What can B cell recombination do that T cell cannot?

A

Somatic HYPERMUTATION– could leading to autoimmunity

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97
Q

CD4 co-receptors

A
  • 55kDa monomer with four Ig-like domains (larger)
  • binds to conserved regions on class 2 MHC
  • binds to signal transduction molecule p56Ick and forms a bridge that also binds to the zeta chains of CD3 (activation or effector functions)
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98
Q

CD8 co-receptor

A
  • 30-38 kDa monomers with one Ig-like domain held together by a disulfide bond
  • alpha-beta heterodimer or alpha-alpha homodimer
  • binds to a conserved region on the Class 1 MHC
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99
Q

Principle of T cells: recognition of self

A
  • T cells do not “see” antigen alone, but only antigen presented to them on the surface of a genetically-identical cell (must recognize self)
  • APCs must come from individuals who have the same alleles at the MHC loci group
  • T cells are antigen-specific and MHC-restricted
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100
Q

When antigen is endocytosed and presented by a dendritic cell:

A
  • associates with Class 2 MHC molecules in the endocytosed vesicle
  • Th1, Th17, Tfh, Treg, Th2 are programmed to recognized peptides on class 2 molecules
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101
Q

Proteins are synthesized within the cell itself:

A
  • class 1 MHC
  • NOT taken up by endocytosis
  • normal self proteins –> mutations
  • internal pathogens such as virus-encoded molecules
  • CTL are programmed to see antigen in association with MHC class 1 molecules
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102
Q

Why is the dendritic cell special?

A
  • It allows some peptides from antigens it has eaten to leak over into its endogenous pathway, so that it can present them on Class 1 AND Class 2 MHC at the same time: CROSS PRESENTATION
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103
Q

How many different MHC1/MHC2 variants can you have?

A
  1. Class 1 MHC molecules = 6 different complexes
  2. Class 2 MHC molecules = 12 different complexes
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104
Q

What MHC proteins are considered MHC3?

A
  • complement proteins
  • TNF-alpha and TNF-beta
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105
Q

MHC1 subclasses

A
  • HLA-A
  • HLA-B
    -HLA-C
  • all of these associate with beta-2 microglobulin
  • inherited via mom and dad which pair with eachother (2 combos x 3 variations)
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106
Q

MHC2 subclasses

A
  • HLA- DP
    -HLA- DQ
  • HLA-DR
  • alpha and beta chains must be paired with same flavor (DR alpha with DR beta, etc.)
  • inherited via mom and dad, which can pair with eachother or themselves (4 combos x 3 variations)
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107
Q

Each locus of Class 1 and 2 MHC is polymorphic giving us:

A
  • unique identity, permitting the recognition of self versus non-self and is an impediment to organ transplantation
  • affects ability to make immune response
  • affects the resistance/susceptibility to infectious diseases
  • affects the susceptibility to autoimmune diseases and allergies
  • most polymorphisms are in the cleft region (antigenic binding site)
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108
Q

Cytosolic pathway

A
  • presentation of antigen on Class 1 molecules
  • requires intracellular protein synthesis of the endogenous antigen
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109
Q

What are defective ribosomal products (DRiPs)?

A
  • proteins that are synthesized incorrectly.
  • associated with MHC 1 class
  • allows recognition and killing of cells that have aberrant DNA and thus produce aberrant proteins
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110
Q

What do virus-infected cells contain that is distinct?

A
  • 20S proteasome
  • induced by IFN-gamma and TNF-alpha
  • proteasome degrades and presents viral proteins on the cell surface through MHC class 1 molecules
  • allows for the recognition and killing of cells that are infected with viruses
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111
Q

Endocytic pathway

A
  • presentation of antigen on MHC class 2 molecules
  • requires the endocytic uptake of exogenous antigen
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112
Q

Endocytic degradation pathway

A
  • exogenous antigens are processed through the endocytic pathway
  • antigens are internalized into APCs through endocytosis or phagocytosis (dendritic/macrophages phagocytose, B cells endocytose)
  • internalized antigens are degraded in phagolysosomes or endosomes
  • the antigenic peptides are associated with MHC class 2 molecules on their cell surface
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113
Q

invariant chain

A
  • MHC class 2 molecules are synthesized on the RER as trimers
  • alpha and beta chain coupled with an invariant chain (CD74)
  • the invariant chain assists in the folding of the class 2 alpha and beta chains, binds to the peptide-presenting site of the class 2 molecule, and assists in the transport of the MHC class 2 molecules from the golgi to the cytoplasmic vesicles
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114
Q

What gradually digests the invariant chain leaving a short fragment (CLIP) bound to the antigen presenting site of the MHC class 2?

A

Proteolytic cleavage

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115
Q

CLIP

A

Class 2-associated invariant chain peptide

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116
Q

assembly of class 2 MHC molecules

A
  • a nonclassical class 2 MHC is required to catalyze the exchange of antigenic peptide for the CLIP– AKA, HLA-DM (which is regulated by HLA-DO)
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117
Q

HLA-B27 polymorphism

A
  • individuals are 90x more likely to develop ankylosing spondylitis (destruction of the vertebral cartilage)
  • also linked to psoriasis, IBS, and Reiter’s syndrome
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118
Q

HLA-B57 polymorphism

A
  • linked to Abacavir hypersensitivity
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119
Q

HLA-DR2 polymorphism

A
  • individuals are 130x more likely to develop narcolepsy
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120
Q

HLA-A3 and HLA-B14 polymorphism

A
  • individuals are 90x more likely to develop hemochromatosis (too much iron absorption which can lead to internal organ damage)
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121
Q

HLA-DQ2 and HLA-DQ8 polymorphism

A
  • linked to Celiac disease
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122
Q

HLA-DR3 polymorphism

A
  • linked to diabetes mellitus type I, Grave’s disease, Addison disease, and Hashimoto thyroiditis
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123
Q

HLA-DR4 polymorphism

A
  • linked to Rheumatoid arthritis, diabetes mellitus type 1, and Addison disease
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124
Q

HLA- B53 polymorphism

A
  • associated with protection against childhood malaria
  • specific global distribution pattern (Ghana frequency is 40% while China and South Africa are 1-2%)
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125
Q

Serum Sickness

A
  • Type 3 hypersensitivity (Bulky Ab-Ag complex depositing everywhere)
  • a syndrome that is characterized by skin rash, joint stiffness, joint pain, facial and extremity swelling, and fever. Sometimes vomiting or respiratory distress happen. It may be mistaken for anaphylaxis.
  • From Sulfonamides, penicillin allergies
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126
Q

Tuberculoid Leprosy

A
  • Few (usually 1–3 lesions), localized, hypopigmented macules, plaques, and/or papules with well-defined, erythematous, and/or raised margins
  • Lesions are dry, scaly, anhidrotic .
  • Hair loss
  • Hyperesthesia of the skin lesion is common and occurs early (hypoaesthesia of the skin develops in later stages).
  • Nerve involvement occurs early but is localized, Asymmetric enlargement of one or many peripheral nerves, Acute neuritis does not occur.
  • not systemic
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127
Q

Lepromatous Leprosy

A
  • Multiple symmetrical macules, plaques, and/or nodules, generalized involvement of the skin
  • Nodules on the face may coalesce → leonine facies
  • Nodules may ulcerate
  • Hypesthesia of the skin lesion is less common and occurs only in the late stages of the disease.
  • Supraciliary and ciliary madarosis
  • nerve involvement occurs late but is more extensive- Acral, distal, symmetrical anesthesia, Usually begins with stocking glove pattern that spreads proximally
  • Systemic involvement includes: nasal stuffiness, epistaxis, hepatomegaly, nontender lymphadenopathy
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128
Q

Type 1 hypersensitivity

A
  • immediate, anaphylactic and atopic
  • IgE, CD4+, Th2 cells
  • increases mast cells, eosinophils, and their mediators (IL4, IL5, IL13)
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129
Q

Type 2 hypersensitivity

A
  • antibody mediated
  • IgM, IgG against surface or extracellular matrix proteins
  • Cellular destruction: opsonization, complement, ADCC
  • inflammation: antibodies block or activate signaling (dysfunction)
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130
Q

Type 3 hypersensitivity

A
  • Immune complex mediated
  • Circulating antigen:antibody complex
    -complement activation, neutrophil attraction, and lysozyme release
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131
Q

Type 4 hypersensitivity

A
  • Delayed, T cell mediated
  • CD4+, Th1, Th17, CD8+ cytotoxic T lymphocytes
  • CD4+ Th cytokine mediated inflammation and macrophage and neutrophil activation
  • Direct target cell killing (CD8+ CTLs)
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132
Q

What is leukemia?

A
  • a group of malignant conditions of hematopoietic stem cells (myeloid or lymphoid) within the bone marrow
  • Results in: uncontrolled proliferation of the malignant stem cell sin the marrow, leukemic cells replace the normal ones, which infiltrates into the peripheral blood and tissues throughout the body
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133
Q

What are the two major types of leukemia?

A
  1. Myeloid
  2. Lymphoid
  • can present as acute or chronic
  • many subtypes due to different mutations
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134
Q

What are the risk factors for leukemia?

A
  • Chromosomal abnormalities (Down syndrome, chrom. instability syndromes)
  • Ionizing radiation
  • Chemicals (benzene)
  • Alkylating agents (Busulfan)
  • Chronic myeloproliferative diseases (polycythemia vera)
  • Proxysmal nocturnal hemoglobinuria
  • Cigarette smoking
  • Immunodeficiency diseases (Wiskott-Aldrich)
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135
Q

What is the most common leukemia/ cancer in children?

A
  • ALL (Acute lymphoblastic leukemia)
  • also the most common cancer in children
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136
Q

What is the most common leukemia in people older than 60?

A
  • CLL (Chronic lymphocytic leukemia)
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137
Q

What is the most common leukemia in people between 40-60?

A
  • AML (acute myeloblastic leukemia)
  • CML (chronic myelogenous leukemia)
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138
Q

What are the pathogeneses of leukemia?

A
  • blocks stem cell differentiation
  • monoclonal proliferation of cells before the block
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139
Q

Pathogenesis of acute leukemia

A
  • block occurs at an early stage of stem cell development
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140
Q

Pathogenesis of chronic leukemia

A
  • block occurs at a later stage in stem cell development
  • some maturation in chronic leukemia
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141
Q

Acute leukemia overview

A
  • poorly differentiated
  • abrupt onset and aggressive with rapid progression
  • high mortality in months
  • peripheral smear: blasts + immature nucleolated cells)
  • bone marrow: blasts >20%
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142
Q

Chronic leukemia overview

A
  • well differentiated
  • Gradual onset and indolent, slow progression
  • survival for years
  • high total leukocyte counts with more mature cells and few blasts
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143
Q

Lymphoma vs leukemia

A
  • Leukemia: cancer arising primarily from the bone marrow from the stem cells
  • lymphoma: a cancer arising primarily from the lymphoid cell in the lymph node
  • NOTE: when lymphoma cells infiltrate the blood and bone marrow it is called the * leukemic phase of lymphoma and is treated like leukemia
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144
Q

Myeloproliferative syndromes (MPS)

A
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145
Q

Myelodysplastic syndromes (MDS)

A
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146
Q

Cancer of the bone marrow will show:

A
  • excess blast cells
  • anemia/ decreased RBC
  • infections/ decreased WBC
  • bleeding/decreased platelets
  • bone pain
  • splenomegaly
  • hepatomegaly
  • lymphadenopathy
147
Q

White blood cell counts are always high in:

A
  • chronic leukemia
  • 90-95%: myeloid cells (left shift cells), basophilia –> CML
  • 90%: lymphocytes –> CLL
148
Q

AML has:

A

+ Auer rods and >20% myeloblasts

149
Q

ALL has:

A
  • Auer rods and >20% lymphoblasts
150
Q

Variable white count in peripheral smear of leukemia

A
  1. Leukemic: increased WBC count and presence of blasts
  2. Subleukemic: blasts are present but no increase in WBC count
  3. Aleukemic: no blasts seen in peripheral smear, WBC count is decreased

** both subleukemic and Aleukemic presentations on peripheral smear exam, bone marrow exam can be diagnostic (will show increased number of blast cells)

151
Q

Sudan black B (SBB) and Myleoperoxidase (MPO) stain

A

Myeloblast stain for enzyme in granules of myeloid and monocytic cells, never found in lymphoid cells

152
Q

PAS stain

A

Lymphoblasts stain for granular PAS pattern in lymphoblastic leukemia

153
Q

Non-specific esterase (NSE) stain

A

Monoblasts stain for monocytic cells

154
Q

Tartrate resistant acid phosphatase (TRAP) stain

A

Hairy cell leukemia stain

155
Q

TdT: terminal deoxynucleotidyl-transferase stain

A

Immature T and B cell stain (Lymphoblasts)

156
Q

Acid phosphatase stain

A

Stains for T cells, lymphoblasts which have a characteristic dot-like focus of intense positivity

157
Q

Hairy cell leukemia

A
  • uncommon (2%), indolent B cell neoplasm arising from memory B cells
  • leukemic cells with fine, hair-like projections
  • Pan-B cell markers (CD19 and CD20), surface immunoglobulin, and CD11c/CD103
  • activating mutations in serine/threonine kinase BRAF
158
Q

Who is most likely to be diagnosed with Hairy cell leukemia?

A
  • middle aged Caucasian males, median age: 55, M:F ratio: 5:1
159
Q

What symptoms are seen in hairy cell leukemia?

A
  • Splenomegaly (90%), sometimes the only finding
  • Pancytopenia (>50% from BM involvement, and splenic sequestration)
  • LN involvement is rare (<10%), and hepatomegaly (20%)
  • infection in 30% of patients- especially atypical mycobacterial infections, unexplained monocytopenia
160
Q

What has a DRY TAP on aspiration during a bone marrow biopsy?

A

Hairy cell leukemia

161
Q

Hairy cell leukemia prognosis

A
  • very good
  • HCL is extremely sensitive to gentle chemo: purine nucleosides, 2-choro-2-deoxyadenosine (complete remission in 85% of cases)
  • BRAF inhibitors: excellent response in tumors that have failed conventional chemo
162
Q

Adult T cell leukemia/lymphoma

A
  • Neoplasm of CD4+ T cells caused by a retrovirus: human T cell leukemia virus type 1, HTLV-1)
  • infection is endemic in southern Japan, the Caribbean basin, and West Africa
  • HTLV-1 can also cause transverse myelitis
163
Q

Symptoms of Adult T cell leukemia/lymphoma

A
  • Skin lesions
  • lymphadenopathy
  • hepatosplenomegaly
  • hypercalcemia
  • malignant lymphocytes in the peripheral blood
  • cells with multi-lobated nuclei (cloverleaf or flower cells)
  • CD4, CD5 (IL2 receptor alpha chain) affected
  • very aggressive, responds poorly to medication
  • median survival time: 8 months
164
Q

Microtubules are:

A

polymers of alpha and beta tubulin that act to separate replicated chromosomes during mitosis

165
Q

Microtubule targeted drugs act in:

A

M phase and induce mitotic arrest in anaphase

  • Vinca alkaloids and taxanes
166
Q

Vinca alkaloids prevent:

A

microtubule assembly

167
Q

Taxanes prevent:

A

microtubule disassembly

168
Q

Vincristine

A

a natural vinca alkaloid produced by the periwinkle cantharanthus roseus plant. It has wide application against solid tumor and liquid cancers

169
Q

Antimicrotubule drugs: Vincristine

A
  • Class: vinca alkaloid, cell cycle specific (M phase)
  • Indications: Leukemias, lymphomas, sarcomas, neuroblastomas, etc
  • Mech of Action: inhibition of microtubule polymerization causing anaphase arrest
  • administered via: IV
  • excreted via: Biliary excretion/feces
  • toxicities: neurotoxicity, constipation, myelosuppression
170
Q

Vinca Alkaloid drugs:

A
  1. Vincristine (natural)
  2. Vinblastine (natural)
  3. Vinorelbine (synthetic)
171
Q

Paclitaxel

A
  • a naturally occurring taxane produced by the Pacific Yew tree, Taxus brevifolia. It enhances microtubule polymerization and prevents depolymerization causing cells to die by mitotic catastrophe
172
Q

Antimicrotubule drugs: Paclitaxel

A
  • Class: taxane antimicrotubule drug, cell specific (M phase)
  • Indications: ovarian cancer, breast cancer, lung cancer (solid)
  • Mech of Action: Stabilization of polymerized microtubules causing anaphase arrest
  • administered via: IV
  • excreted via: Biliary/fecal
  • toxicities: myelosupression, infusion site reactions, sensory neuropathy
173
Q

Other microtubule stabilizing drugs like Paclitaxel

A
  1. Docetaxel (natural)
  2. Cabazitaxel (natural)
  3. Ixabepilone (non-taxane microtubule inhibitor, not effluxed through p-glycoprotein)
  4. Eribulin (non-taxane microtubule inhibitor, not effluxed through p-glycoprotein)
174
Q

Anthracycline antibiotics

A
  • most commonly used antineoplastic drugs in clinical practice
  • Based on structures of compounds derived from streptomyces peucetius
  • Potential mechanisms:
    1. inhibition of topoisomerase II
    2. Intercalation in DNA, blocking DNA and RNA synthesis and causing DNA strand breaks (noncovalent interaction)
    3. Generating ROS through enzyme catalyzed oxidation/reduction
    4. Altering cell membrane fluidity
175
Q

Doxorubicin

A
  • anthrocycline drug
  • solid and hematological cancer effectiveness
  • The red devil
176
Q

How does doxorubicin work on Topoisomerase II?

A
  • it prevents the TopoII from re-ligating the transient break it makes during torsional strain relief.
  • NHEK or HEJ occurs afterwards, potentially creating errors
177
Q

Anthracycline drugs: Doxorubicin

A
  • Class: anthracycline antibiotic, cell cycle non-specific
  • Indications: Breast cancer, lymphomas, sarcomas, lung, etc
  • Mech of Action: topoisomerase II inhibition leading to double stranded DNA breaks
  • administered via: IV
  • excreted via: Biliary excretion in feces
  • toxicities: Neurotoxicity, constipation, muelosuppression, delayed cardiac toxicity limits the lifetime of dose
178
Q

Other anthracycline drugs like doxorubicin

A
  1. Daunorubicin: used for AML, limited solid tumor use
  2. Idarubicin: synthetic, AML induction
  3. Epirubicin: Synthetic, breast/GI cancers
  4. Mitoxantrone: anthracene used for breast/prostate
179
Q

Bleomycin

A
  • metal binding domains and a DNA binding domain. It can bring ferrous iron and cuprous copper into close proximity with DNA in the nucleus, causing superoxide and hydroxyl radicals that cause DNA strand breaks
180
Q

Antibiotic drugs: Bleomycin

A
  • Class: peptide antibiotic, cell cycle non-specific
  • Indications: breast cancer, lymphomas, sarcomas, lung, etc
  • Mech of Action: iron binding and DNA binding domains generate ROS that causes DNA breaks
  • administered via: IM, also IV or intrapleural space
  • excreted via: urine, the kidneys
  • toxicities: dose limiting pulmonary toxicity, skin reactions
181
Q

Antimetabolites are:

A

analogs of intermediates of DNA synthesis. They inhibit specific enzymes and interrupt specific features of nucleic acid metabolism

182
Q

antimetabolites are cell cycle specific in which phase?

A

S phase

183
Q

Classes of antimetabolites include:

A
  1. antifolates
  2. fluorpyrimidines
  3. deoxycytidine analogs
  4. Purine antagonists
184
Q

Which amino acids donate to the “one carbon pool”?

A
  1. Serine (most important)
  2. Glycine
  3. Histidine
  4. Tryptophan
185
Q

Rapidly dividing cells have a high requirement for:

A

deoxynucleotides in order to support genome replication

186
Q

What generates deoxythymidine monophosphate (dTMP) from deoxyuridine monophosphate (dUMP) in a methylation reaction?

A

Thymidylate synthase

187
Q

What is required to regenerate tetrahydrofolate (FH4) to sustain the thymidylate synthase pathway?

A

Dihydrofolate reductase

188
Q

Methotrexate

A

Folate analog that acts as a competitive inhibitor (vmax same, km larger) of dihydrofolate reductase, restricting the folate pool available to support deoxynucleotide synthesis

189
Q

Antifolate drugs: Methotrexate

A
  • Class: Antimetabolite, folate analog, cell cycle specific (S phase)
  • Indications: breast cancer, ALL lymphomas, head/neck
  • Mech of Action: competitive inhibition of DHFR and blocking of deoxynucleotide synthesis
  • administered via: ORAL, parenterally or IM
  • excreted via: urinary excretion
  • toxicities: myelosuppression, renal failure
190
Q

Other folate analog antimetabolites like methotrexate

A
  1. Pemetrexed: mesothelioma, non-small cell lung cancer
  2. Pralatrexate: relapsed T cell lymphoma
191
Q

5-fluorouracil

A
  • a fluoropyrimidine, an analog of the pyrimidine base uracil
  • acts as a non-competitive (decrease in Vmax, km unchanged) inhibitor of thymidylate synthase
  • limits the availability of deoxypyrimidine nucleotides for genome replication
  • used frequently for GI cancers
192
Q

How else can fluoridated nucleotides cause damage?

A

By being substrates of DNA and RNA polymerase

193
Q

How 5-FU works:

A

5-FU + phosphoribosyl pyrophosphate (PRPP) –> nucleotide

5-FU– thymidine phosphorylase + thymidine kinase –> nucleotide

-Creates fluoridated urine (FUTP and FdUTP) that can be incorporated into RNA and DNA, respectively

194
Q

Fluoropyrimidines: 5-FU

A
  • Class: antimetabolite, fluoropyrimidine, cell cycle specific (S phase)
  • Indications: colorectal, breast cancer, head/neck (solid)
  • Mech of Action: non-competitive suicide inhibition of thymidylate synthase and depletion of deoxypyrimidines- misincorportation of fluoridinated nucleotides into RNA and DNA
  • administered via: IV
  • excreted via: urinary / kidneys
  • toxicities: myelosuppression, mucositis, diarrhea, hand-foot syndrome
195
Q

other fluoropyrimidines like 5-FU

A
  1. Capecitibine: orally bioavailable, breast and colon cancer
  2. TAS-102: orally bioavailable, colorectal cancer
196
Q

Cytarabine

A

an analog of the pyrimidine nucleoside deoxycytidine. Cytarabine is phosphorylated to cytarabine triphospgate by cellular kinases. It then inhibits DNA polymerases alpha and beta. If incorporated into DNA, it will create double stranded breaks during next round of replication

197
Q

Deoxycytidine drugs: Cytarabine

A
  • Class: antimetabolite, deoxycytodine analog, cell cycle specific (S phase)
  • Indications: hematologic malginancies only (NO solid tumors)
  • Mech of Action: incorporation of cytarabine nucleotides into DNA
  • administered via: IV
  • excreted via: urinary/kidney
  • toxicities: myelosupression, nausea, vomiting, cerebellar ataxia
198
Q

Other deoxycytidine analog like cytarabine

A
  1. Gemcitabine: fluorinated deoxycytidine analog with broad activity against solid tumors
199
Q

Fludarabine

A
  • A purine analog of adenosine. Has -arabinose rather than ribose sugar, and a fluorinated base
  • it is used to treat various lymphomas and leukemias. pro-drug form is fludarabine phosphate with a phosphate on the 5’ hydroxyl group
200
Q

Fludarabine is phosphorylated to the triphosphate form by:

A

intracellular kinases

  • this form inhibits DNA polymerases and repair enzymes, causing DNA breaks and cell death
201
Q

Other purine antagonists like Fludarabine

A
  1. Cladribine
  2. Clofarabine
202
Q

Purine Antagonist drugs: Fludarabine

A
  • Class: antimetabolite, purine antagonist, cell cycle specific (S phase)
  • Indications: leukemias and lymphomas (blood cancers)
  • Mech of Action: inhibition of nucleic acid metabolism
  • administered via: IV and orally available
  • excreted via: urinary/kidney
  • toxicities: life threatening autoimmune reactions, hemolytic anemias
203
Q

Alkylation is:

A

the transfer of carbons. Alkylation of DNA can occur naturally from endogenous compounds, and from alkylating agents in our environment

204
Q

The goal of treating a cancer patient with alkylating agents is to:

A

kill cancer cells by causing cytotoxic DNA damage and mutations

  • alkylating agents are: cell cycle non-specific (though cancer cells are more susceptible in G1 and S phases
205
Q

The major site of alkylation by therapeutic agents are:

A
  1. N7 of guanine
  2. O6 of guanine
  3. potentially also the phosphodiester backbone of DNA
206
Q

How can cancer cells become resistant alkylating agents?

A

Elevated DNA repair activity (MGMT, AlkB)

207
Q

Nitrogen mustards: mechlorethamine

A

Class: alkylating agent, cell cycle, non-specific
Indications: Hodgkin’s lymphoma, non-Hodgkin’s lymphoma
Mech of action: inter- and intra- strand cross-linking of DNA inhibits DNA replication and causes DNA damage
Absorption via: IV
Excretion: urine/kidneys
Toxicities: myelosuppression: anemia, thrombocytopenia, neutropenia

208
Q

The nitrogen mustard cyclophosphamide requires activation by:

A

Hepatic enzymes to form the cytotoxic, cross-linking agent phosphoramide mustard

209
Q

What is a mechanism of cyclophosphamide resistance?

A

Expression of aldehyde dehydrogenase

210
Q

Phosphoramide mustard alkylates what?

A

N7-guanines, cross-linking nearby bases

211
Q

Nitrogen mustards: cyclophosphamide

A

Class: alkylating agent, cell cycle, nonspecific
Indications: breast, cancer, non-Hodgkin’s, informer, CLL
Mech of action: inactive until metabolized by the liver. Active form makes inter-and intra-strand cross-linking of DNA inhibits DNA replication and causes damage.
Absorption via: orally
Excretion: urine/kidneys
Toxicities: myelosuppression and bladder toxicity

212
Q

Melphalan

A

Combines the essential amino acid phenylalanine with a nitrogen mustard. The drug takes advantage of endogenous amino acid transporters, and is bioavailable orally.

213
Q

Nitrogen mustards: melphalan

A

• Class: alkylating agent, cell cycle, nonspecific
• Indications: multiple myeloma, breast, cancer, ovarian cancer, retinoblastoma
• Mech of action: forms inter-and intra-strand, cross-links inhibiting DNA replication and causes DNA damage
• Absorption via: oral, decreased with food
• Excretion: urine, feces
• Toxicities: myelosuppression

214
Q

Nitrosourea

A

• alkylating agents, derived from nitrosourea source. Siri, lipid soluble, able to penetrate the blood brain barrier. Prodrug.

215
Q

Carmustine

A

• BCNU, forms, interstrand cross-links between guanines and cytosines
• spontaneously degrees into fragments that alkylate DNA and carbamoylyate proteins (O6 of guanine is the worst)

216
Q

Nitrosoureas: carmustine

A

• Class: alkylating agent, cell cycle, nonspecific
• Indications: brain, tumors, Hodgkin’s lymphoma, non-Hodgkin’s, lymphoma, multiple myeloma
• Mech of action: forms interstrand GC cross links, carbomoylates proteins
• Absorption via: IV
• Excretion: urine, exhaled as CO2
• Toxicities: delayed myelosuppression, infertility, secondary malignancies

217
Q

Lomustine

A

A nitrosourea with a similar mechanism of action as carmustine. It is lipid, soluble crosses the BBB and can be used to treat bring answers. *ORALLY AVAILABLE

218
Q

Lomustine spontaneously degrades to chloroethylene ion, which:

A

Alkylates O6 of guanine. Subsequent reactions lead to interstrand ethyl crosslink between N1 of guanine and N3 of cytosine

219
Q

Nitrosoureas: Lomustine

A

• Class: alkylating agent, cell cycle, nonspecific
• Indications: brain tumors, Hodgkins lymphoma, non-Hodgkin’s lymphoma
• Mech of action: forms interstrand G-C cross-links
• Absorption via: oral-complete
• Excretion: urinary/kidneys
• Toxicities: myelosuppression, sterility, secondary malignancies

220
Q

Streptozocin

A

• A nitrosourea bonded to a glucose molecule. Produced by streptomyces achromogenes
• localize to islet cells of the pancreas— can induce type one diabetes and cause hyper/hypoglycemia

221
Q

Nitrosoureas: streptozocin

A

• Class: alkylating agent, cell cycle, nonspecific
• Indications: pancreatic islet cell cancer, carcinoid tumors
• Mech of action: forms interstrand G-C crosslinks
• Absorption via: IV
• Excretion: urinary/kidneys
• Toxicities: dose limiting renal toxicity mild myelosuppression, hyper/hypoglycemia

222
Q

What was the first metal base drug applied to cancer therapy?

A

Cisplatin

223
Q

How does cisplatin enter the cell?

A

Copper transporters or by diffusion. Binds preferentially to the N7 of guanine in the nucleus.

224
Q

Platinum agents: cisplatin

A

• Class: platinum agent, cell cycle nonspecific
• Indications: testicular, cancer, ovarian, bladder
• Mech of action: forms intrastrand G-G crosslinks
• Absorption via: IV or intraperitoneal
• Excretion: urinary/kidneys
• Toxicities: those limiting renal toxicity, myelosuppression, peripheral neuropathy, sterility

225
Q

Carboplatin

A

A second generation platinum agent with the same mechanism of action of cisplatin: intrastrand G-G cross-links. Has fewer toxicities

226
Q

Platinum agents: carboplatin

A

• Class: platinum agent, cell cycle nonspecific
• Indications: ovarian, germ, cell, tumors, head/neck cancers
• Mech of action: forms, intrastrand G-G cross-links
• Absorption via: IV
• Excretion: urinary/kidneys
• Toxicities: myelosuppression, renal, toxicity, peripheral neuropathy, sterility

227
Q

Oxaliplatin

A

• third-generation, platinum agent
• makes a bulkier DNA adduct and can make intrastrand G-G, G-A cross-links and interstrand G-C crosslinks

228
Q

Platinum agents: oxaliplatin

A

• Class: platinum agent, cell cycle nonspecific
• Indications: colorectal cancer, pancreatic cancer
• Mech of action: forms intrastrand G-G and G-A cross-links, interstrand G-G
• Absorption via: IV only
• Excretion: urinary/kidneys
• Toxicities: peripheral sensory neuropathy, and other neural toxicities, myelosuppression

229
Q

Alkylating antibiotic: Mitomycin C

A

• Class: alkylating antibiotic, cell cycle nonspecific
• Indications: gastric, pancreatic, breast, bladder
• Mech of action: forms interstrand G-C
• Absorption via: IV only
• Excretion: hepatobiliary is excretion in feces
• Toxicities: myelosuppression, injection site injury

230
Q

Nonclassical alkylating agents: dacarbazine, procarbazine, temozolomide

A

• bio activated to methyl diazonium ion in the body. Transfers, muscle groups to guanine on O6, N7, and N3-adenine —> causes C-T mutation

231
Q

Dacarbazine

A

• undergoes, metabolism by cyp450 enzymes to form methyl diazonium ion
• transfer is methyl groups to guanine’s O6 to form O6 methyl guanine

232
Q

Nonclassical alkylating agents: Dacarbazine

A

• Class: alkylating agent, cell cycle nonspecific
• Indications: melanoma, Hodgkin’s lymphoma, soft tissue, carcinoma, neuroblastoma
• Mech of action: forms O6-MG
• Absorption via: IV preferred, oral route is slow and variable
• Excretion: urinary, kidneys
• Toxicities: myelosuppression, N/V, injection site injury, mutagenic and carcinogenic secondary malignancies

233
Q

Nonclassical alkylating agents: procarbazine

A

• Class: alkylating agent, cell cycle nonspecific
• Indications: melanoma, Hodgkin’s lymphoma, soft tissue sarcoma, neuroblastoma
• Mech of action: forms O6-MG and oxidative damage, weak MAOI
• Absorption via: complete absorption in GI tract: oral
• Excretion: urinary/kidneys
• Toxicities: myelosuppression, nausea and vomiting, secondary malignancies (AML)

234
Q

Temozolomide

A

• An alkylating agent used to treat astrocytomas and gliomas
• non-enzymatically converted to 4-amino-5-imidazole-carboxamide (AIC) and methyl diazonium cation —> reacts with O6 and N7 on guanine, making methyl guanine

235
Q

Nonclassical alkylating agents: Temozolomide

A

• class: alkylating agent, cell cycle nonspecific
• indications: melanoma, Hodgkin’s lymphoma, soft tissue sarcoma, neuroblastoma
• mech of action: forms O6-MG
• absorption via: Complete oral absorption
• excretion: urinary/kidneys
• toxicities: myelosuppression, nausea and vomiting, mutagenic and carcinogenic

236
Q

Resistance to alkylating agents can occur through:

A
  1. Decreased intake or increased efflux of the drug
  2. Metabolism through alternative pathways (aldehyde dehydrogenase for cyclophosphamide)
  3. Altered DNA repair pathways: increase in activity of pathways that repair lesions or decrease in activity of pathways that stall replication in cause apoptosis
237
Q

Non Hodkgin’s lymphoma (NHL)

A
  • 60% of adult lymphomas
  • 80% or more are derived from the germinal follicle
  • second most common cancer in AIDS
  • 1/3 arise from extranodal sites
  • median age: 50 years
238
Q

What are the childhood NHLs?

A
  • T cell lymphoblastic lymphoma
  • Burkitt lymphoma
  • more aggressive in children than adults
  • mutation produces a block in the development of T/B cell
239
Q

Risk Factors for NHL: viruses

A
  1. EBV (burkitts)
  2. HTLV-1 (adult T cell lymphoma/leukemia)
  3. Hep C (HCV, B cell lymphoma)
240
Q

Risk factors for NHL: autoimmune disease

A
  1. Sjorgren syndrome (salivary gland and GI lymphoma)
  2. Hashimoto thyroiditis (malignant thyroid lymphoma)
241
Q

Risk Factors for NHL: immunodeficiency

A
  1. Helicobacter pylori (low grade malignant lymphoma of stomach)
  2. Chromosome instability syndromes (BLOOM, AIDS)
  3. High dose radiation: risk of hodgkin lymphoma
242
Q

Acute lymphoblastic leukemia/ lymphoblastic lymphoma (ALL)

A
  • aggressive tumors composed of immature lymphocytes (lymphoblasts) predominantly in children and young adults (MANY lymphoblasts in peripheral blood and marrow)
  • pre B cell: 80% of childhood leukemia, peak at 4 years
  • pre T cell: mostly young adult males, 15-20 years
  • T cell ALL can present as mediastinal mass (presenting as SVC-like syndrome)
243
Q

Pathogenesis of ALL

A
  • TdT+, CD19+, CD10+, CD2+, CD7+ (markers of pre-T and pre-B cells)
  • translocation t(12;21) better prognosis
  • translocation t(9;22) worse prognosis (BCR-ABL fusion gene)
244
Q

ALL is associated with what mutation?

A

NOTCH1 mutations

245
Q

Small lymphocytic lymphoma/ Chronic lymphocytic leukemia (SLL)

A
  • age > 60 years, most common adult leukemia
  • CD20+, CD23+, CD5+ B cell neoplasm
  • INCREASED BCL2
  • progresses SLOWLY, indolent, asymptomatic
  • infection secondary to hypogammaglobinemia
    -SMUDGE CELLS (broken lymphocytes) in periphery
  • autoimmune hemolytic anemia
  • Richter transformation
246
Q

Richter transformation

A

CLL/SLL transformation into an aggressive lymphoma (DLBCL)

247
Q

SLL/CLL morphology

A
  • diffuse effacement of lymph nodes
  • sheets of small lymphocytes and scattered larger, actively dividing cells (proliferation centers– pathognomonic)
  • bone marrow, spleen, and liver involved
  • smudge cells
248
Q

Follicular lymphoma

A
  • adult cancer- indolent and painless, waxing and waning course of lymphadenopathy
  • translocation t(14;18) of heavy chain Ig (14) with BCL2 (18) causing an overexpression of BCL2 protein contributing to proliferation
  • CD19, CD20, CD10 and BCL6 + on the surface
249
Q

Morphology of follicular lymphoma

A
  • nodular proliferation
  • tumor cells resemble normal germinal center B cells (small with angular cleaved nuclei – CENTROCYTES)
  • large cells (centroblasts) minor compnent
250
Q

40% of follicular lymphoma patients progress to:

A

DLBCL with median survival less than one year

251
Q

Diffuse Large B cell Lymphoma (DLBCL)

A
  • usually adults, 20% in children, most common NH lymphoma in adults
  • mutation in BCL2 and BCL6 , BCL6 more common
252
Q

DLBCL morphology

A
  • Neoplastic B cells are large (3-4x normal lymphocytes)
  • diffuse pattern of growth–> round to oval nuclei with dispersed chromatin and distinct nucleoli
  • Pan-B cell antigens (CD19 and CD20)
253
Q

Immunodeficiency-associated large B cell lymphoma

A
  • in AIDS, iatrogenic immunosuppression (transplant recipients), and elderly
  • EBV- critical pathogenic role
  • restoration of T cell immunity may lead to regression
254
Q

Primary effusion lymphoma

A
  • subtype of DLBCL
  • may arise within the pleural cavity, pericardium, or peritoneum
  • patients with advanced HIV infections or older adults
  • associated with Kaposi sarcoma (HHV8)
255
Q

Clinical features of DLBCL

A
  • age around 60 years
  • rapidly enlarging, symptomatic mass at one or several sites
  • extra-nodal presentations common (GIT, Brain)
  • usually NO bone marrow involvement
  • treatment: intensive combo of chemo and anti-CD20 immunotherapy
256
Q

Burkitt lymphoma

A

-Endemic in parts of Africa (belt)
- Translocation t(8;14), of c-myc (8) and heavy chain Ig (14) causing dysregulation and overexpression of MYC
- EBV present in 25% of HIV-associated and 15-20% of sporadic
- surface IgM, CD19+, CD20+, CD10+, BCL6 -germinal center B cell origin
- NO expression of BCL2

257
Q

Morphology of Burkitt lymphoma

A

-Starry sky, sheets of lymphocytes with interspersed “tingible body” macrophages
- BM aspirate: basophilic/amphophilic royal blue cytoplasm containing small, lipid-filled vacuoles
- high mitotic index and contains numerous apoptotic cells

258
Q

Clinical features of Burkitt lymphoma

A
  • Children, young adults
  • 30% of childhood NHL
  • maxillary/madibular masses
  • abdominal tumors involving bowel, retroperitoneum, and ovaries in north America
259
Q

Mantle cell lymphoma

A
  • adult males most common
  • from naive B cells found in the mantle zones of normal lymphoid follicles
  • translocation t(11;14) of cyclin D (11) and heavy chain (Ig)
  • CD5+, pan-B cell antigens (CD19+, CD20+), IgM and IgD surface antigens
  • Gi- mucosal lymphomatoid polyposis, aggressive cancer, presenting in late stage disease
260
Q

Clinical features of mantle cell lymphoma

A

-fatigue, lymphadenopathy
- generalized disease involving bone marrow, spleen, liver, and GI tract
- poor prognosis (3-5 years)
- distinguishable from SLL/CLL by absence of proliferation centers and presence of Cyclin D1

261
Q

Extranodal marginal zone lymphomas (MALT-omas)

A

-indolent B cell lymphoma arising from memory B cells
- epithelial tissues affected (stomach, salivary, small and large bowel, lungs, orbit, and breast)
- associated with autoimmune disorders (Sjogran syndrome, hashimoto thyroiditis, H. pylori)
- Translocation, t(11;18) involving the MALT1 and IAP2 genes is highly predictive of the failure of gastric tumors to respond to abx

262
Q

Precursor T cell lymphoblastic leukemia/lymphoma

A
  • 40% childhood lymphomas
  • of thymic origin, primarily involves the anterior mediastinal and cervical nodes (lump in chest presentation)
  • aggressive
    -NOTCH mutations (T cell version of ALL)
263
Q

Mycosis Fungoides and Sezary syndrome

A
  • Tumors of neoplastic Cd4+ T cells, aka cutaneous T cell lymphoma
  • indolent tumors, survival is 8-9 years
  • Phases include: patch–>plaque–> tumor , with tumor leading to sezary syndrome and a poor prognosis (1-3 years)
  • pautrier microabscesses
264
Q

Pautrier microabscesses

A
  • T cells with cerebriform appearance (marked infolding of the nuclear membranes) that infiltrate the epidermis and dermis
  • seen in Mycosis fungoides
265
Q

Sezary syndrome

A
  • characterized by:
    1. generalized exfoliative erythroderma
    2. tumor cells (sezary cells) in the PERIPHERAL BLOOD leading to Mycosis fungoides with a leukemic phase
266
Q

Anaplastic large cell lymphoma

A
  • arises from cytotoxic T cells
  • rearrangements in ALK (anaplastic lymphoma kinase) gene on chr 2p23 –> + ALK
  • children and young adults with LN and soft tissue disease
  • aggressive, but there is targeted therapy for the +ALK
267
Q

Anaplastic large cell lymphoma morphology:

A
  • clustering around venules and infiltration of lymphoid sinuses
  • mimics metastatic carcinoma
  • HALLMARK CELLS: abundant basophilic cytoplasm, prominent golgi zone, and lobulated nucleus (horseshoe or embyroid) with nuclear lobes surrounding the golgi region
  • CD8+
  • translocation, t(2;5) Alk gene fusion)
268
Q

Large granular lymphocytic leukemia

A
  1. T cell
    - mild-moderate lymphocytosis, splenomegaly, lymphadenopathy, or hepatomegaly
    - CD3+ve
  2. NK cell
    - no lymphocytosis or splenomegaly
    - CD3-ve, CD56+ve
    - aggressive
  • acquired mutations in the transcription factor: STAT3
269
Q

Large granular lymphocytic leukemia morphology

A
  • neutropenia and anemia
  • large lymphocytes with abundant blue cytoplasm and a few coarse azurophilic granules on peripheral smear
  • Felty syndrome– LGLL as an underlying cause
270
Q

Felty syndrome

A

Triad of rheumatoid arthritis, splenomegaly, and neutropenia

271
Q

Extranodal NK/T cell lymphoma

A
  • aggressive tumor, usually derived from NK cells that is STRONGLY associated with EBV infection
  • responds well to radiation therapy but is resistant to chemotherapy
272
Q

Prognosis of NHL depends on

A
  1. aggressive, respond well to treatment (Mantle cell, Burkitt, DLBCL)
  2. Indolent, respond poorly to treatment but longer course (SLL, follicular, marginal zone, Waldenstom’s macroglobinemia)
  3. Staging (Ann Arbor) 3-4 is worst
  4. High LDH levels = poor prognosis
273
Q

When growth factor binds EGFR:

A

receptor chains dimerize–> activation of cytoplasmic tyrosine kinase domains –> phosphorylated tyrosines for docking sites for many SH2 domains –> aggregation of proteins at the plasma membrane –> transduction of signals to the nucleus

274
Q

EGFR is:

A
  1. a homodimer of ErbB1
  2. a heterodimer of ErbB1/ErbB2
275
Q

Pathway of activation of EGFR/Ras

A

Ras + GDP (off) –> Ras + GTP (on) –> activates MAP kinase pathways –> increase Myc and AP-1 –> increase expression of growth promoting genes (such as Cyclin D1)

Ras + GTP –> PI3K –> Akt –> Raf –> MEK –> ERK –> cell proliferation

276
Q

Growth factor binding to EGFRs causes:

A
  • a conformational change that exposes dimerization domains which activates tyrosine kinase
277
Q

EGFR inhibitors: Gefitinib

A
  • Class: EGFR small molecule inhibitor
  • indications: metastatic NSCLC with EGFR mutations
  • mech of action: inhibitions of EGFR’s cytoplasmic tyrosine kinase domain
  • Absorption: slow oral
  • exretion via: biliary/feces
  • toxicities: elevated blood pressure, eyelash trichomegaly
278
Q

Other EGFR small molecule inhibitors:

A
  1. Erlotinib (hair repigmentation in NSCLC)
  2. Afatinib
  3. Osemertinib (prolonged QT intervals)
279
Q

EGFR inhibitor: Cetuximab

A
  • Class: monoclonal antibody EGFR inhibitor
  • indications: colorectal cancer with wild type Ras
  • mech of action: inhibition of EGFR’s extracellular ligand binding domain, preventing dimzerization and activation
  • Absorption: IV (monoclonal always IV)
  • excretion via: unknown
  • toxicities: infusion related symptoms, fever, chills, HA, hypotension
280
Q

Other monoclonal EGFR inhibitors

A
  1. Panitumumab: pulm toxicity risk
  2. Necitumumab: cardio pulm arrest risk
281
Q

Which ErbB family member propagates a proliferative signal without any ligand?

A

ErbB2 (HER2)

282
Q

What are the monoclonal antibodies that target ErbB2’s extracellular doman?

A
  1. Trastuzumab
  2. Pertuzumab

– Lapatinib, neratinib, and pazopanib are small molecule tyrosine kinase inhibitors

283
Q

PI3K is a heterodimer of what?

A

p85 (regulatory) and p110 (catalytic) subunits. Mutations in either enzyme can hyperactivate it

284
Q

What mutation decreases how well trastuzumab works?

A

PI3K activating mutations

285
Q

Her2 inhibitors: Trastuzumab

A
  • Class: monoclonal antibody ErbB2 (Her2) inhibitor
  • indications: Her2 overexpressing breast cancer
  • mech of action: Inhibition of ErbB2’s extracellular domains
  • Absorption: IV only
  • excretion via: unknown
  • toxicities: Infusion related symptoms, fever, chills, HA, hypotension, CARDIAC TOXICITY, esp when combined with anthracycline
286
Q

ErbB2 inhibitors: Lapatinib

A
  • Class: small molecule ErbB2 (Her2) tyrosine kinase inhibitor
  • indications: Breast cancer
  • mech of action: inhibition of ErbB2’s intracellular tyrosine kinase domains
  • Absorption: oral
  • excretion via: hepatic/feces
  • toxicities: Diarrhea common, cardiac toxicity, myelosuppression
287
Q

BCR-ABL fusion gene

A
  • translocation, t(9;22) fusing B cell receptor gene with ABL kinase gene causing hyperactive Abl kinase that sustains proliferation
  • leads to CML and other B cell malignancies
  • promotes hallmarks of cancer such as:
    1. Resisting cell death (Bcl2)
    2. sustaining proliferation signals (MAPK and JAK/STAT)
    3. activating invasion and metastasis (FAK)
288
Q

Imatinib

A
  • small molecule inhibitor that was selected to only have activity against Bcr-Abl fusion protein
  • binds in the ATP binding pocket of the Abl kinase domain
  • off target effects are minimized because only malignant cells express the fusion gene
289
Q

Bcr-Abl inhibitors: imatinib

A
  • Class: small molecule Bcr-Abl tyrosine kinase inhibitor
  • indications: CML, acute lymphoblastic leukemia
  • mech of action: Competes with ATP for binding at catalytic site
  • Absorption: orally
  • excretion via: hepatic/feces
  • toxicities: nausea and vomiting (relieved by food). fluid retention (CHF rare)
290
Q

Other Bcr-Abl inhibitors used in CML

A
  1. Bosutinib
  2. Ponatinib
    - mutation of the fusion gene is a common cause of resistance to imatinib: both of these are used for imatinib resistance because they also inhibit other tyrosine kinases (ex. SRO family kinases)
291
Q

Bruton Tyrosine Kinase (BTK)

A

a driver for some B cell lymphomas, and can be targeted with small molecule inhibitors like ibrutinib (used in CLL)

292
Q

BTK inhibitors: Ibrutinib

A
  • Class: small molecule bruton kinase inhibitor
  • indications: CLL, mantle cell lymphoma
  • mech of action: irreversible covalent bonding with cysteine at BTK active site
  • Absorption: orally
  • excretion via: Hepatic/feces
  • toxicities: Bleeding: echymoses, GI or hematuria, myelosuppression, renal toxicity, secondary malignancies
293
Q

What is a newer treatment combo for CLL?

A

pairing BTK inhibition (ibrutinib) with Bcl-2 antagonist (venetoclax)

294
Q

Triple negative breast cancer

A
  • ER -, PR-, HER2-
  • high grade, high Ki67 index
  • NST histology–> metaplastic, adenoid cystic, medullary-like, and secretory)
  • poor prognosis
295
Q

HER2 enriched (non luminal) breast cancer

A
  • ER-, PR-, HER2+
  • high grade, high Ki67 index
  • NST histology–> aggressive disease but responds to targeted therapies
  • intermediate prognosis
296
Q

Luminal B-like, HER2+ breast cancer

A
  • ER+, lower ER and PR expression than luminal-A
  • HER2+ higher grade
  • High Ki67 index
  • NST and pleomorphic histology–> responds to targeted therapies
  • intermediate prognosis
297
Q

Luminal B-like, HER2- breast cancer

A
  • ER+, lower ER and PR expression than luminal-A
  • HER2- higher grade
  • High Ki67 index
  • high risk GES: NST histology –> micropapillary and lobular pleiomorphic histology
  • intermediate prognosis
298
Q

Luminal A-like breast cancer

A
  • Strongly ER+ and PR+, HER2-
  • low proliferation rates
  • low grade
  • low Ki67 index
  • low risk GES, NST histology –> tubular cribriform and classic lobular histo
  • good prognosis
299
Q

Testosterone and estrogen are synthesized from:

A

cholesterol in the ovaries/testes

300
Q

The adrenal gland synthesizes:

A

sex steroid precursors, DHEA and androstenedione

301
Q

What controls the steroid hormone synthesis?

A

hypothalamic-pituitary-gonadal axis

hypothalamus releases GnRH –> stimulates anterior pituitary –> releases LH and FSH –> gonadal tissues express the genes necessary for the conversion of cholesterol to the steroid hormones

  • pulsatile release, GnRH is controlled by feedback inhibition
302
Q

Steroids bind their receptors:

A

intracellularly, causing translocation to the nucleus, dimerization, and binding of the dime to steroid response elements (SRE) in gene promoters. Co regulator proteins then recruit RNA polymerase II to initiate transcription

303
Q

Hypothalamic-pituitary-gonadal axis in males

A

FSH–> Sertoli cells–> spermatogenesis

LH–> Leydig cells–> steroid biosynthesis (testosterone)

304
Q

What is the key enzyme for cholesterol being converted to testosterone in Leydig cells

A

17-alpha-reductase (P450 cyp17)

305
Q

in prostate, testosterone is converted to dihydrotestosterone by

A

5-alpha-reductase. Dihydrotestosterone is a potent activator of the androgen receptor

306
Q

What are used in treatment of benign prostate hyperplasia?

A

5-alpha-reductase inhibitors

307
Q

endocrine therapy in males: Degarelix

A
  • Class: peptide GnRH antagonist
  • Indications: Prostate cancer
  • Mech of action: blocks activation of anterior pituitary cells that release LH and FSH
  • Absorption: Subcutaneous
  • Excretion: feces
  • Toxicities: hot flashes, decreased libido, impotence
308
Q

Endocrine therapy in males: Leuprolide

A
  • Class: peptide GnRH superagonist
  • Indications: prostate cancer
  • Mech of action: Blocks activation of anterior pituitary cells that release LH and FSH
  • Absorption: subcutaneous or IM
  • Excretion: urinary
  • Toxicities: hot flashes, decreased libido, impotence, tumor flare (because at the start of agonism tumor may get worse)
309
Q

Endocrine therapy in males: Abiraterone

A
  • Class: 17-alpha-reductase inhibitors
  • Indications: prostate cancer
  • Mech of action: Blocks the action of 17-alpha-reductase, a CYP P450 enzyme required for testosterone synthesis in Leydig cells
  • Absorption: oral
  • Excretion: Feces
  • Toxicities: fatigue, mild nausea
310
Q

Endocrine therapy in males: Enzalutamide

A
  • Class: antiandrogen
  • Indications: prostate cancer
  • Mech of action: Competitive inhibition of androgen receptor, reduced transcription of pro-growth
  • Absorption: oral
  • Excretion: feces
  • Toxicities: fatigue and weakness, skeletal and muscle pain
311
Q

Hypothalamic-pituitary-gonadal axis in females

A

LH–> stimulation of receptors on ovarian cells–> 17-alpha-reductase expression increases in thecal cells and aromatase expression is increased in granulosa cells –> 17-beta-estradiol (estrogen) is produced

312
Q

What controls the proliferation of mammary epithelial cells?

A

Estrogen

313
Q

What converts cholesterol to testosterone using alpha-17-reductase in females?

A

ovarian thecal cells

314
Q

what cells convert testosterone to estrogen?

A

aromatase expressing granulosa cells

315
Q

Endocrine therapy in females: Tamoxifen

A
  • Class: non-steroidal estrogen receptor modulator
  • Indications: hormone receptor positive breast cancer (luminal), ER+, PR+
  • Mech of action: estrogen receptor competitive mixed agonist antagonist
  • Absorption: oral
  • Excretion: feces
  • Toxicities: menopause symptoms, peripheral edema
316
Q

Endocrine therapy in females: Fulvestrant

A
  • Class: steroidal selective estrogen receptor downregulator
  • Indications: breast cancer, ER+, PR+
  • Mech of action: estrogen receptor competitive antagonist, causes ER degradation (sometimes in combo with pablociclib)
  • Absorption: IM injection 1x a month
  • Excretion: feces
  • Toxicities: weakness, hot flashes, arthralgias
317
Q

Endocrine therapy in females: Letrozole

A
  • Class: non-steroidal aromatase inhibitor
  • Indications: breast cancer extended adjuvant therapy
  • Mech of action: Competitive inhibition of aromatase and blocking estrogen synthesis (sometimes in combo with pablociclib)
  • Absorption: Oral
  • Excretion: feces
  • Toxicities: arthralgias, hot flashes (less common than with antiestrogens)
318
Q

The biologically active form of Vitamin A is:

A

all-trans-retinol, the alcohol trans-retinol can be converted to: aldehyde, carboxylic acid, ester with fatty acid
- retinoic acid is an important regulator of the immune system

319
Q

The retinoic acid receptor functions as:

A

a ligand activated transcription factor (that forms heterodimers to initiate transcription of genes with retinoic acid response elements in their promoters

320
Q

In the absence of ligand, the retinoic acid receptor (RAR) forms a complex with:

A

Histone deacetylase (HDAC) that represses transcription

321
Q

In the presence of all-trans retinoic acid (ATRA), the complex activates:

A

transcription by acetylating histones and initiating trnascription

322
Q

Retinoic acid receptor activation is important for:

A

hematopoiesis and differentiation of myeloid cells

  • in its absence, myeloid progenitor cells proliferate rapdily and never differentiate
323
Q

Acute promyelocytic leukemia

A

-Translocation t(15;17), retinoic acid receptor (RAR-alpha) and the PML protein
- this translocation protein acts as a transcriptional repressor

324
Q

APL therapy: tretinoin

A
  • Class: all trans retinoic acid receptor agonist
  • Indications: acute promyelocytic leukemia (PML) with t(15;17)
  • Mech of action: activation of the PML-RAR fusion protein stimulates differentiation of myeloid precursors
  • Absorption: orally
  • Excretion: fecal (2/3) and urinary (1/3)
  • Toxicities: hypervitaminosis A: HA, conjunctivitis, rash, peripheral edema
325
Q

PARP1

A
  • critical for many DNA repair mechanisms, it recognizes and binds sites of DNA damage, It then adds poly ADP-ribose to itself and recruits DNA damage repair enzymes
    ** the ADP-ribose comes from NAD+
326
Q

What is critical for homologous repair of double stranded DNA breaks?

A
  • BRCA1 and BRCA2
  • mutations result in breast and ovarian cancers
327
Q

What do pharmacological PARP inhibitors do?

A

The “trap” PARP at the site of single stranded DNA breaks, but prevent repair. The unresolved single strand breaks become double stranded breaks – that cannot be recovered via homologous recombination by BRCA1/2 and results in more error prone mechanisms –> Synthetics lethal treatment strategy

328
Q

PARP inhibitors: Olaparib

A
  • Class: PARP inhibitor
  • Indications: breast and ovarian cancers with known or suspected BRCA1/2 mutations
  • Mech of action: Trapping PARP on DNA causes double stranded breaks and synthetic lethality in the absence of BRCA 1/2
  • Absorption: oral
  • Excretion: 1/2 feces, 1/2 urine
  • Toxicities: fatigue, URIs
329
Q

Treatment for CLL

A

BTK inhibition (ibrutinib) with a Bcl2 antagonist (venetoclax)

330
Q

What is the function of Bcl2?

A
  • an apoptotic protein that functions to block cytochrome C release from the mitochondria
331
Q

Apoptotic stimuli induce BH3-only proteins that:

A

form a complex with BAX/BAK that induces mitchondrial permeability and apoptosis
– Bcl2 acts as a “sink” for BH3-only proteins and raises the apoptotic threshold

332
Q

Bcl2-antagonist: Venetoclax

A
  • Class: Small molecule Bcl2 antagonist
  • Indications: Chronic lymphocytic leukemia
  • Mech of action: acts as a BH3-only protein mimetic to lower apoptotic threshold
  • Absorption: Oral
  • Excretion: hepatic/feces
  • Toxicities: tumor lysis syndrome, myelosuppression
333
Q

Clinical finding in acute leukemia

A
  • Abrupt onset of signs and symptoms
  • signs of bone marrow failure, fever, bleeding, fatigue
  • signs of metastatic disease (hepatosplenomegaly, painless lymphadenopathy, bone pain and tenderness)
  • CNS, testicle involvement especially in ALL
  • skin involvement (T cell leukemias)
334
Q

Physical findings of acute leukemia

A
  • weakness, pallor, fatigue
  • infections causing fever (functionally incompetent WBCs)
  • Easy bleeding/bruising
  • Bone pain (periosteal infiltration)
  • bleeding from venipuncture and orifices (DIC) due to release of thromboplastin (AML M3)
335
Q

What causes gum hyperplasia?

A

AML M4 and M5 - infiltration

336
Q

What causes rash and skin nodules?

A

Adult T cell leukemia

337
Q

What has CNS and testicular infiltration?

A

ALL

338
Q

What are the signs of bone marrow failure?

A
  1. neutropenia: infections, fever
  2. Anemia: fatigue, pallor
  3. Thrombocytopenia: bleeding
339
Q

Lab findings in acute leukemia

A
  • variable peripheral WBC count (<10,000 and >100,000), blast cells usually present
  • normocytic to macrocytic
  • thrombocytopenia (usually <100,000)
  • Bone marrow findings: MOST IMPORTANT FOR DIAGNOSIS: Hypercellular with >20% blast cells, usually completely replaced with blast cells
340
Q

Acute myeloid leukemia

A
  • older adults (>50)
  • fatigue, pallor, abnormal bleeding, infections
  • can present as discrete tissue mass (granulocytic sarcoma)
341
Q

Acute myeloid leukemia risk factors:

A
  • Genetic (Down syndrome, Turner, Klinefelter)
  • Chemical/drugs (benzene, alkylating agents)
  • Ionizing radiation, MDS
  • Cytogenetic abnormalities (mutations on chromosome 8, translocation t(8;21)
342
Q

HSC–> Myeloid SC–> Erythroblast–>

A

AML-M6 (acute erythroleukemia)

343
Q

HSC–> myeloid SC–> megakaryoblast–>

A

AML-M7 (acute megakaryocytic leukemia)

344
Q

HSC–> myeloid SC–> myeloblast–>

A

AML-M0-M4 (M0: minimally differentiated AML, M4: acute myelomonocytic leukemia, inv(16))

345
Q

HSC–> myeloid SC–> monoblast–>

A

AML-M4-M5 (M4: acute myelomonocytic leukemia, M5: acute monocytic leukemia)

346
Q

HSC–> Lymphoid SC–> pre-B lymphocyte–>

A

B-ALL-CD10+ve

347
Q

HSC–> lymphocyte SC–> Pro-T lymphocyte–>

A

T-ALL

348
Q

AML with recurrent genetic abnormalities:

A
  • t(8;21)(q22;q22)(AML/ETO) *favorable prognosis

-inv(16), or t(16;16)(p13;q22) (CBF/MYH11)- M4eo *favorable prognosis

  • t(15;17)(q22;q21) *intermediate prognosis
  • (11q23) (MLL fusion gene) - poor prognosis
349
Q

AML with multilineage dysplasia, MDS like features, poor prognosis:

A
  • AML plus dysplasia (>50% of cells of 2 or more myeloid lines)
350
Q

AML therapy-related

A
  • very poor prognosis
  • Alkylating agent, radiation therapy, topoisomerase II inhibitor
351
Q

FAB classification of AML:

A

M0: minimally differentiated AML
M1: AML without maturation
M2: AML with maturation, t(8;21)
M3: acute promyelocytic leukemia, t(15;17)
M4: acute myelomonocytic leukemia, inv(16)
M5: Acute monocytic leukemia
M6: acute erythroleukemia
M7: acute megakaryocytic leukemia

352
Q

AML M3: acute promyelocytic leukemia

A
  • DIC, at presentation of during treatment with ATRA
  • characteristic translocation t(15;17) PML-RAR fusion gene that codes for abnl retinoic acid receptor
  • Treatments with all-trans-retinoic acid helps in maturation of the arrested promyelocytic cells
353
Q

What has plenty of granules are Auer rods?

A
  • Faggot cells (Auer rods)
  • promyelocytes with granules
354
Q

When do you commonly see gum infiltration?

A
  • AML-M5
355
Q

When do you commonly see DIC?

A

AML-M3

356
Q

Morphology of AML

A
  • blasts or promyelocytes > 20% bone marrow cellularity
  • myeloblasts: delicate chromatin, 3-5 nucleoli, fine azurophilic cytoplasmic granules
  • Auer rods
  • Monoblasts, erythroblasts, or megakaryoblasts are also possible
357
Q

Auer rods

A
  • red-staining, rod-like structures fused azurophil granules
  • Seen in myeloblasts (M2 and M3 of AML)
  • not present in myeloblasts in CML
  • particularly numerous in acute promyelocytic leukemia
358
Q

Myelodysplastic syndromes

A
  • bone marrow replacement by clonal proliferation of multipotent stem cell that can differentiate into RBC/WBC/platelets in an ineffective and disordered manner
  • peripheral blood shows cytopenias
  • Further stem cell mutations transform into AML
  • t-MDS : idiopathic, some after chemo/radiotherapy
359
Q

Pathogenesis of myelodysplastic syndromes

A
  • clonal abnormalities
  • monosomy 5/7, with deletions of 5q, 7q, and trisomy 8
  • 5q syndrome
360
Q

5q syndrome

A
  • more common in women
  • severe anemia
  • preserved or elevated platelet counts
  • often responds to treatment with analogs of thalidomide
361
Q

Peripheral smear of myelodysplastic syndromes

A
  • Severe pancytopenia
  • normocytic to macrocytic
  • dimorphic RBCs with a high RDW
  • leukoerythroblastosis
362
Q

Bone marrow findings of myelodysplastic syndromes

A
  • megaloblastoid erythroid precursors, RINGED SIDEROBLASTS
  • WBC precursors with abnormal granules/nuclear maturation
  • megakaryocytes with single nuclear lobe or multiple separate nuclei
  • myeloblasts <20% of granulocytes (If many myeloblasts, think AML)
363
Q

Clinical features of myelodysplastic syndromes

A
  • 50-70 years of age
  • infections, anemia symptoms, hemorrhages
    -response to conventional chemo is poor
  • transformation to AML occurs in 10-40%
  • prognosis is variable

IHO (6 decks)

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