Oncology Flashcards Preview

MDTI > Oncology > Flashcards

Flashcards in Oncology Deck (166):
1

6 modalities/hallmarks of cancer

  1. Growth factor independence (GOF)
  2. Loss of response to anti-growth signals/differentiation signals (LOF)
  3. Resistance to apoptosis
  4. Recruitment of blood/lymph
  5. Invasion and metastasis
  6. Limitless replicative potential

2

Growth factor independence

  • typically related to gain of function oncogenes

3

Proto-oncogenes

normal genes with important roles in regulating division, differentation, survival, movement --> mutate to oncogenes (GOF)

4

PI3K Pathway

 

  • PI3K phosphorylates lipid on the cytoplasmic side of membrane

RTK (e.g. EGF receptor) --> activate PI3K--> converts PIP2 --> PIP3 --> docking site for PH domains (e.g. in AKT)--> AKT/PKB --> phosphorylation of proteins

  • Involved in many signaling events
  • Disregulation can have significant oncogenic downstream effects

5


Warburg effect

elevated AKT activity due to PI3K mutation --> increased glucose transport & glycolysis (basis of PET)

6

PTEN

  • most common mutation leading to elevated PI3K activity
  • PTEN converts PIP3--> PIP2 (opp. of PI3K)
  • usually via deletion of PTEN or silencing of locus
  • LOF is usually more common than GOF

7

Tumor suppressor


genes in which loss of function promotes cancer (e.g. PTEN)

 

8

p53

  • tumor suppressor gene
  • activates cell cycle arrest & apoptosis
  • most cancers have p53 mutation
  • DNA-binding transcription factor
  • regulates
    • p21 cyclin inhibitor
    • GADD45- DNA repair
    • Bax, Puma, Noxa- pro apoptosis
    • MDM2- self-regulation
  • accumulates in cancer cells b/c loss of autoregulation

9

Li-Fraumeni Syndrome

patients with one germ-line mutant copy of p53 gene --> prone to leukemias, sarcomas, breast, brain cancers associated with loss of remaining functional p53 allele in those cells –classic example of “loss-of-heterozygosity” (LOH).

10

Apoptosis

  • highly ordered, ATP-dependent process-proteins, subcellular components dismantled by proteases (“caspases”)and nucleases
  • membrane blebbing produces “apoptotic bodies” containing cellular debris, which are then engulfed by macrophages and other cells
  • avoids release of cellular components that could trigger a damaging inflammatory response.

11

Caspases

  • proteases that use conserved cysteine residue in their active site to cleave other proteins after aspartate residues in apoptosis
    • initiators
    • effectors/exectuioners
  • present as procaspases until stimulus initates apoptosis

12


Intrinsic apoptotic pathway

mitochondrial membrane loses integrity --> cytochrome C released from mitochondria --> binds Apaf 1 to form apoptosome --> recruits procaspase 9 --> cleaves executioner caspases --> apoptosis

13

BCL related proteins

  • promote apoptosis - Bax, Bax
  • inhibit apoptosis - Bcl2
  • apoptosis determined by equilbirium of these stress-responding factors

14

Extrinsic apoptotic pathway (death receptor)

  • Fas (or other TNF death receptor) receptor binds FasL/--> recruits FADD/TRADD---> recruits intiators 8 and 10 which autoactivate and trigger effectors 8/10 --> DISC

15

Ways cancers bypass apoptosis

  1. over expressing antiapoptotics like Bcl2
  2. downregulating proapoptotics like Bax, Bak
  3. losing p53 which induces proapoptotics Bax, Puma, Noxa
  4. downregulating death receptors Fas, Trail

16

Hayflick Limit

  • replicative senescence:
    • most cells: division of cell --> some DNA lost --> limits number of replications
  • if continued replication --> breakage fusion bridge cycle would occur --> inappropriate fusing of chromosomes

17

Telomerase

  • telomerase adds extra telomeric DNA to some some cells (stem cells, lymphocytes)
  • dysregulation ensures stable chromosomes for cancer

18

Angiogenic switch

  • recruitment of blood vessels to ensure tumor growth > 2mm
  • balance between
    • inhibitors
      • statins
      • thrombospondin
    • activators
      • VEGF
      • FGF
      • EGF
      • PDGFB

 

19

Tumor vasculature

highly anomalous because of inconsistent equilibrium between pro/anti angiogenic factors

20

VEGF

  • vascular endothelial growth factor --> stimulates EC division, survival, differentiation, movement --> master regulator
  • main form = VEGF A
  • binds to tks on ECs (VEGFR1 and 2) --> angiogenesis

21

VEGF blockers

antiangiogenic therapy

  • bevacizumab = mab
  • sunitinib/sorafenib = kinase inhibitors

22

Seed and Soil Metastasis

 

  • cancer cells follow venous and lymphatic drainage
  • some tumor cells may adher in or survive better in certain organs

23


Importance of Philadelphia chromosome

  • encodes fusion protein BCR-ABL = oncogene with abnormal tk activity
  • t (9;22) --> BCR intiator, ABL gene
  • present in 100% CML, 30% AML
  • Tx: Gleevec/Imatinib

24


FFPE


Formalin fixed parafin embedded --> cut tumor specimen --> laser capture DNA --> PCR --> identify markers, resistance

25

BRAF mutation

  • GOF V600E most common (val/glu)
  • predicts resistance to Vemurafinib
  • BRAF mutation
    • 40-60% melanoma
    • 40-70% papillary thyroid
    • 10% metstatic colorectal

26

Sequencing Read Length


number of sequential images taken

27


Sequencing Read Depth


number of DNA fragments for a given position

28

Reactive/benign disorders

  • polyclonal expansion of different kinds of cells
    • leukemoid reaction - expansion of granulocytes in response to bacterial infection
    • lymphadenitis- inflammation of lymph nodes

29


Neoplasms

  • clonal expansion of a single cell
  • uncontrolled expnasion --> organ replacement  --> functional compromise --> death

30


Leukemia

  • neoplasms that involve bone marrow and spill into peripheral blood
    • blood forming elements:
      • granulocytes
      • red cells
      • megakaryocytes
    • all lymphoblast-related are leukemias

31


Lymphoma

  • solid mass tumor of lymph nodes, spleen, extranodal sites (GI tract, skin)
  • neoplasm of mature lymphocytes

32


Acute/precursor neoplasm

 

  • immature early undifferentiated state
  • blast
     

33


Chronic/peripheral neoplasm


mature differentiated cell neoplasm

34


Lymphomas- morphology

  • size: small vs large (size of a mature lymphocyte vs. histiocyte nucleus)
  • growth pattern: nodular vs. diffuse
  • morphology is not the best predictor of behavior since some small cell lesions can be aggressive and indolent lesions can be unresponsive to therapy

35


Secondary lymphoid follicles

  • follicle which develops after antigen presentation with B cells undergoing class switch and somatic hypermut.
  • germinal center: C10+BCL6+BCL2- --> need apoptosis working during proliferation so must be bcl2-
    • dark zone: proliferating centroblasts
    • light zone: mature centrocytes
  • mantle of naiive B cells: CD10-BCL6-BCL2+
  • undelrying CD21+ follicular dendritic meshwork
  • mantle of plasma cells

36


Lymphomas- immunophenotype

  • expression pattern of a surface and intracellular proteins in a cell population
    • benign (polytypic) vs. neoplastic (monoclonal)
    • lineage (CD3/T vs CD19/B)
    • stage of diff. (Tdt vs. surface Ig)
    • aberrant expressions
      • CD5+ B cells
      • mature T cells w/o pan-t antigens
  • assessed by:
    • flow cytometry
    • immunohistochemistry

37


Immature B cell markers

Tdt- expressed by immature lesions

CD19

 

38


Mature B cell markers

all: CD19, CD20

mature: k/l light chains

germinal: CD10, BCL6 (secondary follicles)

all except germinal: BCL2

 

39


Immature T cell markers

Tdt

CD1a

cCD3

40

Mature T cell markers

CD2

sCD3

CD5

CD7

 

also: CD4/8

41


Lymphomas-genotype

  • gross chromosomal rearrangements that lead to abnormal gene expression
  • B cells undergo mutlipel rounds of damage --> more common neoplasms
    • Ig rearrangement in marrow
    • somatic hypermut./class switch
  • Examples:
    • Burkitt's = t(8;14) IgH/Myc
    • Follicular = t(14;18) IgH/BCL2

42


What does lymphoma genotype prove?

  1. clonality
  2. specific tumor subtype

 

43

Lymphomas- normal cell counterpart

neoplastic cells recapitulate morphology, immunophenotype of progenitor cells

44

Lymphomas-clinical features

  • variable: asymptomatic vs. constitutional
  • "type B" symptoms: fever, night sweats, weight loss
  • dictated by affected site & tumor biology
    • lymph nodes = lymphadenopathy
    • extranodal = organ dysfunction
    • marrow involvement = suppression
    • plasma cell = bone destruciton

45

Lymphomas-characterization by clinical features

  • lymphoblastic = pediatric
  • extranodal marginal zone = mucosal spread

46


B Cell NHL

  • derived from mature B cells
  • neoplasms capitulate function of progenitors
  • bone marrow involvement common (stage IV) --> interstitial except follicular
  • liver/spleen involvement common
  • difficult to cure
  • can transform to aggressive
  • IgH/14 involved in some important translocations
  1. indolent: follicular, cll/sll, marginal
  2. aggressive: DLBCL
  3. highly aggressive: Burkitt's

47


Follicular lymphoma immunophenotypic profile

B: CD19+/CD20+/CD(2-8)-/

Germinal Center: CD10+

Aberrant: BCL2+

low Ki67 --> disease of cells surving a long time//not a disease of cells proliferating

48

CLL/SLL immunophenotypic profile

B: CD19+/CD20+

T: CD5+

Non-germinal: CD10-/BCL6-/BCL2+

49

Marginal lymphoma immunophenotypic profile

No distinct marker

B: CD19+CD20+

Not Germinal: CD10-/BCL6-/BLC2+

50

Follicular lymphoma- clinical features

  • t(14;18) --> BCL2+
  • General lymphadenopathy
  • BM involvement common (Stage IV) --> represents hematogenous spread
  • nonaggressive
  • spleen and liver involvement common
  • fine diffuse nodularity --> expansion of splenic white pulp
    • in extensive disease --> red pump also
  • occasional peripheral blood involvement --> small cleaved cells
  • extranodal involvement uncommon

51

Follicular lymhoma- prognosis

  • Indolent- waxing/waning course --> 8 years
    • largely incurable
  • Often transforms to diffuse B cell lymphoma --> 1 year survival
  • Tx: observation, symptom relief, anti-CD20

52

Follicular lymphoma- morphology

  • germinal center B cells
  • nodular appearance- lots of germinal centers
    • crowded, back to back
    • lack polarity (thick/thin ends)
    • no tingible body macrophages
    • no discernable mantle
  • paratrabecular aggregates
  • grade 1 = more nodular and more centrocytes -->indolent
  • grade 2/3 = more than 5 centroblasts/hpf

A image thumb
53


CLL/SLL: Chronic lymphocytic leukemia/Small lymphocytic lymphoma

  • spectrum cancer
    • circulating cells --> leukemia
    • solid mass --> lymphoma
  • CLL = most common adult leukemia
  • SLL = uncommon

54

CLL/SLL-clinical features

  • 13q/trisomy 12/deletion 11q/deletion 17p
  • usually asymptomatic//6th decade presentation
  • general lymphadenopathy
  • low grade lymphoma for most of life
  • usually progresses to Stage IV
  • common hepatosplenomegaly
  • peripheral blood involvement
  • immune dysregulation
    • autoimmune RBC/platelet
      • AIHA
      • thrombocytopenia

55


CLL/SLL- prognosis

  • variable survival
  • Group 2 > Group 1 prognosis
  • transformations
    • prolymphocytic leukemia
    • richter's transformation --> DLBCL

56

Richter's transformation

  • transformation of CLL/SLL to DLCBL
  • same mechanism employed in all indolent lymphomas

57


CLL/SLL- morphology

  • unknown source
  • diffuse effacement of architecture
  • proliferation centers: "pseudofollicles"
  • prolymphocytes/paraimmunoblasts
  • small round lymphocytes with condensed chromatin, scant cytoplasm, and fewer large cells. also see smudge cellshttp://o.quizlet.com/i/R6g7uaEb3gdYL63H8gaBSg_m.jpg
  • interstitial marrow infiltrate: nodular or diffuse

58

CLL/SLL Group 1 and 2

  1. unmutated IgV
    • no SHM/naive
    • Zap70+
    • aggressive
  2. hypermutated IgV
    • post GC/mature
    • Zap70-
    • indolent

59


Marginal zone lymphoma

  • 3 diseases
    • nodal marginal zone lymphoma
    • splenic marginal zone lymphoma
    • extranodal marginal zone (MALT) --> most common

60


MALT MZL-clinical features

  • t(1;14) API2-MALT1
  • t(11;18) IgH/BCL10 
  • t(14;18) IgH/MALT-1
  • associated with chronic inflammation (e.g. pylori, jejuni, borrelia, chlamydia)
  • low grade with transformation to DLCBL
  • Tx: antibiotics/antiviral

61

S-MZL

splenic marginal zone lymphoma associated with Hep C

62


MALT/MZL

  1. small lymphocytes
  2. monocytoid margin B cells (lots of clear cytoplasm)
  3. plasma cells
  4. destruction of epithelial structures like glands

63


NF-kB pathway

  • responsible for stimulating cell survival and proliferation
  • MALT--> BCL10 or API2MALT1 --> binds MALT1 --> induction of NF-kB

64


Plasma cells

  • terminally differentiated B cells:
    • CD19+, CD138+, CD56-
      • in lymphoma, CD56+ hone plasma cells to marrow
  • lymph nodes and bone marrow
  • clockface nuclear chromatin, perinuclear clear zone, gray cytoplasm, eccentric nuclei
     

A image thumb
65


Multiple Myeloma

  • plasma cell neoplasm
  • most common lymphoid neoplasm in AA, 2nd most in whites

66

Multiple Myeloma- clinical features

  • multifocal --> areas of hematopoeisis (vertebrae-->emergency!!!), ribs, skull)
  • anemia (from marrow replacement and renal failure)
  • hypercalcemia (osteoclast activation)
  • rouleaux/blood viscosity increase -->neurologic/thrombotic
  • bone destruction
    • pain
    • osteolytic lesions --> "punchout"

Crab Plaits

C - calcium is high
R - renal failure
A - anemia
B - bone disease, bone pain, Bence-Jones protein (a paraprotein)

P - paraproteins (useful for monitoring patient)
L - LDH (again for monitoring)
A - amyloidosis (a complication)
I - immune paresis (suppression of Ig, a complication)
T - thalidomide (treatment)
S - stem cell transplant (treatment)

 

 

A image thumb
67

Multiple Myeloma- morphology

  • increased clusters and sheets of plasma cells
  • replaced marrow
  • destruction and resorption of bone
  • osteopenia (thinning of trabecular bone)
  • flame cell (IgA)
  • mott cell (intracytoplasmic Ig)
  • atypia (wild nuclei)

A image thumb
68


Paraprotein/Bence Jones

  • M (monoclonal component) Ig from plasma cells in monoclonal gammopathies
    • benign = MGUS (monoclonal gammopathy of undetermined significance)
    • malignant = Multiple Myeloma
  • Bence Jones = excess heavy or light chains secreted in MM --> measure in urine--> severity
    • 50% IgG K>L
    • 25% IgA K>L
  • Consequences
    • Cryoglobulinemia (Raynauds)
    • Renal failure
    • Amyloidosis
    • Bleeding
    • Immunosuppression

69

Humoral Immune Paresis

suppression of normal polyclonal Ig production in myeloma patients

70

Cast nephropathy


excess light chains settle out in aggregates in distal nephron forming obstructive tubular casts --> myeloma kidney

71

Amyloidosis

oversecreted clonal serum Ig settle out in beta-pleated sheets to form tissue deposits in end organs (e.g. renal glomeruli)

72


Multiple Myeloma- anemia

  1. cast nephropathy
  2. proximal tubulopathy from hypercalcemia and toxic reabsorption of light chains
  3. amyloidosis

results in uremia/hypovolemia, loss of epo (+marrow infiltration) -->anemia

73


DLBCL

  • common NHL
  • evolves from low grade lymphoma or denovo
  • presents at single site-nodal or extranodal

74

DLBCL-clinical features

  • rapidly enlarging symptomatic mass at single nodal or extranodal site (vs. indolent)
    • commonly GI
    • rare BM involvement
  • associated with immunocompromise
    • EBV

75

DLBCL-gross pathology

  • homoegenous fish-flesh tissue replacement
  • hemorrhage, necrosis, fibrosis

76


DLBCL-morphology

  • CD19+/CD20+/Ig+/Ki67+
  • diffuse architectural defacement
  • large cells
  • mitotically active, invasive, necrotic
  • GCB (CD10+/BCL6+/MUM1) phenotype does better than ABC
  • centroblastic: medium/large, oval nuclei, multiple nucleoli, low cytoplasm
  • immunoblastic:large, single nucleolus, plasmacytoid (cytoplasm)

77

International Prognostic Index (IPI)

  • most useful predictor of prognosis in DLBCL (50% do poorly)

78

Burkitt's Lymphoma

  1. endemic (malaria belt) --> EBV in kids
  2. sporadic (western) -->rare in adults
  3. immunodeficiency --> HIV/EBV

79

Burkitt's Lymphoma- clinical features

  • high LDH
  1. endemic: facial bones (sometimes ovary, kidney, breast)
  2. sporadic: ileocecal/abdominal (sometimes ovary, kidney, breast; rare LN)
  3. immunodef: LN/BM
  • EMERGENCY!!!

80


Burkitt's Lymphoma- morphology

  • Cd19+/CD20+/CD10+/BCL6+/BCL2-/Ki67+ -->germinal
  • monotonous infiltrate of medium cells
  • high proliferation/apoptosis
  • tingible body macrophages
  • round nuclei
  • basophilic
  • starry sky
     

81

cMYC pathway

  • endemic: defective t cell immunity --> EBV B cell proliferation --> t(8,14) --> cMYC overexpression
  • sporadic/immunodef. also cMYC related

82

Cancer screening ages:

Cervical

Colon

Prostate

Breast

Cervical: 21 every 3y

Colon: 50 annual fobt, colonoscopy//fs//dcbe every 10y

Prostate: 45 PSA yearly

Breast: 21 CBE every 3y; 40, annual mammogram

 

83

TNM Cancer Staging

  • T: size/extent of involvement of tumor (1-4)
  • N: nodal involvement 0/1
  • M: presence of metastasis 0/1

84

Cachexia Syndrome

fatigue & weight loss due to inflammatory factors like TNF during cancer

85

Paraneoplastic Syndrome

tumor produces pseudo/hormones:

  • PTH = hypercalcemia
  • gastrin = ulcers
  • EPO = polycythemia
  • paraprotein = hyperviscosity

86

Rationale for radiation therapy

cancer cells are rapidly dividing/less able to repair damage and their DNA is more susceptible to ionizing radiation

87

Direct vs. Indirect ionization

  • Direct = damage directly to DNA
  • Indirect = damage to DNA via reactive intermediates

88


2 methods of radiation delivery

  1. external beam rt (EBRT)
  2. internal rt (brachytherapy)

89

3 main types of EBRT

  1. Photons (x rays from linear accelerator)
  2. Light charged particles (electrons)
  3. Heavy charged particles (protons, carbon)

90


Radiosensitivity

in vitro survival of cells vs. dose

91

Radioresponsiveness

measurable change in tumor size during/after treatment --> correlates with radiosensitivity

92


Therapeutic Index

relative effect of treatment on tumor compared to damage of normal tissue

93

Acute vs. Late Toxicity

cells rapidly turning over (skin, oral mucosa, GI epithelium) respond before other tissue loss

94

Fractionation and the 4 R's of radiobiolo's

  • need to split up RT dose to minimize tissue damage
  1. reassortment
  2. reoxygenation
  3. repair
  4. repopulation

95

Neoadjuvant vs. Adjuvant RT

preop vs. post op decision about how much RT to give to patient

96

Chemotherapy as a radiosensitizer - 5 effects

concurrent chemo during RT can help make radiation work better//help eliminate micrometastases

  1. enhancement of radiation damage
  2. inhibit cell repair
  3. accumulate cells in radiosensitive cell cycle stage
  4. work against hypoxic cells
  5. inhibit accelerated repopulation of tumor cells

97

Bragg Peak Effect

A pronounced peak on the Bragg curve which plots the energy loss of ionizing radiation during its travel through matter. For protons, α-rays, and other ion rays, the peak occurs immediately before the particles come to rest. The phenomenon is exploited in particle therapy of cancer, to concentrate the effect of light ion beams on the tumor being treated while minimizing the effect on the surrounding healthy tissue.

98

Proton therapy in Hodgkin Lymphoma

mediastinal radiation puts heart, lung, breast tissue at risk in young patients --> proton accelerator --> high energy protons

99

Hodgkin Lymphoma

  • lymphoma with
    1. a significant minority of neoplastic Reed-Sternberg cells
    2. a larger and pleomorphic background of non-neoplastic reactive inflammatory cells
  • constitutive activation of NF-kB
  • activation of JAK-STAT
  • relatively uncommon --> bimodal age dist.
  • associated conditions: EBV, immunodeficiency, HIV, social class

 

100

Hodgkin Lymphoma- clinical features

  • painless supradiaphragmatic (cervical) lymphadenopathy
  • anterior mediastinum = nodular sclerosis
  • axial/centripetal node involvement
  • fever, weight loss, night sweats
    • cytokine soup --> B symptoms
  • opportunistic infections  --> TB, fungi, HSV
  • unifocal disease --> predictable lymphatic spread

101

Hodgkin Lymphoma- morphology

  • excisional lymph node biopsy
    • normal nodal architecture is effaced
    • sea of reactive inflammatory cells
    • Reed-Sternberg "owl eye" cell

102

Reed-Sternberg cell

  • germinal center B cell derived
  • associated with Hodgkin Lymphoma
  • owl eye bilobed nucleus
  • abundant cytoplasm
  • eosinophilic nucleoli
  • many variants
  • often express CD30 (nonspecific TNF family)
  •  

103


Classical Hodgkin Lymphoma/CHL

  • diffuse or nodular growth
  • class RS cells
  • CD15+/CD30+/PAX5+CD20+/-/CD45-
  • background = more t cells
  • stage ii or iii

4 types

  1. nodular sclerosis
  2. mixed cellularity
  3. lymphocyte depletion
  4. lymphocyte rich

104

Nodular Sclerosis

  • commonest CHL
  • nodular pattern + fibrotic/sclerotic bands
  • necrosis common
  • lacunar RS cells
  • staging
    1. one nodal
    2. two nodes on same side
    3. both sides of diaphragm
    4. disseminated
    5. A: absence of symptoms
    6. B: presence of weight loss, fever, night sweats
  • Tx: ABVD multidrug chemo (risk of sterility, AML) or BEACOPP
  •  

105


Acute leukemia

 

  • hematologic malignancy in which rapidly progressive marrow failure occurs --> bm replacement by undifferentiated tumor cells --> arrested at blast stage
  • most common pediatric cancer
  • require small number of cooperating mutations (promote growth + impair differentiation)

106


Acute leukemia-clinical features

  • t(9;22) BCR-ABL or t(15;17) PML-RARa
  • abrupt onsent of bone marrow failure
  • pancytopenia of normal blood cells
  • infections, fatigue, bruising, bleeding
  • increased blood viscosity
  • sludging and microthrombi--> leukostasis

107

Acute leukemia-morphology

  • maturational arrest at blast phase
  • cytoplasmic granulation
  • Auer rod: azurophilic cytoplasmic inclusion in myeloblasts --> myeloid related

108

PML-RARa Pathway

  • defective retinoic acid receptor fails to initatie gene expression in response to physiologic dose ofretinoids
  • associated with acute promyelocytic leukemia
  • Tx: ATRA --> restores transcription

109


Left-shift


relative increase in immature hematopoietic development from what is expected

110


Leukemoid Reaction


normal release of polyclonal immature and maturing cells into circulation in response to stress or medications

111

Lymphoid Cells


B/T lymphocytes, plasma cells, NK cells

112

Myeloid Cells

granulocytic, monocytic, erythrocytes, and magakaryocytes

113


Chronic Myeloproliferative Neoplasms/Disorders

  • clonal expansion of transformed stem--> terminally differentiated cells
  • predisposed to transformation to acute leukemia
  • tk dysregulation
  • bone marrow cavity fibrosis
  • hepatosplenomegaly
  1. polycythemia vera = erythrocytes
  2. essential thrombocythemia = platelets
  3. cml = neutrophil, monocyte, eosinophil, basophil

114

Chronic Myelogenous Leukemia (CML)

  • t(9;22) BCR-ABL --> philadelphia chromosome
  • middle aged
  • abnormal growth and proliferation of white blood cells (myeloid)
    • neutrophils and then other granulocytes accumulateFile:Chronic Myeloid Leukemia smear 2009-04-09.JPG
  • Tx: imatinib/Gleevec --> tk inhibitor with specificity for ABL-BCR
    • SE: myelosuppression, fluid retention, muscle cramps

115

Classical MPN-Polycythemia Vera

  • endogenous erythroid colony formation (EEC)--> growt without epo (JAK mutation)
  • upregulation of BCL-X (like BCL2)
  • Tx: phlebotomy, aspirin, hydroxyurea, interferon, Jak2 inhibitors

116

Chronic Myelogenous Leukemia- clinical features

  • commonly asymptomatic -->incidental finding
  • splenomegaly
  • weight loss, fatigue
  • high blood count
  • hyperuricemia --> gout/stones
  • pseudohyperkalemia, hypoxemia, hyopglycemia
  • left shift
  • very high b12, high LDH
  • phases
    1. chronic-months to years
    2. accelerated-1 year
    3. blast crisis (acute leukemia) -3-6 months survival

117


"Classical" MPN

  • Philadelphia chromosome negative
  • excess production of one or more lineages of mature blood cells and/or bone marrow fibrosis
  • complicated by predisposition to bleeding/thrombosis, extramedullary hematopoeisis

118

Classical MPN-Polycythemia Vera-clinical features

  • may be asymptomatic with high hemoglobin
  • clots
  • hypermetabolism (gout, stones, sweating)
  • hyperviscosity (from high hematocrit) --> congestion (e.g. retinal)
  • aquagenic pruritis
  • ruddy cyanosis
  • vasomotor symptoms (erythromelalgia)
  • bleeding
  • splenomegaly

119


Classical MPN-Essential thrombocytosis

  • BCR-ABL-
  • JakV617F
  • lease likely to evolve to AML
  • too many bone marrow megakaryocytes
  • Tx: observation, aspirin, interferon, hydroxyurea

120

Classical MPN-Essential thrombocytosis-clinical features

  • asymptomatic
  • clots
  • bleeding

121


Classical MPN-Primary myelofibrosis (PMF)

  • myeloproliferative disease in which the proliferation of an abnormal type of bone marrow stem cell results in fibrosis, or the replacement of the marrow with collagenous connective tissue fibers
  • highest risk of transformation to AML
  • Tx: palliative, thalidomide, JAK2 inhibitors (ruxolitinib), stem cell transplant

122

Classical MPN-Primary myelofibrosis-clinical features

  • anemia, abnormal platelets and wbc
  • fatigue, weight loss, fever "B" symptoms
  • splenomegaly
  • leukoerythroblastic blood smear
  • bone marrow fibrosis

123

Classical MPN-Primary myelofibrosis-morphology

  • CD34+ -->circulating stem cells escaped from marrow
  • smear:
    • teardrop forms
    • nucleated RBCs
    • left shifted granulocytes

  • bm biopsy:
    • abnormal megakaryocytes
    • intrasinusoidal hematopoeisis
    • osteosclerosis
 

124


p53 vs Rb phosphorylation

 

  • when p53 is phosphorylated = do not enter cell cycle
  • when Rb is phosphorylated = enter cell cycle

125


4 key effects of chemotherapy

 

  1. damage DNA
  2. inhibit DNA synthesis
  3. inhibit DNA replication
  4. inhibit mitosis

126


4 reasons cancer cells are susceptible to chemo

  1. contain mutations
  2. have impaired DNA repair mechanisms
  3. are addicted to specific signals
  4. divide regularly

127

Log-kill model

  • cell kill is proportional to tumor mass
  • chemo killing follows first order kinetics
  • single dose won't affect noncycling cells'
  • probably true for small tumors but not in large:
    1. cumulative toxicity
    2. tumor heterogeneity
    3. development of resistance (by the time enough doses delivered)

128


Norton-Simon hypothesis

 

  • cell-kill is a function of tumor growth rate
    • fast tumors = large % kill
    • indicates dose dense therapy

129


Gompertzian growth


exponential growth of cancer cells cannot go on forever

130


Modes of chemo drug resistance

 

  • intrinsic
    • sanctuary sites
    • chemical properties
  • acquired
    • multidrug resistance
    • enhanced DNA repair
    • mutation of drug targets

131

Acquired resistance- MDR

 

mediated by p-glycoprotein (ATP pumps that remove drugs from cells)

132

Acquired resistance- Enhanced DNA Repair

 

  • mediated via enzymes that repair damaged DNA
    • AGT:
    • PARP1
    • XCCR1: base excision repair
    • cisplatin: DNA excision repair

133

Acquired resistance- alteration of drug targets


drugs that target receptors or enzymes are most prone b/c of gatekeeper mutations in tk's that can up/down regulate enzymatic targets

134

Pharmacologic Sanctuaries

 

  • hard to reach tissues via transport constraint
    • brain/testis
    • high intratumor pressure --> dense tumor stroma

135

Goldie-Coldman Hypothesis

 

  • likelihood that drug-resistant cancer cells are present at diagnosis
  • suggests:
    • multidrug treatment
    • short dose tiem
    • early in cancer is better

136

Chemotherapy Classes

  1. direct DNA damaging agents (cross linkers, alkylators, intercalators) --> S phase
  2. inhibitors of chromatin remodeling (topoisomerase I and II inhibitors) --> S phase
  3. inhibitors of DNA synthesis (pyridine analogs) --> S phase
  4. tubulin interactive drugs (microtubule stablizers/destabilizers) --> M phase

137

Direct DNA Damaging Agents; Cross-linkers-Cisplatin

 

  • stable in aqueous environments with chlrodie
  • binds DNA in cell and forms adducts (b/c of low chloride instability)
  • cell cycle arrest and apoptosis

138

Resistance

Direct DNA Damaging Agents; Cross-linkers-Cisplatin

 

  1. decreased cellular drug uptake
  2. reactive platinum species bind to thiol containing proteins
  3. enhanced repair of DNA adducts
  4. tolerance of DNA adducts

139

Direct DNA Damaging Agents; Alkylating Agents
-Cyclophosphamide & Ifosfamide

 

  • mustard derivatives
  • pro-drugs --> cytotoxic after hydroxylation by cytochrome p450 and breakdown to phosphoramide mustard and acrolein
  • phosphoramide mustard reacts with DNA

140

Resistance

Direct DNA Damaging Agents; Alkylating Agents
-Cyclophosphamide & Ifosfamide

  • DNA repair enzymes
  • decreased cellular permeability
  • reaction of drug with thiols like glutathione

141


Inhibitors of chromatin remodeling-Topoisomerase II Inhibitors-Doxorubicin

  • natural anthracylcine antibiotic
  • enters nucleus and binds DNA --> intercalation of multiple molecules results in a "knot" topoisomerase cannot unwind --> inhibition

142


Inhibitors of chromatin remodeling-Topoisomerase I inhibitors-Topotecan & Irinotecan

  • S-phase specific
  • binds enzyme-DNA complex prevents re-ligation of single strand breaks

143

Resistance

Inhibitors of chromatin remodeling-Topoisomerase inhibitors

 

  • P-glycoprotein
  • membrane pumps
  • detoxifciation with glutathione
  • decreased expression/mutation of topoisomerase
  • enhanced DNA repair
  • decreased metabolic conversion of drug

144


Inhibitors of DNA synthesis- pyridine analogs

 

  • 5FU --> competes with uridine for binding to TS (thymidylate synthase) --> thymidine not synthesized --> DNA replication stop --> S phase arrest
  • methotrexate --> impairs production of dihydrofolate reductase --> no tetrahydfolic acid precursor for TS--> DNA replication stop --> S phase arrest

145

Resistance

Inhibitors of DNA synthesis-pyridine analogs-methotrexate

 

  • decreased cellular transport
  • cellular efflux pumps
  • decreased polyglutamylation
  • increased polyglutamate hydrolases
  • increase in DHFR gene copy number
  •  

146

Tubulin interactive drugs-microtubule stabilizers-taxanes

  • Paclitaxel --> binds B tubulin--> no depolymerization --> inhibition of DNA synthesis --> mitotic block at anaphase --> apoptosis

147

Tubulin interactive drugs-microtubule destabilizers-vincas

  • prevent formation of microtubules

148

Resistance

Tubulin interactive drugs-microtubule stabilizers-taxanes-paclitaxel

 

  • P-glycoprotein
  • microtubule associated proteins (MAPS) which impair binding of taxanes to tubulin

149

Resistance

Tubulin interactive drugs-microtubule destabilizers-vincas

 

  • Efflux by P-glycoprotein
  • tubulin mutations
  • altered expression of tubulin isoforms

150

Inhibition of angiogenesis

  • Bevacizumab blocks VEGF--> no vascular proliferation,permeability, and reduced upregulation of antiapoptosis
  • mTOR inhibitors --> block hypoxia inducible factors --> reduce VEGF production
  • tk inhibitors --> block VEGF 1/2 receptors vascular endothelial cells

151

Anti-CTLA4 drug and mechanism


Ipulimumab: blocks CTLA4 --> upregulates T cell activation

metastatic melanoma

152

Anti-SERM (selective estrogen receptor modulator) drug and mechanism


Tamoxifen

breast cancer

153


Anti-CD20 drug and mechanism


Rituximab: targets mature B cells --> depletion and immune suppression

154


Anti-HER1/2 drug and mechanism


Trastuzumab: blocks epidermial growth factor receptors

breast cancer

155

Anti-c-abl/c-kit/tk inhibitor and mechanism


Imatinib/Gleevac: high specificity for BCR-ABK receptor --> arrest of growth and apoptosis

CML

156

anti-VEGF drug and mechanism


Bevacizumab: binds VEGF --> reduces angiogenesis

 

157


Stem cell classes

  • totipotent = germ cells
  • pluri = stem cells, induced
  • uni/oligo = hematopoeitic

158

TPO mimetics

Romiplostim and Eltrombopag

  • stimultae megakaryocyte proliferation and differentiation

159

Fanconi Anemia

  • recessive xlinked disorder of DNA repair
  • ID: pancytopenia, congenital abnormalities, MDS/AML, bm failure
  • Dx: DEB/MMC cross link test

160

Dyskeratosis Congenita

  • telomeric
  • ID: pancytopenia, leukoplakia, bone marrow failure, nail dystrophy, pigmentation

161


Diamond Blackfan Anemia

  • autosomal dominant ribosomopathy
  • ID: red cell aplasia, congenital abnormalities
  • Dx: red cell adenosine deaminase

162


How do we distinguish acquired from inherited bone marrow failure?

  1. no congenital abnormalities
  2. repsonsive to immunosuppression
  3. not heritable
  4. low risk of transformation

163

Hairy Cell Leukemia

  • NHL B CD103/CD25/CD11c/ANXA1/Cyclin D1 (pl-binding protein)
  • infiltration of spleen, bm, liver, but not lymph nodes
  • ID: pancytopenia, splenomegaly, fried egg cytology
  •  

164

Which HCLv have the worst prognosis?

those with IGHV4-34

165

What genetic lesion is implicated in HCL?

BRAF V600E-->MAP kinase pathway to cell proliferation

166


Main BRAF inhibitor


Vemurafenib