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Aantekeningen Mechanisms of Disease 2

17-10-2016 cancer diagnostics (28-10-2016 watched, )

Macroscopy of tumors
Benign Malignant
Small Relatively large
Well demarcated Poorly demarcated
Slow growing Rapidly growing with hemorrhage and necrosis
Noninvasive Locally invasive
Nonmetastatic Metastatic
Well differentiated Poorly differentiated

- Size
- Completeness
- Tumor location
- Tumor size
- Surgical margins

Microscopial aspects of cancer:

- Special stains
o Histochemical stainings (PAS, alcian blue, etc)
- Immunohistochemistry:
o Needed for analyzing the type of tissue (different tumors require different
o Both prognostic and predictive information
- Molecular assays

17-10-2016 normal blood and hematopoiesis (28-10-16 watched, )

Hematocrit: amount of erythrocytes in blood


- Neutrophils:
o Phagocytosis
o Highly chemotactic (IL-8)
o Granules contain myeloperoxidase, lysozyme
o Attack phagocytosed material by oxidative burst/reactive oxygen species
o Problems with encapsulated bacteria
- Eosinophils:
o Release of granule proteins
o Release of eicosanoids
o Mediate allergic responses and defense against parasites
- Basophils:
o Release of histamine and other mediators
o Bind Fc portion of antigen-specific IgE
o Mediate allergic responses and defense against parasites


- B-cells
o Antibody production
o Cytokine secretion
o Antigen presentation
o Antigen specific immune defense
o Cell-cell signalling
- NK-cells
o Innate immunity: defence against viruses
o Cytotoxic capacity
o Cell-cell signalling
- T-cell
o Cellular cytotoxicity (CD8)
o Cytokine secration
o Cell-cell signalling
o Antigen-specific immune defense

Thrombocytes (platelets):

- Bind to vWF
- Aggregate via Gpllb/llla
- Release mediators from granules
- Activation ...

Definition of stem cells:

- A stem cells must be capable of self renewal and should not be “used up”
- It must be capable of differentiating into a mature functioning cell
- Omni-potent stem cell can deferentiate into any type of cell
- Pluri-potent stem cell can differentiate into more than one type of cell
- Comitted stem cell can only differentiate into one type of cell

17-10-2016 cancer development (28-10-16 watched, )

Characteristics of cancer:

- Uncontrolled growth:
o Beyond normal hyperplasia
o Loss of cell-cell inhibition (loss of intercellular connections)
o Anaplasia (undifferentiated, tumors want to grow instead of differentiating
o Apoptosis defective
- Tendency to invade surrounding tissue
- Tendency to travel beyond site of origin:
o Metastasis may occur late

Mechanisms of carcinogenesis:

- Main causes:
o Age (cancer in older patients are generally less agressive than cancer in younger
o Exogeneous factors:
 Smoking
 Alcohol constumption
 Diet
 Obesity and hormone
 Radiation
o Chronic inflammation:
 Asbestosis
 Inflammatory bowel disease
 Hepatitis
 Mechanisms involved:
 Vasodilatation and increased permeability that alter cellular
response to DNA damage
 By liberating lysosomal enzymes when cells are damaged which
intitates mutations
 By releaseing compiound such as reactive oxygen species that
promote mutations
 By increasing the abundance of leukotrines that are associated with
some cancers
o Viruses
 HPV (HPV E6 inhibits P53)
 Hepatitis B/C
 Ebstein Barr virus
 Human herpesvirus 8
 Most are DNA viruses (exceptions: some retroviruses)
 Mechanism:
 Certain viruses can cause changes in the cell DNA which may lead to
cancer development
o Genetics

17-10-16 Myeloid malignancies

Myloid neoplasia:

1. Disorders of proliferations:
a. Chronic myloid leukemia (CML)
b. Myeloproliferative disorders:
i. Polycythemia vera
ii. Essential thrombocythemia
iii. Myelofibrosis
2. Disorders of differentiation:
a. Myelodysplastic syndromes:
i. RA
ii. RARS
iii. RCMD
iv. RAEB
3. Disorders of differentiation & proliferation:
a. Acute myloid leukemia (AML)
i. De novo AML (progenitor cell disorders)
ii. Secondary AML (stem cell disorder):
1. AML with dysplastic changes
2. Therapy-related AML


- Male, 48 years
- Fatigue
- Physical exam:
o Pale
o Elarged spleen
- Lab test:
o Hb 8,0 mmol/L (>8,5)
o Leukocytes 113 * 109/L (4-10 * 109)
o Platelets 154 * 109/L
- Blood sample:
- Diagnosis:
o CML:
 Stem cell disease
 Driver mutation: BCR/ABL (translocation 9;22)  proliferative advantage
 No mutation in differentation known
 14% of all adult leukemias (still low incidence of 1-1,5/100.000)
 Member of myeloproliferative disease
 Slowly progressive course
 More common in males
 Symtoms:
 Fatigue, wieght loss
 40% asymptomatic
 50% splenomegaly
 20% hepatomegaly
 50% anemia (huge production of leukocytes suppresses the
production of erythrocytes)
 20% thrombocytosis (more platelets)
 Phases:
 Chronic phase
 Accerelerated phase:
o >15% blasts
o Blasts +promyelo’s >30%
o Baso’s >20%
o Platelets<100
o Additional cytogenetic abnormalitites
 Blast phase
o Blood or bone marrow >20% blasts
- Therapy:
o Imatinib (2nd and 3rd generations are also available): BCR/ABL inhibitor
o Allogeneic stem cell transplantation when the patient doesn’t respond to imatinib
o Conventional chemotherapy is also available

Acute myeloid leukemia (AML):

- Peaks at 70th year

- Hypothesis etiology:
o Multiple mutations are necessary for development AML
o Usually combination of different classes of mutations:
 Class 1  proliferation advantage
 Class 2  differentiation stop
o Old concept: leukemic stem cell with many daughter cells
o New concept: multiple AML clones

19-10-16 Cancer biology 1

𝑚𝑢𝑡𝑎𝑡𝑖𝑜𝑛 𝑟𝑎𝑡𝑒 𝑓𝑜𝑟 𝑎 𝑔𝑒𝑛𝑒 ~
𝐶ℎ𝑎𝑛𝑐𝑒 𝑓𝑜𝑟 6 𝑠𝑝𝑒𝑐𝑖𝑓𝑖𝑐 𝑖𝑛𝑑𝑒𝑝𝑒𝑛𝑑𝑒𝑛𝑡 𝑚𝑢𝑡𝑎𝑡𝑖𝑜𝑛𝑠 𝑖𝑛 𝑎 𝑐𝑒𝑙𝑙 ~
Cancer still exists because some mutations cause genome instability, thereby increasing the mutation
rate. Mutation rate for some types of mutation is much higher than 10−7 . Other mechanisms than
mutation can impair gene function and some people carry predisposing mutations

- Part of some cancer viruses

- Contain copies of normal cellular genes (proto-oncogenes) which mutate in activated forms

Normal cells have a tumor suppressor activity that supresses oncogenic effects of tumor cells
Hypo- and hypermethylation can both cause cancer

19-10-16 cancer biology 2

Hallmarks of cancer:

- Sustaining proliferative signaling due to:

o Secreting their own growth factors
o Mutations in cell surface receptors
o Mutations in the intracellular signal molecules
o Mutations in transcription factors
o Mutations in components of the cell cycle control network
- Evading growth suppressors:
o The restriction point (R-point) in the G1 (resting) phase of the cell cycle restricts the
cell from proliferating. Phosphorylation of Rb is required for release of the R-point
o Rb is impaired in >95% of tumor cells
o P53 checks for hyperproliferative signals, damaged DNA, telomere shortening or
hypoxia during G1:
 Stable p53 forces cells to go into cell-cyclearrest, senescence (state of non-
division) or apoptosis
 Mutated in >50% of all tumors
 P53 affected pathways are damaged in >90% of tumors
 (Li Fraumenie syndrome is a hereditary mutation in p53 gene which cause
primary tumors at a young age)
o Wnt is a process which causes proliferation (if APC is impaired the chance of getting
cancer before the age of 40 is 100%)
o Contact inhibition:
 Normal cells will stop dividing when they touch one another
 Tumor cells will start to grow on top of eachother
- Avoiding immune response:
o T-cells will recognize oncogenes when the oncogen is presented by MHC class I
o Possible impairments:
 Failure to produce tumor antigen
 Mutations in the MHC genes or genes needed for antigen processing
 Production of immunosuppressive proteins or expression of inhibitory cell
surface proteins
- Enabling replicative immortality:
o Normal cells have limited proliferative capacity (how much depends on the type of
cell) and wil eventually go in a state of senescence due to telomere shortening
o When telomerase (protein that extends telomeres) gets activated it can cause cancer
- Tumor promoting inflammation
o Cancer enabling effects of inflammation:
 Release of factors that promote proliferation
 Removal of growth suppressors
 Enhanced resistance to cell death
 Increased angiogenesis
 Activating invasion and metastasis
 Evading immune destruction
- Activating invasion and metastasis:
o Very ineffecient process: millions of tumors might get released from their primary
tumor per day, but only a few can metastasise
- Inducing angiogenesis
o Tumor size is limited to 1-2mm unless it has the capacity to create its own blood
- Resisting cell death
o Intrinsic apoptosis is set in motion by p53, but impairment in later steps of the
apoptoic pathway may also cause apoptosis not to take place
o The extrinsic pathway can be impaired due to mutations in the receptors or in later
steps of the pathway
- Deregulating cellular energetics:
o The Warburg effect:
 Tumor cells will produce more lactate than use the oxidative
phosphorylation pathway (only 5% compared to close to 100%)
 This is caused by tumor cells preferring to use glucose as building blocks
(which produces lactate) instead of using it for energy
 (Side effect of lactate is angiogenesis)

19-10-16 genome integrity

Causes of mutation:

- During DNA replication:

o DNA replication errors:
 DNA-polymerase is not perfect: 10−5 (60.000 mistakes/division)
 Exonuclease proofreading raises this to 10−7 (600 mistakes/division)
o Replication of damaged DNA
 Environmentally induced damage (i.e. UV light) and endogenous sources
(free radicals)
 Chemical instability (10.000 lost bases/cell/day)

19-10-16 cancer genomics

Genome scans show large variation in numbers and nature of mutations in types of tumors
Mutation of driver genes accelerates cancer development
Mutation of passenger genes is accidental
Sequencing of tumor genomes facilitates personalized treatment
Tumors are often heterogenous, which complicates molecular analysis and treatment

20-10-16 General principles: nomenclature, grading

Neoplasmas nomenclature:

- Benign epithelials neoplasms (-oma):

o Adenoma: tumor forming glands
o Papilloma: tumor with finger like projections
o Papillary cystadenoma: papillary and cystic tumor forming glands
o Polyp: a tumor, not a true neoplasm, that projects above a mucosal surface
- Malignant epithelia neoplasms (carcinoma):
o Adenocarcinoma:
 Gland forming neoplasm
 Mucin producing tumor
o Squamous cell carcinoma:
 Keratin producing tumor
 Intercellular bridges with desmosomes
o Neuroendocrine carcinoma
o Transtitional carcinoma
o Undifferentiated carcinoma
- Benign mesenchymal neoplasms (-oma):
o Lipoma: fat neoplasm
o Chrondroma: cartilagenous neoplasm
o Leiomyoma: smooth muscle neoplasm
o Rhabdomyoma: striated muscle neoplasm
- Malignant mesenchymal neoplasms (-sarcoma):
o Liposarcoma
o Chrondrosarcoma
o Leiomyosarcoma
o Rhabdomyosarcoma
o Osteosarcoma: osteoid producing tumor
- Others:
o Teratoma:
 Tumors comprised of cells of more than one germ layer
 Arise from pluripotent cells (usually from the gonads)
 Can be benign and malignant
o Hamartoma:
 Disorganized mass of tissue whose cell types are native to the side of the
o Misnomers:
 Melanoma: malignant skin neoplasm
 Seminoma: malignant testicular neoplasm
 Lymphoma: malignant neoplasm of lymphocytes

Typing of tumors:

- Morphology:
o Epithelial, mesenchymal, melanocytic, etc
- Immunohistochemistry:
o Keratin (epithelial), vimentin (mesenchymal), desmin (muscle), melanA
(melanocytic), etc
- Molecular analysis:
o Chromosomal translocations, gene-alterations

Properties of tumors that can serve as guidance for therapeutic purposes:

- Tumor-grade
- Cell cycle information
- Highly specific mutations
- Gene expressions profiles like MammaPrint and OncotypeDX

Tumor heterogeneity and clinical implications

Complexity of heterogeneity:

1. Clonal evolution
2. Genomic mechanisms
3. Metastasis, resistances

Concepts in tumor heterogrneity:

- Cancer stem cells:

o Still not completely proven
o Proven in haemotopoetic malignancies
o Therapeutic importance: treating the stem cells will make the tumor disappear
o Majority of cancer cells have varying degrees of stemness which is also influenced by
the microenvironment

Intratumoral heterogeneity:

- Genetic and phenotypical diversity

- Subclonal architecture differs over time
- Genetic instability is a major source of genetic diversity
- Multiple mechanisms are responsible for genetic instability:
o Base and nucleotide excision repair
o Mismatch repair
o Telomere maintenance
o Double strand break
o DNA replication
o Chromosomal seggragation
- Also influenced by therapies
- Consequences:
o Faulty diagnosis due to sampling errors
o Linked to prognosis and biological behaviour
o Specialized therapy might be needed for all different cells

Numeric abnormalities


- Polyglobuly (increase):
o Definition: Hematocrit >50%
o Mechanisms:
 Reactive: chronic anemia due to COPD, smoking, altitude
 Neoplastic: polycythemia vera
- Anemia (decrease):
o Definition:
 Males: Hb <8,5 mmol/L
 Females: Hb <7,5 mmol/L
o Mechanism: impaired production, increased loss or destruction

Lymphocytopenia (decrease in lymphocytes):

- Certain infections
- Congenital deficiencies
- Immunosuppresive agents, chemotherapy, radiation therapy
- Systemic diseases
- Others (alcohol, malnutrition etc)


- Leukopenia:
o Definition: <4 * 109
o Mechanisms:
 Infections
 Drugs (therapeutic)
 Chemotherapy
- Leukocytosis:
o Definition: >10*109
o Mechanisms:
 Reactive: inflammation, glucocorticoid therapy
 Neoplastic: chronic myeloid leukemia (malignant left shift, CML), chronic
neutrophilic leukemia (CNL)


- Mechanisms:
o Reactive: viral infection, cytokine therapy
o Neoplastic: mature leukemic lymphomas (MLL)


- Neoplastic:
o Myeloid: acute myeloid leukemia (AML)
o Lymphoid: acute lymphoid leukemia (ALL)

Thrombocytosis (increase in platelets):

- Reactive: infection
- Neoplastic: myeloproliferative neoplasms (stem cell disorders):
o Essential thrombocytosis
o Polycythemia vera
o Myelofibrosis

Premelignancy and cancer

Proliferation  atypia/dysplasia  invasion  metastases

Activation of the WNT receptors causes APC to dettach, which in turn causes proliferation
Ductal carcinoma in situ (DCIS):

- A carcinoma growing inside the ductal lumen of the breast

- 40-80% of low grade DCIS will not develop into an invasive cancer
- Can be detected by mammography

Nomenclature of dysplastic regions

Site Name Grading Detection
Oral cavity Squamous cell dysplasia Low/high Follow up after cancer treatment
Mucosal irritation
Oesophagus Barrett’s oesophagus Low/high Follow up
Reflux complaints
Gastric Gastric dysplasia Low/high Helicobacter pylori
Colon IBD-dysplasia/adenoma Low/high Follow up colitis
Cervix CIN lesions (squamous) Low/high Screening
Breast DCIS Low/high Screening
Endometrium Atypical hypertrophia - Vaginal blood loss
Vulva/anus VIN/AIN (squamous) 1-3 Skin/mucosal irritation
Skin M. Bowen epithelium - Skin irritation
Dysplastic nevus changing nevus
Dysplastic lesions:

- Therapy depends on degree of dysplasia

- Exact course is unknown
- Progression rate into invasive cancer is estimated at 40-50%
- Dysplastic regions do not metastise so local excision is sufficient
- Overtreatment is a problem

Population screening programs

Screening programs in the Netherlands:

- Cervical cancer
- Breast cancer
- Colorectal cancer

Hereditary aspects of cancer

Hereditary types of cancer will get cancer earlier in their lifes and multiple types of cancer as well
Frequency of hereditary cancer depends on the tumor type (all tumors: approx. 5%)

- Positive family history

- Young age
- Multiple primary tumors
- Many precursor-lesions
- Congenital abnormalities
- Rare cancer types: retinoblastoma, medullary type of thyroid cancer

Most frequent:

- Hereditary breast and ovarian cancer syndrome (HBOC-syndrome) caused by BRCA1/2

(breast cancer associated genes) genes
- Colorectal syndrome:
o Hereditary non-polyposis colorectal carcinoma, Lynch syndrome caused by MMR-
and EPCAM-genes
- Malignant melanoma caused by p16 and CDK4
- Hereditary diffuse gastric cancer caused by CDH1
- Paraganglioma syndromes caused by SDHB/C/D
- Von Hippel Lindau
- Cowden syndrome
- Neurofibromatosis type 1 and type 2 (NF1/2)
- Juvenile polyposis

Li Fraumeni syndrome:

- Associated cancers:
o Soft-tissue carcinomas
o Osteosarcoma
o Early-onset breast cancer
o Brain tumors
o Adrenocortical carcinoma
o Leukemia (primarily acute leukemia)
- P53 is mutated (autosomal dominant)

P16 mutation (similar to p53):

- Melanomas
- Dysplastic nevi
- Pancreatic cancer

Clinical genetics

Familial diseases which increase the odds of getting breast cancer:

- BRCA1/2
- PTEN/cowden syndomre
- CDH1: hereditary diffuse stomach cancer and lobular breast cancer
- STK11/Peutz Jeghers syndrome
- Neurofibromatosis 1

Familial adenomatous polyposis (FAP):

- Clinical signs:
o >100 polyps
o 100% chance of developing cancer at the age of 35-45
o Stomach polyps (25-60%)
o Other tumors
- Mutation in the APC-gen
- Dominant
- 15-20% de novo mutation

MUTYH associated polyposis (MAP):

- Clinical signs:
o Less polyps than FAP
o Risk of colorectal cancer at 50: 60-70%
o Increased risk of other tumors
- Recessive
o Base excision repair gene
o Removes adenine after it has bound to oxidated guanine


Synthetic lethality:

- Arises when a combination of deficiencies in the expression of two or more genes leads to
cell death, whereas a deficiency in only one of the two genes does not.
- Therapeutic application:
o One pathway deficiency is tumor-specific whereas the other is not
o By inhibiting the second DNA repair pathway, the cell cannot survive  tumor
specific cytotoxicity

Framework oncology and staging

Cancer staging:

- Determine the spread of the disease

- Differ from tumor to tumor:
o Solid tumors:
 Local spread
 Through lymphatics
 Distant (by way of blood)
o Haemotological malignancies:
 Disease extent
 Influence on bone marrow function
- Common elements:
o Location of primary tumor
o Tumor size of number of tumors
o Lymph node involvement
o Cell type and tumor and tumor grade (how closely the tumor cells resemble normal
o Presence or absence of distant metastases

Most used staging principle for solid tumors is TNM:

- T-status (extent of tumor):

o T1-T4
o Size of the tumor and local organs involved
- N-status (regional lymph node involvement):
o N0-N2
- M-status (distant metastases):
o M0: no metastases
o M1: metastases
- cTNM, pTNM, ypTNM:
o C: clinical
o P: pathological
o Yp: pathological after treatment before surgery
o X: not classified
- G-status (how they compare to normal cells):
o GX: cannot be assessed
o G1: well differentiated
o G2: moderately differentiated
o G3: poorly differentiated
o G4: undifferentiated

Stage 0-4:

0. In situ
1. Localised
2. Further local spread and usually spread to nearest lymph nodes
3. Indicates more extensive lymp node involvement
4. Indicates distant spread

Terminology of therapy:

- Curative: treatment aimed at cure

- Palliative:
o Treatment to alleviate symptoms, cure is not intended
o Palliative phase of the disease is not the same as terminal phase
o Best supportive care: treatment in the terminal phase
- Adjuvant:
o Treatment given after primary treatment
o Aimed at micrometastases
- Neoadjuvant:
o Treament given before primary treatment
o (sometimes called induction therapy)
- Primary treatment:
o Main treatment modality
- Systemic (either disease or treatment):
o Affects a number of organs and tissues, or the body as a whole
- Grade ≠ stage  grading is microscopic information while staging is imaging information
- Concomitant treatment: two therapies at the same time
- Sequential treatment: multiple therapies after eachother
- Elective therapy:
o Local treatment of a clinically negative area but with a high risk of involvement

General principles: metastasis


- Breakthrough of the basal membrane intro surrounding tissue: in situ carcinoma  invasive
- Mechanisms involved:
o Malignant cells do not adhere (stick) together to the same extent as normal cells
o Malignant cells show a change in their interaction with surrounding stroma
o Factors produced to help the cells spread faster (scatter factor)
o Altered synthesis of enzymes, which are needed to breakdown the basement
membrane and stroma
o E-cadherine:
 Cadherines are calcium dependent glycoproteins present at the cell
 They interact between cells, and within each cell with the actin skeleton
through cadherine, maintaining polarity
 Reduced expression and alteration in interactions in cancer cells, allow the
cells to move apart
o Integrins:
 Integrins are cell surface glycoproteins composed of two subunits
 They are transmembrane proteins for different components of the basement
 Reduced expression of integrins in malignant cells modifies the contact
between the cell and stroma allowing movement
 Function to provide interactions between cells and macromolecules in
extracellular matrix
o CD44:
 Expressed on normal T-cells
 Used for homing or migration to specific sites
 Many cancer cells express CD44 which enhances metastatic capacity
o Metalloproteinases (MMP) serine, so called matrix degrading enzymes:
 Can modify stroma which allows cells to break throught the basement
membrane and spread
 Required for controlled degradation of componentes of the ECM
 Can be produced by tumor cells as well as fibroblasts (especially cancer
associated fibroblasts)
o Altered enzyme synthesis and interaction:
 Malignant cells synthesize factors that stimulate stromal cells (fibroblasts) to
synthesize more enzymes, that allow the malignant cells to break through
the basement membrane
o Locomotion/motility promoting factors:
 Hepatocytes growth factor/scattering factors:
 Dominantly produced by fibroblasts/CAF
 Normally acts as a paracrine growth factor but in malignant cells in
can act as a autocrine growth factor, stimulating growth
 Binds to MET which activates a pathway that’s responsible for the
invasive growth
 Insulin-like growth factor II
o Angiogenesis also aids invasion due to creating more vessel with thin walls


- The ability of malignant cells into lympatics, blood vessels and cavities and spread to distant
- Not all circulating malignancies will be able to survive at a distant site
- Lung metastases:
o Almost all malignancies can metastasise to the lungs
o Most often:
 Sarcomas, e.g. osteosarcoma
 Carcinomas, e.g. breast, stomach, large intestine
 Kidney
 Testis, e.g. malignant teratoma
- Liver metastases:
o Common site for carcinomas of the large intestine due to the portal vein
o Bronchial carcinoma
o Breast carcinoma
o Melanoma
o Pancreatic cancer
- Metastases in the bone:
o Can cause destruction of the bone
o Most commonly caused by:
 Bronchial carcinoma
 Breast carcinoma
 Thyroid carcinoma
 Renal carcinoma
 Prostate cancer
- Brain metastases:
o Can cause problems in the brain or meninges:
o Most commonly caused by:
 Bronchial carcinoma (both NSCLC and SCLC)
 Malignant melanoma
o Often in late stages of the disease due to the blood-brainbarrier

Pattern of metastatic spread and tumortype:

- Carcinomas:
o Local invasion and spread
o Regional lymph nodes
o Supraregional lymph nodes
o Haematogenous spread (lung, liver, brain, bone)
- Sarcomas:
o Local invasion and destructive growth
o Haematogenous spread (lung, liver)
o No lymphatic spread
- Lymphomas:
o Lymph nodes
o Haematogenous spread (liver, bonemarrow, spleen)

Cancer and immunity

Allogeneic stem cell transplantation and DLI

Graft-versus-host and host-versus-graft both exist

Summary ASCT:

- Chemotherapy and/or radiation for tumor reduction and conditioning of the patient
- Myelosuppression as complication
- Immune suppression with chemotherapy, irradiation and/or T-cell therapy to prevent
- Transplantation of stem cells to obtain recovery of (donor) hematopoiesis in the patient
- Immune suppression after SCT to prevent the donor T-cells from causing graft-versus-host
disease  which in turn may cause infections
- Diseases:
o Genetic disorders of the hematopoietic or lymphapoietic system
o Acquired stem cell disorders
o Hematological malignancies

Allogeneic stem cells are preferred over autologous SCT because the donor cells may provide a very
potent anti-tumor effect
T-cells also possess a graft versus leukemia/lymphoma effect, but need to be removed from the
donor cells to prevent GvHD  it is very important to balance both effects

Surgical oncology background and mechanisms

Surgical oncologists are part of multidisciplinary teams

Types of surgery:

- Curative:
o Preventing metastases is the main priority
o Clips may be used to mark the surgical field for radiotherapy
- Acute:
o Done when perforation, obstruction and bleeding are possible
o Usually a negative prognostic
o “Treat what kills first”
- Palliative:
o Preventing further disease:
 Obstruction  bypass
 Local control  excision
o Treating complications:
 Obstructions
 Fractures
 Seroma (pocket of fluid left after surgery)
- Resection:
o Margins:
 R0: no tumor cells left
 R1: macroscopically no tumors; unable to say whether all microscopical
tumors were removed
 R2: residual tumor left in situ

Medical oncology, breast cancer

Types of therapy:

- Endocrine therapy (aka hormonal therapy)

- Chemotherapy
- Targeted therapy

Factors involved in choosing the correct therapy:

- Patient age, menopausal status, general health

- Tumor estrogen receptor (ER) status (and progesteron receptor (PR, less important) status)
o Endocrine therapy is prefered with a positive ER-status due to it being very effective
- Tumor HER-2 status
o Targeted therapy prefered
- Extent and sites of disease (lymph nodes, lungs, liver, bone)
- Response to previous treatment

Principles of hormonal therapy in breast cancer:

- Hormonal therapy is directed towards tumors whose growth is dependent on hormons:

o Breast cancer (often ER-status positive)
o Prostate cancer (testosteron dependent)
o Endometrial cancer (progesteron dependent)
- Mechanism of action:
o Estrogen stimulate ER which stimulates tumor growth
o Tamoxifen blocks the receptors and sets a inhibitory response in motion
o Tamoxifen is effective in both pre- and postmenopausal women
o Aromatase inhibitors are also used in postmenopausal women
o LHRH (FSH/LH inhibitors) are also used in premenopausal women (though not used
very often since this treatment is chemical castration in essence)

Chemotherapy in metastatic breast cancer:

- Sequential single agent chemotherapy:

o Less toxic than combination chemotherapy
o No data to support optimal sequence
- Combination chemotherapy
o In patients with:
 Rapid clinical progression
 Need for rapid sympoms/disease control
 Life threatening visceral metastases (mostly liver)
- Mixed responses ofter occur due to tumor heterogeneity
- Re-emergence and resistance to the therapy is less likely after a combination of multiple 2/3
- In general there is no cure for metastatic breast cancer

Chemotherapy may be cell phase specific or nonspecific

Common chemotherapy toxicity:

- Chemotherapy is active in cells that divide rapidly

- Because of the cytotoxic effects, chemo is toxic to normal cells that are actively dividing. i.e.:
o Bone marrow
o GI tract
o Hair follicles
- Thus common toxic side effects are:
o Neutropenia, anemia, thrombocytopenia (myelosuppression/bone marrow
o Mucositis, diarrhea (GI tract toxicity)
o Nausea, vomiting
o Alopecia (hair loss)
o Sterility/infertility

Medical oncology, prostate cancer

Prostate cancer often has very high heterogeneity

Usefulness of biomarkers


- A biomarker refers to a measureable indicator of some biological state or condition

- Humans shed small parts of the cells (microparticles, exosomes), proteins, unique chemicals,
DNA and RNA into the bloodstream/environment as evidence of their presence in a certain
- Biomarkers are measured and evaluated to examine normal biological processes, pathogenic
processes, or pharmacological responses to a treatment (therapeutic intervention)
- Ideal markers for diagnosis:
o Should have great sensitivity, specificity and accuracy in reflecting total disease
o A tumor marker should be also prognostic of outcome, predictive of tumor
recurrence and predictive of effectiveness of anti-cancer treatments
- Problems with biomarkers:
o Limited access to tissue: heterogeneity leads to problems with determining correct
treatment. Metastasized tissue might also not be available
o CTCs (circulating tumor cells) might be solution as both primary and metastatic
tumors form CTCs which provides real time information about the patient’s current
o Clinical applications of CTCs:
 Blood testing using CTCs may aid in cancer diagnostics
 CTCs may function as both predictive and prognostic biomarkers for cancer
 CTC numeration may provide inside in spread and invasion of the tumor
 CTCs may provide a investigational platform to elucidate cancer diagnostics
(whole genome/transcriptome sequencing might be available in the near
future at a reasonable cost)

Differences between cancers

Pharmacology of cytostatic drugs

4 different types of drugs:

- Cytostatic drugs: blocks the cell cycle

- Hormonal drugs
- Target therapy: inhibit receptors important for the cell
- (Anti)-coagulants


- 4 different types:
1. Alkylating cytostatics: affect the DNA:
o Prevents helicase (unwinds the DNA) from attaching to the DNA
o Not dependent on cell phase
o Examples:
1. Cyclophosphamide: vomiting, nausea, myelosuppression
2. Cisplatin: severe vomiting and nausea, relatively low
myelosuppression, nephrotoxicity
2. Antimetbolites: affect the DNA synthesis:
o Inhibit the S-phase  inhibition of DNA synthesis
o Examples:
1. Methotrexate: mucositis, myelosuppression, diarrhea
2. Fluorouracil: mucositis, myelosuppression, diarrhea
3. Cytarabine (blocks DNA polymerase): myelosuppression, vomiting,
nausea, diarrhea
3. Antimitotics: block mitosis:
o Affect the N-phase: antimitotics bind to microtubules which induces nucleus
shape alteration which in turn inhibits cell divions
o Examples:
1. Paclitaxel: peripheral oedema, alopecia, bone marrow suppression,
hypersensitivity, cardiac disturbances
4. Topo-isomerase inhibitors: block DNA transcription and DNA duplication
o Affect the G2 phase: inhibits topo-isomerase which unwinds, cuts and ligates
the DNA which inhibits DNA replication
o Examples:
1. Doxorubicine: myelosuppresion, vomiting, nausea, alopecia,
- Affect only on echaracteristic aspect of cancer cell biology: cell division
- No inhibitory effect on invasiveness, loss of differentiation or tendency metstasis
- Induce damage to DNA synthesis and initiate apoptosis
- Main target is cell division in rapidly dividing tissue
- General toxic effects:
1. Bone marrow toxicity (myelosuppression)
2. Impaired wound healing
3. Loss of hair
4. Damage to gastrointestinal epithelium
5. Depression of growth in children
6. Sterility
7. Teratogenicity
8. Nausea and vomiting
- Limitations of cytostatics:
1. Efficacy: tumors can be resistant to cytostatics:
o Primary:
o acquired
2. Predominantly affect rapidly dividing cells
3. Influence all normal cells
4. Have no effect on tumor progression (tissue invasion, metastases, progressive loss of
5. High incidence of side effects

14-11-2016 Primary hemostasis

Trousseau syndrome:

- Thrombosis may be the first sign of malignancies

- Peripheral edema may also occur
- Thrombotic event is the second leading cause of death occuring (second only to dying of the
cancer itself)
- Tumor may express tissue factors which trigger coagulation
- Type of malignancy determines the odds of getting thrombosis (hematological malignancy >
breast cancer)
- Prothrombotic mutations increase the risk of thrombosis when combined with cancer

Idiopathic venous thrombosis  3 year cancer developement: 10%

Provoked venous thrombosis  3 year cancer developement: 1,6%
Single episodes of thrombosis are not clearly associated with cancer
Screening for underlying malignancy with unexplained thrombosis will not improve the chance of

Treatment with low molecular weight heparin is more effective than vitamin K antagonists in cancer
Low dose aspirin reduces the incidence of colorectal cancer (the exact mechanism isn’t clear)
Mechanism of hemostasis

Binding of platelets to collagen via glycoprotein receptors on the platelet memebrance:

- Glycoprotein VI (GP6) and glycoprotein Ia (GP1a) bind to collagen

- Von willebrand factor (vWF) binds to collagen and at high shear vWF binds to glycoprotein Ib
(GP1b) receptor
- After adhesion the platelets change shape and become activated
- Glycoprotein IIb/IIIa receptor is exposed on the surface when the platelets become activated

Release reaction:”

- Alpha granules: vWF, fibrinogen

- Dense granules: serotonin, ADP
- Thromboxane A2 (TxA2): cyclo-oxygenase converts arachidonic acid (AA) into TxA2

Disturbed primary hemostasis

Thrombocytopenia (low platelet count):

- Causes:
o Reduced production:
 Leukemia
 Aplastic anemia
 chemotherapy
o Increased clearance/constumption:
 Immune thrombocytopenic purpura (ITP)
 Disseminated intravascular coagulation (DIC)
o Loss, bleeding

Thromboctopathia (platelet function defect):

- Causes:
o Congenital (defects in platelet associated receptors):
 Storage pool disease:
 Reduction in number....
o Acquired:
 Renal insufficiency:
 Uremia
 Liver cirrhosis
o Medication

Von Willebrand Factor:

- Made in the endothelium from megakaryocytes

- Bleeding disorders caused by inherited defects in the concentration, structure or function of
von Willebrand Factor
- Classification:
o Type 1: partial quantitative deficiency of vWF
o Type 2: qualitative VWF variants (4 types):
 2A: lack of high molecular weight polymers
 2B: vWF can stick to platelets in the circulation, increased affinity of GP1b
due to instant binding
 2M: vWF cannot bind to GP1b
 2N: reduced FVII level, resembles hemophilia A
o Type 3: virtually complete deficiency of vWF


- Screening tests:
o Platelet count
o Bleeding time
o Platelet function test
- Specific tests:
o VWF concentration
o VWF function
o Platelet aggregation

14-11-16 Secondary hemostasis

Conversion (thrombin Iia) of fibrinogen (soluble) to fibrin (insoluble) is necessary for coagulation
Fibrinogen (factor I):

- Abundant plasma protein: normal leves are about 1,5-3 gram/liter

- Two symmetrical half-molecules, each consisting of 3 different polypetide chains: alfa, beta,
- Thrombin cleaves fibrinopeptide A and B from fibrinogen resulting in a fibrin monomer,
which can stick together to form dimers and polymers

Coagulation cascade:

- Sequence of proteolytic reactions

- In part on the surface of activated platelets
- In each step a pro-enzyme is converted to an enzyme
- By the enzyme that was generated during the prior reaction step
- Two different pathways:
o Extrinsic: activation upon contact with tissue factor
o Intrinsic: activation upon contact with surfaces foreign to our body

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14-11-16 secondary hemostasis part 2

Regulation of thrombin generation:

- Initiation:
o Contact with tissue factor
o Activation of pro-enzymes
- Amplification:
o Feedback activation of the pro-cofactors (FV, FVIII)
o Feedback activation of factor XI
- Inhibition:
o Inhibition of the enzymes:
 Tissue factor pathway inhibitor (TFPI)
 Inhibits Xa while generating a Xa-TFPI complex
 The complex inhibts the TF-VIIa complex
  suppresses
 Antitrombin II (ATIII):
 Serine protease inhibitor
 Inhibits thrombin (Iia), Xa, IXa, Xia
 Inhibition accelarates 1000-fold by action heparins
  an
o Inhibition of the cofactors
 Thrombomodulin:
 Transmembrane protein
 Receptor and cofactor thrombin
 Protein C:
 pro-enzyme (serine protease)
 Vitamin K dependent protein
 Protein S:
 Non-enzymatic cofactor for activated protein C (APC)
 Vitamin K dependent protein