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135 Cards in this Set
- Front
- Back
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Cancer |
Uncontrolled growth of abnormal cells in a tissue that is invasive and spreading. |
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Carcinoma |
Neoplasm of epithelial tissue |
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Squamous Cell Carcinoma |
Neoplasm of epithelium lining of a cavity |
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Adenocarcinoma |
Neoplasm of secreting epithelial cells |
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Sarcoma |
Neoplasm of mesenchymal cells |
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Tumour Supressor Gene |
A gene whose normal function is a negative regulator of cell growth (one allele is sufficient). These are downregulated in tumours (need to lose both alleles). |
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Oncogene |
A gene that is a positive regulator of cell growth, even when only on allele is mutated these can promote tumour growth. |
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Hallmark 1: Self Sufficiency in Growth Signals |
Extracellular growth signals + transmembrane transducers + intracellular circuits. |
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Hallmark 2: Insensitivity to Anti-Growth Signals |
Disruption of pRB pathway --> loss of control of progression G1 to S phase. |
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pRB |
Guardian of the restriction point gate. Phosphorylation of this protein causes continuation of the cell cycle G1 to S phase. |
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Hallmark 3: Evasion of Apoptosis |
Increased activity/levels of antiapoptotic agents, decreased activity/levels of proapoptotic agents. |
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Hallmark 4: Limitless Replicative Potential |
Circumvention of senescence and crisis. Increased expression and activity of telomerase. |
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Hallmark 5: Sustained Angiogenesis |
Angiogenic switch. Control of transcription of proangiogenic inducers. Downregulation of angiogenic inhibitors. |
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Hallmark 6: Tissue Invasion and Metastasis |
Changes in expression of adhesion receptors (cadherins, integrins). Activation of extracellular proteases (EMT). |
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Metastasis |
Multistep process leading to the spread of cancer to distant organs resulting intumour implants discontinuous with the primary tumour mass. |
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Density Dependant Inhibition of Growth |
Once normal cells reach a finite density they stop growing. |
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Contact Inhibition of Movement |
Normal cells move away from from each other when they make contact. |
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Anchorage Dependance |
Normal cells need contact with a substratum for growth. |
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Adhesion |
Normal cells are firmly adhered to each other - this is dysregulated in cancer. |
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Collective Migration |
Cancer cells move as a group of cells |
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Mesenchymal Migration |
Cancer cells adopt a mesnchymal phenotype so are very motile and hijack the chronic inflammatory state. |
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Metastatic Heterogeneity |
Some cancers are more likely to metastasise. |
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Metastatic Niche |
Cancer cells produce soluble factors which diffuse and prepare the secondary site for metastasis. |
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Warburg Effect |
Cancer cells preferentially switch to glycolysis even under normal, non-hypoxic conditions. |
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Angiogenesis |
The growth of new capillaries - this is normal during embryogenesis but contributes to all stages of cancer. |
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Intracellular Signalling |
A set of linked biochemical events that connect a specific biological stimulus with a specific cellular response. |
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Kinases |
Catalyse the transfer of the terminal phosphate of ATP to specific residues on target proteins |
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HER2 |
An orphan receptor with no known ligand. It is activated by heterodimerisation with other EGFRs but is overexpressed in cancer cells allowing homodimerisation and therefore constitutive signalling. (oncogene) |
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Transtuzumab |
A monoclonal antiHER2 antibody that causes internalisation and degradation of HER2. |
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Philadelphia Chromosome |
The chromosome resulting from translocation between chromosomes 22 and 9. The breakage and rejoining occurs at the sites of BCR and ABL. |
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BCR-ABL |
A fusion protein as a result of the transcription of the BCR-ABL hybrid gene encoded on the Philadelphia chromosome. |
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Imatinib/Gleevec |
A synthetic ABL kinase inhibitor that blocks the ATP binding pocket of the BCR-ABL tyrosne kinase domain. |
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Slowly Transforming Retrovirus |
Retroviruses that cause tumours after many months of infection due to insertional activation of a cellular oncogene. |
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Acutely Transforming Retrovirus |
Restroviruses that cause tumours rapidly due to insertion of a viral oncogene. |
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Direct Carcinogen |
Viruses that induce viral oncogenes into a host cell (e.g. HPV) or the viral oncogene is modified after integration into a host cell (e.g. Merkel Cell Polyomavirus) and therefore cause cancer |
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Indirect Carcinogen |
viruses that induce chronic inflammation (e.g. HepC) or induce immunosuppression and activates other tumour viruses (e.g. HIV) or prevent apoptosis (e.g. EBV) and therefore cause cancer |
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p53 |
Protects against genetic instability - "guardian of the genome". If DNA damage is beyond repair induces apoptosis, growth arrest senescence and inhibits angiogenesis. |
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Neoplasia |
A mass of cells that have undergone an irreversible change from normality, proliferate in an uncoordinated manner, partially or completely independant of the factors which control normal cell growth. Growth persists even if the initiating stimulus if withdrawn. |
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Maliganant |
Have the capacity for local invasion into surrounding tissues and metastasis to different sites |
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Papilloma |
A benign neoplasm of epithelial cells (squamous or transitional) |
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Adenoma |
A benign neoplasm of glandular epithelium |
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Teratoma |
Neoplasm derived from embryonic germ cells that have the capacity to form representitives of all 3 germ layers |
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Hamartoma |
Not a genuine neoplams but tumour like malformation which may present at birth and stop growing when the host stops growing. |
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Vemurafenib |
Drug that inhibits proliferation and BRAF signalling |
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Trametinib |
Blocks MEK kinase |
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Cancer Immunoediting |
The immune system sculpts or edits the immunogenicity of tumour that may eventually form: Escape |
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Elimination |
Immune mediated destruction of most cancer |
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Equilibrium |
Dynamic equilibrium between immune and surviving tumour cells. The immune response is enough to contain but not full extinguish. |
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Escape |
Tumour cell variants selected in equilibrium grow out in an immunologically intact encironment |
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Criteria for a Good Target Antigen |
Tumour specific |
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Non-Specific T Cell Stimulation |
Immunostimulatory cytokines |
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Ipilimumab |
Monoclonal antibody that blocks CTLA4 on T cells and therefore decreases the negative signal on T cells |
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Pembrolizumab |
Monoclonal antibody which block PD1 so with therefore cannot engage with PDL-1 to produce a negative signal on the T cell response |
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Vaccination |
Tumour cells/lines |
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Adoptive T Cell Therapy |
Infusing whole T cell populations |
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Base Excision Repair |
The altered DNa base is excised in free form by DNA glycosylase and the resulting abasic site is removed and a new nucleotide is added. |
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Nucleotide Excision Repair |
Removal and repair of large adducts (e.g. thymine dimers). Double stranded DNA only and is non-specific recognising distortions, not specific adducts. (endonuclease, exonuclease, polymerase, ligase) |
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Daughter Strand Gap Repair |
A tolerance mechanism in which the gaps opposite thymine dimers that occur during replication are filled. |
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Xeroderm Pigmentosum |
Autosomal recessive disorder in which the patient suffers from extreme sun sensitivity and develop many skin tumours on sun exposed skin. |
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Basal Cell Nebus Syndrome |
Mutation in PTCH1 gene leading to basal cell carcinomas |
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Homologous Recombination Repair |
Double strand break repair that can only occur in S phase when there is a daughter strand present.. |
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Non-Homologous End Joining |
Rejoining of a double strand break which may involve some gap fillng/additionof extra nucleotides at random. This means it is error prone. Useful in that this allows variation in antibodies. |
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C-myc |
Drives the uptake of glucose and glutamine into cancer cells to increase glycolysis. When mutated is constitutively active |
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Screening |
The investigation of asymptomatic people in order to classify them as likely or unlikely to have the disease. People found to be likely to have a disease are invesitgated further to arrive at a final diagnosis and those who are diagnosed to have the disease are treated. |
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Sensitivity |
Of those who have the disease, how many will test positive? |
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Specificity |
Of those who don't have the disease, how many will test negative? |
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Positive Predictive Value |
If the test is positive, what is the probability that the patient has the disease? |
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Negative Predictive Value |
If the test is negative, what is the probability that the patient does not have the diasease? |
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Lead Time Bias |
The period between detection and deathcould be longer with screening thanwith normal presentation and diagnosis simply because we have observed it for longer but in fact there has been no change in the progression of the disease |
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Length Time Bias |
Slowly progressing disease is more likely to be picked up by screening than aggressive disease and is likely to have longer survival time. |
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Selective Oestrogen Receptor Modulators |
Compete with oestrogen for its receptor --> preventing full activation of the receptor --> less gene transcription (but some increase in TGF beta) |
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Aromatase Inhibitors |
Inhibit aromatase, the enzyme responsible for the conversion of testosterone to oestrogen. |
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Fulvesterant |
A drug which is structurally similar to oestrogen and therefore competes for the receptor and binds irreversibly. |
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Goserelin |
Binds LHRH receptors in the anterior pituitary initially increasing FSH/LH release but continuous exposure downregulates release (2 weeks) |
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Neo-Adjuvant |
Therapy given before surgery to shrink the tumour and increase likelihood of successful excision. |
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Adjuvant |
Therapy given alongside surgery to "mop up" any left over malignancy or micrometastasis that could not have been removed by surgery. |
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5 Rs of Radiobiology |
Repair, Repopulation, Redistribution, Reoxygenation, Radiosensitivity |
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Repair |
Radiotherapy causes DNA damage that cancer cells are unable to repair --> cell death |
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Repopulation |
When you give radiotherapy over a long period of time you see regrowth of existing tumour tissues as you kill other tumour cells. Stimulated by the release of inflammatory cytokines. This can lead to failure of radiotherapy. |
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Redistribution |
Tumour cells are redistributed to different phases of the cell cycle. G2 - most radiosensitive, G1 - less radiosensitive (has the whole of S phase to repair DNA damage |
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Reoxygenation |
The centres of tumours are hypoxic, this switches on a genetic programme making them resistant to cell death and DNA damage. During radiotherapy, cells on the outside die first allowing centre cells to be reoxygenated and therefore become more radiosensitive. |
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Gray |
1Gy = 1J/kg a physical quantity describing the amount of energy absorbed from the radiation beam at a given point |
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Tumour Lethal Dose |
The dose of radiation that eradicates a tumour within the treated volume. the total number of surviving cells is proportional to the initial number present and the number killed after each dose. |
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Normal Tissue Tolerance |
Limits the maximum dose. Varies between tissues. Depends on age, comorbidities etc. Depends on type of radiation. |
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Gross Tumour Volume |
The visible tumour as assessed by imaging and clinical assessment |
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Clinical Target Volume |
The area including GTV at risk of macroscopic or microscopic disease |
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Planning Target Volume |
The volume of tissue that should be irradiated to ensure that the CTV is targeted adequately. |
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5-Fluoracil |
Structure is similar to pyrimidine. Inhibits the synthesis of thymine and therefore inhibits DNA replication. |
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Anthracyclines |
Topoisomerase II inhibition, DNA intercalation --> ss and ds breaks, free radical formation. |
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Vinca Alkaloids |
Stops assembly, promotes disassembly of microtubules through high affinity binding to ends. Splaying ans piralling through low affinity binding to ends. Metaphase arrest. |
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Taxanes |
Stabilise microtubules and inhibit dynamic reorganisation. Sustained metaphase/anaphase block. |
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Alkylating Agents |
Add alkyl groups to DNA and cause breaks |
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Platinum Analogues |
Bind to guanine on DNA and form adducts --> apoptosis induction. |
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Reversible Toxicities |
Affects rapidly dividing tissues - compartment repopulation by recruitment of stem cells. dictates time for recovery between cycles. |
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Irreversible cumulative Toxicities |
Affect slow growing cells - dictate maximum safe cumulative exposure |
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Palliative Chemotherapy |
Chemotherapy with non-curative intent |
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M1 Macrophages |
Present in the acute phase of inflammation. Produce ROS. |
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M2 Macrophages |
Present during the wound healing phase of inflammation and in cancers |
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Intratumorial Heterogeneity |
Differences between cancer cells within the primary tumour |
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Intermetastatic Heterogeneity |
Differences between different metastatic lesions |
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Intrametastatic Heterogeneity |
Differences between cells within a metastatic lesion |
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Interpatient Heterogeneity |
No two cancer patients have an identical clinical course |
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gag |
Group specific antigen |
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pol |
RNA dependent DNA polymerase |
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env |
Envelope protein (binds target cell) |
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LTR |
Contains transcription regulatory sequences, promoter and enhancer |
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Dysplasia |
A pre-malignant lesion |
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Characteristics of Viruses |
Variety of structure and complexity Genetic material (DNA or RNA) + protein capsid + membrane envelope Cannot reproduce independently of host cell -all need for translation of mRNA Virus replication normally leads to cell death |
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Histiogenesis |
Tissue of origin of a cancer |
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Differentiation |
The degree to which a neoplasm histologically resembles its tissue of origin |
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Anaplastic |
A tumour that is so poorly differentiated that it is impossible to tell its tissue of origin. |
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Prognostic Factors for Melanoma |
Breslow thickness Ulceration Lymph nodes |
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Sentinel Node |
The first lymph node to be involved with spread of cancer. |
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Hallmarks of Cancer |
Self sufficiency in growth signals Insensitivity to anti-growth signals Evasion of apoptosis Limitless replicative potential Sustained angiogenesis Tissue invasion and metastasis Reprogramming energy metabolism Evading immune destruction |
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Risk Factors for Breast Cancer |
Age High s-e status (high fat diet, high BMI, less children, shorter duration of breast feeding) Previous breast disease Family history (BRCA) Oestrogen exposure (oral contraceptive, HRT, menarche <12, late menopause, no or late child bearing) Alcohol Smoking Radiation exposure |
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Side Effects of of SERMs |
Menopausal symptoms Fatigue Painful joints Nausea Vaginal discharge/discomfort, water retention, weight gain, headaches, depression, hair thinning Increased risk DVT, PE, endometrial cancer |
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Tamoxifen Resistance |
?mutation of oestrogen receptor Chance in balance between coActivators and coRepressors |
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Side Effects of Aromatase Inhibitors |
Hot flushes Vaginal dryness Nausea Rashes Joint stiffness Raised cholesterol Osteoporosis Neurological effects on extremities |
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Prostate Cancer Treatment |
First line - Goserelin Second line - antiandrogen Goserelin + antiandrogen = maximum androgen block Radical porstatectomy Radiotherapy Hormone therapy |
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Socioeconomic Factors for Breast Cancer |
High status (high saturated fat diet) Age at first pregnancy - young = protective factor Number of children - more and breast fed = reduced risk |
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Reproductive Factors for Breast Cancer |
Early onset menarch Late menopause Older age at first pregnancy Nulliparity - each birth reduces risk Longer duration of breastfeeding - decreases risk |
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Lifestyle Factors for Breast Cancer |
Obesity - IGF1 signalling, PI3K pathway, increased oestrogen, increased adipokines Alcohol - acetaldehyde, epigenetics |
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Assumptions of Cytotoxic Chemotherapy (4) |
Tumour growth is exponential, independent of homeostasis but: Each dose results in the same proportional log kill but: - tumours are heterogeneous and large tumours may be more likely to contain drug resistant clones Intensity of dose influences outcome: Different drugs have different kill properties |
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Gompertzian Tumour Growth and Regression |
Size of the growth fraction decreases exponentially with exponential tumour growth Growth fraction size is maximal when the tumour is 37% of its maximum size |
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Clinical Implications of Gompertzian Tumour Growth and Regression |
Clinically untetectable tumours have to highest growth fraction Large tumour mass - small number of cells susceptible to cytotoxic chemotherapy Relapse free and overall survival measurements do not necessarily discriminate between 1 and 10^6 residual cells after treatment |
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Aims of Combination Chemotherapy (3) |
To achieve maximum cell kill with tolerable toxicity To increase kill fraction of resistant cells in a heterogeneous tumour population To prevent or slow the growth of resistant malignant clones |
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Principles of Combination Chemotherapy (6) |
Only drugs shown o be partially effective Avoid overlapping toxicities on single organ systems Optimal dose and schedule Treatment free interval should be shortest compatible with the recovery of the most sensitive normal tissue Monitor response, performance status and toxicity Sequential regimens out-perform alternating regimens |
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Gefitinib |
Inhibits EGFR and therefore inhibits proliferation and stops the antiapoptotic pathway |
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Stratified Medicine |
The right treatment for the right patient |
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Causes of Drug Resistance |
New mutations Alternative signalling pathways Cancer stem cells - not cycling therefore resistant to treatment |
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Lysophosphatidic Acid (LPA) |
Produced by autotoxin and promotes lymphocyte entry into tissues. |
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Sphingosine-1-Phosphate (S1P) |
T cells have receptors for this and follow gradients, therefore it controls T cell migration. Once in a tissue with high levels of this, the receptors on T cells are internalised so that T cells can no longer respond and are retained within the tissue. |
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Tumour Associated Antigens (5) |
Mutated self proteins Overexpressed Lineage specific Abnormal post translationsl modificatio (e.g. underglycosylated MUC1) Viral proteins |
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Evasion of Immune Response (7) |
Loss of HLA I expression Decreased expression of molecules involved in antigen processing/expression Loss of costimulatory expression Loss of adhesion molecule expression Loss of target antigen Inhibit T cell infiltration Immune suppression at tumour site |
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Good Target Antigen (4) |
Tumour specific (to decrease toxicity) Shared amongst patients with the same and different tumour types (widely applicable) Critical for growth/survival of tumour (no antigen loss variants) Lack of immunological tolerance (high avidity T cells against self cells) |
